Linker Design and Impact on ADC Properties

Antibody–drug conjugates (ADCs) represent one of the most complex classes of drugs currently under development. The aim of an ADC is to improve the therapeutic index with respect to traditional chemotherapy by combining the targeting properties of an antibody with a high cytotoxicity payload that is attached via an appropriate linker. The linker represents an important and critical element of the overall ADC design, and the different structural elements of the linker can be evaluated using a developability assessment to modulate ADC functionality, safety, and manufacturability in order to establish an appropriate and stage-specific target product profile (TPP). This chapter describes the many varied and different approaches that have been applied to linker design and its subsequent impact on ADC properties, and ultimately how an optimal linker design drives the success of ADC programs.