Abstract 528: EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy

Abstract

Abstract Interruption of EGFR signaling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumors. EGFR tyrosine kinase inhibitors (TKIs) provide a favorable treatment outcome in EGFR mutation positive NSCLC patients. However, many patients eventually develop progressive disease after treatment. Such acquired resistance limits the long-term efficacy of these EGFR TKIs in the clinic. The mechanisms of acquired resistance include a variety of mutations of the EGFR and crosstalk with the adjacent cMet receptors that allow the tumor to partially compensate the EGFR activity. EMB-01 is an innovative bispecific antibody developed based on EpimAb's proprietary FIT-Ig® platform to target EGFR and cMET on tumor cells simultaneously. The anti-EGFR and anti-cMet Fab-domains in each EMB-01 arm are fused directly in-tandem in a unique crisscross orientation without any mutations or use of peptide linkers to form a final tetravalent binding complex with the corresponding receptors on cell surface. We have demonstrated that EMB-01 can maintain all the biological activity from parental monoclonal antibody (mAb) to block ligand binding and the downstream signal pathway. In addition, such tetravalent binding feature is found to induce significant co-degradation of EGFR and cMET in various tumor cells, and such effect is unattainable by either mAb alone or in combination, demonstrating a unique synergistic function of EMB-01. At equivalent doses, EMB-01 induces significantly stronger anti-tumor activity in PDX and CDX tumor models than that of anti-EGFR mAb or anti-cMet mAb alone. Furthermore, EMB-01 shows significant anti-tumor activity in anti-EGFR mAb resistant tumor model. These results demonstrate the potential benefit of EMB-01 in treating EGFR and/or cMET driven cancers, particularly in cases where patients develop acquired resistance due to secondary EGFR mutations in the kinase domain or cMET activation. Currently, EMB-01 has initiated a Phase I/II clinical trial with advanced/metastatic solid tumors. Citation Format: Fang Ren, Xuan Wu, Dandan Yang, Danqing Wu, Shiyong Gong, Yingxi Zhang, Stephan Lensky, Chengbin Wu. EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 528.