An Overview of the Current ADC Discovery Landscape.

The prototypical ADC mechanism involving antigen-mediated uptake and lysosomal release is both elegantly simple and scientifically compelling. However, recent clinical-stage failures have prompted a reevaluation of this delivery paradigm and have resulted in an array of new technologies that have the potential to improve the safety and efficacy of up and coming programs. These innovations can generally be categorized into seven areas that will be elaborated on in this chapter: (1) Exploiting new payload mechanisms; (2) Increasing the drug-antibody ratio (DAR); (3) Increasing the antibody penetration; (4) Overcoming ADC resistance mechanisms; (5) Increasing the efficiency of ADC uptake and processing; (6) Mitigating off-target payload exposure; and (7) Employment of noncytotoxic payloads. It is our belief that these seven areas capture the current "landscape" of innovations that are taking place in the design of next-generation ADCs. Together, these advancements are reshaping the ADC field and providing a path forward in the face of the recent clinical setbacks.