Abstract 558: MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers.

HER3 (ErbB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Due to its unique kinase-deficient nature, HER3 needs to form heterodimers with EGFR, HER2 or other RTKs to be functionally active. Dimerization is induced by either HER3 ligand (Heregulin, HRG) binding, or overexpression of partner RTKs in a ligand-independent (LI) manner. In both settings, HER3 acts as a critical scaffold coupling the upstream RTKs to efficient PI3K/AKT pathway induction to drive tumor growth and survival. We have developed a potent antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple cancer models with either ligand-dependent or ligand-independent HER3 activities. For ligand-dependent models, we have chosen MDA-MB-175VII, a breast cancer cell-line with known γ-HRG expression, and HMCB, a melanoma cell-line with β-HRG expression. Efficient suppression of cell proliferation by MEDI3379 or 2C2, a precursor of MEDI3379, was observed in both models. This anti-tumor effect is directly due to the abrogation of HER3 activation (as determined by pHER3 formation) and its downstream effector pAKT. Her2-amplified breast cancer models such as BT474 are known to display high ligand-independent HER3 activity that is due to constitutive dimerization of HER2 and HER3. Treatment of BT474 with MEDI3379 led to effective suppression of pHER3, pAKT, and cell-proliferation in vitro. We extended this observation in vivo by exploring the antitumor activity of MEDI3379 in several orthotopic HER2-amplified breast cancer xenografts in nude mice. Consistent with in vitro observations, the BT474 xenograft model responded to MEDI3379 treatment with 65% tumor growth inhibition. In contrast, two published HER3 mAbs (Ab #6 and U1-15) failed to display activity in this ligand-independent model. In conclusion, our findings demonstrated that MEDI3379 is a HER3 antagonist that is effective in models of human cancers driven by both ligand-dependent as well as ligand-independent HER3 activities. Citation Format: Carrasco A. Rosa, Leslie Wetzel, Krista Kinner, Hong Chen, Raymond Rothstein, David Tice, Robert Hollingsworth, Philipp Steiner, Zhan Xiao. MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2013-558