Disrupting the binding of CD47 to SIRPα has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPα blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8+ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPα and CD40L, adjoined by a central Fc domain, termed SIRPα-Fc-CD40L. SIRPα-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPα-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPα-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo These data illustrated that whereas CD47/SIRPα inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage- and T-cell-mediated immunity that significantly enhanced durable tumor control and rejection.

中文翻译：

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CD40增强了CD47阻断下游的I型干扰素反应，弥合了先天和适应性免疫。

通过增强靶向抗体的抗体依赖性细胞吞噬作用（ADCP），破坏CD47与SIRPα的结合已成为一种有前途的针对晚期癌症的免疫治疗策略。在临床上，CD47 /SIRPα阻断通过增加巨噬细胞吞噬肿瘤细胞和增强树突状细胞向CD8 + T细胞交叉表达抗原来诱导抗肿瘤活性。这两个过程均通过CD40信号转导增强。在这里，我们生成了一种新型的双面融合蛋白，该蛋白融合了SIRPα和CD40L的细胞外结构域，并与一个称为SFIRα-Fc-CD40L的中心Fc结构域邻接。SIRPα-Fc-CD40L以高亲和力结合CD47和CD40，并且在不存在Fc受体交联的情况下激活了CD40信号传导。没有溶血，血凝的迹象，在体外或食蟹猕猴中观察到血小板减少或血小板减少。鼠SIRPα-Fc-CD40L在小鼠CT26肿瘤模型中优于CD47阻断和CD40激动剂抗体，并与PD-1和CTLA4的免疫检查点阻断协同作用。SIRPα-Fc-CD40L在巨噬细胞中激活了I型干扰素应答，并在体外和体内增强了ADCP活性靶向抗体的活性。这些数据说明，尽管CD47 /SIRPα抑制作用可以增强肿瘤细胞的吞噬作用，但CD40介导的CD34 /SIRPα激活可以增强肿瘤细胞的吞噬能力。 I型干扰素反应提供了巨噬细胞和T细胞介导的免疫之间的桥梁，大大增强了持久性肿瘤的控制和排斥。鼠SIRPα-Fc-CD40L在小鼠CT26肿瘤模型中优于CD47阻断和CD40激动剂抗体，并与PD-1和CTLA4的免疫检查点阻断协同作用。SIRPα-Fc-CD40L在巨噬细胞中激活了I型干扰素应答，并在体外和体内增强了ADCP活性靶向抗体的活性。这些数据说明，尽管CD47 /SIRPα抑制作用可以增强肿瘤细胞的吞噬作用，但CD40介导的CD34 /SIRPα激活可以增强肿瘤细胞的吞噬能力。 I型干扰素反应提供了巨噬细胞和T细胞介导的免疫之间的桥梁，大大增强了持久性肿瘤的控制和排斥。鼠SIRPα-Fc-CD40L在小鼠CT26肿瘤模型中优于CD47阻断和CD40激动剂抗体，并与PD-1和CTLA4的免疫检查点阻断协同作用。SIRPα-Fc-CD40L在巨噬细胞中激活了I型干扰素应答，并在体外和体内增强了ADCP活性靶向抗体的活性。这些数据说明，尽管CD47 /SIRPα抑制作用可以增强肿瘤细胞的吞噬作用，但CD40介导的CD34 /SIRPα激活可以增强肿瘤细胞的吞噬能力。 I型干扰素反应提供了巨噬细胞和T细胞介导的免疫之间的桥梁，大大增强了持久性肿瘤的控制和排斥。