Drug Design, Development and Therapy (Aug 2020)
Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody
Abstract
Lei Huang,1 Kun Xie,1 Hongwen Li,1 Ruiqin Wang,1 Xiaoqing Xu,1 Kaiming Chen,1 Hua Gu,1 Jianmin Fang1– 3 1Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, People’s Republic of China; 2Department of Neurology, Tongji Hospital, Tongji University, Shanghai, People’s Republic of China; 3Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Hua Gu Tel +86-21-6598-2867Correspondence Email [email protected] Fang Tel +86-21-6598-2878Email [email protected]: Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing.Materials and Methods: A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb’s effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody.Results: BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab.Conclusion: c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.Keywords: c-Met, bispecific antibody, lung cancer, ovarian cancer, checkpoint antibody
