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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Request a sales quoteNonclinical 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.
- Provides in-depth coverage of the process of nonclinical safety assessment and comprehensive reviews of each type of biopharmaceutical
- Discusses the most pertinent international regulatory guidelines
- Covers early derisking strategies and designs of safety assessment programs for novel biopharmaceuticals and vaccines
Pharmaceutical scientists, pharmaceutical toxicologists, geneticists, biochemists, cell biologists, and immunologists working in the area of biologics within academia, small biotechnology, and large pharmaceutical companies, Regulatory Affairs Professionals, Manufacturers, Graduate students, and Postdocs
- 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
- No. of pages: 482
- Language: English
- Edition: 2
- Published: November 16, 2024
- Imprint: Academic Press
- Hardback ISBN: 9780443133442
- eBook ISBN: 9780443133459
LP
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.
CF
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.