Abstract P4-07-05: MEDI3379, an antibody against HER3, is active in HER2-driven human breast tumor models

Abstract

Abstract HER3 (ERBB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Unlike the other HER family members, HER3 lacks intrinsic tyrosine kinase activity and therefore needs to form heterodimers with EGFR, HER2 or other kinase-proficient RTKs to be functionally active. Dimerization is induced by overexpression of EGFR or HER2 in a ligand-independent (LI) manner. In this process HER3 acts as a driver in divergent cancer types including HER2-positive breast cancer (BC) via induction of the PI3K-AKT pathway. Alternatively, heregulin (NRG1/HRG), the major HER3 ligand, induces a conformational shift in HER3 which leads to dimer formation with a partner RTK in a ligand-dependent (LD) manner. We have developed an antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple breast cancer cell lines. We observed effective suppression of constitutive pHER3 and pAKT with MEDI3379, leading to anti-proliferation effects in cell culture models. Preclinical evaluation of MEDI3379 demonstrated antitumor activity in several orthotopic BC xenografts in nude mice which did not express HRG. For example, the BC xenograft model BT474 with amplified HER2 responded to MEDI3379 (65% dTGI). In conclusion, our findings with targeting of HER3 in mouse models support continued development of MEDI3379 for cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-05.