Abstract 873: A novel MET-EGFR bispecific antibody LY3164530 shows advantage over combining MET and EGFR antibodies in tumor inhibition and overcome resistance

Abstract

Abstract The epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition factor (MET) are receptor tyrosine kinases that each plays a key role in cancer signaling. Co-expression and activation of MET and EGFR are found in a number of tumor types, including non-small cell lung, colorectal, gastric, and head and neck cancers (Nanjo et al. 2013). Blocking one receptor tends to up-regulate the other, leading to resistance to single-agent treatment (Engelman et al. 2007). Amplification of MET and/or high levels of HGF expression has been observed in non-small cell lung cancer (NSCLC) patients with intrinsic or acquired resistance to tyrosine kinase inhibitors of EGFR (Engelman et al. 2007; Yano et al. 2011). Conversely, MET-amplified lung cancer cells exposed to MET-inhibiting agents for a prolonged period develop resistance via the EGFR pathway (McDermott et al. 2010). The crosstalk between the MET and EGFR pathways suggests that dual inhibition of these targets may lead to improved outcomes for patients with MET- and EGFR-positive cancers, and that simultaneous inhibition may overcome or delay resistance compared to the blockade of just a single pathway. LY3164530 is an engineered mAb-scFv bispecific antibody that consists of an immunoglobulin G4 (IgG4) antibody to MET and a single-chain variable fragment (scFv) to EGFR fused to the N-terminus of each heavy chain (HC). LY3164530 binds to extracellular domains of MET and EGFR with high affinity and inhibits signaling via both MET and EGFR receptors by blocking ligand binding and internalizing and degrading both receptors. In tumor cells, it binds and co-immunoprecipitates both receptors. LY3164530 has increased avidity binding to MET in cells expressing higher level of EGFR. This increased avidity binding leads to better neutralization of HGF compared to parental MET antibody in these cells. Surprisingly, LY3164530 has superior activity in internalizing/degrading EGFR (wild type and mutant forms) in vitro and in vivo relative to the combination of LY2875358 (i.e., emibetuzumab) and cetuximab in cells expressing high MET and EGFR. In addition, LY3164530 has superior activity in overcoming HGF-mediated resistance to erlotinib, gefitinib, lapatinib, or vemurafenib as compared to the combination of individual monoclonal antibodies targeting these receptors in cell-based assays. In vivo, administration of LY3164530 results in dose-dependent antitumor activity in multiple cell line-derived NSCLC and gastric xenografts. The antitumor activity of LY3164530 is equivalent, and in some cases superior to the combination of emibetuzumab and cetuximab in NSCLC and gastric tumor models. The Phase 1 study with LY3164530 is on-going (NCT02221882). Citation Format: Ling Liu, Wei Zeng, Marcio Chedid, Yi Zeng, Sheng-hung Tschang, Yu Tian, Ying Tang, Jirong Lu. A novel MET-EGFR bispecific antibody LY3164530 shows advantage over combining MET and EGFR antibodies in tumor inhibition and overcome resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 873.