Detection and Quantification of Antibodies to Biopharmaceuticals

MICHAEL G. TOVEY, PhD, INSERM Director of Research in the Laboratory of Biotechnology and Applied Pharmacology, Ecole Normale Supérieure de Cachan, France. He is an Associate Editor of the Journal of Interferon and Cytokine Research and author of more than two hundred articles on interferon, cytokines, and biotechnology.

INTRODUCTION: A PERSPECTIVE ix
Michael G. Tovey CONTRIBUTORS xxi

PART I RISK-BASED STRATEGIES 1

1 Principles of Risk Assessment and Monitoring of Antibody Responses to Biopharmaceuticals 3
Eugen Koren, Erik Foehr, and Charles A. O’Neill

PART II REGULATORY REQUIREMENTS 13

2 Immunogenicity of Therapeutic Proteins: A Regulatory Perspective 15
Susan Kirshner

3 Guidance on Immunogenicity Assessment of Biologically Derived Therapeutic Proteins: A European Perspective 37
Meenu Wadhwa and Robin Thorpe

4 Japanese Regulatory Perspective on Immunogenicity 57
Takao Hayakawa and Akiko Ishii-Watabe

PART III PRINCIPAL TECHNOLOGIES EMPLOYED FOR THE QUANTIFICATION OF ANTI-DRUG ANTIBODIES 81

5 Enzyme Immunoassays and Radioimmunoassays for Quantification of Anti-TNF Biopharmaceuticals and Anti-Drug Antibodies 83
Klaus Bendtzen and Morten Svenson

6 Confirmatory Immunogenicity Assays 103
Eric Wakshull and Daniel Coleman

7 The Use of Pharmacodynamics as a Surrogate Marker for the Detection of Anti-Drug Neutralizing Antibodies 119
Florian Deisenhammer

8 Cell-Based Assays for the Detection of Neutralizing Antibodies to Interferon Beta (IFN-β) and Tumor Necrosis Factor Alpha (TNF-α) Inhibitors 133
Anthony Meager

9 Detection of Neutralizing Antibodies against Interferon Beta by Real-Time RT-PCR 157
Francesca Gilli and Antonio Bertolotto

10 Competitive Ligand-Binding Assays for the Detection of Neutralizing Antibodies 175
Bonnie W. Wu, George R. Gunn III, and Gopi Shankar

11 The Use of Surface Plasmon Resonance for the Detection and Characterization of Antibodies 193
Steven J. Swanson and Daniel Mytych

12 Hypersensitivity Reactions to Biopharmaceuticals: Detection and Quantification of Drug-Specific IgE Antibodies 211
Jörgen Dahlström and Lennart Venemalm

PART IV ASSAY STANDARDIZATION AND VALIDATION 233

13 Standardization and Validation of Immunoassays 235
Daniel Kramer

14 Standardization and Validation of Cell-Based Assays for the Detection of Neutralizing Anti-Drug Antibodies 243
Deborah Finco-Kent and Amy Grenham

15 Standardization of Neutralizing Antibody Unitage by Bioassay Design: Constant Antigen and Constant Antibody Methodology 269
Sidney E. Grossberg, Yoshimi Kawade, and Leslie D. Grossberg

PART V STATISTICAL CONSIDERATIONS 287

16 Cut Points and Performance Characteristics for Anti-Drug Antibody Assays 289
Viswanath Devanarayan and Michael G. Tovey

17 Dilutional Linearity for Neutralizing Antibody Assays 309
David Lansky and Carrie Wager

PART VI ADAPTATION OF ANTI-DRUG ANTIBODY ASSAYS TO CHALLENGING CONDITIONS 319

18 Detection of Antibodies to Biopharmaceuticals in the Presence of High Levels of Circulating Drug 321
Arno Kromminga and Michael G. Tovey

19 Antibody Assays in Animal Research 331
Vera Brinks, Francesca Gilli, Melody Sauerborn, and Huub Schellekens

20 Immunogenicity of Microbial Digestive Enzymes for Oral Replacement Therapy in Pancreatic Exocrine Insufficiency 343
Claudia Berger and Uwe Niesner

PART VII NOVEL TECHNOLOGIES FOR THE QUANTIFICATION OF NEUTRALIZING ANTIBODIES 369

21 Measurement of Biologically Active Drug as an Approach to Detection of Anti-Drug Neutralizing Antibodies 371
Yao Zhuang and Shalini Gupta

22 A Novel One-Step Cell-Based Assay for Quantification of Neutralizing Antibodies to Biopharmaceuticals 383
Christophe Lallemand and Michael G. Tovey

INDEX 399