CD137
癌症研究
医学
炎症
免疫疗法
双特异性抗体
免疫
兴奋剂
免疫系统
抗体
受体
免疫学
内科学
单克隆抗体
作者
Chunxiao Xu,Xueyuan Zhou,Lindsay Webb,Sireesha Yalavarthi,Wenxin Zheng,Somdutta Saha,Rene Schweickhardt,Maria Soloviev,Molly H. Jenkins,Susanne Brandstetter,Natalya Belousova,Marat Alimzhanov,Brian Rabinovich,Amit M. Deshpande,Neil Brewis,Laura Helming
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-12-13
卷期号:12 (2): 195-213
标识
DOI:10.1158/2326-6066.cir-23-0243
摘要
The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by FcγR ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2 TM) in a human IgG1 backbone with LALA mutations to reduce binding to Fcγ receptors. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and TCR/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 TM structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.
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