Research Division, Chugai Pharmaceutical Co., Ltd., Japan.
Research Division, Chugai Pharmaceutical Co., Ltd., Japan.
Mol Immunol. 2014 Mar;58(1):132-8. doi: 10.1016/j.molimm.2013.11.017. Epub 2013 Dec 14.
Enhancing the effector function by optimizing the interaction between Fc and Fcγ receptor (FcγR) is a promising approach to enhance the potency of anticancer monoclonal antibodies (mAbs). To date, a variety of Fc engineering approaches to modulate the interaction have been reported, such as afucosylation in the heavy chain Fc region or symmetrically introducing amino acid substitutions into the region, and there is still room to improve FcγR binding and thermal stability of the CH2 domain with these approaches. Recently, we have reported that asymmetric Fc engineering, which introduces different substitutions into each Fc region of heavy chain, can further improve the FcγR binding while maintaining the thermal stability of the CH2 domain by fine-tuning the asymmetric interface between the Fc domain and FcγR. However, the structural mechanism by which the asymmetrically engineered Fc improved FcγR binding remained unclear. In order to elucidate the mechanism, we solved the crystal structure of a novel asymmetrically engineered Fc, asym-mAb23, in complex with FcγRIIIa. Asym-mAb23 has enhanced binding affinity for both FcγRIIIa and FcγRIIa at the highest level of previously reported Fc variants. The structural analysis reveals the features of the asymmetrically engineered Fc in comparison with symmetric Fc and how each asymmetrically introduced substitution contributes to the improved interaction between asym-mAb23 and FcγRIIIa. This crystal structure could be utilized to enable us to design a more potent asymmetric Fc.
通过优化 Fc 与 Fcγ 受体 (FcγR) 之间的相互作用来增强效应功能是提高抗癌单克隆抗体 (mAb) 效力的一种有前途的方法。迄今为止，已经报道了多种 Fc 工程改造方法来调节相互作用，例如在重链 Fc 区域中去岩藻糖基化或在该区域中对称引入氨基酸取代，并且这些方法仍然有改进 FcγR 结合和 CH2 结构域热稳定性的空间。最近，我们报道了不对称 Fc 工程改造，它在重链的每个 Fc 区域中引入不同的取代，可以通过微调 Fc 结构域和 FcγR 之间的不对称界面，进一步提高 FcγR 结合，同时保持 CH2 结构域的热稳定性。然而，不对称工程化 Fc 提高 FcγR 结合的结构机制仍不清楚。为了阐明该机制，我们解析了新型不对称工程化 Fc，asym-mAb23 与 FcγRIIIa 复合物的晶体结构。asym-mAb23 与 FcγRIIIa 和 FcγRIIa 的结合亲和力均高于之前报道的 Fc 变体的最高水平。结构分析揭示了不对称工程化 Fc 与对称 Fc 的区别，以及每个不对称引入的取代如何有助于改善 asym-mAb23 与 FcγRIIIa 之间的相互作用。该晶体结构可用于帮助我们设计更有效的不对称 Fc。
