Kang, Sun, and Khare et al. engineered “acid-switched” versions of an antibody-drug conjugate (ADC) consisting of HER2-targeting pertuzumab variants conjugated with the cytotoxic drug MAME. The acid-switched ADCs exhibited a significantly lower affinity for HER2 at acidic endosomal pH (~6.0) than at near-neutral extracellular pH. Compared with WT pertuzumab ADC, the modified ADCs had increased intracellular accumulation and lysosomal trafficking in vitro and were more effective in inhibiting tumor growth in mice with xenografts that expressed intermediate levels of HER2. The acid-switched ADCs were well tolerated.
We improve the potency of antibody-drug conjugates (ADCs) containing the human epidermal growth factor receptor 2 (HER2)-specific antibody pertuzumab by substantially reducing their affinity for HER2 at acidic endosomal pH relative to near neutral pH. These engineered pertuzumab variants show increased lysosomal delivery and cytotoxicity towards tumor cells expressing intermediate HER2 levels. In HER2(int) xenograft tumor models in mice, the variants show higher therapeutic efficacy than the parent ADC and a clinically approved HER2-specific ADC.