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A CLDN18.2-Targeting Bispecific T Cell Co-Stimulatory Activator for Cancer Immunotherapy
Cancer Management and Research ( IF 3.3 ) Pub Date : 2021-09-07 , DOI: 10.2147/cmar.s330637
Jie Liang 1 , Huihui Zhang 1 , Yue Huang 1 , Lilv Fan 1 , Fanlin Li 1 , Min Li 1 , Yaping Yan 1 , Junshi Zhang 1 , Zeyu Li 1 , Xuanming Yang 1, 2
Affiliation  

Background: 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.
Methods: 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.
Results: 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.
Conclusion: This work provided proof-of-concept evidence for a new strategy to develop a bispecific co-stimulatory activator for treating CLDN18.2+ tumors.



中文翻译:

用于癌症免疫治疗的 CLDN18.2 靶向双特异性 T 细胞共刺激激活剂

背景:共刺激受体激动剂抗体在临床前模型中显示出有希望的抗肿瘤功效。然而,由于非特异性 T 细胞激活的全身或局部副作用,其临床开发滞后。利用双特异性抗体形式减少肿瘤外免疫激活是共刺激受体激动剂抗体设计的重点。
方法:在本研究中,产生了具有抗 CLDN18.2 和抗 CD28 部分的双特异性抗体。通过体外T细胞共培养测定评估其T细胞共刺激能力。在小鼠肿瘤模型中探讨了其安全性和抗肿瘤功效。
结果:抗CLDN18.2-抗CD28双特异性抗体可以以CLDN18.2依赖性方式共刺激T细胞并增加效应细胞因子的表达。抗 CLDN18.2-抗 CD28 治疗可以减轻肿瘤负荷并增加肿瘤浸润的 T 细胞。包括肿瘤相关巨噬细胞和骨髓源性抑制细胞在内的免疫抑制细胞也减少了,但没有产生全身性副作用。
结论:这项工作为开发治疗 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。

更新日期:2021-09-06
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