Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody

Abstract

Introduction

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

Acknowledgments

This study was supported by grants from the National Basic Research Program of China (973 Program) 2015CB553706 and Shanghai Science & Technology Basic Research Program (18JC1414400). The results shown in 1B,1C were based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. The authors acknowledge the contributions of lab members to the bispecific antibody format design. The authors thank RemeGen, Ltd. for BS001 protein expression.

Disclosure

Jianmin Fang reports being a shareholder of RemeGen Ltd., outside the submitted work. The authors report no other potential conflicts of interest in this work.