抗体效应功能，包括抗体依赖性细胞毒性 (ADCC) 和吞噬作用 (ADCP)，是通过抗体 Fc 区与免疫细胞上存在的 Fcγ 受体相互作用介导的。已使用多种方法来调节抗体 Fc-Fcγ 相互作用，以驱动有效的抗肿瘤免疫反应，包括 Fc 点突变和聚糖修饰。然而，抗体-Fcγ 的强烈结合和 Fc 增强抗体在外周的免疫细胞结合可能会导致不必要的全身细胞因子释放和其他剂量限制性输注相关反应的诱导。在 Fcγ 受体的有效结合（可诱导抗肿瘤活性而不引起全身免疫激活）之间建立平衡是抗体和免疫肿瘤治疗领域持续的挑战。在此，我们描述了一种使用简单的聚乙二醇（PEG）连接体与带有马来酰亚胺连接的抗体链间二硫键缀合的抗体-Fcγ相互作用的可逆化学调节方法。该方法使得能够以减弱的 Fcγ 结合进行治疗的给药，这种结合在体内以时间依赖的方式恢复。该技术应用于效应子功能增强型激动剂 CD40 抗体 SEA-CD40，实验表明，尽管与亲本抗体相比，其保留了功效并改善了药代动力学，但体外以及小鼠和非人灵长类动物中 Fc 诱导的免疫激活显着减少。我们预见，这种简单的模块化系统可以快速应用于因输注后立即与外周 FcγR 结合而遭受全身免疫激活的抗体。

Antibody effector functions including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) are mediated through the interaction of the antibody Fc region with Fcγ receptors present on immune cells. Several approaches have been used to modulate antibody Fc-Fcγ interactions with the goal of driving an effective antitumor immune response, including Fc point mutations and glycan modifications. However, robust antibody-Fcγ engagement and immune cell binding of Fc-enhanced antibodies in the periphery can lead to the unwanted induction of systemic cytokine release and other dose-limiting infusion-related reactions. Creating a balance between effective engagement of Fcγ receptors that can induce antitumor activity without incurring systemic immune activation is an ongoing challenge in the field of antibody and immuno-oncology therapeutics. Herein, we describe a method for the reversible chemical modulation of antibody-Fcγ interactions using simple poly(ethylene glycol) (PEG) linkers conjugated to antibody interchain disulfides with maleimide attachments. This method enables dosing of a therapeutic with muted Fcγ engagement that is restored in vivo in a time-dependent manner. The technology was applied to an effector function enhanced agonist CD40 antibody, SEA-CD40, and experiments demonstrate significant reductions in Fc-induced immune activation in vitro and in mice and nonhuman primates despite showing retained efficacy and improved pharmacokinetics compared to the parent antibody. We foresee that this simple, modular system can be rapidly applied to antibodies that suffer from systemic immune activation due to peripheral FcγR binding immediately upon infusion.