%0 Journal Article
%T Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with Fc¦ÃR affinity
%J -
%D 2019
%R https://doi.org/10.1038/s41467-019-10088-1
%X 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 Fc¦ÃRs, weak agonistic antibodies rely on Fc¦ÃRs to activate 4-1BB. All Fc¦ÃRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating Fc¦ÃR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB+ cells. This suggests balancing agonistic activity with the strength of Fc¦ÃR 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
%U https://www.nature.com/articles/s41467-019-10088-1