期刊
IMMUNOLOGICAL REVIEWS
卷 313, 期 1, 页码 376-401出版社
WILEY
DOI: 10.1111/imr.13164
关键词
alternative pathway; complement protein inhibitors; complement therapeutics; eculizumab; mechanistic foundations of complement
类别
This article explores the progress and challenges in the field of complement therapeutics, with a focus on the side effects of C5 blockade and the redefinition of the mechanistic foundations of the complement cascade.
Over a century after the discovery of the complement system, the first complement therapeutic was approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). It was a long-acting monoclonal antibody (aka 5G1-1, 5G1.1, h5G1.1, and now known as eculizumab) that targets C5, specifically preventing the generation of C5a, a potent anaphylatoxin, and C5b, the first step in the eventual formation of membrane attack complex. The enormous clinical and financial success of eculizumab across four diseases (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD)) has fueled a surge in complement therapeutics, especially targeting diseases with an underlying complement pathophysiology for which anti-C5 therapy is ineffective. Intensive research has also uncovered challenges that arise from C5 blockade. For example, PNH patients can still face extravascular hemolysis or pharmacodynamic breakthrough of complement suppression during complement-amplifying conditions. These side effects of a stoichiometric inhibitor like eculizumab were unexpected and are incompatible with some of our accepted knowledge of the complement cascade. And they are not unique to C5 inhibition. Indeed, exceptions to the rules of complement biology abound and have led to unprecedented and surprising insights. In this review, we will describe initial, present and future aspects of protein inhibitors of the complement cascade, highlighting unexpected findings that are redefining some of the mechanistic foundations upon which the complement cascade is organized.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据