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

Nat Commun. 2019; 
QiXinyue,LiFanlin,WuYi,ChengChen,HanPing,WangJieyi,YangXuan
Products/Services Used Details Operation
… FcγRIII (Sino-Biologicals, 50326-M08H-50) was used. All FcγR were spotted using a Continuous Flow Microspotter (Wasatch Microfluidics) onto a single SensEye G-streptavidin … 7.4. For the His-tagged FcγRIII, biotinylated anti-His IgG1 (GenScript, A00613) was spotted …

摘要

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 immunit... More

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