Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10088-1
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Funding
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2015013]
- Sheng Yushou Foundation
- National Natural Science Foundation of China [81671643]
- National Key Research and Development Program of China [2016YFC1303400]
- Recruitment Program of Global Experts (People's Republic of China)
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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 gamma Rs, weak agonistic antibodies rely on Fc gamma Rs to activate 4-1BB. All Fc gamma Rs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating Fc gamma R-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 gamma R 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.
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