Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science. 2013 Jul 5;341(6141):88-91. doi: 10.1126/science.1238856. Epub 2013 May 30.
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.
CD47 是一种抗吞噬信号，癌细胞利用它来抑制巨噬细胞介导的破坏。在这里，我们对人源 SIRPα 的结合域进行了修饰，将其用作 CD47 的拮抗剂。我们设计了高亲和力的 SIRPα 变体，与野生型 SIRPα 相比，对人源 CD47 的亲和力提高了约 5 万倍。作为高亲和力的 SIRPα 单体，它们能够有效地拮抗癌细胞表面的 CD47，但本身不会诱导巨噬细胞吞噬。相反，它们与所有测试的肿瘤特异性单克隆抗体都表现出显著的协同作用，通过增加体外吞噬作用和增强体内抗肿瘤反应来实现这一点。这种“一石二鸟”的策略针对肿瘤细胞引发免疫反应，同时降低了巨噬细胞激活的阈值，从而为增强治疗性抗癌抗体的疗效提供了一种通用方法。
