Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab's Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

中文翻译：

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人IgG1抗体以靶独立方式抑制血管生成。

异常的血管生成与影响全球近10％人口的疾病有关。最广泛使用的抗血管生成药物是贝伐单抗，这是一种靶向人VEGFA的人源化IgG1单克隆抗体。尽管贝伐单抗不能识别小鼠Vegfa，但它可以抑制小鼠的血管生成。在这里，我们显示贝伐单抗在三种小鼠模型中均不通过Vegfa阻断而抑制血管生成，而是通过FcγRI（CD64）和c-Cbl介导Fc介导的信号传导，从而损害巨噬细胞迁移。其他已批准但不含小鼠靶标的人源化或人源IgG1抗体（阿达木单抗，阿仑单抗，ofatumumab，奥马珠单抗，帕利珠单抗和托珠单抗），小鼠IgG2a和人IgG1-Fc或小鼠IgG2a-Fc的过表达，也抑制了野生型和FcγR人源化的血管生成老鼠。Fcgr1切除或敲低消除了这种抗血管生成作用，Fc裂解，IgG-Fc抑制，Fc-FcγR相互作用破坏或消除FcRγ引发的信号传导。此外，贝伐单抗的Fc区在人源化VEGFA小鼠中增强了其抗血管生成活性。最后，缺乏FcγRI的小鼠表现出增加的发育和病理性血管生成。这些发现揭示了针对FcγRI的出乎意料的抗血管生成功能以及可能涉及的hIgG1疗法的脱靶作用。