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

Xinyue Qi, Fanlin Li, Yi Wu, Chen Cheng, Ping Han, Jieyi Wang () and Xuanming Yang ()
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Xinyue Qi: Shanghai Jiao Tong University
Fanlin Li: Shanghai Jiao Tong University
Yi Wu: Lyvgen Biopharma
Chen Cheng: Shanghai Jiao Tong University
Ping Han: Shanghai Jiao Tong University
Jieyi Wang: Lyvgen Biopharma
Xuanming Yang: Shanghai Jiao Tong University

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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 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.

Date: 2019
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DOI: 10.1038/s41467-019-10088-1

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