文章：

抗人CD47单克隆抗体的抗白血病活性及耐受性

Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies

原文发布日期：2017-02-24

DOI: 10.1038/bcj.2017.7

类型: Original Article

开放获取: 是

英文摘要：

CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices.

摘要翻译： 

CD47是一种广泛表达的细胞表面蛋白，通过与其在吞噬细胞表面表达的配体SIRPα相互作用来抑制细胞的吞噬作用。多种血液系统恶性肿瘤表现出CD47的高表达，提示CD47可能介导了肿瘤的免疫逃逸。我们发现了三种独特的CD47-SIRPα阻断性抗CD47单克隆抗体，它们对人及食蟹猴CD47具有纳摩尔级亲和力，且无红细胞凝集和血小板聚集活性。为表征阻断CD47所激发的抗癌活性，将这些单克隆抗体克隆至效应功能沉默型及效应功能完整型Fc骨架中。效应功能完整型单抗在体外和体内均表现出强效活性，而效应功能沉默型单抗活性微弱，表明阻断CD47仅在存在Fc效应功能时才能产生治疗效果。一项非人灵长类动物研究显示，效应功能完整型单抗IgG1 C47B222-(CHO)在1mg/kg剂量下可使红细胞、红细胞比容和血红蛋白降低超过40%，而效应功能沉默型单抗IgG2σ C47B222-(CHO)在1mg/kg和10mg/kg剂量下对红细胞指标影响甚微。综上所述，我们的研究结果表明靶向CD47是一种具有吸引力的抗癌治疗策略。然而，抗CD47单抗观察到的抗癌活性及其对红细胞指标产生的副作用均依赖于Fc效应功能。

原文链接：

Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies