School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Department of Pathology, the First People's Hospital of Yunnan Province, Kunming 650034, China.
Int Immunopharmacol. 2023 Oct;123:110686. doi: 10.1016/j.intimp.2023.110686. Epub 2023 Jul 25.
Over the last decade, immuno-oncologic drugs especially CD3-engaging bispecific antibodies (biAbs) are experiencing fast-paced evolution, but big challenges still exist in the clinical development of biAbs in solid tumors, especially non-small cell lung cancer (NSCLC). In this study, we choose a ROR1 × CD3 biAb in scFv-Fc format, named R11 × v9 biAb, to investigate its tumor-inhibiting role in NSCLC. Notably, the ROR1-engaging arm binds both human and mouse ROR1. We found that R11 × v9 biAb specifically binds T cells and tumor cells simultaneously, and dose-dependent cytotoxicity was detected for various ROR1 NSCLC cell lines. Further, R11 × v9 biAb mediated T-cell derived proinflammatory cytokine secretion, boosted granzyme B and perforin production from CD8 T cells, and recruited more CD4 T cells and CD8 T cells into the tumor tissues. The antitumor activity of R11 × v9 biAb was confirmed in two xenograft mouse models of ROR1 NSCLC. Importantly, no harmful side effects were observed in these in vivo studies, warranting further preclinical and clinical studies of R11 × v9 biAb in NSCLC.
在过去的十年中，免疫肿瘤药物，特别是 CD3 结合双特异性抗体（biAbs），正在经历快速发展，但在实体瘤，特别是非小细胞肺癌（NSCLC）中，biAbs 的临床开发仍然存在巨大挑战。在本研究中，我们选择了一种 ROR1×CD3 的 scFv-Fc 格式的双特异性抗体，命名为 R11×v9 双抗，来研究其在 NSCLC 中的肿瘤抑制作用。值得注意的是，该 ROR1 结合臂可结合人和鼠的 ROR1。我们发现 R11×v9 双抗可特异性地同时结合 T 细胞和肿瘤细胞，并检测到对各种 ROR1 NSCLC 细胞系的剂量依赖性细胞毒性。此外，R11×v9 双抗介导 T 细胞衍生的促炎细胞因子分泌，增强 CD8 T 细胞中颗粒酶 B 和穿孔素的产生，并招募更多的 CD4 T 细胞和 CD8 T 细胞进入肿瘤组织。R11×v9 双抗在两种 ROR1 NSCLC 的异种移植小鼠模型中证实了其抗肿瘤活性。重要的是，这些体内研究未观察到有害的副作用，这为 R11×v9 双抗在 NSCLC 中的进一步临床前和临床研究提供了依据。
