Department of Medicine, University of Arizona, Tucson, AZ, USA.
Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Blood Rev. 2018 Nov;32(6):480-489. doi: 10.1016/j.blre.2018.04.005. Epub 2018 Apr 14.
Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.
血液系统恶性肿瘤表达高水平的 CD47，作为一种免疫逃避机制。CD47-SIRPα 触发一连串事件，抑制吞噬作用。临床前研究支持几种抗体介导的 CD47-SIRPα 阻断模型，导致细胞死亡信号、带有应激信号的细胞吞噬作用和肿瘤特异性 T 细胞反应的启动。目前正在临床试验中研究四种不同的旨在靶向恶性肿瘤中 CD47-SIRPα 相互作用的抗体分子：Hu5F9-G4、CC-90002、TTI-621 和 ALX-148。Hu5F9-G4 是一种人源化抗 CD47 阻断抗体，目前正在四项不同的 I 期临床试验中进行研究。这些研究可能为治疗性双特异性抗体奠定基础。抗 CD20（利妥昔单抗）和抗 CD47 的双特异性抗体（CD20-CD47SL）融合也在临床前模型中显示出对淋巴瘤的协同作用。这篇综述总结了大量支持在白血病、淋巴瘤和多发性骨髓瘤中使用旨在靶向 CD47-SIRPα 相互作用的抗体的临床前证据和新兴临床数据。
