Nonclinical Development of Biologics, Vaccines and Specialty Biologics

2nd Edition - November 16, 2024
Editors: Lisa M. Plitnick, Claudette L. Fuller
Language: English
Hardback ISBN:
9 7 8 - 0 - 4 4 3 - 1 3 3 4 4 - 2
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 1 3 3 4 5 - 9

Nonclinical Development of Biologics, Vaccines and Specialty Biologics, Second Edition, is a complete reference devoted to the nonclinical safety assessment of novel biopharma… Read more

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Nonclinical Development of Biologics, Vaccines and Specialty Biologics, Second Edition, is a complete reference devoted to the nonclinical safety assessment of novel biopharmaceuticals, vaccines, cell and gene therapies, and oncology therapeutics. Updated and revised, the new edition compares and contrasts these types of biologics with one another and with small molecule drugs, while incorporating the most current and essential international regulatory guidelines. This book discusses the different types of biologics, as well as early characterization strategies, principles of study design, nonclinical pharmacokinetics and pharmacodynamics, nonclinical assays, and regulatory guidelines. A coedited book with chapters authored by leading experts in the field, this comprehensive reference provides critical insights to all researchers involved in early through late-stage biologics.

Title of Book
Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Acknowledgments
Section I. Development of biopharmaceuticals
Chapter 1. Overview of biopharmaceuticals and comparison with small-molecule drug development
Introduction
Routes of administration
Nonclinical species for toxicology testing
Carcinogenicity assessment
Best practices in toxicology program design in the wake of the COVID-19 pandemic
Classes of biopharmaceuticals
Chapter 2. Nonclinical development of monovalent and polyvalent biopharmaceuticals
Introduction
Monovalent biopharmaceuticals
Polyvalent biopharmaceuticals
Scientific rationale for PVBs
Technology and formats
Chemical cross-linking and hybridoma fusion approaches
Recombinant formats using engineered protein scaffolds
General challenges and considerations
Understanding expression, regulation, and distribution of all targets
Understanding target biology
Effector function
Species selection
Tissue cross-reactivity study
Pharmacokinetics
Molecular properties
Immunogenicity
Selection of starting dose
Summary of challenges
T cell–dependent bispecific antibody biotherapeutics
Catumaxomab (EpCAM/CD3 multitargeting full-length antibody)
MT110 (EpCAM/CD3 TDB, BiTE format)
Case Example 4: Formation of ADAs limited the conduct of sub-chronic (3-month) or chronic toxicology studies
Dual-targeting antibodies
Oncology
Coagulation disorder
Hemophilia
Ocular disease
Age-related macular degeneration
Bispecific antibodies of endogenous receptor ligands for CNS delivery of biotherapeutics across blood–brain barrier
Combination therapeutics
Case study: SARS-CoV-2 antibody cocktail
Summary
Chapter 3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines
Introduction
Species selection
Selecting a relevant species
Screening paradigms
Use of tissue cross-reactivity assays
When a relevant species cannot be identified?
Study design considerations for repeat-dose studies
Safety pharmacology endpoints
Dose selection
Route of administration
Recovery periods for repeat-dose studies
Immunogenicity
Reproductive and developmental toxicity
Species selection considerations
Studies for the assessment of reproductive toxicity
Fertility and early embryonic development (FEED): stages A and B
Embryo-fetal development (EFD) and enhanced pre- and post-natal development (ePPND): stages C and D and C through F
Genotoxicity and carcinogenicity
Genotoxicity
Carcinogenicity
Special considerations for anticancer drugs
First-in-human (FIH) clinical trial
Nonclinical safety program considerations
Dealing with the data—NOAEL considerations
Translation of nonclinical data to clinical trial dose selection
Summary
Chapter 4. Early de-risking strategy for biotherapeutics
Introduction
Establishing a safety profile for biotherapeutics in discovery and early development
General safety considerations related to biotherapeutics in discovery and early development
Target liability assessment
In vivo studies
Antibody-based modalities
Monoclonal antibody therapies
Effector modified antibodies
Bispecific and multimer antibody modalities
Other recombinant (nonantibody) protein therapeutics
Growth factors
Recombinant cytokines
Evaluation of immunotoxicity
Immunosuppressive biotherapeutics
Immunostimulatory biotherapeutics
Tumor lysis syndrome (TLS), first dose effect and cytokine release syndrome (CRS) induced by mAbs
TGN1412 case study
Hypersensitivity reactions
Can we better address potential off-target toxicity?
Hematologic toxicity
Bevacizumab case study
LY2541546 (antisclerostin) case study
Omalizumab case study
AMG X case study
mAbY.1 case study
Summary
Chapter 5. Novel biopharmaceuticals: Pharmacokinetics, pharmacodynamics, and bioanalytics
Introduction
Absorption, distribution and elimination of biopharmaceuticals
Absorption
Distribution and elimination: Nonspecific processes
mAbs, mAb fragments, and mAb constructs
Therapeutic proteins and peptides
Distribution and elimination: Target-mediated processes
Monoclonal antibodies
Therapeutic proteins and peptides
Modifications and impact on PK and biodistribution
“Metabolism” and biodistribution for biopharmaceuticals
Immunogenicity and impact on PK and biodistribution
Pharmacokinetics and pharmacodynamics
PK methods
Representative PK for molecule types
Pharmacodynamics, PK/PD methods and examples
Model types and examples
Nonclinical to clinical translation
Human PK projections
Exposure response: Determining minimum and maximum targets for FIH dosing
Bioanalytics
Method development guidances and regulations
Methods and platforms
Immunoassays
LC-MS
Assays
Drug exposure
Biomarkers: Target engagement
Immunogenicity assessment
Summary
Section II. Vaccines
Chapter 6. Introduction to vaccines and adjuvants
Introduction
The two arms of the immune system
Regulation of vaccines
US FDA definition of a vaccine
Impacts of current vaccines on human health
The science (and business) of vaccinology
Vaccine platforms can accelerate development and approval of new vaccines
Are adjuvant platforms feasible?
“Outbreaks, they’re inevitable. But turning into a pandemic, that’s optional”
WHO's 10 major threats to global health
Other vaccines needed for serious infectious diseases
Antimicrobial resistant bacteria
“There Was a Fungus Among Us”
Parasitic diseases
Therapeutic vaccines
Platforms for therapeutic vaccines
Complexity of vaccines from a product quality perspective
Nonclinical testing
Vaccine development using the Animal Rule
WHO threat #8—Vaccine hesitancy (and the importance of vaccinology education)
Summary
Chapter 7. Regulatory aspects of nonclinical vaccine development
Introduction
Regulatory guidelines (Table 7.1)
Alternate approaches
Repeat-dose toxicity evaluation (Table 7.2)
Developmental toxicity
Biodistribution
Environmental risk assessment
Genotoxicity and carcinogenicity
Safety pharmacology
Neurovirulence
Conclusion
Chapter 8. Special considerations for the nonclinical safety assessment of vaccines
Introduction
De-risking strategies for vaccines
General de-risking strategies for vaccines
De-risking strategies for specific vaccine types
Vaccines with adjuvants
Therapeutic vaccines
Pharmacokinetics and pharmacodynamics assessments
Assays
Ligand-binding assays
Cell-mediated immune response assays
Functional assays
Differences in the nonclinical safety assessment of vaccines and biopharmaceutical drugs
Summary
Section III. Specialty biologics and indications
Chapter 9. Preclinical development of viral vector gene therapies
Background: Vectors and applications
Delivering gene therapy products: Nonviral and viral vectors
Nonviral vectors
Viral vectors
Nonintegrating viral vectors
Integrating viral vectors
Therapeutic applications and beyond
General considerations regarding chemistry manufacturing and controls (CMC): Viral vectors manufacturing, characterization, and testing
Early decisions regarding CMC
Vector development
Producer cell line selection (upstream process)
Product format and formulation (downstream process)
Product characterization and potency assays
Product characterization – quality attributes
Potency assays
Nonclinical development
Principles of nonclinical development
Selection of test article for nonclinical studies
Justification for route and method of administration for nonclinical studies
Selection of animal model and or species for nonclinical efficacy studies
Pharmacologic efficacy assessments
Study design, dose selection and justification of endpoints
Pharmacodynamics and pharmacokinetics
Pharmacodynamics and minimal efficacious dose (MED)
Pharmacokinetics – biodistribution, shedding, and persistence
Nonclinical safety evaluation
General toxicity
Justification of dose
Justification of delivery method
Justification of the test system
Considerations for study designs, safety endpoints and safety pharmacology
Considerations for immunogenicity in toxicology studies
Developmental and reproductive toxicity (DART)
Genotoxicity: Insertional mutagenesis, carcinogenicity, and germline transmission
Translating nonclinical data to regulatory success
An ever-evolving regulatory landscape
Considerations for dose extrapolation
Clinical trial design
Expansion cohort trial designs
Master clinical protocols to support multiple drugs or multiple patient subpopulations
Innovative trial designs and clinical trials for rare diseases
Control subjects, placebo groups, and use of real-world data
Use of surrogate endpoints
Ethical considerations and weighing risk/benefit
Lessons learned from clinical trials to guide future development
Hepatotoxicity
Neurotoxicity
Cardiotoxicity
Immunogenicity
Linking immunity and nonclinical findings
Capsid/vector envelope immune responses
Transgene immune responses
On the use of immunosuppressants in nonclinical studies
Insertional mutagenesis
Conclusions
Chapter 10. Considerations for nonclinical studies conducted to support the development of cellular therapies
Introduction
Basic principles based on regulatory guidance
Species selection
Study design components
Development challenges
Challenges associated with stem cell therapies
Tumorigenicity
Inappropriate stem cell migration
Cell fate
Immune rejection
Challenges associated with CAR-T cell therapies
CRS and neurotoxicity
On-target and off-target, off-tumor toxicity
Graft-versus-host disease (GVHD) and rejection associated with allogeneic engineered T cells
T-cell receptor cross-reactivity
Insertional mutagenesis and clonal dominance
Conclusion
Chapter 11. Biological therapies for cancer
Introduction
Global regulatory guidances
General principles of toxicology assessments
Nonclinical studies and principles of study design
Specialty toxicology assessments
Safety pharmacology
Developmental and reproductive toxicology (DART)
Genotoxicity and carcinogenicity
Immunotoxicity
Tissue-binding study
Pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD)
Nonclinical development of marketed biologics
Monoclonal antibodies
Rituximab
Bevacuzimab
Trastuzumab
Ipilimumab
PD-1 blockade and DART
Development of relatlimab as a combination immunotherapy
Recombinant analogs of endogenous human proteins (interferons, cytokines, enzymes)
Roferon-A
Summary
Chapter 12. Considerations in the development of pluripotent stem cell–based therapies
Introduction
Definitions, regulations, and therapeutic applications
Human embryonic stem cells
Induced pluripotent stem cells
Regulations
Therapeutic applications
Other applications: In vitro toxicology testing and disease modeling
Important early decisions: Chemistry, manufacturing, and controls
Manufacturing process
Raw materials
Testing
Manufacturing scale
Critical decisions in cell line selection
Cell line characterization
Product characterization
Pluripotency and the potential for tumorigenicity
Determining a threshold for residual stem cells
Kinetics, chromosomal stability, differentiation status, and cellular attributes
Potency assays
Product lot release specifications
Nonclinical development
Principles of nonclinical development
Selection of test article for nonclinical studies and key manufacturing considerations
Justification for route and method of administration for nonclinical studies
Selection of animal model(s) and/or species for nonclinical studies
Genetically immunocompromised models
Pharmacologic efficacy assessments
Study design, dose selection and justification of pharmacologic endpoints
Pharmacologic mechanism of action
Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Pharmacokinetics (absorption, distribution, metabolism, and excretion)
Human-specific markers
Reporter genes, edited cells, and Y chromosomes
PET, SPECT, MRI, and bioluminescence
Special considerations for species and model selection for assessment of toxicity
Safety pharmacology
Toxicity assessments
General toxicity
Reproductive and developmental toxicity
Genetic toxicity
Tumorigenicity assessment
Local tolerability
Translating nonclinical data to clinical application
Considerations for dose extrapolation
Clinical considerations and endpoints
Global regulatory guidance
Ethical and political issues
Clinical studies of PSC-derived therapeutic candidates
Pioneers in translating to human trials
Reflection on clinical investigations to date and looking forward
Summary
Index

Lisa M. Plitnick

Dr. Lisa M. Plitnick is a Distinguished Scientist in Nonclinical Drug Safety, Merck Research Laboratories, Merck and Co., Inc. Lisa joined Merck in 2002 and currently serves as the Therapeutic Area Lead for Vaccines and a Nonclinical Safety Leader on vaccine and biologic development teams spanning early and late development. Lisa is also the Scientific and Regulatory Advisor for the in Vivo Biologics Release Testing Group in the Merck Manufacturing Division. Lisa co-edited the first edition of this book, Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics and has written and/or contributed to book chapters and peer-reviewed journal articles on biologics and vaccines. Lisa received a M.S. and Ph.D. in Immunology from the Albany Medical College. Following her graduate work she did a postdoctoral fellowship with a focus on Immunotoxicology in the Curriculum in Toxicology at the University of North Carolina in cooperation with the US Environmental Protection Agency, Dow Chemical and DuPont.

Affiliations and expertise

Merck Research Laboratories, Merck and Co., Inc., West Point, PA, USA

Claudette L. Fuller

Dr. Claudette Fuller is currently Vice President, Global Head of Non-Clinical Safety & Toxicology at Genmab where she leads an exceptional international team in the development of oncology and immunology biologics. She is deeply committed to the advancement of new approach methods (NAMs) to replace in vivo toxicology with robust in vitro and in silico/AI approaches. Previously, she was an Executive Director, Therapeutic Area Leader for the Immunology and Infectious Disease Portfolios, and Compound Leader for immuno-oncology biologics and vaccines in Nonclinical Drug Safety at Merck Research Laboratories, Merck & Co., Inc. She was an Immunotoxicology and Nonclinical Lead at GSK where her focus was therapeutics for autoimmune disorders. Dr. Fuller completed her PhD in immunology at the University of Virginia and her postdoctoral work at the National Cancer Institute. She’s also had the opportunity to serve as an ad hoc instructor at both Baylor, College of Medicine and Johns Hopkins, Bloomberg School of Public Health.

Affiliations and expertise

Vice President, Global Head of Non-Clinical Safety & Toxicology, Genmab, Princeton, NJ, USA

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