Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China.
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, 200240, Shanghai, China.
Nat Commun. 2019 May 20;10(1):2141. doi: 10.1038/s41467-019-10088-1.
Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy.
靶向 4-1BB 的单克隆抗体激动剂（mAb-AG）刺激 T 细胞反应，在临床前模型中显示出强大的抗肿瘤活性，但由于疗效低（Utomilumab）或严重的肝毒性（Urelumab），其临床开发受到阻碍。在这里，我们表明同种型和内在激动性强度共同决定了抗 4-1BB mAb-AG 的疗效和毒性。虽然内在强激动性的抗 4-1BB 可以在没有 FcγRs 的情况下激活 4-1BB，但弱激动性抗体依赖 FcγRs 来激活 4-1BB。所有 FcγRs 都可以交联抗 41BB 抗体以增强共刺激，但激活 FcγR 诱导的抗体依赖性细胞介导的细胞毒性通过删除 4-1BB 细胞来损害抗肿瘤免疫。这表明平衡激动活性和 FcγR 相互作用的强度是设计具有最佳治疗性能的 4-1BB mAb-AG 的一种策略。作为这一概念的证明，我们开发了 LVGN6051，这是一种人源化的 4-1BB mAb-AG，在癌症免疫治疗的小鼠模型中，它在没有肝毒性的情况下显示出高抗肿瘤疗效。
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