In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft tick Ornithodoros moubata
In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft tick Ornithodoros moubata
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DOI：
10.1074/jbc.m609858200
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发表时间：
2007-03-16
影响因子：
4.8
通讯作者：
Harris, Claire L.
中科院分区：
文献类型：
--
作者：
Hepburn, Natalie J.;Williams, Anwen S.;Harris, Claire L.
补体(C)在炎症性疾病中的作用促使人们寻找能够抑制失调的补体激活的药物。其中许多试剂在级联反应的早期阶段抑制C3转换酶。然而，全身性C抑制的缺点，特别是在慢性疾病的长期治疗中，是由于无法调理复合体和外来细胞以及溶解病原体而导致的感染和免疫复合体疾病的增强。最近在软蜱的唾液腺中发现了一种CS结合蛋白，这使得一种末端途径特异性试剂OMCL的开发成为可能，该试剂有可能在不影响关键生理过程的情况下缓解疾病。在这里，我们证明了OMCL具有广泛的跨物种活性。给啮齿类动物静脉注射OMCL后，OMCL完全消融补体溶血活性，并随着C5的重新合成而逐渐恢复。OMCL的循环半衰期为30h，与其他小型生物制剂相比，清除速度要慢得多。使用C5充足和C5缺乏的小鼠，我们发现延长的半衰期是由于与血浆C5的结合。C5与OMCL结合的表面等离子体共振分析证实，结合亲和力高，解离速度慢。OMCL对正常Lewis大鼠被动移植所致的实验性自身免疫性重症肌无力有明显的预防作用。OMCI消融了临床疾病，减少了C3和C9在神经肌肉交界处的沉积，并显著减少了该部位的细胞渗透。这些数据为补体介导的疾病的靶向治疗提供了令人兴奋的前景，而不会对补体的调理作用产生不利的抑制。
The involvement of complement (C) in inflammatory diseases has driven the search for agents capable of inhibiting dysregulated complement activation. Many of these reagents inhibit the C3 convertases during the early stages of the cascade. However, a drawback of total systemic C inhibition, particularly in long-term treatment of chronic disease, is potentiation of infection and immune complex disease due to an inability to opsonize complexes and foreign cells and to lyse pathogens. Recent identification of a CS-binding protein in the salivary gland of the soft tick Ornithodoros moubata has enabled development of a terminal pathway-specific reagent, OmCl, with potential to ameliorate disease while leaving key physiological processes unaffected. Here we demonstrated that OmCl has broad cross-species activity. When given intravenously to rodents, OmCl totally ablated complement hemolytic activity, which gradually restored as C5 was resynthesized. The circulating half-life of OmCl was 30 h, demonstrating a much slower clearance than other small, biological agents. Using C5-sufficient and C5-deficient mice we showed that prolonged half-life was due to binding to plasma C5. Surface plasmon resonance analysis of C5 binding to OmCl confirmed a high binding affinity with a slow dissociation rate. OmCl was effective in preventing experimental autoimmune myasthenia gravis induced by passive transfer in normal Lewis rats. OmCI ablated clinical disease reduced C3 and C9 deposition at the neuro-muscular junction, and effected a marked reduction in cellular infiltration at this site. These data offer exciting prospects for targeted treatment of complement-mediated diseases without the detrimental inhibition of the opsonic roles of complement.