FDA-approved anti–PD-L1 monoclonal antibodies (mAbs) bear the IgG1 isotype, whose scaffolds are either wild-type (e.g., avelumab) or Fc-mutated and lacking Fcγ receptor (FcγR) engagement (e.g., atezolizumab). It is unknown whether variation in the ability of the IgG1 Fc region to engage FcγRs renders mAbs with superior therapeutic activity. In this study, we used humanized FcγR mice to study the contribution of FcγR signaling to the antitumor activity of human anti–PD-L1 mAbs and to identify an optimal human IgG scaffold for PD-L1 mAbs. We observed similar antitumor efficacy and comparable tumor immune responses in mice treated with anti–PD-L1 mAbs with wild-type and Fc-mutated IgG scaffolds. However, in vivo antitumor activity of the wild-type anti–PD-L1 mAb avelumab was enhanced by combination treatment with an FcγRIIB-blocking antibody, which was co-administered to overcome the suppressor function of FcγRIIB in the tumor microenvironment (TME). We performed Fc glycoengineering to remove the fucose subunit from the Fc-attached glycan of avelumab to enhance its binding to the activating FcγRIIIA. Treatment with the Fc-afucosylated version of avelumab also enhanced antitumor activity and induced stronger antitumor immune responses compared with the parental IgG. The enhanced effect by afucosylated PD-L1 antibody was dependent on neutrophils and associated with decreased frequencies of PD-L1 + myeloid cells and increased infiltration of T cells in the TME. Our data reveal that the current design of FDA-approved anti–PD-L1 mAbs does not optimally harness FcγR pathways and suggest two strategies to enhance FcγR engagement to optimize anti–PD-L1 immunotherapy.

中文翻译：

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PD-L1 抗体的 Fc 糖工程利用 Fcγ 受体提高抗肿瘤功效

FDA 批准的抗 PD-L1 单克隆抗体 (mAb) 具有 IgG1 同种型，其支架为野生型（例如 avelumab）或 Fc 突变型且缺乏 Fcγ 受体 (FcγR) 参与（例如 atezolizumab）。IgG1 Fc 区与 FcγRs 结合的能力的变化是否使 mAb 具有更好的治疗活性尚不清楚。在本研究中，我们使用人源化 FcγR 小鼠来研究 FcγR 信号转导对人抗 PD-L1 mAb 抗肿瘤活性的贡献，并确定 PD-L1 mAb 的最佳人 IgG 支架。我们在使用具有野生型和 Fc 突变 IgG 支架的抗 PD-L1 mAb 治疗的小鼠中观察到相似的抗肿瘤功效和可比的肿瘤免疫反应。然而，野生型抗 PD-L1 mAb avelumab 的体内抗肿瘤活性通过与 FcγRIIB 阻断抗体联合治疗得到增强，共同给药以克服 FcγRIIB 在肿瘤微环境 (TME) 中的抑制功能。我们进行了 Fc 糖工程以从 avelumab 的 Fc 连接聚糖中去除岩藻糖亚基，以增强其与激活 FcγRIIIA 的结合。与亲本 IgG 相比，使用 Fc-afucosylated 版本的 avelumab 治疗也增强了抗肿瘤活性并诱导更强的抗肿瘤免疫反应。无岩藻糖基化 PD-L1 抗体的增强作用依赖于嗜中性粒细胞，并与 PD-L1 频率降低有关 与亲本 IgG 相比，使用 Fc-afucosylated 版本的 avelumab 治疗也增强了抗肿瘤活性并诱导更强的抗肿瘤免疫反应。无岩藻糖基化 PD-L1 抗体的增强作用依赖于嗜中性粒细胞，并与 PD-L1 频率降低有关 与亲本 IgG 相比，使用 Fc-afucosylated 版本的 avelumab 治疗也增强了抗肿瘤活性并诱导更强的抗肿瘤免疫反应。无岩藻糖基化 PD-L1 抗体的增强作用依赖于嗜中性粒细胞，并与 PD-L1 频率降低有关+骨髓细胞和 TME 中 T 细胞浸润增加。我们的数据表明，目前 FDA 批准的抗 PD-L1 mAb 设计并未最佳地利用 FcγR 通路，并提出了两种增强 FcγR 参与以优化抗 PD-L1 免疫疗法的策略。