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


中文翻译：

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新型 c-Met/CD3 双特异性抗体抑制 c-Met 过表达肿瘤


简介： c-Met 或肝细胞生长因子 (HGF) 受体的过度表达通常在肿瘤活检中观察到，并且通常与患者生存率较差相关，这使得 HGF/c-Met 通路成为癌症治疗中有吸引力的分子靶点。已经探索了许多基于抗体的治疗策略来阻断癌症中的 c-Met 或 HGF；然而，临床疗效非常有限，表明单独阻断 c-Met 信号是不够的。因此，另一种方法是开发针对 c-Met 过表达癌症的免疫治疗策略。 c-Met/CD3 双特异性抗体 (BsAb) 可以桥接 CD3 阳性 T 淋巴细胞和肿瘤细胞，从而有效杀死肿瘤细胞。

材料和方法：使用新型 BsAb 平台生成双特异性抗体 BS001，它可结合 c-Met 和 CD3。利用蛋白质印迹和 T 细胞介导的杀伤测定来评估 BsAb 对肿瘤细胞增殖、存活和信号转导的影响。利用皮下肿瘤小鼠模型分析双特异性抗体及其与PD-L1抗体联合治疗的体内抗肿瘤作用。

结果： BS001 在体外显示出有效的 T 细胞介导的肿瘤细胞杀伤作用。此外，BS001 抑制肿瘤细胞中 c-Met 的磷酸化和下游信号转导。在A549肺癌异种移植模型中，BS001抑制肿瘤生长并增加激活的CD56 ⁺肿瘤浸润淋巴细胞的比例。 BS001 与 Atezolizumab（一种抗程序性细胞死亡蛋白 1-配体 (PD-L1) 抗体）的体内联合治疗显示出比单一疗法更有效的肿瘤抑制作用。同样，在 SKOV3 异种移植模型中，BS001 显示出显着的肿瘤生长抑制功效，并且在超过一半的接受 BS001 和 Pembrolizumab 联合治疗的小鼠中未观察到肿瘤复发。

结论： c-Met/CD3双特异性抗体BS001在体外和体内表现出有效的抗肿瘤活性，这是通过两种不同的机制实现的：通过抗体介导的T细胞杀伤肿瘤细胞和通过抑制c-Met信号转导。


关键词: c-Met, 双特异性抗体, 肺癌, 卵巢癌, 检查点抗体