Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
复制标题
通过平衡激动强度与 FcγR 亲和力优化 4-1BB 抗体用于癌症免疫治疗
DOI：
10.1038/s41467-019-10088-1
复制
发表时间：
2019-05-20
影响因子：
16.6
通讯作者：
Yang, Xuanming
中科院分区：
文献类型：
--
作者：
Qi, Xinyue;Li, Fanlin;Yang, Xuanming
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.
