T-Cell Recruitment Tumor Lysis Via A Novel C-Met/Cd3 Bispecific Antibody

Anti-receptor tyrosine kinases (RTKs) therapy has been used for the treatment of a number of solid tumors in clinic. C-MET, also known as the hepatocyte growth factor receptor (HGFR), is a representative member of the RTK family. C-MET overexpression is commonly observed in tumor biopsies and associated with poor patient survival. Various kinase inhibitor and monoclonal antibody (e.g. Emibetuzumab and Onartuzumab) have been developed to block the HGF/c-MET interactions, however, those kinase-inhibiting-based therapeutics have shown limited success in clinical trials. There is an urgent need to develop new treatments targeting c-MET to overcome these limitations. Bispecific antibodies that recruit immune cells to the tumor microenvironment have been considered as effective therapeutic candidates. An example of this design strategy is the FDA-approved bispecific antibody blinatumomab. In this study, we have constructed an asymmetric bispecific antibody, which binds both c-MET and CD3, using a novel platform that is monovalent to epitope. Our c-MET/CD3 bispecific antibody showed potent T-cell mediated tumor cells killing in vitro. Meanwhile, this antibody inhibited the phosphorylation of c-MET and downstream signal transduction in tumor cells due to its monovalent nature. In c-MET-overexpressing lung cancer and ovarian cancer xenograft models, c-MET/CD3 bispecific antibody inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. Moreover, in vivo combination therapy with FDA-proved PD-1/PD-L1 antibodies showed higher tumor inhibition than monotherapy in above two tumor models. Collectively, the novel c-MET/CD3 bispecific antibody can provide immunotherapy for c-MET-overexpressing tumors which conventional antibody or small molecular inhibitor might not. These findings also support the immunotherapeutic effects on combination of T-cell dependent bispecific antibody and immune checkpoint blockade. Citation Format: Lei Huang, Kun Xie, Ruiqin Wang, Hua Gu, Jianmin Fang. T-cell recruitment tumor lysis via a novel c-MET/CD3 bispecific antibody [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 535.