Chemical Linkers in Antibody-Drug Conjugates aims to shine a detailed light on the various key attributes of chemical linkers in ADCs, for drug-to-antibody ratio, for stability, for release mechanism of payload, for pharmacokinetics, for stability determination, and for efficacy and safety.

Description based upon print version of record. 5.3.6 Less Hydrophobic Val-Ala- and Ala-Ala-linker in PBD Dimer and Indolinobenzodiazepine Pseudodimer ADCs.

Intro -- Title -- Copyright -- Contents -- Chapter 1 Introduction to Antibody-Drug Conjugates -- 1.1 ADCs -- A Historical Perspective -- 1.2 Structure and Mode of Action of ADCs -- 1.3 Marketed and Clinical ADCs -- 1.4 Targets and Antibodies -- 1.5 Payloads -- 1.6 Conjugation Chemistries -- 1.7 Linkers in ADCs -- The Crucial "Part in the Middle" -- References -- Chapter 2 Antibody Conjugation Technologies -- 2.1 Introduction -- 2.2 The Art of mAb-to-ADC Conversion -- 2.3 Conjugation Technologies in Marketed and Clinical-stage ADCs -- 2.3.1 Mercapto Group (-SH) -- 2.3.2 Amino Group (-NH2). 2.3.3 Carbonyl Group (-C(O)R) -- 2.3.4 Amido Group (-C(O)NHR) -- 2.3.5 Azido Group (-N3) -- 2.4 Miscellaneous Functional Groups for Antibody Conjugation -- 2.4.1 Phenol (Tyrosine Sidechain) -- 2.4.2 Methyl Thioether (Methionine Sidechain) -- 2.4.3 Imidazole (Histidine Sidechain) -- 2.4.4 N-terminal Aminogroup -- 2.5 Discussion -- References -- Chapter 3 Linker Design and Impact on ADC Properties -- 3.1 Key Mechanistic Requirements of an ADC -- 3.2 ADC Developability -- 3.3 Functionality -- Decreasing the Minimum Effective Dose -- 3.3.1 ADC Processing and Drug Release Mechanism 3.3.2 Linker Types and Drug Release Mechanisms -- 3.3.3 Linker Design and ADC Efficacy -- 3.4 Safety -- Increasing the Maximum Tolerated Dose -- 3.4.1 Stability Evaluation and Contribution of ADC Linkers -- 3.4.2 Effect of Linker Type on the Catabolism of ADC -- 3.4.3 PK Considerations and Hydrophobicity -- 3.5 Manufacturability -- Accelerating Investigational New Drug Filing -- 3.6 Summary -- How Optimal Linker Designs Drive Successful ADC Programs -- 3.6.1 Future ADC Linker Designs and Further Impact on ADC Properties -- Abbreviations -- References Chapter 4 Non-cleavable Linkers: Permanently Linked, for Better or for Worse -- 4.1 Introduction -- 4.1.1 History of Non-cleavable Linkers -- 4.2 Design of Non-cleavable Linkers -- 4.2.1 Metabolism and Trafficking -- 4.2.2 Modulation of Activity -- 4.3 Clinical data for ADCs Made with Non-cleavable Linkers -- 4.3.1 Maytansinoid-based ADCs -- 4.3.2 Auristatin-based ADCs -- 4.3.3 Other Molecules -- 4.4 Pre-clinical Data for Novel Non-cleavable Drug-linkers: Beyond First-generation Maytansinoid and Auristatin Non-cleavable Drug-linkers -- 4.5 Concluding Thoughts -- References Chapter 5 Protease-sensitive Linkers -- 5.1 Introduction and Scope of the Chapter -- 5.2 Cathepsins -- Lysosomal Enzymes Suitable for ADC Activation -- 5.3 Cathepsin B-cleavable Linker -- 5.3.1 Evolution of Cathepsin B-cleavable Val-Cit Linker -- 5.3.2 Case Studies of Approved ADCs with Val-Cit Cleavable Linkers and ADCs Undergoing Pivotal Clinical Trials -- 5.3.3 Premature Payload Release of Val-Cit-PABC-MMAE ADCs -- 5.3.4 The Hidden Cleavage Force Behind Cathepsin B -- 5.3.5 ADC Design for Specific Cleavage by Cathepsin B