Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond

伊库利珠单抗 补体系统 阵发性夜间血红蛋白尿 免疫学 非典型溶血尿毒综合征 医学 补体成分5 凝集素途径 补语(音乐) 替代补体途径 免疫系统 生物 遗传学 基因 表型 互补
作者
Eleni Gavriilaki,Régis Peffault de Latour,Antonio M. Risitano
出处
期刊:Blood [Elsevier BV]
卷期号:139 (25): 3571-3582 被引量:26
标识
DOI:10.1182/blood.2021012860
摘要

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.
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