Abstract 952: The bispecific antibody MCLA-129 impairs NSCLC tumor growth by targeting EGFR and c-MET, inhibiting ligand-induced signaling and promoting ADCC and ADCP
Authors: David J. de Gorter, Alexandre Deshiere, Martijn van Rosmalen, Christian Wohn, Berina Eppink, Tristan Gallenne, Rinse Klooster, Li Mao, Wenxin Xu, Liang Deng, Qingyu Shu, Wei Liu, John de Kruif, Mario Di Matteo, Massimiliano Mazzone, Mark Throsby, Cecile A. Geuijen
Journal: Cancer Research (2021)

Abstract MCLA-129 is an ADCC-enhanced common light chain bispecific human IgG1 Biclonics® antibody specifically targeting the receptor tyrosine kinases EGFR and c-MET. It inhibits activation and downstream signaling of EGFR and c-MET induced by their respective ligands EGF and HGF and promotes elimination of tumor cells via Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cell-Mediated Phagocytosis (ADCP). MCLA-129 was developed to overcome c-MET signaling-dependent EGFR TKI-resistance mechanisms and was identified during an unbiased screening campaign with a focus on inhibition of ligand-induced proliferation and migration of cancer cells. Selectivity of MCLA-129 for tumor cells is achieved by simultaneously targeting both EGFR and c-MET. MCLA-129 blocks EGF and HGF binding to EGFR and c-MET, respectively, and consequently inhibits their ligand-induced phosphorylation. MCLA-129 was shown to bind critical residues on EGFR and c-MET for EGF and HGF ligand binding. GlymaxX® low fucose glycoengineering technology was used to enhance the mononuclear cell ADCC activity of the bispecific antibody. MCLA-129 demonstrated potent dose-dependent ADCC and ADCP against all NSCLC cell lines tested, which positively correlated with the EGFR and c-MET expression levels on the target cells. Significant inhibition of tumor growth of NCI-H1975EGFR L858R, T790M and HCC827/ER1EGFR del (E746, A750), c-MET amplified NSCLC cell line derived tumors was observed following MCLA-129 treatment. MCLA-129 can overcome HGF-mediated EGFR-TKI resistance, as demonstrated by testing a non-ADCC enhanced version of this antibody in a panel of NSCLC cell lines in vitro and orthotopic tumors in vivo showing that it inhibits EGFR and c-MET activity. Significant tumor regression was observed following treatment of immunodeficient xenograft NSG-hHGFki mice bearing orthotopic tumors established from HCC827EGFR del (E746, A750) cells. In addition, in an acquired erlotinib EGFR TKI resistance model, treatment of mice harboring tumors as big as &amp;gt;500 mm3 led to significant reduction of tumor size which persisted after the treatment period. Taken together these data demonstrate that MCLA-129 is a potent inhibitor of tumor growth applying various mechanisms of action, including inhibition of c-MET and EGFR signaling, ADCC and ADCP. MCLA-129 holds promise as a potential treatment for patients with NSCLC and other cancers, and warrants clinical evaluation. Citation Format: David J. de Gorter, Alexandre Deshiere, Martijn van Rosmalen, Christian Wohn, Berina Eppink, Tristan Gallenne, Rinse Klooster, Li Mao, Wenxin Xu, Liang Deng, Qingyu Shu, Wei Liu, John de Kruif, Mario Di Matteo, Massimiliano Mazzone, Mark Throsby, Cecile A. Geuijen. The bispecific antibody MCLA-129 impairs NSCLC tumor growth by targeting EGFR and c-MET, inhibiting ligand-induced signaling and promoting ADCC and ADCP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 952.