Characterization of a novel T cell-engaging bispecific antibody for elimination of L1CAM-positive tumors

作者：Yuan Yuan, Junyan Li, Jie Chen, Lei Han, Lei Wang, Yali Yue, Junjun Liu, Baohong Zhang, Yunsheng Yuan, Mingyuan Wu, Yanlin Bian, Yueqing Xie, Jianwei Zhu · 发表于：Biomedicine & Pharmacotherapy · 年份：2024 · DOI：10.1016/j.biopha.2024.116565 · 被引用次数：10 · 研究领域：CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research、Immunotherapy and Immune Responses

Neural cell adhesion molecule L1 (L1CAM) is a cell-surface glycoprotein involved in cancer occurrence and migration. Up to today, L1CAM-targeted therapy appeared limited efficacy in clinical trials although quite a few attempts by monoclonal antibody (mAb) or chimeric antigen receptor T-cell therapy (CAR-T) have been reported. Therefore, the development of new effective therapies targeting L1CAM is highly desirable. It has been demonstrated that T cell-engaging bispecific antibody (TCE) plays an effective role in cancer immunotherapy by redirecting the cytotoxic activity of CD3 + T cells to tumor cells, resulting in tumor cell death. In this study, we designed and characterized a novel bispecific antibody (CE7-TCE) based on the IgG-(L)-ScFv format, which targets L1CAM and CD3 simultaneously. In vitro , CE7-TCE induced specific killing of L1CAM-positive tumor cells through T cells. In vivo , CE7-TCE inhibited tumor growth in human peripheral blood mononuclear cell/tumor cell co-grafting models. To overcome the adaptive immune resistance (AIR) that impairs the efficacy of TCEs, we conducted a combination therapy of CE7-TCE with Pembrolizumab (anti-PD1 mAb), which enhanced the anti-tumor activity of CE7-TCE. Our results confirmed the feasibility of using L1CAM as a TCE target for the treatment of solid tumors and revealed the therapeutic potential of CE7-TCE combined with immune checkpoint inhibitors. • A novel L1CAM-targeted T cell engaging bispecific antibody that has been dev...