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Chi tiết tài liệu

Antibody-Drug Conjugates: The 21st Century Magic Bullets for Cancer

Tác giả: Wang, Jeffrey; Shen, Wei-Chiang; Zaro, Jennica L.

Chủ đề: Medicine; Drug

Nhà xuất bản: Springer

Năm xuất bản: 2015

Loại tài liệu: Book

Mô tả vật lý: 248 p.

Định danh: 978-3-319-13081-1

Ngôn ngữ: en

Liên kết: AAPS Advances in the Pharmaceutical Sciences Series;Book 17

Đọc trực tuyến

Tải tài liệu

Fourteen comprehensive chapters are divided into six sections including an introduction to ADCs, the ADC construct, development issues, landscape, IP and pharmacoeconomics, case studies, and the future of the field. The book examines everything from the selection of the antibody, the drug, and the linker to a discussion of developmental issues such as formulations, bio-analysis, pharmacokinetic-pharmacodynamic relationships, and toxicological and regulatory challenges. It also explores pharmacoecomonics and intellectual properties, including recently issued patents and the cost analysis of drug therapy.

About the Editors
Contents
Contributors
Index
Cover
AAPS Advances in the Pharmaceutical Sciences Series
Title pages
Introduction
- Chapter-1
  - Antibody–Drug Conjugates: A Historical Review
    - References
The ADC Construct
- Chapter-2
  - Payloads of Antibody–Drug Conjugates
    - 2.1 Introduction
    - 2.2 Maytansinoids
      - 2.2.1 Chemistry and Anticancer Activity
      - 2.2.2 Mechanism of Action
      - 2.2.3 Early Preclinical and Clinical Experiences
      - 2.2.4 ADC Development
    - 2.3 Auristatins
      - 2.3.1 Chemistry and Anticancer Activity
      - 2.3.2 Mechanism of Action
      - 2.3.3 Early Preclinical and Clinical Experiences
      - 2.3.4 ADC Development
    - 2.4 Calicheamicins
      - 2.4.1 Chemistry and Anticancer Activity
      - 2.4.2 Mechanism of Action
      - 2.4.3 Early Preclinical Experiences
      - 2.4.4 ADC Development
    - References
- Chapter-3
  - Selecting an Optimal Antibody for Antibody-Drug Conjugate Therapy
    - 3.1 Target Selection for an ADC
      - 3.1.1 Characteristics of an Optimal ADC Target
      - 3.1.2 Selection and Validation of Tumor-Associated Targets Using Omics Approaches
    - 3.2 Antibody Characteristics
      - 3.2.1 Optimal Antibody Characteristics
      - 3.2.2 Engineering pH Dependence of Antibody Binding
      - 3.2.3 Engineering Fc-Mediated Interactions
    - 3.3 Agnostic Approach to Antibody Production
    - 3.4 Target-First Approach to Antibody Generation
      - 3.4.1 Considerations and Preparation of Target for Antibody Screening
      - 3.4.2 Approaches to Antibody Isolation
    - 3.5 Screening for Internalization and Intracellular Trafficking
      - 3.5.1 Screening by Microscopy and Flow Cytometry
      - 3.5.2 Screening for Intracellular Toxin Delivery
    - 3.6 Payload Conjugation Strategies
    - 3.7 Conclusions and Perspectives
    - References
- Chapter-4
  - Linker Design for Antibody–Drug Conjugates
    - 4.1 Introduction
    - 4.2 Sites of Attachment and Reactive Chemical Moieties on Linkers
    - 4.3 Types of Linkers
      - 4.3.1 Noncleavable Linkers
      - 4.3.2 Cleavable Linkers
        
        4.3.2.4 β-Glucuronide Linker
        
        4.3.2.1 Acid-labile Linkers
        
        4.3.2.2 Reducible Linkers
        
        4.3.2.3 Peptide Linkers
    - 4.4 Effect of Linkers on the Activity and Safety of ADC
      - 4.4.1 Linker and Intracellular Processing/Activation
      - 4.4.2 Linkers to Overcome MDR
      - 4.4.3 Linkers to Improve Activity in Solid Tumors
      - 4.4.4 Linker Stability in Plasma
      - 4.4.5 Linker Stability and Activity of ADCs
      - 4.4.6 Linker Stability and Safety
        
        4.4.6.1 Effect of Linker on Liver Detoxification of ADC and Biodistribution
        
        4.4.6.2 Effect of Linkers on Safety in Clinic: Inverse Correlation of Stability and Safety
    - References
Development Issues
- Chapter-5
  - Formulation Development for Antibody-Drug Conjugates
    - 5.1 Introduction
    - 5.2 Stability of Thio-Succinimide Linker
      - 5.2.1 Mechanism of Degradation Pathways
      - 5.2.2 Characterization of Thio-Succinimide Hydrolysis of ADC
    - 5.3 Effect of DAR on ADC Stability
      - 5.3.1 Determination of DAR and Drug Load Distribution
      - 5.3.2 Aggregation
    - 5.4 Formulation Considerations
      - 5.4.1 pH and Buffer
      - 5.4.2 Antioxidants
      - 5.4.3 Surfactants
      - 5.4.4 Liquid Versus Lyophilized Formulation
    - References
- Chapter-6
  - Bioanalytical Assay for Characterization of Antibody-Drug Conjugates (ADCs)
    - 6.1 Introduction
    - 6.2 Typical Bioanalytical Methods for ADCs
      - 6.2.1 LBAs
        
        6.2.1.1 ELISA-Based Binding Assays
        
        6.2.1.2 Cell-Based Binding Assays
        
        6.2.1.3 Other Types of Binding Assays
      - 6.2.2 UV/Vis Spectroscopy
      - 6.2.3 MS Based Assays
      - 6.2.4 Chromatography-Based Assay
        
        6.2.4.1 RP-HPLC
        
        6.2.4.2 HIC
        
        6.2.4.3 Other Types of Chromatography
    - 6.3 General Assay Validation Considerations
    - 6.4 Challenges and Future Perspective
    - 6.5 Conclusion
    - References
- Chapter-7
  - Pharmacokinetics/Pharmacodynamics and Disposition of Antibody-Drug Conjugates
    - 7.1 Introduction
    - 7.2 Analytical Strategy and Its Application in ADC Selection and Optimization
    - 7.3 Disposition of an ADC and Its Implication on PKPD
      - 7.3.1 Absorption
      - 7.3.2 Distribution
      - 7.3.3 Metabolism and Elimination
    - 7.4 Application of PK in ADC Optimization
    - 7.5 PKPD Modeling for ADCs
    - 7.6 Conclusions
    - References
- Chapter-8
  - Regulatory Considerations
    - 8.1 Introduction
    - 8.2 Regulatory Review
      - 8.2.1 Organization of the Application
      - 8.2.2 Meetings with FDA
    - 8.3 Chemistry, Manufacturing, and Controls
      - 8.3.1 Monoclonal Antibody
      - 8.3.2 Drug-Linker
      - 8.3.3 Conjugated Bulk Drug Substance and ADC Drug Product
      - 8.3.4 Quality Aspects of Comparability
    - 8.4 Nonclinical Study Requirements
    - 8.5 Discussion and Conclusions
    - References
Landscape, IP and Pharmacoeconomics
- Chapter-9
  - Major ADC Companies, Current Clinical Trials, Recent Patents Issued and Patent Applications, and Cost Analysis of Drug Therapy
    - References
    - 9.1 Introduction
    - 9.2 Major ADC Developing and Contract Manufacturing Companies
      - 9.2.1 Seattle Genetics, Inc.
      - 9.2.2 ImmunoGen, Inc.
      - 9.2.3 Genentech, Inc./Hoffmann-La Roche Ltd.
      - 9.2.4 Pfizer, Inc.
      - 9.2.5 Agensys, Inc.
      - 9.2.6 Celldex Therapeutics
      - 9.2.7 Progenics Pharmaceuticals, Inc.
      - 9.2.8 ADC CMOs
    - 9.3 Major ADC Clinical Trials
    - 9.4 Recent ADC Patents and Patent Applications
    - 9.5 Cost and Outcomes Considerations
    - 9.6 Additional ADC Resources
    - 9.7 Conclusions
Case Studies
- Chapter-10
  - Mylotarg: Revisiting Its Clinical Potential Post-Withdrawal
    - 10.1 Introduction
      - 10.1.1 The Antibody: Gemtuzumab
      - 10.1.2 The Target Antigen: CD33
      - 10.1.3 The Drug: Calicheamicin
      - 10.1.4 The Conjugation Chemistry and Hydrazone Linker
      - 10.1.5 Approval Process, Post-marketing Analysis, and Withdrawal
    - 10.2 Recent Clinical Studies
      - 10.2.1 AML15
      - 10.2.2 AML16 Trial
      - 10.2.3 ALFA0701 Trial
      - 10.2.4 AML 2006 Trial
      - 10.2.5 AML17 Trial
    - 10.3 Summary and Prospective Future for GO
    - References
- Chapter-11
  - ADCETRIS: A Regulatory Case Study of a New Generation Antibody-Drug Conjugate
    - 11.1 ADCETRIS Description
    - 11.2 SGN-30
    - 11.3 ADCETRIS Regulatory Timeline
    - 11.4 Early Days: Phase 1 and the Food and Drug Administration
    - 11.5 Pivotal Trial Regulatory Agreements
    - 11.6 Nonclinical and Clinical Pharmacology Development
    - 11.7 Phase 2 Registrational Trials and AETHERA
    - 11.8 Phase 2 Clinical Data
    - 11.9 Chemistry, Manufacturing, and Controls Plan
    - 11.10 After Phase 2 and Onward to the Biologics License Application
    - 11.11 A Changing Landscape
    - 11.12 The Biologics Licensing Application
    - 11.13 Meeting with the Committee
    - 11.14 Confirmatory Trials
    - 11.15 Chemistry, Manufacturing and Controls Issues during the Review
    - 11.16 Biologics Licensing Application Approval
    - 11.17 After Biologics Licensing Application Approval
    - 11.18 Conclusion
    - References
- Chapter-12
  - Ado-Trastuzumab Emtansine
    - 12.4 Trastuzumab–HER2 Interaction
    - 12.1 Introduction
    - 12.2 Chemistry
    - 12.3 HER2 and the EGF Receptors Family
    - 12.5 Mechanisms of Action
    - 12.6 Metabolism and Pharmacokinetics
    - 12.7 Preclinical Efficacy and Toxicity Studies
    - 12.8 Clinical Studies
    - 12.9 Perspectives
    - References
- Chapter-13
  - The Antibody—Drug Conjugate Glembatumumab Vedotin (CDX-011) and Its Use in Treatment of Breast Cancer
    - 13.1 Introduction
    - 13.2 GPNMB as a Therapeutic Target
    - 13.3 Glembatumumab Vedotin
    - 13.4 Preclinical Models
    - 13.5 GPNMB and Triple-Negative Breast Cancer
    - 13.6 Clinical Trials of Glembatumumab Vedotin
      - 13.6.1 Toxicity Profile
      - 13.6.2 Clinical Trials on the Horizon
    - 13.7 Conclusion
    - References
From Today to Tomorrow
- Chapter-14
  - Summary and Future Directions of ADCs
    - 14.1 Summary on the Current Status of ADC Design
      - 14.1.1 Molecular Targets
      - 14.1.2 Antibody Considerations
      - 14.1.3 Chemical Conjugation Strategies
        
        14.1.3.1 Engineered Cysteine Residues
        
        14.1.3.2 Incorporation of Unnatural Amino Acids
      - 14.1.4 Enzymatic Conjugation
      - 14.1.5 Linkers
      - 14.1.6 Cytotoxic Payloads
    - 14.2 Conclusions
    - References