Biotechnology of plasma proteins 9781439850268, 1439850267

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Biotechnology of Plasma Proteins Roger L. Lundblad

Biotechnology of Plasma Proteins

P R O T E I N S C I E N C E S E R I E S SERIES EDITOR Roger L. Lundblad Lundblad Biotechnology Chapel Hill, North Carolina, U.S.A.

PUBLISHED TITLES Application of Solution Protein Chemistry to Biotechnology Roger L. Lundblad Approaches to the Conformational Analysis of Biopharmaceuticals Roger L. Lundblad Biotechnology of Plasma Proteins Roger L. Lundblad Chemical Modification of Biological Polymers Roger L. Lundblad Development and Application of Biomarkers Roger L. Lundblad

Biotechnology of Plasma Proteins

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2013 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20120615 International Standard Book Number-13: 978-1-4398-5027-5 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www. copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-7508400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

This work is dedicated to the three Mikes: Grifith, Martinez, and Wood, who taught me more than I ever wanted to know about the plasma biz.

Contents Preface.......................................................................................................................ix Acknowledgments .....................................................................................................xi Author .................................................................................................................... xiii Chapter 1

Blood, Plasma, Cells, and Other Biological Fluids .............................. 1

Chapter 2

Plasma Fractionation and Plasma Protein Products ........................... 19

Chapter 3

Methods for the Analysis of Plasma and Plasma Protein Fractions ......47

Chapter 4

Albumin ............................................................................................. 83 Structure of Albumin ......................................................................... 86 In Vitro Chemical Modiication of Albumin ................................... 101 Albumin as a Carrier ........................................................................ 113 Ligand-Binding by Albumin ............................................................ 121 Puriication and Characterization of HSA for Clinical Use............. 123 Biological Activity of Albumin ........................................................ 125 Enzymatic Activity of Albumin ....................................................... 126 Clinical Use of Albumin .................................................................. 129 Albumin as Diagnostic/Biomarker .................................................. 132 Pharmacokinetics of Albumin ......................................................... 133 Analytical Methods for Albumin Including Use of Albumin as Standard for Analytical Methods................................................. 134 Albumin as Excipient ....................................................................... 136 Conclusion ........................................................................................ 136 References ........................................................................................ 136

Chapter 5

Plasma Immunoglobulins ................................................................. 183

Chapter 6

Factor VIII and von Willebrand Factor ............................................ 233 von Willebrand Factor ...................................................................... 253 Economic Issues Impacting the Hemophilia Business .................... 255 Conclusions and Future Directions .................................................. 257 References ........................................................................................ 257

vii

viii

Chapter 7

Contents

Plasma Proteinase Inhibitors ............................................................ 285 Antithrombin .................................................................................... 285 α1-Antitrypsin (α1-Antiprotease Inhibitor, SERPINA1) ................... 293 Heparin Cofactor II (SERPIND1) .................................................... 301 α2-Macroglobulin ............................................................................. 301 Tissue Factor Pathway Inhibitor .......................................................304 α2-Antiplasmin ................................................................................. 311 C1-Inhibitor (C1-Esterase Inhibitor) ................................................. 315 Plasminogen Activator Inhibitor-1 ................................................... 319 Protein C Inhibitor (Plasminogen Activator Inhibitor-3) ................. 322 References ........................................................................................ 323

Chapter 8

Vitamin K–Dependent Proteins ....................................................... 367

Chapter 9

Miscellaneous Plasma Proteins ........................................................ 401 Fibrinogen ........................................................................................ 401 Fibrin Sealant ...................................................................................402 Autologous Fibrin Sealant ................................................................408 Fibrinogen and Tissue Soldering ......................................................408 Thrombin and Fibrin Foam .............................................................. 410 Fibrinogen Plastics ........................................................................... 411 Thrombin .......................................................................................... 412 Plasminogen and Plasmin ................................................................ 412 Butyrylcholinesterase ....................................................................... 415 Fibronectin ....................................................................................... 415 References ........................................................................................ 417

Preface For some time, I had been wanting to write this book and inally, there was an opportunity. Had I thoroughly understood the task, I would have chosen a less complex topic. The entire book could have been devoted to albumin alone. As indicated at several instances in the text, I was continually realizing how little I knew about some of the topics, despite having worked with plasma proteins for some 50 years, and I hope that the reader will likewise ind some new information. The other point is that plasma fractionation is a mature industry and there are those that promised its demise after the development of recombinant factor VIII some 20+ years ago. Contrary to that prediction, the industry has grown and undergone some consolidation. In addition, a new facility for plasma fractionation has been developed in Brazil and perhaps in other geographies as well. An aggressive program on blood safety has made plasma products safe. While some therapeutics such as factor VIII and factor IX have seen successful recombinant products, other therapeutics such as albumin and intravenous immunoglobulin continue to be dominated by plasma products. Sophisticated methods of analysis, such as mass spectrometry, have increased our understanding of the complexity of plasma, while other works have shown the importance of classic plasma proteins in extravascular function. I hope that the reader inds this work interesting and is encouraged to answer some of the many remaining questions about plasma proteins. Roger L. Lundblad Chapel Hill, North Carolina

ix

Acknowledgments The author is indebted to the editorial staff of CRC Press/Taylor & Francis Group in Boca Raton for their patience and support. In particular, he wants to acknowledge the contributions by Barbara Norwitz, who perhaps merits sainthood, and Jill Jurgensen, to this work. It takes a bit of time for an author to truly understand the importance of the editorial staff in the production of a book. The author is also indebted to the Library of Congress and the Libraries of the University of North Carolina at Chapel Hill for maintaining collections of excellence.

xi

Author Roger L. Lundblad is a native of San Francisco, California. He received his undergraduate education at Paciic Lutheran University and his PhD in biochemistry at the University of Washington. After his postdoctoral work in the laboratories of Stanford Moore and William Stein at The Rockefeller University, he joined the faculty of the University of North Carolina at Chapel Hill. He joined the Hyland Division of Baxter Healthcare in 1990. Currently, Dr. Lundblad works as an independent consultant at Chapel Hill, North Carolina, and writes on biotechnological issues. He is an adjunct professor of pathology at the University of North Carolina at Chapel Hill.

xiii

1

Blood, Plasma, Cells, and Other Biological Fluids

Biotechnology has entered our culture as something that solves many problems in health and agriculture. There is also a belief that biotechnology is something that appeared in the twentieth century. Biotechnology is deined as the use of biological methods and entities such as enzymes and/or organisms to produce a product. Given this broad deinition, biotechnology can range from baking bread, making yogurt, and brewing beer to the use of recombinant DNA technology to produce therapeutic proteins. So, when a “talking head” is pontiicating about the biotechnology industry, it may be about beer, bread, or Betaseron®. A similar confusion exists in the use of the term biopharmaceutical.1 In the context of the current work, biotechnology is used to describe the use of human blood plasma as a starting material for the manufacture of therapeutic products. Where relevant, the production of recombinant products based on plasma proteins is discussed as is the use of a protein as a diagnostic analyte. The use of blood plasma as a source of biomarkers is not discussed in detail, and the reader is referred to other sources.2–4 In my previous books, I had written the irst chapter irst, which seemed to make some sense. As I have matured (a colleague at Iowa suggested that I pass on candles for the birthday cake this year as a contribution to stemming global warming), I have noticed that the irst chapters appear to have been (a) written by someone else (guilt falls on a cat, Callee, who shares my domicile) or (b) written by the author in one of his earlier states of mind. This time, the irst is last; however, the last is not irst. I want to emphasize that, despite having spent most of my professional career working on blood coagulation proteins (there was a brief time of sanity in New York), I really found out how much I did not know about plasma proteins until I started writing this book. There were a number of epiphanies but none for me was larger than inding that substantial quantities of plasma proteins are in the extravascular space; in some instances such as with serpins, there is signiicant function in the extravascular space. An examination of physiology texts5–8 will provide a number of functions for blood, including oxygen transport, nutrient and hormone transport, and temperature regulation. Other functions such as hemostasis are intended for the maintenance of the integrity of the vascular system. Schaller and colleagues9 recently published an excellent book on the molecular and structural biology of the plasma proteins. These researchers developed a list of eight classes of plasma proteins ranging from proteins secreted by hard tissues (classical plasma proteins) to foreign proteins contributed by pathogenic and nonpathogenic organisms. They were then discussed by function, starting with blood coagulation and ending with transport and storage. I was encouraged to see that these workers also had a category for additional proteins, as the current work includes Chapter 9 1

2

Biotechnology of Plasma Proteins

(Miscellaneous Plasma Proteins). With reference to Schaller and colleagues,9 the current work is directed toward the use of “classical plasma proteins” and includes immunoglobulins, which would fall into a bit of a gray zone with their classiication system. I have no quarrel with their classiication and would note that several of their categories such as tissue leakage proteins, aberrant secretions, and receptor ligands are also diagnostic target/biomarkers. It is useful to appreciate that the extensive use of blood for the diagnosis of systemic disorders is a somewhat recent practice and the development/application of biomarkers is an even more recent practice2–4 in the sense that blood has been used in religious rites and furniture manufacture for centuries. Body water is divided into intracellular and extracellular luid.10 The bulk of body water (approximately 70%) is intracellular luid, with the remainder (30%) being extracellular luid. The extracellular luid can be, in turn, allocated between extravascular luid and intravascular luid, which are in dynamic equilibrium.10 Extravascular luid can be further divided into interstitial luid and transcellular luid. Transcellular luid includes luids such as cerebrospinal luid, synovial luid, and ocular luid (aqueous humor of the eye). There is luid and solute exchange between the various compartments of the extravascular luid, but the exchange is variable according to the compartment. The ratio of IgG in cerebrospinal luid to plasma is 0.003, while it is 0.80 for urea, which demonstrates the relative impermeability of the cerebrospinal barrier.11 For comparison, the ratio of IgG concentration between interstitial luid and plasma is 0.52 while albumin is 0.62.12 The exchange of luid between the intravascular luid and the extravascular space is dependent on the physiological state of the individual.13,14 There is also a local variation in distribution.15,16 Bar and coworkers15 observed that insulin stimulated the movement of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) from the vascular space to the tissue in an isolated beating heart of rat, while there was no effect on IGFBP-2 but a decrease in endothelial cell IGF binding protein. Juweld and coworkers16 observed that while the concentration of albumin is higher than that of IgG in normal tissue, the ratio approaches unity in the inlamed tissue. Reed and Rubin17 suggest that the edema response in inlammation is of functional signiicance in promoting the diffusion of plasma protein into the inlamed tissue. The transcapillary escape rate (transport from the intravascular space to the extravascular space) of albumin, IgG, and IgM increased in angiotensinII-induced hypertension; the relative increase was much higher for IgG and IgM than for albumin.18 Transport from the vascular space depends on endothelial permeability; transport of plasma proteins can occur either by transcellular or by paracellular processes.19,20 As can be surmised from the material cited earlier as well as the material on individual proteins to be presented in later chapters, a substantial portion of a given plasma protein can be found in the interstitial space, as the volume of extravascular luid is two to three times the size of the plasma volume.21,22 Consider, for example, the interstitial luid of skin that contains a substantial amount of albumin with considerable exchange with plasma.23 Binding of drugs to albumin is suggested to improve distribution over the tissues.24 In this study,24 it was found that the diffusion of a drug to deeper tissues after topical application is facilitated by binding to albumin. Other recent studies emphasize the importance of protein binding of drugs as a critical factor in early drug development.25,26

3

Blood, Plasma, Cells, and Other Biological Fluids

The number of unique proteins reported in human blood plasma has increased because of the sophistication of analytical techniques. Thus, while there were “... more than 100 ...” proteins isolated from plasma in 1980,27 the number in 2011 varies from approximately 1000 to 4000 (Table 1.1). The work by Schaller and colleagues was mentioned earlier,9 which emphasized the diversity of contributions TABLE 1.1 Number of Proteins in Various Biological Fluids Fluida

Number

Comment

Reference

Plasma

4590

[139]

Plasma

3654

Plasma

2928

Plasma

>3000

Plasma

697

Plasma Plasma

2698 1175

Plasma

1929

Source of plasma and anticoagulant not provided. Sample depleted of albumin and IgG prior to analysis by high-performance liquid chromatography (HPLC) (reversephase and cation exchange techniques)/mass spectrometry (MS). There are proteins that interact with albumin and/or IgG that are removed in the depletion step Pooled plasma from trauma patients (12); conditions of storage and anticoagulant not provided. Samples depleted of 12 major proteins prior to analysis (stated to be 96% of the total plasma protein mass) Ethylenediaminetetraacetic acid (EDTA) plasma was obtained and depleted of six major proteins prior to analysis. Peptides were obtained by protease digestion and separated by strong cation exchange or reverse-phase technique. Efluent fractions were assayed by mass spectrometry This igure is cited in this chapter. Also, these researchers noted that 10 proteins constituted 90% of the mass in plasma Pooled EDTA plasma from two male subjects; depletion of six most abundant proteins (albumin, transferrin, haptoglobin, α1-antitrypsin, IgA, and IgG);b analysis was done by gel electrophoresis/HPLC/mass spectrometry Number is cited by these researchers The data were collated from four different data sets to obtain 1175 distinct gene products Advanced computational methods were used to analyze combined data sets obtained by various analytical techniques. A total of 20,433 distinct peptides were identiied and used to establish a highly nonredundant set of 1929 proteins with a false discovery rate of 1%

[140]

[141]

[142]

[29]

[143] [144] [145]

(continued)

4

Biotechnology of Plasma Proteins

TABLE 1.1 (Continued) Number of Proteins in Various Biological Fluids Fluida

Number

Comment

Reference

Interstitial luid

525

Tumor interstitial luid from a head-and-neck carcinoma; it suggests that tumor interstitial luid may have a high proportion of tumor-speciic proteins with potential as biomarkers. A total of 208 proteins were common to plasma, 402 common to saliva, and 180 common to an ovarian cell line

[30]

Urine

1543

Use of SDS-PAGE/RP-HPLC with protease digestion of efluent fractions followed by MS analysis. Approximately half the proteins were membrane proteins as determined by Gene Ontology analysis

[146]

Urine

>1500

Many were membrane-bound proteins

[147]

Amniotic luid

842

LC/MS/MS and 2-D SDS PAGE/LC/MS/MS of 16 samples. A total of 36% of the proteins in amniotic luid were also found in plasma

[148]

Cervical– vaginal luidc

150

Two-dimensional HPLC, 2-D electrophoresis with mass spectrometric analysis identiied 150 unique proteins, of which 77 were unique to cervical–vaginal luid while 56 were also found in serum and 17 in amniotic luid

[149]

Perilymph

71

LC/MS/MS used to identify the proteins in human perilymph; 271 proteins identiied with 71 proteins common among the four individual samples

[150]

Saliva

2290

Approximately 27% of the whole saliva proteins were found in plasma. Note that this was whole saliva, not individual glandular (parotid, submaxillary) salivasd

[6]

Synovial luid

135

A total of 135 “high abundance” proteins were identiied in synovial luid. Unique proteins were deduced from mass spectrometric analysis of peptides obtained from the digestion of samples from SDS-PAGE. A total of 18 proteins were found to result from the cutaneous puncture procedure and removed from the reference set

[151]

Cerebrospinal luide

264–2630

As with the analysis of plasma and serum, the number of proteins identiied increased with increasing analytic sophistications. The results suggested considerable individuality as well as signiicant differences in aging

[152–155]

5

Blood, Plasma, Cells, and Other Biological Fluids

TABLE 1.1 (Continued) Number of Proteins in Various Biological Fluids Fluida Brain extracellulare luid

a b

c

d

e

Number 27

Comment 2D-SDS PAGE of a microdialysate showed approximately 160 spots, while MALDITOF-MS provided support for 95 proteins. It is suggested that after consideration of posttranslational modiications and proteolysis, data supported 27 individual proteins

Reference [156]

All luid sources are human. Depletion of the most abundant proteins from plasma has been shown to also remove proteins in addition to the “most abundant proteins.”157 Analytical results can also be inluenced by the storage temperature of plasma158 and the anticoagulant used.159 Cervical–vaginal luid has also been found useful for the measurement of fetal ibronectin and/ or insulin-like growth factor binding protein-1 for the prediction of preterm labor.160 Whole saliva is comprised of secretions from the submaxillary gland, parotid gland, sublingual, and minor salivary glands. In addition, there is contribution, except with edentulous individuals, from gingival crevicular luid, considered to be an ultrailtrated sample of plasma. There are some data obtained from the proteomic analysis of glandular saliva.161,162 Cerebrospinal luid ills the ventricles and subarachnoid space of the brain and the spinal cord, while brain extracellular luid occupies the extracellular space within the brain. The brain extracellular luid is derived from cerebral endothelium and is rigidly controlled by the blood–brain barrier, while cerebrospinal luid is derived from the choroid plexus.163 Cerebrospinal luid is characterized by a much lower protein concentration than plasma, and there is an inverse relationship between the hydrodynamic radius of a protein and the concentration in cerebrospinal luid.

to the plasma proteome. These researchers estimate that there are approximately 500 “true” plasma proteins, which is consistent with the estimates of Frank Putnam years ago.28 Schaller and coworkers9 also suggest that the variance in glycosylation and other aspects of posttranslational processing such as the proteolysis observed with factor VIII described in Chapter 6 contribute to the large number of protein species in plasma. The data cited in Table 1.1 are consistent with the suggestion that as analytical techniques improve, the number of protein species identiied in plasma will increase. The number obtained by Schenk and coworkers29 (697) is close to the estimate of Schaller and coworkers6 but far less than that obtained by other researchers. I did ind it interesting that the number estimated by Schaller and colleagues9 and the value obtained by Schenk and coworkers29 are close to that obtained for interstitial luid (525) by Stone and coworkers.30 The workers showed that there were 208 proteins in interstitial luid, which were also found in plasma. The collection of interstitial luid does present considerable technical challenges.31,32 The relationship of interstitial luid and plasma is important, considering the large amounts of “plasma” proteins found in the extracellular luid. It may well be that while certain proteins such as those involved in hemostasis may have a primary function inside the

6

Biotechnology of Plasma Proteins

vascular system to protect the primary functions of oxygen and nutrient transport, other plasma proteins may have more critical roles outside of the vascular bed. Considering the above then, what criteria did I use for inclusion? The major criterion was established intravascular function with demonstrated commercial interest in a therapeutic product. Having said that, there are two outlying proteins— α1-antitrypsin and heparin cofactor 2—where the major function is outside of the vascular bed. In the case of α1-antitrypsin, local application in the lung is the effective therapeutic mode (Chapter 7), not a systemic application, while with heparin cofactor 2, a function is yet to be deined, although it is most likely within the interstitial space. In addition to α1-antitrypsin and heparin cofactor 2, it is most likely that antithrombin and immunoglobulins function in the extravascular space. Prothrombin (and thrombin) are somewhat unique in extravascular function.33,34 There are several proteins that I considered and discarded as candidates for Chapter 9.* These include the following: • Haptoglobin is a glycoprotein in plasma, which is responsible for binding free hemoglobin and returning the hemoglobin (and iron) to the liver to prevent the loss of hemoglobin by urine.35,36 Fucosylated haptoglobin is suggested as a biomarker for pancreatic cancer.37 • α1-Acid glycoprotein (orosomucoid) is an acidic glycoprotein with a mass of approximately 43 kDa.38,39 The function of α1-acid glycoprotein has not been described, but there is a suggestion of immunomodulation.40 α1-Acid glycoprotein is an acute phase protein.41 • Vitronectin, also known as serum spreading factor, is an adhesive protein that is found in both the plasma and the extracellular matrix.42–44 The major function of vitronectin appears to be outside of the vascular system. There are studies on the interaction of vitronectin with urokinase receptor45,46 and plasminogen activator inhibitor-147 as well as suggestion of its importance in bacterial pathogenesis.48 • Ceruloplasmin is a plasma protein responsible for the binding and transport of copper.49,50 While a function other than copper transport has not been identiied, ceruloplasmin has been suggested to have a role in oxidation/ reduction.51 There has been speciic interest in the role of ceruloplasmin in brain function.52,53 Ceruloplasmin has a long history of use in the diagnosis of copper homeostasis such as Wilson’s disease54 and is more recently associated with cardiovascular risk.54,55 • Prekallikrein, also known as Prekallikrein or Fletcher factor, together with high-molecular-weight kininogen, also known as Fitzgerald factor, participates with factor XII and factor XI in the contact phase of blood coagulation.56,57 Prekallikrein has a molecular mass of 88 kDa and a concentration in plasma of approximately 30 mg/L,58 which is the precursor of plasma *

Most of these concepts were thrust upon me in one of my former lives by well-meaning individuals who considered such concepts to be potential commerical products. One learns rapidly that good (and even) great science may not be a good commercial product but a good commercial product does require good science.

Blood, Plasma, Cells, and Other Biological Fluids

kallikrein. Plasma kallikrein catalyzes the formation of kinins from highmolecular-weight kininogen.59 Prekallikrein deiciency is rare and, while associated with a prolonged partial thromboplastin time, is not associated with a bleeding diathesis.60,61 The presence of prekallikrein activator (factor XIIa) in therapeutic plasma fractions can result in hypotension.62–64 It should be noted that plasma kallikrein is an enzyme that is different from tissue kallikrein.65–67 It has been suggested that “oversulfated” heparin/oversulfated chondroitin sulfate68 can “activate” prekallikrein to kallikrein, which then activates prothrombin.69 Other studies have shown that “oversulfated” chondroitin sulfate can result in kinin formation presumably through the activation of prekallikrein.70 • High-molecular-weight kininogen, also known as Fitzgerald, Williams, or Flaujeac factor, is a component of the contact activation system56,57 and a precursor of kinins such as bradykinin.59 High-molecular-weight kininogen has a molecular weight of 120 kDa and is present in plasma at a concentration of 80 mg/L.58 Excess production of kinins from high-molecularweight kininogen can result in hereditary angioenema (deiciency of C1 inhibitor)71 and vasculitis.72 • Transferrin is the plasma protein responsible for the binding and transport of iron, although its function is also suggested in the immune system.73 Transferrin and transferrin receptors are targets for chemotherapy.73–75 Transferrin with ferritin is responsible for the homeostatic regulation of iron,76 and its deiciency can cause clinical issues.77 Deiciency can arise from a variety of causes, including liver disease, but the congenital deiciency is quite rare. The normal level of transferrin in blood is 2–3 gm/L with a half-life of 8 days. Therapeutic applications have been suggested for both the holoprotein and the apoprotein,78 but none have achieved clinical application. The recombinant protein has been produced and is being considered for a range of applications, including atransferrinemia, age-related macular degeneration, ischemia/reperfusion injury, diabetes, and bacterial infection.79 • IGFBPs are a family of proteins that bind and, thus, regulate the activity of IGFs.80–82 There are two forms of IGF, IGF-I and IGF-II, which are bound primarily to IGFBP-3 in plasma, which is associated with a glycoprotein, acid-labile subunit (ALS) yielding a complex with a mass of approximately 150 kDa.82,83 IGFBP can be isolated from the Cohn Fraction IV of human plasma.84 It is likely that IGFBPs have functions other than the regulation of IGF,83 but there is no indication for a therapeutic product. The multiplicity of IGFBPs also confounds the development of a therapeutic product. The various IGFBPs do have somewhat different roles in the regulation of IGFs. IGFBP-3 is responsible for binding the two major forms of IGF in plasma, IGF-I and IGF-II,83 while IFG-I concentration varies widely and has been demonstrated to inhibit IGF function in both in vitro and in vivo studies.85 An additional complication for a therapeutic product is the posttranslational modiication of IGFBP-1, in particular phosphorylation, associated with function.86–90 While an opportunity does not exist for a therapeutic

7

8

Biotechnology of Plasma Proteins

preparation of IGFBP, IGFBP-3,91 IGFBP-2,92 and IGFBP-793 have been suggested as therapeutic targets. • Lipoproteins and apolipoproteins are of great importance in the transport of lipids.94,95 It is important to distinguish between high-density lipoproteins and low-density lipoproteins (HDL and LDL) for determining cardiovascular risk.96–100 There was some interest in the use of lipoproteins for drug delivery,101 and recombinant lipoproteins have been developed for drug delivery as well as for possible therapeutic application in sepsis and atherosclerosis.102 Subsequent work suggested that lipoproteins (HDL or LDL) were of little value in delivering chemotherapeutic drugs to tumor cells in culture.103 More recent work104 has demonstrated the use of a fusion protein between a HDL and a protein transduction domain, TAT,105 to deliver doxirubin into tumor cells. The use of HDL and/or apolipoprotein A-I (the principal protein component of HDL) as a therapeutic approach to atherosclerosis has been suggested.106 Technical approaches suggested by Shah and coworkers106 include enhancing HDL synthesis, decreasing the clearance of apolipoprotein A-I, parenteral administration of apolipoprotein A-I, and peptide mimetic based on apolipoprotein A-I. • β2-Microglobulin is an example of a shed protein as described by Schaller and colleagues,9 as it is not secreted from either a solid tissue such as liver or a lymphoid cell nor is it leaked from damaged cells such as enzymes from cardiac tissue or liver tissue. β2-Microglobulin is present in all nucleated cells, where it is associated with major histocompatibility complex (MHC) class 1 and CD1 complex.107–110 β2-Microglobulin has a molecular mass of approximately 11 kDa and is present in plasma at a low concentration (1–3 mg/L) and can form amyloid in kidney failure. The reader is directed to an excellent review by Heegaard.111 The concentration of β2-microglobulin is elevated in a variety of conditions.112–118 The fractionation of human blood plasma can be considered to be a mature industry, with the basic technology, alcohol fractionation, dating back at least to 70 years. Many of the products described in the current work have been approved biologics for more than 60 years. The challenge that I faced in assembling both the chapters that follow and the brief list mentioned earlier is in distinguishing between proteins in which the major function is considered to occur within the vascular space and those proteins that are transported for primary function at an extravascular site. The distinction between these two categories is not as clear as one would like. Some proteins such as factor VIII, α2-macroglobulin, and the von Willebrand factor appear to function primarily within the vascular system in the absence of disease, while heparin cofactor 2 is considered to function primarily in the extravascular space. Chang and coworkers found less than 1% (plasma level is 100%) factor V, factor VIII, or the von Willebrand factor in synovial luid.119 These researchers did ind substantial amounts of antithrombin (74%) and α2-macroglobuln (13%); prothrombin was present at a concentration of 21%, while factor IX was present at a concentration of 10%. Miller and coworkers120 found substantial amounts of plasma protein in lymph including ibrinogen; ibrinogen antigen was substantially higher

Blood, Plasma, Cells, and Other Biological Fluids

9

than functional activity, and there were substantial amounts of D-dimer. These researchers also observed higher factor VIIa activity in lymph than in plasma; factor VII activity was lower in lymph (35%) than in plasma (110%). Other researchers have reported substantial amounts of ibrinogen in interstitial luids.121–123 Worm reported on the concentration of albumin, transferrin, IgG, and α2-macroglobulin in skin suction blister luid obtained from patients with skin disease compared to a control population.124 The ratio of the concentration of plasma albumin to interstitial luid was lower in the patient population (0.46 vs. 0.55); the ratios of the concentration of IgG (0.39 vs. 0.43), transferrin (0.45 vs. 0.48), and α2-macroglobulin (0.22 vs. 0.21) were closer to the control group. Similar results were observed by other researchers.125 Thrombin/thrombin-like activity has been demonstrated to function in the extravascular space,126–128 but the synthesis of the prothrombin has also been demonstrated in the extravascular space,129 suggesting that extravascular synthesis of prothrombin may be a signiicant factor, as well as extravasation.130 Jacob and coworkers130 suggest in their work on protein C that there is physiological heterogeneity of the vascular barrier where a particular plasma protein will be present at a discrete vascular site. Local differences in vascular permeability have been discussed previously with respect to insulin15 and local accumulation of IgG at focal sites of inlammation.16 Clearly, vascular permeability is a complex area with a variety of mechanisms.131 There is also an active extravascular ibrinolytic system,132 which is discussed in Chapters 7 and 9. López and Nowak133 suggested that a small derivative of hirudin, dipetarudin, showed rapid distribution over the extravascular space where it could inhibit thrombin; thrombin has been suggested to promote tumor growth.134 In subsequent work, López and coworkers modiied dipetarudin with polyethylene glycol.135 The monosubstituted derivative had pharmacokinetics similar to that of the unmodiied dipetarudin, while the disubstituted derivative demonstrated much slower clearance to the extravascular compartment. The aforementioned information suggests that, at least with our current information, there are some plasma proteins such as factor VIII and the von Willebrand factor (Chapter 6) in which the intravascular function is clear. Many, if not all, of the other classical plasma proteins appear to have signiicant functions in the extravascular space, and such functions may have regional speciicity. It is clear that more work is needed in this area to understand the factors inluencing the distribution between intravascular space and extravascular space. As shown by the dipetarudin results cited earlier,135 PEGylation may have a major inluence on the distribution over the extravascular space in addition to the effects on renal clearance as part of its effect on pharmacokinetics. Human plasma has been a valuable source of biological products for the past 70 years, and the information gathered from the development of plasma proteins has proved vital to the development of recombinant therapeutic proteins. Some of the plasma-derived therapeutics such as factor VIII and factor IX have had clear paths to clinical success, while others, most notably the serpins, have had a more dificult path to clinical success. It is my opinion that the concept of biological degeneracy, as elaborated by Gerry Edelman and Joe Gally,136 can provide insight into why the application of the therapeutics has been so dificult. The modulation of plasminogen activator inhibitors can be a useful target for RNAi therapeutics.137,138

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154. Pan, S., Zhu, D., Quinn, J.F., et al., A combined dataset of human cerebrospinal luid proteins identiied by multi-dimensional chromatography and tandem mass spectrometry, Proteomics 7, 469–473, 2007. 155. Schutzer, S.E., Liu, T., Natelson, B.H., et al., Establishing the proteome of normal human cerebrospinal luid, PLoS One 5, e10980, 2010. 156. Maurer, M.H., Proteomics of brain extracellular luid (ECF) and cerebrospinal luid (CSF), Mass Spectrom. Rev. 29, 17–28, 2010. 157. Yadev, A.K., Bhardwaj, G., Basak, T., et al. A systematic analysis of eluted fractions of plasma post immunoafinity depletion: Implications in biomarker discovery, PLOS ONE 6, e24442, 2011. 158. Lee, D.H., Kim, J.W., Jeon, S.Y., et al., Proteomic analysis of the effect of storage temperature on human serum, Ann. Clin. Lab. Sci. 40, 61–70, 2010. 159. Kim, H.J., Kim, M.R., So, E.J., and Kim, C.W., Comparison of proteomes in various human plasma preparations by two-dimensional gel electrophoresis, J. Biochem. Biophys. Meth. 70, 619–625, 2007. 160. Cooper, S., Lange, I., Wood, S., et al., Diagnostic accuracy of rapid phIGFBP-1 or predicting preterm labor in symptomatic patients, J. Perinatol. (in press). 161. Walz, A., Stühler, K., Wattenberg, A., et al., Proteome analysis of glandular parotid and submandibular–sublingual saliva in comparison to whole human saliva by twodimensional gel electrophoresis, Proteomics 6, 1631–1639, 2006. 162. Quintana, M., Palicki, O., Lucchi, G., et al., Inter-individual variability of protein patterns in saliva of healthy adults, J. Proteomics 72, 822–830, 2009. 163. Segal, M.B., Extracellular and cerebrospinal luids, J. Inher. Metab. Dis. 16, 617–638, 1993.

2

Plasma Fractionation and Plasma Protein Products

The various plasma-derived proteins described in the current work are frequently included in the ield of transfusion medicine.1–7 It is also clear that the development of blood collection and storage method was essential to the provision of plasma for fractionation. It is useful then to briely consider the history of transfusion medicine as a preamble to plasma fractionation and plasma protein products. The late Bernard Ficarra compiled an excellent collection of essays on the history of medicine,8 including one chapter on the history of transfusion medicine.9 Ficarra noted both the historical importance of blood in human sacriice and the custom of oral blood consumption as a therapeutic. Considering the current interest in the oral delivery of protein therapeutics,10,11 the oral consumption of blood is an early example of this technology. The oral administration of protein therapeutics for hemophilia was described in the 1930s.12,13 Early work14 on the clinical characterization of the Cohn fractionation products showed that oral albumin was not as effective as intravenous albumin in maintaining the nitrogen balance in human subjects. While there were earlier attempts at transfusion such as that described for Pope Innocent VIII in 1492, Ficarra9 described the seminal role of Francis Felli in the discovery of blood transfusion in 1654 followed by the demonstration of the effectiveness of venipuncture using a quill by Christopher Wren in 1656. Notwithstanding these early observations, James Blondell, an English physician, is usually given the credit for the irst successful blood transfusion in 1818 for the treatment of an obstetrical hemorrhage. The irst use of blood transfusion for the treatment of hemophilia was reported by Lane in 1840.15 The second half of the nineteenth century saw considerable advances in the use of blood transfusion in a variety of clinical situations with a remarkable number of positive outcomes. The great majority of the early work on blood transfusion was performed in England and has been the subject of an excellent review by McLaughlin.16 This early work showed that the transfer of blood from a healthy donor to a patient had therapeutic value, but there were major technical obstacles to the general use of transfusion medicine. Early work had deined the species speciicity of blood transfusion, but blood serotyping in human subjects had to wait for development until 1907.17 In addition to the blood type compatibility issue, there were two other major technical problems that required resolution: the coagulation (or fermentation) of blood, which meant that the donor and the recipient could not be separated in space (location), and the lability of the blood, which meant that it was dificult to separate the donor and the recipient in time. Blood clots when it is removed from the circulatory system, and it is suggested that the endothelial lining of the vascular provides a nonthrombogenic surface. An immense amount of effort has been expended over 19

20

Biotechnology of Plasma Proteins

the past 50 years in an attempt to develop a nonthrombogenic surface with limited success.18,19 The porcelain and metal containers that were used in the 1800s did not allow the collection of blood without the formation of a clot. Early attempts to preserve blood in a liquid state involved using the method of deibrillation (deibrination; frequently, a wire whip not unlike those used in cooking was used) of blood to remove ibrin.16 While deibrillation was somewhat effective, there was considerable use of tubes and other devices for physically connecting a donor and a recipient. There was some use of parafin-coated containers for the collection of blood for transfusion,20 which allowed the limited separation of a donor and a recipient. The use of phosphate to prevent blood coagulation was introduced by Hicks in 1869.21 Phosphate salts were used for some time as an anticoagulant without an understanding of the mechanism, as it was not until sometime later that the role of calcium ions in blood coagulation was suggested by several groups,22,23 and even later when citrate was observed to serve as an anticoagulant,24 permitting the physical separation of a donor and a recipient. The use of citrate as an anticoagulant was extremely useful under battleield conditions in World War I,25 most likely resulting in the irst transfusion service. Robertson did state that parafin coating was not required for blood collection, although he emphasized that the time between the collection and the transfusion should be kept to a minimum to ensure the safety and eficacy of the product. The direct use of serum will be discussed later in this chapter. The discovery of the anticoagulant properties of citrate solved one of the two aforementioned problems—the one of location. The issue of time remained a problem, awaiting a solution. As with the alcohol fractionation of plasma, World War I also played an important role. While Edwin Cohn (see below) was a logical candidate to drive the alcohol fractionation, it could be argued that Peyton Rous was an unlikely individual26 to have made the seminal observation on the effect of saccharides on red blood cell viability. Rous, at the Rockefeller Institute for Medical Research, established that, at least with the technology available during 1915–1918, there was no substitute for red blood cells in transfusion medicine. Rous continued to do some work in this area for several years but eventually returned to his work on the role of viruses in tumor development, resulting in the discovery of the Rous sarcoma virus and a Nobel prize.27 Rous and Turner28 reported in 1916 that the presence of glucose resulted in an extended in vitro viability of red blood cells. Subsequent work on the physiology of the red blood cells29 resulted in the development of the ACD (acid–citrate–dextrose) anticoagulant.30 More details on this work can be obtained from Mollison’s excellent review on the use of citrate and glucose in early transfusion medicine.31 The citrate/glucose method permitted the development of blood banks (Cook County, 193632)* and subsequently the plasma fractionation industry. Early blood banks were a little like early inancial banks in that the recipient and family/friends could make “deposits” to an “account” from which blood could be withdrawn. As with inancial banks, blood banks have changed over time, with a large volunteer *

There is mention of a blood bank during World War I and then later during the Spanish Civil War, both of which predate the Chicago blood bank. It has also been reported that the Mayo Clinic in Rochester, Minnesota, established a blood bank in 1935.

Plasma Fractionation and Plasma Protein Products

21

population used as donors; rarely are “paid” donors used for blood banks. With some exceptions,* blood banks operate separately from the plasma fractionation industry. Blood banks do offer a variety of products, including packed red blood cells, platelet concentrates, whole blood, fresh plasma, fresh frozen plasma, and cryoprecipitate.33 Blood is an expensive commodity whose cost may increase due to a variety of challenges,34 including increased screening, storage, and transfusion costs. An excellent study35 on the cost of blood transfusions in Sweden published in 2005 indicated a cost of €702 for a 2-unit allogeneic red blood cell transfusion and €598 for a 2-unit autologous red blood cell transfusion (both surgery patients). Similar costs are reported for Greece36 and the United Kingdom.37 A recent study by Shander and coworkers38 reported the costs of blood transfusion at four hospitals in the United States; the per unit cost of red blood cell transfusions to surgical patients ranged from US$ 522 to 1083 (mean US$ 761±294). While blood is a inite resource, there is little competition between blood banks* and the plasma fractionation industry for “raw material.” The study also suggested that biotechnology will permit the production of some blood factors currently derived from plasma,39 such as factor VIII, factor IX, and antithrombin, which might drive down the demand for plasma; however, there does not appear to be a viable alternative for intravenous immunoglobulin at the time of this writing (November, 2011). Speculation regarding the future of plasma-derived biopharmaceutical products is presented below. There had been sporadic attempts in the early twentieth century to identify unique fractions from blood for the treatment of disorders such as hemophilia (see Chapter 6), but such efforts were suspended for various reasons. It is fair to say that World War II was the driver of large-scale fractionation of plasma in the United States, England, and Germany. The blood plasma program was part of a much larger program on the use of blood in World War II, which is described in some detail in a volume from the Ofice of the Surgeon General of the Department of Army.40 Students of history as well as students of product development and product management would be well served by reading the preface by Brigadier General Douglas B Kendrick. Several points that deserve consideration some 50 years later have been stated. First, unless effort is made, lessons learned with respect to a response to an unusual situation, in this case the treatment of battleield casualties, are easily lost. Second, supporting administrative infrastructure is not readily regained when lost. Finally, the provision of blood and blood products requires a separate administrative structure, which explains why hospitals have a separate transfusion service. The use of serum as a therapeutic deserves mention. Serum was used early as a vehicle for passive immunization41 and has been largely replaced by plasma-derived intravenous immunoglobulin fraction or, in some cases, monoclonal antibody42 (Chapter 5). Prior to the resolution of the anticoagulation problem discussed previously, serum was seen as an effective treatment modality.43 Even today, albumin is frequently referred to as serum albumin, relecting its early characterization from a *

The American Red Cross collects blood that is used for red cells, platelets, and fresh frozen plasma. In addition, it recovers plasma from red cell preparations, which is used for plasma fractionation (see http://www.redcross.org). The plasma fractionation process mostly uses plasma collected by plasmapheresis at donor centers.

22

Biotechnology of Plasma Proteins

serum, rather than a plasma, source.44 Current literature frequently refers to the serum concentration of a protein therapeutic.45 The use of serum did present some problems,46 but its use continued through the 1930s.47 The infusion of serum can produce thrombosis, but such an effect is markedly enhanced by stasis.48 The literature during this period of time could be confusing as discussed by Strumia and coworkers,47 noting that the terms “serum” and “plasma” were frequently used interchangeably in the literature; Sapan and Lundblad have noticed that this practice has continued.49 Some plasma products (see Chapter 8) such as Autoplex could be considered serum protein derivatives based on analysis,50 as could be the recombinant factor VIIa.51 The irst part of the twentieth century saw a transition from donor-to-donor transfusion to the collection of blood from the donor as separate from the administration of blood to the recipient based on the development of anticoagulants. The next issue to be addressed was the container for collection and storage of whole blood. Parafin-coated containers were used in the later part of the nineteenth century, and sterilized glass bottles were introduced in the 1920s for the collection of blood but were replaced some 20–40 years later by plastic bags.52 Lozner and Taylor53 published a study in 1942 describing the “activating” effect of glass surfaces on blood coagulation when compared to parafin-coated tubes or lusteroid (nitrocellulose) tubes. It is fair to say that the transition from glass containers to plastic containers is as important as the ACD anticoagulant for the development of the plasma fractionation industry. Dr. Carl B. Walter, Dr. Walter Murphy, and colleagues at Harvard Medical School54–56 are given the credit for the development of the plastic bag for blood transfusion, working with Fenwal Laboratories (later part of Baxter-Travenol). As a historical note, the late Dale Smith led the commercial development of plastic bags for transfusion at Baxter. In the original study,54 Walter described a procedure for the collection of blood into a plastic bag through a small ion-exchange (sulfonated polystyrene) column that removed calcium and other divalent cations that were required for coagulation.* The blood collected in this manner was stable for 10 days, but a transition to collection in acid–citrate–dextrose preserving red cell function was accomplished in 1952.55,57 Plastic bags were originally composed of polyvinyl54,58 with phthalate as a plasticizer; other plastics and plasticizers have been developed.59 The use of phthalates as a plasticizer has created concern59,60 and remains controversial till now.61,62 Phthalate-free polyvinyl bags are currently available. Plasma fractionation as such came into its own as a process with the leadership of Professor E.J. Cohn during World War II40 and has evolved into an international business.63–66 Quite simply, the Cohn fractionation process67,68 uses the combined effect of pH, ionic strength, and organic solvent (solvent polarity) on the solubility of proteins69–71 to obtain several fractions (Table 2.1). The effect of alcohol on protein solubility has been known for some time, as has the effect of ionic strength on the effect *

The author has used a similar method to collect blood and observed differences when compared to the blood collected in EDTA.296 Other researchers have noted an effect of citrate other than calcium binding on blood coagulation.297 Chelating agents will, of course, remove cations other than calcium from whole blood with still largely unknown consequences. However, given the history of blood safety, it is unlikely that the use of citrate has a deleterious effect; there was an early report on the adverse effects of citrate.298

23

Plasma Fractionation and Plasma Protein Products

TABLE 2.1 Cohn Fractions from Human Plasmaa Cohn Fractionb I

Conditionsc 8% ethyl alcohol; pH 7.2; I = 0.14/−3°C

II

Contentsd Fibronectin217–225 ADAMTS 13 (vWF-cleaving protease)226 Glycosaminoglycans are also found in Cohn Fraction IV-1 and in smaller amounts in Cohn Fraction II + III 227 C1r subunit of the irst component of complement228,229 Factor VIIIe von Willebrand Factorf Fibrinogeng Immunoglobulin G230

IIIh

25% ethyl alcohol; pH 6.9; I = 0.09/−5°C

Mannan-binding lectin protein231,232 Eighth component of complement233 Basic proteins234 α2-Macroglobulini Factor IX235 H-icolin (Hakata antigen)236 P-icolin (P35)237 Apolipoprotein A-I and A-IIj

IVk

18% ethyl alcohol; pH 5.2; I = 0.09/−5°C (IV-1) 40% ethyl alcohol; pH 5.8; I = 0.09/−5°C (IV-4)

Antithrombin238,239 Apotransferrin (IV-4)240,241 Butyrylcholinesterase (IV-4)242 Protein C (IV-1)243 Ceruloplasmin (IV-1)l Basic somatomedin (IV-1)244,245 α1-Antiproteinase inhibitorm Protein C246,247 Support of cell culturen Insulin-like growth factor activity248 Insulin-like growth factor binding protein (SmBP)249,250 Immunosuppressive activity251,252 Inhibitor of acid lipase253 α-Galactosidase a254 Acid-activated plasma kallikrein255 Vitamin D–binding protein (Gc globulin)256,257 Lipoproteino Lipid258 Haptoglobin259 Plasminogenp (continued)

24

Biotechnology of Plasma Proteins

TABLE 2.1 (Continued) Cohn Fractions from Human Plasmaa Cohn Fractionb Vq VIr

Conditionsc 40% ethyl alcohol; pH 4.8; I = 0.11/−5oC

Contentsd Albumin260,261 Serine–threonine rich galactoglycoproteins

VIIt a

b

c

d

e

f

g h

i

j

The Cohn Fraction designation is taken from the Cohn Fraction Method 6 with the understanding that various manufacturers have added modiications that are proprietary in nature. Such modiications could include the combination of II + III into a single step and subsequent modiications of step IV, which eliminates the need for a IV-4 precipitation step. Fibrinogen, the von Willebrand factor, and factor VIII are now processed from the cryoprecipitate step.81,160,262 See footnote a and also see http://www.sanquin.nl/Sanquin-eng/sqn_From_blood_to_medicine.nsf/All/Plasma-Fractionation—Medicines-Derived-From-Plasma.html. From the Cohn Method 6 process as presented by Pennell.160 The conditions shown for Fraction III are for II + III. This list can be, at best, considered partial, as there is some disagreement regarding the deinition of plasma protein and the discovery of many proteins since the development of proteomic technology for protein identiication. The dificulty here, as discussed in the text, is the deinition, as many of the new, trace proteins may not it within the classical deinition of Putman.263 The separation between fractions is not absolute, and a protein or protein fraction (i.e., immunoglobulin) can be “spread” over several fractions, with a major quantity in one fraction. Such overlap is common with most precipitation puriication technologies such as ammonium sulfate.264 As an example, apolipoprotein C-II can be found in Fraction V.265 In the classic process of Cohn fractionation, factor VIII is found in the Cohn Fraction I, and this was an early source of factor VIII therapeutic products.266 The introduction of the cryoprecipitate step removed the bulk of factor VIII, ibrinogen, and the von Willebrand factor. The von Willebrand factor is present in the Cohn Fraction I but is removed in the cryoprecipitation step as is the situation with factor VIII. When factor VIII is puriied from the cryoprecipitate, it would appear that a unique form of the von Willebrand factor can be associated with factor VIII after subsequent puriication.267 See Chapter 6 for further discussion on this issue. Fibrinogen is one of the best-known constituents of the Cohn Fraction I.268,269 The Cohn Fraction III may be a historic footnote except for research purposes. I know of no commercial plasma fractionation process that yields a discrete Fraction III; processes have been optimized for the recovery of starting material for intravenous immunoglobulin and products such as α1-antitrypsin. In another development, the cryoprecipitate procedure has markedly decreased the value of a discrete Cohn Fraction I. More recent work on the puriication of IgG from plasma shows puriication from Fraction I + II + III.270 Thus, the older literature describes the puriication of factor IX from the Cohn Fraction III.271 More recent studies have used the Cohn Fraction IV-1 as a source of prothrombin complex concentrate.272 See Chapter 8 for additional details on prothrombin complex concentrates. There have been various suggestions for the therapeutic use of α2-macroglobulin over the last several decades, including its use as a transport vehicle.273,274 There have been suggestions for the use of apolipoprotein A-I as a therapeutic.275,276

Plasma Fractionation and Plasma Protein Products

25

TABLE 2.1 (Continued) Cohn Fractions from Human Plasmaa k

l

m

n

o

p q

r

s t

Fraction IV is taken to include material derived from Fraction IV-1 and Fraction IV-4. Fraction IV is considered to contain α-globulins,277 while β-globulins and γ-globulins are found in Fractions I–II–III. Fraction IV products have never been the economic drivers for plasma fractionation (see text), and the Cohn Fraction was considered a waste fraction from which albumin could be recovered.278 I would note that, at one point in time, the green color of the IV-1 paste was used (anecdotally) as a critical product attribute.279 α1-Proteinase inhibitors have previously been described as α1-antitrypsin.280,281 Somatomedin is also known as insulin-like growth factor, and there is less reference in the current work to somatomedin and more to insulin-like growth factor. The ability of serum to support cell culture activity is well accepted. Certain Cohn Fractions have been studied for their ability to support cell culture. Bovine Cohn IV-1 was found to substitute for bovine serum in the growth of Giardia lamblia. It was of interest that only goat, horse, and bovine Cohn IV-1 could support the growth of Giardia lamblia; agglutinating antibodies inhibitory factors in canine, human, rabbit, and rat fractions.282–284 The Cohn Fraction IV also stimulated the production of NGF from murine L cells.285 Earlier work had suggested that the Cohn Fraction IV could replace albumin as a cell culture supplement.286 Lipoprotein (β-lipoprotein) is also described as being present in the Cohn Fraction I + II + III,287,288 the Cohn Fraction III,289 and the Cohn Fraction III-O.290 Plasminogen has also been obtained from the Cohn Fraction III.291,292 The Cohn fractionation process is also applied to other species, most notably, bovine plasma. In particular, the Cohn Fraction V from bovine plasma (bovine serum albumin) has been used in cell culture.293,294 Fraction VI is derived from the supernatant fraction from the Cohn V precipitation step and has been poorly characterized. As described by Kendrick40 in Chapter XIII, Fraction VI “consists of the large amount of salts, especially citrates, and the small amount of protein left in the mother liquor following the removal of these various precipitates…” Peptides and acidic proteins have been obtained from this material. Found in the supernatant fraction from the Cohn V precipitation.295 A Cohn Fraction VII is mentioned by Pennell.160

of alcohol.72 Cohn was trained as a physical chemist at the University of Chicago and was a member of the Department of Physical Chemistry at Harvard Medical School for many years. During his long tenure at Harvard, he worked with other outstanding scientists such as John Edsall69 and George Scatchard.*,73 Cohn’s early work with E.J. Henderson concerned the physical chemistry of seawater74 and later on the physical *

A consideration of the contributions of biomedical scientists to World War II provides interesting stories. A number of scientists like Edsall, Scatchard, Hans Neurath, Peter Medawar, Erwin Chargaff, William Stein, Stanford Moore, and others made largely unknown contributions to the national effort and then moved on after the war to take up distinguished academic careers, sometimes in areas quite disparate from their work during World War II.

26

Biotechnology of Plasma Proteins

chemistry of bread.75 This latter work was done in collaboration with the Department of Defense and Professor Cohn was Lieutenant Cohn. While Cohn was interested in other problems during the period from 1920 to the mid-1930s, he never lost his primary interest in proteins76–80 and was well positioned to work on plasma fractionation during World War II.40 The original Cohn process has gone through modiications over the years, and alternative methods of fractionation have been developed.81 Despite advances in separation technology, the initial step in plasma fractionation remains ethanol fractionation. Kistler and Friedl82 have summarized the technical and economic advantages of ethanol fractionation. Most of the recent changes in plasma fractionation are intended to improve the yields of speciic fractions; as such, most of the technical information is proprietary in nature. The original process has been modiied by various manufacturers such that a cryoprecipitate fraction83,84 is removed and a Fraction I may or may not be obtained as a separate fraction. Fraction II and Fraction III may be obtained in a single step, and Fractions I–II–III may also be obtained in a single step following the cryoprecipitation step. Fraction IV may be obtained as Fraction IV-1 and Fraction IV-4. Fraction V is mostly albumin. Fraction VI is derived from the supernatant fraction obtained from the Fraction V step. Fraction VI has been poorly characterized, and there are only a few papers on this fraction.85–88 Plasma protein fraction is a plasma fraction similar to albumin.89–91 The processing of plasma into various products is not dissimilar to the fractionation of crude oil into various products. In a discussion of the economics of plasma fractionation, Burnouf92 noted the analogy of the reining process of oil where various derivative fractions and subfractions such as propane and butane are used to make fuel gas, light naphtha for gasoline, gas oils for lubricants, and residue for asphalt.93,94 Curran94 divides the petroleum industry into four separate technology and business areas: extraction of crude oil, transportation of oil to reinery, the reinery process, and marketing. Similarly, the plasma industry is divided into four areas: donor centers, refrigerated transport to a manufacturing process, the fractionation process, and distribution and sales. The reader is also directed to a chapter by Professor Angela Creager (Princeton) in Private Science.95 Professor Creager provides a unique view of the development of the plasma business at an important time in the ield of science in the United States. It was a time when there was considerable concern about the involvement of companies in plasma and the role of patents. Therefore, I strongly encourage anyone who is interested in the current state of commercial biotechnology to read this work by Professor Creager. The Cohn fractionation process was developed for the production of albumin, although the other proteins, most notably immune serum globulins (Chapter 5) and ibrin foam/ibrin ilm (Chapter 9), together with thrombin, were considered to be of value in 1945.96 The growth of the plasma fractionation industry slowed down for a period of time after World War II, with albumin (see Chapter 4) being the dominant product.97,98 There was some work on the development of factor VIII products (see Chapter 6) and intramuscular immunoglobulin (see Chapter 5).99,100 Albumin continued to be the economic driver for the fractionation of plasma until the 1960s, when the development of intermediate-purity factor VIII concentrates101 established hemophilia treatment as the economic driver for plasma fractionation (see Chapter 6). The subsequent development of recombinant factor VIII preparations in the 1980s, combined with the recognition of the value of intravenous immunoglobulin (IVIG)

Plasma Fractionation and Plasma Protein Products

27

in immunomodulation, resulted in IVIG replacing factor VIII as the economic driver for the plasma fractionation business.64 Other products derived from plasmas that were developed in the 1970s included the prothrombin complex concentrates, which have been largely replaced by single-factor IX concentrates from either plasma or recombinant sources. Activated prothrombin complex concentrates (see Chapter 8), while still in use, have been replaced by recombinant factor VIIa products, which are also being used for factor VII replacement in vitamin K–antagonist intoxication and liver disease. As an aside, it is the author’s sense that there are a large number of commercial entities seeking to capitalize on the use of factor VIIa as a general hemostatic agent quite separate from the aforementioned uses (see Chapter 8). The end of World War II resulted in the dismantling of the government infrastructure established for plasma fractionation during the conlict. During the past 50 years, a number of private companies have been involved in commercial plasma fractionation, including CSL in Australia; Grifols (Probitas), Immuno, Octapharm, Sanguin, and Behring in Europe; and Hyland, Cutter, Armour, and others in the United States. There are also efforts at the national level for fractionation aimed at ensuring self-suficiency for blood and blood products.63–66 This includes a new fractionation, plant being built in Brazil.65 Curling and Bryant64 have presented an excellent review of the plasma product industry in 2005; the reader is also referred to an article by Burnouf102 published in the same time period. Burnouf notes that the production of plasma-based therapeutics has never met the demand. Having said that, Burnouf also notes that it will be necessary to develop both new products and new indications for existing therapeutic products. The manufacture of biological products from human blood plasma has always been a challenging proposition. First, there is the issue of supply of raw material. Blood plasma for fractionation is usually obtained from commercial sources using paid donors.* This occurs at donor centers that are owned by either the fractionator or another company dedicated to plasma collection. Plasma, as a raw material, contributes to about 50% of the cost of the manufacturing process,64 with the *

I am embarrassed to say that after the current manuscript was sent to the publisher, I became aware of a book entitled Blood, Plasma and Plasma Proteins: A Unique Contribution to Modern Healthcare (ed. J.L. Valverde, IOS Press, Amsterdam, Netherlands, 2006). This book is an extraordinary collection of contributions on blood and plasma fractionation. The emphasis is more on the business side including plasma procurement and manufacturing. Victor Grifols, contribution entitled “Financing plasma proteins: Unique challenges” emphasizes the importance of IVIG and albumin as drivers of plasma fractionation. IVIG products require approximately 20 million liters of plasma, albumin slightly less, while plasma factor VIII requires half that amount, with much less required to factor IX. This disparity is suggested to relect the availability of recombinant factor VIII and factor IX. The related chapters by Peter Rankin (“Perilous economics of the plasma protein therapeutics industry”) and Thierry Burnouf (“Plasma proteins: Unique biopharmaceuticals—unique economics”) also discuss this product pricing and the related problem of cost allocation. A somewhat related issue, selfsuficiency, is discussed by Valverde (“The political dilemma of blood and plasma derivatives”). The issue of volunteer, nonremunerated donors versus paid donors is a complicated problem. As a result, the United States is self-suficient because of paid donors, while there are few other countries that can be self-suficient with volunteer donors. Valverde does suggest that the production and distribution of puriied plasma proteins obtained via plasma fractionation is a global business. It then follows that the regulation of the plasma fractionation is in desperate need of harmonization as discussed by von Hoegen and Gustafson in their chapter entitled “The importance of greater regulatory harmonization.”

28

Biotechnology of Plasma Proteins

cost balanced between acquisition, including storage and transport, and qualiication. The HIV tragedy of the 1980s and other viral cases have presented issues with blood-derived therapeutics.103 A substantial portion involves analytical costs including the cost of nucleic-based assays for virus testing as part of an overall strategy to ensure safety against viruses. It is noted that the methodology for viral testing continues to develop,104 and it is possible that multiplexed methods will reduce the cost of testing and increase the safety against viruses. The risk of infection resulting from a blood transfusion is estimated to be 1 in 1,000,000 for a unit of blood in the case of hepatitis C virus (HCV), 1 in approximately 300,000 in the case of hepatitis B virus (HBV), and approximately 1 in 3,000,000 in the case of HIV.105 Now these are single-unit odds, so these cannot be directly applied to the risk with the chronic use of a biological such as factor VIII for hemophilia A but might be reasonable for an acute-use product such as antithrombin. For a better sense of risk, I recommend the reader a book106 by James Walsh, which discusses how risk affects everyday life. Walsh’s book was published in 1998 and, as such, odds will have changed, and the following are presented to put the aforementioned odds in perspective. First, the lifetime odds of being struck by lightning are 1 in 30,000; death by excessive alcohol consumption, 1 in 100; and death by motor accidents, 1 in 60. I will grant you that these numbers are not directly comparable to the blood safety numbers, but they are useful in driving the analysis of risk rather than coping with the fog of uncertainty. Notwithstanding the safety of human blood in most geographies107 and determined efforts to guarantee safety in others,108 there is a tendency to emphasize the production of recombinant protein in protein-free cell culture systems.109,110 This approach appears to be based on a concept of zero-risk rather than risk versus beneit/cost. In the case of variant Creutzfeldt–Jakob disease, the theoretical potential of epidemic discussed in 1999111,112 never materialized.113,114 While the potential for blood transfusion via cellular elements exists, transmission via protein therapeutics has not been demonstrated.114 Aversion to plasma-derived therapeutics would appear to be based more on perceived uncertainty rather than on a deined risk. In the case of nonblood plasma substitutes for albumin, there are issues quite separate from the basic colloid substitution issue.115 As cost management becomes an increasing concern in health care, there will be an increased use of evidence-based medicine in the use of blood products.116–120 As an example, the oldest plasma protein therapeutic, albumin, and its use is still a topic of discussion,117,120 which is complicated by issues with therapeutic substitutes.115 In addition, it would appear that therapeutic effectiveness must be established by the plasma-derived product in which the recombinant product would be regarded as a follow-on biologic or biosimilar product.121 It is my opinion that there are products derived from plasma, such as albumin and IVIG, which (1) have strong safety records and (2) cannot be duplicated by recombinant DNA technology, in the case of IVIG (see Chapter 5). In the case of albumin, while recombinant albumin has been produced,122,123 the economics do not appear to be favorable for reasonable competition for the plasma-derived product; this could change with the use of novel recombinant product systems such as tobacco124 or algae.125 When recombinant factor VIII was produced by several companies in the 1980s, there was some thought that all therapeutic proteins would be produced by recombinant DNA technology, and there was considerable effort to

Plasma Fractionation and Plasma Protein Products

29

remove all proteins from the cell culture media and as excipients in the inal drug product. However, as of 2010, of the many intrinsic plasma proteins, only recombinant forms of factor IX, the von Willebrand factor, thrombin, and antithrombin have been licensed as biologicals in the United States. As noted earlier, recombinant albumin remains under development, as does α1-antitrypsin.126–128 The point that I am trying to make is that biologicals derived from human blood are safe within the reasonable limits of risk. The paramount issue regarding the current use and future development of plasmaderived biologicals relates to the risk of infection from a known or unknown pathogen. I trust that the reader understands that I do consider this a serious issue but that the risk of infection should be considered in light of therapeutic value and societal cost. The HIV tragedy described earlier has been a learning experience for the plasma industry and has resulted in the development of objective and subjective screening techniques for donors and donated blood. The increased appreciation of zoonotic disease emphasizes the importance of the unknown pathogens in products obtained from blood.129–133 The risk from the transfusion of blood is known (see above), and the risk from puriied protein fractions obtained from blood is less than that for whole blood134–139 with the removal by various processing steps demonstrated by various researchers.140–145 It is not unreasonable to suggest, at least for the sake of argument, that the risk of a plasma-derived therapeutic should be balanced with the cost of the plasma-derived product as compared to a recombinant product. The question then arises as to how much risk will the society accept and at what cost, which is a question of signiicance across all sectors of health care.146–148 As an example, recombinant factor VIII products are available at a substantial premium compared to plasma-derived factor VIII with essentially equivalent therapeutic equivalence.* Mantovani and colleagues149 presented an excellent study on the complex nature of treatment choice in hemophilia showing the combined importance of safety against viruses, inhibitor development, and infusion frequency. These researchers noted that product choice, when there is cost discrepancy between therapeutically equivalent products, is important when resources are limited. Other researchers have also provided an insight into this issue.150 Outcome analysis is used for other therapeutic approaches for determining the value,151 and it is clear that regardless of geography and reimbursement processes, resource allocation will be an increasing problem in health care.152 I would be remiss if I do not mention the current issue between recombinant human thrombin and bovine plasma–derived thrombin when there is a strong effort by supporters of bovine thrombin to preserve market share.153 Here, the issue is the development of antibodies against the bovine proteins, with little thought given to diseases caused by potential pathogens from bovine sources, such as variant Creutzfeldt–Jakob disease, which has driven the development of “protein-free” therapeutics. Robert154 argues that plasma fractionation will increase at a greater rate if intravenous immunoglobulin is approved for use in the case of Alzheimer disease. I do not *

As an example, a study conducted by a group of Italian researchers published in 2005299 using data from 2002 reported that the cost for a second-generation recombinant product (albumin-free formulation) was some 140% of a highly puriied plasma-derived product.

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necessarily agree with this speciic conclusion (see Chapter 5) but do see an increase in the use of intravenous immunoglobulin (again see Chapter 5). There are a variety of potential indications for intravenous immunoglobulins in immunomodulation.155 Since it is unlikely that polyclonality is required for immunomodulation indications, there would be a pathway to a second-generation therapeutic product from the fractionation of an intravenous immunoglobulin active pharmaceutical ingredient. A similar argument can be made for infectious diseases in which it is clear that donor plasma could be selected for action against speciic pathogens,156,157 suggesting that donor plasmas could be preselected for the presence of antibodies of value in infectious diseases, as it is likely that a maximum therapeutic effect will be obtained from a polyclonal antibody preparation (see Chapter 5). It is of some interest that, considering the studies on the presence of antibodies for measles virus in intravenous immunoglobulin cited previously,156 one of the irst applications of human immune serum globulin was in the treatment of measles.158 The Cohn fractionation procedure was developed well in advance of the various separation technologies that are currently available for commercial biotechnology in the twenty-irst century. A perspective may be obtained by considering reviews by Taylor in 1953159 and a bit later by Pennell in 1960.160 Taylor159 reviews the state-of-the-art protein puriication during the mid-twentieth century. The available techniques were based on differential solubility, physical methods such as ultracentrifugation, preparative electrophoresis (free-boundary electrophoresis), and adsorption/elution from insoluble salts as well as the use of partition chromatography. Partition chromatography was developed by Gordon and coworkers161 in 1943 to separate amino acids and found application for proteins in the work by Martin and Porter in 1951.162 Adsorption chromatography for proteins on silica gel was reported by Shepard and Tiselius in 1949.163 The latter paper163 is prescient of hydrophobic interaction chromatography. The use of chromatography was in the earliest stage of development when Cohn and colleagues developed the alcohol fractionation scheme, and it would be some 40 years before Michael Grifith and colleagues in the Hyland Division of Baxter Healthcare applied immunoafinity chromatography for the puriication of plasma factor VIII,164 and other groups applied it for albumin and IgG.*,165–170 Lihme and colleagues171 have recently described the use of expanded bed chromatographic systems for the fractionation of plasma. I would be remiss if I do not mention some additional considerations about protein puriication. Protein puriication can be pursued for different goals as discussed by Linn.172 In the case of plasma fractionation, the goal is maximal recovery of the product with as few impurities as possible and no contaminants. Here, purity is relative, as impurities may be tolerated as long as they do not present a safety risk. As an example, consider the development of ultrapure factor VIII preparations (see Chapter 6). Here, the goal was not as much to obtain pure factor VIII as it was to eliminate the ibrinogen, which was a substantial impurity in therapeutic factor VIII preparations in the 1970s.173–175 The problem is that the *

It is important to understand that the introduction of column chromatography into a manufacturing environment based on iltration and centrifugation for separation technologies is a challenging proposition.300

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half-life of ibrinogen is approximately 80 h,176 which is substantially longer than the 12–16 h half-life of factor VIII (see Chapter 6). It is critical to keep an account of the puriication and maintain a record.177 If one is willing to learn from the past (see Preface in Kendrick40) and do a rigorous analysis of development costs,178 it is possible to argue for the development of new plasma protein therapeutics. Admittedly, this is dependent on the unique nature of intravenous immunoglobulins, allowing most of the cost to be borne by those products.* Four issues impinge on the future of plasma-derived biopharmaceutical products. First, the emergence of another “HIV-like” pathogen would be devastating for the industry, limiting the market to only absolutely unique biopharmaceuticals such as intravenous immunoglobulin. Second, new indications for existing products such as the use of intravenous immunoglobulin in Alzheimer disease would increase plasma demand.179 Third, there is potential for the development of new products.92,180 This could be done with a change to the basic Cohn fractionation process, thereby eliminating any inluence on the licensure of existing products. A recent example is the development of α1-antitrypsin from the Cohn Fraction IV.181,182 Where there is a change in process that might inluence a downstream product, for example, a change in the processing of the Cohn Fraction I–III to maximize intravenous immunoglobulin yields might inluence the Cohn IV process, advanced characterization technologies,183 combined with insight gained through the considerations of biosimilars184,185 and Quality-by-Design (QbD),186 should facilitate the approval of changes. Fourth is the potential for the establishment of new markets for the existing products. Curling and Bryant, in their review of the plasma fractionation industry in 2005,64 observed that the developing economies represent an underserved market for all biopharmaceuticals, including the plasma-derived biologicals. The use of plasma-derived biologicals in developing economies raises the perennial issue of the self-suficiency of resources.187–190 Blood could be collected in the local geography and processed either locally or in another geography using contract manufacturing. The reader is referred to an article by Farrugia,62 which discusses the international movement of plasma and contract manufacturing. Human blood plasma for fractionation into products can be separated on the basis of the source.191–193 “Recovered” plasma is obtained from whole blood after the separation of red blood cells, while “source” plasma is collected from donors by plasmapheresis.† When I did not have any direct knowledge, I had assumed that plasmapheresis had been invented as a process either during World War II or shortly thereafter. Therefore, it was a bit of a surprise to the author‡ that plasmapheresis was developed in 1913 by a group from Johns Hopkins194 who coined the term using , the Greek αφαίρεσις (removal or withdrawal). Plasmapheresis allowed the repeated use of qualiied donors in commercial plasma collection centers.61 There are some *

†

‡

In the spirit of full disclosure, the author (1) does not have a business background and (2) knows little, if anything, about cost allocation in commercial plasma fractionation. The term apheresis is frequently used in place of plasmapheresis. Plasmapheresis is used to describe the removal of plasma, with the cellular elements returned to the donor. Apheresis is a term used to describe the removal of speciic elements such as platelets or granulocytes, with the return of red blood cells and plasma to the donor.301 Apheresis is frequently used as a therapeutic process.302 An informal survey of colleagues suggested that the author is not alone in this matter.

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differences in the quality of source plasma as compared to recovered plasma, but these differences do not inluence the product safety.156,191–193,195–197 One example of quality difference can be illustrated by the studies of Audet and coworkers,156 who found higher titers of measles antibody in recovered plasma versus source plasma, while Planitzer and colleagues196 found higher titers of echovirus antibody in source plasma as opposed to recovered plasma. It is of interest to note that plasmapheresis was introduced in the United Kingdom as a method for harvesting hyperimmune plasma for various indications.195 It can be argued that “local” plasma is invaluable in relecting the local immune experience,198,199 which would then be critical in guarding against local pathogens200 such as the H1N1 virus.201,202 Not all geographies have the same quality of plasma collection,108 and there may be different standards for the processing and storage of human plasma; there are differences between EU standards and U.S. standards for human plasma.62 There are, however, WHO standards for the collection and processing of blood and blood products, which could be used for harmonization.203–205 The differences between the U.S. and EU standards63 are concerned with screening (to the extent that the author has information, all manufacturers use the EU standards) and processing and storage temperatures (which center on the eutectic point of human plasma). There are signiicant economic issues in considering local versus imported materials.65 For example, in Brazil, the cost of imported plasma protein products for 2006 was more than US$ 300,000,000, approximately half of which was for intravenous immunoglobulin. This has encouraged the development of a new organization, Hemobrás,206 in Brazil for plasma fractionation. It is assumed that the new facility will use the existing technology that combines the Cohn fractionation and column chromatography. Considering some of the above discussion, newcomers to the fractionation business would ind it useful if they start “from scratch” using new technologies. This might be of particular value when the product might be used only within the geography where it is generated and would not have the burden of following the regulatory norms of the United States or the European Union. Chromatography of intact plasma is complicated by the viscosity of the starting material and the associated tendency to clog the ilter. The use of expanded bed chromatography207–209 offers a solution to these problems, and it has been used by Lihme and coworkers for the puriication of therapeutic proteins from plasma.171 A complementary approach would incorporate the cryoprecipitate step and process the cryopoor plasma. The cryoprecipitate can be used as it is presently used for therapeutic products,210–212 while the cryopoor plasma can be processed by chromatography to yield therapeutic protein preparations such as C-1 inhibitor,213 factor IX,214 factor VIIa,215 and prothrombin complex.216 The latter study216 used the supernatant fraction from Cohn I rather than cryosupernatant fraction.

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243. Lee, J.J., Bruley, D.F., and Kang, K.A., Manipulation of the afinity between protein and metal ions by imidazole and pH for metal afinity puriication of protein C from Cohn fraction IV-1. Adv. Exp. Med. Biol. 614, 93–100, 2008. PubMed PMID: 18290318. 244. Svoboda, M.E., Van Wyk, J.J., Klapper, D.G., et al., Puriication of somatomedin-C from human plasma: Chemical and biological properties, partial sequence analysis, and relationship to other somatomedins, Biochemistry 19, 790–797, 1980. 245. Bala, R.M. and Bhaumick, B., Puriication of a basic somatomedin, from human plasma Cohn fraction IV-1, with physicochemical and radioimmunoassay similarity to somatomedin-C and insulin-like growth factor, Can. J. Biochem. 57, 1289–1298, 1979. 246. Tadepalli, S.S., Bruley, D.F., Kang, D.A., and Drohan, W., Separation of protein C from fraction IV of the Cohn process using immobilized metal afinity chromatography, Adv. Exp. Med. Biol. 428, 639–644, 1997. 247. Wu, H. and Bruley, D.F., Homologous human blood protein separation using immobilized metal afinity chromatography: Protein C separation from prothrombin with application to the separation of factor IX and prothrombin, Biotechnol. Prog. 15, 928–931, 1999. 248. Van der Brande, J.L., Hoogerbrugge, C.M., Beyreuther, K., et al., Isolation and partial characterization of IGF-like peptides from Cohn fraction IV of human plasma, Acta Endocrinol. (Copenhagen) 122, 683–695, 1990. 249. Martin, J.L. and Baxter, R.C., Insulin-like growth factor-binding protein from human plasma. Puriication and characterization, J. Biol. Chem. 261, 8754–8760, 1986. 250. Blum, W.F., Jenne, E.W., Reppin, F., et al., Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I, Endocrinology 125, 766–772, 1989. 251. Miller, F. and Habicht, G.S., Serum-derived immunosuppressive substances. II. An evaluation of various sources for an endogenous regulator of lymphocyte activation, Int. Arch. Allergy Appl. Immunol. 55, 228–238, 1977. 252. Bednarik, T., Cajthamlova, H., Losticky, C., et al., Study on immunosuppressive activity of α-globulin fraction of human blood plasma, Czech. Med. 6, 107–115, 1983. 253. Gorin, E., Gonen, H., and Dickbuch, S., A serum protein inhibitor of acid lipase and its possible role in lipid accumulation in cultured ibroblasts, Biochem. J. 204, 221–227, 1982. 254. Bishop, D.F., Wampler, D.E., Sgouris, J.T., et al., Pilot scale puriication of α-galactosidase A from Cohn fraction IV-1 on human plasma, Biochim. Biophys. Acta 524, 109–120, 1978. 255. Sampaio, C.A. and Grisolia, D., Human plasma kallikrein. Preliminary studies on hydrolysis of proteins and peptides, Agents Actions 8, 125–131, 1978. 256. Jørgensen, C.S., Christiansen, M., Laursen, I., et al., Large-scale puriication and characterization of non-glycosylated Gc globulin (vitamin D-binding protein) from plasma fraction IV, Biotechnol. Appl. Biochem. 44, 35–44, 2006. 257. Christiansen, M., Jørgensen, C.S., Laursen, I., et al., Protein chemical characterization of Gc globulin (vitamin D-binding protein) isoforms: Gc-1f, Gc1a, and Gc-2, Biochim. Biophys. Acta 177, 481–492, 2007. 258. Waugh, W.H., Iron chelation by dibasic amino acid prevents glycoprotein insolubilities: A strategy to inhibit age-related macular degeneration?, J. Appl. Res. 4, 208–214, 2004. 259. Dalton, J. and Podmore, A., Enriched haptoglobin polymers for the treatment of disease, U.S. Patent Application, US20080293623 A1 20081127, 2008. 260. Scatchard, G., Strong, L.E., Hughes, W.L., Jr., et al., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXVI. The properties of solutions of human serum albumin of low salt content, J. Clin. Invest. 24, 671–679, 1945. 261. Cohn, E.J., Hughes, W.L., Jr., and Weare, J.H., Preparation and properties of serum and plasma proteins; crystallization of serum albumins from ethanol water mixtures, J. Am. Chem. Soc. 69, 1753–1761, 1947. 262. Blombäck, B. and Hanson, L.A. (eds.), Plasma Proteins, John Wiley and Sons, Chichester, 1979.

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263. Putman, F.W., Perspectives, in The Plasma Proteins, 2nd edn., ed. F.W. Putman, Chapter 1, Academic Press, New York, 1975. 264. Dixon, M. and Webb, E.C., Enzymes, 2nd edn., Chapter 2, Academic Press, New York, 1964. 265. Ostlund-Lindqvist, A.M. and Boberg, J., Presence of apolipoprotein-CII in commercially available albumin fractions, Clin. Sci. 56, 99–100, 1979. 266. Berntorp, E., Factor VIII concentrates, in Hemophilia, eds. C.D. Forbes, L. Aledort, and R. Madhok, R., Chapter 17, Chapman & Hall, London, 1997. 267. Fricke, W.A. and Yu, M.Y., Characterization of von Willebrand factor in factor VIII concentrates, Am. J. Hematol. 31, 41–45, 1989. 268. Edsall, J.T., Ferry, R.M., and Armstrong, S.H., Jr., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XI. The proteins concerned in the blood coagulation mechanism, J. Clin. Invest. 23, 557–565, 1944. 269. Ferry, J.D. and Morrison, P.R., Chemical, clinical, and immunological studies on the products of human plasma fractionation. XVI. Fibrin clots, ibrin ilms, and ibrinogen plastics, J. Clin. Invest. 23, 566–571, 1944. 270. Tanaka, K., Sawatani, E., Dias, G.A., et al., High quality of human immunoglobulin G puriied from Cohn fractions by liquid chromatography, Braz. J. Med. Biol. Res. 33, 27–30, 2000. 271. Wickerhauser, M. and Sgouris, J.T., Development of large-scale fractionation method. II. Isolation of a factor IX concentrate (prothrombin complex) for clinical use, Vox. Sang. 22, 137–160, 1972. 272. Andary, T.J., Berkebile, R.L., Thomas, W.R., and Tse, D.C., Therapeutic enzyme concompositions, U.S. Patent 4286056 A 19810825, 1981. 273. Mehl, J.W., O’Connell, W., and Degroot, J., Macroglobulin from human plasma which forms an enzymatically active compound with trypsin, Science 145, 821–822, 1964. 274. Tsuji, A., Oda, R., Sakiyama, K., et al., Lysosomal enzyme replacement using α2-macroglobulin as a transport vehicle, J. Biochem. 115, 937–944, 1994. 275. Peitsch, M.C., Kress, A., Lerch, P.G., et al., A puriication method for apolipoprotein A-I and A-II, Anal. Biochem. 178, 301–305, 1989. 276. Brinkman, N., Bigler, D., Bolii, F., and Foertsch, V., Methods for puriication of alpha-1antitrypsin and apolipoprotein A-I, International Patent, WO2009025754 A2 20090226, 2009. 277. Bednarik, T., Cajthamlova, H., Losticky, C. et al., Immunoelectrophoretic study of the pasteurized alpha-globulin of human plasma, Cesko-Slovenska Farmacie 31, 168–170, 1982. 278. Belew, M., Peterson, E.A., and Porath, J., A high-capacity hydrophobic adsorbent for human serum albumin, Analyt. Biochem. 151, 438–441, 1985. 279. Deutsch, H.F., Kasper, C.B., and Walsh, D.A., Rapid method for preparation of crystalline human ceruloplasmin from Cohn fraction IV-1, Arch. Biochem. Biophys. 99, 132– 135, 1962. 280. Glaser, C.B., Karic, L., and Fallat, R., Isolation and characterization of alpha-1-antitrypsin from the Cohn fraction IV-1 of human plasma, Prep. Biochem. 5, 333–348, 1975. 281. Chen, S.X., Hammond, D.J., Klos, A.M., et al., Chromatographic puriication of human α1-proteinase inhibitor from dissolved Cohn fraction IV-1 paste, J. Chromatogr. A 800, 207–218, 1998. 282. Lujan, H.D., Byrd, L.G., Mowatt, M.R., and Nash, T.E., Serum Cohn fraction IV-1 supports the growth of Giardia lamblia in vitro, Infect. Immun. 62, 4664–4666, 1994. 283. Bignold, L.P., Rogers, S.D., and Harkin, D.G., Effects of plasma proteins on the adhesion, spreading, polarization in suspension, random motility and chemotaxis of neutrophil leukocytes on polycarbonate (Nucleopore) iltration membranes, Eur. J. Cell. Biol. 53, 27–34, 1990.

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284. Glasser, L., Fiederlein, R.L., and Huestis, D.W., Liquid preservation of human neutrophils stored in synthetic media at 22 degrees C: Controlled observations on storage variables, Blood 66, 267–272, 1985. 285. Houlgette, R., Wion, D., and Brachet, P., Serum contains a macromolecular effector promoting the synthesis of nerve growth factor (NGF) in L cells, Biochem. Biophys. Res. Commun. 150, 723–730, 1988. 286. Ng, P.K. and Dobkin, M.B., Cell-growth medium supplement, U.S. Patent 4452893 A 19840605, 1984. 287. Abdelnoor, A.M., Harvie, N.R., and Johnson, A.G., Neutralization of bacteria- and endotoxin-induced hypotension by lipoprotein-free human serum, Infect. Immun. 38, 157–161, 1982. 288. Miles, G.L., Taylaur, C.E., and Wilkinson, P.A., Comparison of methods for separating blood plasma lipoproteins, Nature 206, 191–192, 1965. 289. Kaplan, J. and Sunblad, L., Immunochemical determination of β-lipoproteins, Scand. J. Clin. Lab. Invest. 24, 61–68, 1969. 290. Blaton, V. and Peeters, H., Subunits of low- and high-density lipoproteins, Protides Biol. Fluids 16, 707–716, 1969. 291. Oesterreicher, S., Blum, W.F., Schmidt, B., et al., Interaction of insulin-like growth factor II (IGF-II) with multiple plasma proteins: High afinity binding of plasminogen to IGF-II and IGF-binding protein-C, J. Biol. Chem. 280, 9994–10000, 2005. 292. Liu, T.H. and Mertz, E.T., Studies on plasminogen. IX. Puriication of human plasminogen from Cohn fraction-3 by afinity chromatography, Can. J. Biochem. 49, 1055–1061, 1971. 293. Congote, L.F., Extraction of an erythrotropin-like factor from bovine serum albumin (Cohn fraction V), In Vitro Cell Dev. Biol. 23, 361–366, 1987. 294. Jenkins, N., Castro, P., Menon, S., et al., Effect of lipid supplements on the production and glycosylation of recombinant interferon-γ expressed in CHO cells, Cytotechnology 15, 209–215, 1994. 295. Schmid, K., Mao, S.K., Kimura, A., et al., Isolation and characterization of a serinethreonine-rich galactoglycoprotein from human plasma, J. Biol. Chem. 255, 3221–3226, 1980. 296. Kingdon, H.S., Lundblad, R.L., and Dingman, G., Factors affecting the evolution of factor XIa during blood coagulation, J. Lab. Clin. Med. 85, 826–831, 1975. 297. Schneider, D.J., Tracy, P.B., Mann, K.G., and Sobel, B.E., Differential effects of anticoagulants on the activation of platelets ex vivo, Circulation 96, 2877–2883, 1997. 298. Bernheim, B.M., Whole blood transfusion and citrated blood transfusion, JAMA 77, 275–279, 1921. 299. Mantovani, L.G., Monzini, M.S., Mannucci, P.M., et al., Differences between patients’, physicians’ and pharmacists’ preferences for treatment products in haemophilia: A discrete choice experiment, Haemophilia 11, 589–597, 2005. 300. Ehrnberg, H. and Sjoberg, N., Technological discontinuities, competition and irm performance, Technol. Analysis Strategic Manage., 7, 93–107, 1995. 301. Vamvakas, E.C., The relative safety of pooled whole-blood-derived platelets prepared by the buffy-coat method versus single-donor (apheresis) platelets, Clin. Lab. 56, 263– 279, 2010. 302. Shelet, S.G., Practical considerations for planning a therapeutic apheresis procedure, Am. J. Med. 123, 777–784, 2010.

3

Methods for the Analysis of Plasma and Plasma Protein Fractions

There are two different aspects of analytical biochemistry that can be applied to the characterization of plasma and plasma protein fractions. The irst is the type of characterization used in the biochemical and biophysical characterization of proteins as practiced in the academic departments of biochemistry and chemistry.* The second is the type of analytical science used for the assay of plasma proteins during the commercial puriication and product release. It has been acknowledged that these two areas overlap, but I would posit that assays are developed in basic science departments and then used for biopharmaceutical products. Mass spectrometry is an example that is commonly applied to the characterization of recombinant proteins but infrequently, if at all, in the plasma business.† Early methods for the characterization of blood plasma were irst based on electrophoretic methods1–3 as developed by Tiselius.4–8 The development of the electrophoretic analysis of protein is the subject of an excellent review9 by Righetti, which was published in 2005. Tiselius developed moving-boundary or free-boundary electrophoresis, in which colloids such as proteins migrate in free solution. In his original application, Tiselius used optical methods to measure the protein boundaries.10 This technique required substantial protein concentration but could provide information on macromolecular interactions without matrix interference.11 Optical methods are also used to measure the boundaries in analytical ultracentrifugation.12–14 A variation of free-boundary electrophoresis has been used to purify intravenous immunoglobulin (IVIG) from plasma.15 Free-boundary electrophoresis was initially replaced by zonal electrophoresis,16 irst on paper,17 then on starch,18 later on agarose,19 and today by capillary electrophoresis as described later in this book. Hjertén20 introduced a rotating column *

†

The question is whether an analytical result is relevant to the safety and eficacy of a product. While a inding may be of great scientiic interest, such a result may not be relevant to the critical product attributes. An example is provided by the carbohydrate analysis of human factor VIII (see Chapter 6), where there are differences in glycosylation patterns between the protein product in Chinese hamster ovary (CHO) cells and that produced in baby hamster kidney (BHK) cells, both of which are different from the native human protein. Furthermore, Schiestl and coworkers412 reported signiicant changes in the chemical properties of several approved protein drugs likely resulting from changes in the manufacturing process. Such changes were not associated with label changes and all products remained on the market, suggesting that the changes were considerably acceptable by the various regulatory agencies. While mass spectrometry is not, to the best of my knowledge, used in the production and the release of human serum albumin, this technique is used in the current studies of albumin, such as glycation.155

47

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for electrophoresis for the reduction of zonal instability, which was later commercialized as the Rotofor by BioRad,21 and it has been in steady use in preparative isoelectric focusing.22–26 More advanced technologies combining electrophoresis, isoelectric focusing, chromatography, and mass spectrometry are being used for the proteomic analysis of blood plasma and serum; these technologies will be discussed later. Electrophoresis of intact serum is still used in clinical chemistry27 mostly for the detection of monoclonal gammopathies.28 Early work by Tiselius4,5 resulted in the veriication of the albumin and globulin components of blood serum and the separation of globulins into α-, β-, and γ-globulins.3 The terms albumin and globulin were introduced in the 1800s on the basis of the solubility differences between the two groups of proteins.29 The globulin fraction was further separated into various fractions such as pseudoglobulin and euglobulin, again by differing solubility characteristics.30 The work of later researchers demonstrated the heterogeneity of these fractions.31 The application of more advanced analytical technologies, as described later, demonstrated an even more complex picture of human blood plasma. Free-low electrophoresis is similar to free-boundary electrophoresis in the absence of a supporting matrix such as paper, starch, or polyacrylamide gel. Briely, free-low electrophoresis is a continuous system in which a sample is introduced into a buffer solution that lows between two plates in an electric ield, and proteins, subcellular organelles, and cells are separated on the basis of particle charge.32–35 This technology has been extensively used for subcellular organelles and cells.36–41 Free-low electrophoresis is of value for the prefractionation of cells, subcellular organelles, and polyprotein complexes prior to proteomic analysis.42,43 Free-low electrophoresis has also been applied to proteins.44–48 A commercial apparatus for analytical free-low electrophoresis is available from BD-diagnostics.49 A free-low system that is capable of therapeutic fractionation has been developed by Gradipore.50 It is possible to operate free-low electrophoresis as zone electrophoresis, isotachophoresis, and isoelectric focusing.51 Free-low electrophoresis appears to be more useful for sample preparation than for analysis. Given the absence of potential matrix effects, free-low electrophoresis might be useful for the study of protein–protein interactions and other biopolymer–ligand interactions. An example is provided by the study on the interactions of aptamers with protein targets (IgE, human immunodeiciency virus reverse transcriptase) using gradient micro free-low electrophoresis.52 Another example is the study of the binding of follicle-stimulating hormone (FSH) to solubilized plasma membrane receptor.53 Fieldlow fractionation, which has both analytical and preparative capabilities, is a more recent application of free-boundary electrophoresis.54–56 A number of new separation and analytical technologies were developed between 1945 and 1975, including practical ion-exchange chromatography for proteins, gel iltration, polyacrylamide gel electrophoresis (PAGE), scanning UV-VIS spectrophotometers, and analytical ultracentrifugation. However, compared to 2011, the laboratory research in protein separation and characterization was primitive and required substantial amounts of proteins. As a point of reference, consider the contents of a book on analytical techniques for plasma proteins57 that contained chapters on the measurement of protein concentration, electrophoresis, immunoprecipitation, immunoelectrophoresis, radioimmunoassay, analytical isoelectric focusing, and

Methods for the Analysis of Plasma and Plasma Protein Fractions

49

molecular weight determination.* These techniques are old, but they are still useful for the manufacture of plasma-derived therapeutic proteins. There may be more sophisticated instrumentation, but the biochemical and immunochemical principles underlying the assay remain the same. Another issue is the deinition of plasma protein. In 1975, Putnam58 discussed the question of what a plasma protein is. Among the criteria mentioned are primary function in the vascular space, synthesis in the reticuloendothelial systems or liver rather than endocrine tissue, actively secreted into blood rather than as a result of tissue damage, presence in plasma after the neonatal period, and an appreciable circulatory half-life (Chapter 1). Putnam also noted the dynamic range of plasma proteins. Thus, in 1975, Frank Putnam described 53 well-characterized proteins from plasma.58 Several years later, Heide and coworkers59 listed 100 well-characterized plasma proteins. About a decade later in 1984, Putnam60 listed a further increase in the number of plasma proteins but observed problems posed by the new functions ascribed to the old names, isoforms, and posttranslational modiications. More than three decades later, Anderson and coworkers61 compiled a list of 1,175 distinct gene products in the plasma proteome. This list was obtained by merging the data obtained by four different methods, but, as the authors note, it may not contain lowabundance proteins such as cytokines and protein/peptide factors such as S100B.62 It is estimated that there are some 21,000 gene products in the human proteome.63 Considering the dificulty involved in the validation of biomarkers,64 it is not surprising that there are only approximately 200 assays available for the discrete components in plasma or serum.65 It is granted that the issue of identiication as a plasma protein is of importance only in the analysis of intact plasma and/or serum. The primary goal of this book is to discuss the biotechnology of the plasma proteins with an emphasis on the protein therapeutic products that can be derived from human blood plasma. Notwithstanding the current interest in biomarkers, I am interested in these proteomic approaches only as those that directly address the blood-derived biopharmaceutical products.66–68 This will be discussed in greater detail later. That leaves, then, the consideration of various assays that are of value in the development and manufacture of plasma biopharmaceutical products. As an aside, the term biopharmaceutical has no regulatory or true scientiic meaning and is loosely considered to be a drug substance that is produced by biotechnology but has gained acceptance in the greater pharmaceutical community.69–72 The reader is directed to Rader’s analysis of biopharmaceutical73 for a more thorough consideration of this issue. The point is, at least according to this author, that the term biopharmaceutical is mostly useless as a descriptor in the current biotechnology world; thus, this work is concerned with the protein therapeutic products derived from plasma. The determination of the activity and the structure of a protein therapeutic product is a critical activity in the development, manufacture, and use of such a material. At the onset, the actual measurement is but one step in the analytical process. The reader is directed to an excellent chapter by Chris Burgess on analytical quality *

These researchers used a recombinant factor manufactured by Baxter Healthcare and obtained from a hemophilia treatment center. It is assumed that the inal drug product, Recombinate, was used in these studies instead of an active pharmaceutical ingredient (API).

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management.74 The history of a sample used for the measurement of the activity is of particular importance for samples that may have been retained from production lots and for samples obtained from the recipients of products.75,76 The use of DNA proiling permits the unambiguous identiication of blood/plasma/tissue samples from human subjects.76,77 The measurement of the activity of a biological product is one of the several critical quality attributes that may be used to follow a manufacturing process as well as the activity of the API and inal drug product. The measurement of activity is also one of the several quality attributes that are used to evaluate the stability of the inal drug product. Before I leave activity in the discussion of activity measurement (activity measurement will be discussed in greater detail later with regard to speciic proteins), I would like to note that there is no real activity measurement for albumin, no real measurement for the immunomodulation activity of IVIG, and the measurement for factor VIII activity is problematic.78 Additional details on the development and validation of assays are described later. The chemical and physical characterizations are performed for several reasons, including (1) fuse in the manufacturing process to demonstrate that the process produces a reproducible product, (2) to gain regulatory approval for the marketing of the product, and (3) to provide information to the responsible health-care provider. Within the context of the current book, chemical characterization refers to the determination of the chemical structure of a protein, which would include primary structure (amino acid sequence), alignment of disulides, and determination of posttranslational modiications including glycosylation and glycation (if present). A iner analysis might include the determination of oxidation and the formation of β-aspartic acid. Physical characterization includes those techniques used to measure protein conformation.79 Publications should arise from such activities and, assuming that a researcher can sneak some from the legal department, such publications can provide support for the approval and reimbursement by third-party payers.80–85 The instrumentation available for the physical and chemical characterization of proteins in 2011 is impressive including mass spectrometry,86–95 which has largely supplanted the classical approaches to protein structure that involve the chemical and enzymatic fragmentation of a protein followed by the use of the Edman degradation to determine an amino acid sequence. A combination of mass spectrometry with chromatography or electrophoresis provides an elegant and sensitive approach to both the determination of structure and the establishment of purity for proteins. It is then somewhat unfortunate that most, if not all, plasma proteins exhibit some degree of heterogeneity. The heterogeneity may be minor as in the oxidation of the sulfhydryl group in albumin96 or from glycation.97 The glycosylation of proteins is a complex process resulting in O- and N-linked glycan chains. Thus, it is a bit surprising that there is remarkably little variation in N-glycan proiles in a normal population,98 and heterogeneity in the glycosylation of plasma proteins is observed mostly in certain disease states.99–102 Considering the great interest103 regarding the importance of glycosylation as a critical product attribute in the biosimilar area,104–106 it is surprising that, with the exception of the various blood coagulation factors of therapeutic importance, there is little work on the glycosylation of human plasma proteins in the peer-reviewed literature.107,108 Bruce Mackler notes that the concern in the biosimilar area is that glycosylation differences

Methods for the Analysis of Plasma and Plasma Protein Fractions

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between the branded product and the biosimilar product may present a major hurdle to the approval of a biosimilar product.103 However, Mackler also notes that this is an opportunity for solid science to make the case for the importance of such differences. Speciically, it is important to understand that differences in glycosylation may or may not inluence product safety and eficacy. The structure and function of glycan chains on several of the blood coagulation factors, including factor VIII, factor IX, protein C, and factor VII/VIIa, have been the subject of investigation (see Chapters 6 and 8, for more details). The interest here is conceptually related to the biosimilar problem mentioned earlier in that there was great interest in understanding any differences between the protein isolated from plasma and that produced by recombinant DNA technology. In the case of factor VIII, the glycosylation pattern of the recombinant form produced in CHO cells was different from that observed with the material produced in BHK cells, both of which differed from native factor VIII.109,110 The differences in glycosylation do not appear to be related to any differences in recovery, circulatory half-life, or hemostatic effectiveness as judged by comparative clinical studies.111 Fay and coworkers observed that the removal of approximately 50% of the carbohydrate from plasma-derived factor VIII with a mixture of exoglycosidases and endoglycosidases had no effect on activity or circulatory half-life.112 In more recent studies, Kosloski and coworkers113 subjected recombinant factor VIIIc to a mixture of endoglycosidases114 and observed a decrease in its biological activity (one-stage partial thromboplastin time) but no change in immunogenicity. There are two studies, one somewhat older, that I have found quite useful in placing the glycosylation in perspective. The irst study, by Baynes and Wold115 published in 1976, examined the role of glycan in the circulatory half-life of bovine pancreatic ribonuclease (RNase) in normal and nephrectomized rats. RNase A contains no carbohydrate; RNase B possesses a single, simple N-linked oligosaccharide, while RNases C and D possess a single, complex N-linked oligosaccharide (biantennary [two sialic acids] in the case of C and tetraantennary [four sialic acids] in the case of D). All four RNase species are cleared quite rapidly in normal mice, consistent with the role of the kidney in the clearance of small proteins. RNase A is cleared quite slowly (9–10 h) in the nephrectomized rat, RNase B is cleared in 15 min, and RNases C and D are cleared in 11–17 h. The removal of the terminal mannose residues from RNase B extends the clearance to that observed in the case of RNase A. These researchers concluded that an increase in the complexity of glycosylation did not affect the circulatory half-life and that the exposure of mannose was the determining factor in clearance. The late Finn Wold was one of the premier protein chemists in the latter part of the twentieth century and a cofounder of The Protein Society, while John Baynes has been a leader in the characterization of glycoproteins. More recently,116 Skropeta presented an excellent review on the role of glycans in the biological activities of glycoproteins. First, glycosylation appears to have a major role in the secretion of proteins. The author is also familiar with a number of unpublished experiments on the importance of glycosylation in the expression of recombinant proteins from mammalian cell hosts, such as CHO cells or BHK cells. Skropeta also reviewed the diverse effects of glycoengineering on the biological activity of enzymes. This is a superb review article that also covers the effects of glycosylation on stability.

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The study of blood plasma for the purpose of identifying as-yet undescribed proteins and the characterization of “new” and “old” proteins can be labeled plasma proteomics, where such a term would imply the study of all plasma proteins. A quick PubMed search yielded approximately 1,200 citations for the phrase “human blood plasma proteomics,” of which a vast majority of citations describe the search for a biomarker, while a much smaller number of citations address the characterization of plasma and/or serum.117–126 I have previously noted64 that the majority of studies on the identiication of biomarkers use blood plasma or serum as the source. We have previously commented127,128 on distinguishing between serum and plasma as a sample for clinical analysis and for the preparation of samples for proteomic analysis.129 A recent study by Siev and coworkers130 reports that serum and plasma can be used interchangeably for antibody detection assays for mycobacterial antigens but not for other antigens in which there are differences between plasma and serum samples. Serum or plasma can be used, depending on the biomarker, but the sample source and processing must be clearly stated. Proteomics can be described as the study of all of the proteins, and thus, plasma proteomics is the study of plasma proteins. This is admittedly redundant with the previous comment but is meant to reemphasize that proteomics is an area of study and not a technical approach. As noted by the author,129 protein chemistry has evolved into proteomics. Thus, for all practical purposes, there are no unique laboratory techniques in proteomics but rather the adaptation of classical solution protein chemistry to the study of small samples. The techniques in proteomics include chromatography, electrophoresis, mass spectrometry, and bioinformatics. There is no question that the combination of mass spectrometry and bioinformatics is the dominant factor in proteomics. Proteomics has been used in the identiication and characterization of “new” proteins in tissues in biological luids with the goal of identifying biomarkers that are useful in the diagnosis and prognosis of a disease with an emphasis on cancer. There are several studies that use proteomics for the characterization of products in transfusion medicine including therapeutic proteins.131–135 As stated earlier, proteomics is an area of study and not a technical approach. Two of these studies132,134 use a prefractionation step, followed by electrophoresis and/or chromatography, enzymatic fragmentation, and mass spectrometric analysis. Bioinformatic techniques are used to interpret the mass spectrometry results and allow the identiication of the proteins from a database.136,137 This is a classical approach to the identiication of protein biomarkers.64 Two of the other studies133,134 use the process of digestion of samples with proteases followed by the separation of peptides using high-performance liquid chromatography (HPLC) and analysis by mass spectrometry. One of the studies uses proteomic technology to study prothrombin complex concentrates.131 While this product seems to have been bypassed by a combination of technology and marketing, a prothrombin complex concentrate that contains factor VII is of considerable value.136–141 This study on the prothrombin complex concentrates131 provides information on the composition of this material, which is not available from the use of earlier technologies and will be most useful in establishing quality attributes for the processing of derivative products such as factor IX, antithrombin, or α1-antitrypsin. The proteomic technologies will be most useful in identifying the contaminants and/or impurities in

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plasma protein products, but of less value in ensuring the product identity when compared to other available technologies such as activity determination, immunological assays, spectroscopy, and analytical ultracentrifugation.79 Several of the techniques used in proteomics, such as mass spectrometry, HPLC, and electrophoresis, are of individual value in the characterization of plasma protein fractions. Mass spectrometry is the most important tool in modern protein chemistry, with approximately 60,000 citations on PubMed and a similar number on SciFinder. In the case of proteins, the direct applications of mass spectrometry include the assessment of chemical modiications, the determination of hydrogen/deuterium exchange, and the study of protein–protein interactions. There is a much larger application of mass spectrometry in the identiication of proteins as biomarkers.64 The current work is directed toward the description of the technology that has direct importance in the biotechnological development of plasma proteins and, as such, will focus on the application of mass spectrometry in the development of plasma protein preparations as biopharmaceuticals. The characterization of the posttranslational modiication of plasma proteins is of critical importance in the characterization of such proteins as biopharmaceutical products and for setting a standard as a “branded” product for the qualiication of recombinant products.142–153 The major posttranslational modiication (see above) is glycosylation in that most plasma proteins, with the exception of albumin, have signiicant glycosylation; albumin does undergo glycation.154–156 Other posttranslational modiications include γ-carboxylation of glutamic acid, O-sulfation of tyrosine, β-hydroxylation of aspartic acid, and transpeptidation. Mass spectrometry has been used to characterize the γ-carboxylation of proteins.157 Several plasma proteins of therapeutic importance contain γ-carboxyglutamic acid, but I could not ind any direct use of mass spectrometry for the characterization of this modiication in factor IX, factor VIIa, or activated protein C. Mass spectrometry is used for the characterization of the glycan moieties present in these proteins.158–162 There is also considerable literature on the use of mass spectrometry to study glycans in other proteins of interest.163 The problem of pathogens in the plasma supply for fractionation was discussed in Chapter 2. Mass spectrometry can be used to establish the presence of viral and bacterial pathogens164–168 and could be of value in establishing the presence of such materials in the active pharmaceutical intermediate. Mass spectrometry has been used to determine the presence of contaminants in the prothrombin complex concentrate131 and factor VIII preparations.169 Ahrends and coworkers170 used mass spectrometry to characterize the proteins in the Cohn Fraction IV-4. These researchers also compared displacement chromatography with gradient chromatography for the separation of tryptic peptides prior to mass spectrometry (electrospray ionization). Thiele and coworkers66 used proteomics to evaluate the potential changes in plasma due to viral inactivation with solvent/detergent or methylene blue/light. Some changes were observed at higher methylene blue concentrations. These researchers also used proteomic technologies to evaluate quality in red blood cell concentrates and platelet concentrates. It would appear that the greatest use of mass spectrometry is in the detection of contaminants and impurities in either an API or a inal drug product. A recent example is the application of mass spectrometry for the characterization of heparin.170–176 The author recognizes that heparin is not a plasma protein but its therapeutic activity is coupled to a plasma

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protein, antithrombin (Chapter 8). In the case of heparin, given the small size and relative lack of complexity, the combination of nuclear magnetic resonance (NMR) and mass spectrometry establishes the correct structure(s) and the presence of impurities such as oversulfated chondroitin sulfate.177 Chromatography is a term used to describe the separation of materials on a matrix. The terms chromatogram and chromatography were introduced by Tsweet in 1906 for describing the separation of various colored compounds derived from plants; in Tsweet’s studies, a green material, chlorophyll, was separated from a yellow compound, a carotenoid.178 Over the ensuing 50 years, various developments took place,179–181 but it was not until the development of cellulosic ion-exchange matrices by Sober and Peterson182 and gel iltration by Jerker Porath and Per Flodin183 that chromatography was of practical value for protein puriication. It took some time though for these materials to become readily available from commercial sources; the author was still preparing carboxymethyl cellulose by the reaction of chloroacetic acid and cellulose in 1963 in a scene similar to the opening moment in Macbeth. A few years later, I was in the laboratories of Stanford Moore and William Stein at the Rockefeller University in New York where I could perform two amino acid analyses per day. I recall complaining to Professor Moore about the slow performance, and he pointed out that the current method was a lot better than the several weeks required for bacterial assay for amino acids, which was the state-of-the-art technique when he and Bill started their work in the late 1930s. Ion-exchange resins such as Dowex and Amberlite were introduced following World War II and found considerable use in the industrial sector for water puriication and chemical processing. Attempts to use these cross-linked polystyrene/polyacrylate resins for protein puriication were mostly unsuccessful because of the irreversible binding to the matrix (see below). HPLC is routinely used to evaluate the purity of proteins. Having said that, it must be recognized that there are many types of HPLC, including the ultrahighperformance liquid chromatography (uHPLC).184 HPLC is really a term used for the instrumentation rather than a speciic separation technology in which a solvent is pumped through a matrix consisting of very small particles (usually silica). That said, the term HPLC is most often used for the chromatography on a matrix, where hydrocarbon chains are bound to a matrix; this is called reverse-phase chromatography. Size-exclusion chromatography (SEC) can separate proteins (and other molecules) on the basis of hydrodynamic radius, while ion-exchange matrices separate proteins on the basis of charge. In the absence of a speciic molecular interaction as with afinity chromatography or immunoafinity chromatography, the separation of proteins is based on the use of size or charge. HPLC is a plumbing and detection system that can be used with a variety of chromatographic matrices such as ion-exchange, size-exclusion, reverse-phase, and afinity. The matrices must have the physical characteristics provided by particle size and stability to provide an acceptable low rate and resolution at high pressure. The generic advantages provided by the HPLC technology are analysis speed and sensitivity. HPLC and uHPLC are used primarily for the analysis and characterization of plasma protein therapeutics. Conventional chromatography uses matrices that are similar to those used for HPLC; the dimensions of the chromatographic columns used in the commercial

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biotechnology are quite different from those used for HPLC, frequently looking like relatives of R2D2 from Star Wars. They are operated at much lower pressures than HPLC or uHPLC systems. Chromatographic columns, with the exception of afinity matrices, can be operated in either a gradient mode or an isocratic mode.185 The isocratic mode is much easier to use in a manufacturing setting than a gradient system. Ion-exchange chromatography is used for both the puriication and the characterization of biopharmaceutical proteins.186–200 As noted in Chapter 2, chromatography is used only infrequently in plasma protein puriication for the manufacture of biopharmaceuticals. It is used more extensively for the puriication and characterization of therapeutic proteins produced by recombinant DNA technology. One problem is that most plasma proteins as well as recombinant proteins tend to exhibit some heterogeneity when subjected to chromatography on the current high-resolution ionexchange matrices. Johnson and coworkers200 observed heterogeneity in a monoclonal antibody where isoforms differed in that one heavy chain contained an amidated proline residue. The most common intrinsic heterogeneity in plasma proteins is a difference in glycosylation resulting in multiple glycoforms.201,202 Heterogeneity is also derived during processing, resulting in oxidation199 and succinimide formation.188,192,193 Wang and coworkers199 showed that the conformation inluenced the separation of an oxidized monoclonal antibody (t-butyl hydroperoxide) on cationexchange chromatography. While chromatography at pH 5.5 provided a minor resolution of the oxidized antibody from the native proteins, chromatography at pH 4.0 provided a signiicant resolution; the oxidized antibody is also separated from the native protein by afinity chromatography on a protein A column. It is suggested that a difference in the protein conformation is responsible for the resolution of the oxidized and native proteins. The conformational change has been suggested to be responsible for the change in chromatographic behavior of prothrombin in the presence and absence of calcium ions.203 Other studies on the inluence of conformation on the behavior of proteins on ion-exchange chromatography include the early studies on the effect of urea on the behavior of bovine albumin on anion-exchange chromatography.204 In these studies, Withka and coworkers showed that the loss of native bovine serum albumin structure in the presence of urea could be measured by the changes in behavior on a diethylaminoethanol (DEAE) matrix. These researchers also studied the effect of conformation on the behavior of proteins on SEC where a more rapidly migrating species was observed on denaturation with urea (4.8 M); oddly enough, there was little change in the amount of dimer. These researchers also studied the effect of urea denaturation on the cation-exchange (sulfonated matrix) chromatography of trypsin and lysozyme. Urea had a biphasic effect on the chromatography of trypsin with an increase in retention at low (0.5 M) urea concentrations while a decrease in retention at higher urea concentrations. There is a decrease in retention for lysozyme at all urea concentrations. Similar results for lysozyme were reported by Yamamoto and coworkers.205 Urea was not present in the chromatography solvent in these experiments; the samples were treated with 8.0 M urea. Cole had previously observed the necessity for the inclusion of urea in the chromatography of proteins on ion-exchange resins; in the absence of urea, proteins were irreversibly adsorbed onto ion-exchange resins.206 Voitl and coworkers207 observed that human serum albumin was resolved into two peaks on chromatography on a strong

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cation-exchange matrix (sulfoethyl). Rechromatography of either the major or the minor peak resulted in the formation of two fractions, indicating an equilibrium process in the sample. Only a single peak was observed on a carboxylate matrix. Chromatography was performed at pH 5.0, below which a pH transition would be expected. Experiments with monoclonal antibodies208 do not suggest a conformational change with unmodiied proteins or in the absence of ligands. A further analysis by Voitl and coworkers209 supports the hypothesis that there are two conformations produced by an interaction with the strong cation-exchange matrix. Thus, in these studies, the matrix creates an apparent heterogeneity. Hou and coworkers210 showed that the protein conformation does inluence the behavior of a protein on ionexchange matrices, but such changes are complicated and dependent on the protein. Ideally, the interaction between a protein and a charged matrix would depend on the net particle charge on the protein. Surface charges are not distributed equally, and “patches” do exist where positively charged, negatively charged, or neutral/hydrophobic amino acids would be clustered together on the surface of a protein. In the case of thrombin, the anion-binding exosites211 are likely responsible for binding to the cation-exchange matrices.212,213 SEC refers to a technique that separates molecules on the basis of hydrodynamic volume (Stoke’s radius) using a cylindrical column with laminar luid low. There are two “types” of SEC: gel permeation chromatography is taken to mean the separation of organic compounds in apolar solvents,214 while gel iltration is taken to refer to the separation of materials in aqueous solvent systems.215–219 Gel iltration (most frequently referred to as SEC) is commonly used in the study of proteins and peptides, while there is little use of gel permeation chromatography in the protein chemistry laboratory. Gel permeation is used extensively in polymer chemistry. Gel iltration is commonly assumed to separate proteins on the basis of size and is used most frequently in the assessment of the aggregation of protein APIs in the inal drug product.220–225 It is recognized that analytical ultracentrifugation does provide the “gold standard” for assessing protein aggregation.226–229 It is noted that albumin (see Chapter 4) is provided as a solution that has undergone pasteurization, and visual inspection229 for particulate material is used in addition to gel iltration.205 Matrix effects cannot be ignored in SEC.231–236 Tarvers demonstrated an apparent decrease in the molecular weight of prothrombin in the presence of calcium ions as determined by gel iltration.237 Lundblad238 observed that the behavior of human prothrombin changed in the presence of calcium ions, suggesting the exposure of a hydrophobic patch that bound to the matrix and, thus, the decreased molecular weight of prothrombin observed by Tarvers in the presence of calcium ions. An interaction of aromatic compounds with dextran gels (Sephadex) has been known for some time.239 Martenson presented an excellent review on the use of gel iltration to study conformational changes.240 A conformational change that increases the axial ration of proteins will change the gel iltration behavior.241,242 It is strongly recommended that a change in behavior on gel iltration suggesting a change in size be validated by analytical ultracentrifugation. Hydrophobic interaction chromatography (HIC)243–246 is used for the puriication and characterization of proteins. It is useful because HIC, as with gel iltration, offers a method that is orthogonal to ion-exchange technique.247 There is great interest in

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the use of HIC in manufacturing biopharmaceuticals.248,249 I do not know of any direct application to plasma proteins. Extracorporeal HIC has been used in combination with IVIG in the treatment of autoimmune disease.250 HIC is used for the puriication and characterization of immunoglobulins251–253 and albumin.254–257 It has been suggested that proteins undergo conformational changes on binding to HIC matrices.258–262 The binding of the protein to the HIC matrix can result in denaturation, which, in turn, is dependent on mobile-phase modiiers.263 The effect of modiiers on the behavior of α-lactalbumin on HIC has been used as a model system. Wu published a well-cited paper in 1986264 on the effect of protein conformation on HIC with an emphasis on the mobile-phase composition. These researchers showed that α-lactoglobulin underwent a temperature-induced conformation change on an HIC column resulting in two peaks, the latter eluting and growing at the expense of the early peak; calcium ions stabilized α-lactoglobulin, while the presence of magnesium ions resulted in destabilization. A more recent work by Jones and Fernandez265 conirmed the presence of two peaks in the HIC of α-lactalbumin and showed by hydrogen-exchange that the second peak was mostly unfolded. There are a number of other studies on the inluence of protein conformation on binding to HIC matrices.266–273 One useful example is the increased binding of human prothrombin to an HIC matrix in the presence of calcium ions.238 This type of binding has been referred to as pseudoafinity chromatography by Yan.274 The metal ion–dependent binding of vitamin K–dependent proteins to antibodies is well known and was used by Smith275 to purify factor IX. The use of p-chlorobenzylamido-agarose to purify thrombin276 is an interesting example of what appears to be speciic hydrophobic afinity chromatography. Hydrophobic afinity chromatography has the potential to be used in biopharmaceutical manufacturing,277 while the speciicity of metal ion– induced changes in chromatographic behavior has the potential to be used as a surrogate measure of function for proteins, such as factor IX, where the function is dependent on calcium ions. Afinity chromatography, most notably immunoafinity chromatography, has been considerably used for the puriication of recombinant proteins. Afinity chromatography is based on a biologically signiicant interaction between the solute and the speciic binding ligand on the matrix.278 The classic model used a competitive inhibitor bound to a matrix such as the use of amidine derivatives in the afinity chromatography of trypsin.279 Immunoafinity chromatography is based on the interaction of antibodies and speciic epitopes on an antigen. Most often, an antibody is used to purify an antigen, but an antigen can also be used to purify an antibody. An example of the latter is the use of autoantibodies to identify speciic antibodies in polyclonal antibody preparations. Immunoafinity chromatography has been used to purify blood coagulation factor VIII from plasma for therapeutic use.280–284 A speciic immunoglobulin G (IgG) population responsible for the immunosuppressive effect of IVIG in autoimmune myasthenia gravis can be obtained from bulk IVIG by immunoafinity chromatography.285 The choice of an antibody for immunoafinity chromatography is not trivial. Early work with polyclonal antibodies required drastic conditions for elution because of the high afinity of polyclonal binding; the development of monoclonal antibodies, the use of batch binding for the selection of an antibody, and the conditions for application and elution made immunoafinity

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chromatography a more reasonable choice for use with labile plasma proteins, such as factor VIII.286–289 While batch evaluation using enzyme-linked immunosorbent assay (ELISA) systems was (and is) useful for antibody selection and the optimization of binding and elution conditions,290–292 surface plasmon resonance technology may be more rapid.288,293 It is possible to achieve immunoafinity puriication using batch ELISA technology on polystyrene microplates.294,295 As a general consideration for immunoafinity chromatography, it is useful to have a speciic, “weak” antibody for immunoafinity chromatography such that drastic conditions are not required for the elution of the material of interest. There is a different critical attribute for an antibody used for capture in an ELISA assay where high afinity is a desirable quality. Thompson and coworkers296 report a method for the use of ELISA-elution technique to select polyol-sensitive monoclonal antibodies for use in immunoafinity chromatography. There are other examples where ELISA-elution technique has proved useful for antibody selection for immunoafinity chromatography.297–300 Antibodies are the most common biospeciic ligand used for afinity chromatography of plasma proteins. However, there are other speciic ligands that have proved useful. Heparin is likely the best example. Heparin binds to a substantial number of plasma proteins,301,302 but it binds more tightly to antithrombin. Antithrombin can be prepared from plasma by afinity chromatography on heparin–agarose.303–307 Afinity chromatography is rarely used for characterization. IgG can be puriied by afinity chromatography on protein A308,309 or protein G.310,311 Lectin afinity chromatography can be used to evaluate glycosylation quality.312 Lectins may also be used as probes in microarray technology for the characterization of glycosylation.313 Lectin afinity chromatography may also be used for the puriication of IgA and IgM immunoglobulins.314–316 Lectin binding has been used to monitor the in-process glycosylation during biopharmaceutical manufacturing.317 Mass spectrometry, however, remains the method of choice for the characterization of glycosylation.318 Electrophoresis is used extensively to demonstrate the purity of protein preparations. While electrophoresis may be performed in the absence of a supporting matrix, as discussed for free-boundary electrophoresis earlier, this technique is usually performed with a supporting matrix. Capillary electrophoresis is also an example of zone or free-boundary electrophoresis. Capillary electrophoresis offers the advantages of speed and sensitivity—attributes of importance when the sample volume is limited.319 While there is some suggestion that capillary electrophoresis suffers from the problems of sensitivity and reproducibility,320,321 this technique has been found useful for the characterization of biopharmaceutical proteins.322–327 As with the other separation technologies, capillary electrophoresis can be coupled with mass spectrometry for analysis.328 Polyacrylamide matrices are usually used for proteins; agarose matrices may be used for very high-molecular-weight proteins such as the von Willebrand factor.329,330 PAGE is used in the presence or absence of sodium dodecyl sulfate (SDS); when used in the presence of SDS, the technology is referred to as sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In principle, the detergent denatures the protein and binds to the denatured protein to yield a negatively charged particle that will migrate in a cross-linked polyacrylamide gel with a velocity inversely proportional to the molecular weight. SDS-PAGE is frequently used to demonstrate protein purity,331 but can also be used to measure a functional attribute such

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as the cleavage of factor VIII by thrombin.332,333 SDS-PAGE can yield misleading results such as heterogeneity induced by sample processing.334 Proteins with extensive glycosylation stain poorly with Coomassie blue stains.335–337 There is a good recent article on staining for proteomic research that is quite useful338 as well as a review by Steinberg.339 This techniques is, as mentioned earlier, used primarily for the characterization of the purity of the inal product. Native gel electrophoresis is a method of electrophoresis in a polyacrylamide gel (or other matrix or under free-boundary conditions); native gel electrophoresis is most often used to characterize the interaction of proteins with other proteins or nucleic acids.340,341 Blue native electrophoresis is a technique that has been used to study membrane protein complexes.342–344 The use of blue native electrophoresis preserves the native state of the protein, permitting the use of conformationally sensitive antibodies345 and assays for enzymatic activity.346 Solid-phase-speciic binding assays are used extensively in the study of plasma proteins. The assay is based on the immobilization of a speciic binding agent to a matrix such as a microplate, capture of the analyte by the immobilized binding agent, and detection of the bound analyte most often by a monoclonal antibody coupled to a signal generation system such as peroxidase. Immunoassays are based on the “speciic” interaction between an antibody and an epitope on the analyte. The basic approach involves immobilizing an antibody in a microplate, adding the sample, and then using another antibody linked to a signal that can be measured and used as a measure of the amount of analyte captured by the antibody. This type of process can be used in other binding assays as described by Englebienne.347 Examples that substantiate the importance of the study of plasma proteins include the collagen binding of the von Willebrand factor,348,349 the use of immobilized ibrinogen to bind C1q and gC1q-R,350 and the use of immobilized glycoconjugates to measure glycan-binding proteins.351 The binding of proteins such as ibronectin352 and ibrinogen353 can result in the exposure of neoantigens. A pull-down assay354 is a variation of a solid-phase binding assay, which can be used for the study of protein–protein interactions.355,356 The most common binding assay used in plasma protein biotechnology is the immunoassay. The most common immunoassays are the ones that are based on solidphase interactions such as ELISA, but solution-phase assays such as nephelometry are still used in some cases.357–363 Immunoelectrophoresis is used for the diagnosis of von Willebrand’s disease.364 Rocket immunoelectrophoresis365 has been used to measure prothrombin366 and serpins367 in plasma. Many of these older methods may still be used in the quality control of some of the older plasma protein therapeutics such as albumin. It is dificult to meet the cost of developing and validating a new assay to replace an existing, approved assay; a new assay is worth developing only when the instrumentation and reagents for the approved assay are no longer available. On the other hand, a new assay, for example, the Coomassie blue dye–binding assay, frequently referred to as the Bradford assay, cannot be substituted for the biuret or Kjeldahl assay without a serious consideration of protein quality.368 Solidphase immunoassays may use a solid matrix such as a microplate for ELISA, microbeads as used in the Luminex systems for multiplex assays,369 or surface plasmon resonance systems.370 Surface plasmon resonance systems, as with nephelometry, are label-free assay systems.371 While it is a generalization, immunoassays may be said to measure the mass, while activity assays measure the function. An example is

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blood coagulation where CRM+ mutants of factor IX have a defective protein that is immunologically similar to native factor IX.372–374 An ELISA tended to underestimate the potency of a Newcastle vaccine attenuated by chemical modiication (formaldehyde or β-propiolactone)375 but was still useful in deining its quality. A competitive ELISA technique was found to be useful in the evaluation of the potency of hepatitis B vaccines.376 Keller377 used ELISA to evaluate the quality of formaldehyde-modiied botulinum neurotoxin toxoid for vaccine purposes. These latter studies represented an attempt to reduce the use of animals in the testing of biologicals.378 Karnaukhova and colleagues379 developed an ELISA technique that is useful for the determination of active α1-antitrypsin in various matrices; proteolysis and aggregation (heat) resulted in the loss of activity but retention of immunological reactivity. In a conceptually related study, López-Expósito and coworkers380 showed that the proteolysis of ovalbumin reduced but did not eliminate the IgG or IgE reactivity. The production of allergoids from allergens involves the chemical modiication of lysine residues.381 Retention of antigenic reactivity upon chemical modiication, heating, and proteolysis was an integral metric in the early work on the epitope concept.382 The early work on the importance of native antigen structure in immunological reactivity was reviewed by Boyd in 1954.383 H. Gideon Wells, working at the University of Chicago in 1908, published work on the stability of egg albumin as an antigen (sensitizing substance) when subjected to chemical modiication or digestion with proteases. Using an anaphylaxis model, he showed that heating did not eliminate immunological reactivity (horse serum) and nor did iodination. The sensitizing antigen, egg albumin, was subjected to the action of a crude preparation of proteases (Pancreatin, a mixture of digestive enzymes including amylase, proteases, and lipases) for 10 days; antigenic activity was reduced and continuing digestion for 129 days resulted in only small additional decrease in antigenic activity. In a later publication,384 immunological reactivity was further reduced when the incubation of horse serum with Pancreatin385 had been continued for 314 days; biuret reactivity was absent. While the biuret reaction is reasonably speciic, it does lack sensitivity.368 The sensitivity of the biuret reaction depends on the peptide size,386 where the molar extinction coeficient for the biuret reaction with triglycine is 33.5, tetraglycine is 48, and insulin is 670. Noda demonstrated a linear relationship between the peptide size (the number of peptide bond linkages) and the extinction coeficient. Hortin and Meilinger also demonstrated the low reactivity of peptides with the biuret reagent.387 There was also a difference in the spectral characteristics of the reaction product of the biuret reagent with small peptides as compared to albumin. Hortin and Meilinger did report that asparagine and histidine demonstrated high reactivity with the biuret reagent. Taking these observations into account, while Wells did not observe biuret reactivity in his long-term digests, this does not exclude the presence of smaller peptides with low biuret reactivity, which retain their epitopic reactivity. Landsteiner388 showed that small peptides (Mr 600–1000, 8–12 amino acids) derived from the peptic hydrolysis of silk were competitive inhibitors of the precipitin reaction and therefore retained the immunological reactivity of the original epitope on the silk protein. Early researchers, including Wells384,385 and Wornall,389,390 observed that while the treatment of a protein under strongly alkaline conditions (pH > 11) reduced or eliminated antigenicity, the treatment with acid or less rigorous alkaline

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conditions (pH < 11) did not have the same effect. Nitration or iodination did not eliminate antigenicity and, in the case of nitration, created a new epitope(s). Nitration was accomplished either with nitric acid (producing xanthoproteins) or with tetranitromethane (producing nitrated proteins). Xanthoprotein is an older term used for proteins nitrated with nitric acid; nitrated proteins were used as substrates for proteases.391 Today, it is well known that the nitration of tyrosine residues in proteins creates a neoantigen that can be measured by speciic antibodies.392 Natural antibodies, mostly IgM, serve an important function in recognizing the oxidationspeciic epitopes.393–395 Aggregation is likely the most signiicant factor for product immunogenicity.396–399 Note that we are discussing immunogenicity, not antigenicity. The aggregation of a native protein, as discussed earlier, tends to eliminate the existing epitopes. A recent work400 on birch pollen allergens showed that aggregation reduced antigenicity but did not affect immunogenicity. Other recent observations relevant to the loss of antigenicity on aggregation include observations on the aggregation of recombinant hepatitis B surface antigen401 and virion protein 1 of equine rhinitis A virus.402 It is, however, important to note that aggregation does increase immunogenicity.403–406 This chapter has focused on what would be considered the classical methods for protein analysis. Methods directed at conformational analysis have largely been ignored, and the reader is referred to other works in this area.407–409 The author has a few suggestions based on his own personal experience with assays and assay development: 1. Do not develop a new assay unless it is absolutely necessary. Even if there is an obvious technical advantage in changing a method, the wise will evaluate the cost of change, which includes validation and training. 2. Do not depend on an assay for product release that uses the last instrument of its type from the sole manufacturer for which there are no more spare parts. 3. Make sure that the senior management clearly understands the cost of change, including validation as well as risk.410,411

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317. Xu, W., Chen, J., Yamasaki, G., et al., Lectin binding assays for in-process monitoring of sialylation in protein production, Mol. Biotechnol. 45, 248–256, 2010. 318. Jiang, H., Wu, S.L., Karger, B.L., and Hancock, W.S., Characterization of the glycosylation occupancy and the active site in the follow-on protein therapeutic: TNK-tissue plasminogen activator, Anal. Chem. 82, 6154–6162, 2010. 319. Krull, I.S. and Mazzeo, J.R., Capillary electrophoresis: The promise and the practice, Nature 357, 92–94, 1992. 320. Tripodi, V., Flor, S., Dobrecky, C., et al., Novel and highly sensitive mixed-polymeric electrokinetic chromatography system for determination of contaminants and impurities of heparin samples, Electrophoresis 31, 3606–3612, 2010. 321. Liu, Y., Fu, X., Bai, Y., et al., Improvement of reproducibility and sensitivity of CE analysis by using the capillary coated dynamically with carboxymethyl chitosan, Anal. Bioanal. Chem. 399, 2821–2929, 2011. 322. Benavente, F., Gimémez, E., Olivieri, A.C., et al., Estimation of the composition of recombinant erythropoietin mixtures using capillary electrophoresis and multivariate calibration methods, Electrophoresis 27, 4008–4015, 2006. 323. Apostol, I., Miller, K.J., Ratto, J., and Kelner, D.N., Comparison of different approaches for evaluation of the detection and quantitation limits of a purity method: A case study using a capillary isoelectrofocusing method for a monoclonal antibody, Anal. Biochem. 385, 101–106, 2009. 324. Jaworska, M., Cygan, P., Wilk, M., and Anuszewska, E., Capillary electrophoresis with indirect UV detection for the determination of stabilizer and citrates present in human albumin solutions, J. Pharm. Biomed. Anal. 50, 90–95, 2009. 325. Dalmora, S.L., D’Avila, F.B., da Silva, L.M., et al., Development and validation of a capillary zone electrophoresis method for assessment of recombinant human granulocyte colony-stimulating factor in pharmaceutical formulations and its correlation with liquid chromatography methods and bioassay, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877, 2471–2476, 2009. 326. Lacher, N.A., Roberts, R.K., He, Y., et al., Development, validation, and implementation of capillary gel electrophoresis as a replacement for SDS-PAGE for purity analysis of IgG2 mAbs, J. Sep. Sci. 33, 218–227, 2010. 327. Alahmad, Y., Taverna, M., Mobdi, H., et al., A validated capillary electrophoresis method to check for batch-to-batch consistency during recombinant human glycosylated interleukin-7 production campaigns, J. Pharm. Biomed. Anal. 51, 882–888, 2010. 328. Kuzyk, M.A., Smith, D., Yang, J., et al., Multiple reaction monitoring-based, multiplexed, absolute quantitation of 45 proteins in human plasma, Mol. Cell. Proteomics 8, 1860–1877, 2009. 329. Jin, Y. and Manabe, T., Analysis of PEG-fractionated high-molecular-mass proteins in human plasma by non-denaturing micro 2-DE and MALDI-MS PMF, Electrophoresis 20, 3613–3621, 2009. 330. Ledford-Kraemer, M.R., Analysis of von Willebrand factor structure by multimer analysis, Am. J. Haematol. 85, 510–514, 2010. 331. Rhodes, D.G. and Loue, T.M., Determination of protein purity, Meth. Enzymol. 463, 9–19, 2009. 332. Fulcher, C.A., Roberts, J.R., Holland, L.Z., and Zimmerman, T.S., Human factor VIII procoagulant protein. Monoclonal antibodies deine precursor–product relationships and functional epitopes, J. Clin. Invest. 76, 117–124, 1985. 333. Eaton, D., Rodriguez, H., and Vehar, G.A., Proteolytic processing of human factor VIII. Correlation of speciic cleavages by thrombin, factor Xa, and activated protein C, Biochemistry 25, 505–512, 1986. 334. Burgess, R.R., Important but little known (or forgotten) artifacts in protein biochemistry, Meth. Enzymol. 463, 813–820, 2009.

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335. Leung, J.P., Eshdal, Y., and Marchesi, V.T., Colonic tumor membrane-associated glycoprotein: Isolation of antigenically-active peptides after chemical cleavage, J. Immunol. 119, 664–670, 1977. 336. Peterson, D.M., Hirst, A., and Wehring, B., Comparison of normal and Bernard-Soulier platelet membrane glycoproteins. Isoelectric characteristics and surface radiolabel, J. Lab. Clin. Med. 100, 26–36, 1982. 337. Casanova, M., Lopoez-Ribot, J.L., Martinez, J.P., and Sentandreu, R., Characterization of cell wall proteins from yeast and mycelial cells of Candida albicans by labeling with biotin: Comparison with other techniques, Infect. Immun. 60, 4898–4906, 1992. 338. Miller, I., Crawford, J., and Gianazza, E., Protein stains for proteomic applications: Which, when, why?, Proteomics 6, 5385–5408, 2006. 339. Steinberg, T.H., Protein gel staining methods: An introduction and overview, Meth. Enzymol. 463, 541–563. 340. Seeman, N.C., Chen, J.H., and Kallenbach, N.R., Gel electrophoretic analysis of DNA branched junctions, Electrophoresis 10, 345–354, 1989. 341. Miernyk, J.A. and Thelen, J.J., Biochemical approaches for discovering protein–protein interactions, Plant J. 53, 597–609. 2008. 342. Schägger, H., Cramer, W.A., and von Jagow, G., Analysis of molecular masses and oligomeric states of protein complexes by blue native electrophoresis and isolation of membrane protein complexes by two-dimensional native electrophoresis, Anal. Biochem. 217, 220–230, 1994. 343. Grandier-Vazeille, X. and Guérin, M., Separation by blue native and colorless native polyacrylamide gel electrophoresis of the oxidative phosphorylation complexes of yeast mitochondrial solubilized by different detergents: Speciic staining of the different complexes, Anal. Biochem. 242, 248–254, 1996. 344. Thangthaeng, N., Sumien, N., Forster, M.J., et al., Nongradient blue native gel analysis of serum proteins and in-gel detection of serum esterase activities, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 386–394, 2011. 345. Zickermann, V., Wumaier, Z., Wrzesniewska, B., et al., Native immunoblotting of blue native gels to identify conformation-speciic antibodies, Proteomics 10, 159–163, 2010. 346. Choi, N.S., Choi, J.H., Kim, B.H., et al., Mixed-substrate (glycerol tributyrate and ibrin) zymography for simultaneous detection of lipolytic and proteolytic enzymes on a single gel, Electrophoresis 30, 2234–2236, 2009. 347. Englebienne, P., Immune and Receptor Assays in Theory and Practice, CRC Press, Boca Raton, FL, 2000. 348. Popov, J., Zhukov, O., Ruden, S., et al., Performance and clinical utility of a commercial von Willebrand factor collagen binding assay for laboratory diagnosis of von Willebrand disease, Clin. Chem. 52, 1965–1967, 2006. 349. Komorowic, E., McBane III, R.D., Charleworth, J., and Fass, D.N., Reduced high shear platelet adhesion to the vascular media: Defective von Willebrand factor binding to the interstitial collagen, Thromb. Haemst. 87. 763–770, 2002. 350. Li, P.D., Galanakis, D.K., Ghebrehiwet, B., and Peerschke, E.I.B., The receptor for the globular “heads” of C1q, gC1q-R, binds to ibrinogen/ibrin and impairs its polymerization, Clin. Immunol. 90, 360–367, 1999. 351. Leppänen, A. and Cummings, R.D., Fluorescence-based solid-phase assays to study glycanbinding protein interactions with glycoconjugates, Meth. Enzymol. 478, 241–264, 2010. 352. Grinnell, F. and Feld, M.K., Adsorption characteristics of plasma ibronectin in relation to biological activity, J. Biomed. Mater. Res. 15, 363–381, 1981. 353. Hu, W.J., Eaton, J.W., Ugarova, T.P., and Tang, L., Molecular basis of biomaterialmediated foreign body reactions, Blood 98, 1231–1238, 2001. 354. Kiel, C., Beltrao, P., and Serrano, L., Analyzing protein interaction networks using structural information, Annu. Rev. Biochem. 77, 415–441, 2008.

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355. Wang, X., Peng, Y., Ma, Y., and Jahroudi, N., Histone H1-like protein participates in endothelial cell-speciic activation of the von Willebrand factor promoter, Blood 104, 1725–1732, 2004. 356. Wilton, R., Yousef, M.A., Saxena, P., et al., Expression and puriication of recombinant human receptor for advanced glycation end products in Escherichia coli, Protein Expr. Purif. 47, 25–35, 2006. 357. Kanoh, Y., Egawa, S., Baba, S., and Akahoshi, T., Association of IgG N-linked oligosaccharide chains and proteases in sera of prostate cancer patients with and without α2-macroglobulin deiciency, J. Clin. Lab. Anal. 23, 125–131, 2009. 358. Mátrai, Z., Németh, J., Miklós, K., et al., Serum β2-microglobulin measured by immunonephelometry: Expression patterns and reference intervals in healthy adults, Clin. Chem. Lab. Med. 47, 585–589, 2009. 359. Bradwell, A.R., Harding, S.J., Fourrier, N.J., et al., Assessment of monoclonal gammopathies by nephelometric measurement of individual immunoglobulin kappa/lambda ratios, Clin. Chem. 55, 1646–1655, 2009. 360. Di Stasio, E., Romitelli, F., Lancellotti, S., et al., Kinetic study of von Willebrand factor self-aggregation induced by ristocetin, Biophys. Chem. 144, 101–107, 2009. 361. Balakrishnan, K., Andrei-Selmer, L.C., Selmer, T., et al., Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against amyloid-β, J. Alzheimer’s Dis. 20, 135–143, 2010. 362. de Kat Angelino, C.M., Raymkers, R., Teunesen, M.A., et al., Overestimation of serum κ chain concentration by immunonephelometry, Clin. Chem. 56, 1188–1190, 2010. 363. Kwon, K.A., Kim, S.H., Oh, S.Y., et al., Clinical signiicance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer, BMC Cancer 10, 203, 2010. 364. Michiels, J.J., Berneman, Z., Gadisseur, A., et al., Classiication and characterization of hereditary types 2A, 2C, 2D, 2E, 2M, 2N, and 2U (unclassiiable) von Willebrand disease, Clin. Appl. Thromb. Hemost. 12, 397–420, 2006. 365. Bjerrum, O.J., Ingild, A., Lowenstein, H., and Weeke, B., Quantitation of human IgG by rocket immunoelectrophoresis at pH 5 by use of carbamylated antibodies. A routine laboratory method, Clin. Chim. Acta 46, 337–343, 1973. 366. Pajdak, W., Radwan, J., and Guzik, T.J., Cleavage of prothrombin bound in immune complexes results in high thrombin enzymatic activity, J. Physiol. Pharmacol. 55, 477–484, 2004. 367. Nielsen, H.M., Minthon, L., Londos, E., et al., Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies, Neurology 69, 1569–1579, 2007. 368. Sapan, C.V., Lundblad, R.L., and Price, N.C., Colorimetric protein assay techniques, Biotechnol. Appl. Biochem. 29, 99–108, 1999. 369. Vistnes, M., Christensen, G., and Omland, T., Multiple cytokine biomarkers in heart failure, Expert Rev. Mol. Diagn. 10, 147–157, 2010. 370. Thillaivinayagalingam, P., Gommeaux, J., McLoughlin, M., et al., Biopharmaceutical production: Application of surface plasmon resonance biosensors, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 878, 149–153, 2010. 371. Lausted, C., Hu, Z., Hood, L., and Campbell, C.T., SPR imaging for high throughput, label-free interaction analysis, Comb. Chem. High Throughput Screen. 12, 741–751, 2009. 372. McGraw, R.A., Davis, L.M., Lundblad, R.L., et al., Structure and function of factor IX: Defects in haemophilia B, Clin. Heamatol. 14, 359–383, 1985. 373. Mikami, S., O’Brine, D.P., Mellars, G., et al., Studies on immunological assay of vitamin-K dependent factors. III. A double monoclonal immunoradiometric assay for factor IX antigen, Br. J. Haematol. 62, 513–524, 1986. 374. Tsang, T.C., Bentley, D.R., Mibashan, R.S., and Giannelli, F., A factor IX mutation, veriied by direct genomic sequencing, causes haemophilia B by a novel mechanism, EMBO J. 7, 3009–3015, 1988.

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375. Jagt, H.J., Bekkers, M.L., van Bommel, S.A., et al., The inluence of the inactivating agent on the antigen content of inactivated Newcastle disease vaccines assessed by the use of the in vitro potency test, Biologicals 38, 128–134, 2010. 376. Cuervo, M.L., Sterling, A.L., NIcot, I.A., et al., Validation of a new alternative for determining in vitro potency in vaccines containing hepatitis B from two manufacturers, Biological 36, 375–382, 2008. 377. Keller, J.E., Characterization of new formalin-detoxiied botulinum neurotoxoids, Clin. Vaccine Immunol. 15, 1374–1379, 2008. 378. European Convention for the protection of vertebrate animals used for experimental and other scientiic purposes, ETSNo. 123, Strasbourg, France. Council of Europe, March, 1986. 379. Karnaukhova, E., Golding, B., and Ophir, Y., Development and evaluation of an ELISA for quantiication of human alpha-1-proteinase inhibitor in complex biological mixtures, Biologicals 35, 285–295, 2007. 380. López-Expósito, I., Chicón, R., Belloque, J., et al., Changes in the ovalbumin proteolysis proile by high pressure and its effect on IgG and IgE binding, J. Agric. Food Chem. 56, 11809–11816, 2008. 381. Maasch, H.J. and Marsh, D.G., Standardized extracts modiied allergens—Allergoids, Clin. Rev. Allergy 5, 89–106, 1987. 382. Singer, S.J., Structure and function of antigen and antibody proteins, in The Proteins, 2nd edn., ed. H. Neurath, Vol. III, Chapter 15, pp. 269–357, Academic Press, New York, 1965. 383. Boyd, W.C., The proteins of immune reactions, in The Proteins, eds. H. Neurath and K. Bailey, Vol. II, Pt. B., Chapter 22, pp. 755–844, Academic Press, New York, 1954. 384. Wells, H.G., Studies on the chemistry of anaphylaxis, J. Infect. Dis. 6, 506–522, 1909. 385. Wells, H.G., Studies on the chemistry of anaphylaxis, J. Infect. Dis. 5, 449–483, 1908. 386. Noda, Y., On the biuret reaction with peptides, Bull. Chem. Soc. Jpn. 40, 1264–1265, 1967. 387. Hortin, G.L. and Meilinger, B., Cross-reactivity of amino acids and other compounds in the biuret reaction: Interference with urinary peptide measurements, Clin. Chem. 51, 1411–1419, 2005. 388. Landsteiner, K., Serological reactivity of hydrolytic products from silk, J. Exp. Med. 75, 269–276, 1942. 389. Wornall, A., The immunological speciicity of chemically altered proteins, J. Exp. Med. 51, 295–317, 1930. 390. Johnson, L.R. and Wornall, A., CXLII. The immunological properties of alkali-treated proteins, Biochem. J. 26, 1202–1213, 1932. 391. von Pechmann, E., Über die enzymatische hydrolyse von xanthoproteinen und deren verwendung zur colorimetrischen bestimmung proteolytische fermente, Biochem. Zeitschrift 321, 248–250, 1950. 392. Drăguşanu, M., Petre, B.-A., and Przybylski, M., Epitope motif of an anti-nitrotyrosine antibody speciic for tyrosine-nitrated peptides revealed by a combination of afinity approaches and mass spectrometry, J. Pept. Sci., 17, 184–191, 2011. 393. Chou, M.Y., Hartvigsen, K., Hansen, L.F., et al., Oxidation-speciic epitopes are important targets of innate immunity, J. Intern. Med. 263, 479–488, 2008. 394. Schwartz-Albiez, R., Monteiro, R.Z.C., Rodriguez, M., et al., Natural antibodies, intravenous immunoglobulin and their role in autoimmunity, cancer and inlammation, Clin. Exp. Immunol. 158(Suppl. 1), 43–50, 2009. 395. Binder, C.J., Natural IgM antibodies against oxidation-speciic epitopes, J. Clin. Immunol. 30(Suppl. 1), S56–S60, 2010. 396. van Beers, M.M., Sauerborn, M., Gilli, F., et al., Aggregated recombinant human interferon beta induces antibodies but no memory in immune-tolerant transgenic mice, Pharm. Res. 27, 1812–1824, 2010.

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397. Richard, J. and Prang, N., The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor, IDrugs 13, 550–558, 2010. 398. van Beers, M.M., Jiskoot, W., and Schellekens, H., On the role of aggregates in the immunogenicity of recombinant human interferon beta in patients with multiple sclerosis, J. Interferon Cytokine Res. 30, 767–775, 2010. 399. Singh, S.K., Impact of product-related factors on immunogenicity of biotherapeutics, J. Pharm. Sci. 100, 354–387, 2011. 400. Zaborsky, N., Brunner, M., Wallner, M., et al., Antigen aggregation decides the fate of the allergic immune response, J. Immunol. 184, 725–735, 2010. 401. Tieugabulova, D., Falcon, V., Penton, E., et al., Aggregation of recombinant hepatitis B surface antigen induced in vitro by oxidative stress, J. Chromatogr. B Biomed. Sci. Appl. 736, 153–166, 1999. 402. Kriegshaeuser, G., Kuechier, E., and Skern, T., Aggregation-associated loss of antigenicity observed for denatured virion protein 1 of equine rhinitis A virus in an enzymelinked immunosorbent assay, Virus Res. 143, 130–133, 2009. 403. Zhao, H.L., Xiue, D., Wang, Y., et al., Elimination of the free sulfhydryl group in the human serum albumin (HSA) moiety of human interferon α2b and HSA fusion protein increases its stability against mechanical and thermal stress, Eur. J. Pharm. Biopharm. 72, 405–411, 2009. 404. Fradkin, A.H., Carpenter, J.F., and Randolph, T.W., Immunogenicity of aggregates of recombinant human growth hormone in mouse models, J. Pharm. Sci. 96, 3247–3264, 2009. 405. Rademecker, R.P., Renard, E., and Scheen, A.J., Circulating insulin antibodies: Inluence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control, Diabetes Metabol. Res. Rev. 25, 491–501, 2009. 406. Nezlin, R., Interactions between immunoglobulin G molecules, Immunol. Lett. 132, 1–5, 2010. 407. Kyte, J., Structure in Protein Chemistry, 2nd edn., Garland Science, New York, 2007. 408. Lundblad, R.L., Approaches to the Conformational Analysis of Biopharmaceuticals, CRC Press, Boca Raton, FL, 2010. 409. Sherwood, D. and Cooper, J., Crystals, X-rays and Proteins: Comprehensive Protein Crystallography, Oxford University Press, New York, 2011. 410. Wallace, K.K. and Moreira, A.R., Changes in biologics regulations: Impact on the development and validation of the manufacturing processes for well-characterized products, in Validation of Biopharmaceutical Manufacturing Processes, Chapter 13, pp. 170–179, American Chemical Society, Washington, DC, 1998. 411. White, F.M., The potential cost of high-throughput proteomics Sci. Signal. 4, pe8, 2011. 412. Schiestl, M., Stangler, T., Torella, C., et al., Acceptable changes in quality attributes of glycosylated biopharmaceuticals, Nat. Biotechnol. 29, 310–312, 2011.

4

Albumin

I started this chapter in the middle of a North Carolina winter, and it is now the beginning of a North Carolina summer. In retrospect, I see that I started with an incredible amount of naivety in expecting that this chapter would be inished in early spring. Albumin is much more complex than a standard for protein determination or even a bottle of opaque solution coming out of pasteurization in the manufacturing plant. I admit that I have been humbled by this chapter and by the distinguished group of scientists who worked on albumin in the days of World War II. The material has been assembled in a manner that I hope is most useful to those interested in the development of albumin as a biotechnology product. I would be remiss if I did not irst direct the reader to the comprehensive treatise on albumin by Theodore Peters,1 which was published in 1996. He notes that the irst isolation of albumin was accomplished from urine in 1500. The term albumin dates back to 1853 when work was done on vegetable and egg proteins.2 Thus, the substance derived from egg white was described as an albuminoid substance. The term albumin was used to describe the natural substances that were later identiied as proteins; for example, ibrin was described as coagulated albumin. The name albumin is derived from L. albus (white), as the various protein precipitates obtained from acidiied urine, egg white, or serum were white in color. Albumen, an early German term for protein,1 was the preferred term as late as 19033 and is used to describe the protein obtained from the egg white of various birds.4 Any student interested in the history of albumin is directed to both Peter’s work on albumin1 and Sandor’s broader consideration of plasma proteins.2 Sandor states that the separation of albumin from serum was irst described by Denis in 18405 and Panum in 1852.6 There was some tension between various investigators at this time as to who discovered what and when and what to call the material that had been discovered. It gives me some pleasure to realize that the same battles fought today over priority were fought much earlier with similar intensity. It would appear that Denis was also one of the irst (if not the irst) to use dialysis in the preparation of proteins.1 The initial classiication of proteins was based on solubility,5–9 with such a classiication applicable to both animal and plant proteins.10 In this scheme, albumin was described as being soluble in water and heat-coagulable, prolamines were soluble in alcohol, and globulins were soluble in neutral salt solutions. The differential solubility of albumin and the several globulin fractions11 formed the basis for the alcohol fractionation of plasma described in Chapter 2. The late Charles Tanford presented an excellent discussion of the contributions of Cohn and Edsall to the development of a globular model for a protein based on these earlier studies on protein solubility.12 This work had the by-product of providing the necessary basic science underlying the development of the alcohol fractionation of plasma (see Chapter 2).

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Much of the early work13–16 on protein chemistry was performed with ovalbumin, as the preparation of this protein from eggs was more facile than the preparation of albumin from plasma or serum; the albumins, casein, and gelatin were the only proteins available in a reasonably homogeneous form and substantial quantity in the early part of the twentieth century.17 The investigation of food allergies was another driving force for the study of the immunochemistry of ovalbumin.18–21 Studies on the conversion of ovalbumin to plakalbumin22,23 provided some of the basis for the developing concept of limited proteolysis in the mechanism of the action of serpins.24 It is also important to note that the Hofmeister classiication of electrolytes25,26 is based on Hofmeister’s fundamental work on the effect of salts on ovalbumin, which was published in 1888.27 Ovalbumin continues to be an important model protein for studies on protein chemistry28,29 and immunology.30,31 The presence of two phosphorylated residues in ovalbumin has allowed this protein to serve as a model for the study of phosphoproteins.32,33 Human albumin shares extensive homology with bovine albumin,34,35 and bovine serum albumin (BSA) was evaluated for therapeutic use during World War II.36 The development of BSA as a parenteral therapeutic continued until 1943 when there was a second fatality due to “serum sickness” following the administration of the bovine product.37 A program for the development of human albumin had started in 194037 under the direction of Edwin Cohn (see Chapter 2), and human serum albumin (HSA) continues to have considerable clinical use (see below). There is a remarkably high prevalence of human anti-BSA immunoglobulin G (IgG) in the normal population showing prior exposure to the bovine antigen. Andersen and coworkers38 detected anti-BSA IgG in 95% (99 of 104 individuals in a gender-mixed population) of blood donors, while Mogues and coworkers39 found anti-BSA antibodies in 55% of the blood donor population at their institution. Mogues and coworkers39 did note that the elevated levels of anti-BSA antibody were not associated with a speciic clinical event. There are, however, sporadic reports of adverse reactions to therapeutics containing BSA as an excipient.40–43 Currently, BSA is an important model protein for studies in solution chemistry as well as a standard used in methods for the determination of protein concentration. It should be noted that most researchers with an interest in the relationship between structure and function in albumin consider the human and bovine proteins equivalent. Albumin in human plasma (HSA) constitutes approximately 40% of the total body albumin, with the remainder scattered in the various extravascular spaces.44 Hughes described albumin as an interstitial protein rather than a plasma protein in 1954.9 Rothschild and coworkers45 used 131I-labeled HSA to determine the tissue distribution of albumin in several individuals with terminal diseases. These researchers observed that 4–5 days were required for complete tissue equilibration. The major amount of radiolabel was found in plasma (40%) with 18% in skin and 15% in muscle; there was a minor amount in heart, lungs, kidney, and spleen. The presence of a large amount of interstitial luid in skin is thought to be responsible for the albumin in skin.46 A word of comment on the Rothschild study45 is appropriate before continuing the discussion. One of the coauthors, Rosemary Yalow, was a recipient of the Nobel Prize in Physiology or Medicine in 1977. She was the second woman to be awarded a Nobel Prize. The prize recognized the development of the radioimmunoassay by Yalow and Berson. Sherman Berson died in 1972 and did not share the Nobel Prize. The presence of albumin in the

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extravascular space has been known for more than 50 years.44,45 Increased leakage into the extravascular space is considered to be responsible for lower HSA concentrations in acute-phase reactions and other clinical situations.47–49 The term transcapillary escape rate50 is used to describe the process. The amount of work published on HSA prior to 1940 is sparse indeed. A search for publications on “HSA” appearing prior to 1940 using SciFinder yielded 14 papers; some 24,403 papers have appeared since 1940. It is important to recognize that 1940 was well before the advent of chromatographic techniques for protein puriication, and albumin was then separated from the globulins on the basis of solubility.2,51 Notwithstanding the lack of sophisticated techniques, crystalline HSA was prepared by two groups before 1940.52,53 Oswald52 obtained serum albumin from ascites luid, while Adair and Taylor53 obtained serum albumin from serum heated at 56°C for 25 min. The globulin fraction was removed in half-saturated ammonium sulfate prior to the crystallization of albumin. Most of the work prior to 1900 focused on the characterization of albumin (albumen) as a colloid. The properties of albumin as a colloid are discussed in greater detail next. Examples of this work included the differential iltration of colloids and crystalloids by C.J. Martin in 189654 and the differential heatdenaturation (heat-coagulation) of albumin (albumen) by Hewlett in 1892.55 Kylin56 determined the isoelectric point of human serum albumin and found several components, varying from four to six. The molecular weight of HSA was estimated by Roche and coworkers in 1935 to be 69,000 da.57 It is of interest to note that some years later, the molecular weight of HSA was estimated to be 67,000 da by sodium dodecyl sulfate (SDS)-electrophoresis58 or by analytical ultracentrifugation.59 The irst clinical application of HSA is likely that of Mann in 1918,60 who used homologous serum to treat shock in a canine model. It seems like the therapeutic effect observed with the infusion of serum in the canine shock model was due to the albumin present in the serum. The current work on HSA can be traced to activities on both sides of the Atlantic Ocean before and during World War II.61 This book,61 which was edited by General Douglas Kendrick (U.S. Army), compiled all of the various projects associated with the procurement, processing, and use of blood during World War II. It is one of a multivolume set assembled to ensure that the knowledge gained during World War II would not be lost. General Kendrick states in the Preface to this volume that information gained in World War II should have been readily available for the Korean conlict, but the totality of information was not available for implementation. This disconnect in the availability of information served as the basis for the compilation of the volume entitled Blood Programs in World War II,61 so that such issues would not be future problems. Even some 50 years later, the material in this volume has considerable value to current biotechnology. The clinical need was illustrated in a landmark study by Ebert and coworkers62 on the effect of blood loss on circulatory collapse. This group of researchers, including Eugene Stead, Jr., who later built the Department of Medicine at Duke University after serving at Emory University, established that luid replacement was not adequate but could be effectively treated with plasma or whole blood. The removal of blood was followed by a slow recovery of plasma volume and the replacement of a normal plasma protein complement. The infusion of saline was not suficient to return the circulatory volume to normal. As a note, Eugene Stead is also known for

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his work in establishing the profession of physician assistant. Several years later, Heyl and coworkers36 demonstrated the effectiveness of HSA from the Cohn alcohol fractionation process in the treatment of acute blood loss. The rationale for this approach was provided by Scatchard and coworkers63 in their study on the osmotic pressure of plasma and albumin, in which they reported an increase of approximately 20 mL of plasma volume per gram of albumin. This is an example of albumin acting as a colloid, with a colloid being deined as an amorphous substance that does not diffuse through membranes such as dialysis membranes and is not readily crystallized. Other examples of colloids include dextrans; colloids are thought to be responsible for the osmotic properties of blood. Crystalloids are chemicals such as sodium chloride, which readily diffuse through membranes and can be readily crystallized. There is a lively debate on the relative merits of colloids and crystalloids for therapeutic use.64–68 There appears to be little doubt as to the intrinsic safety of albumin, but questions regarding its eficacy in all clinical situations remain.69–71 There has been concern that plasma volume expanders such as dextran, gelatin, and hydroxyethyl starch have a negative effect on hemostasis.72 I would again be remiss if I did not note in passing that George Scatchard (cited earlier) developed the mathematical procedures for evaluating the binding of molecules to receptors, including the binding of ions to proteins.73 This procedure is visualized graphically by what is known as a Scatchard plot.74

STRUCTURE OF ALBUMIN HSA is a single-chain protein with a molecular weight of approximately 67 kDa.75–79 A study by Debaiczyk and coworkers77 on the sequence of HSA derived from cDNA clone obtained from isolated mRNA showed the presence of a hydrophobic propeptide followed by a basic propeptide. The mature protein contains 585 amino acids with 17 disulide bonds and one free sulfhydryl group. The disulide bonds and the free sulfhydryl groups have been suggested to be involved in the redox function of albumin.80–82 The disulide pattern in the recombinant albumin produced in Pichia pastoris is the same as the pattern in the albumin derived from human plasma.83 The crystal structure of HSA has been reported by He and Carter84 and later by Sugio and coworkers,85 showing a three-domain structure representing a heart-shaped conformation. Leggio and coworkers86 showed the formation of a somewhat expanded conformation for HSA.87 The crystal structure of horse serum albumin has been reported to be similar to that of HSA.88 The binding of 2,3,5-triiodobenzoic acid to HSA is slightly tighter than it is to horse serum albumin, but the binding sites observed in the crystal structure are similar. A schematic structure of albumin is shown in Figure 4.1. J. L. Oncley, one of the members of the Cohn laboratory group,11,12 published a review of his work on the dielectric constant and structure of HSA in 2003.89 Oncley discussed the frustration of obtaining different values of the dipole moment with different albumin preparations. Working with Howard Dintzis, Oncley determined that the variation in the value of the dipole moment was related to the fatty acid content of the albumin preparation. Later work established the effect of fatty acids on albumin conformation.90 As will be shown later, the effect of fatty acids on albumin conformation is one of the several examples of the solution structure of HSA being

87

Albumin Cysteine 34

IIIB IB

SH IA

Site 2 IIA

IIIA

Tyr411

Site 1 IIB

Lys199

FIGURE 4.1 A schematic structure of albumin. This work has been adapted from various reviews, including Sugio et al.,85 Kragh-Hansen et al.,424 Quinlin et al.,685 Kratz421 and Leggio et al.86 It must be emphasized that the drawing is schematic and lacks the detail of a crystal structure. In particular, the Sudlow sites are not as discrete as shown but may overlap.873 There are also discrete binding sites for fatty acids, which are not shown.

inluenced by the binding of ligands and solvent properties. As an aside, Oncley’s interest in the study of albumin was driven by his interest in the use of the dielectric constant to measure the properties of proteins in solution91 and the availability of puriied albumin in the Cohn laboratory.89 The measurement of the dielectric constant of a protein is a potentially powerful technique that can be complex to interpret92 but can provide useful information.93,94 Oncley and coworkers used the determination of the dielectric constant (relaxation time) in postulating an elongated ellipsoid shape for HSA. Following up on his initial frustrations on the presence of fatty acid in his albumin samples that provided erratic results, Oncley and coworkers used studies on the dielectric constant to establish a change in solution behavior on the binding of fatty acids.95 Later studies by other researchers using dynamic light scattering96 suggested a compact conformation at pH 7.4 (Stokes radius of 60 Å), which increases to approximately 80 Å at pH 8.0 or pH 5.4. The effect of pH on albumin conformation is discussed in more detail later. Further support for the conformational lexibility of albumin is provided by studies with poly(ethylene)glycol (PEG). Farruggia and coworkers97 observed that PEG 1000 destabilized the HSA, while PEG 10000 stabilized the HSA. These researchers suggested that the smaller PEG molecules are small enough to get inserted into the hydrophobic regions of the protein, while the high-molecular-weight PEG would be excluded. There is another explanation based on the crowding concept. The highmolecular-weight PEG could be functioning as a more effective crowding agent,98,99 forcing the HSA into a more compact and likely more stable conformation. Ragi and coworkers100 studied the interaction of PEG 3500 with HSA and observed little change in its helical content at a low concentration with a reduction in α-helix and an increase

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Biotechnology of Plasma Proteins

in β-turn at a higher concentration (1 mM). A binding (afinity) constant of 4.12 × 105 M for PEG was observed by these researchers. These researchers suggested that PEG stabilized at low concentrations but destabilized at high concentrations. The discrepancy in results with PEG may be due to contaminants such as peroxides.101 The effect of pH on the conformation of albumin has been a subject of study for the past 60 years. While the extremes of pH are unlikely to be of any direct physiological signiicance, the study of the transitions has been useful in understanding the factors involved in the binding of drugs and other organics. The conformational transition at a low pH is called the N → F transition. The initial observation of this phenomenon was reported by Luetscher102 in 1949 and was based on electrophoretic heterogeneity at a low pH. Foster103 has reviewed the earlier titration data on HSA and reported anomalous behavior below the isoelectric point. Electrophoretic heterogeneity at pH 4.0 was not observed by Schmid in the presence of Zn2+ with HSA with a blocked sulfhydryl group.104 Schmid later observed105 that the electrophoretic heterogeneity at pH 4.0 did depend on the buffer anion; the heterogeneity decreased with the increasing size of aliphatic acid in the solvent. The N (normal) → F (fast) transition was based on the faster rate of migration of albumin in free-boundary electrophoresis at an acidic pH.102 It should be noted that these changes in electrophoretic mobility do not represent heterogeneity in either HSA or BSA; electrophoretic mobility is observed with genetic variants.106 Tanford and coworkers107 studied the titration behavior of BSA and HSA and observed anomalies below pH 4.3 and above pH 10.3, which suggested an expansion of the protein. Subsequent work108 showed that BSA expanded in a solution below pH 4.3 and above pH 10.5 on the basis of the changes in the intrinsic viscosity. The observed changes were fully reversible. Wilting and coworkers109 used circular dichroism (CD) to study the conformation changes in HSA with or without warfarin in the pH range of 6–9. A change in molar ellipticity as a function of pH (5 → 9) was similar for HSA in the presence or absence of warfarin; a change occurred over a smaller pH range (5 → 8) in the presence of 2.5 mM CaCl2. Kasai-Morita and coworkers110 used intrinsic luorescence to demonstrate warfarin-binding increases with an increasing pH. An earlier work111 showed that the base transition could either increase or decrease the binding of drugs; the binding of indomethacin increased the binding of L-tryptophan and quinidine, with no change in the binding of salicylic acid or phenytoin. In other studies by Kosa and coworkers,112 it is suggested that the N (normal) → B (base) transition has a role in the binding and release of ligands. The ionization of histidyl residues in domain I is suggested by Bos and coworkers to be responsible for the N → B transition.113 The N → B transition is similar to the N → F transition but is not associated with a change in electrophoretic mobility. The binding of zinc to albumin is associated with a conformational change that is similar to that observed in the base transition.114 There is a further conformational transition observed in BSA when the pH is lowered from 4.0 to 2.0, which is characterized by a marked increase in the frictional ration.115 This conformational change is referred to as the F → E transition, which is also reversible, and likely involves the full extent of protein unfolding permitted by the 17 disulide bonds; the F → E transition has also been referred to as the acid expansion.116 Geisow and Beaven subjected HSA to digestion with pepsin at an acidic pH117 and observed that there was a difference in digestion patterns (electrophoretic

89

Albumin

analysis) between pH 3.7 and pH 3.5; there were also small differences in the patterns obtained with HSA and BSA. Subsequent work from this laboratory118 showed that the change in intrinsic luorescence in several isolated fragments (P44, residues 1–386; P29, 49–307 representing the amino–terminal portion of HSA) was less than that observed in the intact protein. This suggested that the carboxyl terminal portion of HSA is critical for N → F transition. Bilirubin bound to both fragments showed CD changes that were similar to those observed with the binding of bilirubin to intact albumin. These researchers also studied the binding of 8-anilinonaphthalene1-sulfonate to the large fragments and obtained results consistent with binding site(s) conined to the P44 fragment. Earlier, Weber and Young119 had subjected a BSAdimethylaminonapthalene-1-sulfonate complex to digestion with pepsin, observing a decrease in luorescence polarization. Weber and Young conducted their digestion studies at pH 2.0, while Geisow and Beaven worked at either pH 3.5 or pH 3.7. A consideration of the two studies suggests that the F → E transition (at pH 2.0) likely involved further conformational change in the albumin molecule, relecting the protonation of additional side chain carboxyl groups. While the average pKa for the β-carboxyl of aspartic acid in proteins is 3.5, the range is 0.5–9.2; for the γ-carboxyl of glutamic acid, the average pKa is 4.2 with a range of 2.1–8.8.120 Foster summarized the various acid–base transitions for BSA in 1977 (Table 4.1).121 The base transition at pH 11.3 is associated with a major structural transition with exposures of six “buried” tyrosine residues.122,123 While albumin is resilient to acid and organic solvents, this protein can be denatured by heat or by the addition of chaotropic agents. Since albumin can be pasteurized in the inal manufacturing step to provide safety from infectious agents, there has been considerable interest in studying the effect of heat on albumin.124–127 The cited studies show the inactivation of viral pathogens.125,127–129 There is an occasional problem with aggregation.130 Roelands and coworkers131 showed that repeated heating at 56°C interspersed with storage at 4°C resulted in reversible dimerization, with gelation occurring with 25% albumin after eight steps of heating. Finlayson and coworkers132 subsequently demonstrated the reversal of dimerization of HSA by

TABLE 4.1 pH Transitions in Albumin Designation

Transition pH

E F (N → F) A N B (N → B)

2.7 3.6–3.9 5.5 Native (pH 7) 9–9.5

Source: Adapted from Foster, J.F., in Albumin, Structure, Function, and Uses, eds. V.M. Rosenoer, M. Oratz, and M. Rothschild, pp. 53–84, Oxford/Pergammon, New York, 1977.

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Biotechnology of Plasma Proteins

heating for 10 h at 60°C in the presence of acetyl–tryptophan and sodium caprylate. Kolthoff and Tan133 observed that BSA heated (70°C) in the presence of a mercurial agent demonstrates reversible aggregation (the aggregated material is made 8 M in urea and diluted 10-fold); in the absence of a “blocking agent,” the aggregation is irreversible due to the disulide exchange. Renaturation in the initial presence of a chaotropic agent is similar to the process used for bacterial recombinant proteins expressed as exclusion bodies.134 More recently, Moriyama and coworkers135 have reported that the helicity of BSA decreased with increasing temperature; half of the helicity was lost at 80°C, while 16% of the helicity remained (66% initial) after heating at 130°C. The presence of SDS offered protection against the helicity lost on heating up to a temperature of 90°C. Nuclear magnetic resonance (NMR) studies of SDS demonstrated the maintenance of surfactant structure up to a temperature of 130°C. Lohner and coworkers136 have reported that HSA is less stable to thermal denaturation in the N form but is protected by benoxaprofen or warfarin. Pico137 has described the thermal denaturation of HSA as a classical two-step process that proceeds through an “unfolded state,” which is reversible, and then proceeds to a terminally denaturated state. Pico notes that the second, irreversible step is quite slow. Michnik138 used differential scanning calorimetry (DSC) to show that ethanol decreased the thermal stability of HSA. Chaotropic agents, such as urea or guanidine, have also been used to study the conformation of HSA. Wallevik139 observed the reversible denaturation of HSA with guanidine (1–2.5 M); the process at pH 5.6 or 9.2 is a multistage process, while at pH 2.6, the process is continuous. Aoki and coworkers140 studied the denaturation of BSA with urea; guanidine was used to demonstrate that the changes observed were not due to carbamylation. These researchers used acrylamide gel electrophoresis (native electrophoresis)141 to measure the conformational change. The incubation of BSA with 5.0 M urea at pH 9.0 resulted in the formation of a dimer and aggregates as well as an altered monomer fraction; if the BSA was modiied with p-chloromercuribenzoate, the altered monomer fraction was not observed. The effect of the sulfhydryl group modiication133 on conformation change induced by heating has been mentioned earlier. The denaturation of HSA modiied with acrylodan (6-acroyl-2dimethylamino naphthalene) was studied by González-Jiménez and Cortijo.142 These researchers observed a transition at approximately 6.0 M urea at pH 7.4 as measured with a luorescent probe; the modiication of albumin with acrylodan did not result in conformational change as measured by CD. These researchers also reported denaturation with guanidine hydrochloride. It is noted that acrylodan is considered speciic for the modiication of sulfhydryl groups in proteins.143–145 The modiication of the sulfhydryl group128 has been shown to inluence conformational change with heating. Fatty acids that bind to HSA stabilize HSA from denaturation with guanidine hydrochloride146 or urea.147 Mendez and coworkers148 observed that glycated HSA was slightly more stable than native HSA to denaturation with guanidine hydrochloride. The studies on the effect of heat and chaotropic agents on albumin are consistent with albumin as a lexible protein relatively resistant to denaturation. The results suggest that the modiication of cysteine 34 inluences protein stability. As the conformational lexibility of albumin is likely critical for binding, the next section will consider conformation studies that do not involve heating or chaotropic agents.

91

Albumin

Auranoin is a gold-containing drug (Figure 4.2) that was developed to treat rheumatoid arthritis but is of current interest for cancer therapeutics;149–152 it reacts with the cysteine residue in albumin.153 Work by Christodoulou and coworkers154 using 1H NMR showed that the reaction of auranoin with BSA is associated with a conformational change as measured by changes in the resonance of His3 (1H NMR). These latter researchers also cite the failure of cathepsin to degrade mercaptalbumin, while albumin modiied at Cys34 is degraded, suggesting a conformation change. A more recent work by Talib and coworkers155 showed that a prior modiication of Ac H O H O

Ac

Et

O

Au

S

O H

P

Et

O

Ac H

Et

H Ac Auranofin

+ Albumin*

HS

Et Et

Albumin

HS

Et P

Au

Albumin*

S

Et

Et

P

Au

Au

S

S

Albumin

Et

RSH

R

S

Au

S

R

Albumin*

S

Albumin

+ Et Et

P

O

Et

FIGURE 4.2 The structure of auranoin and its reactions with albumin. The reaction is reversible via a mixed disulide exchange mechanism as well as conversion of the triethylphosphine to the corresponding oxide by a slower reaction. It is suggested that a particular conformation of albumin designated by an asterisk is the reactive species.153,157,158

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Biotechnology of Plasma Proteins

albumin with iodoacetamide blocked the reaction with AuPEt3Cl (Figure 4.2); the mixed disulide of cysteine with HSA was also less reactive. A consideration of the early work of Christodoulou and coworkers154 and the more recent work of Talib and coworkers155 suggests that while the reaction of gold with the thiolate anion is preferred, it is possible that the reaction with the cysteine-mixed disulide of HSA occurs with auranoin but at a much slower rate. The reduced rate of reaction with the mixed disulide and possible lack of reaction with an oxidized cysteine might provide an insight into the variable clinical response to gold-containing drugs. The interaction of auranoin with albumin is critical to the pharmacokinetics of the drug as 80% of the gold is bound to albumin after the administration of the drug. However, as with all things, the mechanism of albumin may be a bit more complex. First, there may be a difference between albumin in vivo and the isolated commercial product (human or bovine) with respect to the amount of mercaptalbumin. Christodoulou and coworkers in a later study156 used 1H NMR as a surrogate measure of the chemistry of Cys34 to show that more than 90% of the albumin in human blood plasma was mercaptalbumin. These researchers suggested that the modiication of Cys34 with auranoin resulted in a conformation transition that was consistent with their earlier observations.154 Subsequently, Roberts and coworkers157 presented a careful kinetic analysis of the reaction of auranoin and the isopropyl analog with BSA. These results show that the kinetics of the reaction of auranoin with BSA are complex. The dependence of the reaction rate on conformation provides an explanation for the lack of consistent second-order kinetics. The reaction is reversible via a disulide exchange mechanism. The reader is referred to Ahmad and coworkers158 for a current review of metal-based therapeutics. Ohkubo159 showed that HSA modiied with a mixed disulide with either cysteine or glutathione showed differences in solvent perturbation spectroscopy compared to native HSA. Triluoroethanol, a mimic of anesthetics, inluences protein conformation,160 according to considerable studies on albumin,161,162 including an increasing susceptibility to chemical modiication with acrolein.163 Anesthetics such as propofol and halothane have been reported to bind to HSA164 at sites that bind fatty acids; the binding of propofol or halothane is associated with only minor changes in the crystal structure. Earlier studies165 from another group of researchers have shown tight binding of these two drugs. Lund and coworkers166 used chromatography on phenyl-agarose to separate HSA into two fractions, one of which was bound to the column (R or retained) and the second fraction appeared in the column void volume (NR or not retained). The R fraction was eluted with 8 M ethylene glycol. Chromatography on octyl-agarose resulted in complete retention; if 1 M ethylene glycol was included, the elution pattern was similar to that observed on phenyl-agarose. The separation was reversible, supporting the concept of conformational heterogeneity. The binding was minimum at pH 6.0 with an increase in the binding up to a pH of 9.0, where the binding remained constant with increasing pH; the pH dependence is consistent with a functional group with a pKa of 7.3. These researchers had previously demonstrated heterogeneity on immunoelectrophoresis with phenyl-agarose that relected ligand (fatty acid, bilirubin) binding.167 These researchers did not mention the possible inluence of the modiication at Cys34 upon separation on hydrophobic afinity matrices. Proteins

Albumin

93

such as albumin undergo conformational changes upon binding to matrices such as phenyl-agarose.168 Huang and coworkers169 used cross-linking with diimidoesters (disuccinimidyl glutarate and disuccinimidyl suberate) to show a conformational change in HSA on the binding of fatty acids. Michnik and others170 used DSC to show that UVC (254 nm) irradiation caused a conformational change in HSA; aggregation also occurred under these conditions. There is a difference between defatted albumin and native albumin. Normally, HSA is not glycosylated, but there are some variants with N-glycosylation.171 Glycosylation in domain I extended the circulatory half-life, while glycosylation in either domain II or domain III had no signiicant effect.172 Myeloperoxidase modiies methionine, tryptophan, and tyrosine in HSA, but this reaction occurs after secretion.173 While the modiications of HSA, such as glycation, oxidation, and nitrosylation, which are discussed later, do result in modiied proteins, I do not consider such modiications to be posttranslational modiications such as γ-carboxylation, sulfation, and phosphorylation, which are enzyme-catalyzed reactions.174 Some modiications such as the reaction with 4-hydroxy-2-nonenal175 or homocysteine thiolactone176 are the result of the enzymatic modiication of a precursor to form an active species. As with other plasma proteins with signiicant circulatory half-lives, albumin is subject to nonenzymatic glycation177–181 with a marked increase in diabetes where the advanced glycation end product (AGE) is suggested to play an important role in the various pathologies.182–185 Glycated albumin has been proposed as a marker for diabetes similar to glycated hemoglobin.186 Glycation of HSA shows speciicity with respect to the site of modiication and modifying sugar. Reducing sugars that are in equilibrium between a closed-ring form (pyranose form) and an open-chain structure possessing an aldehyde function (carbonyl) can react with unprotonated amino groups in proteins (primarily ɛ-amino groups of lysine residues; Figure 4.3).187 The reactivity of a given sugar is dependent on the amount of sugar in the carbonyl form. Thus, galactose, which has 0.02% carbonyl, reacts with hemoglobin more rapidly than glucose, which has 0.002% carbonyl.187 The glycation of HSA by galactose has been studied by Frost and coworkers,188 who reported that the sites modiied have also been reported to be modiied by glucose with the exception of Lys414. While the modiication of Lys414 by glucose was not reported by Frolov and Hoffmann,189 the modiication of this residue was reported by Barnaby and coworkers.190 It should be emphasized that the modiication occurs quite slowly and the pattern observed can depend on whether the modiication is “trapped” by borohydride reduction. Frost and coworkers have discussed the potential lability of the modiication of Lys414. Most studies conirm the early observations of Garlick and Mazer191 that Lys525 is the principal site of modiication. Iberg and Flückiger192 identiied four principal sites of in vivo glycation with glucose in HSA—Lys199, Lys281, Lys439, and Lys525—with a third of the total modiication at Lys525. While there is a major site of glycation of HSA with glucose, glycation of HSA does yield a heterogeneous product as would be expected from the studies on the reaction of trinitrobenzenesulfonic acid (TNBS) with HSA as reported by Goldfarb,193 who was able to identify three groups on the basis of reactivity. Goldfarb also suggested that TNBS bound to HSA prior to the reaction (Figure 4.4). Andersson and coworkers194 studied the reaction of

94

Biotechnology of Plasma Proteins O

OH H

C

HC

Carbonyl form (0.002%)

H

Hemiacetal form

CHO H

H OH

OH

H H

HO H

OH

HO

OH

H

O

HO H

OH

OH

H

H

R

CH2OH

O H2N

H

H2 C

B O

CH2

HO

CH2

CH2

CH2

CH2

CH2

CH2

N

NH

NH

CH

CH

CH2

OH

HO

H

OH H

HO

Maillard product O

HO

H

H

OH

H

OH

H

OH

H

OH

H

OH

H

OH

CH2OH Schiff base

CH2OH Eneaminol

CH2OH Amadori product

FIGURE 4.3 Nonenzymatic glycation of proteins. A reducing sugar or analog, such as methylglyoxal, reacts with the ɛ-amino groups forming a Schiff base in a reversible reaction (the stabilization of the Schiff base by reducing agents, such as sodium cyanoborohydride, is not shown). The reaction of a reducing sugar, such as glucose (shown), is dependent on the amount of sugar in the carbonyl form.187 The Schiff base can also proceed through a series of steps to form an Amadori product.192,874 Boronic acidbased afinity chromatography can be used to separate glycated albumin from native protein.178,875–877

95

Albumin NO2

NH2

+ NO2

O2N SO3

N H

2,4,6-Trinitrobenzenesulfonic acid O

NO2

Lysine

NO2

O2N NH

N H O Albumin + TNBS

Albumin TNBS

Trinitrophenylated albumin

FIGURE 4.4 Reaction of trinitrobenzenesulfonic acid (TNBS) with proteins. TNBS reacts with amino groups in albumin and other proteins. Albumin was found to have three classes of amino groups based on reactivity with TNBS.193 This and later work identiied the most reactive lysyl residue and suggested the formation of a complex between TNBS and albumin prior to reaction.196

TNBS with BSA, observing that TNBS did bind preferentially to certain sites on the protein prior to the reaction; palmitate decreased the rate of reaction of TNBS with BSA presumably by competition for the same binding site. Kurono195 reported that the reaction of TNBS with HSA did follow Michaelis–Menten kinetics. Subsequent work by Kurono and coworkers196 showed that the fast-reacting site is Lys199 and suggested that the proximity of Trp214 was important for binding speciicity. Lys199 is a signiicant site for glycation as discussed earlier. Glycation of HSA does result in a conformational change,197–202 which may be related to the pathogenic effects described earlier. Glycation of recombinant HSA resulted in a decreased circulatory half-life in a rat and an increased hepatic uptake in a mouse model.199 As cited earlier, while AGEs are formed due to the reaction of glucose with HSA, which are suggested to be involved in the pathogenesis of diabetes,200 there is no evidence to

96

Biotechnology of Plasma Proteins O

ONOO− Peroxynitrite

O2 + NO

N

SH

NO

S

H 2C

Nitric oxide

H2C

+ CH

CH

SH

N H

N H

O

O

S-nitrosocysteine O

H2C CH N H O

N S O

O

O

CH2 H N N H

HO NH2

OH O

Glutathione

FIGURE 4.5 Nitric oxide and peroxynitrite and formation of S-nitrosyl cysteine in albumin. The single cysteine residue in albumin is subject to nitrosylation, and S-nitrosoalbumin is considered a biologically signiicant in vivo repository for nitric oxide.878 The in vivo S-nitrosylation can be mediated either by nitric oxide synthase879 or by reaction with peroxynitrite derived from nitric oxide and superoxide.880 The synthesis of S-nitrosoalbumin using S-nitrosoglutathione as a donor is also shown.252 Dahm and coworkers881 suggest preferential formation of protein thiols via transnitrosylation from S-nitrosothiols.

support the cross-linking of HSA upon the nonenzymatic reaction of glucose with HSA as observed with other proteins.192 Glycation is one of the several important in vivo modiications of albumin; other important modiications are oxidation and S-nitrosylation.202–204 Oxidation and nitrosylation are considered to be related physiological events.205–207 The in vivo oxidation of functional groups in proteins is mediated by reactive oxygen species, such as superoxide, hydrogen peroxide, and hydroxyl radical, and usually involves the oxidation of cysteine, cystine, and methionine residues.208 Nitration and nitrosylation reactions are mediated by reactive nitrogen species, including nitric oxide and peroxynitrite (Figure 4.5).209 Peroxynitrite is formed via an oxidative stress mechanism, while nitric oxide may be formed directly by nitric oxide synthase and used in situ or can be transferred to glutathione to form S-nitrosoglutathione. Nitric oxide and peroxynitrite (which can be formed by the reaction of reactive oxygen species) can work at cross purposes in homeostasis.210 The in vivo oxidation of proteins can result in a complex mixture of products. In the case of HSA, there is a single free sulfhydryl group that can be oxidized to form a mixed disulide with cysteine or glutathione or oxidized to sulfenic, sulinic, or sulfonic acids (Figure 4.6).211 The chemistry of the sulfhydryl group as derived from an

97

Albumin

SH N H

Reduction

CH

O

HC

Oxidation H2C

CH2

N H

S O

S

Cysteine

H2C CH

Reduction

Oxidation

H

HO

N H

O S

S

Cystine O H 2C

H 2C

CH

CH N H

N H

RSH O

O

Mixed disulfide

Cysteine sulfenic acid

HO

O S H2C CH N H O

Cysteine sulfinic acid OH O

S

O

H2 C CH N H O Cysteine sulfonic acid

FIGURE 4.6 Oxidation/reduction reactions of cystine and cysteine in proteins. Shown is the oxidation pathway from cysteine to cysteine sulfonic acid. Cysteine may also be oxidized to cystine, presumably through cysteine sulfenic acid. Mixed disulides may also occur via the sulfenic acid derivative.882–885

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Biotechnology of Plasma Proteins

in vitro modiication is discussed later. In addition, oxidation can modify other groups such as lysine, resulting in carbonyl derivatives (Figure 4.7).212 Various techniques have been developed for the analysis of oxidized HSA.213 However, it is clear that oxidized HSA is heterogeneous, given the number of possible derivative forms. Temple and coworkers214 identiied the sites of carbonylation in HSA resulting from metalcatalyzed oxidation (Fe3+/ascorbic acid) or oxidation with hypochlorous acid. Metalcatalyzed oxidation modiied Lys97 and Lys186, while hypochlorous acid modiied Lys130, Lys257, Lys438, Lys499, and Lys598. The reader is referred to a work by Maisonneuve and coworkers215 for a discussion on the speciicity of carbonylation in proteins. A comparison of the lysyl residues in HSA modiied by various reagents is shown in Figure 4.7. Only a few of the residues modiied by glucose or galactose are modiied with 4-hydroxy-trans-2-nonenal (4-HNE) (Lys199 and Lys525), one residue is modiied with hypochlorous acid (Lys438/439), and there is no overlap with those residues modiied with Fe3+/ascorbic acid. Bar-Or and coworkers216 reported cysteinylation of Cys34 forming a disulide in albumin from single individuals and commercial albumin preparations. The extent of cysteine modiication was higher in commercial albumin preparations than in albumin from single donors. Nitrosylation of cysteine was also observed in both preparations as was the loss of the N-terminal Asp-Ala dipeptide glycation observed only in the commercial albumin preparations. The authors suggest that the administration of albumin preparations with a high amount of modiied cysteine could have negative consequences. Subsequent work by this group217 showed a correlation between the loss of the Asp-Ala dipeptide and the formation of the diketopiperazine derivative as well as a correlation between this combination and in vitro immunosuppressive activity. Further work suggested that the diketopiperazine derivative is responsible for the immunosuppressive activity.218 Lysine is also modiied by a reaction with aspirin (acetylsalicylic acid) in a variety of proteins,219–226 including albumin,227 where it has an effect on glycation.228 The acetyl function in aspirin is an “active” acetyl group similar to the acetyl group in p-nitrophenyl acetate, which is also known to acetylate the lysine residues in proteins.229 Lockridge and coworkers230 have reported the extensive modiication of HSA with p-nitrophenyl acetate, including the acetylation of Try411 and the modiication of numerous other sites; these researchers suggest that this extensive modiication is responsible for the observed catalytic activity, not the result of turnover at a catalytic site. This is discussed later in the section on enzyme activity. The acetylation of albumin by aspirin (Figure 4.8) dates back to the early observations of Hawkins and coworkers.227,231 Jacobsen232 modiied HSA with a variety of reagents, including acetylsalicylic acid (aspirin), acetic anhydride, and N-acetylimidazole, all of which would result in the acetylation of the protein. Aspirin modiied 1.4 amino groups (from a total of 57), while acetic anhydride modiied 56 amine residues as well as 10 phenolic hydroxyl groups; N-acetylimidazole modiied 22 amino groups and 4 hydroxyl groups. In a subsequent work in 1975, aspirin was demonstrated by Walker233 to modify Lys199 in HSA. Recently, Liyasova and coworkers234 showed the acetylation of Lys199, Lys402, Lys519, and Lys525 in HSA with 0.2 mM aspirin; higher concentrations of aspirin resulted in a more extensive modiication. Bohney and coworkers235 established Lys190 as the primary site of modiication with pyridoxal-5′-phosphate.

99

Albumin −O

H3C

O

O O NH HC NH

O

H N

H N

N H

N H (a)

H3C

(c)

H N

O N H

NH

(b)

HO

H3C N

O

O

CH3

HO NH NH

H N

CHO

H2N O (d)

NH2 N H

H N

O (e)

N H (f)

O

H N N H (g)

HN

O

O OH

HO

(i) (h)

HO

FIGURE 4.7 Structures of some chemically modiied lysine residues in proteins. (a) Nɛ-Acetyllysine providing charge neutralization.886 (b) Nɛ-Succinyllysine providing charge reversal.887 (c) 2-Aminoadipyl residue obtained from metal-catalyzed oxidation of proteins.214 (d) Nɛ-Methyllysine and (e) Nɛ-Dimethyllysine, which are obtained by reaction with formaldehyde followed by reduction with sodium cyanoborohydride providing charge preservation.888 (f) The Michael addition product derived from the reaction of a lysyl residue with 4-hydroxy-2-nonenal. (g) The Schiff base derived product (after reduction) derived from the reaction of a lysyl residue with 4-hydroxy-2-nonenal.889 (h) and (i) are products derived from the reaction of a lysyl residue in albumin with 16α-hydroxyestrone.890

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Biotechnology of Plasma Proteins

NH O CH2 O

CH3

CH2 O

HO

O

CH2

H N

H N

Acetylsalicylic acid (aspirin) 2-(acetoxy)benzoic acid 2-acetoxylbenzoid acid

N H O

OH

CH3 O NH CH2

NH

CH2 O

O

CH3 Acetaminophen; paracetamol; N-(4-hydroxyphenyl)acetamide

CH2

H N

H N N H O

P450

Protein

OH

O

CH2 S

NH

N

O

O CH3

CH3

FIGURE 4.8 Reaction of aspirin and acetaminophen with albumin. Shown is the reaction of aspirin [2-(acetoxy)benzoic acid] with the ɛ-amino group of lysine to yield Nɛ-acetyllysine.234 Also shown is the conversion of acetaminophen to N-acetyl-p-benzoquinoneimine intermediate and one of the suggested reaction products with albumin. This speciic modiication is suggested to involve Cys34.365,891

Albumin

101

Both aspirin (acetylsalicylic acid) and the hydrolysis product, salicylic acid, bind to albumin, and the albumin–salicylate complex may be responsible for the hypersensitive allergic response observed with aspirin.236–241 Nitrosylation and nitration of HSA occur during periods of oxidative stress. Nitrosylation occurs at Cys34.242 Nitrosylation (Figure 4.5) is a reversible reaction and does affect ligand binding by HSA; ligands also affect the nitrosylation of HSA by nitric oxide.243 The concentration of nitrosylated albumin in blood has been determined to be approximately 200 nM,244 and S-nitrosoalbumin has a half-life of 5.5 h in heparinized blood in vitro.245 As the in vivo half-life of nitric oxide is quite short (ca. 0.1 s),246,247 HSA can serve as a reservoir for physiologically signiicant circulating nitric oxide.248 Ascorbic acid can cause the release of nitric oxide249 S-nitrosylated derivatives, with such an effect being responsible for the increased bioavailability of nitric oxide.250 It has been suggested that ascorbate (Figure 4.9) may have a role in the release of nitric oxide radical from nitrosylated albumin.251 S-Nitrosylated HSA has a cytoprotective effect and is being developed as a therapeutic product for reperfusion injury.252 Jourd’heuil and coworkers253 observed the nitrosylation of both Trp214 and Cys34, with the products having different redox sensitivity to reactions with reduced glutathione and/or ascorbate. Peroxynitrite is derived from the reaction of nitric oxide and superoxide anion 254 and reacts with tyrosine, tryptophan, and cysteine residues in proteins (Figure 4.10).255–257 A reaction with tyrosine yields 3-nitrotyrosine, which is the product obtained on reaction with tetranitromethane (TNM).258 Nitrated proteins, including HSA, can be detected in plasma samples using an ELISA technique.259 It is suggested that the formation of 3-nitrotyrosine in HSA by peroxynitrite is a biomarker for oxidative stress.260,261 Harrohalli and coworkers used site-directed mutagenesis to suggest that Trp214 is the principal site of nitrosylation in HSA.262 Sonnenschein and coworkers263 have reported the formation of S-nitrosothiols via the intermediate formation of N-nitrosotryptophan (Figure 4.5).

IN VITRO CHEMICAL MODIFICATION OF ALBUMIN HSA and BSA have been used as model compounds for the characterization of reagents developed for the modiication of proteins. Chemical modiication of these proteins has also been used to understand the in vivo modiications described earlier. Finally, the in vitro studies provide an insight into the function of HSA as a scavenger as described later. Albumin contains the usual amounts of potential nucleophiles, such as amino groups, carboxyl groups available for modiication, 17 disulide bonds, and a single thiol group on cysteine-34. The free sulfhydryl group (Cys34) in HSA poses an interesting question regarding its potential function. However, the author posits that the presence of ive free sulfhydryl groups in factor VIII is a much bigger puzzle (see Chapter 6). There is a free sulfhydryl group in ibroblast growth factor-1, which is considered to be vestigial.264 Mutagenesis of this cysteine residue increases the functional half-life of ibroblast growth factor-1.265 Zhao and coworkers266 observed that the mutation of cysteine to serine in the HSA moiety of human interferon-α2b-HSA fusion protein increased the stability, reduced the aggregation, and decreased the immunogenicity resulting from

102

Biotechnology of Plasma Proteins HO

OH

H2C

HO

C H

OH

H2 C O

C H

−2e−

O

+2e− HO

O OH

O Dehydroascorbic acid

Ascorbic acid Cupric

Cuprous

O HN

CH

C

O

NH HN

CH2

CH

S

CH2

N

SH

C

NH

+ NO

O NO2

NO2

HOOC

HOOC

+

S

SH

S

SH

COOH

COOH

NO2

NO2 .

TRP

TRP

FIGURE 4.9 Ascorbic and dehydroascorbic acid. Ascorbic acid can serve as a reducing agent for cupric ions, causing oxidative damage mediated via cuprous ion and superoxide.892,893 Ascorbate can also cause the release of nitric oxide from S-nitrosylated derivatives.894 It is also suggested that ascorbate can reduce disulide bonds as such in dithiobis (2-nitrobenzoic acid).895,896 Ascorbate can also reduce protein-free radicals.897

103

Albumin Peroxynitrite ONOO−

O−

OH NO2

HOONO Peroxynitrous acid

N H

N H O

Tetranitromethane C(NO2)4

O 3-Nitrotyrosine

NO2 HN Peroxynitrite

HN

ONOO−

CH2 H2N

CH

CH2 C

OH H2 N

CH

C

OH

O O 6-Nitrotryptophan

FIGURE 4.10 Reactions of peroxynitrite and tetranitromethane with amino acid residues in albumin. Tyrosine residues may be nitrated by either peroxynitrite or tetranitromethane in proteins.898 Peroxynitrite has been shown to modify a tryptophanyl residue in albumin.257

mechanical and thermal stress. There was a difference in the pharmacokinetic behavior. However, the sulfhydryl group of albumin does appear to have a distinct function(s), which is described later. I would add the comment that at one time, it was thought that extracellular proteins such as albumin or factor VIII had only disulide bonds and that proteins with free sulfhydryl groups were only found inside the cell.267–269 Cysteine 34 is present in various forms in HSA, including the various oxidation states and mixed disulide forms described earlier. In addition, dehydroalanine derived from Cys34 has also been reported (Figure 4.6).270 As a result of these various modiications, commercial albumin derived from plasma as well as recombinant albumin demonstrated heterogeneity of cysteine residues.271 The majority of the modiied Cys34 was present as a mixed disulide with cysteine. Plasma-derived albumin had 55% free Cys34, while the recombinant preparation had 83% free Cys34. Ghiggeri and coworkers272 found 0.49 mol of free sulfhydryl group per mole of HSA [5,5′-dithiobis-(2-nitrobenzoic acid), DTNB] (Figure 4.11) in proteins obtained from

104

Biotechnology of Plasma Proteins O +H N 3

OH SH

[O]

CH2 Albumin

CH

C

O−

+H

3N

CH

CH2

CH2

SH

S

S

S

CH2

CH2

NO2

C

O−

Albumin

Albumin

NO2

O

+ NH3

COO−

RSSR CH2 N CH2

R

S

S

S

S

S

S

S

S

CH2

CH2

CH2

CH2

Albumin (a)

Albumin (b)

Albumin (c)

CysSSR

Albumin

FIGURE 4.11 Mixed disulide formation in albumin. Albumin in vivo has 60%–70% of Cys34 as free thiol, with the remainder present as mixed disulide or oxidized cysteine.899 The albumin-mixed disulide can undergo disulide exchange with thiols in plasma, such as homocystine.900 Also shown are the products of reaction of the thiol in albumin with 5,5′-dithiobis(2-nitrobenzoic acid), 2,2′-bis-(5-nitropyridine).272,290,301

healthy subjects. Aćimovic and coworkers273 found 0.76 mol of sulfhydryl group per mole of HSA (commercial product) in their studies. Early workers also came to the conclusion that there were less than stoichiometric amounts of the sulfhydryl group in albumin.1,103 The amount of sulfhydryl group reactivity in albumin is reduced on storage in solution, with the decrease being most rapid at neutral pH. Hughes274 was able to isolate HSA with a stoichiometric amount of sulfhydryl by the crystallization of albumin from plasma as the dimer using mercuric chloride (Figure 4.12). The mercuric ion is removed by cysteine, yielding an albumin with a stoichiometric amount of sulfur; this albumin is referred to as mercaptalbumin.275 A novel approach to mercaptalbumin has been developed by Carlsson and Svenson.276 These researchers used covalent chromatography on S-thiopyridyl-derivatized agarose (activated thiol Sepharose; Sepharose-coupled glutathione modiied with 2,2′-dithiopyridyldisulide; Figure 4.11) to prepare bovine mercaptalbumin. Funk and coworkers277 used

105

Albumin O

O

H N

H N

N H

HC

N H

CH2

HC CH2 S

SH

Hg HgCl2

SH

S

H2C

H N

CH

H2C

H N

CH

N H

N H O

O

Methylmercury (CH3Hg+)

CH3

RSH

SH

Hg

H2C

H N

CH

S N H

H2C

H N

CH

O

N H O

FIGURE 4.12 Reaction of mercuric compounds and organomercurial derivatives. Mercuric ion (mercuric chloride) and organic mercurial compounds, such as methyl mercury, can react with Cys34 in albumin.901 As shown, while mercuric ion forms a tight bond between two sulfhydryl groups, this interaction has been used to purify mercaptalbumin.275 Methylmercury, an environmental toxin, also binds to the sulfhydryl group in albumin.901

S-thiopyridyl agarose to remove mercaptalbumin as a method for enriching albumin containing derivatized Cys34. The reactivity of the sulfhydryl group at Cys34 depends on prior modiication (refer to the various studies on the presence of oxidized products and mixed disulides earlier) and nucleophilicity; the nucleophilicity depends, in part, on the pKa

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Biotechnology of Plasma Proteins

of the functional group;278 in this case, the thiolate anion is the reactive species. The pKa for an “average” sulfhydryl group in a protein is 8.3–8.7.279 The pKa for the sulfhydryl group in HSA is approximately 7.8–8.0.280–282 Lower values for the pKa have been suggested,283 but the value determined by Spiga and coworkers281 has been obtained by a reaction with DNTB and the value determined by Bruschi and coworkers280 has been obtained by electrophoretic titration. The thiol–disulide reaction between HSA and cystine had a pH optima of approximately 8.2.282 A pKa value of 5.0 for the sulfhydryl group in HSA was cited by Narazaki and coworkers283 referring to the pKa value obtained by Lewis and coworkers284 using potentiometric titration. A pKa value of 9.0 (e.g., 1 M NH4OH)

O R

HN

S

+

R′

OH HN

N H

O

FIGURE 4.13 Reaction of cyanide with disulide bond in albumin. Cyanide reacts with disulide bonds in a disproportionation reaction, yielding a thiocyanate and sulfhydryl group.326 Cleavage at the modiied cysteine residue can be accomplished by providing a biomarker for cyanide exposure.322

coworkers273 examined the role of HSA in binding methylglyoxal in their work, emphasizing the importance of the hydrophobic environment around Cys34 in its scavenging activity. Tryptophan-214 is considered to play a role in providing this hydrophobic environment.334–336 Another example of scavenging or detoxiication is the study on the reaction of acrylamide with the sulfhydryl group albumin.337 Glycation has been described earlier, and other reactive aldehydes, including nonenal derivatives and methyl glyoxal, react with various functional groups (Figure 4.14), including sulfhydryl, amino, imidazole, and guanidino.338–341 TNM is a classic reagent for the nitration of tyrosine residues in proteins.342–344 It is of personal interest to the author who worked with this reagent some 30 years ago and was informed by a reviewer on a grant application to the National Institutes of Health that nitrotyrosine would never be of signiicance. The reaction of TNM with proteins (Figure 4.10) has been reviewed; modiication occurs primarily at tyrosine residues, but nitration of tryptophan does occur as well as oxidation of cysteine and

110

Biotechnology of Plasma Proteins H C

CH2

O

C H

H2 C

H C

1,3-Butanediene

H3 C

H C H Crotonaldehyde

O CH2

CH C H

H2C

O H3C HN OH

S CH3

CH3

O

O NH

P450

N

S

O OH HN Aminoacetophen [N-(4-hydroxyphenyl)acetamide] H3C

O

FIGURE 4.14 Reaction of electrophilic derivatives with albumin.365,902

methionine.345 TNM reaction for the modiication of HSA has been used as a model system for the nitration reaction, while other studies focus on the use of TNM for the identiication of functional sites on HSA protein. Malan and Edelhoch258 were able to modify half of the tyrosine residues in HSA with TNM at pH 8.0 and studied the spectral characteristics of the modiied protein. These researchers reported differences in the spectral characteristics allowing separation of the modiied tyrosyl residues into three groups. Fehske and coworkers346 also reported the modiication of half the tyrosine residues in HSA with TNM but reported that the modiication of two tyrosine residues decreased the binding afinity for tryptophan or benzodiazepine; there was one rapidly reacting tyrosyl residue. Subsequent work

Albumin

111

from this group.347 identiied the highly reactive tyrosine residues as Tyr411. Kim and coworkers348 used afinity capillary electrophoresis to show modiication of Trp214 and Tyr411 with 2-hydroxy-5-nitrobenzyl bromide and TNM, respectively. Modiication with TNM affected the indole–benzodiazepine binding site with no effect on warfarin binding; modiication of tryptophanyl residues with 2-hydroxy-5nitrobenzyl bromide did affect warfarin binding. Šantrůček and coworkers349 modiied HSA with TNM or iodine and observed that Ty411 readily iodinated but reacted poorly with TNM; Tyr161 and Tyr263 also showed differences in reactivity between iodine and TNM. Tyrosine 411 is also modiied by organophosphorous agents as are other tyrosine residues in HSA.350 Some of these reactions of Cys34 need to be discussed in more detail from the perspective of site-speciic chemical modiication. In addition, there are other modiication reactions, which should be considered before moving into a consideration of oxidation. The reaction of a sulfhydryl group and other functional groups in a protein can be a complex process that is dependent on the presence of other functional groups.292 Barron351 classiied sulfhydryl groups in proteins as being freely reacting, sluggish, or masked. Webb352 suggested that there is a continuum from highly reactive to unreactive. In the case of albumin, the cysteine may be unavailable due to prior modiication. The results of modiication at an extreme pH would suggest that there are steric factors that inluence modiication of Cys34 at neutral pH. However, with product characterization, the issue of disulide cleavage/disulide exchange in albumin293,294,353 has the potential to complicate the interpretation of the results. Assuming that disulide exchange or cleavage is not an issue, it could be argued that there is an increased sulfhydryl exposure at low pH and elevated pH. The problem of prior modiication by mixed disulide formation or oxidation has been discussed earlier. That leaves the issue of the effect of the local environment on the modiication of Cys34. Stewart and colleagues354 suggest the importance of Tyr84, His39, and Asp38 in the enhanced reactivity of Cys34. Several other researchers have discussed the importance of His39 in the reactivity of Cys34. One result of the microenvironment for Cys34 at neutral pH is a low pKa of 5–8.2 (see above). For the purposes of the current discussion, it is assumed that results obtained with BSA, while quantitatively different from HSA, may be used to interpret experimental results obtained with HSA. Cys34 is not available, either from the formation of a mixed disulide or oxidation, in approximately 50% of albumin in vivo, which may have consequences for the antioxidant activity of HSA. Anraku and coworkers355 observed that the oxidation of Cys34 in hemodialysis patients correlated with the thiol content and suggested that some 40% of the antioxidant activity of HSA occurs in vivo. This value was obtained from a consideration of the antioxidant activity of C34S HSA. Wilson and coworkers356 cited work showing that iodoacetamide reacts with the thiol in BSA while there is no reaction with iodoacetic acid. This difference in reactivity has been observed by other researchers and usually indicates the presence on anionic sites such as glutamic acid or aspartic acid, close to the cysteine residue being modiied.345 Wilson and colleagues studied the reaction of DTNB and other disulides with BSA. They reported a rate of 70/m/s for the reaction of DTNB with BSA at pH 8.5 compared to a calculated rate of 2.5 × 105/m/s for DTNB with

112

Biotechnology of Plasma Proteins

an unhindered thiol under the same conditions. A neutral, hydrophobic disulide, such as diethyl disulide, demonstrated a higher rate of reaction (45/m/s) than the calculated rate with unhindered thiol (0.7/m/s) under the same conditions (pH 8.0). Cystamine disulide showed a higher rate of reaction with BSA (1 × 103/m/s) than with the unhindered disulide (3.66 × 102/m/s). While not directly relevant to the speciic albumin problem, Gitler and colleagues357 have demonstrated that cationic detergents enhance the reactivity of sulfhydryl groups in proteins by lowering the pKa (presumably increasing nucleophilicity). Takeda and coworkers299 showed an increase in the rate of reaction of DTNB with BSA in the presence of urea with a suggestion of saturation kinetics in the reaction, which would indicate the formation of a reagent–BSA complex prior to the modiication of Cys34. Zhang and coworkers301 studied the reaction of DTNB as well as a zwitterionic derivative [5-(2-aminoethyl)dithio-2-nitrobenzoate, ADNB] (Figure 4.11) with BSA, canine serum albumin, and equine serum albumin. The objective was to assess the importance of Glu82 in the reactivity of Cys34 (it should be noted that Cys34 is a conserved residue in all serum albumins). The rate of reaction of the neutral reagent, ADNB, was 190 times more rapid that that observed with DTNB, which carries a negative charge. ADNB was sixfold more reactive than DTNB with canine albumin where Glu82 is replaced by an aspartic acid residue. The two reagents, ADNB and DTNB, were equally reactive with equine albumin where Glu82 is replaced by an alanine residue. This group also observed an increase in the rate of modiication with DTNB with increased ionic strength; the effect of ionic strength was also observed by Wilson and coworkers.356 In a study that adds to the results obtained by Zhang and colleagues,301 Stewart and coworkers358 studied the effect of site-speciic mutagenesis of HSA on reaction with DTNB. The rate of reaction of DTNB with the Tyr84Phe mutant was some 170-fold more rapid than the rate with the wild-type protein (pH 9.0) and fourfold more rapid with His39Leu (pH 9.0); the rate of reaction of the His39Leu was less than the wildtype at pH < 7.5. The decrease in rate below pH 7.5 would be consistent with the suggested role of His39 in decreasing the pKa of Cys34. These researchers also suggest that the hydroxyl group of Tyr84 forms a hydrogen bond with the thiolate anion, which would decrease reactivity. In more recent work, Spiga and coworkers359 have studied the reaction of DTNB with the various serum albumins to gain more insight into structural features inluencing Cys34 reactivity. HSA and BSA showed similar reactivity with DTNB at pH 7.4 (~75/m/s) at pH 7.4, while the rate reaction was faster with rat (7.4 × 102/m/s) or porcine (2.6 × 103/m/s) albumin. This group suggests the presence of additional anionic sites in the vicinity of Cys34. The reader is directed to several earlier effective studies that provide insight into the inluence of surrounding functional groups on sulfhydryl reactivity. Chaiken and Smith360,361 and Gerwin362 showed major differences in the reactivity of chloroacetic acid and chloroacetamide with a cysteine residue at active sites of papain and streptococcal proteinase, respectively. The reaction of the chloroacetamide, a neutral reagent, showed a sigmoidal curve when rate was plotted versus pH with either papain or streptococcal proteinase consistent with the critical importance of the thiolate anion in the reaction. The reaction of chloroacetic acid with either papain or streptococcal proteinase shows a bell-shaped curve when reaction rate is plotted versus pH. Chaiken and Smith postulated that the enhanced reactivity of papaion at pH 5–6 is due to the electrostatic

Albumin

113

interaction of chloroacetate with the imidazole ring of histidine and/or the enhanced ionization of the cysteine residue by the imidazolium ions. Thus, there is ample support from other systems for the role of His38 in enhancing the reaction of Cys34 in albumin. As stated earlier, there is a report of the modiication of Cys34 in HSA with iodoacetamide but not with iodoacetate. Cysteine 34 in HSA is a point of attachment of a variety of electrophilic agents,175 such as chemical warfare agents and other chemical toxins including α,β-unsaturated aldehydes (Figure 4.14).363 Another example is provided by the reaction of metabolites of 1,3-butanedione (Figure 4.14) with albumin where reaction occurs at multiple sites.364 Another example is provided from the studies of Damsten and coworkers365 who showed that N-acetyl-pbenzoquinoneimine, which is derived from the action of P450 on acetaminophen (Figure 4.8), reacts with Cys34 in HSA. Modiication of lysine residues in albumin has been somewhat less studied than sulfhydryl reactivity. The studies of Goldfarb with TNBS193 have been cited earlier and have provided a basis for classifying side chain amino groups on the basis of reactivity. Succinylation of albumin has been the subject of considerable study over the past several years. Part of this work has been directed at the preparation of succinylated HSA as a therapeutic agent against HIV.366–370 Scavenger receptors were originally described as receptors for oxidized and acetylated low-density lipoproteins, and succinylation can be used to target soluble antigens to cytotoxic T lymphocytes.371 There are a variety of studies where succinylation has been used to target albumin to scavenger receptors in various tissues.372–374 Lysine residues in albumin are available for succinylation and such modiication does cause signiicant change in conformation375,376 (succinylation causes charge reversal), while guanidation (creates more basic residue) has a lesser effect.377 Table 4.2 reviews lysine modiication in albumin.

ALBUMIN AS A CARRIER The circulating half-life of HSA is about 20 days.44–46,378 Bennhold and Kallee379 reported a half-life of 16 days for 131I-labeled albumin in a normal subject and 50–70 days in a subject with analbuminemia. As an aside, analbuminemia (congenital absence of albumin) is a comparatively rare condition with apparently minor clinical consequences.380–382 The half-life of albumin does decrease in critically ill patients as does cholinesterase.383 Anraku and coworkers384 found that substantial oxidation of HSA with chloramine T (50 mM chloramine T; 15 μM HSA, pH 8.0, 1 h) resulted in a protein with a decrease in circulatory half-life in mice (8.7 vs. 20 min) and increased uptake (146 vs. 13 μL/h) in liver. Modiication at lower concentrations of chloramine T (10 μM) did not result in a signiicant change in either circulatory half-life or liver uptake. This group385 also showed that metal ion–catalyzed oxidation of Arg410 reduces half-life; reduced half-life was also observed for the R410A mutant. Earlier studies by Anhorn and others386 observed the pharmacokinetics of human albumin in rabbits. Human plasma albumin was shown to have a half-life in rabbits of approximately 6 days (143 h); modiication with 2-phenyl-4-ethoxy methylene oxazolone386 decreased the half-life to 3.3 days (79.9 h). 2-Phenyl-4-ethoxy methyl oxazolone [(E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one; oxazolone]

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Biotechnology of Plasma Proteins

TABLE 4.2 Modification of Lysine Residues in Human Serum Albumin

Lysine 12 93 97 130 159 186 195 199 212 233 257 276 281 414 438/439e 499 525 598 a

b c d e

Fe3+/ Ascorbic Acid

HOCL

4-HNEa

MDAb

Glycation (Glucose)c

Glycation (Galactose)d

+ +

+

+ + + + + +

+ + +

+

+

+ + +

+ + + +

+ +

+

+

+

4-Hydroxy-2-nonenal.338 Lysine modiication by 4-HNE can occur via Schiff base formation, as with glycation (Lys195) or both Schiff base and Michael addition (Lys199 and Lys525). Malondialdehyde.872 A number of studies on glycation with glucose are cited in the text. From Frost et al.187 There is some confusion in the literature about the location of this residue in the amino acid sequence of HSA. The sequence obtained from albumin mRNA by Dugaiczyk and coworkers77 has the lysine residue at position 439.

was one of the earliest described haptens387,388 (described as pro-antigenic in its ability to combine with a protein to produce a new antigen387). Oxazolone is a potent skin sensitizer in forming stable products with lysine and sulfhydryl groups in proteins (Figure 4.15). The half-life of albumin has encouraged the development of fusion proteins with biologically active peptides. The fusion protein between albumin and interferon-β has a half-life of 36–40 h compared to 8 h for interferon-β and retained useful biological activity.389 A fusion protein between albumin and interleukin-2 (IL-2) demonstrated longer circulatory half-life (6–8 h vs. 19–57 min for recombinant IL-2) with retention of therapeutic eficacy.390 Other useful albumin fusion products have been obtained with recombinant antibody fragments,391 hirudin,392 butyrylcholinesterase,393 blood coagulation factor IX,394 and tumor necrosis factor (TNF).395 This approach396 is

115

Albumin

O

O

N

N

O

O NH2

O Oxazolone

C H2

CH2

NH

CH2

CH2

CH2

CH2

SH CH2

CH2 CH2

C H2

S

N O

O O

C H2

S O O

Additional products with protein nucleophiles

HN

Hippuryl derivative

FIGURE 4.15 The structure of oxazolone and related compounds and their reaction with albumin. The reaction of oxazolone [(E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)] with lysine and sulfhydryl residues in proteins is shown.387,903

based on the recycling of albumin by the neonatal Fc receptor (FcRn).397–399 The study by Andersen and coworkers399 cites the failure of an albumin variant to interact with the FcRn receptor, providing an explanation for the analbuminemic state where the catabolic rate is increased due to lack of albumin recycling. IgG is also recycled by the same mechanism.400–402 McCurdy and coworkers403 prepared rabbit serum albumin with an N-terminal hexahistine tag and rabbit serum albumin with the

116

Biotechnology of Plasma Proteins

N-terminal hexahistidine tag where Cys34 is replaced by an alanine (C34A). Both of these proteins had the same half-life (~5 days). A dimer of the C34A protein joined by a hexahistidine spacer had a half-life of 3.0 days; this was not expected as, in principle, a larger protein should demonstrate slower clearance. While a certain part of the prolongation of half-life is due to the use of FcRn recycling, a large portion is due to decreased renal clearance as a result of increased size as is observed with PEGylation.404,405 These fusion proteins are examples of the use of genetic engineering to attach a biopharmaceutical protein to an albumin carrier. Techniques of solution chemistry may also be used to attach “drugs” to albumin to improve pharmacokinetics.406,407 The example of nitrosylation of albumin to prepare a therapeutic agent for the delivery of nitric oxide408 has been mentioned earlier.252 Ishima and coworkers409 evaluated the use of an albumin variant (albumin Liprizzi), R410C, as a nitric oxide carrier; a half-life of 20.4 min was observed in a mouse model. In subsequent work,410 this group engineered sites of additional carbohydrate attachment in HSA and prepared nitrosylated albumin-targeted nitric oxide delivery to the liver. Antiviral nucleoside analogs (luorodeoxyuridine) have been coupled to lactosaminated human albumin via the imidazolide derivatives (Figure 4.16).411–413 99mTc-Labeled lactosaminated albumin has been used for imaging the hepatic asiaoglycoprotein receptor in liver,414 proving superior to the previously developed 99mTc-galactosyl-albumin415 (lactose is 4-O-β-d-galactopyranosyl-d-glucose). The 99mTc is bound to the lactosaminated albumin after reduction of lactosaminated albumin (~70 mm 2-mercaptoethanol at approximately pH 8.3, 37°C, 1 h). Analysis of the reduced albumin showed 21 sulfhydryl groups (Ellman’s reagent). Lee and Hirose416 have shown that reduced albumin retains considerable structure. Kim and coworkers417 coupled glucagon-like peptide to albumin with retention of biological activity and improved pharmacokinetics. Warnecke and coworkers418 have used maleimide chemistry to couple carboplatin drugs to Cys34 of HSA. Several groups have coupled insulin to HSA, also with maleimide chemistry.419,420 Schechter and coworkers419 developed the insulin– albumin conjugate as a prodrug as did Warnecke and coworkers for the carboplatin– albumin conjugate (Figure 4.17).418 The general use of albumin as a carrier for drugs and drug products has been reviewed by Kratz421 and by Sasson and coworkers.422 Sasson and coworkers422 were able to obtain prolongation of half-life by improving noncovalent binding of prodrugs to albumin. Drugs that contain a sulfhydryl function can bind to albumin as demonstrated by the reaction of bucillamine derivatives and HSA,423 providing for the reversible association of a sulfhydryl-containing drug and HSA (Figure 4.18).424,425 Captopril is a sulfhydryl-containing drug (Figure 4.18), which can react with albumin to form a mixed disulide.426 The captopril–HSA complex may be involved in adverse reactions.427,428 The effect of Cys34 modiication on albumin conformation has been mentioned earlier.133,354 As an example, Glowacki and Jakubowski429 observed the oxidation of cysteine-enhanced homocysteinylation at lysine residues. Thus, it is not surprising that the modiication of albumin with captopril results in conformation change.430,431 A novel approach takes advantage of the propensity of Cys34 to form mixed disulide bonds. Wu and coworkers432 engineered a cysteine on the C-terminus of glucagon-like peptide-1 and formed a mixed disulide with HSA. The key to using Cys34 as a point of chemical attachment depends on

117

Albumin O F NH

N

O N

O

P

O

O

N H

O−

H

H

H OH

O F NH

N

O

O H2 C

Protein

H N

P

O

O H

O−

H

H

H OH

Glucose

Galactose H

H HO

H OH

H

H

OH

HO

Point of attachment to protein O

O O

H

HO

H

H OH OH

H

OH OH

Lactose

FIGURE 4.16 The coupling of luorodexoyuridine to lactoaminated albumin using imidazolide chemistry. Shown is the structure of the imidazolide derivative of luorodeoxyuridine.411,413

the availability of the thiolate anion. Commercial albumin, either plasma-derived or recombinant, is modiied at Cys34 either by oxidation or mixed disulide formation. As such, it is necessary to convert the modiied cysteine to free cysteine in order to maximize product formation. Kratz and coworkers407,421 used dithiothreitol to reduce the Cys34 residue in human albumin, while Jeong and coworkers414 used 2-mercaptoethanol to reduce more than half of the disulide bonds. A variety of approaches,

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N

CH2

H2 C

O

CH3

N

SH

+

H N

O

N H

O N-ethylmaleimide

CH3

S O H N

O

N H

O

O

O O O

O

Carboplatin

O O

NH2

Pt

H2N

O O

O

O

N O O

NH2

O

Pt O

O NH2

FIGURE 4.17 Coupling of carboplatin and carboplatin prodrug to albumin using maleimide chemistry. Shown at the top is the reaction of N-ethylmaleimide to cysteine. Below are labile maleimide derivatives of carboplatin developed for coupling to Cys34 of albumin.418,421

including afinity chromatography on a thiol-agarose matrix, were mentioned earlier for the production of mercaptoalbumin. Albumin, both human and bovine, as well as ovalbumin, is used as a carrier for small molecules, including peptides, for the development of antibodies. The preactivation of albumin with divinylsulfone has seen some use433,434 as has the iodoacetyl ester of N-hydroxysuccinimide433,435 (Figure 4.19). The latter work by Houen and coworkers435 performed the modiication with the carrier protein (ovalbumin) adsorbed to an ion exchange matrix. Other conjugate chemistries have been used with BSA and ovalbumin for the preparation of immunogens.436–439 One example is the glutaraldehyde coupling of Nɛ-carboxymethyllysine to albumin as a hapten for the generation of antibodies against AGEs.440 Thierse and coworkers441 were able to use HSA as a carrier for metal ions as haptens. There are several studies on the technology of using albumin for hapten production, and

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Albumin Cysteine O

CH3 O H3C

C

H N

C

H C H2C

SH pKa = 8.39

C

OH

SH pKa = 10.22

Bucillamine[N-(2-mercapto-2-methylpropanoyl--cysteine] CH3 O H3 C

C

O H N

C

H C

C

OH CH3

H2 C

SH pKa = 10.50

S

N-(3,3-dimethyl-1-mercaptobutyryl)--methyl--cysteine HO O O C H2 C

C HC

HS

H C

CH CH2

CH3 H2C

CH2 Captopril 1-[(2S)-3-mercapto-2-methyl-1oxypropyl]--proline HO O H2 C HS H2 C

C HC

H C

CH3 H2 C S

S

R

O

C CH

HO CH2

O H2 C

CH2 S

C HC

S Cys34 in albumin

H C

CH3 H2 C

H2C

O

C CH

CH2 CH2

+ RSH

FIGURE 4.18 Reversible association of sulfhydryl-containing drugs with Cys34 in human serum albumin. Shown is the example of a structure of bucillamine and related compounds.423 Either sulfhydryl could react with Cys34 to form a covalent complex. Also shown is a bucillamine derivative, N-(3,3-dimethyl-1-mercaptobutyryl)-S-methyl-l-cysteine, which was used in a subsequent study to show binding differences between normal and pathological serum.904 The structure of captopril, an antihypertensive drug with a sulfhydryl group, is also shown as is the reaction of captopril with Cys34 in albumin.

they are worth consideration.442–445 Jenkinson and coworkers446 used studies with p-phenylenediamine–albumin adducts to show that such adducts are determinants in patients with contact dermatitis. It has been known for some time that bead-like structures for the delivery of drugs can be manufactured from albumin.447–449 Albumin has been used with

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Biotechnology of Plasma Proteins O

OH O +

H2 C

C H

OH

S

C H

CH2

O Divinylsulfone

O H2 C O

H2 C

S

C H

CH2

R

O

NH RNH2

CH2

OH R

CH2

RSH S

O

CH2

S

O

CH2

CH2

H2C O

O

S

O OH

CH2 H2C O OH

FIGURE 4.19 Use of divinylsulfone or haloalkyl for coupling to albumin. Divinylsulfone and N-hydroxysuccinimide ester of iodoacetic acid. These can be used to activate albumin prior to the coupling of a smaller molecule.433

poly(lactide-co-glycolide) for encapsulation of tetanus vaccine.450 These researchers used spray-drying for the preparation of microcapsules. Heparin-coated albumin has been used as a matrix to bind the basic ibroblast growth factor,451 anti-mucus antibody has been coupled to albumin microspheres via carbodiimide chemistry in developing a drug delivery system with delayed gastrointestinal transit,452 and the RGD (arginine-glycine-aspartic acid) peptide has been coupled to albumin microsphere for targeting tumor cells.453 Albumin microspheres have been used to deliver radionucleotides.454,455 Albumin has been used to coat calcium alginate microspheres to improve

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stability.456,457 Albumin-coated magnetic beads have been used to measure drug– albumin interactions458 and, after attachment of antibody, to measure biomarkers.459

LIGAND-BINDING BY ALBUMIN Albumin is well known for binding metal ions, other cations, anions, including fatty acids, and various drugs. The structure of albumin has been discussed in several earlier sections. Briely, albumin has two major binding sites (sites I and II) and other sites such as Cys34 and metal ion binding sites.424,460 Site I binds large heterocyclic compounds and dicarboxylic acids, and examples include warfarin, bilirubin, and salicylates,424 while site II binds smaller molecules such as indoles and diazepam. The designation of site I and site II on albumin stems from the early work of Sudlow and coworkers,461,462 and the sites are occasionally referred to as Sudlow Site I and Sudlow Site II.463–465 The binding sites for metal ions are separate from the Sudlow sites.466 Albumin also binds fatty acids at several sites, which may overlap with Sudlow sites.467–471 Crystallographic analysis of binding of myristic acid (C14; tetradecanoic acid) to HSA showed six binding sites.471 As noted by Curry and coworkers,472 0.1–2 mol of fatty acid are bound per mole of albumin under normal physiological conditions and there are likely three high afinity sites for the binding of fatty acids. Other researchers have suggested seven binding sites,473 while other studies suggest the binding of eight myristic acids.474 The binding of fatty acids to albumin is associated with conformational change in albumin475–484 and can change the characteristics of the site of interaction on the albumin molecule such as the binding of warfarin.485,486 The binding of fatty acids inluences the polarity of the microenvironment around Cys34480 inluencing the redox properties of albumin.487 Site I is located in subdomain IIA and contains the single tryptophanyl residue (Trp214) in albumin,424 and it has been reported that the modiication of Trp214 with 2-hydroxy5-nitrobenzyl bromide inluences the binding of warfarin.348 Bromocresol purple is used to measure albumin and binds to the warfarin-binding site (site I) and a site II region as well.488 Sudlow Site I is frequently referred to as the warfarin-binding site,489–495 with the binding to albumin being of importance for the pharmacokinetics of this anticoagulant drug.496–498 There are clinical situations where the administration of a drug can cause an increase in the effective concentration of warfarin, most likely by competition for the same binding site on albumin such as observed for zafirkukast.498 In another situation, there was a decrease in the effective concentration of warfarin with a high-protein diet.499 Site II is frequently referred to as the indole site or diazepam site346,500–508 to distinguish it from site I, the warfarin site. The binding of molecules to site II is stereospeciic, and immobilized albumin can be used for chiral separations.509–517 While site I is referred to as the warfarin site, it is not a homogeneous site but contains regions of differing speciicity.490 As noted, modiication of the sole tryptophan (Trp214) in HSA with 2-hydroxy-5-nitrobenzyl bromide inluences warfarin binding with little effect of azopropazone; however, azopropazone can displace warfarin from HSA as effectively as azopropazone can displace itself (14C-labeled drug). Diazepam that binds to site II has little effect on the binding of either warfarin or azopropazone to HSA. Subsequently, Yamasaki and coworkers518 proposed

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the existence of three binding regions within site I: site Ia, which was characterized by the binding of the marker ligand acenocoumarol; site Ib, which was characterized by the binding of the marker ligand dansyl-asparagine (DNSA); and site Ic, which was characterized by the binding of the marker ligand phenylbutazone. These sites overlap but are separate from site II (diazepam site) and a third site referred to as binding area III (digitoxin). The digitoxin site, referred to as site 2 by Sjöholm and coworkers,519 was determined by the study of binding to HSA immobilized by emulsion polymerization in polyacrylamide microparticles.520 Subsequent work has shown some peculiarities in digitoxin binding by albumin,521,522 but studies by Hage and Sengupta523 using high-performance liquid chromatography (HPLC) with an immobilized HSA matrix to measure binding show clearly that digitoxin binds to albumin, independent of site I or site II. More recently, Yamasaki and coworkers524 extended their earlier studies on site I subregions showing interaction between site Ib (binding of dansyl-L-asparagine, DNSA) and site Ic (n-alkyl p-aminobenzoates). pH has an effect with higher binding of DNSA at alkaline pH. This group had previously reported a change in the spatial relationship between site I and site II caused by the N → B transition.525 The importance of understanding the N → B transition for drug binding by albumin has been discussed earlier. Albumin also binds heme526,527 and such binding has encouraged the development of heme–albumin as an oxygen carrier in artiicial blood development.528–530 Heme binding to HSA also inluences the binding of other ligands.531–533 Ascenzi and coworkers have advanced the concept of allostery in a monomeric protein base on the binding of heme to HSA binding.534 In this model, albumin is envisioned as a protein with three discrete domains with independent binding characteristics, but able to interact, inluencing the binding characteristics of another domain much in the same way as the binding of an effector to one subunit in an oligomeric protein. It can be concluded that albumin is responsible for the bound portion of drugs in the circulation and serves as a reservoir for the release of these drugs over time. Other compounds, including medication, can compete for the binding of drugs to albumin and inluence pharmacokinetics. It is also clear that fatty acid binding can inluence the binding of drugs to albumin. Albumin is also important for binding metal ions, with the binding of zinc of particular importance. I commend the reader to an excellent article535 by Fehske and coworkers, published in 1981, where they concluded that “Thus, the structure and the location of drug binding sites of HSA might be more complicated than it seemed a few years ago ….” It would seem like the same comment holds true some 30 years later, and it is clear that albumin is a lexible molecule capable of complex interactions in the circulation. The various sites can be probed by various techniques. Modiication of HSA with 2-hydroxy-5-nitrobenzyl bromide affects warfarin binding, while TNM modiication affects indole/benzodiazapine binding.347,348 Phillips and Marmorstein536 studied the binding of 6-nitrotryptophan to HSA; binding was associated with a blue shift and hyperchromicity. These changes are similar to those observed with transfer into apolar solvent and were used to determine a K D of 8 × 10−5 M and stoichiometric binding (n = 0.95). There are a number of studies on the binding of tryptophan by HSA, suggesting 104 –105 M binding constants for tryptophan and HSA and that such binding is inluenced by the state of the albumin protein.537–541 Pressure denaturation

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of HSA eliminated binding at site II (based on dansylsarcosine binding) at pressures above 300 MPa, while warfarin binding was retained.542 This study also observed the effect of urea denaturation, and dansylsarcosine binding was lost in 6 M urea, while retaining warfarin binding. Data cited earlier show that modiication of the single tryptophanyl residue (Trp214) inluences binding in site I, while modiication of Tyr411 inluences binding in site II. A variety of the site probes used are also luorescent, such as DNSA, and cause changes in the intrinsic luorescence of the protein, or exhibit other spectral changes. An example of the latter is provided by the studies of Yamasaki and coworkers524 on the subregions of site I, where changes in the CD spectra and luorescence anisotropy of DNSA bound to site Ic were inluenced by the binding of n-butyl-p-aminobenzoate (and related n-alkyl-p-aminobenzoates).

PURIFICATION AND CHARACTERIZATION OF HSA FOR CLINICAL USE The Cohn fractionation process described in Chapter 2 was driven by the clinical requirements of albumin. The Cohn Fraction V contains albumin and is usually the last biotherapeutic obtained in the Cohn fractionation. Plasma protein fraction (PPF) is similar to albumin with lower protein concentration (~5%) and is obtained from the Cohn Fraction IV-4.543,544 PPF, however, is not the same as 5% albumin; albumin is supplied as a 5% solution and 25% solution. Albumin is provided as a liquid formulation, which is subjected to pasteurization in the inal manufacturing step.545–553 The pasteurization process has been demonstrated to inactivate various pathogens, such as hepatitis virus545 and, more recently, H1N1 virus.550,553 Sodium caprylate and N-acetyl-tryptophan were included as stabilizers for albumin.554,555 Pinya Cohen has described the development of stabilizers for use in the pasteurization process for albumin.556 The albumin derived from plasma fractionation (the Cohn Fraction V) was obtained as a powder in the original process and supplied to the U.S. Navy (by contract) as a 25% solution to minimize the space required for transport.557 This contract also called for stability at 50°C, as the product would be shipped and used in tropical climates.558 The basic work on thermal stability of human albumin was led by George Scatchard, more famous to most from the Scatchard plot as discussed earlier. In the irst study,559 Scatchard and others showed that the 25% solution of HSA was stable at pH 6.8 in 0.3 M NaCl for 16 h at 50°C and that storage in the cold was not an obligate requirement. The salt concentration was required for stability. In subsequent studies,560 Scatchard and coworkers built on studies561 by Ballou and coworkers who demonstrated stabilization of albumin by alkyl acids and nonpolar anions, such as N-acetyltryptophan, and developed a pasteurization process for albumin, obviating the earlier requirement for the addition of merthiolate for bacteriostasis. Boyer and Luck continued their studies at Stanford for a period after World War II on interaction of fatty acids and other organics,562–566 which led to studies such as that by Yu and Finlayson554 cited earlier providing strong scientiic support for the manufacture. Other researchers, including John Edsall, contributed to this understanding.567–569 Paul D. Boyer worked on the albumin project at Stanford University with J. Murray Luck. Boyer went onto UCLA for an illustrious career on enzyme chemistry, including winning the Nobel Prize in Chemistry in 1997; he was

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also a founder of the Molecular Biology Institute at UCLA. Luck stayed in Palo Alto and retired in 1965, having served on Stanford faculty since 1926. He is best known for starting the nonproit enterprise “Annual Reviews.” The point here, as with other individuals who worked on blood during World War II, is that these representatives of the “greatest generation” made outstanding contributions to the early biotechnology of blood and then moved onto incredibly distinguished careers in academia, all of which begs the question as to whether albumin is really a dull protein. Protein aggregation has been observed with albumin and is suggested to be due to proteins other than albumin.548,552 The inluence of proteins other than albumin on the stability of therapeutic preparations was, in fact, demonstrated in early studies on albumin by Scatchard and coworkers560 and more recently by Lin and coworkers.552 Lin and coworkers suggest that contamination of albumin with haptoglobin was responsible for the observed aggregation in albumin preparation. Lin and coworkers suggest that haptoglobin, being the less stable protein, aggregates and entraps albumin, which is present at a much higher concentration. Girard and coworkers570 used a variety of techniques to demonstrate heterogeneity in HSA used as an excipient for recombinant human growth hormone. Aggregation can be measured by gel permeation chromatography.571 There has been some recent work on the process of plasma albumin production. Johnston and coworkers572 used caprylate at a low pH to provide an additional viral inactivation step in the manufacture of albumin. This was based on the ability of unionized caprylate to disrupt the lipid membrane of enveloped viruses. More recent work has used proteomic technologies, such as 2-DIGE, for the characterization of albumin.573 There has been considerable activity directed toward the development of recombinant HSA in the past two decades.574–582 These studies have shown that recombinant albumin is safe and effective. On the positive side, the absence of glycosylation and other posttranslational modiications (see above) permits production in a variety of cells, including prokaryotic systems, which should allow for more eficient manufacture in large quantities. On the negative side, the drivers (pathogen issues) that resulted in the production of products, such as recombinant factor VIII (see Chapter 6), are not signiicant for plasma albumin because of the pasteurization step. In work cited earlier, there may be greater availability of Cys34, but it is not clear whether this quality is signiicant, as mercaptalbumin can be easily obtained from albumin isolated from blood plasma. Approved products include Delta’s Recombumin, which was originally marketed by Sanoi-Pasteur but currently a product of Novozymes. Recombinant albumin has also been developed in Japan.582,583 Recombinant HSA has been used as a biomaterial584 and has served as a cell culture additive.585 There has also been radiobiopharmaceutical application with labeling with 99mTc for lung perfusion imaging.586,587 In an approach that did not use recombinant HSA but was suitable for use with the recombinant protein, Hoppmann and coworkers588 did couple an HER2 Afibody analog to HSA (previously modiied with metal ion chelator [1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide]) using a bifunctional crosslinking agent. Preclinical studies suggest that the recombinant albumin is as effective as plasma albumin.589 While it is dificult to evaluate its potential use as a replacement for plasma HSA, there may well be a market for specialized products such as S-nitroso-albumin.252

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125

The manufacture of plasma-derived HSA is based on the alcohol fractionation scheme developed by Cohn (Chapter 2), which provides a precipitate fraction that is then dissolved and subjected to pasteurization. Recombinant HSA is puriied from yeast culture media by chromatographic techniques.574,590 Curling and colleagues591 developed an ion exchange method for the puriication of albumin from human plasma based on earlier work by Björling.592 There have been subsequent studies on the use of chromatography to obtain albumin of higher purity and/or to remove potential pathogens.593–596 One commercial product, Albumex, is produced by CSL Bioproducts using chromatography.597,598 Chromatography on histidyl-Sepharose 4B was used to separate glycated albumin from native albumin599 as well as chromatography on phenyl boronate columns.600 A phenyl boronate matrix is also used to capture glycated albumin for mass spectrometry.601 Kremer602 developed a method for isolated smaller quantities of HSA from plasma, which has been used for ligandbinding studies.603 As a inal note, albumin is sometimes referred to as a commodity when compared to other therapeutics, as albumin is in “competition” with other colloids and crystalloids for luid therapy. On the other hand, while not directly relevant to HSA, bovine albumin is considered too complex to be a commodity.604

BIOLOGICAL ACTIVITY OF ALBUMIN The aforementioned early work on albumin focused on its role in oncotic pressure (osmotic pressure, colloid osmotic pressure, which is one of the four Starling forces that affect net iltration from the capillaries).605,606 Thus, the clinical application of albumin as described earlier was driven, in part, by studies showing the effect of albumin on osmotic pressure. The drug-binding activity is described earlier as is the transport of fatty acids, redox activity, and a role in detoxiication, while the putative catalytic activity of albumin is described later. There is some reason to think that the transport function may be more critical than the oncotic function in certain clinical situations.607 There are some other observations on the biological activity, which, while not extensively described, should be mentioned. Wilkinson and McKay608 showed that native HSA does not elicit a chemotactic response in neutrophils, while acidiication (pH 2–4), reduction/carboxymethylation, or foam denaturation of HSA produced material that was chemotactic for neutrophils. More recently, Körmöczi and coworkers609 produced a modiied protein that binds to and stimulates neutrophils via oxidation of HSA by neutrophil-derived reactive oxygen intermediates (superoxide anion, hydrogen peroxide, and hydroxyl radical). Polzer and colleagues610 observed that HSA oxidized with hypochlorous acid binds to the GP120 proteins on HIV-1 variants blocking interaction with CD4. More recent work by Mera and cowokers611 showed that albumin from hemodialysis patients possessed decreased antioxidant activity and stimulated neutrophil oxidative burst. These researchers found an altered conformation for the oxidized HSA with increased exposure of hydrophobic amino acids. Jaisson and coworkers612 found that carbamylated HSA was an inhibitor of neutrophil oxidative burst. Lang and colleagues613 reported that albumin had anti-inlammatory effects that were not dependent on thiol content. In vitro studies with bovine aortic endothelial cells showed that HSA (70%– 85% oxidized with ~25% resistant to reduction with 2-mercaptoethanol or sodium

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borohydride) inhibited binding of neutrophil-derived myeloperoxidase and blocked the hypochlorous acid-mediated release of adenine. The binding of neutrophils to the endothelial cells was enhanced by hydroxyethyl starch. It should be noted that Powers and coworkers614 had earlier reported that 25% HSA modulated adhesive interaction between neutrophils and endothelium in a shock model. Collison and coworkers615 showed that glycated albumin (AGEs) bound to neutrophils with mixed consequences (inhibited transendothelial migration and Staphylococcus aureusinduced but not fMLP-induced production of reactive oxygen species). Binding of glycated albumin to neutrophils was blocked by antibodies to either receptor for advanced glycation end products (RAGE) or Nɛ-carboxymethylsine, an AGE in albumin.616 However, it is not clear that the ability of albumin to modulate inlammation is translated into clinical effectiveness.617 In work cited earlier, Wilkinson and McKay608 suggested that the exposure of hydrophobic regions was important in HSA stimulation of neutrophils. In subsequent work,618,619 Wilkinson and McKay observed that the modiication of HSA with hydrophobic derivatives increased chemotactic activity. Wilkinson later reviewed the importance of hydrophobic interactions in the nonspeciic stimulation of phagocytic cells.620

ENZYMATIC ACTIVITY OF ALBUMIN The enzymatic activity of albumin has been debated over the last 50 years or more since the paper by Tove in 1962621 describing the hydrolysis of β-naphthyl esters by BSA. The late Dr. Samuel Tove was a distinguished and lively member of the faculty at North Carolina State University for more than 35 years. Tove was also a careful researcher who could take advantage of laboratory observations. In the course of his studies on lipid metabolism, Tove observed the hydrolysis of β-naphthyl palmitate. The activity was lost on thermal denaturation (autoclave, 15 min, 120°C), and chromatography on DEAE-cellulose did not separate the hydrolytic activity from albumin protein. As Tove noted, there had been an observation on the relationship of plasma esterase activity and activity ascribed to albumin. Casida and Augustinsson622 had studied the reaction of 1-naphthyl-N-methylcarbamate (Sevin insecticide) with various animal plasmas and human plasma fractions. The reaction was followed by the release of 1-naphthol. Hydrolytic activity was observed with various human animal plasmas as well as with human plasma fraction V. These researchers also used other ester substrates, including p-nitrophenyl acetate. They concluded that albumin possessed intrinsic esterase activity. Chapuis and coworkers623 stated that the effect of serum albumin on the hydrolysis of p-nitrophenyl acetate was irst observed in 1951, but the citation to the source is not available. The work by Chapuis and colleagues623 suggested that the esterase activity of HSA preparations might be due to contamination with cholinesterase. The contaminant issue has been consistent over the years. The relationship of plasma esterase activity with enzymatic activity of albumin dates back, at least, to the work by Kunkel and Ward624 at the Rockefeller Institute for Medical Research in 1947. Patients with infectious hepatitis or cirrhosis showed defective function of plasma esterase (acetylcholine) that parallels changes in albumin concentration. Although administration of

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HSA increased plasma esterase activity in nephrotic patients, there was no effect on plasma esterase activity in cirrhotic patients until there was an improvement in liver function. These results were interpreted as albumin supplying a component important for liver function. One rather interesting part of this study was the use of diisopropyl phosphoroluoridate (intramuscular administration) to inhibit plasma esterase in cirrhotic, nephrotic, and normal individuals. This particular observation adds to the chemical lore of early albumin research. Before heat treatment was developed for albumin,121 merthiolate (thimersol and sodium ethylmercurithiosalicylate)625,626 was used in early albumin preparations.627 I also found mention of the use of azides to preserve biologicals (albumin) as a resource at the Library of Congress628 but could not determine the exact citation. As far as I could tell, there was a lack of adverse reactions to these materials. Much of the work on the enzymatic activity of albumin used p-nitrophenyl esters such as p-nitrophenyl acetate. p-Nitrophenyl acetate is an extremely sensitive substrate for a variety of enzymes with vastly different speciicity. While it is generally accepted that either BSA or HSA accelerates the rate of hydrolysis of p-nitrophenyl acetate, the question of its mechanism remains unanswered. There are studies on the reaction of p-nitrophenyl acetate with proteins, which can be useful. A paper from Brian Hartley’s laboratory at Cambridge is instructive for the evaluation of the work on the esterase activity of albumin. Hartley was a very bright protein chemist, who laid much of the foundation for modern scientists. Hartley and Kilby629 studied the reaction of p-nitrophenyl acetate with chymotrypsin, insulin, and some low-molecular-weight compounds. While chymotrypsin is a protease with speciicity for peptide bonds where the carboxyl group is contributed by an aromatic amino acid, such as tyrosine or phenylalanine, this enzyme as well as other proteases, such as thrombin, can catalyze the hydrolysis of p-nitrophenyl acetate.630,631 As demonstrated in these studies, the major site of hydrolysis occurs at the enzyme-active site and, depending on solvent conditions and the acyl group, a stable O-acyl derivative can be obtained. Hartley and Kilby629 observed that the reaction of chymotrypsin with diisopropyl phosphoroluoridate, which modiies the active-site serine with concomitant inactivation of the enzyme-catalyzed reaction with peptide, anilide, and many esterase substrates, results in a modiied protein, which still promotes the hydrolysis of p-nitrophenyl acetate. The native enzyme exhibited a “burst” of p-nitrophenol production, which is not observed with the inactivated chymotrypsin. Hartley and Kilby629 further observed that simple tyrosine-like compounds could stimulate the hydrolysis of p-nitrophenyl acetate as could insulin. It is suggested that the observed hydrolysis of p-nitrophenyl acetate by inactivated chymotrypsin, tyrosine derivatives, and insulin involves the participation of amino and phenolic groups. Park and coworkers at Vanderbilt showed that p-nitrophenyl acetate was a substrate for 3-phosphoglyceraldehyde dehydrogenase.632 This activity required a free sulfhydryl group but, unlike the dehydrogenase activity, it did not require the coenzyme NAD (DPN). Another observation that deserves consideration is provided by De Caro and coworkers,633 who reported that a peptide chain fragment (336–449) derived from porcine pancreatic lipase by chymotrypsin could catalyze the hydrolysis of p-nitrophenyl acetate. Small peptides containing histidine and cysteine (Z-His-Ala-Gly-Gly-Cys-NH2) or histidine, cysteine, and aspartic acid

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(Z-His-Ala-Asp-Gly-Cys-NH2) have been shown to demonstrate saturation kinetics in the hydrolysis of p-nitrophenyl acetate.634 These various observations suggest that there are a variety of mechanisms for a protein to accelerate the hydrolysis of p-nitrophenyl acetate. The issue of a contaminant being responsible for the observed activity of albumin was discussed by Tove in his 1962 paper,621 and Chapuis and coworkers623 ascribed the observed activity in albumin to contamination with cholinesterase. Cholinesterase activity is present in plasma635 and is found in the Cohn Fraction IV.636 There is current interest in butyrylcholinesterase,637–639 which is found in the Cohn Fraction IV-4.640 The relationship between the observed total cholinesterase activity and the butyrylcholinesterase activity in plasma is not clearly understood (Chapter 9). There is a suggestion of association of butyrylcholinesterase with albumin.641 According to this author, while cholinesterase activity may well be a contaminant of albumin preparations, the esterase activity observed by the various researchers is likely intrinsic to the albumin protein. The hydrolysis of p-nitrophenyl acetate by BSA (bovine mercaptalbumin; 0.86 mol sulfhydryl per mole of protein) was reported by Tildon and Ogilivie in 1972.642 They observed a “burst” reaction followed by a steady-state hydrolysis of p-nitrophenyl acetate. Analysis of BSA after the reaction showed the presence of O-acetyl groups (hydroxamic acid), and spectral (UV) analysis suggested the formation of O-acetyltyrosine. The data are consistent with the modiication of two tyrosine residues. Comparison of the rate of reaction of p-nitrophenyl acetate with tyrosine showed a 500-fold increase with BSA. The “burst” reaction was abolished when the BSA was treated with 8.0 M urea. Means and Bender643 reported that one site in HSA was acetylated quite rapidly by p-nitrophenyl acetate; the reaction was somewhat more rapid at alkaline pH after the removal of bound fatty acids. These researchers also observed inhibition of the reaction of p-nitrophenyl acetate with HSA by long-chain fatty acids (e.g., octanoate, myristate, and palmitate). Kurono and colleagues have also made an important series of contributions to our understanding of the reaction of p-nitrophenyl esters and other esters with HSA.644–650 A number of researchers also suggest that there is one strongly reactive site on HSA, which is located near Try411, that is involved in catalytic activity and also reacts with diisopropyl phosphoroluoridate and related organophosphorous compounds.651–660 p-Nitrophenyl acetate tends to a nonspeciic, highly reactive substrate for hydrolysis and, since albumin has multiple functional groups and the ability to bind organic compounds with some speciicity, it is not surprising that albumin can catalyze the hydrolysis of p-nitrophenyl acetate. It is more surprising that albumin does have enzymatic activity toward more complex low-molecular-weight compounds, implying enhanced speciicity. Rigg and Baird661 observed alkaline phosphatase activity in commercial preparations of HSA. These researchers, as others,633,641 did suggest that the observed activity might not be intrinsic to the albumin but an indication of an enzyme associated with the particular preparation of albumin. Elsbach and Pettis662 reported phospholipase A2 activity associated with albumin preparations; phospholipase activity in albumin was also reported by Singleton and Killian.663 Cha and Kim664 reported peroxidase activity in albumin, which was enhanced by either reduced glutathione or dithiothreitol; the activity was inhibited by iodoacetate. These

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researchers subsequently demonstrated the presence of thioredoxin-dependent lipid peroxidase activity in albumin.665 Yang and coworkers666 have reported the conversion of prostaglandin 15-keto-PGE2 to 15-keto-PGA2 and 15-keto PGB2 by albumin in reactions involving several basic amino acid residues. Sogorb and coworkers667 reported the hydrolysis of carbaryl (1-napthalene methylcarbamate; methyl carbamic acid 1-naphthyl ester) by rabbit albumin. The speciic activity of rabbit albumin (4.6 nmol/h/mg protein) is higher than that for human albumin (3.2 nmol/h/mg protein). A kcat of 7.1 × 10−5/s and a K M of 240 μM were obtained at pH 7.4 (37°C). The activity was strongly inhibited by fatty acids (caprylic acid) and fatty acid derivatives (p-nitrophenyl butyrate). This group later showed that albumin was a physiologically signiicant catalyst in the detoxiication of carbaryl668 and paraoxon.669 Another group670 has made the remarkable inding that BSA retains robust esterase activity (p-nitrophenyl palmitate) at 160°C. One group has reported the hydrolysis of RNA oligonucleotides.671–673 Jones and coworkers674 demonstrated intrinsic proteolytic activity in native and recombinant HSA preparations under reducing conditions. The proteolytic cleavage was speciic to cleavage at Arg18-Ala199 in synaptosomal-associated protein 25 (SNAP25).

CLINICAL USE OF ALBUMIN The clinical use of albumin can be separated into three different areas, two of which are related to similar biological properties, while the third is based on the availability of albumin in bulk. The irst is the original use of albumin as a plasma expander,36,675,676 which continues to the present day with perhaps more scrutiny.677–679 There is evidence for an increased use of albumin for clinical situations other than blood loss, but it is clear that there is continuing controversy over the use of albumin as a parenteral drug.680–683 The author is not a clinician and does not feel competent enough to comment on the ongoing use of albumin as a parenteral drug. There are several recent reviews, articles, and chapters on the clinical use of albumin.684–686 The second clinical application used albumin in an extracorporeal shunt in liver failure.687,688 This clinical approach is frequently referred to as “bridge to transplant.” 689 Liver failure presents a plethora of clinical problems, some of which are related to the failure of the liver to synthesize albumin, which can bind toxic materials. Riordan and colleagues690 separated extracorporeal liver support into two broad and somewhat overlapping categories. The term artiicial is used to describe a system that does not contain a biological component, while the term bioartiicial would describe a system that used hepatocytes in a bioreactor or liver tissue. Bañares and Catalina691 have summarized the various extracorporeal systems in an excellent review. The technical issue or clinical problem is the development of toxic materials in the circulation resulting from the failure of the liver and kidney to remove these toxic materials. Liver failure can also result in the development of hepatorenal disease,692 which adds an additional complication to the problem of in vivo blood puriication. It is possible to remove some of the toxic materials by dialysis, but substances such as bilirubin that are bound tightly to albumin are not readily removed by common renal dialysis methods,693 although there are some new, promising technologies

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such as plasma diailtration.694 Plotz and coworkers693 did develop albumin coupled to agarose as a method for the afinity removal of free and bound bilirubin from blood. In 1997, Kaplan and Epstein695 reviewed the various approaches to the management of this clinical situation, which are discussed later. While this article has an approximate date, consideration of this work and that cited earlier provided a background to the clinical and technical issues. Early attempts to address this problem used extracorporeal circulation using cadaveric liver696 or porcine liver.697 A more sophisticated approach has used isolated porcine hepatocytes698–701 and more recently, stem cells differentiating into hepatocytes.702 The use of porcine hepatocytes, while demonstrating considerable success, did have histocompatibility issues.701 Miki and coworkers702 showed that the use of 3D bioreactor technology was useful in promoting the differentiation of human stem cells into primary adult hepatocytes. HSA has been used in extracorporeal support devices, as this protein binds many toxins (vida infra), is relatively inexpensive, and is accepted by the regulatory community. The use of albumin was irst demonstrated for extracorporeal detoxiication by Etteldorf and coworkers in 1961703 and by Grollman and Odell in 1962704 using peritoneal dialysis. Falkenhagen and colleages developed plasma sorption as a combination of plasma iltration and plasma perfusion over an adsorbent as an approach to hepatic failure.705,706 Hemoperfusion is a technique that uses extracorporeal circulation through an adsorbent, such as ion exchange resin and charcoal.707 HSA has been used to coat the adsorbent material to improve biocompatibility.708,709 The current technical approach for albumin dialysis, which is described by Kaplan and Epstein695 as ingenious, is the molecular adsorbent recirculating system (MARS) described by Stange and coworkers in 1993.710 The system is based on a high lux dialysis system with an albumin circulating on the dialysate side. The retentate side of the dialysis membrane is impregnated with albumin. The principle is based on the selectivity of albumin on the dialysate side to remove both free and albumin-bound toxins on the retentate side. The albumin on the dialysate side circulates in a loop passing through a combination of ion exchange and charcoal columns to regenerate the albumin.711,712 The third area of application is the use of albumin as a tissue solder. Casein from milk and blood proteins have been used as adhesives713 in bonding wood and other materials.714 It is noted that bovine albumin is used with glutaraldehyde as a surgical adhesive and suture support,715 which is marketed as Bioglue.716,717 Bioglue has seen considerable clinical use in a variety of applications.718–724 The use of the bovine material has not been without complication, including one foreign body reaction.724 Tissue soldering or laser soldering is a wound closure technology that uses an exogenous macromolecule, usually a protein, as patch material or solder in sealing a wound. The use of protein solders dates back to 1988 with studies by Poppas and coworkers725 on urethral surgery. Subsequent work from another group established the value of including a dye to increase the sensitivity of the system.726,727 The classic deinition of a solder is a metallic alloy used for uniting metal surfaces or parts, while a patch is deined as a piece of material attached to something to repair a hole or a tear so as to strengthen or protect a weak area.728 Tissue soldering uses a protein that is “melted” to repair a lesion or strengthen a weak area. Tissue soldering has the advantage over laser

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welding in providing greater bond strength, lesser collateral tissue damage, and a wider parameter window for providing a satisfactory bond or seal.729 The tissue solder must establish an adhesive bond with tissue and cohesive bonds within the solder. Establishment of an appropriate balance between adhesion and cohesion is essential to the formation of a strong bond between opposing tissue surfaces. The primary requisite for a solder is the ability to form strong adhesive/cohesive bonds in response to laser irradiation or other thermal challenge. The observed physical effect of laser irradiation/heat is to denature or melt the protein. Protein denaturation can be deined as a physical, intramolecular change in the native protein structure.730 Denaturation is not a chemical change but a conformation change in the protein and is not associated with the cleavage of protein bonds. However, the use of the term, even in 1954, has become so broad as to obfuscate its value.731 Denaturation is not an irreversible process and, in fact, is used in the processing of recombinant proteins expressed as inclusion bodies in bacterial systems.732–735 Aggregation, the subsequent loss of solubility, and loss of biological activity are the most commonly observed manifestations of protein denaturation. Aggregation results from the exposure of aromatic amino acids/hydrophobic regions,736–739 which then interact with other proteins via hydrophobic interactions.740–744 Aggregation is the property of protein denaturation that is important in laser soldering. The key in laser soldering is the precise application of energy to denature the protein to produce a useful aggregate with suficient adhesive and cohesive properties.745 An issue, therefore, in the development of this technology is the measurement of “melting of the solder” with respect to the application of energy. Measurement of the physical changes such as aggregation or loss of activity is likely occurring too late in the “melting” process to be of value. The abundance of albumin as a material, combined with the extensive clinical experience as a parenteral drug, made it a reasonable choice for a solder material to be used in tissue welding. As noted elsewhere, blood has been used as glue in the wood industry with some success, and it is likely that the albumin content was responsible for the adhesive property.746 Albumin is also noted for its ability to interact with various dyes, and the binding of bromocresol green and bromocresol purple is used for the clinical assay of albumin.747 This is likely an advantage when dyes are included to improve energy transfer from lasers. The ability of albumin (or any protein) to serve as a tissue solder is based on the ability of the protein to “melt” on denaturation and subsequently congeal (aggregate). Differing from, for example, metals, proteins can aggregate without cooling. As such, you need a protein that will “melt” at a temperature that will not cause collateral tissue damage during the process of coaptation.748 The “melting” of albumin can be measured by DSC. The Tm for defatted (fatty acid–free) human albumin is approximately 65°C, and there are species differences in albumin thermal stability, with bovine albumin considered less stable (lower Tm).749,750 The binding of fatty acids to albumin increases thermal stability (higher Tm).751,752 The goal of tissue soldering or tissue welding is to establish a strong bond with satisfactory coaptation with acceptable collateral tissue damage. Reduction of thermal damage is a major part of this goal. Thus, the use of fatty acid–free albumin is highly desirable. Second, the use of a homogeneous product will produce a “tighter”

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Tm, which will allow more uniform heating/denaturation of the solder. Finally, the inclusion of a suitable dye in the solder permits lower energy input.753 Indocyanine green is the best example754 with an adsorption maximum of 805 nm and is used with diode laser (808 nm). Application of albumin solders to human clinical surgery has been limited to urology studies,755 which seem to have been successful. A particularly intriguing application has been the fabrication and use of stents using congealed albumin.756–758 In these studies, the 25% commercial human albumin is concentrated by ultrailtration to 50% and then further concentrated to yield a gel that can be fabricated into a structure. Another group has also developed an albumin stent referred to as Bioweld.759 Genipin is a cross-linking agent that has increased bond strength of albumin solder welds.760 Development of albumin solders continues.761

ALBUMIN AS DIAGNOSTIC/BIOMARKER HSA is modiied in vivo by a variety of environmental agents and drug metabolites. One example is the modiication of tyrosine and serine residues by organophosphorous compounds such as pesticides.350 HSA is also modiied by electrophilic agents derived from the metabolism of compounds, such as 1,3-butanediene364 and acetoaminophen.365 Modiication of HSA with HNE is suggested as a biomarker for systemic oxidative stress.338 Albumin is modiied by α,β-unsaturated aldehydes, such as crotonaldehyde derived from cigarette smoke.363 Albumin modiied by cyanide has been described earlier as a biomarker for cyanide exposure.322,323 The concentration of albumin in blood has been suggested as a biomarker for nutritional status but may be more relective of a disease state.762,763 Ischemia-modiied albumin is an albumin-derived biomarker of increasing interest. Ischemia-modiied albumin is deined as a defect in the binding of cobalt.764 Ischemia-modiied albumin is produced during myocardial ischemia and is considered to be a biomarker for that clinical condition.765 Following the development of ischemia-modiied albumin as a biochemical event and as a biomarker based on cobalt binding has been challenging. As far as the author could ascertain, a 1993 patent766 preceded the publication’s substance on ischemia-modiied albumin. Studies on the interaction of cobalt with albumin date back to studies with BSA by Rao and Lal767,768 in the 1950s. These researchers showed that modiication of lysine residues in BSA with methyl alcohol/HCl eliminated cobalt binding, while acetylation with acetic anhydride did not appear to affect binding. Nandedkar and colleagues769 showed that cobalt (Co2+) added to either human or rabbit plasma in vitro preferentially bound to albumin. These researchers subsequently demonstrated preferential binding in vivo using a rabbit model system.770 Lakusta and Sarkar771 studied the binding of Co2+ to tripeptide analogs to the amino terminus of HSA. Cobalt binding was studied as a model of zinc binding. These researchers reported that while Co2+ is a useful analog of Zn2+ binding to proteins, it is less useful with small peptides. The data did suggest that a histidyl residue and a carboxyl group were involved in the binding of zinc and cobalt to albumin. Trueba and coworkers772 observed a conformational change in BSA, with cobalt nitrate associated with binding to carboxyl groups. Later,773 Sadler and coworkers suggested the

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involvement of a lysine residue (Lys4) in addition to the N-terminal Asp-Ala-His sequence in binding Co2+. The formation of ischemia-modiied albumin has been suggested to involve modiication of the amino terminal sequence of HSA with reactive oxygen species,774 resulting in decreased binding of Co2+. Roy and coworkers775 showed that the hydroxyl radical (generated by the Fenton reaction) could modify albumin in human serum to form ischemia-modiied albumin. Ischemia-modiied albumin was not formed in serum with either hydrogen peroxide or superoxide. These researchers do not comment on the stability of ischemia-modiied albumin. It is clear that there is a narrow window (4–5 h) for the detection of ischemia-modiied albumin.775–778 It is not clear as to whether this suggests reversibility of modiication or rapid removal of the modiied albumin. Notwithstanding these issues, ischemia-modiied albumin has generated interest in the diagnosis of myocardial ischemia.778–784 However, there is evidence to suggest that the expression of ischemia-modiied albumin is somewhat nonspeciic, relecting other ischemic conditions and oxidative stress.785–791 A group of researchers from Genoa have identiied an oxidized form of albumin where Cys34 is converted to a sulfonic acid derivative in patients with focal glomerulosclerosis.792–795

PHARMACOKINETICS OF ALBUMIN A half-life of 15–20 days is commonly accepted for HSA.44–46,379,796–799 As with other proteins, chemical modiication can decrease half-life. Studies have shown that the oxidation of HSA by chloramine-T800 has a major effect on albumin, reducing binding of ligands, such as warfarin; there is also a shorter half-life for the oxidized proteins. Earlier studies by Berson and coworkers44 showed that “heavily iodinated” albumin was cleared somewhat more rapidly (t1/2, 10 days) than albumin with a lower degree of modiication (t1/2, 17 days). Gamsjäger and coworkers801 reported a half-life of 11.8 days for albumin in a retrospective study of more than 1400 intensive care unit patients. As discussed earlier, a substantial amount of albumin is outside the vascular space. Ding and coworkers802 observed a half-life of approximately 13 days (307 h) for albumin modiied with 5-aminoluorescein via triazine chemistry. Albumin dimer has been suggested to have lower vascular permeability than native HSA.803 An earlier study with an albumin dimer suggested a more rapid clearance.804 Albumin is also subject to renal clearance805 as well as to tubular reabsorption.806,807 Thus, the renal handling of albumin is a complex process808 that may relect albumin conformation.809 Clavant and Comper809 observed that a batch of tritiated BSA (tritium incorporated by reductive methylation810) showed accelerated renal clearance (fractional clearance determined with perfused rate kidney). 14C-Labeled rat serum albumin (reductive methylation with 14C-labeled formaldehyde811) has a lower fractional clearance. Heating at acid pH (70°C at pH 3) markedly reduced fractional clearance, while heating at basic pH (70°C at pH 12.5) increased fractional clearance. The acid expansion transition (N → F transition) described earlier could explain the reduced fractional clearance; the base treatment likely results in the rupture of the disulide bonds, resulting in the “extension” of the albumin molecule with an increase in lexibility. Rennke and Venkatachalan812 compared the clearance of

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dextran with that of horseradish peroxidase, both of which have a Stokes–Einstein radius of 2.85 nm. Dextran has a fractional clearance rate of 0.485, whereas the horseradish peroxidase has a fractional clearance of 0.068. These researchers suggest that shape and lexibility are important factors in glomerular iltration. It is not unreasonable, then, to speculate that the base-treated albumin in the Clavant studies809 has its structure disrupted by disulide bond cleavage and such a structure is more lexible than the native protein. Nevertheless, molecular size as expressed by Stokes–Einstein radius is considered a major factor in renal clearance but not the only factor.813 Lundström and coworkers814 showed that bikunin, which is similar in size to albumin (Stokes–Einstein radius of ~3.6 nm), has a fractional clearance rate some 80-fold higher than that of albumin. These authors argue that the increased lexibility of bikunin is responsible for the increased rate of clearance. Nephrotic syndrome is a kidney disorder815 characterized by high protein content in the urine (proteinuria816,817) and a decreased plasma protein concentration. Plasma albumin concentration in the circulation is markedly decreased in nephrotic syndrome.818–820 The value of 15–20 days is considerably longer than the half-lives of the various coagulation factors, which are of similar shape and size but similar to that of IgG. It is not surprising then that IgG and albumin share a protection receptor mechanism, in which the protein after endocytosis is not presented for lysosomal degradation but rather returned to the circulation.821–823 The processing of IgG seems a bit more complicated than that of albumin,824 and the function of the neonatal receptor is more diverse than just recycling.825 The role of the FcRn receptor in maternal transmission of immunoglobulin is an example of the complex function of the FcRn receptor. The comparatively long half-life has encouraged the use of albumin as a fusion partner for therapeutic use and has been discussed earlier. It is not clear if prolongation consistent with the recycling of albumin has been achieved. It seems more likely that, as with PEGylation,826 prolongation of half-life relects primarily decreased renal clearance, although decreased proteolysis by endogenous serum proteases may also be a factor.827,828

ANALYTICAL METHODS FOR ALBUMIN, INCLUDING USE OF ALBUMIN AS STANDARD FOR ANALYTICAL METHODS The measurement of albumin in serum or plasma can be accomplished by a variety of methods. The early approaches were based on the Tselius free-boundary electrophoretic system described in Chapter 3, as used by Longsworth and coworkers to determine the albumin/globulin ratio,829 and/or the differential solubility of the albumin fraction and globulin fraction of plasma.830–832 The albumin/globulin ratio was popular as a diagnostic tool.2,829,832 The albumin/globulin ratio is no longer used extensively in human medicine but is still of great interest in veterinary medicine.833–835 Current approaches to the measurement of albumin in plasma and serum use dye binding, immunonephelometry, immunoturbidity, radial immunodiffusion, and “dipstick.” 836,839 Point-of-care methodology has been developed for the measurement of albumin in urine.838,839 The clinical measurement of albumin in blood uses the spectral changes on the binding of bromcresol green or bromcresol purple.840 The relatively speciic binding

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of dyes by albumin in plasma and serum has been known for some time. It was possible to locate citations to work in the early part of the last century when albumin was used as a medium for printing. The development of dye-binding for the analysis of albumin in serum and urine has been reviewed by Peters1 and Doumas and Peters.840 Before the days of pH meters, which provide a value for the pH of the solution together with a personality analysis of the operator, pH in solution was measured with a series of dyes that underwent spectral changes at certain pH.841 Following an observation by Klotz and Walker842 observed that the presence of protein caused changes in the observed spectrum of dyes used for the measurement of pH; the spectrum of a dye in combination with a protein may differ in intensity (hyperchromic or hypochromic) and wavelength for maximum absorbance (red or bathochromic shift or blue or hypsochromic shift). This change in the absorbance characteristics of dyes bound to protein stimulated efforts over the next 20 years to make this method useful for the speciic measurement of albumin in serum, but it was not until the work of Doumas and coworkers that this resulted in the use of bromcresol green for the measurement of albumin.843 The use of bromcresol green for albumin measurement remains popular,844 and the binding reaction remains under study.845–847 Before moving on, it would be useful to spend some time on Irving Klotz. Klotz was one of the several giants of physical biochemistry in the period immediately following World War II. Professor Klotz spent his career at Northwestern University and made major contributions to our understanding of receptor–ligand interactions,848 providing a strong foundation for pharmaceuticals and biopharmaceuticals directed at cell surface receptors. Dye binding to albumin is used for purposes other than determination of albumin concentration. Carroll849 used a dye–albumin complex (Orange I-BSA) as a substrate for proteolytic enzymes. Tang and coworkers850 used albumin labeled with two different luorophores (lucifer yellow and rhodamine) as a substrate for proteases. Lucifer yellow luorescence was quenched by rhodamine; subtilisin reduced the luorescence-quenching transfer. A similar approach used relief of luorescence quenching of a luorophor-labeled albumin to visualize ibroblast cell migration in a hydrogel subject to proteolytic degradation.851 Most methods for the determination of protein concentration in solution require the use of a reference standard. The author has published a review on the methods for the determination of protein concentration,852 and it is clear that BSA is the reference standard of choice. It is best to purchase a standard solution of BSA; if a “homemade” standard is prepared, it should be validated by either absorbance at 280 nm or amino acid analysis such as for the clinical albumin standard.853,854 However, BSA as a standard is a generalization and may not be useful for all assays and all proteins855 with serious potential consequences for therapeutic proteins.856 BSA is used far more often than the human protein as a standard for the determination of protein concentration as well as for other analytical methods. Yang and coworkers used both BSA and ovalbumin as model proteins for the study of nitration,857 while Mortstedt and coworkers used BSA as a model protein for oxidation studies.858 A number of other researchers have used albumin as a model protein for the development of techniques involving mass spectrometry.859–863 In a study cited earlier,802 Ding and coworkers used HSA labeled with

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5-aminoluorescein to discriminate between brain tumor tissue and normal tissue for glioma surgery.

ALBUMIN AS EXCIPIENT Albumin, both of bovine and human origin, has a long history of being used to stabilize biologicals.864,865 There are few studies on any effect, other than stability, produced by the inclusion of HSA (or BSA) as an excipient/stabilizing agent. Zhi and coworkers at Roche866 showed that the presence of albumin did not affect the pharmacokinetics/bioequivalency of interferon α-2a in volunteer human subjects. Hawe and Friess867 observed that the inluence of excipients, including albumin on the freezing process, must be considered to avoid collapse and product stability problems during lyophilization. This is a useful study that employed DSC, cryomicroscopy, and powder x-ray diffraction to study the effect of excipients on the freezing process. In a later study,868 the same researchers observed that the positive effect of NaCl on the stabilization of a hydrophobic cytokine was due to an effect on HSA and subsequent overall stabilization of the product. In one interesting recent study, Warren and coworkers869 observed that progastrin-releasing peptide assay standards were far more stable in BSA pasteurized at pH 3.0 than at neutral pH.

CONCLUSION Albumin continues to be a protein with many facets remaining to be explored: • Further research is needed to ind out whether the binding of fatty acids is useful just for transport or whether there is a more sophisticated function in pathologies, such as metabolic syndrome.870,871 • The molecular basis for the development of ischemia-modiied albumin needs to be clariied. Regardless of speciicity, it is an interesting transition that might provide more information about oxidative stress and the binding of fatty acids. • The MARS system has the potential of serving as a viable “bridge-to-transplant,” which may be more critical with an aging population. • The potential of albumin as a drug carrier should be explored in more detail. There is considerable potential for the S-nitroso product and for albumin as a carrier of prodrugs.

REFERENCES 1. Peters, T., Jr., All About Albumin. Biochemistry, Genetics, and Medical Applications, Academic Press, San Diego, CA, 1996. 2. Sandor, G., Historical developments of the physicochemical and immunological methods of protein identiication and separation, in Serum Proteins in Health and Disease, Chapter 1, pp. 3–51, Williams & Wilkins, Baltimore, MD, 1966. 3. Index Medicus, Carnegie Institute of Washington, 1903. 4. Deeming, D.C., Double-yolked pheasant eggs provide an insight into the albumen secretion in bird eggs, Br. Poult. Sci. 52, 40–47, 2011.

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29. Ishimaru, T., Ito, K., Tanaka, M., et al., The role of the disulide bridge in the stability and structural integrity of ovalbumin evaluated by site-directed mutagenessis, Biosci. Biotechnol. Biochem. 75(3), 544–549, 2011. 30. Martos, G., Lopez-Exposito, I., Becharitiwon, R., et al., Mechanisms underlying differential food allergy response to heated egg, J. Allergy Clin. Immunol. 127(4), 990–997, 2011. 31. Lundblad, L.K., Rinaldi, L.M., Poynter, M.E., et al., Detrimental effects of albuterol on airway responsiveness requires airway inlammation and is independent of β-receptor afinity in murine models of asthma, Respir. Res. 12(1), 27, 2011. 32. Stensballe, A., Andersen, S., and Jensen, O.N., Characterization of phosphoproteins from electrophoretic gels by nanoscale Fe(III) afinity chromatography with off-line mass spectrometry analysis, Proteomics 1, 207–222, 2001. 33. Novotna, L., Hruby, M., Benes, M.J., and Kucerova, K., Immobilized metal afinity chromatography of phosphorylated proteins using high performance sorbents, Chromatographia 68, 381–386, 2008. 34. Bradshaw, R.A. and Peters, T., Jr., Amino acid sequence of peptide 1–24 of rat and human serum albumins, J. Biol. Chem. 244, 5582–5589, 1969. 35. Brown, J.R., Structural origins of mammalian albumin, Fed. Proc. 35, 2141–2144, 1976. 36. Heyl, J.T., Gibson 2nd, J.G., and Janeway, C.A., Studies on the plasma proteins. V. The effect of concentrated solutions of human and bovine serum albumin on blood volume after acute blood loss in man, J. Clin. Invest. 22, 763–773, 1943. 37. Blood Programs in World War II, ed. D.B. Kendrick, The Human and Bovine Albumin Programs, Chapter 12, Ofice of the Surgeon General, Department of the Army, United States Publishing Ofice, Washington, DC, 1964. 38. Andersen, D.C., Koch, C., Jensen, C.H., et al., High prevalence of human anti-bovine IgG antibodies as the major cause of false positive reactions n two-site immunoassays based on monoclonal antibodies, J. Immunoassay Immunochem. 25, 17–30, 2004. 39. Mogues, T., Li, J., Coburn, J., and Kuter, D.J., IgG antibodies against bovine serum albumin in humans—Their prevalence and response to exposure to bovine serum albumin, J. Immunol. Meth. 300, 1–11, 2005. 40. Moneret-Vautrin, A., Wal, J.M., Guillet-Rossof, F., et al., Bovine serum albumin immunization: A new risk of allergy during protocols for in vitro fertilization, Allergy 46, 228–234, 1991. 41. Linetsky, E., Kenyon, N., Li, H., et al., Increased immunogenicity of human vertebral body marrow after processing in bovine versus human serum albumin, Transplant. Proc. 29, 1960, 1997. 42. Mackensen, A., Dräger, R., Schlesier, M., et al., Presence of IgE antibodies to bovine serum albumin in a patient developing anaphylaxis after vaccination with human peptide-pulsed dendritic cells, Cancer Immunol. Immunother. 49, 152–156, 2000. 43. Pagán, J.A., Postigo, I., Rodriguez-Pacheco, J.R., et al., Bovine serum albumin contained in culture medium used in artiicial insemination is an important anaphylaxis risk factor, Fertil. Steril. 90, 2013.e17–2013.e19, 2008. 44. Berson, S.A., Yalow, R.S., Schreiber, S.S., and Post, J., Tracer experiments with I131 labeled serum albumin: Distribution and degradation studies, J. Clin. Invest. 32, 746– 768, 1953. 45. Rothschild, M.A., Bauman, A., Yalow, R.S., and Berson, S.A., Tissue distribution of I131 labeled human serum albumin following intravenous administration, J. Clin. Invest. 34, 1354–1358, 1955. 46. Bert, J.L., Pearce, R.H., and Mathieson, J.M., Concentration of plasma albumin in its accessible space in postmortem human dermis, Microvasc. Res. 32, 211–223, 1986. 47. Henriksen, J.H. and Schlichting, P., Increased extravasation and lymphatic return rate of albumin during diuretic treatment of ascites in patients with liver cirrhosis, Scand. J. Clin. Lab. Invest. 41, 589–599, 1981.

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862. Shin, S., Yang, H.J., and Kim, J., Effects of temperature on ultrasound-assisted tryptic protein digestion, Anal. Biochem. 414, 125–130, 2011. 863. Tanaka, N., Nagasaka, K., and Komatsu, Y., Selected reaction monitoring by linear iontrap mass spectrometry can effectively be applicable to simultaneous quantiication of multiple peptides, Biol. Pharm. Bull. 34, 135–141, 2011. 864. Edsall, G. and Wyman, L., Human serum albumin as a stabilizing agent for Schick toxin, Am. J. Public Health Nations Health 34, 365–367, 1943. 865. Levine, L., Ipsen, J., and McComb, J.A., Adult immunization—Preparation and evaluation of a combined luid tetanus and diptheria toxoid for adult use, Am. J. Hyg. 73, 20–35, 1961. 866. Zhi, J., Teller, S.B., Satoh, H., et al., Inluence of human serum albumin content in formulations on the bioequivalency of interferon α-2a given by subcutaneous injection in healthy male volunteers, J. Clin. Pharmacol. 35, 281–284, 1995. 867. Hawe, A. and Friess, W., Physiochemical characterization of the freezing behavior of mannitol–human serum albumin formulation, AAPS Pharm Sci. Tech. 7, 94, 2006. 868. Hawe, A. and Friess, W., Stabilization of a hydrophobic recombinant cytokine by human serum albumin, J. Pharmaceut. Sci. 96, 2987–2999, 2007. 869. Warren, D.J., Nordlund, M.S., and Paus, E., Formulation of immunoassay calibrators in pasteurized albumin can signiicantly enhance their durability, J. Immunol. Meth. 35, 145–147, 2010. 870. Weinberg, J.M., Lipotoxicity, Kidney Int. 70, 1560–1566, 2006. 871. Solbu, M.D., Jenssen, T.G., Eriksen, B.O., and Toft, I., Changes in insulin sensitivity, renal function, and markers of endothelial dysfunction in hypertension—The impact of microalbuminuria: A 13-year follow up study, Metabolism 58, 408–415, 2009. 872. Odhiambo, A., Perlman, D.H., Huang, H., et al., Identiication of oxidative posttranslational modiication of serum albumin in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension of sickle cell anemia, Rapid Commun. Mass Spectrom. 21, 2195–2203, 2007. 873. Matsuda, R., Anguizola, J., Joseph, K.S., and Hage, D.S., High-performance afinity chromatography and the analysis of drug interactions with modiied proteins: Binding of gliclazide with glycated human serum albumin, Anal. Bioanal. Chem. 401, 2811–2819, 2011. 874. Liggins, J. and Furth, A.J., Role of protein-bound carbonyl groups in the formation of advanced glycation endproducts, Biochim. Biophys. Acta 1361, 123–130, 1997. 875. Yatscoff, R.W., Tevaarwerk, G.J.M., and MacDonald, J.C., Quantiication of nonenzymatically glycated albumin and total serum protein by afinity chromatography, Clin. Chem. 303, 446–449, 1984. 876. Rohovec, J., Machmeyer, T., Alme, S., and Peters, J.A., The structure of the sugar residue in glycated human serum albumin and its molecular recognition by phenylboronate, Chem. Eur. J. 9, 2193–2199, 2003. 877. Watkins, N.G., Neglia-Fisher, C.I., Dyer, D.G., et al., Effect of phosphate on the kinetics and speciicity of glycation of proteins, J. Biol. Chem. 262, 7207–7212, 1987. 878. Stamler, J.S., Jaraki, O., Osborne, J., et al., Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin, Proc. Natl. Acad. Sci. USA 89, 7674– 7677, 1992. 879. Yang, Y. and Loscalzo, J., S-Nitrosoprotein formation and localization in endothelial cells, Proc. Natl. Acad. Sci. USA 102, 117–122, 2005. 880. Arteel, G.E., Briviba, K., and Sigs, H., Protection against peroxynitrite, FEBS Lett. 445, 226–230, 1999. 881. Dahm, C.C., Moore, K., and Murphy, M.P., Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite. Implications for the interaction of nitric oxide ith mitochondria, J. Biol. Chem. 281, 10056–10065, 2006.

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882. Tochinskii, I.M. and Metzer, D.M., in Sulfur in Proteins, The chemical properties of SH groups. Sulfhydryl Reagents, Chapter 1, pp. 3–71, Oxford/Pergammon, New York, NY, 1981. 883. Xu, G. and Chance, M.R., Radiolytic modiication of sulfur-containing amino acid residues in model peptides: Fundamental studies for protein footprinting, Anal. Chem. 77, 2437–2449, 2005. 884. Kettenhofen, N.J. and Wood, M.J., Formation, reactivity, and detection of protein sulfenic acids, Chem. Res. Toxicol. 23, 1633–1646, 2010. 885. Rehder, D.S. and Borges, C.R., Cysteine sulfenic acid as an intermediate in disulide bond formation and nonenzymatic protein folding, Biochemistry 49, 7748–7755, 2010. 886. Shaw, B.F., Schneider, G.E., Bilgicer, B., et al., Lysine acetylation can generate highly charged enzymes with increased resistance toward irreversible inactivation, Protein Sci. 17, 1446–1455, 2008. 887. Glocker, M.O., Borchers, C., Fiedler, W., et al., Molecular characterization of surface topology in protein tertiary structures by amino-acylation and mass spectrometric peptide mapping, Bioconjug. Chem. 5, 583–590, 1994. 888. Means, G.E., Reductive alkylation of amino groups, Meth. Enzymol. 47, 469–478, 1977. 889. Fenaille, F., Guy, P.A., and Tabet, J.-C., Study of protein modiication by 4-hydroxy2-nonenal and other short chain aldehydes analyzed by electrospray ionization tandem mass spectrometry, J. Am. Soc. Mass Spectrom. 14, 215–226, 2003. 890. Bucala, R. and Cerami, A., Characterization of antisera to the addition product formed by the nonenzymatic reaction of 16α-hydroxyestrone with albumin, Mol. Immunol. 20, 1289–1292, 1983. 891. Lohmann, W., Hayen, H., and Karst, U., Covalent protein modiication by reactive drug metabolites using online electrochemistry/liquid chromatography/mass spectrometry, Anal. Chem. 80, 9714–9719, 2008. 892. Shinar, E., Navok, T., and Chevion, M., The analogous mechanisms for enzymatic inactivation induced by ascorbate and superoxide in the presence of copper, J. Biol. Chem. 258, 14778–14783, 1983. 893. Zhu, B.Z., Antholine, W.E., and Frei, B., Thiourea protects against copper-induced oxidative damage by formation of a redox-inactive thiourea–copper complex, Free Radic. Biol. Med. 32, 1333–1338, 2002. 894. Liu, M., Hou, J., Huang, L., et al., Site-speciic proteomics approach for study of protein S-nitrosylation, Anal. Chem. 82, 7160–7168, 2010. 895. Landino, L.M., Koumas, M.T., Mason, C.E., and Alston, J.A., Ascorbic acid reduction of microtubule protein disulides and its relevance to protein S-nitrosylation assays, Biochem. Biophys. Res. Commun. 340, 347–352, 2006. 896. Giustarini, D., Dalle-Donne, I., Colombo, R., et al., Is ascorbate able to reduce disulide bridges? A cautionary note, Nitric Oxide 19, 252–258, 2008. 897. Gebicki, J.M., Nauser, T., Domazou, A., et al., Reduction of protein radicals by GSH and ascorbate: Potential biological signiicance, Amino Acids 39, 1131–1137, 2010. 898. Abello, N., Kerstjens, H.A., Postma, D.S., and Bischoff, R., Protein tyrosine nitration: Selectivity, physicochemical and biological consequences, denitration, and proteomics methods for the identiication of tyrosine-nitrated proteins, J. Proeome Res. 8, 3222– 3238, 2009. 899. Ogaswara, Y., Mukai, Y., Togawa, T., et al., Determination of plasma thiol bound to albumin using afinity chromatography and high-performance liquid chromatography with luorescence detection: Ratio of cysteinyl albumin as a possible biomarker of oxidative stress, J. Chromatogr. B 845, 157–163, 2007. 900. Sengupta, S., Webbe, C., Majors, A.K., et al., Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine–cysteine-mixed disulide and cystine in circulation, J. Biol. Chem. 276, 46896–46904, 2001.

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901. Li, Y., Yan, X.-P., Chen, C., et al., Human serum albumin-mercurial species interactions, J. Proteome Res. 6, 2277–2286, 2007. 902. Kirkman, C.R., Albertini, R.J., Sweeney, L.M., and Gagas, M.C., 1,3-Butanedione I. Review of metabolism and the implications to human health and assessment, Crit. Rev. Toxicol. 40, 1–11, 2010. 903. Natsch, A., Gfeller, H., Kuhn, F., et al., Chemical basis for the extreme skin sensitization potency of (E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one, Chem. Res. Toxicol. 23, 1913–1920, 2010. 904. Narazaki, R. and Otagiri, M., Covalent binding of a bucillamine derivative with albumin in sera from healthy subjects and patients with various diseases, Pharm. Res. 14, 351–354, 1997.

5

Plasma Immunoglobulins

It is necessary to have clarity on the deinitions when discussing immunoglobulins and their complex interactions in humoral immunology and cellular immunology. A list of deinitions as understood within the current work is given in Table 5.1. It is also useful to have a brief orientation to the several immunoglobulins found in human plasma and some of their characteristics (Table 5.2). Immunoglobulins comprise some one-third of the total plasma protein, with immunoglobulin G (IgG) as the major component.1 The readers are directed to several early reviews for a discussion on the history of gamma (γ)-globulins and the development of the current nomenclature.2–4 Figure 5.1 shows a schematic drawing of IgG, emphasizing more on the function than on the chemical structure. The IgG molecule can be divided into two important functional regions.5 The variable regions of the light chain and the heavy chain at the aminoterminal form a structure, which is recognized as the antigenic determinant or epitope; this structure is called the paratope. At the carboxyl terminal, the Fc domain binds various receptors that serve for transport across the epithelial surface or are present on the effector cells that are responsible for phagocytosis or antibody-dependent cell-mediated cytotoxicity. Limited proteolysis has been useful in the study of the structure and the function of immunoglobulins and, as described later, was used on early immune serum globulin (ISG) preparations to reduce adverse reactions. Papain or trypsin cleaves the IgG molecule above the hinge region, resulting in two Fab fragments, each of which contains the paratope that can bind the antigenic determinant; thus, Fab is monovalent. Pepsin cleaves the IgG below the hinge region, preserving the disulide bonds between the two heavy chains and thus yielding the bivalent F(ab)2′. These derivatives lack the heavy chain and therefore cannot interact with effector cells; they can neutralize pathogens (bacteriostatic) but cannot mobilize the cytotoxic mechanisms to destroy pathogens (bacteriocidal). Fab and F(ab)2′ fragments are useful for imaging tumors and for delivering chemotherapeutic agents to tumor sites. The F(ab)2′ material has been successfully used as a therapeutic product (Gamma-Venin) for 40 years. The F(ab)2′ product is also known as 5S intravenous immunoglobulin (IVIG) as a measure of its sedimentation constant and has a shorter half-life (approximately 2 days).6 The major commercial immune globulin is γ-globulin, better known as immunoglobulin G (IgG), which is available as an intramuscular immune globulin (IMG), as an IVIG, and, more recently, as a subcutaneous product (SCIG). Only small amounts of that product may be given by intramuscular injection, and this technique is limited to high-titer immune globulins.7,8 There has been only limited development of the members of immunoglobulin classes, other than IgG, as therapeutic products. There has been some interest in a therapeutic concentrate of immunoglobulin M (IgM).9,10 A humanized monoclonal IgM, panobacumab, has been evaluated for pharmacokinetics and safety in patients with Pseudomonas aeruginosa pneumonia.11

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TABLE 5.1 Immunology Definitions Term Active Immunization Antibody

Antigen

Antigenic Determinant

Anti-idiotypic Antibody

Autoantibody

Allogeneic Serum Autologous Serum

Bactericidal Bacteriostatic Biotherapy

Definition and Comment

References

The process of establishing immunity by vaccinating with an immunogen. A protein in the body that is either naturally occurring or elaborated in response to an antigenic stimulus that reacts with a speciic antigen. An antibody may be secreted in the blood or lymphatic luid. A substance that binds to an antibody or T-cell receptor. An antigen is frequently considered equivalent to an immunogen. Also known as epitope, it is a speciic structure in an immunogen that binds to a speciic antibody containing a paratope directed against that determinant/epitope. A determinant may be either conformation or linear in nature. A conformational determinant is based on the three-dimensional structure of the immunogen, while a linear determinant is based on a sequence of monomer units within a polymeric immunogen. A conformational determinant may also be known as a discontinuous epitope, while a linear determinant is also known a continuous epitope. A conformational epitope is frequently lost on the denaturation of a protein. An antibody directed against the idiotopes in a speciic antibody. Some interest has been evinced in the use of anti-idiotypic antibodies as vaccines. An antibody directed against the normal constituents of an organism; autoantibodies are responsible for autoimmune diseases. Serum obtained from a dissimilar individual of the same species. Serum obtained from the same individual (per Oxford Dictionary of English Language, 2004), although it is frequently used in place of homologue to indicate serum from the same species. Bacteria or pathogen destroyed (“killed”) frequently by phagocytosis. An agent that prevents bacteria or pathogen from reproducing. A term introduced to distinguish the use of biological substances, such as blood, serum, and tissue extracts, as therapeutics from chemical therapeutics. Currently, it is used to differentiate the use of biologics, such as monoclonal antibodies, from chemotherapy.

[406] [407]

[407]

[412–417]

[408–411]

[418–420]

[421–423] [424–426]

[427] [428–430] [407,431–433]

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TABLE 5.1 (Continued) Immunology Definitions Term Camelid

Cellular Immunology

Convalescent Serum Hapten

Heterologous Serum

Homologous Serum Humoral Immunology

Hyperimmune Globulin

Idiotope Idiotype Immunogen

Definition and Comment

References

A term used to describe a unique antibody protein found in the sera of members of the Camelidae family. This antibody lacks the light chain and has been expressed as a recombinant protein. Immunological phenomena based on the functions of cells of lymphoid tissues such as B lymphocytes and T lymphocytes in biological tissues and luids. Specialized cells in cellular immunology include dendritic cells and natural killer cells. It should be noted that the differentiation between cellular immunology and humoral immunology is somewhat artiicial. Convalescent serum is obtained from individuals recovering from speciic infectious diseases. A substance which, by itself, is an immunogen but can react with an antibody. A hapten, such as dinitrophenol, is immunogenic when combined with a protein. Serum usually obtained from different species (but reference was found using heterologous to distinguish from autologous serum). Serum obtained from the same species. Immunological reactions involving proteins, such as antibodies and lectins and other biological macromolecules, occurring in the various physiological luids. Hyperimmune globulins can be regarded as a current example of products developed from convalescent serum. Hyperimmune globulin preparations can be regarded as a puriied immunoglobulin product containing a high amount of antibody directed against a speciic pathogen. Starting plasma can be derived from convalescent individuals, donors screened for speciic immunoglobulin reactivity, or immunized individuals. Hyperimmune globulin preparations may also be achieved by the addition of humanized monoclonal antibodies to an immune globulin preparation. An epitope found (usually) within the variable region of an antibody. The collection of idiotopes found within a speciic antibody molecule. A substance that can react against components of cellular immunity (B cells and T cells) and also react with the products of the responses of cellular immunity. Immunogen structure/design is of considerable interest in vaccine development. It is also known as a complete antigen.

[434–436]

[64]

[437–439] [440,441]

[442,443]

[444] [445]

[142,295,446]

[407,447] [407–409] [412,448–450]

(continued)

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TABLE 5.1 (Continued) Immunology Definitions Term

Definition and Comment

References

Immunogenic

The property of being an immunogen.

Immune Globulin

A generic name given to preparations of IgG that are derived from plasma. Such preparations may be intravenous immune globulins (IVIG) or intramuscular immunoglobulins. There was early oral administration of immune globulins.

Immunity

The mechanism(s) by which an organism is enabled to resist disease.

Immunology

The study of immunity.

Immunomodulation

The modiication of the immune response; used most frequently in cancer therapeutics but does have a broader range of applications.

[407,454,455]

Immunotherapy

Immunotherapy is a term originally used to describe the use of active or passive immunization and was later modiied to include any therapeutic approach to the suppression or enhancement of the immune system, including the use of cells, genes, and gene products including proteins and microRNA products.

[407,456–460]

Intramuscular Immune Globulin

A therapeutic preparation of plasma immune globulins (γ-globulins) given by intramuscular injection. Early problems with intravenous use of immune globulins made intramuscular injection the preferred route of administration. While intramuscular injection has been largely supplanted by intravenous methods, intramuscular can be an effective strategy.

[461,462]

Intravenous Immune Globulin (IVIG)

A therapeutic preparation of plasma immune globulin (γ-globulins) administered directly into the venous circulation (parenteral drug). These preparations were not readily available until some 30 years after the irst use of immune globulins.

[138,463–466]

Immunization

The process of establishing immunity.

Monoreactive Antibody

An antibody that reacts with a single antigen/epitope.

Passive Immunization

The process of establishing immunity by the transfer of antibody from the donor to the recipient. In the case of IVIG, there are many donors.

[471–473]

Paratope

The structure within the Fab portion of an immunoglobulin that recognizes a speciic epitope on an immunogen. An antibody that can react with more than one antigen. A polyreactive antibody is not to be confused with a polyclonal antibody/polyclonal antibody product. A monoclonal antibody may be polyreactive.

[474,475]

Polyreactive antibody

[407,451,452] [24,453]

[407] [407]

[467] [238,468–470]

[476–478]

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TABLE 5.1 (Continued) Immunology Definitions Term Reagin

Serum

Serum Therapy

a

Definition and Comment

References

Reagin is a term used originally to describe all antibodies and was later restricted to describe antibodies in allergic and hypersensitivity reactions; it has been largely supplanted by the term IgE to describe these antibodies. Reagin is still used to describe a speciic antibody in syphilis. The fluid obtained after the clotting of blood. Serum is not plasma; plasma is obtained from blood most frequently after the collection of whole blood in an anticoagulant such as citrate or heparin. Serum has a slightly lower protein concentration than plasma, and the two materials should not be confused with each other. That said, it is essential to go to the original study to make sure that serum is not confused with plasma. The use of serum as a vehicle for passive immunization. Convalescent serum was preferred for serum therapy.a

[407,479–481]

[485,486]

[482–484]

The term serum therapy has been used more recently to describe the use of autologous serum or umbilical cord serum for the treatment of various corneal problems.487–489

An IgM-enriched immunoglobulin has been suggested to be useful in Gram-negative sepsis.12 Bovine milk has been suggested as a source of immunoglobulin A (IgA).13,14 Immunoglobulin E (IgE) is also known as the reaginic antibody4 and is a therapeutic target,15 although engineered antibodies of IgE class have therapeutic potential.16 There are two therapeutic concepts driving the use of native and recombinant immunoglobulins. The irst is passive immunization, which is the transfer of immunity from a donor to a recipient, and it is considered as an approach to neutralize viral and microbial pathogens. The second is immunomodulation or immunotherapy, where therapeutic immunoglobulins modulate cellular immunity inluencing pathologies, such as inlammatory neuropathies. This separation of therapeutic concepts is based more on the history and is somewhat artiicial, as it proves most dificult to separate the immunomodulation effects from the antipathogen effects in passive immunization.17 Passive immunization, also known earlier as passive acquired immunity, is achieved by the transfer of an immunoglobulin from a donor to a recipient; in the case of IVIG, there are many donors. Active immunization, also known as active acquired immunity, is achieved by vaccination with a suitable immunogen. Passive immunization was also known as serum therapy, as early work used both homologous and heterologous sera. Though there were adverse reactions, such as serum sickness, these therapeutic approaches were quite useful. The readers are directed to several sources

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Biotechnology of Plasma Proteins

TABLE 5.2 Immunoglobulins Found in Human Plasmaa MWb (kDa)

t1/2 (Days)

(mg/dL)c,d

Comment

IgG

150

24

700–1600e

The most common immunoglobulin in plasma. Major function is protecting against pathogens and facilitating opsonization of viral and bacterial pathogens.f The action can be either bacteriostatic or bacteriocidal or both. IgG in plasma comprises various subclasses: IgG1, IgG2, IgG3, and IgG4. These subclasses have various characteristics. IgG1 is the major subclass with somewhat less IgG2; there are relatively small amounts of IgG3 and IgG4. It comprises 80+% plasma immunoglobulin.

IgA

160

6

70–400

It provides protection against pathogens, primarily viral or bacterial,f with emphasis on mucosal secretion (mucosal immunity). Subclasses IgA1, IgA2. The plasma form is a monomer, while the mucosal secretory product is a dimer or tetramer with an associated J chain of molecular mass of 15 kDa containing one N-linked glycan. More IgA is synthesized per day than IgG, but approximately one-half is catabolized in the liver and the remainder is transported to external secretion.

IgM

900

5

30–360

IgD

190

2.8g

N/A

It provides early protectionf against pathogens; a polymeric form (pentamer; closed ring including ive IgG and a J chain) of IgG, it is considered to be an early immunoglobulin with function linked to IgD; IgM may be the most ancient of the immunoglobulins. As with IgA, there is a secretory form of unknown function. Though the precise function is not known, increasing evidence suggests (1) relationship with IgM and (2) important in immunomodulation. Phylogenetic research suggests that IgD is an early immunoglobulin like IgM.

Immunoglobulin

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Plasma Immunoglobulins

TABLE 5.2 (Continued) Immunoglobulins Found in Human Plasmaa Immunoglobulin IgE

a b c d e f

g

MWb (kDa)

t1/2 (Days)

(mg/dL)c,d

175

2.4g

N/A

Comment Associated with mast cells, this is responsible for allergic responses such as hypersensitivity and anaphylaxis.

The material in this table has been adapted from several sources including.490–497 Approximate values. Concentration in plasma (reference interval). Adult values given. Further data on IgG subclass values can be obtained from.498 Resistance is frequently used to describe the innate ability of an organism to neutralize (resist) a pathogen or toxin produced in a disease (adapted from499). The above resistance refers to the ability of an immunoglobulin to neutralize (bacteriostatic) or kill (bacteriocidal) pathogens or toxins. From Salonen et al.500

that review the early work on passive immunization.18–21 A puriied immune globulin, ISG,22 was developed as part of the Cohn fractionation process for human plasma during World War II.23 ISG was considered a by-product of the fractionation process, as the goal was to produce albumin.23 There were some early clinical studies using this material, most notably on the prophylaxis and prevention of measles.24,25 General Kendrick’s book on blood programs during World War II23 is very interesting and the lessons learned are still as valuable as they were some 50 years ago. Initially, the ISG preparations derived from human plasma were of limited use, as there were signiicant adverse reactions from early intravenous use, which in turn limited the intramuscular administration of ISG. There was also limited understanding of the market for polyvalent ISGs, as primary immune deiciency was described only in 1952.26–28 Early studies on the stability of ISG prepared by the Cohn fractionation process demonstrated fragmentation on storage.29,30 This fragmentation, which resulted in the reduction of anticomplement activity, was attributed to the presence of plasmin in the ISG preparation; the anticomplement activity had been suggested to be responsible for the adverse reactions associated with the parenteral use of the ISG.31 Barandun and coworkers31 reviewed the various approaches developed to reduce the anticomplement activity of ISG. The use of pepsin or plasmin resulted in derivatives with reduced or no anticomplement activity while retaining the ability to form complexes with antigens. An immunoglobulin fraction treated with pepsin did have a markedly reduced half-life (10–14 hours)32 and loss of Fc function (see Figure 5.1), while an immunoglobulin preparation treated with plasmin had a longer half-life (18–20 days)32 with a variable retention of Fc function.33 Exposure to low pH (pH 4.0) had a variable effect on the anticomplement activity but did retain full Fc function. Milt Mozen and colleagues at Cutter in Berkeley34 subjected an ISG to limited reduction with dithiothreitol followed by carboxyamidomethylation with the

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Biotechnology of Plasma Proteins

Fab fragment Fab 2 Hinge Fc

+ Fc fragments

3

1

IgG Mild reduction F(ab)′2

SH SH Fab′

FIGURE 5.1 A schematic presentation of IgG and its derivatives. The IgG molecule is a homodimer of a heterodimer; only a single chain is shown to represent the heterodimer unit. The IgG molecule is divided into two major functional domains: the Fab region, which contains the paratope that recognizes the antigen (epitope), and the Fc domain, which binds to speciic receptors (Fc receptors) on target cells such as macrophages.5,519 The primary site of glycosylation of IgG is in the Fc domain (1); only a single site is shown in this igure, but glycosylation occurs on the heavy chain in both of the heterodimers. Glycosylation can occur in the Fab region but is considered unusual. It is also possible to have glycosylation only on one heavy chain in an Fc fragment. Papain (2) cleaves IgG above the “hinge” region to yield Fab fragment, which is a monomer of a heterodimer fragment, which is monovalent in binding antigen.520 Pepsin (3) cleaves IgG below the “hinge” region to yield the F(ab)′2 fragment, which is a dimer of the heterodimer Fab; the Fab′ monomer can be obtained from F(ab)′2 by mild reduction.521 Cleavage of IgG similar to that observed with pepsis can be obtained with matrix metalloproteinases and may be important for IgG function in the extravascular space.522 This illustration does not consider the issue of immunoglobulin subtypes.523

reduction of anticomplement activity and retention of Fc function. The problem was resolved through the development and implementation of changes in the manufacturing strategies,27,35 resulting in the current IVIG products.36,37 IVIG is deined as a sterile preparation of immunoglobulins prepared from human plasma. The 2004 edition of the British Pharmacopoeia38 deines human normal immunoglobulin as “a liquid or freeze-dried preparation containing immunoglobulins, mostly IgG … prepared from pooled material from not fewer than 1000 donors.” The use of a larger pool (10,000–40,000 donors) is suggested by other workers.39 The larger the pool, the more diverse is the antibody population. The current IVIG products40 are approved for use in the treatment of primary immune deiciencies, prevention of cytomegalovirus infection after bone marrow transplantation, prevention of hepatitis B infection after liver transplantation,41–45 and treatment of selected secondary immune deiciencies.46,47 However, the off-label use of IVIG is extensive.47–49 Darabi and coworkers50 reviewed the use of IVIG at Massachusetts

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191

General Hospital for the calendar year 2004. The major use was for chronic neuropathy treatment, with considerably less use for primary immune deiciency (primary hypogammaglobulinemia) treatment. This poses a problem, as supporting documentation for such off-label use is not always available.49–55 Studies with careful clinical end points do show the effectiveness of IVIG in chronic inlammatory demyelinating polyradiculoneuropathy (CIDP),56 and there is ongoing work on the development of molecular markers (biomarkers) to measure therapeutic responses.57 Unsworth and Wallington58 discuss the risk of IVIG use, suggesting restricted use to those applications where there is evidence-based effectiveness. The off-label use of IVIG is further complicated by possible differences between various commercial preparations of IVIG.59–63 The use of IVIG in immunomodulation is discussed later, although it is dificult to separate the humoral activity of IVIG from its activity in cellular immunology.40,64 The ability of antibodies to neutralize and destroy pathogens, such as bacteria and viruses (humoral activity), is the better understood function of IVIG—the application in infectious diseases. However, even the application of IVIG in infectious diseases is quite complicated beyond bacteriostatic and bactericidal activities.40 There is a solid technology that does make it possible to identify the antibodies in an IVIG preparation that react with speciic pathogens as well as establish the integrity of the Fc domain necessary for phagocytosis. IVIG products from different manufacturers (and hence potentially different manufacturing processes) exhibit differences in activity against some pathogens.65–70 These differences appear to be based on the fractionation process rather than the geographical source, as Matejtschuk and coworkers70 evaluated an IVIG product (Vigam) prepared either from plasma sourced in the United States or plasma sourced in the United Kingdom; the difference then was based on the geographical source rather than on the manufacturing process. The products were evaluated for composition (e.g., aggregates, monomer, dimer, IgG class, etc.) and reactivity against various viral and bacterial pathogens. There were modest differences between the U.S. product and the U.K. product; however, as the authors note, with large enough donor pools, there should be no differences in eficacy on the basis of the geographical source of the plasma. That is not to say that there is no potential for a difference in the quality of the IgG, resulting from the geographical source, and it is possible to make advantageous use of such a difference in the development of a therapeutic product. In the case of H1N1 virus, the use of plasma (convalescent plasma) obtained from the pandemic sites permitted the manufacture of a hyperimmune product.71–73 Changes in donor population, vaccination policies, and a decrease in a speciic disease prevalence can affect the quality attributes of the donor plasma pool, which in turn will affect the product attributes.74,75 Additional discussion on the use of IVIG in passive immunization is presented later. The manufacture of IVIG by necessity (large number of donors) starts with a large volume of plasma (500–2500 L, depending on the capacity of the manufacturing facility), and the crude starting material for actual manufacturing (e.g., the Cohn Fraction II + III) is obtained from the starting plasma after a prior separation step, such as cryoprecipitation.76,77 The cryoprecipitation step is essential and is equivalent to the original Cohn I step.37 An alcohol precipitation step is then used to obtain a protein fraction equivalent to Cohn II + Cohn III (see Chapter 2). The supernatant

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fraction from this step is taken on for the preparation of Cohn IV (source of antithrombin, α1-antitrypsin, factor IX) and Cohn V (source of albumin and plasma protein fraction). The crude immunoglobulin (II + III paste) can be either taken on directly for the manufacture of IVIG or stored frozen for subsequent use. At least four physical and/or chemical environmental transitions to the IgG molecule have occurred, prior to the speciic IVIG-manufacturing steps: irst, divalent cations are removed by an anticoagulant; second, the plasma is frozen; third, the plasma is allowed to slowly thaw into the cryoprecipitate slurry; and fourth, the plasma is precipitated with alcohol (20%–25% by volume, approximately 4 M) at pH 5.2 (−5°C). If the precipitate is frozen subsequent to processing, there is a ifth challenge to the protein. This is followed by solubilization of the paste and various fractionation steps, leading to the equivalent of an active pharmaceutical ingredient (API), which is then formulated to yield a inal drug product, which might be a liquid or a lyophilized solid.78–80 For a protein, this is the equivalent of being a lineman/ linebacker in American football for a number of years; as this is the author’s experience, he can attest to the fact that it is mostly functional but never quite the same as the original. The effect of alcohol on plasma proteins is discussed in Chapter 7, with speciic reference to the formation of latent forms of protein protease inhibitors. A consideration of the literature reveals little information on the effect of alcohol and/or freeze/ thaw cycles on immunoglobulin structure/function. Successive freeze/thaw cycles do promote aggregation.81–85 Recent studies by St-Amour and coworkers86 suggest that the conditions of alcohol fractionation (30% ethanol) can “activate” the cryptic autoreactive IgG present in the starting plasma; low pH (20,000 kDa (40 monomer units).431 There is a distribution of vWF multimers in plasma over this molecular weight range, which can be visualized with agarose cell electrohoresis.432–435 The synthesis of vWF is observed in endothelial cells and megakaryocytes; it is stored in the Weibel–Palade bodies in the endothelial cells and in α-granules in the platelets and is found in plasma and in the extracellular matrix.436 There are some small structural differences in platelet vWF and plasma vWF,437,438 but such differences do not appear to affect the function of either vWF in primary hemostasis.438 vWF is processed by a metalloprotein, ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin-like domains-13).439–442 Very large vWF multimers are found in the deiciency of ADAMTS-13, resulting in thrombotic thrombocytopenic purpura.443–448 The potential of a recombinant ADAMTS-13 for the treatment of thrombotic thrombocytopenic purpura is being considered.448–451 The incidence rate of thrombotic thrombocytopenic purpura has been determined;452 such information will help determine the feasibility of product development. von Willebrand’s disease (vWD), the absence of normal vWF function, was described by Erik von Willebrand early in the last century, but it was a complicated journey from the early clinical observations to the deinition of syndrome.453 vWD is heterogeneous on presentation, with bleeding ranging from mild to severe and difference in multimer distributions.410,454 Type I is a partial deiciency with modest clinical issues, and Type III is a total deiciency with severe consequences. Type II vWF is characterized by a loss of high-molecular-weight multimers. The short note by Marques and Fritsma454 is an excellent review of everything that most people ever need to know about vWD. The identiication and diagnosis of

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vWD have been a challenge for many years.455–459 Additional complication is provided by potential artifacts resulting from sample processing. Böhm and coworkers460 have observed a cold-induced loss of vWF in citrated whole blood and suggested that the loss of high-molecular-weight multimers may be the relection of vWF binding to glycoprotein Ib on the platelets. vWD is the most common of the various hemorrhagic diatheses, with an incidence ranging between 0.1% and 2%.454,461 The most severe form of vWD, type III, is quite rare. It is possible to use some of the low-purity factor VIII concentrates and cryoprecipitate to treat vWD, but a plasma product is available 462–466 and a recombinant product is in development.467–469 Given the relatively small number of type III vWD patients and the availability of established plasma-derived therapeutic products, it may be dificult to establish a business strategy for the recombinant product. It is possible to treat vWD with desmopressin (DDAVP; 1-desamino-8-D-arginine vasopressin),470–472 and it is also useful for diagnosis.473

ECONOMIC ISSUES IMPACTING THE HEMOPHILIA BUSINESS The factor VIII “business” is a mature business, and with an increasing number of providers with essentially functionally similar recombinant products, it can be suggested that the market will move more toward a commodity rather than toward a specialty product. With an increased number of providers, it is unlikely that the availability/pricing behavior suggested for recombinant factor VIII in 1994474 is possible now. Here, it was suggested that providers of recombinant products were not interested in supplying the lower-cost plasma-derived products for HIV-infected individuals even when this cohort might not beneit from the recombinant product. Evaluation of the factor VIII business is of critical importance in determining the investment in the development of new therapeutic products. This is of particular importance in the current medical landscape. Regardless of geography and/or national health policy, there is a limit to the amount of resources available to support health care.475 I commend Iserson’s paper475 that was published in 1992; it is obvious that we have not learned much in the past 20 years, as we face the same problems of resource allocation even today. The care for hemophilia must it into a larger program for health-care delivery and be subject to the same evolving trends represented by evidence-based medicine476 for decisions on therapeutic approaches. Hemophilia is an expensive disease both in inancial477 and human resources.478,479 The issue of the cost of factor VIII products477 has been a matter of concern for at least 40 years480,481 and interest in this issue has only increased with the advent of more sophisticated products. Between 1972/73 when Green480 and Lazerson481 published their observations and 1995, ultrahigh-purity and recombinant factor VIII concentrates (Table 6.1) became available at a much higher cost. Nauenberg and Sullivan474 reported that the annual cost of factor VIII therapy increased from $10,000 to $60,000 in 1991. It is argued (accurately) that these materials provided a much better QoL for the hemophiliac.482 In 1995, Tuddenham and Laffan483 asked the question as to whether the more advanced therapeutic products (which at that time contained

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albumin as an excipient*) provided suficient advantage to justify increased cost. It is noted that since that time there is a more advanced factor VIII product, which was manufactured and formulated in the absence of exogenous albumin.†,484 The development of factor VIII therapeutics beyond the ultrapure plasma-derived products is driven by safety considerations based on potential viral contamination.483 There has been no documented transmission of HIV by a factor VIII concentrate for at least 20 years,‡,482,485 and current methods for screening blood donations have markedly reduced the risk of known pathogen transmission.486 While recombinant products would presumably provide zero-risk of pathogen transmission,482 it is dificult to establish the true cost-effectiveness of the ultrahigh-purity/recombinant products.487 Hay and coworkers487 do emphasize the importance of “personalized medicine” in treatment decisions. The issue of safety is confounded by other issues such as inhibitor development, which is discussed next. The economics of hemophilia care are somewhat complicated by discussions on the value of prophylaxis versus on-demand,488,489 with most recent data supporting the cost-effectiveness of prophylaxis.490 The paper by Brown and Aledort488 was a meeting report discussing methods for assessing the impact of various treatment regimens in hemophilia and the use of QoL metrics to measure effectiveness. Incorporation of QoL and pharmacoeconomic considerations will be required in the design of future clinical trials. While viral safety is the most visible issue, development of inhibitors is also of importance in assessing product safety.491 Gringeri491 discussed the continuing question as to whether there is increased inhibitor formation with recombinant factor VIII products. Immunogenicity is a problem with most protein biopharmaceuticals and can result from formulation.492–496 Patients view viral safety as the most important product attribute, but inhibitor development is also a strong consideration.497 An earlier study,498 which involved patients, providers, and pharmacists, provided a more complex picture that varied with the extent of the disease (moderate vs. severe). Recombinant factor VIII is the product of choice in developed countries§ with the potential of plasma-derived products available in other geographies.499–503 It is not clear that all geographies will produce the three major plasma products—albumin, factor VIII, and IVIG—and it is also clear that there are restraints on full self-suficiency.504 This short section on economics and factor VIII has not mentioned gene therapy. Pasturized plasma-derived human albumin is considered to be a safe product continually being evaluated (Chapter 4).544,545 † Notwithstanding Veder’s question as to whether factor VIII is a protein,116 factor VIII, plasma-derived or recombinant, is a protein, and a therapeutic containing factor VIII contains protein. ‡ The risk of hepatitis B transmission via blood transfusion in the United States is estimated to be approximately 1 in 300,000, and for both hepatitis C and HIV, transmission risk is greater than 1 in 1 million.486 Notwithstanding these impressive numbers, there is a perception that suficient risk still exists (risk is discussed in Chapter 2) and there is substantial ongoing work to approach zero risk.546–549 § Financial pressures on allocation of health-care resources do have an impact on products used in a given geography, but there is pressure to provide the recombinant products.535 Geographies where there is interest in plasma-derived therapeutic products other than factor VIII such as IVIG likely wish to have national self-suficiency, and it may be dificult to rationalize the use of recombinant factor VIII. For a general discussion.536 However, this was some time ago, and it is clear from the work in India, Brazil, and Iran that the developing world is moving into the plasma business (see Chapter 2). *

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This is, in part, a relection of the author’s skepticism and the dificulties in achieving a reasonable business model.55 However, to be fair, it is clear that full achievement of gene therapy would provide a solution to the problem of treating hemophilia on a global basis.505

CONCLUSIONS AND FUTURE DIRECTIONS* • A continued increase in the number of suppliers has the potential to describe factor VIII as a commodity product such as albumin. The same argument cannot be made for IVIG, relecting the large number of existing and potential indications. • It is unlikely that a modiication of factor VIII, for example, with poly(ethylene) glycol, is likely to provide a useful product. • It is unlikely that a factor VIII mimetic can be developed that would be competitive with existing factor VIII products. • Without a quantum leap in tissue-speciic vector delivery, it is unlikely that gene therapy will be successful. • Genotyping of previously untreated hemophilia A patients506–508 is critical to solving the factor VIII inhibitor problems. • Advances in the formulation for factor VIII products to function outside the “cold chain” are essential for use in many developing geographies. • Emphasis should be placed on drug delivery methods and devices to achieve the full promise of prophylaxis. While considerably more work is required, it is possible that the use of prophylaxis recommended for factor VIII inhibitor patients509 may reduce inhibitor development.510 Prophylaxis is demonstrated to be more effective than on-demand therapy.490 • Oral delivery of potentially hemostatic agents requires further investigation. The results obtained in the 1930s158,162 are solid and should not be disregarded simply on the basis of less-sophisticated analytical technologies.

REFERENCES 1. Haberichter, S.L., Jacobi, P., and Montgomery, R.R., Critical independent regions in VWF propeptide and mature VWF that enable VWF storage, Blood 101, 1384–1391, 2003. 2. Dong, J.-F., Moake, J.L., Nolasco, L., et al., ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under lowing conditions, Blood 100, 4033–4039, 2002. *

This discussion is concerned only with factor VIII. The deiciency of factor IX, hemophilia B, is discussed in Chapter 8. The hemophilia B business is not as large as hemophilia A as there are far fewer deicient individuals. Nevertheless, there are a number of “players” in the hemophilia B business and more players are considering entering the business. Factor IX is less complex than factor VIII, and gene therapy for hemophilia B has been somewhat more successful than that for hemophilia A. vWF deiciency is also a much smaller business opportunity than hemophilia A, and a number of therapeutic opportunities exist for a less-demanding deiciency.

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531. Nauenberg, E. and Sullivan, S.D., Firm behavior in the U.S. market for factor VIII: A need for policy?, Soc. Sci. Med. 39, 1591–1603, 1994. 532. Suiter, T.M., First and next generation native rFVIII in the treatment of hemophilia A. What has been achieved? Can patients be switched safely?, Semin. Thromb. Hemost. 28, 277–284, 2002. 533. Voorberg, J. and van den Brink, E.N., Phage display technology: A tool to explore the diversity of inhibitors to blood coagulation factor VIII, Semin. Thromb. Hemost. 26, 143–150, 2000. 534. Mersich, C., Billes, W., Paginger, I., and Jungbauer, A., Peptides derived from a secretory yeast library restore factor VIII activity in the presence of an inhibitory antibody, Biotechnol. Bioeng. 98, 12–21, 2007. 535. Hermans, C., Brackmann, H.H., Schinco, P., and Auerswald, G., The case for wider use of recombinant factor VIII concentrates, Crit. Rev. Oncol. Hematol. (in press). 536. Farrugia, A., Product delivery in the developing world: Options, opportunities and threats, Haemophilia 10(Suppl. 4), 77–82, 2004. 537. Nemerson, Y., Tissue factor and hemostasis, Blood 71, 1–8, 1988. 538. Pedersen, A.H., Lund-Hansen, T., Bisgaard-Franzen, H., et al., Autoactivation of human recombinant coagulation factor VII, Biochemistry 28, 9331–9336, 1989. 539. Soejima, K., Mizuguchi, J., Yuguchi, M., et al., Factor VIIa modiied in the 170 loop shows enhanced catalytic activity but does not change the zymogen-like property, J. Biol. Chem. 276, 17229–17235, 2001. 540. Persson, E. and Olsen, O.H., Current status on tissue factor activation of factor VIIa, Thromb. Res. 125(Suppl. 1), S11–S12, 2010. 541. Gertler, A., Walsh, K.A., and Neurath, H., Catalysis by chymotrypsinogen. Demonstration of an acyl-zymogen intermediate, Biochemistry 13, 1302–1310, 1974. 542. Aronson, D.L. and Mustafa, A.J., The activation of human factor X in sodium citrate: The role of factor VII, Thromb. Haemost. 36, 104–114, 1976. 543. White II, G.C., Roberts, H.R., Kingdon, H.S., and Lundblad, R.L., Prothombin complex concentrates: Potentially thromogenic materials and clues to the mechanism of thrombosis in vivo, Blood 49, 159–170, 1977. 544. Jeong, E.K., Sung, H.M., and Kim, I.S., Inactivation and removal of inluenza A virus H1N1 during the manufacture of plasma derivatives, Biologicals 38, 652–657, 2010. 545. Groenevald, A.B., Navickis, R.J., and Wilkes, M.M., Update on the comparative safety of colloids: A systematic review of clinical studies, Ann. Surg. 253, 470–483, 2011. 546. Alter, H.J., Stramer, S.L., and Dodd, R.Y., Emerging infectious diseases that threaten the blood supply, Semin. Hematol. 44, 32–42, 2007. 547. Allain, J.P., Stramer, S.L., Carneiro-Proietti, A.B., et al., Transfusion-transmitted infectious disease, Biologicals 37, 71–77, 2009. 548. Vamvakas, E.C., Relative risk of reducing the lifetime blood donation deferral for men who have had sex with men versus currently tolerated transfusion risks, Transfus. Med. Rev. 25, 47–60, 2011. 549. Lindholm, P.F., Annen, K., and Ramsey, G., Approaches to minimize infection risk in blood banking and transfusion practice, Infect. Disord. Drug Targets 11, 45–56, 2011.

7

Plasma Proteinase Inhibitors

It is estimated that plasma proteinase inhibitors constitute some 10% of the total plasma proteins.1 Most of the proteinase inhibitors inhibit serine proteinase such as thrombin and are known by the collective term serpins (serine proteinase inhibitors).2,3 Serpins are considered to have a common reaction mechanism that can be considered as a stabilized acyl-enzyme intermediate.4 While the formation of an enzyme–inhibitor complex is reversible to the point of the formation of this intermediate, progression through the complete reaction results in the transition of the inhibitor from a virgin or native state to a modiied form which is inactive.5 A partial list of human plasma proteinase inhibitors is presented in Table 7.1. This list may be incomplete as new inhibitors continue to be discovered and the physiological relevance of others has not been irmly established.6–8 It is of some interest that Laskowski and Kato commented some 30 years ago4 that the precise physiological function of inhibitors is not known. Two plasma proteinase inhibitors—antithrombin (SERPINC1; earlier known as antithrombin III) and α-antiproteinase inhibitor (SERPINA1; earlier known as α-1-antitrypsin)—are of signiicant importance, as biopharmaceutical products and their complexes with proteases such as thrombin–antithrombin9 are valuable biomarkers. Other plasma proteinase inhibitors, such as tissue factor pathway inhibitor (TFPI)10,11 and C1 esterase inhibitor,12,13 are also of interest as commercial products, but do not have the project maturity of antithrombin and α-1-antitrypsin. One of the major advantages of inhibitors such as antithrombin is that they are biological buffers that react with enzymes such as thrombin in an equilibrium reaction similar to that of a substrate and enzymes; thus, it is most unlikely that hemorrhagic events are of importance as adverse events. Other inhibitors are heparin cofactor II, α2-macroglobulin, and α2-antiplasmin (SERPINF2 will also be discussed). Finally, both antithrombin and α1-antitrypsin have potentially important functions tangential to their function as inhibitors, while the antiprotease function of α2-macroglobulin may be truly secondary to other activities.

ANTITHROMBIN Antithrombin was not suficiently characterized as a protein to be included in Frank Putnam’s list of puriied plasma proteins in 1960.14 Antithrombin did merit inclusion in the second list15 published in 1975, in which it was deined as an α2-globulin of molecular weight 65,000 and a plasma concentration of 17–30 mg/100 mL. Commercial preparations have been derived from human plasma and recombinant DNA technology. The half-life of infused antithrombin is 2–3 days in normal subjects with either a recombinant or a plasma-derived product.16–18 There are only 285

Thrombin, factor Xa, factor IXa, factor XIIa, factor VIIa, matriptase

Leukocyte elastase; trypsin, plasmin, caspase-3

Many

65 kDa; 170–300 mg/L (2–5 μM); t1/2 = 2–3 days

50 kDa; 100–200 mg/L (4–8 μM); t1/2 = 3–5 days

720 kDa (tetramer; a dimer of disulide-linked dimers; monomer is 120 kDa); 2000 mg/L; 3 μM; t1/2 = 8–11 days (n = 6)

Inhibitor

Antithrombin (SERPINC1)

α1-Antitrypsin (α1-proteinase inhibitor; SERPINA1)

α2-Macroglobulin

Target Protease(s)d

Molecular Weight;a Plasma Concentration;b Half-Lifec

TABLE 7.1 Some Protease Inhibitors Found in Human Plasma Comments Originally described as antithrombin III and considered to be the primary inhibitor of thrombin and factor Xa. Reaction with target proteases is greatly accelerated by heparin. Plasma-derived and recombinant products are available for therapeutic use; approved for use in hereditary deiciency and in the study regarding its use in sepsis. Activity unrelated to blood coagulation is still being explored. α1-Antitrypsin deiciency is associated with chronic obstructive pulmonary disease. Severe deiciency results in abnormal protein retained in the hepatocyte, causing ibrosis. Plasma-derived and recombinant therapeutic products are available and gene therapy is being developed. It is clear that α1-antitrypsin has biological activity beyond protease inhibition. α2-Macroglobulin is not a serpin and “inactivates” enzymes by a trapping mechanism that does not modify the enzyme-active site of the target protease. The trapped target protein may retain full activity toward small substrates but greatly reduced activity toward high molecular substrates. α2-Macroglobulin has diverse biological activities in addition to inhibition of proteinase, including the binding of biologically active peptides such as cytokines.

References

[794–798]

[12,787–793]

[4,81,785,786]

286 Biotechnology of Plasma Proteins

65–70 kDa; 50–60 mg/L; ~1 μMe

65 kDa; 90 mg/L; approximately 1 μM; t1/2 = 2–3 days

71 kd; 70 mg/L; ~1 μM, t1/2 = 32.7 h

45–50 kDa, 20 μg/L; ~0.6 nM; t1/2 = 5–30 minf

α2-Antiplasmin (fast-acting plasmin inhibitor; SERPINF2)

Heparin cofactor II (SERPIND1)

C1-inhibitor (C1-esterase inhibitor; SERPING1)

Plasminogen activator inhibitor-1 (SERPINE1) Urokinase-type plasminogen activator; tissue plasminogen activator, thrombing

C1s, factor XIIa, factor XIa, plasmin, MASP-2, hepatitis virus NS3

Plasmin, trypsin α2-Antiplasmin is the primary protein inhibitor of plasmin in blood. α2-Antiplasmin can be covalently bound to ibrinogen in the circulation. There is interest in modifying α2-anitiplasmin activity to improve ibrinolysis. α2-Antiplasmin contains two disulide bridges, which can be reduced without losing activity and one cysteine that may or may not be in a mixed disulide. While heparin cofactor II can inhibit thrombin, it is not considered an important factor in the control of intravascular hemostasis. The majority of heparin cofactor II is in the extravascular space. Deinition of function for heparin cofactor II has not been accomplished. C1-inhibitor is the primary control of the classic pathway of complement formation by blocking the action of C1s on C2C4. C1-inhibitor also inhibits other proteases. The amino-terminal segment is rich in carbohydrate and may be important for C1-inhibitor function in inlammation. Plasminogen activator inhibitor-1 (PAI-1) is present in plasma in very low concentration and has a relatively short half-life for a native serpin. PAI-1 is a metastable protein that has stabilized interaction with vitronectin, both in the circulation and in the extravascular space. PAI-1 inhibits tissue plasminogen activator in the vascular space and urokinase-type plasminogen activator in the extravascular space. PAI-1 is synthesized and secreted from a variety of cell/tissue sources, including the endothelium and vesicular adipose tissue. PAI-1 has a broad range of activities, which may or may not be associated with protease inhibition. (continued)

[811–815]

[581,806–810]

[273,803–805]

[799–802]

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57 kDa; 5.3 mg/L; 80–100 nM; t1/2 = 23 h

47 kDa(intracellular); 60–70 kDa (glycosylated and secreted)

Plasminogen activator inhibitor-2 (SERPINB2)

Molecular Weight;a Plasma Concentration;b Half-Lifec

Protein C inhibitor (SERPINA5); plasminogen activator inhibitor-3

Inhibitor

Urokinase-type plasminogen activator; tPA

Activated protein C, thrombin, factor Xa, urokinase, plasma kallikrein

Target Protease(s)d

TABLE 7.1 (Continued) Some Protease Inhibitors Found in Human Plasma

Protein C inhibitor (PCI) is the most signiicant of the various plasma protein proteinase inhibitors of activated protein C. PCI has a broad speciicity and a broad tissue distribution, suggesting that a critical function has yet to be described. The high concentration in semen has suggested a role in reproductive physiology. Plasminogen activator inhibitor-2 is present in the plasma of pregnant women being derived from the placenta. Plasminogen activator inhibitor-2 is also derived from other sources, including leukocytes and macrophages. Plasminogen activator inhibitor-2 is also suggested as a biomarker for certain tumors. As with other serpins in blood, a speciic role or roles remains to be elucidated.

Comments

[681,779,820–827]

[765,766,816–819]

References

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g

f

e

d

c

b

a

53 kDa; ~4 mg/L; 73 nM

N/A

Thrombin-activatable ibrinolysis inhibitor (TAFI) was puriied from plasma as carboxypeptidase U, which exists in a precursor form bound to plasminogen. Once activated by thrombin, TAFI leaves carboxyl terminal lysine from ibrin decreasing ibrin afinity for plasminogen and decreasing the rate of ibrinolysis.

[828–833]

Approximate; accuracy depends on method(s) used. mg/L; molar concentration. Half-life given is for terminal phase in a two-compartment model. Many of the serpins are approximately equally distributed between intravascular and extravascular space. Signiicant targets listed; may not include all potential targets. Possibly considering how much α2-antiplasmin is covalently linked to ibrinogen.533 α and β phases for elimination. In the presence of heparin or vitronectin.

Thrombin-activatable ibrinolysis inhibitor (carboxypeptidase U; TAFI)

Plasma Proteinase Inhibitors 289

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limited studies on the pharmacokinetics of the transgenic product,19,20 showing a shorter half-life for the recombinant product. The transgenic protein does differ in glycosylation patterns with respect to the plasma-derived protein,21,22 and it is possible that such differences inluence the half-life. The half-life of antithrombin is decreased in acquired antithrombin deiciency states.23–25 The decreased half-life in acquired antithrombin deiciency is likely a result of the increased rate of clearance of antithrombin–enzyme complexes. When thrombin is injected into the circulation, it appears to be immediately complexed with antithrombin.26–28 Coagulant enzymes such as factor VIIa and factor IXa, which are not rapidly inactivated by antithrombin, persist in the circulation for a longer period of time.29–31 Studies on the pharmacokinetics of antithrombin have, however, demonstrated a complex behavior that is seen with many other protein therapeutics. Two-compartment32 and three-compartment33 models have been proposed for the pharmacokinetics of antithrombin. A common observation in antithrombin pharmacokinetics studies is the rapid equilibration with the extravascular space.34 Collen and coworkers32 estimated that 45% of the antithrombin remained in the intravascular pool, while Carlson and coworkers33 estimated that 40% of the antithrombin was in the intravascular pool. Carlson and coworkers proposed a three-compartment model where 10% of the antithrombin was bound to the vascular wall in a noncirculating fraction. Both of these groups used radiolabeled proteins and demonstrated that the rapid initial loss of infused material was not due to denatured protein. Carlson and coworkers had performed earlier studies in a rabbit model system,35 where the issue of protein denaturation secondary to the iodination process was addressed by a “irst pass” of radiolabeled material through a rabbit, and plasma containing radiolabeled antithrombin was taken to a second rabbit. Antithrombin is active as a protease inhibitor in the extravascular space with matriptase.36 Variant forms of antithrombin are present in individuals with congenital antithrombin deiciency.37,38 Luxembourg and coworkers described 87 different mutations in a cohort of 272 patients with antithrombin deiciency. Thus, antithrombin deiciency is a heterogeneous disorder that is inherited as an autosomal defect, with most of the subjects being heterozygous.38 Mutations range from benign to clinically signiicant. Antithrombin deiciency is usually characterized by 50%–60% of normal activity. Antithrombin is glycosylated, and there is a naturally occurring form, β-antithrombin, which lacks glycosylation at asparagine-135.39 The presence of these two isoforms of antithrombin in normal plasma was established by Carlson and Atencio in 1982.40 However, these researchers noted that there were earlier studies that suggested the presence of multiple molecular forms. Peterson and Blackburn41 showed that the isoforms differed in glycosylation and afinity for heparin. The variant form with less carbohydrate has increased afinity for heparin. Later studies42,43 demonstrated that glycosylation at Asn135 inhibited the conformational change of antithrombin in the presence of heparin. There are variant forms of antithrombin in normal plasma and therapeutic concentrates, some with novel properties, relecting altered conformation. The thrombin–antithrombin complex can undergo cleavage44–46 resulting in the formation of a two-chain, disulide-linked derivative, which has lost inhibitory activity but

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acquired antiangiogenic activity.47 Latent antithrombin (L-antithrombin) is a conformationally altered form of antithrombin that can be formed by heating (60°C) in the presence of citrate to avoid polymerization.48,49 Latent antithrombin has lost anticoagulant activity, including the ability to bind heparin tightly, but has acquired activity as demonstrated by O’Reilly and coworkers47 and Larsson and coworkers.50 Larsson and coworkers51 subsequently showed that a second conformationally altered form of antithrombin was formed in conditions of heat and citrate as shown by Wardell and coworkers.49 This form was designated prelatent antithrombin and was characterized by the retention of anticoagulant activity, heparin binding, and antiangiogenic activity. Karlsson and Winge52 used hydrophobic afinity chromatography to separate latent and native antithrombin. Subsequent work by these researchers53 demonstrated that heparin afinity was more effective and could separate prelatent, latent, and native antithrombin. These researchers and others54 have demonstrated the presence of prelatent and latent antithrombin in commercial concentrates most likely arising from the heating step used for viral inactivation. Latent antithrombin can also be found in recombinant antithrombin expressed in Chinese hamster ovary cells.55 Latent antithrombin and cleaved antithrombin are also found in normal blood plasma.56,57 It was suggested that elevated levels of latent antithrombin might be a risk factor for thrombosis on the basis of the association with the native antithrombin.58 However, Corral and coworkers59 have demonstrated that latent antithrombin does not pose a risk for thrombosis. These researchers also showed that latent human antithrombin and native human antithrombin were cleared at the same rate in a rat model system. A variety of mechanisms exist to control the blood coagulation process, including antithrombin. Other regulatory proteins such as TFPI and α2-macroglobulin are discussed elsewhere in this chapter, and other proteins such as protein C and protein S are discussed in Chapter 8. This chapter focuses on antithrombin, and it is useful to clarify some terminology before moving forward. A variety of phenomena have been described as antithrombin. Thus, thrombin is adsorbed to ibrin and released on ibrinolysis; this “antithrombin” activity was known as antithrombin I.60–62 Antithrombin II60 was a term used to distinguish progressive antithrombin activity from heparin cofactor activity.63,64 There was occasional use65 of ATII/III to describe these activities. Briginshaw and Shanberge63 were able to physically separate the two activities. Pratt and coworkers64 provide an excellent review of the development of heparin cofactor II, which is the term used now to describe antithrombin II. Antithrombin IV66 was described to have the ability to immediately inhibit thrombin upon formation. Antithrombin activity has been described in blood platelets,67 most likely relecting the various binding modes of thrombin to platelets.68 Verstrate69 provided some clariication in showing that there is one antithrombin which was designated as antithrombin III. Current nomenclature has dropped the Roman numeral designation, resulting in the use of the term antithrombin. However, there are other serpins in blood which can inhibit thrombin but which have other designations. Antithrombin as a physiological function has been known for more than 100 years but it was poorly understood.70,71 Steady progress in the understanding of antithrombin occurred over the years.72–75 The current world of antithrombin can be traced to the work of Bob Rosenberg and his colleagues at Harvard.76 I remember when

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Bob presented the work at a Gordon Conference in the early 1970s. It was very well received and brought clariication into a cloudy ield. Subsequent work by Mike Grifith at the University of North Carolina at Chapel Hill77 and others clariied the fundamental relationship between antithrombin and heparin. While the reaction is greatly accelerated by the presence of heparin, antithrombin is a kinetically signiicant inhibitor (3.36 × 105 M/min) of thrombin.78 Antithrombin also inhibits other coagulation proteases, including factor Xa, in a reaction that is also accelerated by heparin. The use of low-molecular-weight heparin enhances the speciicity of the inactivation of factor Xa and is thought to be easier to manage79 with respect to adverse reactions, but there is the question regarding clear clinical advantage.80 The effect of heparin on the reaction of antithrombin with factor Xa is thought to relect the effect of a speciic heparin sequence on the conformation of antithrombin, while the reaction of antithrombin with thrombin in the presence of heparin is thought to involve a template process.81 There are two problems with the clinical use of antithrombin. The irst, which is discussed in more detail later, is the necessity of the early use of antithrombin in the clinical course of acquired antithrombin deiciencies such as sepsis. The second is the need for supranormal levels of antithrombin in the treatment of acquired antithrombin deiciencies.82 Inherited deiciency of antithrombin poses a similar therapeutic issue. A recent paper from a group of German researchers35 described the molecular basis of antithrombin deiciency. These researchers noted that inherited antithrombin deiciency is mostly heterozygous, leading to observed levels of 50%–60% of normal values (reference range); a decreased concentration of antithrombin is associated with an increased risk of thrombosis. As with acquired antithrombin deiciency, successful treatment of inherited antithrombin deiciency may require the initial establishment of higher than normal levels (120%) followed by maintenance at greater than 80%.83 While antithrombin is approved for use in congenital deiciency, the anticipated market is in acquired antithrombin deiciency, where even higher levels are used with marginal success.84,85 It is noted that in the pediatric study described earlier, the four subjects with disseminated intravascular coagulation/organ failure were treated with high-dose antithrombin in the absence of heparin with success. In addition to antithrombin, there are other SERPINS (antithrombin is SERPINC1) in the blood such that it is remarkable that blood does clot.86 The molar excess of inhibitors to enzymes is substantial,87 suggesting that enzymes should be inactivated immediately on formation. It is likely that the separation of clot formation from bulk solution is critical for protecting the activated enzymes from premature inactivation,88,89 as demonstrated by the effect of phospholipid, calcium ions, and factor V on the inactivation of factor Xa by antithrombin.90 Walker and Esmon90 do make the observation (which I missed some 30 years ago) that as antithrombin levels are extrapolated to ininity, the protective effect was eliminated and the rate of inhibition was accelerated. Reeve91 modeled the various reactions in coagulation to show that there was a reasonable explanation for increased susceptibility to thrombosis associated with modest reductions in antithrombin concentration. As cited earlier, there are studies84,85 in which there is a suggestion that antithrombin may be of value in acquired antithrombin deiciency such as that seen in sepsis.92,93 In

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addition to these studies, there are other studies that support therapeutic effectiveness in sepsis94,95 when given at high levels and early in the clinical course.96 Inthorn and coworkers94 observed that antithrombin concentrate eliminated disseminated intravascular coagulation in severe sepsis. The multiorgan dysfunction (MOD) syndrome is a complex problem. Haire97 has an excellent discussion of the relationship of systemic inlammatory response syndrome (SIRS), MOD, and sepsis; sepsis can be deined as SIRS resulting from infection. He observes that the risk of progression from singleorgan dysfunction to MOD is substantial when antithrombin level was less than 84% of normal level. In previous studies, Haire and coworkers95 as well as Eid and coworkers96 emphasize the importance of the early use of antithrombin concentrate in obtaining a favorable therapeutic outcome. The following conclusions can be derived from the aforementioned information; it is understood that the data are not as solid as one would wish: • Congenital antithrombin deiciency is a heterogeneous disorder. • Acquired antithrombin deiciency is observed in a variety of clinical situations such as MOD in hematopoietic stem cell transplantation and sepsis. This is likely a relection of disseminated intravascular coagulation. Disseminated intravascular coagulation is relieved by the administration of antithrombin concentrate. • High levels of antithrombin concentrate may have a therapeutic effect in sepsis and related clinical problems. The effect is variable in a challenging the clinical population. A successful clinical outcome is dependent on early diagnosis and early use of the therapeutic product. • The conformational variants of the antithrombin, latent antithrombin and prelatent antithrombin, which have antiangiogenic activity, may be important in the therapeutic magic and variability of antithrombin in acquired antithrombin deiciency. It should be noted that this concept has been addressed by Heemskerk98 in a short comment.

α1-ANTITRYPSIN (α1-ANTIPROTEASE INHIBITOR, SERPINA1) α1-Antiprotease inhibitor (originally known as α1-antitrypsin) is a signiicant component of blood present at a concentration of 100–200 μg/mL.99–101 α 2-Macroglobulin has a similar concentration and is an eficient inhibitor of proteases97 but is secondary to α1-antitrypsin as a general physiologic proteinase inhibitor as α1-antitrypsin is small (and therefore has a higher molar concentration).102 α1-Antitrypsin is considered to be an acute phase protein.103–109 Serum levels of α1-antitrypsin increase during pregnancy110–112 and with the use of oral contraceptives.113 A cDNA for human α1-antitrypsin coding for a mature polypeptide of 394 amino acid residues has been isolated and sequenced114,115 and expressed in an Escherichia coli system yielding an unglycosylated protein with a mass of 45 kDa with antiproteinase activity.116,117 Recombinant α1-antitrypsin has been developed for clinical use as a parenteral drug118,119 and gene therapy is being developed.120

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The mature α1-antitrypsin protein contains three carbohydrate chains (12% carbohydrate) and has a molecular mass of approximately 50 kDa.121–125 It is an α1-globulin (see Chapter 3), originally referred to as the 3.5 α1-glycoprotein,3 and contains a free cysteine residue.121,126 The presence of cysteine in α1-antitrypsin could be inferred from Laurell’s studies127 in 1970, showing the in vivo formation of a complex between immunoglobulin κ chains and α1-antitrypsin. Tomasi and Hauptman128 demonstrated α1-antitrypsin binding to IgA by the formation of disulide bonds. Musiani and coworkers129 showed that α1-antitrypsin maintains protease inhibitor activity when bound to IgA. Vaerman and coworkers130 showed that both albumin and α1-antitrypsin are bound via a disulide bridge to the same cysteine residue in the α-chain of IgA. IgA with bound α1-antitrypsin is found in fecal material, suggesting a serum origin of this material.131 Serum albumin also has a free sulfhydryl group (Chapter 4), which has been under considerable study. It is, thus, a bit surprising that the cysteine residues in α1-antitrypsin have been of little apparent interest. Grifiths and workers126 comment on this lack of interest in their paper on the reactivity of this cysteine residue in recombinant human albumin. In a work cited earlier, Crawford121 established the presence of one mole of cysteine/protein by performic acid oxidation as well as S-carboxymethylcysteine after reaction with iodoacetate. Musiani and Tomasi123 found one mole of cysteine/mole protein after reaction with iodoacetamide. Laurell and coworkers132,133 used disulide exchange to purify α1-antitrypsin from human plasma. Pierce and coworkers134 showed that conversion of α1-antitrypsin to a mixed disulide with cysteine improved resolution of α1-antitrypsin phenotypes. The pKa of the cysteine group in α1-antitrypsin has been determined to be 6.85 based on the pH dependence of reaction with hydrogen peroxide.126 This is approximately 1–1.5 pH units below the pKa of cysteine residues measured in glutathione (pH 9)135 and in a model pentapeptide (pH 8.6),136 but not unlike the average value (pH 6.8) for 25 proteins.137 The range for pKa values in proteins is 2.5–11.1, similar to that observed in albumin (Chapter 4). Naor and Jensen137 used computational methods to provide the basis for the low pKa of Cys232 in α1-antitrypsin, suggesting that the formation of a hydrogen bond with an amide is factor-responsible. The sulfhydryl group can be converted to the S-nitrosyl derivative by reaction with nitric oxide and the S-nitrosylated derivative has bacteriostatic activity.138,139 Subsequent work by this group showed that S-nitrosylated α1-antitrypsin has a protective effect on ischemia-reperfusion injury.140 The nitrosylation did not inluence the inhibition of trypsin or elastase. α1-Antitrypsin is a product of hepatocytes,141 although other sites of synthesis have been suggested.142 Putnam and coworkers141 showed that liver transplantation could cure the most severe deiciency of α1-antitrypsin (PiZZ) and that the phenotype (see later) of α1-antitrypsin matched that of the transplanted liver. Liver transplantation is used for the treatment of PiZZ α1-antitrypsin deiciency,143 where the abnormal protein is retained in the hepatocyte,144 which causes liver ibrosis.145 α1-Antitrypsin is considered to have a circulatory half-life of 3–5 days. Makino and Reed99 showed that there was a rapid distribution of α1-antitrypsin into the extravascular space after administration of partially puriied α1-antitrypsin to three patients who were homozygous for α1-antrypsin deiciency. Jones and coworkers146 studied the clearance of native and desialylated (disialylated) α1-antitrypsin using radiolabeled protein in

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healthy human subjects (type MM). Approximately 50% of the native radiolabeled protein was taken rapidly to the extravascular space, while the desialylated protein was cleared from the circulation in a process associated with the uptake of radiolabel into the liver. The ratio of the amount of native α1-antitrypsin in the extravascular space to that in the intravascular space was approximately unity. α1-Antitrypsin deiciency is a complex disorder arising either from a congenital problem associated with the synthesis of defective protein or from an in vivo posttranslational modiication such as oxidation.142 The genetics of α1-antitrypsin deiciency is complicated and beyond the scope of this work. Sufice it to say that there are a range of variants from normal MM to the ZZ and Znull deiciencies.142,147 The reader is directed to several excellent discussions of this problem.148–151 α1-Antitrypsin deiciency is considered to be the major issue in the etiology of chronic obstructive pulmonary disease (COPD).152 The existence of α1-antitrypsin phenotypes was irst detected by Laurell and Eriksson in 1963 on the altered electrophoretic (paper/agar gel) pattern of α-globulin serum obtained from subjects with α1-antitrypsin deiciency.153 Subsequent work by Laurell154 using electrophoresis and immunoelectrophoresis to study serum samples from normal and α1-antitrypsin–deicient subjects obtained results, which showed that α1-antitrypsin heterogeneity could be explained either by multiple forms of α1-antitrypsin in serum or by the binding of α1-antitrypsin to another material. This study and a later study155 provided data, suggesting a relationship between α1-antitrypsin deiciency and obstructive lung disease. Fagerhol and Laurell156 used electrophoresis to identify homozygous variants of α1-antitrypsin and heterozygotes and developed Pi as an abbreviation to describe the polymorphic forms. Most of the variants are not associated with a major decrease in activity.157 Fagerhol157 showed that the MZ variant had the lowest activity (15% with 100% value from MM homozygous population) of seven phenotypes. The homozygous ZZ variant has only 15% activity. α1-Antitrypsin obtained its name on the basis of its ability to inhibit trypsin. As our understanding of the function of this protein increased, it was clear that while α1-antitrypsin did inhibit trypsin, the primary in vivo target was neutrophil elastase in preventing pulmonary damage.158–160 The broad spectrum of protease inhibition exhibited by α1-antitrypsin led Pannell and coworkers161 to use α1-antiproteinase inhibitor to refer to α1-antitrypsin. A committee on serpin nomenclature was convened in 1999 at the request of the HUGO Gene Nomenclature Committee, which suggested that SERPIN be used as the gene symbol for serpins.162 SERPINA1 was suggested as the term for α1-antiproteinase inhibitor/α1-antitrypsin. It is not clear whether α1-proteinase inhibitor or SERPINA1 has been greeted with enthusiasm by the scientiic community; a PUBMED search exclusive for α1-proteinase inhibitor garnered 1093 citations in June 2011, while SERPINA1 garnered 9. Thus, the author is comfortable with the use of α1-antitrypsin in the current work. The emphasis to this point has been the description of the protein and the congenital deiciency states. It is also important to note that the issue with pulmonary disease and α1-antitrypsin is the ability of neutrophil elastase to degrade pulmonary tissue (elastin), and α1-antitrypsin serves to inhibit this process. Likewise, it is important to note that α1-antitrypsin is an acute phase reactant and blood levels will increase with inlammation. COPD is a local disease resulting from the destruction of the

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pulmonary tissue by neutrophil elastase, which is enhanced by a decrease in systemic levels of α1-antitrypsin. Effective prophylaxis requires inhibition of neutrophil elastase in the pulmonary bed, not in the circulation; α1-antitrypsin can inhibit pulmonary elastase, but delivery of therapeutic α1-antitrypsin must occur in the pulmonary bed. The molecular basis of α1-antitrypsin deiciency has been reviewed by Brantly and coworkers;144 the clinically signiicant ZZ has an allelic frequency of 0.01–0.02 in the caucasian population and is essentially absent in the black or Asian population. The presence of PiZZ also results in liver disease (see above). While COPD can result from the PiZZ deiciency state (≤ 1% of COPD can be ascribed to PiZZ individuals), the dominant cause of COPD is tobacco use, with occupation exposure and air pollution also being factors.163 Smoking (and other airborne reactive substances) results in the oxidation of a methionine residue at the “active site” of α1-antitrypsin.164–167 Oxidants such as myeloperoxidase derived from neutrophils can also contribute to in situ oxidation of α1-antitrypsin. To the naive person, such as the current author, it was a bit of a surprise then to ind that systemic levels of α1-antitrypsin are largely unchanged and sometimes increased in individuals who smoke cigarettes.168–171 As pointed out by Ogushi and coworkers,172 while there is compelling evidence for the protease–antiprotease concept173,174 for the development of emphysema in α1-antitrypsin deiciency, it was somewhat more dificult to rationalize the development of emphysema in cigarette smokers with normal or supranormal blood levels of α1-antitrypsin. There are several studies that provide some insight into this issue. First, the development of emphysema in cigarette smokers depends on individual phenotype. Mittman and coworkers175 showed that α1-trypsin deiciency predisposed individuals who smoked cigarettes to the development of emphysema; individuals with intermediate deiciency (heterozygotes with approximately 50% trypsin inhibitory capacity176) who smoked were far more likely to develop emphysema than a control of normal population who smoked. Lieberman176 had previously noted that homozygous-deicient individuals (ZZ) developed emphysema at 34 years of age, while heterozygotes developed emphysema at 44 years of age. The development of pulmonary pathology with smoking is a local, rather than a systemic, event.177 Hill and coworkers177 showed a reduction in interleukin-8 levels in ex-smokers with decreased neutrophil inlux. Individuals with α1-antitrypsin had greater airway inlammation. Ogushi and coworkers172 showed that the α1-antitrypsin isolated from the lavage luid of smokers was similar to that of α1-antitrypsin isolated from the lavage luid obtained from nonsmokers; proteins isolated from the lower respiratory tract showed decreased rate of reaction of α1-antitrypsin obtained from smokers compared to nonsmokers; the rate of inactivation of neutrophil elastase by α1-antitrypsin obtained from the lower respiratory tract of normal individuals was twice that of α1-antitrypsin from the lower respiratory tract of smokers. In addition to environmental oxidants, inactivation of α1-antitrypsin can be effected by the action of myeloperoxidase derived from neutrophils.178 This information is intended to support the use of α1-antitrypsin as a prophylactic agent for the treatment of pulmonary disease, secondary to α1-antitrypsin deiciency. The problem is that a therapeutic (α1-antitrypsin) is needed for local, not systemic, action in the lower lung. Aboussouan and Stoller179 suggest that only 2%–3% of the product is delivered to the pulmonary site with parenteral administration of an α1-antitrypsin therapeutic product.

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The development of replacement/augmentation therapy with α1-antitrypsin for the treatment of COPD was suggested by the demonstration of a relationship between the α1-antitrypsin concentration and disease.155 Makino and Reed99 observed that it is impractical to give whole blood plasma to patients for hereditary α1-antitrypsin deiciency (PiZZ, 15%–25% activity180,181). Gadek and coworkers182 used a fraction derived from human plasma by poly(ethylene)glycol precipitation to restore protease–antiprotease173,174 balance in the lung; this was determined by the measurement of elastase inhibitory activity in the lower respiratory tract. The development of a plasma therapeutic α1-antitrypsin dates to the work of Michael Coan and coworkers183–187 at Cutter Laboratories in Berkeley, California, resulting in Prolastin-C,188 which is/was a product of Talecris Biologicals (Clayton, NC); Talecris is a successor to part of Bayer, which purchased Cutter Laboratories; Talecris has just been purchased by Grifols, a plasma product company based in Spain, which also purchased Alpha Therapeutics (Los Angeles, CA) from the Green Cross. Grifols also has a therapeutic product (Trypsone), Baxter Healthcare produces Aralast,189,190 and Zemaira is a product of CSL Behring. To the best of the author’s knowledge, these products are obtained from the Cohn Fraction IV(IV-1) (see Chapter 2). This fraction also serves as a source for the manufacture of antithrombin and the vitamin K–dependent factors (see Chapter 8). Development of α1-antitrypsin was initiated to maximize the use of this material, particularly after recombinant factor IX created marketing issues for the plasma-derived product. So, to some extent, the Cohn Fraction IV-1 was a waste fraction that was available for use.185 The same rationale was used for the puriication of ibrinogen for ibrin sealant from cold precipitate (see Chapters 2 and 9). It is quite likely that a superior product could be obtained by alternative puriication procedures.191,192 It is noted that a new process for puriication of α1-antitrypsin from the Cohn Fraction IV-1 had been developed, resulting in an improved product.193 It is not clear as to whether this work has resulted in a commercial product; Baxter has a new α1-antitrypsin product, Aralast-NP, but it was not possible to ind literature on this product. It is noted that the Baxter process193 provides a 15% yield from starting plasma, while the Cutter/Bayer/Talecris process185 provides a 50% yield from the Cohn Fraction IV (which has an approximate 40% yield from plasma) so that both processes have approximately the same yield. The Cutter/Bayer/Talecris group194 improved the yield from the Cohn Fraction IV-1 by 60%–70%. It is likely that the yield could be improved by using one of the alternative puriication processes.191,192 The development of alternative processes is discussed in Chapter 2. α1-Antitrypsin, as with antithrombin, can adopt a latent conformation195 associated with the loss of inhibitory activity. Lomas and coworkers195 prepared latent α1-antitrypsin by heating at 67°C in 0.7 M sodium citrate. The loss of activity could be partially reversed by refolding from 6.0 M guanidine hydrochloride. Latent α1-antitrypsin could be separated from the native protein by chromatography on a strong anion-exchange matrix (Q-Sepharose); resolution was also possible on native gel electrophoresis. Heating in the absence of citrate under these conditions of time and temperature resulted in polymerization of the protein and loss of activity. Lomas and coworkers195 did observe some polymerization with 0.7 M sodium citrate. Subsequent work from this group196 demonstrated the presence of latent α1-antitrypsin in a commercial preparation of α1-antitrypsin. It was suggested

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that the heat step used for viral inactivation185 could be responsible for the presence of latent α1-antitrypsin in the inal drug product. However, this step involves heating at 60°C for 10 h in the presence of 0.38 M citrate, and Bottomley and Tew197 observed that 0.5 M sodium citrate stabilized α1-antitrypsin. Coan and Mitra198 had previously observed that 0.5 M sodium citrate (in the presence of sucrose) stabilized α1-antitrypsin to pasteurization (60°C/10 h). These results suggest that heat treatment is not responsible for the presence of latent α1-antitrypsin in the commercial product. The proteins in the Cohn Fraction IV and albumin fraction have been exposed to substantial concentrations of ethanol for a considerable period of time and, depending on the manufacturing process, the Cohn Fraction IV, the parent material for the α1-antitrypsin, may be frozen prior to subsequent processing. The concentration of ethanol is approximately 0.91 mole fraction for the preparation of the Cohn Fraction II + III, increasing to 0.163 for the preparation of the Cohn Fraction IV-1.199 There are also changes in ionic strength and pH and, while these processes occur in the cold, it takes days to complete the entire fractionation process.200 An organic solvent such as ethanol must be added to a concentrated protein solution such as plasma or cryo-poor plasma slowly to avoid local denaturation. Ethanol has been demonstrated to destabilize protein stucture,201–203 and St-Amour and coworkers204 demonstrated the unmasking of a cryptic IgG during ethanol plasma fractionation. These researchers describe this “unmasking” as a consequence of the “slightly denaturing” conditions of the Cohn fractionation. Denaturation originally referred to a process resulting in the loss of solubility but has evolved into a process deined as change in conformation without change in the covalent structure,205,206 which can be reversible or irreversible.207 Ethanol has been demonstrated to have an effect on the conformation of α1-antitrypsin. Jirgensons208 showed that the conformation of α1-antitrypsin was altered in the presence of 25% ethanol as shown by the changes in circular dichroism spectra. It was possible to reverse the changes by solvent exchange, but the extent of reversal depended on the time and temperature of ethanol exposure. These results provide the basis for the loss of α1-antitrypsin activity from starting plasma to the Cohn Fraction IV-1 precipitate.209 Zimmerman210 reported modiication of the Cohn Fraction IV-1 extraction step, which improved the yield of α1-antitrypsin. The assurance of reproducible alkaline pH of the Tris buffer and the addition of leuptin increased the yield of active material from the Cohn Fraction IV-1 paste. The leuptin likely blocks degradation by alcohol-stimulated proteases.211,212 Proteolytic inactivation of α1-antitrypsin by neutrophil metalloproteinases is thought to occur in vivo.213–215 The studies described have resulted in the development of several therapeutic concentrates derived from plasma and investigation in recombinant products and gene therapy. The use of α1-antitrypsin concentrates is referred to as an augmentation therapy rather than replacement therapy, as the therapy increases existing concentration. The use of therapeutic concentrates of α1-antitrypsin has given mixed results.216 Positive results have been obtained using augmentation therapy with individuals with severe α1-antitrypsin deiiciency,217 and such therapy appears to halt, but not reverse, further decline in COPD patients.218 Other researchers219,220 have suggested that intravenous augmentation therapy is not justiied on the basis of eficacy and cost. However, as noted by both Kueppers218 and Tonelli and Brantly,220 the therapeutic concentrates of α1-antitrypsin are the only therapeutic option, other than liver

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transplantation, for the treatment of severe α1-antitrypsin deiciency. There are, however, other options for the treatment of acquired COPD.221–224 Several groups have advanced a personalized medicine approach to the parenteral use of α1-antitrypsin concentrates, which are therapeutically eficacious and cost-effective.225,226 The major issue with the use of α1-antitrypsin therapeutic concentrate is that the use is local, but parenteral administration is a systemic therapy.179 Since the need for therapeutic products is in the lower lung, it made sense to consider direct delivery to the pulmonary system. The author has had some experience in this area and is well aware that the pulmonary administration of a protein product is not a trivial exercise.227–229 The advantage is that α1-antitrypsin does not need to be adsorbed into the systemic circulation but is active in the lung. The major problem is formulating the protein product into a form that can be delivered by aerosol or related devices.227 It is possible that this is one problem that may be amenable to nanotechnology approaches.227 Hubbard and coworkers230 established a proof of principle for pulmonary delivery of α1-antitrypsin in an animal model. Sometime later, Kropp and coworkes231 showed that radiolabeled α1-antitrypsin could be delivered via inhalation to provide eficacy; 14.2% of administered α1-antitrypsin could be delivered to the pulmonary site, while 2% was delivered by parenteral means. Continued development of aerosol technology has led to a steady improvement in eficiency.232,233 The varied information presented earlier suggests that the parenteral use of therapeutic concentrates of α1-antitrypsin is useful with appropriate patient selection and pharmacokinetic analysis. Development of a pulmonary drug delivery system would be preferable to parenteral administration. The use of gene therapy for α1-trypsin deiciency234 is a potentially useful approach with the caveat that this is a technology still attempting to achieve anything close to the original expectations and/or concerns. Gene therapy for α1-antitrypsin deiciency is complicated in that severe (PiZZ) deiciency is associated with both liver and lung pathologies.235 The liver concern stems from the deposition of abnormal protein in the hepatocyte; as described by Greene and coworkers,235 this is a toxic gain-of-function mutation. COPD is the pulmonary disorder stemming from the loss of function as a result of the gain-of-function mutation. A gene therapy approach to the treatment of severe α1-antitrypsin deiciency must have two approaches: one is downregulation of the production of abnormal protein in the liver,234 while the other approach must solve augmentation of function in the lung. Considerable progress has been made in the development of expression systems for α1-antitrypsin236,237 and methods to deliver gene expression to the lung.238–241 Other biological activities of α1-antitrypsin may well be more commercially signiicant than the use in augmentation therapy for α1-antitrypsin deiciency. Work with latent antithrombin discussed earlier showed that while inhibitor activity was lost, antiangeogenic activity was generated. A latent form of α1-antitrypsin, which has lost inhibitor activity, but there was no comment about new activities, has been described.195 Breit and coworkers242 demonstrated that α1-antitrypsin inhibited lymphocyte response to phytohemagglutinin, suggesting that α1-antitrypsin could modulate the activation of T cells by monocytes. This study was based on immunological abnormality such as rheumatoid arthritis in individuals with α1-trypsin deiciency. A relationship is suggested between immune disorders and α1-antitrypsin.243,244

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Lindström and coworkers244 do advise careful interpretations of changes in α1-antitrysin in patients with vasculitis, as α1-antitrypsin is an acute phase reactant, and deiciency could be masked by changes secondary to the presence of inlammation. Banda and coworkers245 showed that human α1-antitrypsin was inactivated by murine macrophage elastase; inactivated human α1-antitrypsin was a potent chemotactic factor for human neutrophils, suggesting a role in promoting inlammation. Stockley and coworkers246 showed that intact α1-antitrypsin inhibited neutrophil migration in response to FMLP, while oxidized α1-antitrypsin or a peptide cleaved from α1-antitrypsin increased cell migration. These researchers suggest that the observed inhibition of chemotaxis results directly from the protease-inhibitory activity; α1-antichymotrypsin is more potent as an inhibitor of chemotaxis, while antileukoprotease is less effective. The oxidized and cleaved forms of α1-antitrypsin are present in diseased lung tissue and might function to regulate the early phase of inlammation. The results do suggest that α1-antitrypsin has divergent effects on cell migration measured in vitro. There are a number of other studies247–252 that address the role of α1-antitrypsin in the inlammatory response, but considerable additional work is required to provide clariication. Bergin and coworkers253 showed that α1-antitrypsin could bind to IL-8, preventing the interaction of IL-8 with CXCR1 (chemokine receptor 1); α1-antitrypsin also binds to neutrophil membranes, thereby decreasing FcγIIIb release. Both these processes serve to regulate chemotaxis and may be important in the role of α1-antitrypsin in augmentation therapy. Subramaniyam and coworkers254 presented data (mouse model) showing that early administration of α1-antitrypsin enhances lipopolysaccharide (LPS)-induced cytokine/chemokine production in the pulmonary tissue. The general concept is that α1-antitrypsin has anti-inlammatory properties, while proteolysis/oxidation generates proinlammatory activity. There are also several studies on the role of α1-antitrypsin in angiogenesis.255–257 There is one report258 suggesting that elevated α1-antitrypsin is a risk factor for arterial ischemic stroke in childhood based on the inhibition of activated protein C; an earlier report259 suggested that a relationship between elevated levels of α1-antitrypsin and stroke is a function of elevation of inlammation-sensitive proteins (acute-phase proteins). There is another suggestion that α1-antitrypsin is a factor in the development of atherosclerosis on the basis of the inhibition of neutrophil elastase.260 Zsila261 has suggested a chaperone-like function for α1-trypsin in the clearance of defective proteins. Congote and colleagues have published a series of papers describing the activity of a C-terminal peptide derived from α1-antitrypsin in stimulating the proliferations of breast and liver cancer cells,262 blocking human immunodeiciency virus (HIV-1) infection,263 and promoting wound healing.264 There is certainly a collection of eclectic information concerning α1-antitrypsin, and it is possible that there are potential products to be obtained from a careful study of this area. It would be useful to know the effect of the Cohn fractionation process on the various observed activities. Four other plasma proteinase inhibitors require mention before moving to the complement issue. Several have been considered for development as therapeutic products but have not developed suficient traction for commercial development. Clarity of function is a major obstacle as product development has been a challenge with both antithrombin and α1-antitrypsin where it can be argued that function is understood.

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Heparin cofactor II has been mentioned earlier in comparison to antithrombin and later with respect to the generation of chemotactic products resulting from proteolysis. α2-Macroglobulin is a large protein with a usual mechanism and an increasingly diverse number of putative functions. TFPI acts by inhibiting a complex involved in the “extrinsic coagulation pathway” and α2-antiplasmin inhibitor inhibits the ibrinolytic system.

HEPARIN COFACTOR II (SERPIND1) Heparin cofactor II is similar to antithrombin in that it is an inhibitor of thrombin in a reaction that can be stimulated by heparin. Heparin cofactor II may have been described earlier as antithrombin II60,63,64 or as one of the progressive antithrombin activities in plasma. While substantial portions of antithrombin and α1-antitrypsin are in the extravascular space, an even greater proportion of heparin cofactor II is found in the extravascular space.265,266 Hatton and coworkers265 proposed a threecompartment model for heparin cofactor II with 20% distribution in the intravascular space and 60%–70% in the extravascular space. It is then not surprising that heparin cofactor II is not thought to be an important factor in the regulation of solution blood coagulation but likely functions at the vascular wall or in the extravascular space.267 The tissue distribution data support this concept as well as the stimulation of the heparin cofactor II reactions by dermatan sulfate268 and smooth muscle cells.269 Heparin cofactor II was puriied and characterized by Tollefsen and coworkers270 at Washington University in Saint Lous, Missouri. Washington University has been responsible for major contributions to our understanding of hemostasis. Heparin cofactor II was shown to have a molecular weight of 65 kDa and is present in plasma at a concentration of approximately 1 μM.260 Heparin cofactor II inhibits thrombin in the absence of heparin (5 × 105 M/min) and is accelerated by the presence of heparin (4 × 108 M/min), resulting in a stabilized acyl-enzyme form which is inactive. Heparin cofactor II is not effective in the inhibition of factor Xa.223 Heparin cofactor II deiciency has been reviewed by Tollefsen271 and is not considered to be a signiicant issue in thrombosis risk. Heparin cofactor II will inhibit thrombin bound to ibrin in the presence of dermatan sulfate but not in the presence of heparin.272 Liaw272 and coworkers suggest that dermatan sulfate forms a ternary complex with thrombin and ibrin, which is not formed by heparin. Current thinking273 suggests that heparin cofactor II is important in the response to arterial injury. There is continued interest274 in the role of heparin cofactor II and dermatan sulfate in arterial lesions, but it is not clear whether such a role represents a therapeutic opportunity. A recent study275 showed that recombinant lamprey (Lampetra luviatrilis) angiotensinogen could inhibit human α-thrombin; primary sequence analysis shows considerable homology between the lamprey angiotensinogen and heparin factor II. Chemotactic products can be derived from heparin cofactor II.276–280

α2-MACROGLOBULIN α2-Macroglobulin is present in plasma at a concentration of approximately 2 mg/mL and is an α2-globulin on the basis of electrophoretic migration, which is found in the

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Cohn Fraction II-III from alcohol fractionation of plasma.281–283 α2-Macroglobulin is unusual for a plasma protein in that it is a tetramer of 180 kDa subunits284 with a molecular weight of 720 kDa for the mature protein. α2-Macroglobulin has been reported to have a frictional ratio285 of 1.67, but some lower values have been reported.286 The value for frictional ratio argues for an asymmetric protein, but Kyte287 suggests caution in the interpretation of this assumption in the absence of intrinsic viscosity data. I was unable to ind intrinsic viscosity measurements for α2-macroglobulin; extracorporeal elimination of α2-macroglobulin has been shown to reduce blood viscosity improving luidity.288,289 Asymmetry of α-macroglobulin is also supported by electron microscopy.290 α2-Macroglobulin has the ability to bind reversibly or irreversibly to a variety of proteins and peptides.291 A variety of proteases bind to α2-macroglobulin via a reaction involving proteolysis of a “bait” region, which exposes an internal thioester resulting in the formation of a lysyl-γ-glutamyl peptide bond similar to those formed in transpeptidation reactions.292 The thioester bond is also seen in complement components C3 and C4.293–295 As with α2-macroglobulin, activation of complement component C4 exposes the thioester bond for reaction with various nucleophiles. The thioester in both complement C3 and α2-macroglobulin can also be exposed by reaction with primary amines.295 Mitchell and coworkers295 observed that activation of complement component C3 with methylamine enabled the formation of C3–protein complexes that are similar to those formed by physiological activation. A broad spectrum of proteases reacts with α2-macroglobulin,284 with broadspectrum proteases (digestive proteases) reacting more rapidly than more speciic proteases (regulatory proteases). Proteolysis of the “bait” region is associated with a conformational change in α2-macroglobulin.296 Native electrophoresis shows a transition from a “slow” form to a “fast” form. Electrophoresis under denaturing conditions shows 100 kDa and 85 kDa components as well as a 100 kDa component bound to the protease. This conformational change is associated with exposure of a hydrophobic region that is important in binding to the α2-macroglobulin receptor/ low-density lipoprotein receptor-related protein (CD91).297 The transpeptidation reaction of activated α2-macroglobulin as a consequence of activation results in the formation of a covalent bond with the protease. Differing from the reaction of proteases with antithrombin and α1-antitrypsin, which involves the enzyme active site, the reaction between α2-macroglobulin and protease allows for retention of activity.298 α2-Macroglobulin is one of several protease inhibitors in blood which inactivates enzymes in blood coagulation. Together with α1-antitrypsin, α2-macroglobulin can also inhibit enzymes unrelated to blood coagulation such as elastase, trypsin, and chymotrypsin. The ability to cleave a residue or residues in the “bait” region seems to be the major determinant of speciicity. Enzymes such as elastase or trypsin, which are digestive enzymes, are inhibited quite rapidly by α2-macroglobulin (6.4 × 105 M/s for pancreatic elastase299), while thrombin is inhibited more slowly (4.2 × 102 M/s).78,299 Downing and coworkers78 estimated that α2-macroglobulin is more than tenfold less effective than antithrombin in the inhibition of thrombin. Sottrup-Jensen284 argues that α2-macroglobulin is a broad-spectrum inhibitor that could trap proteases released from other inhibitors, proteases involved in ibrinolysis

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and tissue remodeling, as well as proteases associated with invading pathogens.300 Chu and coworkers301 suggest that α2-macroglobulin is a protease-activated sensor for signal transmission. Borth302 and Chu and Pizzo303 summarized the broad spectrum of activities exhibited by activated α2-macroglobulin. α2-Macroglobulin was shown to activate B cells and T cells more than 30 years ago.304,305 James306,307 has reviewed the early work on the interaction between cytokines and α2-macroglobulin. James observes that much of the earlier observations on the effect of α2-macroglobulin on immune cells could be explained by bound bioactive substances.306 Binding to α2-macroglobulin results in activity modulation and clearance.308 Binding to α2-macroglobulin can also inluence the determination of cytokines in immunoassays.309 Binding of cytokines involves the “fast” or activated form of α2-macroglobulin, which would imply the rapid clearance of these complexes. On the other hand, complexes of peptides/proteins with α2-macroglobulin seem to persist long enough to permit consideration of isolation of cytokine complexes with α2-macroglobulin.310,311 In the latter study, Burgess and coworkers311 suggested that α2-macroglobulin complexes could be used as biomarkers for prostate cancer. French and workers312 showed that native α2-macroglobulin could form complexes with partially unfolded proteins; complexes were not formed with activated α2-macroglobulin. However, activation of the soluble complex by a protease could facilitate removal. Webb and coworkers313 suggested that α2-macroglobulin can regulate growth by binding the transforming growth factor beta (TGFβ). TGFβ can bind to native α2-macroglobulin, but binding is enhanced in a plasma–α2-macroglobulin complex; a similar effect was seen with thrombin. Native α2-macroglobulin has also been shown to form complexes with apolipoprotein E314 and with an osteogenic growth peptide.315 Complexing of antigen with α2-macroglobulin enhanced immunogenicity and has been proposed for use in vaccine manufacture.316–318 Another group has proposed the use of peptide–α2-macroglobulin complexes for the development of cancer vaccines.319–321 α2-Macroglobulin and its derivative forms have the potential to be used as biomarkers. Their use as a biomarker in prostate cancer has been described earlier.311 Prostate-speciic antigen, a member of the tissue kallikrein family, has been shown to form a complex with α2-macroglobulin.322,323 Misra and coworkers324 have reported that α2-macroglobulin forms a complex with prostate-speciic antigen, which binds to GRP78 on the surface of prostate cancer cells, activating the cells potentially and promoting more aggressive behavior. The levels of the TGFβ–α2-macroglobulin have been reported to be elevated in prostate cancer325 and may be of prognostic beneit. α2-Macroglobulin is used on a member of a multivariate test (FibroTest) for liver ibrosis.326–328 It has also been used in combination with vitamin D–binding protein and apolipoprotein A1 to evaluate liver ibrosis in hepatitis C.329 A highmolecular-weight protein, which could induce cardiac hypertrophy in rats, was found by Rajmanickam and coworkers330 and later identiied as a cardiac isoform of α2-macroglobulin that has differences in the region binding to the α2-macroglobulin receptor, but with identity in the sequence responsible for the interaction with growth factors.331 These researchers suggested that the differences in the receptor-binding region explain the change in targeting from liver to cardiac tissue. Injection of the puriied protein into normal rats resulted in the development of cardiac hypertrophy.332

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Subsequent work showed the presence of this protein in humans associated with cardiac hypertrophy333 and suggested that the isoform may be of particular importance for cardiac changes in HIV and diabetic patients.334 α2-Macroglobulin has been suggested as a biomarker for glaucoma335 and is suggested to be neurotoxic on the basis of interaction with nerve growth factor blocking a neuroprotective effect via the TrkA receptor. Oh and coworkers336 suggested that α2-macroglobulin is a biomarker for the radiation of pneumonitis in lung cancer patients. There has been considerable interest in the involvement of α2-macroglobulin in Alzheimer’s disease.337–341 It is an acute-phase protein, so speciicity as a biomarker is complicated by the consideration of Alzheimer’s disease as an inlammatory disorder,342–344 and a recent review on biomarkers in Alzheimer’s disease345 did not include α2-macroglobulin. There is some interest in the potential function of it as a chaperone,346,347 and it has been shown that α2-macroglobulin inhibits β2-microglobulin amyloid formation.348 It is also suggested that complex formation of amyloid β-peptide prevents clearance across the blood–brain barrier.349 Both α1-antitrypsin and α2-macroglobulin are acute-phase proteins in that there can be a greater than 25% change (positive) in the concentration following an inlammatory stimulus.350 While acute-phase response implies a positive change in concentration, there are proteins such as albumin, apolipoproteins, and transferrin that are negative acute-phase reactants.351 Acute-phase response/inlammation is a confounding factor in the identiication of speciic biomarkers in pathologies such as Alzheimer’s disease and cancer, which have substantial inlammatory components.352

TISSUE FACTOR PATHWAY INHIBITOR When I started work on the proteins participating in blood coagulation in 1962, the blood coagulation process was viewed as a combination of two pathways: the intrinsic pathway and the extrinsic pathway. The conceptual separation between the two pathways is not very rigid today; however, the extrinsic concept continues in the literature.353 A defect in either pathway results in a bleeding problem. Current work in hemostasis supports the concept of the initiation of coagulation by tissue factor (extrinsic) followed by ampliication through the interactions of factor IX and factor VIII (intrinsic).354 This overlap between the extrinsic system and the intrinsic system has given rise to the use of the term tissue factor pathway to refer to the extrinsic pathway. Tissue factor is also known as tissue thromboplastin, which is considered to be a complete thromboplastin as opposed to the phospholipid derived from platelets (platelet factor 3) which is a partial or incomplete thromboplastin. The partial thromboplastin time derives its name from this distinction.355,356 The partial thromboplastin time (PTT) assay is used for the monitoring of heparin therapy and for the evaluation of hemophilia A and hemophilia B (see Chapters 6 and 8, respectively) initiated by glass or similar material.357–359 The prothrombin time (PT)360 is the diagnostic application of tissue factor and is used to monitor vitamin K antagonist therapy. The assay was developed using crude thromboplastin preparations derived from lung. Comparison of data between laboratories was a major

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consideration as this assay was developed,360,361 and the controversy resulted in the International Normalized Ratio (INR).362 The sequence of reactions is initiated by the interaction of tissue factor with factor VII, forming factor VIIa in an autocatalytic reaction. The factor VIIa/tissue factor complex can then activate factor IX to factor IXa, providing a link between the extrinsic system and the intrinsic system. The factor VIIa/tissue factor complex also converts factor X to factor Xa; factor X is also converted to factor Xa by factor IXa. Factor Xa converts prothrombin to thrombin followed by platelet aggregation and ibrin formation. TFPI binds to factor Xa and subsequently to factor VIIa/tissue factor, forming a quaternary complex resulting in inhibition of the activity of factor VIIa. As such, TFPI functions to regulate the extrinsic pathway by inhibiting the activity of factor VIIa.363 However, a recent study of the clearance of recombinant factor VIIa364 shows persistence in plasma after parenteral administration for hours, not minutes as with other activated coagulation factors such as thrombin or factor Xa (see earlier), with the formation of complexes with antithrombin and α2-macroglobulin. Seligsohn and coworkers365 had previously reported the persistence of factor VIIa in the circulation after administration of factor IX concentrates. A congenital deiciency of tissue factor or TFPI has not been reported, suggesting that this could be a lethal mutation.366 A decrease in the plasma concentration of TFPI may be associated with an increased risk of thrombosis,366–368 and TFPI is reduced in disseminated intravascular coagulation but not in severe liver disease.369 The primary site of TFPI synthesis is the endothelial cell with contribution from platelets;370 so hepatic disease should not affect plasma levels unless related to a secondary disease process.371 The expression of TFPI is reduced in sepsis372,373 and may contribute to the associated coagulopathy.374 TFPI has been known in the past as placental protein 5,375 extrinsic pathway inhibitor,376 and lipoprotein-associated inhibitor.377 Placental protein 5 has subsequently shown to be identical with TFPI-2.337–380 Placental protein 5 was shown to interact with heparin381–385 and was suggested to be a product of tumors.386,387 Nisbet and coworkers387 found placental protein 5 to be present in a high percentage of gestational trophoblast tumors; one case had high levels of “free” placental protein 5 and disseminated intravascular coagulation. Jin and coworkers379 observed that expression of PP5/TFPI-2 decreased the invasive potential of human choriocarcinoma cells. The inhibition of tissue factor/factor VII by a plasma factor was described by Carson388 in 1981 who assigned the activity to plasma high-density lipoproteins. Inhibition of tissue factor/VIIa in plasma requiring factor Xa was subsequently observed by Morrison and Jesty.389 Sanders and coworkers390 observed the inhibition of tissue factor/factor VIIa by a factor in plasma in a reaction that requires factor Xa. Subsequent work from the Rapaport laboratory presented data supporting a two-step process for the reaction of extrinsic pathway inhibitors.391,392 The irst step is the reaction of the plasma factor, designated as extrinsic pathway inhibitor,391 with factor Xa, followed by a second reaction where the factor Xa–extrinsic pathway inhibitor is reacted with tissue factor/factor VIIa, forming a quaternary complex.392 Huang and coworkers393 observed that the rate of inhibition of factor Xa by TFPI was reduced in the presence of calcium ions, but subsequently the rate of inactivation increased by

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phospholipid and factor Va, suggesting that factor Xa was more rapidly inactivated when present in the prothrombinase complex. This would appear to be contrary to the observations by Walker and Esmon90 who observed a decrease in the rate of factor Xa inactivation by anthrombin in the presence of other components of the prothrombinase complex. Later, Baugh and coworkers394 suggested that the inactivation of factor Xa by TFPI occurred mostly rapidly when factor Xa was physically close to tissue factor/factor VII. Broze and coworkers isolated lipoprotein-associated coagulation inhibitor produced in HepG23 (human hepatoma) cells395 in 1987 in a process that used afinity chromatography with immobilized bovine factor Xa using elution with benzamidine, a competitive inhibitor of factor Xa, to obtain the puriied inhibitor. Early work used factor Xa inactivated with diisopropylluorophosphate and was unsuccessful; the use of active factor Xa was also successful, yielding a homogeneous product (sodium dodecyl sulfate-polyacrylamide gel electrophoresis, SDS-PAGE) with a mass of approximately 39 kDa. The isolated material bound radiolabeled factor Xa (Western blot) and inhibited tissue factor-initiated clotting. The puriied material did not bind to factor Xa modiied at the enzyme active site with either diisopropyl phosphoroluoridate or the peptide chloromethylketone. The Washington University group subsequently isolated the lipoprotein-associated coagulation inhibitor from human plasma using a combination of hydrophobic afinity chromatography, ionexchange chromatography, and factor Xa afinity chromatography.396 The various studies cited resulted in a mechanism of action where TFPI is a multivalent protease inhibitor.397 There are other examples of multivalent protease inhibitors,4 including inter-α-trypsin inhibitor (inter-α-inhibitor).398–401 There is no evidence of a relationship between inter-α-inhibitor and TFPI.402 Factor Xa is not inhibited by inter-α-inhibitor but is weakly inhibited by bikunin (SPINT2)401 derived from interα-inhibitor.402 Earlier work with recombinant placental bikunin403 showed potent inhibition of human plasmin, plasma and tissue kallikrein, and factor XIa with lesser activity against factor Xa, factor XIa, and tissue factor/factor VIIa. Placental bikunin is composed of two linked Kunitz domains; individual domains were also expressed and showed reduced potency. Structural analysis of TFPI has been accomplished by molecular biology techniques.404,405 Wun and coworkers404 presented data supporting the basic structure of TFPI as three linked Kunitz domains with a negatively charged amino-terminal region and a positively charged carboxyl region. The sequence derived from the cDNA predicts several glycosylation sites which have been subsequently identiied by Nakahara and coworkers.405 Subsequent analysis of an endothelial cell library by Northern blotting demonstrated the presence of two separate messages—one a 1.4 kb domain and the other a 4.0 kb region,406 which contained the 1.4 kb message—for the expression of lipoprotein-associated coagulation inhibitor. One Kunitz domain binds factor Xa followed by the binding of factor VIIa/tissue factor to a second Kunitz domain. A precise function for the third domain remains to be established, but it has been suggested that the third domain interacts with plasma lipoproteins407 and cell surfaces387,408–410 and is important in the protein S stimulation of factor Xa inhibition by TFPI.411 The designation of a protease inhibitor domain as a Kunitz domain is based on a nomenclature developed some 30 years ago.4 The term

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Kunitz is derived from Moses Kunitz who was responsible for much of the early work on protease inhibitors.412 The Kunitz domain is based on the structure of a pancreatic trypsin inhibitor, which was the irst to be crystallized, and from soybean trypsin inhibitor.413,414 The author met Professor Kunitz when they were both at the Rockefeller University in New York City. While Kunitz was at the end of his career, he remained a vital member of the community. I can recall the day when he came down the hall with a handful of papers to ind Stanford Moore; Professor Kunitz had just been elected to membership in the National Academy of Sciences and needed help with the associated paperwork. As a further note, the Worthington Biochemical Corporation owes its start to Kunitz, as Charles Worthington was a laboratory assistant with Kunitz at the Princeton laboratories of the Rockefeller Institute. While I do not know this, I suspect that Professor Kunitz would be somewhat embarrassed by the term “Kunitz domain.” At a time when computers trump laboratory work, it is useful to designate regions on proteins as domains, and homology is used to identify related domains. These domains, which usually have structural or functional implications, are named after an index protein resulting in, for example, sh3 domains, kinase domains, pdz domains, egf domains, and so on. As noted previously, the Kunitz domain is based on the structure of a pancreatic trypsin inhibitor; as far as I know, this is the only example of a protein domain named after a scientist. A deinition of a Kunitz domain was suggested by Markland and Ladner in the 1998 U.S. patent,415 which consisted of 50–60 amino acid sequence homologous to the bovine pancreatic trypsin inhibitor; there is particular reference to the position of the disulide bonds.4 The irst use of a Kunitz domain in the literature appears in the work of Hochstasser and Wachter416 in 1979. These researchers prepared a “Kunitz-type proteinase inhibitor” from inter-α-trypsin inhibitor by digestion or by isolation from urine. This material had an approximate molecular weight of 8 kDa, and the primary structure analysis showed homology with bovine pancreatic trypsin inhibitor. Kunitz domains are found in proteins such as amyloid precursor proteins, which are not intuitively identiied as protease inhibitors; the soluble form of amyloid precursor proteins is a potent protease inhibitor, also known as protease nexin 2.417 Kunitz domains may have function(s) other than protease inhibition suggested by possible roles in inlammation and tissue remodeling.418 Finally, Kunitz domains are not a prerequisite for inhibitor function, as α1-antitrypsin, for example, does not contain a Kunitz domain.419 Studies on the distribution of TFPI in the body suggest that the presence of TFPI in the vascular space is a secondary phenomena, with the focal point of activity in the extravascular space. Some 80%–90% of TFPI is associated with the endothelial cell surface420 and the TFPI in plasma is associated with lipoprotein.421 A small amount of TFPI is produced by platelets.422 Tissue factor pathway is also subject to proteolytic degradation, resulting in degradation and loss of activity.418,423,424 Kothari and coworkers reported that while thrombin increased tissue factor activity in endothelial cell and pleural mesoendothelial cell culture, plasmin increased tissue factor activity by inactivating cell-associated TFPI.425 In addition to the heterogeneity associated with the binding to lipoprotein and limited proteolysis, Piro and Broze reported two forms of TFPI—TFPIα and TFPIβ—which are suggested

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to differ in the extent of glycosylation and the chemistry of attachment to the endothelial surface.426,427 In addition, there is TFPI-2.380 TFPI-2 expression in monocytes is stimulated by thrombin.428 Schuepbach and coworkers429 showed that endothelial cell tissue factor activity is enhanced by activated protein C in a mechanism involving cleavage of TFPI with the release of the irst Kunitz domain, which is thought to interact with tissue factor/factor VIIa. TFPI is released from the endothelial cell surface with heparin.430–436 Harenberg and coworkers437 reported that the heparininduced mobilization of TFPI could be reversed by protamine; these researchers also reported that dermatan sulfate was much less effective than heparin in the mobilization of TFPI, implying speciicity in the structure of sulfated glycosaminoglycans in the reaction. Valentin and coworkers438 reported that the presence of heparin and TFPI may inluence coagulation assays. Heparanase is an enzyme that hydrolyzes the heparan sulfate proteoglycans on the endothelial surface; it is thought that these highly negatively charged proteoglycans are responsible for binding the positively charged carboxyl terminal region of TFPI.437 Heparanase has been shown to release TFPI, creating a procoagulant effect.439,440 TFPI has been suggested to have activities other than those in coagulation;441 however, the caveat must be made that, in principle, TFPI controls the expression of other biologically active substances such as factor Xa, thrombin, and plateletderived growth factors. Animal model studies have shown that TFPI exhibits antiangiogenic and antimetastatic activity,442 and it is possible that some of the nonanticoagulant activity of low-molecular-weight heparin might be related to the release of TFPI.434,435 Tissue factor is suggested to promote angiogenesis;443–446 such inhibition of tissue factor and/or tissue factor expression can be antiangiogenic.447–449 A second form of TFPI—TFPI-2—is upregulated in tumor cells and appears to induce apoptosis and inhibit angiogenesis.450 In addition to TFPI-2, there are alternatively spliced forms of TFPI—TFPIα and TFPIβ—that are produced by endothelial cells;451 both TFPIα and TFPIβ induce apoptosis in breast cancer cells.452 It is reported that the expression of TFPIα and TFPIβ is developmentally regulated; both TFPIα and TFPIβ are expressed in murine embryonic tissue, while only TFPIβ is expressed in murine adult tissue.453 Van Den Boogaard and coworkers454 reported that recombinant TFPI reduced bacterial growth (Streptococcus pneumonia) in a murine model of community-acquired pneumonia with concurrent antibiotic therapy. There was a decrease in neutrophil iniltration into pulmonary tissue and reduction in cytokines and chemokines with the use of recombinant TFPI; however, these effects were only observed in the absence of antibiotics. Other researchers455 have demonstrated an antibacterial effect of TFPI fragments in vitro against resistant E. coli. Regnault and coworkers456 show a positive relationship between increased free TFPI and arterial stiffness and suggest that free TFPI increases as vascular wall function deteriorates, with a possible relationship between free TFPI and cardiovascular risk. The aforementioned studies provide a limited basis for the use of TFPI as a diagnostic tool and as a therapeutic agent. The studies by Regnault and coworkers456 are suggestive, but as the authors note, a substantial longitudinal study is required to establish its value as a predictive biomarker. A clinical trial on the use of recombinant TFPI in community-acquired pneumonia showed a reduction in some

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coagulation-based biomarkers (prothrombin fragment 1 + 2, thrombin–antithrombin) and there was no effect on mortality.457 An earlier clinical trial458 with TFPI in sepsis suggested a reduction in the mortality, but there was no signiicant difference between the treated and the control groups. A subsequent larger trial459 in severe sepsis showed no difference in mortality (all-cause 28-day mortality) between treated and placebo; there was an increase in bleeding in the treatment group. This is not unlike the trials with antithrombin, which suggest to the writer who is not a clinician, that success will require more careful patient selection and also a better understanding of the relationship between free TFPI and TFPI bound to endothelial cells. In work cited earlier, Regnault and coworkers456 suggest that increased plasma TFPI is predictive of cardiovascular death. Earlier studies by Morange and coworkers460 reported that free plasma TFPI was associated with the severity of cardiovascular damage on admission but not independently related to outcome; free soluble tissue factor was predictive of cardiovascular mortality in acute coronary syndrome. This information suggests that TFPI functions bound to a membrane and that plasma levels may be an indication of vascular pathology.461–468 Kamikura and colleagues461 observed elevated plasma TFPI in patients with acute myocardial infarction and suggested that it was released from ischemic tissues. This same research group 462 observed elevated TFPI in disseminated intravascular coagulation and suggested that such elevation was a result of injury to the vascular endothelium. Mitchell and coworkers463 presented data suggesting that TFPI is elevated in atherosclerosis as a result of endothelial dysfunction. Yasuda and coworkers464 showed elevated TFPI in acute pancreatitis. Decreases in free TFPI were observed in COPD patients,465 resulting in increased thrombin generation. Golino and coworkers466 observed consumption of TFPI in acute coronary syndrome and Ignjatovic and coworkers467 observed an increase in TFPI with heparin administration in coronary bypass surgery. Golino and coworkers466 also reported an increase in TFPI with heparin administration. Van Dreden and coworkers468 reported a decrease in TFPI in factor V Leiden. The use of TFPI as a parenteral therapeutic or biomarker is complicated, and the extremely rapid clearance of TFPI from the circulation is characterized by a rapid dissociation/reassociation from the vascular endothelium. Donahue and coworkers469 studied the disposition of TFPI during cardiopulmonary bypass; as would be expected, the administration of heparin resulted in the release of TFPI and the administration of protamine resulted in a decrease of full-length TFPI while free TFPI antigen and total plasma TFPI remained elevated. Electrophoresis/Western blot analysis showed that TFPI remaining in the solution after protamine was a 38 kDa form missing the C-terminal domain. Kemme and coworkers470 observed an increase in the rate of TFPI release at low-dose heparin, which did not increase with additional heparin and decreased upon stopping heparin administration. The most striking aspect of studies on the pharmacokinetics of TFPI is the very rapid irst phase (α-phase) of clearance, which is on the order of seconds to minutes, followed by a second phase (β-phase), which is in the range of 1–3 h.471 The α-phase likely represents the rapid association of TFPI with sulfated proteoglycans on the vascular endothelium and, as would be expected, the administration of heparin decreased the rate of clearance of full-length TFPI (recovery at 2 min for

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full-length TFPI of 3.2 min vs. 45.9 min in the presence of low-molecular-weight heparin).472 These researchers showed that the α-phase for a TFPI derivative lacking the C-terminal positively charged domain (two-domain TFPI) was longer (recovery at 2 min of 48.8%) and was not inluenced by heparin to the same extent as the fulllength material (70.5 min). This group subsequently reported473 that a nonglycosylated derivative lacking the Kunitz domain 3 (two-domain TFPI) had similar α-phase clearance to the glycosylated two-domain TFPI but a longer β-phase. Other studies also support a very rapid clearance of TFPI.474 There has been considerable interest in the use of factor VIIa to treat factor VIII inhibitors (see Chapter 6). Van’t Veer and coworkers475 have suggested that the rapid inactivation of tissue factor/factor VIIa by TFPI, combined with the absence of factor VIII in hemophilia A or factor IX in hemophilia B, is responsible for the hemorrhagic diathesis in these disorders. Erhardtsen and coworkers476 demonstrated a shortening of the bleeding time in “hemophilic rabbits” with an antibody against TFPI, suggesting that this might be an approach to the treatment of hemophilia. Liu and coworkers477 reported inhibition of TFPI with nonanticoagulant sulfated polysaccharides and suggested that this as an approach for the treatment of the hemophiloid disorders. More recently, an aptamer, which inhibits TFPI, has been developed as an approach to treat hemophilia.478,479 There does not appear to be a rationale for the use of TFPI as a parenteral drug, as the clearance rate is quite rapid. It could be argued that the rapid clearance increases concentration at the site of action. On the other hand, a deiciency state with consequences remains to be demonstrated. The rapid clearance is likely due to rapid binding to the vascular wall; however, the β-phase is quite rapid as well and likely represents renal clearance. It is possible that modiication with poly(ethylene)glycol would decrease renal clearance and might decrease binding to the vascular wall. However, it is not clear that TFPI functions in the luid phase and probably requires membrane binding to function. Inhibition of TFPI is a mechanism by which the activity of factor VIIa would be increased in those providing a therapeutic approach to the treatment of hemophilia. This seems to the author to be a somewhat convoluted approach to solving a clinical problem. A bit of history on the development of factor VIIa might be useful here (see also Chapter 8). It is also useful to consider Walt Kisiel’s relections480 on the development of factor VIIa which resulted in the development of the Novo Nordisk product (Novo7 RT) for the treatment of hemophilia A patients with inhibitors. Prothrombin complex concentrates were plasma therapeutic concentrates derived from the Cohn Fraction IV and were used to treat patients with factor IX deiciency (Christmas disease) and liver disease.481 Physicians also found some of these concentrates to be useful in the treatment of hemophilia A patients with inhibitors.482 Thrombogenic activities were found in these early prothrombin complex concentrates,483 raising concern about their continued clinical use.484 The companies responsible for the manufacture of the prothrombin complex concentrates made changes in the manufacturing process resulting in therapeutic products that were not thrombogenic but were no longer as useful in the treatment of factor VIII inhibitors. As a result, prothrombin complex concentrates, which were deliberately activated, were developed for the treatment of factor VIII inhibitor patients starting with Autoplex.485–487 Analysis of the composition of Autoplex showed the presence

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of large amounts of factor VIIa and factor IXa with smaller amounts of factor Xa.29 It was not unreasonable then to use puriied factor VIIa for the treatment of inhibitors in hemophilia A patients, and an approach, such as the use of a speciic aptamer, which would decrease the activity of TFPI, would be expected to increase factor VIIa activity.

α2-ANTIPLASMIN α2-Antiplasmin (SERPINF2, fast-reacting inhibitor of plasmin) is the primary physiological inhibitor of plasmin, the enzyme responsible for the dissolution of ibrin clots (ibrinolysis). Plasmin is derived from plasminogen in the vascular space by tissue plasminogen activator (tPA) and by urokinase in the extravascular/interstitial space. The reader is recommended to a group of excellent reviews on the ibrinolytic system.488–493 α2-Antiplasmin was originally described as the fast-reacting plasmin inhibitor of plasma494 as opposed to a slower-acting inhibitor, subsequently shown to be α2-macroglobulin. α2-Antiplasmin was shown to be distinct from α1-antitrypsin;495 The former has been shown to inhibit both chymotrypsin and trypsin.496 The rate of inactivation of chymotrypsin by α2-antiplasmin was similar to those observed for plasmin (~7 × 105 M/s), while trypsin is inhibited more rapidly (1.3 × 107 M/s) than plasmin. Nobar and coworkers497 observed the rapid inhibition of trypsin by antiplasmin and by antithrombin; the inhibition of trypsin by α2-antiplasmin was more rapid than by α1-antitrypsin. Levi and coworkers498 developed speciic immunoassays for plasmin–protease inhibitors in plasma. As would be expected, the majority of plasmin was associated with α2-antiplasmin with a far smaller amount complexed with α2-macroglobulin; smaller amounts of plasmin were associated with antithrombin, α1-antitrypsin, or C1 inhibitor. The distribution did depend on the subject; patients with DIC or on thrombolytic therapy had higher levels of plasmin–α1-antitrypsin and plasmin–antithrombin than did healthy controls. A later study by Banbula and coworkers499 showed that whole blood had increased plasmin inhibitor activity. C1-inhibitor is susceptible to digestion by plasmin;500,501 Brown and coworkers500 suggest that susceptibility of Ci-IHN, to digestion by plasmin relects the presence of a partially denatured, polymerized form of Ci-INH, which is formed on storage or on heating. Latent forms of antithrombin and α1-antitrypsin with reduced potency as inhibitors have been described earlier. Both α2-antiplasmin and C1-inhibitor are inactivated with proteolytic digestion by elastase derived from neutrophils.502 Another consideration is the overall mechanism, with the exception of α2-macroglobulin, for protease inhibition by protein inhibitors which involves the formation of a stabilized acyl-enzyme or tetrahedral intermediate.4,503 Sazonova and coworkers504 converted α2-antiplasmin from an inhibitor to a substrate for plasmin by using a monoclonal antibody and suggested that binding of the monoclonal body promoted the dissociation of the acyl-enzyme/tetrahedral intermediate to cleaved peptide chains and free enzyme. Congenital deiciency of α2-antiplasmin is a rare disorder,505 with some 40 cases reported until 2008. Acquired deiciency of α2-antiplasmin is observed in a variety of clinical conditions, including liver cirrhosis.506,507 Decreased α2-antiplasmin is also seen in disseminated intravascular coagulation.507 Whether congenital or acquired, α-antiplasmin deiciency is characterized by increased bleeding.508,509

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α2-Antiplasmin deiciency can also occur with ibrinolytic therapy.510 Simpson and coworkers511 have recently shown that plasmin generation in plasma was enhanced by α2-antiplasmin deiciency or excess tPA; plasmin generation was decreased with ibrinogen deiciency. Treatment of α 2-antiplasmin deiciency (excess ibrinolysis) is based on the use of plasmin inhibitors. The major inhibitor is ɛ-aminocaproic acid (EACA; 6-aminohexanoic acid; Amicar).512 ɛ-Aminocaproic acid is used to treat α2-antiplasmin deiciency as well as to supplement endogenous α2-antiplasmin513,514 in various surgical procedures with more use since the removal of aprotinin (bovine pancreatic trypsin inhibitor; Trasylol) from the market.515 Aprotinin is a potent inhibitor of plasmin516 and was included in early ibrin sealant products to improve derivative product stability.517 Aprotinin was removed from the market as a result of adverse reactions but is in the process of a clinical trial to provide more information.518,519 As far as I know, there is neither a plasma-derived α2-antiplasmin therapeutic nor one obtained by recombinant DNA technology. I do recall being in meetings, both industrial and academic, where such a product was discussed. Such a product never came to fruition most likely because of the very rare nature of congenital deiciency, the complex nature of the acquired deiciency being secondary to a primary pathology, and the success of EACA and aprotinin. The clinical concerns regarding α2-plasmin activity have focused on increasing focal ibrinolysis (reducing the effectiveness of α2-antiplasmin). The use of a monoclonal antibody to convert α2-antiplasmin from an inhibitor to a substrate504 was mentioned earlier. Lee and coworkers520 identiied an enzyme (antiplasmin-cleaving enzyme) that converts native α2-antiplasmin, a single polypeptide chain of 464 residues with an N-terminal methionine, to a 452 residue with an N-terminal asparagine. The 452 residue inhibitor is cross-linked to ibrin521 more rapidly than the native protein, providing more resistance to clot lysis. Lee and coworkers520 observed that clot lysis times were reduced as the amount of the 452 residue material decreases. These researchers suggest that blocking the activity of the antiplasmin-cleaving enzyme would promote ibrinolysis. α2-Antiplasmin is a single-chain protein of molecular weight 65–70 kDa containing four carbohydrate side chains in the human protein together with a sulfated tyrosine residue.493,522 The sequence of what appeared to be the mature protein was determined by cDNA technology in 1987 by two groups.523,524 These researchers presented data supporting a 452 residue mature protein with an N-terminal asparagine associated with a 30+ residue signal peptide. Lijnen and coworkers525 reported the sequence of a 452 residue human α2-antiplasmin obtained by classical protein chemistry with two differences from the cDNA sequence. Glucosamine-based carbohydrate is present in four asparagine residues. Högstorp and Carlin526 showed that glycosylation was not necessary for the secretion of α2-antiplasmin from rat hepatocytes in culture or for subsequent binding to plasminogen kringles. These researchers obtained evidence for two disulide bonds. Koyama and coworkers527 subsequently isolated two forms of α2-plasmin inhibitor from plasma and Hep G2 cell culture by the use of immunoafinity chromatography. The major component isolated from plasma was the 452 residue protein, while a 464 residue protein with N-terminal methionine was isolated from the serum-free conditioned media from Hep G2 cells. In a work cited

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earlier, Lee and coworkers420 described an enzyme, antiplasmin-cleaving enzyme, which converted the high-molecular-weight form (464 residues) to the lower-molecularweight form (452 residues). The x-ray crystal structure of a truncated form of the murine protein has been reported.528 The sum of the various structural studies supports a model containing a serpin domain529,530 with amino- and carboxyl-terminal extensions. The carboxyl terminal contains multiple lysine residues, which interact with plasminogen kringles,529 and the amino-terminal region can be cross-linked to ibrin531,532 and ibrinogen533 in transpeptidation reactions catalyzed by factor XIIIa. Mosesson and coworkers533 showed that α2-antiplasmin was covalently linked to ibrinogen via a transpeptidation reaction catalyzed by factor XIII providing resistance to ibrinolysis. This work provided considerable insight into an earlier observation by Mosesson and Finlayson534 who demonstrated heterogeneity of puriied human plasma ibrinogen on DEAE-cellulose chromatography. There was one fraction with proibrinolytic activity and another fraction with ibrinolysis inhibitory activity; inhibition was demonstrated against both trypsin and plasmin. It is possible to identify this inhibitory activity as α2-antiplasmin covalently bound to ibrinogen. Mosesson and coworkers533 showed at least stoichiometric amounts of α2-antiplasmin associated with ibrinogen, which implies a higher concentration of α2-antiplasmin in plasma (10–15 μM) than the ~1 μM value, that is generally accepted.493 This observation would imply resistance to ibrinolysis intrinsic within plasma ibrinogen. There are several subsequent studies which suggest that this is the situation. Jámbor and coworkers535 showed that the addition of a polyclonal antibody to the whole increased observed ibrinolytic activity as measured by thromboelastography. When I was just starting in graduate school years ago, the use of the thromboelastogram along with the two-stage assay for factor VIII seemed to have vanished from the landscape. The two-stage assay has been reinvented as the chromogenic assay, while the use of the thromboelastogram is gaining in popularity.536,537 There are, of course, several reasons for the increased ibrinolysis observed by Jámbor and coworkers, such as the lack of cross-linked ibrin, but it is not unreasonable to consider the lack of α2-antiplasmin incorporation into ibrinogen as a possibility. Mutch and workers538 showed that a model thrombus in a Chander loop539,540 prepared from factor XIII–deicient blood supplemented with a factor XIII therapeutic concentrate was more resistant to ibrinolysis than with a thrombi prepared from unsupplemented blood. In a related study, Tsurupa and coworkers541 showed noncovalent binding of α2-antiplasmin to ibrin and ibrinogen bound to a surface; binding was not shown to occur with ibrinogen in solution. Zamarron and coworkers542 used monoclonal antibodies to demonstrate conformational changes in ibrinogen bound to a surface similar to those seen in the conversion of ibrinogen to ibrin. There are observations of differences in the relationship of α2-antiplasmin with the resistance to ibrinolysis. Morris and coworkers543 found that ibrin (crude ibrinogen and bovine thrombin) prepared from blood obtained from patients with chronic thromboembolic pulmonary hypertension is resistant to lysis, but there was no relationship between resistance to lysis and content of α2-antiplasmin. The reactive center loop (RCL) is located in the serpin domain of α2-antiplasmin.544,545 Initiation of the cleavage of a speciic peptide bond in the RCL by the target protease results in a conformational change in the serpin with stabilization of the

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tetrahedral intermediate/acyl enzyme.546 The RCL in α2-antiplasmin contains the “active site,” Arg364-Met,365 for interaction with plasmin as shown by Shieh and Travis.547 Identiication of this site was accomplished by using trypsin instead of plasmin to form a complex with α2-antiplasmin and taking the mixture directly to the Sequenator. α2-Antiplasmin, depending on species, contains three or four cysteine residues. The human protein has four cysteine residues, two of which are participants in a single disulide bond, with the other two either in a mixed disulide or a free cysteine.548 The bovine protein549 and rabbit protein550 have three cysteine residues with one disulide and present either as a free cysteine residue or mixed disulide. The study on the human protein548 reports differences in the interpretation obtained from earlier primary structure studies.525 It is not possible to resolve this without further study, but it is not consequential as the sulfhydryl/disulide is not important for the function (or structure). Reduction of the disulide bond does not markedly inluence inhibitor activity (9.5 × 106 M/s for native protein vs. 5.3 × 106 M/s for the reduced protein).548 Both the native and reduced proteins unfolded at 3.0 M urea (transverse urea gradient—polyacrylamide gel electrophoresis551–553). The complex of either protein, native or reduced α2-antiplasmin, with trypsin was stable to at least 8.0 M urea using the same analytical techniques. The implication here is that α2-antiplasmin is more stable in the complex than in free solution as is trypsin as measured by physical techniques. Trypsin, as judged by analytical ultracentrifugation, undergoes unfolding between 3.0 M and 5.0 M urea.554 Delaage and Lazdunski555 observed that the binding of trypsin to a protease inhibitor stabilized the bound trypsin to denaturation in the presence of urea as measured by exposure of tyrosine and tryptophan residues when measured by difference spectroscopy. These researchers suggest that stability of trypsin increases with increasing points of contact with the inhibitor. Stevens and Doskoch556 showed that while the eight disulide bonds of lima bean trypsin inhibitor in free solution were reduced with dithiothreitol in the loss of inhibitory activity against either trypsin or chymotrypsin, only one disulide bond was susceptible to reduction when the inhibitor was complexed to trypsin. It would appear that α2-antiplasmin increases in stability in a complex with plasmin. The x-ray structure of α2-antiplasmin was reported by Law and workers.528 These researchers noted that the C-terminal extension could serve as a binding site to move the RCL of α2-antiplasmin into position to act as a “substrate” for plasmin. These researchers also note that α2-antiplasmin is an F-clade serpin,557 suggesting potential antiangiogenic activity as discussed earlier for antithrombin. There are few studies on the stability and conformation of α2-antiplamin, as there was little interest in the development of a therapeutic product, derived either from plasma or via recombinant DNA technology. Implicit in the discussion of the formation of the α2-antiplasmin complex is the suggestion that α2-antiplasmin undergoes a conformation change on the binding to and formation of a complex with plasmin. This concept is supported in studies by Plow and coworkers558 who demonstrated differences in antigenic determinants in α2-antiplasmin on the formation of a complex with plasmin and later by circular dichroism studies.559 Nilsson and coworkers559 also showed that the reduction of α2-antiplasmin, which does not result in the loss of activity, does result in major changes in structure (circular dichroism). Solvent–detergent is a method developed at the New York Blood Center to inactivate lipid-enveloped

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viruses such as HIV.560,561 Solvent–detergent treatment of plasma results in decreased α1-antitrypsin activity and total inactivation of α2-antiplasmin; antithrombin activity is unchanged.562 Subsequent work from another laboratory563 demonstrated that Triton X-100 detergent was responsible for the inactivation of α2-antiplasmin. While the removal of aprotinin presented problems to the management of excess ibrinolysis,564 EACA appears to be useful but still presents problems.565 The use of EACA to prevent unwanted ibrinolysis in hemophilia566–568 stems from the observation that a trypsin inhibitor in peanuts was useful in hemophilia.567 Presently, there appears to be more interest in plasminogen activator inhibitor-1 (PAI-1) as a therapeutic target.569–571 Treatment of congenital deiciency of α2-antiplasmin with whole plasma appears to be satisfactory572 with the caveat that α2-antiplasmin activity may be variable; EACA can be useful.527,568 The lack of the need for an α2-antiplasmin therapeutic product does not necessarily suggest the lack of therapeutic opportunities based on modulation of α2-antiplasmin. One study suggests that a decrease in α2-antiplasmin is necessary for plasmin activity to remove the ibrin matrix in a wound prior to the development of granulation tissue.573 Another more recent study574 suggests that a decrease in α2-antiplasmin upregulates the release of vascular endothelial growth factor (VEGF), inducing angiogenesis. Hatziapostolou and coworkers575 observed that EACA inhibited angiogenesis as well as endothelial cell proliferation, while α2-antiplasmin enhanced these effects. These researchers also showed that EACA and α2-antiplasmin had different effects on angiostatin production. Van Leer and coworkers576 showed that there is a ibrinolytic optimum for in vitro alveolar wound healing. The importance of α2-antiplasmin in the regulation of plasmin is also supported by the decrease of α2-antiplasmin in hepatocellular cancer development in hepatitis B-infected patients; a decrease in α2-antiplasmin resulted in increased degradation of the extracellular matrix.577 In support of this observation, Chan and coworkers578 observed downregulation of the SERPINF2 gene expression in hepatocellular carcinoma. These observations (and many others) emphasize the importance of the ibrinolytic system in wound healing in that plasmin, as with thrombin, is a regulatory multifunctional protease. As an example, Lei and coworkers579 suggest that plasmin is the major protease for processing platelet-derived growth factor in the development of proliferative vitreoretinopathy. α2-Antiplasmin, at high concentration, inhibits human kallikrein H5, which may be involved in tumorogeneis.580 It would appear that most of the actions of α2-antiplasmin are directed at the inhibition of plasmin. Compared to the other serpins, there is not much information on the structure of human α2-antiplasmin, nor has it been the subject of direct study. Most of the work has focused on its role as a component in ibrinolysis. Antiangiogenic and other cell-based activities have been ascribed to α2-antiplasmin, but it is dificult to differentiate a speciic effect of α2-antiplasmin from the inhibition of plasmin.

C1-INHIBITOR (C1-ESTERASE INHIBITOR) Complement is another blood system which, as with coagulation and ibrinolysis, involves a sequential series of protein interactions resulting in a inal physiological event. The binding and activation of the C1 complex, composed of C1q and a dimer

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of two dimers, C1r and C1s, to antigen–antibody complexes via C1q result irst in the activation of C1r and subsequently of C1s.581 The binding and activation of the C1 component of complement depends on antibody–antigen density with IgG antibodies582–584 but not with IgM antibodies.585 C1r and C1s are both serine proteases, and C1s, after activation by C1r, forms the C4bC2a complex by the limited proteolysis of C4 and C2. The C4bC2a functions as the C3 convertase, which activates the remaining pathway.586 C1-esterase (C1s587) was identiied by Ratnoff and Lepow in 1957.588 An inhibitor to C1-esterase was partially puriied from serum by Pensky and colleagues589 in 1961. The reader is commended to several other sources for a discussion of complement and the regulation of complement.590,591 There are several earlier books592–596 that the author found quite useful and, inally, after more than 40 years of pretending, inally understood complement ixation. The book by Osler595 and the one by Kabat and Mayer593 were of particular value. C1-inhibitor (C1-esterase inhibitor; C1 INH) inhibits C1r and C1s in classical pathway of complement as well as plasma kallikrein and blood coagulation factor XIIa.597,598 The deiciency of C1-inhibitor results in the clinical problem of hereditary angioedema.598–600 Hereditary angioedema is a suficiently large clinical problem that a therapeutic concentrate has been developed by plasma fractionation.601,602 The incidence of hereditary angioedema is approximately 1 in 50,000,603 while acquired angioedema is a comparatively rare disorder with few reported cases.600,604 The reader is directed to an extremely useful chapter by Davis,598 which discusses the gene structure, expression, and molecular defects in hereditary angioedema. It should be noted that the use of a low-molecular-weight inhibitor of plasma kallikrein has proved useful in the treatment of hereditary angioedema.605,606 Andogen and androgen derivatives have been useful607,608 but are being supplanted by other therapeutic options.608 In addition to inhibiting the C1 activities, C1-inhibitor also inhibits plasma kallikrein and factor XIIa (activated Hageman factor).609,610 Given the spectrum of activities, C1 INH has a role in inlammation and other disorders.611,612 Dorresteijn and coworkers612 observed the anti-inlammatory action in the absence of complement activation. Thorgersen and coworkers613 observed anti-inlammatory activity of C1 INH in the absence of protease inhibitor activity; these studies were performed using E. coli challenge in vitro in porcine and human blood. C1-inhibitor is a bit unusual compared to other serpins in that it contains a large amount of carbohydrate (25%–30% by mass) in an approximate 100 amino acid extension amino-terminal from the serpin domain.598,614 The heavily glycosylated amino-terminal domain is suggested to be important in the role of CI INH in inlammatory disorders.614 Early studies on the puriication and characterization of C1 INH suggested a glycoprotein consisting of 478 amino acids with a single amino-terminal asparagine with a molecular mass of 104 kDa.615–617 Perkins and coworkers618 used neutron scattering to determine the structure of C1 INH. The results of the analysis were consistent with an Mr of 76 kDa and a length of 16–19 nm. The length is far greater than can be accommodated by the serpin domain, and these authors suggested that the length was due to the elongated structure of the N-terminal domain of 113 residues with most of the covalently linked carbohydrates. This suggests an asymmetric protein compared to α1-antitrypsin (length 7.0–7.8 nm). The asymmetry of the

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protein explains the high molecular values obtained in earlier studies. Jack Kyte has an excellent discussion of factors inluencing the physical measurement of the protein structure, which is quite useful in understanding this problem when a protein is clearly not a sphere.619 It is not unusual for glycosylated proteins to show anomalous behavior on gel iltration (size exclusion chromatography) or SDS-PAGE.598,620–624 Analytical ultracentrifugation can present similar problems but can be managed.625 Ye626 has developed a useful approach for the determination of molecular mass by a combination of gel iltration and multiangle light scattering of the efluent fractions to measure protein and glycoprotein molecular weights with some accuracy. Mass spectrometry has proved useful for the determination of the molecular weights of glycoproteins627,628 and avoids the problems associated with the earlier techniques of gel iltration and SDS-PAGE. There is a substantial amount of information regarding the function of C1 INH and somewhat less on the chemistry of this protein. The mechanism of action for protease inhibition is a mechanism based on homology with other serpins, most notably α1-antitrypsin618,629–631 where there is inactivation via reaction within the RCL.544 The RCL of C1 INH is short compared to other serpins and elongation did not improve reactivity with plasma kallikrein.632 The reaction of C1 INH with C1s was shown by Harpel and Cooper633 to form an apparently covalent complex that could be dissociated by hydroxylamine,634 suggesting an ester linkage between the enzyme and the inhibitor. Lennick and coworkers635 studied the interaction of C1 INH with C1s and obtained a second-order rate constant of 6.0 × 104 M/s at 30°C in the absence of calcium ions; the reaction rate was modestly enhanced (35-fold) in the presence of heparin. Heparin was suggested to bind to both the protease and the inhibitor. Subsequent work from other researchers has shown interaction of heparin with the protease and with the serpin domain of C1 INH.636,637 Murray-Rust and coworkers636 showed that binding of heparin and dextran sulfate to C1s enhanced activity at low concentration and inhibited activity at high concentrations. Heparin has been demonstrated to have a modest effect on the reaction between human plasma kallikrein and C1 INH.638 C1 inhibitor is the major plasma protein inhibitor of factor XIIa,639,640 but the few studies on the effect of heparin on the reaction suggest little effect of heparin.641,642 It should be emphasized that when the action of C1 INH is examined in complex systems such as contact activation, the kinetic importance of individual reactions is dificult to determine with reasonable accuracy.643–646 Complicating this is the demonstration of the inactivation of factor XIa by C1 INH647 in a reaction that is stimulated by heparin. C1 inhibitor can inhibit a number of plasma proteases, with inhibition of plasma kallikrein being the one for which there is clear clinical support in hereditary angioedema; it is not known whether there are others. Type III hereditary angioedema occurs with normal functional and antigenic levels of C1 INH.648,649 Zuraw and Christiansen648 note that the primary mediator of swelling in hereditary angioedema is bradykinin derived from high-molecular-weight kininogen presumably by the action of plasma kallikrein generated from prekallikrein in contact activation.650–652 A gain-of-function mutation653 in factor XII has been discussed by Zuraw and Christiansen648 to explain the clinical indings with normal levels of C1 INH in type III hereditary angioedema.

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C1-inhibitor is similar to other serpins in that C1 INH has important function(s) other than protease inhibition.654,655 It must be acknowledged that this statement is based on observations in complex systems such that inhibition of protease(s) cannot be excluded as part of the observed physiological effect. Cheng and coworkers656 observed that C1 INH prevented LPS-induced vascular permeability. Liu and coworkers657 showed that C1 INH prevented endotoxin shock by binding LPS; binding involved the glycosylated amino-terminal domain C1 INH. Cai and coworkers658 presented studies supporting a role for C1 inhibitor in the regulation of leukocyte adhesion. All of these functions are based on the amino-terminal 113 residue segment which contains most of the carbohydrates of C1 INH. Gesuete and coworkers659 evaluated the use of a recombinant form of C1 INH in a murine model for stroke. Recombinant C1 INH (intravenous) markedly reduced cerebral damage resulting from ischemia and was shown to bind to mannose-binding lectin (MBL); plasma-derived C1 INH had no effect. There are, as would be expected, differences between the plasma-derived protein and the recombinant protein. Mannose-binding lectin is part of the lectin pathway of complement activation and C1 INH is a potent inhibitor of the mannose-binding lectin-associated serine protease-2 (MASP-2), the enzyme responsible for cleaving the C2 and C4 components of complement.660 Osthoff and coworkers661 have reported that deiciency of MBL is associated with a favorable outcome in ischemic stroke patients and suggest that mannose-binding lectin is a target for patients with ischemic stroke where thrombolytic intervention is contraindicated. Earlier studies662 from another laboratory had suggested that deiciency of MBL results in better outcome with stroke in mouse models and human patients. Morrison and coworkers663 suggested that while the deiciency of MBL results in some protection in an ischemic mouse model, it is suggested that “redundant complement pathway activation” may negate the positive effects of MBL deiciency. However, the combination of binding MBL and subsequent blocking of the lectin pathway and the classical pathway might be useful. Tomasi and coworkers664 have used a rat model to demonstrate that C1 INH with a mutant prourokinase is effective in stroke and may be safer than tPA. Banz and Rieben665 have reviewed the role of complement and complement inhibitors in ischemia–reperfusion. C1 inhibitor can modulate the activity of a large number of enzymes and heparin may inluence the reaction with some proteases. The most exciting prospect is ischemic stroke where recombinant C1-INH may prove useful. The usefulness of rC1-INH in ischemic–reperfusion injury appears to depend on the carbohydrate component, and information on the structural differences between the plasmaderived protein and the recombinant protein is critical for explaining the differences observed between the plasma-derived material and the recombinant protein described by Gesuete and coworkers.659 There is some work on the characterization of the carbohydrate sidechains in the recombinant protein expressed in rabbits,666,667 but no direct comparison with the human protein. Wolff and coworkers668 have expressed C1 INH in baculovirus, and Bos and coworkers669 have expressed C1 INH in Pichia. Both proteins were glycosylated but the pattern of glycosylation was different from the plasma protein and differed between the two expression systems. The protein expressed in the baculovirus system was smaller (SDS-PAGE) than the

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plasma-derived protein and possessed one-half of the speciic activity.668 The authors suggest that the lower molecular mass relects a decreased extent of glycosylation. The C1 INH expressed in Pichia pastoris had equivalent inhibitor activity as the plasma-derived protein toward C1s, plasma kallikrein, factor XIIa, and factor XIa; covalent complex formation was demonstrated for C1s and factor XIIa. Lamark and coworkers670 expressed an N-terminal truncated form of C1 INH (98–478), which had inhibitor activity against C1s and appeared to form a complex with C1s; integrity of disulide bonding is critical. The bulk of the data suggests that the effectiveness of C1 INH as a protease inhibitor requires the entire protein, including the amino-terminal extension, and the glycosylation is critical for biological function614,657,658,671 in inlammatory disorders and ischemic–reperfusion injury.659 Glycoengineering672,673 of the oligosaccharide chains will likely prove useful, considering the observed differences between the plasma-derived product and the recombinant product.659 The recombinant product is available674 and has been shown to be clinically effective in hereditary angioedema.675 However, there are other promising approaches to the management of hereditary angioedema, such as ecallantide.676 More work is required on the understanding of the role of the carbohydrate moiety in C1 INH biological function before the expanded use of recombinant C1 INH in ischemia–reperfusion injury.

PLASMINOGEN ACTIVATOR INHIBITOR-1 There are several plasminogen activator inhibitors,677 including plasminogen activator-2678 and plasminogen activator inhibitor-3, which is also known as protein c inhibitor.679,680 Plasminogen activator-2 is suggested as a primary inhibitor of the urokinase-type plasminogen activator, but there may be a broader function.681 However, the major factor regulating plasminogen activation is plasminogen activator inhibitor-1. Plasminogen activator inhibitor-1, which inhibits both tissue plasminogen activator and urokinase-type plasminogen activator, is a 45–50 kDa single-chain glycoprotein (15%–20% carbohydrate).682–691 The protein is present in plasma at a concentration of 20 μg/L.692,693 Plasminogen activator inhibitor-1 is an acute-phase protein and, as such, the concentration is quite variable694 and markedly increased in trauma patients.693 Plasminogen activator inhibitor-1 is also affected by circadian variation695–698 and there is speculation that this increase in PAI-1 activity might have a role in susceptibility to acute myocardial infarction. Plasminogen activator inhibitor-1 is associated in vivo with vitronectin, which can serve as a cofactor in the reaction with some proteases such as thrombin.699–703 Binding to vitronectin also maintains PAI-1 in an active conformation as opposed to the latent conformation.704–706 Plasminogen activator inhibitor-1 is a metastable protein707,708 somewhat similar to antithrombin and α1-antitrypsin, which also have latent conformations.709,710 Active PAI-1 binds to vitronectin, while latent PAI-1 does not bind to vitronectin. Plasminogen activator inhibitor-1 is unstable in solution and readily converts to the latent conformation.711 Metal ions and vitronectin have a major effect on the stability of PAI-1. The t1/2 for native PAI-1 in a 100 mM Tris buffer, pH 7.4, at 37°C is 1.14 h (measured by inhibition of tissue plasminogen activator), which is increased to 1.51 h in the presence of vitronectin. Metal ions had a differential effect, type 1 metal ions (i.e., magnesium, calcium) modestly increased the stability of PAI-1 in the presence

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or absence of vitronectin, while type II metal ions (i.e., copper, cobalt) decreased stability in the absence of vitronectin, but there was a major increase in the stability in the presence of vitronectin (and somatomedin).712 Deiciency of PAI-1 is very rare and is associated with mild to moderate bleeding.713,714 Plasminogen activator inhibitor-1 is thought to control the activity of tissue plasminogen activator in the vascular space and urokinase-type plasminogen activator on cell surface and in the extravascular space.715 Plasminogen activator inhibitor-1 is synthesized and secreted from a variety of tissues, with the endothelium likely being the most important for the regulation of vascular ibrinolysis.716–719 It is possible to determine the number of tPA–PAI-1 complexes in blood720,721 and these are considered risk factors for myocardial infarction.722 The tPA–PAI-1 complex is elevated in type 2 diabetics as is PAI-1 while tPA activity is decreased.723 There is increasing evidence that an increase in PAI-1 predisposes to thrombosis.724–727 Thus, as with α2-antiplasmin, there is more concern about excessive PAI-1 activity and therapeutic approaches to modulate PAI-1 activity.728–731 However, the broad range of suggested PAI-1-mediated effects presents challenges for speciic function-targeted effects. Examination of the data for tPA and PAI-1 shows that while there is substantial complex formation, free tPA remains even with excess PAI-1. In the study by Sahli and coworkers,723 PAI-1 was markedly elevated in type 2 diabetics as was tPA– PAI-1 complex compared to nondiabetic controls. tPA activity was modestly reduced compared to nondiabetic controls (0.40 ± 0.36 IU/mL vs. 0.82 ± 0.47 IU/mL). It is, however, not clear that the assay measured tPA enzyme activity as such but rather the binding of tPA to immobilized antibody.732 Studies on a irst-generation recombinant ibrinolytic agent did have two approaches to the measurement of tPA which actually measured catalytic activity.733 Seifried and coworkers733 used a coupled assay with plasminogen and a CNBr fragment of ibrinogen, with the hydrolysis of H-D-Val-Leu-Lys-p-nitroanilide generating the signal.734 A second assay used ibrin plates prepared from plasminogen-rich bovine ibrinogen to measure tPA in acid-treated plasma samples. Samples were obtained from normal volunteers after a bolus infusion of tPA. Tissue plasminogen-activator and antigen demonstrated similar pharmacokinetics showing persistence of activity. These studies were discussed later by Tanswell.735 Plasminogen activator inhibitor-1 does appear to be depleted during thrombolytic therapy but does “rebound” following cessation of thrombolytic therapy.736–738 Paganelli and coworkers737 showed that the increase in PAI-1 was more pronounced following streptokinase than with tPA; there was no change in PAI-1 in patients subjected to percutaneous transluminal coronary angioplasty (PTCA). There is another issue regarding the reaction of PAI-1 with plasminogen activators, which appears to be unresolved. Lindahl and coworkers739 showed that the tPA– PAI-1 complex slowly dissociated at physiological pH and ionic strength. Takada and Takada740 suggested that the tPA–PAI-1 complex retained the ability to activate plasminogen and such activity was enhanced by the presence of ibrin. These studies were performed using zymography with SDS-PAGE gels, and it is suggested that SDS dissociated the complex with the release of active enzymes as these researchers subsequently observed for the α2-antiplasmin–plasmin complex.741 There are other studies on the characterization of the tPA–PAI-1 complex,742,743 but none that addresses the

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stability of this complex in the circulation. Nilsson and coworkers744 evaluated the anticoagulant condition on the storage stability of the tPA–PAI-1 complex in plasma samples stored for at least 8 years at −70°C and observed lower values in acidiied citrated plasma (Stabilyte) than in citrated plasma, Ethylenediaminetetraacetic acid (EDTA) plasma, or serum. The highest values were obtained in EDTA plasma and serum and were attributed to the formation of complex on sample storage. HernestålBoman and coworkers745 showed that the concentration of tPA–PAI-1 complex decreased to a quantitatively negligible, but statistically signiicant extent on storage at −80°C for more than 11 years. The bulk of the information would suggest that the tPA–PAI-1 complex is stable on the formation and will not dissociate to form active tPA before the clearance of the complex from the circulation. Plasminogen activator inhibitor-1 is important in thrombosis and hemostasis but is likely more important for reasons other than vascular biology. The extravascular effects appear to be related to the inactivation of urokinase-type plasminogen activator as well as mechanisms still poorly understood but presumably unrelated to intravascular function; these effects will be discussed only briely. The expression of PAI-1 gene is highly responsive to changes in cell shape such as disruption of microtubule network and shear stress.746 PAI-1 gene expression is elevated in asthma, suggesting its potential as a biomarker and therapeutic target.747 Recent studies from this group748 have shown that cyclic adenosine monophosphate (AMP) induces PAI-1 expression in mast cells. Expression of PAI-1 in brain has an antiapoptotic effect on neurons and appears to be neuroprotective.749 Increased expression of PAI-1 gene is observed with oxidative challenge and results in tissue ibrosis.750 The proibrotic activity is suggested to be caused by the ability of PAI-1 to recruit macrophages into the interstitial space. The expression of PAI-1 gene is increased by inlammatory stimuli, such as TNF, IL-1, and IL6, while PAI-1 expression in vascular tissue is decreased by statins.751 Statins (simvastatin) reduces dexamethasone-induced expression of PAI-1 in human bone marrow adipocytes.752 Plasminogen activator inhibitor-1 is suggested to have value as a biomarker for a variety of diseases. Schmitt and coworkers found that both urokinase-type plasminogen activator and PAI-1 reached a high level of utility for a prognostic and predictive breastcancer biomarker in tumor tissue extracts.753–755 These researchers also developed techniques for the measurement of urokinase-type plasminogen activator and PAI-1 in formalin-ixed, parafin-embedded tissue sections.672 Malinowsky and coworkers756 reviewed the role of PAI-1 in tumor-associated processes such as extracellular matrix degradation, cell adhesion, and cell migration. PAI-1 functions in association with urokinase-type plasminogen activator and PAI-1 in tumor progression and metastasis and as such is an attractive target for therapeutic intervention.757 An increase in PAI-1 expression is associated with the progression of obesity-related cancers such as colorectal cancer.758 Plasminogen activator inhibitor-1 is synthesized and secreted by visceral adipose tissue and is considered an adipokine.759,760 Plasma levels of PAI-1 increase with the use of glucocorticoid during inlammation.761 Shen762 reported an increase in PAI-1 expression in endothelial cells by oxidized or glycated LDL. Cesari and coworkers have reviewed the various age-related disorders in which PAI-1 might be useful as a biomarker.763 The road to the development and validation of biomarkers is dificult,352 and it is not clear

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whether PAI-1 will be useful. However, the ongoing study cited755 earlier might prove most useful in node-negative breast cancer. There might be some value to PAI-1 as a biomarker in cancer, but it is not clear whether it is more useful than currently available diagnostics; it is possible that continued work in the biomarker area will yield better understanding of various pathologies. There does not appear to be any value to the development of PAI-1 as a therapeutic product. As suggested earlier, there is more interest in inhibiting PAI-1 activity. However, given the diverse actions of PAI-1, speciicity will be a challenge.

PROTEIN C INHIBITOR (PLASMINOGEN ACTIVATOR INHIBITOR-3) The presence of an inhibitor of activated protein C (APC) in plasma was established by Canield and Kisiel in 1982.764 Protein C inhibitor (PCI; SERPINA5) is found in blood and other biological luids, including semen.765 Laurell and coworkers765 reported that the concentration of PCI in plasma is 5.3 mg/L, while the concentration in semen is 220 mg/L. The half-life of 125I-labeled PCI in a rabbit model was 23.4 h while the half-life of the APC PCI was 19.6 min.766 Laurell and coworkers766 did observe that the APC–PCI complex is somewhat unstable; similar instability was not observed for the complex of APC with α1-antitrypsin. PCI inhibits a number of proteases, including APC, thrombin, factor Xa, trypsin, chymotrypsin, and plasma kallikrein767,768 with a reaction mechanism767,769 shown by other serpins.544 The reaction of PCI with APC, thrombin, and urokinase is modestly accelerated by heparin.770 The identity of PCI with plasminogen activator inhibitor-3 was established by Stief and coworkers771 in 1987. A consideration of the literature suggests that there is no strong evidence for a critical role of PCI in hemostasis or thrombosis. Also, as noted by Cooper and Church,768 APC might not be the primary target for PCI in the circulation. There is a suggestion of PCI function in tissue regeneration and tumor growth.772–774 Given the high concentration of PCI in semen,765 there was great interest in a possible function for PCI in male reproductive physiology775–777 but little recent activity. Table 7.1 lists two other inhibitors which are not discussed in the text. Plasminogen activator inhibitor-2 is thought to function primarily inside the cell778 or in the extravascular space as an inhibitor of urokinase-type plasminogen activator779 and lacks deinition of function.681 Thrombin-activatable ibrinolysis inhibitor (carboxypeptidase U) does not inhibit proteases but rather inluences the ibrinolytic process by making ibrin less likely to promote plasminogen activation. There is more discussion of TAFI in Chapter 9, but it is noted that there is substantial interest in developing inhibitors of TAFI activity.780–782 It is possible to conclude that, with the exception of antithrombin, the various plasma proteinase inhibitors are intended to function in the extravascular space rather than in the intravascular space. It is my sense that only the development of therapeutic concentrates of antithrombin and α1-antitrypsin has merit. Antithrombin has potential as a parenteral drug for antithrombin deiciency, but the successful use of an antithrombin product in the larger acquired deiciency market will require the

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early identiication of opportunity and aggressive use of the therapeutic product. Parenteral use of an α1-antitrypsin concentrate has potential for severe α1-antitrypsin deiciency with the caveat that liver ibrosis may be more critical than pulmonary dysfunction. The larger market for COPD will require the development of local delivery to the lower lung. It is possible that gene therapy such as the one developed by Neurologix for Parkinson’s disease783 would provide insight into device development for this purpose. There are observations that, with the exception of α2-macroglobulin, a substantial amount of every other inhibitor is in the extravascular space; however, both heparin cofactor II and plasminogen activator inhibitor-2 appear to function only in the intravascular space. Redundancy in speciicity of inhibition might imply our lack of understanding of function; alternatively, one could consider an extremely thoughtful article by Joe Gally and Gerry Edelman on degeneracy in biological systems.784 It is likely that the most effective approach to therapeutic intervention via plasma protein proteinase inhibitors other than antithrombin and α1-antitrypsin will involve modulation of gene expression.

REFERENCES 1. Travis, J. and Salvesen, G.S., Human plasma proteinase inhibitors, Annu. Rev. Biochem. 52, 655–709, 1983. 2. Boswell, D.R. and Carroll, R.W., The clinical signiicance of the serpins—A family of plasma enzyme inhibitors, Rec. Adv. Clin. Immunol. 4, 1–17, 1986. 3. Boswell, D.R. and Carroll, R.W., Genetic engineering and the serpins, BioEssays 8, 83–87, 1988. 4. Laskowski, M. and Kato, I., Protein inhibitors of proteinases, Ann. Rev. Biochem. 49, 593–626, 1980. 5. Travis, J. and Salvesen, G.S., Human plasma proteinase inhibitiors, Ann. Rev. Biochem. 52, 655–709, 1983. 6. Huang, X., Rezaie, A.R., Broze, G.J., Jr., and Olson, S.T., Heparin is a major activator of the anticoagulant serpin, protein Z-dependent protease inhibitor, J. Biol. Chem. 286, 8740–8751, 2011. 7. Hackeng, T.M. and Rosing, J., Protein S as cofactor for TFPI, Arterioscler. Thromb. Vasc. Biol. 29, 2015–2020, 2009. 8. Halili, M.A., Ruiz-Gómez, G., Le, G.T., et al., Complement component C2, inhibiting a latent serine protease in the classical pathway of complement activation, Biochemistry 48, 8466–8472, 2009. 9. Parker, B., Augeri, A., Capizzi, J., et al., Effect of air travel on exercise-induced coagulability and ibrinolytic activation in marathon runners, Clin. J. Sport Med. 21, 126–130, 2011. 10. Laterre, P.-F., Opal, S.M., and Abraham, E., A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia, Crit. Care 13, R36, 2009. 11. Van Den Boogaard, F.E., Brands, X., Schultz, M.J., et al., Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inlammatory and antimicrobial effects in murine pneumococcal pneumonia, J. Thromb. Haemost. 9, 122–132, 2011. 12. Emlen, W., Li, W., and Kirschink, M., Therapeutic complement inhibition: New developments, Semin. Thromb. Hemost. 36, 660–668, 2010. 13. Wasserman, R.L., Levy, R.J., Bewtra, A.K., et al., Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angiodema attacks, Ann. Allergy Asthma Immunol. 106, 62–68, 2011.

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812. Güngör, Y., Kayatas, M., Yildiz, G., et al., The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients, Ren. Fail. 33, 169–175, 2011. 813. D’Elia, A.V., Fabbor, D., Driul, L., et al., Plasminogen activator inhibitor-1 gene polymorphisms in pre-eclapsia, Semin. Thromb. Hemost. 37, 97–105, 2011. 814. Cho, S., Kang, J., Lyttle, C., et al., Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma, Ann. Allergy Asthma Immunol. 106, 371–377, 2011. 815. Mazouni, C., Bonnier, P., Romain, S., and Martin, B.M., A nomogram predicting the probability of primary breast cancer survival at 2- and 5-years using pathological and biological tumor parameters, J. Surg. Oncol. 103, 746–750, 2011. 816. Malmström, E., Mörgelin, M., Malmsten, M., et al., Protein C inhibitor—A novel antimicrobial agent, PLoS Pathog. 5, e1000698, 2009. 817. Fortenberry, Y.M., Brandal, S., Bialas, R.C., and Church, F.C., Protein C inhibitor regulates both cathepsin L activity and cell-mediated tumor cell migration, Biochim. Biophys. Acta 1800, 580–590, 2010. 818. Suzuki, K., Hepatocyte growth factor activator (HGFA): Its regulation by protein C inhibitor, FEBS J. 277, 2223–2229, 2010. 819. Bijsmans, I.T., Smits, K.M., de Graeff, P., et al., Loss of serpinA5 protein expression is associated with advanced-stage serous ovarian tumors, Mod. Pathol. 24, 463–470, 2011. 820. Radtke, K.P., Wenz, K.H., and Heimburger, N., Isolation of plasminogen activator inhibitor-2 (PAI-2) from human placenta. Evidence for vitronectin/PAI-2 complexes in human placenta extract, Biol. Chem. Hoppe Seyler 371, 1119–1127, 1990. 821. Scherrer, A., Kruithof, E.K., and Grob, J.P., Plasminogen activator inhibitor-2 in patients with monocytic leukemia, Leukemia 5, 479–486, 1991. 822. Jensen, P.H., Lorand, L., Ebbesen, P., and Gliemann, J., Type-2 plasminogenactivator inhibitor is a substrate for trophoblast transglutaminase and Factor XIII. Transglutaminase-catalyzed cross-linking to cellular and extracellular structures, Eur. J. Biochem. 214, 141–146, 1993. 823. Kruithof, E.K.O., Baker, M.S., and Bunn, C.L., Biological and clinical aspects of plasminogen activator inhibitor type 2, Blood 86, 4007–4024, 1995. 824. Astedt, B., Lindoff, C., and Lecander, I., Signiicance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy, Semin. Thromb. Hemost. 24, 431–435, 1998. 825. Robbie, L.A., Dummer, S., Booth, N.A., et al., Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leukocytes in patients with severe sepsis, Br. J. Haematol. 109, 342–348, 2000. 826. Hellgren, M., Hemostasis during normal pregnancy and puerperium, Semin. Thromb. Hemost. 29, 125–130, 2003. 827. Syrjänen, S., Naud, P., Sarian, L., et al., Up-regulation of plasminogen activator inhibitor-2 is associated with high-risk HPV and grade of cervical lesion at baseline but does not predict outcome of high-risk HPV infections or incident CIN, Am. J. Clin. Pathol. 132, 883–892, 2009. 828. Wang, W., Hendriks, D.F., and Sharpé, S.S., Carboxypeptidase U, a plasma carboxypeptidase with high afinity for plasminogen, J. Biol. Chem. 269, 15937–15944, 1994. 829. Foley, J.H., Cook, P.F., and Nesheim, M.E., Kinetics of activated thrombin-activatable ibrinolysis inhibitor (TAFIa)-catalyzed cleavage of C-terminal lysine residues of ibrin degradation products and removal of plasminogen-binding sites, J. Biol. Chem. 286, 19280–19286, 2011.

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830. Nesheim, M., Wang, W., Boffa, M., et al., Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and ibrinolysis, Thromb. Haemost. 78, 386–391, 1997. 831. Heylen, E., Van Goethem, S., Willemse, J. et al., Development of a sensitive and selective assay for the determination of procarboxypeptidase U (thrombin-activatable ibrinolysis inhibitor) in plasma, Anal. Biochem. 396, 152–154, 2010. 832. Julian-Vague, I., Morange, P.E., Aubert, H., et al., Plasma thrombin-activatable ibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the North and South of Europe, Arteriocler. Thromb. Vasc. Biol. 22, 867–873, 2002. 833. Willemse, J.L., Heylen, E., Nesheim, M.E., and Hendriks, D.F., Carboxypeptidase U (TAFIa): A new drug target for ibrinolytic therapy?, J. Thromb. Haemost. 7, 1962– 1971, 2009.

8

Vitamin K–Dependent Proteins

The vitamin K–dependent proteins are characterized by (1) their dependence on vitamin K for the synthesis of a mature, functional protein and (2) the presence of γ-carboxyglutamic acid (GLA) in the amino-terminal portion of the mature protein. The vitamin K–dependent proteins, with the exception of prothrombin, are modest, globular proteins with molecular weights between 50 and 70 kDa and are present in the plasma at low concentrations. A list of the characterized vitamin K– dependent proteins of biotechnological interest is presented in Table 8.1. In addition to the plasma proteins, γ-carboxylation occurs in the proteins found in the bones and cartilage.1–3 There has been recent interest in the role of Vitamin K in hard tissue function4–7 with an emphasis on osteoporosis,8,9 which may be associated with γ-carboxylation.9 As Vermeer and Theuwissen note, inadequate dietary Vitamin K is a modiiable risk factor for osteoporosis. The synthesis of the vitamin K–dependent proteins, as the name suggests, requires the presence of vitamin K, originally described by Henrik Dam in 1935.10 At the same time, dicoumarol was identiied by Karl Paul Link, at the University of Wisconsin, as the hemorrhagic agent in spoiled sweet clover. The story of the discovery of dicoumarol and the subsequent development of warfarin as an anticoagulant was provided by Link in 1959.11 Warfarin derives its name from the Wisconsin Alumni Research Foundation. Warfarin and a number of its derivatives are still widely used, despite the advent of several new direct enzyme inhibitors of thrombin and factor Xa.12 These drugs are discussed in the following text in greater detail and may impact the use of warfarin. Warfarin derivatives have a long record of use and physicians are mostly comfortable with their use. Vitamin K antagonists require continued laboratory monitoring and are sensitive to diet. Genetic polymorphism (warfarin resistance) can also result in a variable response to warfarin in the target population,13–15 suggesting that genotyping might be useful in determining a patient’s suitability for warfarin therapy.16 Proteins induced by the absence of vitamin K (PIVKA) are the uncarboxylated forms of the vitamin K–dependent proteins, which are found in the circulation17 in the presence of the vitamin K antagonist or in the absence of the dietary vitamin K, and were observed to be inhibitors of coagulation.18,19 More recently, PIVKA-II (uncarboxylated prothrombin) has been used as a biomarker for liver function.20–23 PIVKA has also been used as a biomarker for hard tissue disorders.24–26 The use of PIVKA-II has been suggested as an alternative marker for vitamin K antagonist

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TABLE 8.1 Vitamin K–Dependent Plasma Proteins Protein Factor II (Prothrombin) Factor VII Factor IX (Christmas factor) Factor X (Stuart–Prower factor) Protein C Protein S Protein Z

Plasma Concentration

Molecular Weight (kDa)b

Mg/L

nM

Half-Life

72

100–150

1400–2000

2–3 days

50 57

0.5 4.5–5

10 80–90

3–6 h 18–24 h

57

8–10

140–170

30–40 h

62 69 62

4–5 21–25 2.2

60–80 300–360 35

6h 40 h