Cancer Management and Research (Sep 2021)
A CLDN18.2-Targeting Bispecific T Cell Co-Stimulatory Activator for Cancer Immunotherapy
Abstract
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 Yang1,2 1Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China; 2Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of ChinaCorrespondence: Xuanming YangSheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People’s Republic of ChinaTel +86-21-34204065Email [email protected]: 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.Keywords: CLDN18.2, CD28, bispecific antibody, cancer immunotherapy
