Abstract：
Colorectal cancer is a major global health burden, with limited efficacy of traditional treatment modalities in improving survival rates. However, recently advances in immunotherapy has improved treatment outcomes for patients with this cancer. To address the continuing need for improved treatment efficacy, this study introduced a novel tri-specific antibody, IMT030122, that targets EpCAM, 4-1BB, and CD3. We evaluated the pharmacological efficacy and mechanism of action of IMT030122 in vitro and in vivo. In in vitro studies, IMT030122 exhibited differential binding to antigens and cells expressing EpCAM, 4-1BB, and CD3. Moreover, IMT030122 relied on EpCAM-targeted activation of intracellular CD3 and 4-1BB signaling and mediated T cell cytotoxicity specific to HCT116 colorectal cancer cells. In vivo, IMT030122 demonstrated potent anti-tumor activity, significantly inhibiting the growth of colon cancer HCT116 and MC38-hEpCAM subcutaneous grafts. Further pharmacological analysis revealed that IMT030122 recruited lymphocytes from peripheral blood into colorectal cancer tissue and exerted durable anti-tumor activity, predominantly by promoting the activation, proliferation, and differentiation of CD8T cells. Notably, IMT030122 still exhibited anti-tumor efficacy even in the presence of significantly depleted lymphocytes in colorectal cancer tissue. The potent pharmacological activity and anti-tumor effects of IMT030122 suggest it may enhance treatment efficacy and substantially extend the survival of patients with colorectal cancer in the future.
摘要：
结直肠癌是全球主要的健康负担,传统治疗方式在提高生存率方面的功效有限。然而,免疫治疗的最新进展改善了这种癌症患者的治疗效果.为了满足对改善治疗效果的持续需求，这项研究引入了一种新型的三特异性抗体，IMT030122，目标是EpCAM，4-1BB,和CD3。我们在体外和体内评估了IMT030122的药理功效和作用机制。在体外研究中，IMT030122表现出与抗原和表达EpCAM的细胞的差异结合，4-1BB,和CD3。此外，IMT030122依赖于EpCAM靶向的细胞内CD3和4-1BB信号的激活和介导的对HCT116结直肠癌细胞特异性的T细胞毒性。在体内,IMT030122显示出有效的抗肿瘤活性，显著抑制结肠癌HCT116和MC38-hEpCAM皮下移植瘤的生长。进一步的药理学分析显示，IMT030122从外周血中招募淋巴细胞进入结直肠癌组织并发挥持久的抗肿瘤活性，主要通过促进激活，扩散,和CD8T细胞的分化。值得注意的是,即使在结肠直肠癌组织中存在显著耗竭的淋巴细胞,IMT030122仍表现出抗肿瘤功效。IMT030122的有效药理活性和抗肿瘤作用表明，它可能会增强治疗功效，并在未来显着延长结直肠癌患者的生存期。
