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首页> 外文期刊>Drug Design, Development and Therapy >Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody
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Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody

机译：通过新型C-Met / CD3双特异性抗体抑制C-Met过表达肿瘤

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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.
机译：简介：在肿瘤活组织检查中通常观察到C-Met或肝细胞生长因子（HGF）受体的过度表达，并且通常与患者存活率差，其使HGF / C-Met途径成为癌症治疗的有吸引力的分子靶标。已经探讨了许多基于抗体的治疗策略来阻止癌症中的C-Met或HGF;然而，临床疗效已经非常有限，表明单独阻断C-Met信号是不够的。因此，替代方法是为C-Met-过表达癌症制定免疫疗法策略。 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，导致有效的肿瘤细胞杀伤。材料和方法：使用新颖的BSAB平台产生双特异性抗体，结合C-Met和CD3的BS001。利用蛋白质印迹和T细胞介导的杀伤测定来评估BSAB对肿瘤细胞中细胞增殖，存活率和信号转导的影响。用于分析双特异性抗体的体内抗肿瘤作用及其与PD-L1抗体的体内抗肿瘤作用的皮下肿瘤小鼠模型。结果：BS001显示有效的T细胞介导的肿瘤细胞在体外杀死。此外，BS001抑制肿瘤细胞中C-Met和下游信号转导的磷酸化。在A549肺癌异种移植模型中，BS001抑制肿瘤生长，增加了活化的CD56肿瘤浸润淋巴细胞的比例。在atezolizumab的BS001的体内组合治疗中（抗程序化细胞死亡蛋白1-配体（PD-L1）抗体）显示比单疗法更有效的肿瘤抑制。类似地，在Skov3异种移植模型中，BS001在肿瘤生长抑制中显示出显着的疗效，并且在用BS001和PEMBROLIZUMAB的组合处理的一半以上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，其通过两种杰出机制实现：通过抗体介导的肿瘤细胞杀死T细胞并通过抑制C-Met信号转导。

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