Division of Hematology, University of Toronto, Toronto, Ontario, Canada; Divison of Medical Oncology & Hematology, University Health Network, Toronto, Ontario, Canada.
Division of Hematology, University of Toronto, Toronto, Ontario, Canada; Divison of Medical Oncology & Hematology, University Health Network, Toronto, Ontario, Canada.
Transfus Med Rev. 2019 Oct;33(4):256-265. doi: 10.1016/j.tmrv.2019.09.004. Epub 2019 Oct 22.
Dysregulation of the complement system underlies the pathophysiology of many diseases. Renewed interest in complement occurred with the recognition that its therapeutic inhibition was possible. Terminal complement blockade with the anti-C5 monoclonal antibody eculizumab significantly changed management and clinical outcomes of patients with paroxysmal nocturnal hemoglobinuria, and served as a proof of concept for other complement-mediated diseases. Eculizumab is also approved for atypical hemolytic uremic syndrome and myasthenia gravis. Multiple new disease indications have been identified, and novel complement inhibitors are in various stages of development, with several currently in human trials. Beyond C5, these new drugs block proximal complement, pathway-specific targets, convertase activity, and anaphylatoxin function. Though monoclonal antibodies are still common, peptides, RNAi, and small molecule inhibitors provide the opportunity for different administration routes and schedules. Several challenges still exist or will soon present themselves, including mitigation of infection risk, effective monitoring strategies, and how to choose between therapeutics when more than one is available. In this review, we will describe the lessons learned from the "eculizumab era," present many of the novel therapeutics currently or soon to be in trials, and highlight some of the challenges that will require attention as the field progresses.
补体系统的失调是许多疾病的病理生理学基础。人们重新认识到补体的治疗抑制是可能的，这引起了人们对补体的兴趣。抗 C5 单克隆抗体依库珠单抗对阵发性夜间血红蛋白尿患者的治疗阻断，显著改变了患者的治疗管理和临床结局，为其他补体介导的疾病提供了概念验证。依库珠单抗也被批准用于非典型溶血性尿毒症综合征和重症肌无力。已经确定了多种新的疾病适应症，并且新型补体抑制剂处于不同的开发阶段，目前有几种正在进行人体试验。除了 C5 之外，这些新药还可以阻断补体途径的近端、特定靶点、转化酶活性和过敏毒素功能。尽管单克隆抗体仍然很常见，但肽、RNAi 和小分子抑制剂为不同的给药途径和方案提供了机会。目前或即将进行临床试验的许多新型治疗方法仍然存在或即将面临一些挑战，包括降低感染风险、有效的监测策略以及在有多种治疗方法可供选择时如何进行选择。在这篇综述中，我们将描述从“依库珠单抗时代”中吸取的经验教训，介绍目前或即将进行临床试验的许多新型治疗方法，并强调该领域发展所需要关注的一些挑战。
