Immunotoxicology Strategies for Pharmaceutical Safety Assessment

DANUTA J. HERZYK, PHD, is the Senior Scientific Director in the Safety Assessment Department of Merck Research Laboratories. She previously worked in immunologic toxicology for GlaxoSmithKline. A member of the Society of Toxicology, Drug Information Association, and American Association of Immunologists, Dr. Herzyk has published over forty articles. She serves on the editorial board of Perspectives in Experimental and Clinical Immunotoxicology. JEANINE L. BUSSIERE, PHD, is an Executive Director of Toxicology at Amgen. She is the author or coauthor of eight book chapters and approximately fifty articles. She is on the editorial board of Journal of Immunotoxicology. Dr. Bussiere is a member of the Society of Toxicology, American College of Toxicology, and Drug Information Association.

Preface ix

Contributors xi

Introduction to Immunotoxicology xvii
Jack H. Dean

Part I Current Regulatory Expectations For Immunotoxicity Evaluation Of Pharmaceuticals 1

1 Current Regulatory Expectations for Immunotoxicity Evaluation of Pharmaceuticals 3
Kenneth L. Hastings

Part II Weight of Evidence Review: A New Strategy In Immunotoxicology 11

2.1 Clinical Pathology as Crucial Insight into Immunotoxicity Testing 13
Ellen Evans

2.2 Histomorphology of the Immune System: A Basic Step in Assessing Immunotoxicity 27
Patrick Haley

2.3 Need for Specialized Immunotoxicity Tests 45
Kazuichi Nakamura

2.4 Specific Drug-Induced Immunotoxicity: Immune-Mediated Hemolytic Anemia 55
Raj Krishnaraj

Part III Nonclinical Core Immunotoxicity Testing In Drug Development 65

3.1.1 T Cell-Dependent Antibody Response Tests 67
Joseph R. Piccotti

3.1.2 Natural Killer Cell Assay and Other Innate Immunity Tests 77
Lisa Plitnick

3.1.3 Cellular Immune Response in Delayed-Type Hypersensitivity Test 87
Karen Price

3.2 Evaluation of Drug Effects on Immune Cell Phenotypes 103
Laurie Iciek

Part IV Extended Immunotoxicology Assessment: Ex Vivo Models 125

4.1 Functional Cellular Responses and Cytokine Profiles 127
Elizabeth R. Gore

4.2 Application of Flow Cytometry in Drug Development 141
Padma Narayanan, Renold J. Capocasale, Nianyu Li, and Peter J. Bugelski

Part V Extended Immunotoxicology Assessment: In Vivo Models 161

5.1 Animal Models of Host Resistance 163
Gary R. Burleson and Florence G. Burleson

5.2 Approaches to Evaluation of Autoimmunity 179
Danuta J. Herzyk

Part VI Immunotoxicity Testing In Biopharmaceutical Development 189

6.1 Differentiation between Desired Immunomodulation and Potential Immunotoxicity 191
Jeanine L. Bussiere and Barbara Mounho

6.2 Relevant Immune Tests across Different Species and Surrogate Models 199
Jeanine L. Bussiere

6.3 Antidrug Antibody Responses in Nonclinical Studies and Their Implications 209
Barbara Mounho

Part VII Development of Vaccines 217

7.1 Pharmacological Immunogenicity and Adverse Responses to Vaccines 219
Mary Kate Hart, Mark Bolanowski, and Robert V. House

7.2 Immunotoxicological Concerns for Vaccines and Adjuvants 229
Catherine Kaplanski, Jose Lebron, Jayanthi Wolf, and Brian Ledwith

Part VIII Testing For Drug Hypersensitivity 239

8.1 Systemic Hypersensitivity 241
Raymond Pieters

8.2 Nonclinical Models to Assess Respiratory Hypersensitivity Potential 257
Curtis C. Maier

Part IX Testing For Developmental Immunotoxicity 271

9.1 Developmental Immunotoxicity in Rodents 273
Rodney R. Dietert and Leigh Ann Burns-Naas

9.2 Developmental Immunotoxicity in Nonhuman Primates 299
Pauline L. Martin and Eberhard Buse

Part X New Methods In Assessing Immunomodulation, Immunotoxicity, and Immunogenicity 319

10.1 Alternative Animal Models for Immunomodulation and Immunotoxicity 321
Peter J. Bugelski

10.2 Animal Models for Preclinical Comparative Immunogenicity Testing 345
Daniel Wierda

10.3 T Cell Epitopes and Minimization of Immunogenicity 361
Harald Kropshoffer and Thomas Singer

Part XI Bridging Immunotoxicology To Clinical Drug Development 373

11 Bridging Immunotoxicology to Clinical Drug Development 375
Ian Gourley and Jacques Descotes

Index 385