Bispecific antibody AP402 targets p95HER2 and induces costimulation through CD137 to improve efficacy for HER2-positive tumors.

backgroundOutcomes for HER2-positive cancers have been greatly improved by trastuzumab and other HER2-targeted therapies. However, many tumors express a truncated p95HER2 variant that lacks the extracellular trastuzumab binding site. Since these tumors exhibit resistance and more aggressive disease phenotypes, the AP402 bispecific antibody was developed to target p95HER2 and engage activated T cells toward tumor cells via CD137 engagement.

methodsAP402 was characterized in terms of binding, anti-tumor activity and safety using in vitro and in vivo models. Using p95HER2- and full-length HER2-expressing tumor cells, antibody-dependent cellular cytotoxicity (ADCC) assays were performed. AP402-mediated T cell activation was evaluated by measuring IFN-γ production. In vivo anti-tumor efficacy was tested in humanized p95HER2-transgenic tumor models and patient-derived xenograft (PDX) models. The safety profile was assessed with cytokine release assays and a toxicology study in cynomolgus monkeys.

resultsAP402 induced ADCC in p95HER2-expressing tumor cells and also showed activity against full-length HER2-positive cells. In addition, the CD137-binding arm robustly activated T cells in a p95HER2-binding-dependent manner. In humanized p95HER2-transgenic breast and lung tumor mouse models and in PDX models of p95HER2-positive breast cancer, AP402 significantly reduced tumor weights and volumes. Cytokine release assays and in vivo toxicology studies suggested the molecule has low risk of adverse effects.

conclusionAP402 is a promising therapeutic agent for p95HER2-positive cancers with dual functions of targeting p95HER2 and enhancing p95HER2-dependent T cell activation. These functions may overcome resistance to current HER2-targeted therapies, and the favorable safety profile of AP402 suggests excellent potential for clinical application.