Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity.

ABSTRACT: 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

SUBMITTER: Qi X 

PROVIDER: S-EPMC6526162 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature