CR2-Mediated Targeting of Complement Inhibitors: Bench-to-Bedside Using a Novel Strategy for Site-Specific Complement Modulation
CR2-Mediated Targeting of Complement Inhibitors: Bench-to-Bedside Using a Novel Strategy for Site-Specific Complement Modulation
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DOI：
10.1007/978-1-4614-4118-2_9
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
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作者：
Holers, V. Michael;Rohrer, Baerbel;Tomlinson, Stephen
最近批准的第一个人类补体途径导向疗法，以及备受瞩目的遗传关联研究，激发了生物制药界对开发调节补体系统的药物的新兴趣。然而，在补体抑制剂广泛应用于炎症和自身免疫性疾病之前，必须克服巨大的挑战。这些挑战包括：（1）定义引起人体组织损伤的补体途径和效应机制，并确定每种途径的相对重要性是否因疾病而异；（2）使用传统的小分子或生物方法阻断或调节补体蛋白的功能，这些补体蛋白的循环水平非常高且周转率相对较快，特别是在急性和慢性自身免疫性疾病的情况下；（3）在使用全身活性补体阻断剂时避免感染性并发症或补体其他重要生理功能的损害。本章将回顾解决治疗开发中这些挑战的数据，重点是开发一种新策略，通过使用人补体受体 2 型 (CR2/CD21) 的重组部分（CR2/CD21）靶向抑制剂来阻断特定补体途径，该重组部分专门针对局部补体 C3 激活位点，其中 C3 片段被共价固定。最近，这些 CR2 靶向蛋白中的第一个已进入人类疾病阵发性睡眠性血红蛋白尿症的 I 期研究。使用 CR2 靶向抑制剂的小鼠转化研究结果强烈表明，补体治疗开发的指导原则很可能是集中于开发策略，通过物理定位治疗抑制作用来尽可能精确地调节途径。
Recent approval of the first human complement pathway-directed therapeutics, along with high-pro file genetic association studies, has catalyzed renewed biopharmaceutical interest in developing drugs that modulate the complement system. Substantial challenges remain, however, that must be overcome before widespread application of complement inhibitors in inflammatory and autoimmune diseases becomes possible. Among these challenges are the following: (1) defining the complement pathways and effector mechanisms that cause tissue injury in humans and determining whether the relative importance of each varies by disease, (2) blocking or modulating, using traditional small molecule or biologic approaches, the function of complement proteins whose circulating levels are very high and whose turnover rates are relatively rapid, especially in the setting of acute and chronic autoimmune diseases, and (3) avoiding infectious complications or impairment of other important physiological functions of complement when using systemically active complement-blocking agents. This chapter will review data that address these challenges to therapeutic development, with a focus on the development of a novel strategy of blocking specific complement pathways by targeting inhibitors using a recombinant portion of the human complement receptor type 2 (CR2/CD21) which specifically targets to sites of local complement C3 activation where C3 fragments are covalently fixed. Recently, the first of these CR2-targeted proteins has entered human phase I studies in the human disease paroxysmal nocturnal hemoglobinuria. The results of murine translational studies using CR2-targeted inhibitors strongly suggest that a guiding principle going forward in complement therapeutic development may well be to focus on developing strategies to modulate the pathway as precisely as possible by physically localizing therapeutic inhibitory effects.