PF-06804103, a site-specific anti-HER2 antibody-drug conjugate for the treatment of HER2-expressing breast, gastric, and lung cancers.

The approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2-specific antibody-drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential of targeting HER2-expressing solid tumors with ADCs. Here, we detail the discovery of PF-06804103, an anti-HER2 ADC designed to have a widened therapeutic window compared to T-DM1. We utilized an empirical conjugation site screening campaign to identify the engineered kK183C and K290C residues as those that maximized in vivo ADC stability, efficacy and safety for a 4 DAR ADC with this linker-payload combination. PF-06804103 incorporates the following novel design elements: (1) a new auristatin payload with optimized pharmacodynamic properties, (2) a cleavable linker for optimized payload release and enhanced anti-tumor efficacy and (3) an engineered cysteine site-specific conjugation approach that overcomes the traditional safety liabilities of conventional conjugates and generates a homogenous drug product with a drug-antibody ratio (DAR) of 4. PF-06804103 shows (1) an enhanced efficacy against low HER2-expressing breast, gastric and lung tumor models, (2) overcomes in vitro and in vivo acquired T-DM1 resistance, and (3) an improved safety profile by enhancing ADC stability, pharmacokinetic parameters and reducing off-target toxicities. Herein, we showcase our platform approach in optimizing ADC design resulting in the generation of the anti-HER2 ADC PF-06804103. The design elements of identifying novel sites of conjugation employed in this study serve as a platform for developing optimized ADCs against other tumor-specific targets.