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Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
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Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
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Journal Article
Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity
2019
Overview
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.
Agonistic 4-1BB antibodies developed for cancer immunotherapy have suffered from either hepatotoxicity or insufficient anti-cancer activity. Here the authors determine the contribution of FcγR binding and agonistic strength to these outcomes, and engineer a 4-1BB antibody with potent anti-tumor effect and no liver toxicity in mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 13/51
/ 82/80
/ 82/83
/ Animals
/ Antibodies, Monoclonal, Humanized - immunology
/ Antibodies, Monoclonal, Humanized - pharmacology
/ Antibodies, Monoclonal, Humanized - therapeutic use
/ Antibody-dependent cell-mediated cytotoxicity
/ Cancer
/ Cell Line, Tumor - transplantation
/ Drug Screening Assays, Antitumor
/ Humanities and Social Sciences
/ Humans
/ Immunity
/ Liver
/ Melanoma, Experimental - immunology
/ Melanoma, Experimental - therapy
/ Mice
/ Science
/ Toxicity
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology
/ Tumors
