The synthesis and biological characterization of multiple degrader antibody conjugates (DACs) bearing a heterobifunctional VHL-dependent proteolysis targeting chimera (PROTAC) payload is described. The conjugated molecule (A515) potently and extensively degrades the BRM protein (also known as SMARCA2) in cell-based assessments and exhibits moderate degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). A CD71-targeting DAC that utilizes A515 as a payload and employs a disulfide-based linker affords strong, antigen-dependent efficacy in an H1944 xenograft model. Similarly, a Trop2-targeting DAC-bearing A515 that incorporates a protease-cleavable linker provides potent BRM degradation outcomes in HCC515 in vitro assessments along with encouraging antigen-dependent antitumor activity in several HCC515-based xenograft experiments. Structure-activity relationship information based on in vitro BRM degradation results and single-dose in vivo pharmacodynamic experiments is also provided for several additional CD71 and Trop2-targeting DACs in which the nature of the linkers and the A515 attachment sites are varied.
Dockrey et al. (Sun,) studied this question.