Antibody Drug Conjugates: Preclinical Considerations

Abstract

The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

Fig. 1

Schematic illustration of the parameters that impact the pharmacological properties of ADCs and considerations for antigen target selection. a The properties of the antibody, type of linker, payload class, and payload drug conjugation methodology are critical preclinical considerations. b Selection and characterization of the antigen target, confirmation of internalization, and intracellular trafficking to the lysosomal compartment are key factors