Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells
Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells
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DOI：
10.1158/1535-7163.mct-08-0201
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Desjarlais, John R.
中科院分区：
文献类型：
--
作者：
Richards, John O.;Karki, Sher;Desjarlais, John R.
Fc介导的效应器功能对某些单抗的治疗效果的贡献促使人们努力加强与Fcγ受体(Fc Gamma R)的相互作用。虽然早期的目标是增强Fc-Gamma RIIIa结合和自然杀伤(NK)细胞抗体依赖的细胞介导的细胞毒性(ADCC)，但其他相关细胞类型，如巨噬细胞，依赖于额外的激活受体，如Fc-Gamma RIIA。在这里，我们描述了一组具有不同Fc Gamma R亲和力的工程Fc变体，包括一种新的取代G236A，它相对于FcyRIIB选择性地增强了与Fc Gamma RIIA的结合。含有这种取代的变异体具有高达70倍的Fc-Gamma RIIA亲和力和15倍的Fc-Gamma RIIA/Fc-Gamma RIIb比率，并介导巨噬细胞对抗体包裹的目标细胞的吞噬增强。具有这种替代的特定的双重和三重组合变异体能够同时表现出高NK介导的ADCC和高巨噬细胞吞噬能力。此外，我们还使用了这组独特的变异体来定量探讨单个Fc-Gamma R对NK细胞和巨噬细胞介导的效应功能的相对贡献。这些实验表明，Fc-Gamma RIIA对巨噬细胞的影响最大，令人惊讶的是，抑制性受体Fc-Gamma RIIb对效应器功能几乎没有影响。这里描述的吞噬功能的增强提供了改善针对癌症的治疗性抗体的性能的潜力。
The contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fc gamma receptors (Fc gamma R). Although an early goal has been enhanced Fc gamma RIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as Fc gamma RIIa. Here, we describe a set of engineered Fc variants with diverse Fc gamma R affinities, including a novel substitution G236A that provides selectively enhanced binding to Fc gamma RIIa relative to FcyRIIb. Variants containing this substitution have up to 70-fold greater Fc gamma RIIa affinity and 15-fold improvement in Fc gamma RIIa/Fc gamma RIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual Fc gamma R to effector functions mediated by NK cells and macrophages. These experiments show that Fc gamma RIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor Fc gamma RIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers.