Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fcγ-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab), and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor-seeking immune cells. Mol Cancer Ther; 16(9); 1887–97. ©2017 AACR .

中文翻译：

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IdeS对内源性IgG的酶促失活增强了治疗性抗体的功效

内源性血浆IgG设置了一个免疫阈值，该阈值决定了肿瘤定向治疗性抗体的活性。内源性抗体使细胞抗体受体饱和，限制了抗体依赖性细胞介导的细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP）。在这里，我们展示了如何使用细菌酶IdeS对IgG进行酶促裂解，以清空高亲和力和低亲和力Fcγ受体，并清除整个内源性抗体库。使用体外模型，肿瘤动物模型以及先前在IdeS进行的临床试验中收集的血清的离体分析，我们显示了用IdeS清除竞争性血浆抗体水平如何解除对细胞抗体受体的阻滞。我们显示了针对乳腺癌（曲妥珠单抗），结肠癌（西妥昔单抗）的治疗性抗体，去除内源性IgG后，可增强淋巴瘤（利妥昔单抗和阿仑单抗）。总体而言，IdeS被证明是重新启动人抗体库的有效工具，并产生了一个窗口，可将治疗性抗体优先加载到效应细胞上，从而创建了一批专门寻找肿瘤的免疫细胞。分子癌疗法；16（9）; 1887–97。©2017 AACR。