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Cytotoxic payloads for antibody--drug conjugates
Antibody-drug conjugates are a promising areas of anticancer drug discovery, conveying several advantages, including the ability to select likely responders, efficient delivery of cytotoxic agents and reduced toxicity. This book describes payloads used to date and novel payloads that may be used clinically in the future.
Cover; Cytotoxic Payloads for Antibody-Drug Conjugates; Preface; Contents; Chapter 1 -- Introduction to Antibody-Drug Conjugates (ADCs); 1.1 Introduction to Cancer; 1.2 Cancer Treatments; 1.3 Antibody-Drug Conjugates (ADCs); 1.3.1 Mechanism of Action of ADCs; 1.3.2 Antibody Selection; 1.3.3 Linker Design; 1.3.3.1 Cleavable Linkers; 1.3.3.2 Non-cleavable Linkers; 1.3.4 Payload Selection; 1.3.5 Conjugation of Payload; 1.3.5.1 Conjugation via Lysine Residues; 1.3.5.2 Conjugation via Thiol Groups; 1.3.5.3 Site-specific Conjugation; 1.3.5.4 Click Chemistry for Conjugation
1.3.5.5 Other Types of Conjugation1.3.6 Analytical Characterisation of ADCs; 1.3.6.1 Drug to Antibody Ratio (DAR); 1.3.6.2 Determination of Unconjugated Payload Content in an ADC; 1.3.6.3 Hydrophobicity Prediction; 1.4 Conclusions; References; Chapter 2 -- Design Factors Important for Antibody-Drug Conjugate (ADC) Payloads; 2.1 Introduction; 2.2 The Challenges in Making Effective ADCs; 2.3 Distribution of ADCs into Tumour Tissue; 2.3.1 Diffusion and Extravasation of ADCs; 2.3.2 Effect of Linker-Payload on ADC Distribution into Tumour Tissue
2.3.3 The Effect of Target Antigen Density on ADC Distribution2.4 Retention of ADCs by Tumour Tissue; 2.5 Uptake and Metabolism of ADCs by Cancer Cells; 2.5.1 Release of Cytotoxic Payload in Tumour Tissue; 2.5.2 Trafficking and Release of Cytotoxic Payload in Tumour Tissue; 2.5.3 Payload Metabolites and Bystander Killing; 2.6 Design Factors Important for the Safety of ADCs; 2.7 ADCs and the Tumour Microenvironment; 2.8 Summary; Acknowledgements; References; Chapter 3 -- Use of Molecular Modelling Techniques in Antibody-Drug Conjugate (ADC) Payload Discovery and Development; 3.1 Introduction
3.2 Molecular Modelling of MMAE/MMAF Payloads3.3 Molecular Modelling of C8-linked Pyrrolobenzodiazepines (PBDs); 3.3.1 Molecular Modelling Studies of C7-linked PBD Dimers; 3.3.2 Molecular Modelling of C8/C2-linked and C2/C2-linked PBD Dimers; 3.4 Conclusion and Future Perspective; References; Chapter 4 -- Auristatin Payloads for Antibody-Drug Conjugates (ADCs); 4.1 Discovery of the Auristatins; 4.2 Mechanism of Action; 4.3 Activity; 4.4 Synthetic Availability and Analogues; 4.5 Validation of Auristatins Payloads for ADC Technology; 4.5.1 Auristatin E and Related Conjugates
4.5.2 Development of Brentuximab Vedotin (ADCETRIS)4.5.3 More MMAE Conjugates; 4.5.4 Novel Linker Technologies; 4.5.5 Extending the Range of Auristatin E- type Molecules; 4.6 Development of Monomethyl Auristatin F; 4.6.1 MMAF Properties; 4.6.2 Development of Alternative Ways of Linking MMAF to an Antibody; 4.6.3 C-Terminus- linked Auristatin F Conjugates; 4.7 Conclusions; References; Chapter 5 -- Maytansinoid Payloads for Antibody-Drug Conjugates (ADCs); 5.1 Introduction; 5.2 Maytansinoids: Structure-Activity Relationships (SARs); 5.3 Synthesis of Maytansinoid-ADCs
edited by David E. Thurston and Paul J.M. Jackson.
Cambridge : Royal Society of Chemistry, [2019]