激动型 CD40 抗体通过抑制性 Fcγ 受体结合发挥佐剂和抗肿瘤活性。
Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies.
机构信息
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
出版信息
Science. 2011 Aug 19;333(6045):1030-4. doi: 10.1126/science.1206954.
Abstract
CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies (mAbs) with the inhibitory Fcγ receptor FcγRIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating FcγR binding, hence capable of cytotoxicity, or for inhibitory FcγRIIB binding, revealed that enhancing FcγRIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for FcγRIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.
摘要
CD40 是肿瘤坏死因子受体 (TNFR) 超家族的成员，表达于抗原呈递细胞 (APC) 上，对免疫激活至关重要。虽然已开发出针对 CD40 的激动性抗体用于免疫治疗，但它们的临床疗效受到限制。我们发现，激动性 CD40 单克隆抗体 (mAb) 的 Fc 结构域与抑制性 Fcγ 受体 FcγRIIB 的共交联是免疫激活所必需的。对增强 FcγR 结合以增强细胞毒性或增强抑制性 FcγRIIB 结合能力的 CD40 mAb 进行直接比较表明，增强 FcγRIIB 结合可赋予免疫刺激活性和更强的抗肿瘤反应。这种增强 CD40 介导的免疫激活对 FcγRIIB 的意外需求，对 TNFR 激动性抗体作为治疗药物的设计具有直接意义。
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