Liang Jie, Zhang Huihui, Huang Yue, Fan Lilv, Li Fanlin, Li Min, Yan Yaping, Zhang Junshi, Li Zeyu, Yang Xuanming
Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
Cancer Manag Res. 2021 Sep 7;13:6977-6987. doi: 10.2147/CMAR.S330637. eCollection 2021.
Co-stimulatory receptor agonist antibodies have shown promising antitumor efficacy in preclinical models. However, their clinical development lags due to systemic or local adverse effects of non-specific T cell activation. Utilization of a bispecific antibody format to reduce off-tumor immune activation is a focus of co-stimulatory receptor agonist antibody design.
In this study, a bispecific antibody with anti-CLDN18.2 and anti-CD28 moieties was produced. Its T cell costimulation ability was evaluated in T cell coculture assay in vitro. Its safety and anti-tumor efficacy were explored in mouse tumor models.
Anti-CLDN18.2-anti-CD28 bispecific antibody could co-stimulate T cells and increase the expression of effector cytokines in a CLDN18.2-dependent manner. Treatment of anti-CLDN18.2-anti-CD28 could reduce tumor burden and increase tumor-infiltrated T cells. Immunosuppressive cells including tumor-associated macrophages and myeloid-derived suppressor cells were also reduced without systemic adverse effects.
This work provided proof-of-concept evidence for a new strategy to develop a bispecific co-stimulatory activator for treating CLDN18.2 tumors.
共刺激受体激动剂抗体在临床前模型中已显示出有前景的抗肿瘤疗效。然而，由于非特异性T细胞激活的全身或局部不良反应，它们的临床开发滞后。利用双特异性抗体形式来减少肿瘤外免疫激活是共刺激受体激动剂抗体设计的一个重点。
在本研究中，制备了一种具有抗CLDN18.2和抗CD28部分的双特异性抗体。在体外T细胞共培养试验中评估其T细胞共刺激能力。在小鼠肿瘤模型中探索其安全性和抗肿瘤疗效。
抗CLDN18.2-抗CD28双特异性抗体能够以CLDN18.2依赖的方式共刺激T细胞并增加效应细胞因子的表达。抗CLDN18.2-抗CD28治疗可减轻肿瘤负担并增加肿瘤浸润T细胞。包括肿瘤相关巨噬细胞和髓系来源抑制细胞在内的免疫抑制细胞也减少，且无全身不良反应。
这项工作为开发用于治疗CLDN18.2肿瘤的双特异性共刺激激活剂的新策略提供了概念验证证据。
