Therapeutic Proteins E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 666

Veröffentlichungsjahr: 2012

Beschreibung

For this ready reference, the internationally renowned authority in the field, Roland Kontermann, has assembled a team of outstanding contributors from industry and academia to convey the worldwide knowledge on modifying therapeutic proteins in order to optimize their pharmacological potential. The result is a comprehensive work covering all approaches and aspects of the topic in one handy volume, making this indispensable reading for companies and research institutions working on the development of biopharmaceuticals.

Leseprobe

Table of Contents

Cover

Related Titles

Title page

Copyright page

Preface

List of Contributors

Part One: General Information

1 Half-Life Modulating Strategies – An Introduction

1.1 Therapeutic Proteins

1.2 Renal Clearance and FcRn-Mediated Recycling

1.3 Strategies to Modulate Plasma Half-Life

1.4 Half-Life Extension Strategies Applied to a Bispecific Single-Chain Diabody – A Case Study

1.5 Conclusion

2 Pharmacokinetics and Half-Life of Protein Therapeutics

2.1 Introduction

2.2 Basic Principles of Pharmacokinetics

2.3 Pharmacokinetics of Protein Therapeutics

2.4 Summary and Conclusions

Part Two: Half-Life Extension through Chemical and Post-translational Modifications

3 Half-Life Extension through PEGylation

3.1 Introduction

3.2 Preparation and Physico-Chemical Characterization of PEGylated Proteins

3.3 Pharmacokinetic (PK) Behavior of PEGylated Proteins

3.4 Safety of PEGylated Proteins

3.5 Conclusions

4 Half-Life Extension of Therapeutic Proteins via Genetic Fusion to Recombinant PEG Mimetics

4.1 Introduction

4.2 Mechanisms to Retard Kidney Filtration Using Conjugates of Drugs with Polymers

4.3 Naturally Occurring Repetitive Amino Acid Sequences

4.4 Gelatin-Like Protein Polymers

4.5 Elastin-Like Polypeptides

4.6 Polyanionic Polymers

4.7 Genetic Polymers™

4.8 XTEN Polypeptides

4.9 Glycine-Rich Homo-Amino-Acid Polymers

4.10 PASylation® Technology

4.11 Conclusions and Outlook

5 Half-Life Extension through O-Glycosylation

5.1 Introduction

5.2 The Role of O-Linked Oligosaccharide Chains in Glycoprotein Function

5.3 Designing Long-Acting Agonists of Glycoprotein Hormones

5.4 Conclusions and Summary

6 Polysialic Acid and Polysialylation to Modulate Antibody Pharmacokinetics

6.1 Introduction

6.2 Polysialic Acid in Nature

6.3 PSA Biosynthesis and Biodegradation

6.4 Pharmacological Effects of PSA

6.5 PSA Conjugation: Polysialylation for Therapeutic Applications

6.6 Summary

7 Half-Life Extension through HESylation®

7.1 Introduction

7.2 Hydroxyethyl Starch (HES)

7.3 Clinical Use of HES

7.4 HES Metabolism and Toxicology

7.5 HESylation® – Conjugation of Hydroxyethyl Starch to Drug Substances

7.6 HES–Protein Conjugates – Two Case Studies

7.7 Summary and Conclusion

Part Three: Half-Life Modulation Involving Recycling by the Neonatal Fc Receptor

8 The Biology of the Neonatal Fc Receptor (FcRn)

8.1 Homeostasis of Albumin and Immunoglobulin

8.2 Neonatal Fc Receptor Biochemistry

8.3 FcRn Function: Recycling

8.4 FcRn Function: Transport

8.5 FcRn Function: Mucosal Immune

8.6 Therapeutic Implications of FcRn

8.7 Conclusions

9 Half-Life Extension by Fusion to the Fc Region

9.1 Introduction

9.2 Immunoglobulin G

9.3 Strategies to Increase Cytokine Serum Stability and Half-Life

9.4 Methods to Construct Fc-Fusion Dimeric Proteins

9.5 Choice of Host for Expression

9.6 Purification of Fc Fusion Proteins

9.7 Demonstration of Biological Activity in Fc Constructs In Vitro and In Vivo

9.8 Pharmacokinetics

9.9 Applications of Fc Fusion Proteins

9.10 Immunogenicity

9.11 Conclusion

10 Monomeric Fc Fusion Technology: An Approach to Create Long-Lasting Clotting Factors

10.1 Introduction

10.2 Neonatal Fc Receptor and Interaction with Immunoglobulin G

10.3 Traditional Fc Fusion Proteins

10.4 Monomeric Fc Fusion Proteins Show Improved Biologic Properties

10.5 Summary

Acknowledgments

11 The Diverse Roles of FcRn: Implications for Antibody Engineering

11.1 Introduction

11.2 FcRn: Early Characterization and Diverse Expression Patterns

11.3 The Molecular Details of FcRn–IgG Interactions

11.4 FcRn Is Expressed Ubiquitously throughout the Body Where It Serves Multiple Functions

11.5 The Cell Biology of FcRn and Its Intracellular Transport of IgG

11.6 The Molecular Determinants of FcRn Trafficking

11.7 Engineering IgG–FcRn Interactions

11.8 Inhibitors of FcRn Function

11.9 Engineering Mice with Altered FcRn Function

11.10 Concluding Remarks

Acknowledgments

12 Half-Life Extension by Fusion to Recombinant Albumin

12.1 Introduction

12.2 Recombinant Albumin Fusion Proteins

12.3 Albumin Fusion to Complex Proteins

12.4 Recombinant Albumin Fusion Technology

12.5 Technological Advantages and Challenges

12.6 Pharmacokinetics of Recombinant Albumin Fusion Proteins

12.7 Preclinical Efficacy

12.8 Clinical Efficacy

12.9 Future Perspectives

12.10 Conclusion

Acknowledgments

13 AlbudAb™ Technology Platform – Versatile Albumin Binding Domains for the Development of Therapeutics with Tunable Half-Lives

13.1 Introduction

13.2 The Domain Antibody

13.3 Key Considerations for AlbudAb™-Based Molecules

13.4 Challenges of Albumin as a Target

13.5 Interactions of Albumin with AlbudAbs™

13.6 Bio-Analytical Characterization of AlbudAb™ Leads

13.7 Production of AlbudAb™ Fusions

13.8 Purification of AlbudAbs™

13.9 Biodistribution of AlbudAbs™

13.10 Summary and Conclusion

14 Half-Life Extension by Binding to Albumin through an Albumin Binding Domain

14.1 Introduction

14.2 Albumin Binding Domains and Engineered Derivatives

14.3 Albumin Binding Domains and Half-Life Extension In Vivo

14.4 Albumin Binding Domains and Immunogenicity

14.5 Bispecific Albumin Binding Domains for Novel Target Binding and Long Half-Life

14.6 Conclusion

Acknowledgments

15 Half-Life Extension by Binding to Albumin through Small Molecules

15.1 Albumin and Albumin Binders

15.2 Albumin-Binding Insulin Derivatives

15.3 “Albu” Tagging Technology

15.4 Concluding Remarks

Part Four: Half-Life Extension with Pharmaceutical Formulations

16 Half-Life Extension with Pharmaceutical Formulations: Liposomes

16.1 Rationale

16.2 Prospects of Liposomes as Drug Carriers and Their Pharmacokinetic Properties

16.3 Entrapment of Therapeutically Relevant Proteins in PEGylated Liposomes

16.4 Noncovalent Complex Formation of Proteins and PEGylated Liposomes

16.5 Conclusions

17 Half-Life Extension with Pharmaceutical Formulations: Nanoparticles by the Miniemulsion Process

17.1 Introduction

17.2 Polymeric Nanoparticles

17.3 Particles Obtained by Radical Polymerization and Their Functionalization

17.4 Other Polyreactions in Miniemulsion

17.5 Formation of Nanocapsules and Their Functionalization

17.6 Encapsulation of Markers and Detection of Nanoparticles in Biological Systems

17.7 Release of Materials

17.8 Conclusion

Acknowledgment

Index

Related Titles

Wang, W., Roberts, C. J. (eds.)

Aggregation of Therapeutic Proteins

2010

ISBN: 978-0-470-41196-4

Dübel, S. (ed.)

Handbook of Therapeutic Antibodies

Technologies, Emerging Developments and Approved Therapeutics

2010

ISBN: 978-3-527-32902-1

Jorgenson, L., Nielson, H. M. (eds.)

Delivery Technologies for Biopharmaceuticals

Peptides, Proteins, Nucleic Acids and Vaccines

2010

ISBN: 978-0-470-72338-8

An, Z. (ed.)

Therapeutic Monoclonal Antibodies

From Bench to Clinic

2009

ISBN: 978-0-470-11791-0

Jensen, K. (ed.)

Peptide and Protein Design for Biopharmaceutical Applications

2009

ISBN: 978-0-470-31961-1

Walsh, G. (ed.)

Post-translational Modification of Protein Biopharmaceuticals

2009

ISBN: 978-3-527-32074-5

Behme, S.

Manufacturing of Pharmaceutical Proteins

From Technology to Economy

2009

ISBN: 978-3-527-32444-6

The Editor

Prof. Dr. Roland Kontermann

University of Stuttgart

Institute of Cell Biology and Immunology

Allmandring 31

70569 Stuttgart

Germany

Cover Syringe: Corbis Images

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

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A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Preface

At the end of 2011, roughly 200 biologics were approved for therapeutic applica­tions and more than 600 were under clinical development. Many of these protein drugs, such as hormones, growth factors, cytokines, coagulation factors, and enzymes, are small in size and are rapidly cleared from circulation. Half-life extension strategies have therefore become increasingly important to improve the pharmacokinetic and pharmacodynamic properties of protein therapeutics, but also for reasons of compliance. Several half-life extension strategies are already utilized in approved drugs, including PEGylation, hyperglycosylation, binding to human serum albumin, and fusion to an immunoglobulin G (IgG) Fc region. However, there is a strong need for new strategies not only to further improve the pharmacokinetic properties but also to facilitate production and application of these half-life extended drugs. These strategies include those that increase the hydrodynamic radius of the drug, thus aiming at reducing the renal clearance, but also strategies that implement recycling by the neonatal Fc receptor (FcRn), which is responsible for the extraordinary long half-life of IgG molecules and serum albumin. In the past 5 to 10 years the field has experienced a rapid growth in the establishment of novel half-life extension strategies, including the application of novel hydrophilic polymers, the generation of recombinant PEG mimic polypeptide chains, and the development of various albumin-binding molecules. Furthermore, the half-life of IgG molecules was altered by engineering of the Fc region, which opens new opportunities for the development of next-generation antibody drugs.

This book is written by renowned experts in the field and is intended to provide a comprehensive overview of the various established but also emerging half-life extension strategies. It can be expected that in the near future many of these technologies will be evaluated in clinical trials and become established strategies to prolong the half-life and thus to improve the pharmacokinetic and pharmacodynamic properties of therapeutic proteins.

Stuttgart, October 2011

Roland Kontermann

List of Contributors

Gerd Bendas

University of Bonn

Pharmaceutical Department

Pharmaceutical Chemistry

An der Immenburg 4

53121 Bonn

Germany

Uli Binder

XL-protein GmbH

Lise-Meitner-Strasse 30

85354 Freising

Germany

Alan J. Bitonti

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Graeme J. Carroll

University of Notre Dame

Australia (Fremantle)

Department of Rheumatology

Fremantle Hospital and University of Western Australia

Perth, WA 6959

Australia

Chen Chen

Imperial College London

Department of Life Sciences

Exhibition Road

London SW7 2AZ

UK

Antony Constantinou

Imperial College London

Department of Life Sciences

Exhibition Road

London SW7 2AZ

UK

Mahendra P. Deonarain

Imperial College London

Department of Life Sciences

Exhibition Road

London SW7 2AZ

UK

Jennifer A. Dumont

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Fuad Fares

Department of Biology and Human Biology

Faculty of Natural Sciences

University of Haifa

Mount Carmel, Haifa 31095

Israel

Fredrik Y. Frejd

Affibody AB

Gunnar Asplunds Allé 24

SE-17163 Solna

Sweden

and

Uppsala University

Unit for Biomedical Radiation Sciences

Department of Oncology

Radiology and Clinical Immunology

Rudbeck Laboratory

75185 Uppsala

Sweden

Astrid Hartung

University of Bonn

Pharmaceutical Department

Pharmaceutical Chemistry

An der Immenburg 4

53121 Bonn

Germany

Christopher Herring

Biopharm Research and Development

GlaxoSmithKline

Thomas Hey

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg

Germany

Jalal A. Jazayeri

School of Biomedical Sciences

Charles Sturt University

Wagga Wagga, NSW 2678

Australia

Simona Jevševar

Sandoz Biopharmaceuticals

Lek Pharmaceuticals d.d.

Kolodvorska 27

SI-1234 Menges

Slovenia

Xiaomei Jin

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Jonghan Kim

Harvard School of Public Health

Department of Genetics and Complex Diseases

665 Huntington Avenue

Boston, MA 02115

USA

Helmut Knoller

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg

Germany

Roland E. Kontermann

University of Stuttgart

Institute of Cell Biology and Immunology

Allmandring 31

70569 Stuttgart

Germany

Meni Kunstelj

Sandoz Biopharmaceuticals

Lek Pharmaceuticals d.d.

Kolodvorska 27

SI-1234 Menges

Slovenia

Katharina Landfester

Max Planck Institute for Polymer Research

Ackermannweg 10

55128 Mainz

Germany

Alvin Luk

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Volker Mailänder

Max Planck Institute for Polymer Research

Ackermannweg 10

55128 Mainz

Germany

Bernd Meibohm

University of Tennessee Health Science Center

College of Pharmacy

Departments of Pharmaceutical Sciences

874 Union Avenue

Suite 5p

Memphis, TN 38163

USA

Hubert J. Metzner

CSL Behring GmbH

Preclinical Research and Development Department

Emil-von-Behring-Str. 76

35041 Marburg

Germany

Anna Musyanovych

Max Planck Institute for Polymer Research

Ackermannweg 10

55128 Mainz

Germany

Dario Neri

Swiss Federal Institute of Technology (ETH)

Institute of Pharmaceutical Sciences

Department of Chemistry and Applied Biosciences

Wolfgang-Pauli-Strasse 10

8093 Zurich

Switzerland

Raimund J. Ober

University of Texas Southwestern Medical Center

Department of Immunology

6000 Harry Hines Blvd.

Dallas, TX 75390

USA

University of Texas at Dallas

Department of Electrical Engineering

Richardson, TX 75083

USA

Robert T. Peters

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Glenn F. Pierce

Biogen Idec Hemophilia

9 Fourth Avenue

Waltham, MA 02451

USA

Joerg Scheuermann

Swiss Federal Institute of Technology (ETH)

Institute of Pharmaceutical Sciences

Department of Chemistry and Applied Biosciences

Wolfgang-Pauli-Strasse 10

8093 Zurich

Switzerland

Oliver Schon

Biopharm Research and Development

GlaxoSmithKline

Stefan Schulte

CSL Behring GmbH

Preclinical Research and Development Department

Emil-von-Behring-Str. 76

35041 Marburg

Germany

Arne Skerra

XL-protein GmbH

Lise-Meitner-Strasse 30

85354 Freising

Germany

and

Technische Universität München

Lehrstuhl für Biologische Chemie

Emil-Erlenmeyer-Forum 5 85350 Freising-Weihenstephan

Germany

Sabrina Trüssel

Swiss Federal Institute of Technology (ETH)

Institute of Pharmaceutical Sciences

Department of Chemistry and Applied Biosciences

Wolfgang-Pauli-Strasse 10

8093 Zurich

Switzerland

Peter Vorstheim

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg

Germany

E. Sally Ward

University of Texas Southwestern Medical Center

Department of Immunology

6000 Harry Hines Blvd.

Dallas, TX 75390

USA

Thomas Weimer

CSL Behring GmbH

Preclinical Research and Development Department

Emil-von-Behring-Str. 76

35041 Marburg

Germany

Part One: General Information

1

Half-Life Modulating Strategies – An Introduction

Roland E. Kontermann

1.1 Therapeutic Proteins

With roughly 200 biologics approved for therapeutic applications and more than 600 under clinical development [1], biotechnology products cover an increased proportion of all therapeutic drugs. Besides monoclonal antibodies and vaccines, which account for more than two-thirds of these produces, hormones, growth factors, cytokines, fusion proteins, coagulation factors, enzymes and other proteins are listed. An overview of the different classes of currently approved protein therapeutics is shown in Table 1.1. Except for antibodies and Fc fusion proteins, many of these proteins possess a molecular mass below 50 kDa and a rather short terminal half-life in the range of minutes to hours. In order to maintain a therapeutically effective concentration over a prolonged period of time, infusions or frequent administrations are performed, or the drug is applied loco-regional or subcutaneously utilizing a slow adsorption into the blood stream. These limitations of small size protein drugs has led to the development and implementation of half-life extension strategies to prolong circulation of these recombinant antibodies in the blood and thus improve administration and pharmacokinetic as well as pharmacodynamic properties.

Table 1.1 Proteins used as therapeutics.

1.2 Renal Clearance and FcRn-Mediated Recycling

The efficacy of protein therapeutics is strongly determined by their pharmacokinetic properties, including their plasma half-lives, which influence distribution and excretion. Although a small size facilitates tissue penetration, these molecules are often rapidly cleared from circulation. Thus, they have to be administered as infusion or repeated intravenous (i.v.) or subcutaneous (s.c.) bolus injections in order to maintain a therapeutically effective dose over a prolonged period of time, or are restricted to loco-regional treatment. The rapid elimination of these small molecules mainly occurs by renal filtration and degradation [2] (see also Chapter 2). A comparison of the half-lives of plasma proteins reveals the threshold for rapid excretion to be in the range of approximately 40–50 kDa, demonstrating that the size of the molecules is one of the determining factors (Figure 1.1). The glomerular filtration barrier is formed by the fenestrated endothelium, the glomerular basement membrane (GBM) and the slit diaphragm located between the podocyte foot processes [3]. The fenestrae between the glomerular endothelial cells have diameters between 50–100 nm, thus, allowing free diffusion of molecules. It was suggested that the slit diaphragm represents the ultimate macromolecular barrier, forming an isoporous, zipper-like filter structure with numerous small, 4–5 nm diameter pores and a lower number of 8–10 nm diameter pores [4–6]. In addition to size, the charge of a protein contributes to renal filtration. It has been suggested the proteoglycans of the endothelial cells and the GBM contribute to an anionic barrier, which partially prevents the passage of plasma macromolecules [3]. Consequently, the size of a protein therapeutic, that is, its hydrodynamic radius, and also its physiochemical properties, that is, charge, represent starting points in order to improve half-life. Interestingly, two kinds of molecules, serum albumin and IgGs, exhibit an extraordinary long half-life in humans. Thus, human serum albumin (HSA) has a half-life of 19 days and immunoglobulins (IgG1, IgG2 and IgG4) have half-lives in the range of 3 to 4 weeks [7, 8]. These long half-lives, which clearly set albumin and IgG apart from the other plasma proteins (Figure 1.1), are caused by a recycling process mediated by the neonatal Fc receptor (FcRn) [9–11] (see also Chapters 8 and 11). FcRn, expressed for example by endothelial cells, is capable of binding albumin and IgGs in a pH-dependent manner. Thus, after cellular uptake of plasma proteins through macropinocytosis, albumin and IgG will bind to FcRn in the acidic environment of the endosomes. This binding diverges albumin and IgG from degradation in the lysosomal compartment and redirects them to the plasma membrane, where they are released back into the blood plasma because of the neutral pH. This offers additional opportunities to extend or modulate the half-life of proteins, for example, through fusion to albumin or the Fc region of IgG [12].