Abstract 4751: Simultaneous inhibition of EGFR, HER2 and HER3 by an antibody mixture provides broad and potent tumor inhibition. (2013)

Abstract Deregulation of HER family members plays an important role in the development and progression of human cancer, and EGFR and HER2 are also clinically validated targets in many cancer indications. Accumulating evidence indicates, however, a high degree of HER family cross-talk and compensatory signaling leading to resistance upon therapeutic intervention with one of the receptors. Simultaneous targeting of more than one HER family receptor in vivo is frequently able to overcome resistance to the initial drug and the combined treatment is often also more efficacious than single-receptor targeting alone. Blocking of signaling from more than one HER family member may thus be necessary to effectively treat cancer and limit drug resistance. We have generated Sym013, a mixture of monoclonal antibodies specifically targeting EGFR, HER2 and HER3. Preclinical testing has shown that Sym013 displays potent growth inhibitory activity in a broad range of cell lines of diverse tissue origin and genetic background, including cell lines with acquired resistance to cetuximab, trastuzumab, or pertuzumab. Sym013 effectively inhibits all three targets simultaneously and thus prevents compensatory receptor up-regulation/activation, a commonly observed cellular response that can lead to drug escape when a single receptor is targeted. Furthermore, Sym013 is highly efficacious in the presence of EGFR and HER3 ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. Overall, simultaneous targeting of three receptors provides broader efficacy than targeting of a single receptor or any combination of two receptors in the HER family. The ability to simultaneously inhibit EGFR, HER2 and HER3 in cancer cells in vitro also translates into broad and efficacious tumor growth suppression in vivo. All three target specificities have been demonstrated to contribute to the efficacy of Sym013 in vivo, and there is a clear benefit of combining HER family target specificities compared to single-receptor targeting. Sym013 is also highly efficacious in hard-to-treat KRAS mutated patient-derived pancreatic cancer models, and is frequently able to overcome resistance to HER family targeted therapeutics. Our data suggest that a mixture of antibodies, which simultaneously inhibits EGFR, HER2 and HER3, is superior to existing targeted therapies in dealing with both primary and acquired resistance due to intra-tumor heterogeneity and plasticity in terms of HER family dependency. Citation Format: Johan Lantto, Mikkel W. Pedersen, Helle J. Jacobsen, Thomas T. Poulsen, Ida Kjær, Klaus Koefoed, Jette W. Sen, Dietmar Weilguny, Bolette Bjerregaard, Christina R. Andersen, Ivan D. Horak, Michael Kragh. Simultaneous inhibition of EGFR, HER2 and HER3 by an antibody mixture provides broad and potent tumor inhibition. [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 4751. doi:10.1158/1538-7445.AM2013-4751