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NONCLINICAL DEVELOPMENT
OF BIOLOGICS, VACCINES AND
SPECIALTY BIOLOGICS
SECOND EDITION
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NONCLINICAL
DEVELOPMENT OF
BIOLOGICS,
VACCINES AND
SPECIALTY
BIOLOGICS
SECOND EDITION
Edited by
LISA M. PLITNICK
MRL, Merck & Co., Inc., Rahway, NJ, United States
CLAUDETTE L. FULLER
Non-Clinical Safety and Toxicology, Genmab, Plainsboro, New Jersey, United States
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Notices
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our understanding, changes in research methods, professional practices, or medical treatment may become
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methods they should be mindful of their own safety and the safety of others, including parties for whom
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liability for any injury and/or damage to persons or property as a matter of products liability, negligence or
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material herein.
ISBN: 978-0-443-13344-2
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Publisher: Stacy Masucci
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Typeset by TNQ Technologies
Contents
Contributors ix
Preface xi
Acknowledgments xiii
I
Development of biopharmaceuticals
1. Overview of biopharmaceuticals and
comparison with small-molecule drug
development
Christina de Zafra, Eric Harstad, and Amy Kim
Introduction 3
Routes of administration 6
Nonclinical species for toxicology testing 7
Carcinogenicity assessment 9
Best practices in toxicology program design in the
wake of the COVID-19 pandemic 9
Classes of biopharmaceuticals 11
References 14
2. Nonclinical development of monovalent
and polyvalent biopharmaceuticals
Karin Staflin, Chandrashekhar K. Korgaonkar,
Padma Kumar Narayanan, Rodney A. Prell, Donna W. Lee,
Wendy G. Halpern, and Anu Connor
Introduction 20
Monovalent biopharmaceuticals 21
Polyvalent biopharmaceuticals 21
Technology and formats 23
General challenges and considerations 28
Summary of challenges 35
T celledependent bispecific antibody
biotherapeutics 35
Dual-targeting antibodies 43
Combination therapeutics 49
Summary 50
References 51
3. Regulatory guidelines and their
application in the nonclinical evaluation of
biological medicines
Claudette L. Fuller, Maggie Dempster, and Marque D. Todd
Introduction 58
Species selection 61
Study design considerations for repeat-dose
studies 66
Immunogenicity 71
Reproductive and developmental toxicity 74
Species selection considerations 74
Studies for the assessment of reproductive
toxicity 76
Genotoxicity and carcinogenicity 81
Special considerations for anticancer drugs 84
First-in-human (FIH) clinical trial 86
Summary 89
References 90
Further reading 93
4. Early de-risking strategy for
biotherapeutics
Padma Kumar Narayanan, Anna Dahlman, and Ping Peng
Introduction 96
Establishing a safety profile for biotherapeutics in
discovery and early development 97
General safety considerations related to
biotherapeutics in discovery and early
development 97
Evaluation of immunotoxicity 110
Can we better address potential off-target toxicity?
116
Summary 122
References 122
Further reading 129
v
5. Novel biopharmaceuticals:
Pharmacokinetics, pharmacodynamics, and
bioanalytics
Sieto Bosgra and Manish Gupta
Introduction 132
Absorption, distribution and elimination of
biopharmaceuticals 132
Modifications and impact on PK and
biodistribution 140
“Metabolism” and biodistribution for
biopharmaceuticals 144
Immunogenicity and impact on PK and
biodistribution 145
Pharmacokinetics and pharmacodynamics 146
Nonclinical to clinical translation 150
Bioanalytics 152
Summary 166
Acknowledgment 166
References 166
II
Vaccines
6. Introduction to vaccines and adjuvants
Deborah L. Novicki
Introduction 180
Impacts of current vaccines on
human health 193
The science (and business) of vaccinology 193
“Outbreaks, they’re inevitable.
But turning into a pandemic, that’s
optional” 199
WHO’s 10 major threats to global health 201
Therapeutic vaccines 205
Complexity of vaccines from a product quality
perspective 209
Nonclinical testing 210
Vaccine development using the
Animal Rule 211
WHO threat #8dVaccine hesitancy (and the
importance of vaccinology education) 213
Summary 217
References 218
7. Regulatory aspects of nonclinical
vaccine development
Lisa M. Plitnick
Introduction 227
Regulatory guidelines 228
Repeat-dose toxicity evaluation 231
Developmental toxicity 233
Biodistribution 234
Environmental risk assessment 234
Genotoxicity and carcinogenicity 235
Safety pharmacology 235
Neurovirulence 236
Conclusion 236
References 236
8. Special considerations for the
nonclinical safety assessment of vaccines
Jayanthi J. Wolf
Introduction 240
De-risking strategies for vaccines 240
General de-risking strategies for vaccines 242
De-risking strategies for specific vaccine types 244
Pharmacokinetics and pharmacodynamics
assessments 246
Assays 246
Ligand-binding assays 247
Cell-mediated immune response assays 247
Functional assays 248
Differences in the nonclinical safety assessment of
vaccines and biopharmaceutical drugs 248
Summary 250
References 250
III
Specialty biologics and indications
9. Preclinical development of viral vector
gene therapies
Mary S. Newman, Eloise Hudry, Jacqueline Brassard, and
Justine J. Cunningham
Abbreviations 256
Background: Vectors and applications 258
CONTENTSvi
General considerations regarding chemistry
manufacturing and controls (CMC):
Viral vectors manufacturing, characterization,
and testing 270
Nonclinical development 273
Translating nonclinical data to regulatory
success 283
Lessons learned from clinical trials to guide future
development 290
Conclusions 300
References 301
10. Considerations for nonclinical studies
conducted to support the development of
cellular therapies
Michael W. Bolt and Padma Kumar Narayanan
Introduction 314
Basic principles based on regulatory guidance 316
Development challenges 321
Conclusion 342
References 342
11. Biological therapies for cancer
Gautham K. Rao, Claudette L. Fuller, and Karen D. Price
Introduction 350
Global regulatory guidances 351
General principles of toxicology assessments 352
Nonclinical studies and principles of study
design 355
Tissue-binding study 359
Nonclinical development of marketed
biologics 364
Monoclonal antibodies 366
Rituximab 367
Bevacuzimab 369
Recombinant analogs of endogenous human proteins
(interferons, cytokines, enzymes) 387
Summary 390
References 391
Further reading 396
12. Considerations in the development of
pluripotent stem cellebased therapies
Justine J. Cunningham, Alexandra Capela, Catherine Priest, and
Eugene P. Brandon
Introduction 400
Important early decisions: Chemistry, manufacturing,
and controls 407
Nonclinical development 419
Translating nonclinical data to clinical
application 436
Global regulatory guidance 437
Clinical studies of PSC-derived therapeutic
candidates 438
Summary 441
References 443
Index 451
CONTENTS vii
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Contributors
Michael W. Bolt Preclinical Safety Assessment,
Vertex, Boston, MA, United States
Sieto Bosgra Clinical Pharmacology & Quanti-
tative Science, Genmab, Utrecht, the Netherlands
Eugene P. Brandon BrainXell Therapeutics, San
Diego, CA, United States
Jacqueline Brassard Brassard Toxicologic Pa-
thology Consultancy Corporation, Tustin, CA,
United States
Alexandra Capela Vita Therapeutics, Baltimore,
MD, United States
Anu Connor Ipsen, Cambridge, MA, United
States
Justine J. Cunningham REGENXBIO, Rock-
ville, MD, United States
Anna Dahlman Non-clinical Safety & Toxicol-
ogy, Genmab, Plainsboro, NJ, United States
Maggie Dempster GSK, Collegeville, PA,
United States
Christina de Zafra Drug Safety Research &
Development, Pfizer Research & Development,
Pfizer Inc., South San Francisco, CA, United
States
Claudette L. Fuller Non-Clinical Safety and
Toxicology, Genmab, Plainsboro, NJ, United
States
Manish Gupta Translational & Quantitative
Sciences, Genmab, Princeton, NJ, United States
Wendy G. Halpern Safety Assessment, Gen-
entech, South San Francisco, CA, United States
Eric Harstad Drug Safety Research & Devel-
opment, Pfizer Research & Development,
Pfizer Inc., South San Francisco, CA, United
States
Eloise Hudry Novartis Institutes for BioMedical
Research, Cambridge, MA, United States
Amy Kim Oncology Research, Pfizer Oncology
Division, Pfizer Inc., South San Francisco, CA,
United States
Chandrashekhar K. Korgaonkar Regeneron
Pharmaceuticals, Inc, Tarrytown, NY, United
States
Donna W. Lee Safety Assessment, Genentech,
South San Francisco, CA, United States
Padma Kumar Narayanan Preclinical and
Clinical Development Sciences, Wave Life Sci-
ences, Lexington, MA, United States
Mary S. Newman Alchemy Development Part-
ners, LLC, San Geronimo, CA, United States
Deborah L. Novicki DL Novicki Toxicology
Consulting LLC, Marlborough, MA, United
States
Ping Peng Non-clinical Safety & Toxicology,
Genmab, Plainsboro, NJ, United States
Lisa M. Plitnick MRL, Merck & Co., Inc., Rah-
way, NJ, United States
Rodney A. Prell Safety Assessment, Genentech,
South San Francisco, CA, United States
Karen D. Price Janssen, Research and Develop-
ment, Springhouse, PA, United States
Catherine Priest Neurona Therapeutics, South
San Francisco, CA, United States
Gautham K. Rao Genentech, Department of
Safety Assessment, South San Francisco, CA,
United States
Karin Staflin Safety Assessment, Genentech,
South San Francisco, CA, United States
Marque D. Todd Renaissance Consulting, Inc.,
Escondido, CA, United States
Jayanthi J. Wolf Regulatory Affairs and Quality
Assurance, Atea Pharmaceuticals Inc., Boston,
MA, United States
ix
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