Abstract 2719: MM-141, a novel bispecific antibody co-targeting IGF-1R and ErbB3, blocks ligand-induced signaling and demonstrates antitumor activity

Abstract

Abstract Monoclonal antibodies have significantly advanced our ability to treat cancer, but most patients do not show durable responses to therapy. This, in part, can be explained by the tumor cells responding to two or more growth factors in a redundant fashion. We show that cancer cell lines frequently rely on Insulin-like growth factor 1 (IGF-1) and Heregulin (HRG) signaling to support their survival and proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel bispecific antibody, MM-141, for co-targeting of ErbB3 and IGF-1R. MM-141 blocks IGF-1, IGF-2, and HRG binding to IGF1R and ErbB3, and causes downregulation of these receptors. MM-141 inhibits phosphorylation of IGF1R and ErbB3 as well as downstream activation of the PI3K/Akt pathway. In our in vitro and in vivo testing, MM-141 displays potency in the presence of single or multiple ligands, over a broad range of receptor profiles. Inhibition of growth by MM-141 has been observed in vitro as well as in vivo in multiple xenograft models including human pancreatic cancer (BxPC-3) and human prostate cancer (DU145). MM-141 does not bind the insulin receptor, thus reducing the risk of metabolic side effects. Our in vivo and in vitro studies reveal that MM-141 has favorable pharmaceutical properties and pharmacokinetic profiles. We are advancing MM-141 into preclinical development. Taken together, these results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2719. doi:1538-7445.AM2012-2719