Immunogenicity of Biopharmaceuticals

Transcription

1 Immunogenicity of Biopharmaceuticals

2 Biotechnology: Pharmaceutical Aspects Volume I: Pharmaceutical Profiling in Drug Discovery for Lead Selection R.T. Borchardt, E.H. Kerns, C.A. Lipinski, D.R. Thakker, B. Wang Volume II: Lypophilization of Biopharmaceuticals H.R. Constantino, M.J. Pikal Volume III: Methods for Structural Analysis of Protein Pharmaceuticals W. Jiskoot, D.J.A. Crommelin Volume IV: Optimizing the Drug-Like Properties of Leads in Drug Discovery R.T. Borchardt, E.H. Kerns, M.J. Hageman, D.R. Thakker, J.L. Stevens Volume V: Prodrugs: Challenges and Rewards, Parts 1 and 2 V.J. Stella, R.T. Borchardt, M.J. Hageman, R. Oliyai, H. Maag, J.W. Tilley Volume VI: Solvent Systems and Their Selection in Pharmaceutics and Biopharmaceutics P. Augustijns, M.E. Brewster Volume VII: Drug Absorption Studies: In Situ, In Vitro and In Silico Models C. Ehrhardt, K.J. Kim Volume VIII: Immunogenicity of Biopharmaceuticals M. van de Weert, E. H. Møller

3 Immunogenicity of Biopharmaceuticals Marco van de Weert University of Copenhagen Copenhagen, Denmark Eva Horn Møller University of Copenhagen Copenhagen, Denmark

4 Editors Marco van de Weert University of Copenhagen Copenhagen, Denmark Eva Horn Møller University of Copenhagen Copenhagen, Denmark ISBN: e-isbn: Library of Congress Control Number: American Association of Pharmaceutical Scientists All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper springer.com

5 Preface The last few decades have seen a rapid rise in novel drugs that mimic the compounds found in the body, such as peptides, proteins, oligonucleotides, certain therapeutic vaccines and genes. These products, especially when derived from biotechnological processing, are commonly referred to as biopharmaceuticals, although the classification as biopharmaceuticals differs slightly between Europe and the USA. Currently, these compounds constitute about 50% of all new drugs in pre-clinical development and about 25 30% of all new approved drugs. Biopharmaceuticals are strikingly different from low molecular weight drugs. Their delicate and complex nature, as well as their poor absorption through biological membranes, renders them a tough challenge for the scientist that wants to develop a rugged therapeutic for the market. As a result, delivery of these compounds is usually by injection or infusion, and the formulation is often unique for each new biopharmaceutical. Some of the analytical and formulation challenges of biopharmaceuticals have been addressed in two previous volumes in these series (volume II: Lyophilization of Biopharmaceuticals and volume III: Methods for Structural Analysis of Protein Pharmaceuticals). Biopharmaceuticals also introduce another challenge, usually absent for low molecular weight drugs, which is the ability to provoke an unwanted immune response. This immune response not only can reduce the effectiveness of the therapy, but can also lead to serious and life-threatening side-effects. Most biopharmaceuticals are to some extent immunogenic, and as a result the regulatory agencies insist that for protein pharmaceuticals potential antidrug antibody formation is studied during drug development. As many patents are expiring for first-generation biopharmaceuticals, biogeneric products (also termed biosimilars) are approaching the market. The risk of an immune response is a major concern in development of these biosimilars, especially since biopharmaceuticals are often too complex to characterize in full detail. Minor differences between two products may, however, lead to a big difference in immunogenicity, which may not be picked up in small clinical trials of short duration. The focus of this book is this potential unwanted immune response to biopharmaceuticals. The book is essentially divided into three parts: The first five chapters give a general overview of the nature, causes and (clinical) implications of immunogenicity of biopharmaceuticals, as well as of the prediction and analysis of immunogenicity. The next six chapters present specific cases of immune responses to biopharmaceuticals. The final chapter contains a v

6 vi Preface discussion on risk management of potential unwanted immunogenicity during the drug development process. The reader will note that the primary focus in all but one chapter is on unwanted immunogenicity of protein pharmaceuticals. This is due to the fact that these constitute the vast majority of biopharmaceutical products and that experience with other biopharmaceuticals is very limited. However, we believe that the concepts discussed in this book will be valid for non-protein biopharmaceuticals also. Regrettably, this book cannot give a definite answer to the question what factors cause unwanted immunogenicity, and what to do about it. Our insights into many of the mechanisms are still too limited to provide a clear answer. However, the book outlines the present state of knowledge and provides some potential explanations and caveats. The book should assist those working in early drug development of biopharmaceuticals and allow them to define potential areas of concern as early as possible. It will also serve the formulation scientist, who is responsible for preparing a stable and safe product. Awareness of some of the risk factors for immunogenicity development can aid in preventing future failure of the product. Pharmacologists and clinicians working with biopharmaceuticals may also benefit from this book, as it gives potential explanations for several observations and provides discussions on the methodology used to determine and quantify the immune response. Finally, the book will be of interest to academics, from M.Sc. upwards, working with biopharmaceuticals. It shows that there is still much to learn in this area, and it contains a number of warnings for those developing novel biopharmaceuticals and advanced drug delivery systems. The editors hope that this book will contribute to the development of better and safer biopharmaceuticals. We also hope that this book can promote a concerted effort in elucidating the important risk factors that lead to immunogenicity. Marco van de Weert Eva Horn Møller

7 Contents 1. Immune Reactions Towards Biopharmaceuticals a General, Mechanistic Overview... 1 Camilla Foged and Anne Sundblad 2. Clinical Aspects of Immunogenicity to Biopharmaceuticals Simona Malucchi and Antonio Bertolotto 3. Assessment of Unwanted Immunogenicity Meenu Wadhwa and Robin Thorpe 4. Models for Prediction of Immunogenicity Erwin L. Roggen 5. Immunogenicity of Biopharmaceuticals: Causes, Methods to Reduce Immunogenicity, and Biosimilars Marco van de Weert and Eva Horn Møller 6. Case Study: Immunogenicity of rhepo Arno Kromminga and Gilbert Deray 7. Case Study: Immunogenicity of Interferon-Beta Klaus Bendtzen and Arno Kromminga 8. Case Study: Immunogenicity of Insulin Henriette Mersebach, Fannie Smith, Thomas Sparre and Lisbeth Bjerring Jensen 9. Case Study: Immunogenicity of Factor VIII Silke Ehrenforth and Stephanie Seremetis 10. Case Study: Immunogenicity of Natalizumab Meena Subramanyam 11. Case Study: Immunogenicity of Anti-TNF Antibodies Klaus Bendtzen 12. Heparin-Induced Thrombocytopenia Carmel A. Celestin and John R. Bartholomew 13. Presenting an Immunogenicity Risk Assessment to Regulatory Agencies Paul Chamberlain Subject Index vii

8 Contributors John R. Bartholomew Section of Vascular Medicine, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, United States of America Klaus Bendtzen Institute for Inflammation Research (IIR), Rigshospitalet National University Hospital, BioMonitor ApS, Copenhagen, Denmark Antonio Bertolotto Centro di Riferimento Regionale Sclerosi Multipla, Hospital San Luigi, Orbassano, Turin, Italy Carmel A. Celestin Section of Vascular Medicine, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, United States of America Paul Chamberlain biologica Consulting, France Gilbert Deray Groupe Hospitalier Pitié-Salpêtrière, Paris, France Silke Ehrenforth Global Development, Novo Nordisk A/S, Bagsværd, Denmark Camilla Foged Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark ix

9 x Contributors Lisbeth Bjerring Jensen Global Development, Antibody Analysis, Novo Nordisk A/S, Måløv, Denmark Arno Kromminga Institute for Immunology, Clinical Pathology, Molecular Medicine (IPM), Hamburg, Germany Simona Malucchi Centro di Riferimento Regionale Sclerosi Multipla, Hospital San Luigi, Orbassano, Turin, Italy Henriette Mersebach Global Development, Novo Nordisk A/S, Bagsværd, Denmark Eva Horn Møller Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark Erwin L Roggen Novozymes AS, Bagsværd, Denmark elro@novozymes.com Stephanie Seremetis Global Development, Novo Nordisk A/S, Bagsværd, Denmark sest@novonordisk.com Fannie Smith Global Development, Novo Nordisk A/S, Bagsværd, Denmark fsm@novonordisk.com Thomas Sparre Global Development, Novo Nordisk A/S, Bagsværd, Denmark tspa@novonordisk.com Meena Subramanyam Biogen Idec, Inc., Cambridge, MA, United States of America meena.subramanyam@biogenidec.com Anne Sundblad Department of Medicine, Division of Hematology, Karolinska University Hospital and Institute, Stockholm, Sweden anne.sundblad@ki.se

10 Contributors xi Robin Thorpe Biotherapeutics group, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, United Kingdom Marco van de Weert Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark Meenu Wadhwa Biotherapeutics group, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, United Kingdom