Tailoring anti-complement therapeutics
Tailoring anti-complement therapeutics
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DOI：
10.1042/bst0301019
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发表时间：
2002-11-01
影响因子：
3.9
通讯作者：
Morgan, BP
中科院分区：
文献类型：
--
作者：
Harris, CL;Fraser, DA;Morgan, BP
补体是免疫系统的核心组成部分，在免疫监视中发挥重要作用。然而，使补体发挥其生理作用的活性产物可能不适当地靶向自身组织并引起病理。补体介导的炎症和组织破坏是类风湿性关节炎和痴呆等多种疾病病理学的重要驱动力。二十年前，没有可以用于治疗的药剂来抑制补体的活化，但是对体内补体的自然控制的理解的增加显著改变了这种情况。认识到模拟自身细胞上和血浆中存在的补体调节蛋白的作用的药物可以有效地控制补体的病理活化，这为在疾病中使用抗补体疗法打开了大门。在这里，我们将审查发展的抗补体治疗剂从第一代代理商，这是未经修改的天然调节剂的重组形式，最近的战略，使更好的药物。我们将描述针对疾病部位的抗补体活性的策略，并延长药剂的血浆半衰期。最后，我们将说明一种新的方法来提供抗补体剂，使前药，仅在疾病部位激活，从而最大限度地减少系统性补体抑制的有害影响。
Complement is a core component of the immune system, which performs vital roles in immune surveillance. However, the active products that enable complement to perform its physiological roles can inappropriately target self tissues and cause pathology. Complement-mediated inflammation and tissue destruction is an important drive to pathology in diseases as diverse as rheumatoid arthritis and dementia. Two decades ago there were no agents that could be used therapeutically to inhibit the activation of complement, but increased understanding of the natural control of complement in vivo has markedly changed this situation. The realization that drugs mimicking the action of the complement regulatory proteins present on self cells, and in plasma, could effectively control pathological activation of complement has opened the door to the use of anticomplement therapy in disease. Here we will review the development of anticomplement therapeutics from the first generation agents, which are unmodified recombinant forms of natural regulators, to recent strategies for making better drugs. We will describe strategies for targeting the anticomplement activity to the site of disease, and for extending the plasma half-life of the agent. Finally, we will illustrate a novel approach to the delivery of anticomplement agents, making prodrugs that are activated only at disease sites thus minimizing the deleterious effects of systemic complement inhibition.