Hematology Department, G Papanicolaou Hospital, Thessaloniki, Greece.
French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Blood. 2022 Jun 23;139(25):3571-3582. doi: 10.1182/blood.2021012860.
Complement is an elaborate system of innate immunity. Genetic variants and autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition. Eculizumab, the first-in-class complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor, ravulizumab, and a C3 inhibitor, pegcetacoplan, have also now been approved for PNH. Novel agents, such as factor B and factor D inhibitors, are under study, with very promising results. In this era of several approved targeted complement therapeutics, selection of the proper drug must be based on a personalized approach. Beyond PNH, complement inhibition has also shown efficacy and safety in cold agglutinin disease, primarily with the C1s inhibitor of the classical complement pathway sutimlimab, as well as with pegcetacoplan. Furthermore, C5 inhibition with eculizumab and ravulizumab, as well as inhibition of the lectin pathway with narsoplimab, is being investigated in transplantation-associated thrombotic microangiopathy. With this revolution of next-generation complement therapeutics, additional hematologic entities, such as delayed hemolytic transfusion reaction or immune thrombocytopenia, might also benefit from complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting complement in hematologic diseases, focusing on (1) complement biology for the clinician, (2) complement activation and therapeutic inhibition in prototypic complement-mediated hematologic diseases, (3) hematologic entities under investigation for complement inhibition, and (4) other complement-related disorders of potential interest to hematologists.
补体是先天免疫系统的一个精细系统。导致补体过度激活的遗传变异和自身抗体与多种人类疾病有关。其中，血液系统疾病阵发性睡眠性血红蛋白尿症（PNH）仍然是补体激活和抑制的典型模型。首个补体抑制剂依库珠单抗于 2007 年被批准用于 PNH。为了满足一些未满足的需求，长效 C5 抑制剂 ravulizumab 和 C3 抑制剂 pegcetacoplan 也已被批准用于 PNH。新型药物，如因子 B 和因子 D 抑制剂，正在研究中，结果非常有前景。在有几种已批准的靶向补体治疗药物的时代，正确选择药物必须基于个体化方法。除了 PNH，补体抑制在冷凝集素病中也显示出疗效和安全性，主要是使用经典补体途径的 C1s 抑制剂 sutimlimab，以及 pegcetacoplan。此外，用依库珠单抗和 ravulizumab 抑制 C5，用 narsoplimab 抑制凝集素途径，正在移植相关血栓性微血管病中进行研究。随着下一代补体治疗药物的革命，其他血液学实体，如延迟性溶血性输血反应或免疫性血小板减少症，也可能受益于补体抑制剂。因此，本文旨在描述针对血液系统疾病中补体的最新知识，重点介绍（1）临床医生的补体生物学，（2）典型补体介导的血液系统疾病中的补体激活和治疗性抑制，（3）正在研究用于补体抑制的血液学实体，以及（4）对血液学家有潜在兴趣的其他补体相关疾病。
