Prevention of experimental autoimmune myasthenia gravis by rat Crry-Ig: A model agent for long-term complement inhibition in vivo
Prevention of experimental autoimmune myasthenia gravis by rat Crry-Ig: A model agent for long-term complement inhibition in vivo
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DOI：
10.1016/j.molimm.2007.06.144
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发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Harris, Claire L.
中科院分区：
文献类型：
--
作者：
Hepburn, Natalie J.;Chamberlain-Banoub, Jayne L.;Harris, Claire L.
尽管补体在先天免疫中起着重要作用，但其参与许多炎性病理，因此已成为治疗靶标。产生用于抗补体治疗的大多数药剂在血浆中具有短半衰期，或者是小鼠或人来源的，从而限制了它们在疾病的鼠模型或短期治疗中的使用。在这里，我们描述了基于大鼠补体抑制剂Crry的长效大鼠治疗剂的产生。各种可溶性形式的Crry的表征表明，氨基末端的四个短的共识重复结构域所需的充分的监管和Ob-binding活动。将这些结构域与大鼠IgG 2a Fc融合产生了有效的补体抑制剂（rCrry-Ig），其循环半衰期从单独Crry的7 min延长至rCrry-Ig的53 h。rCrry-Ig全身给药超过5周产生了对重组试剂的弱免疫应答，然而，这主要是IgM性质，不会中和Crry功能或导致试剂从血浆中清除。在重症肌无力大鼠模型中给予rCrry-Ig完全消除了临床疾病，而缺乏免疫球蛋白Fe结构域的可溶性Crry引起了部分应答。rCrry-Ig不仅消融临床疾病，而且还防止C3和C9在神经肌肉接头处的沉积，并抑制该部位的细胞浸润。该药剂的长半衰期和低免疫原性将可用于大鼠慢性炎症性疾病模型的治疗。(c)2007爱思唯尔有限公司保留所有权利。
Despite its vital role in innate immunity, complement is involved in a number of inflammatory pathologies and has therefore become a therapeutic 14 target. Most agents generated for anti-complement therapy have short half-lives in plasma, or have been of mouse or human origin, thereby limiting their use either to murine models of disease or to short-term therapy. Here we describe the generation of a long-acting rat therapeutic agent based on the rat complement inhibitor, Crry. Characterisation of various soluble forms of Crry demonstrated that the amino-terminal four short-consensus repeat domains were required for full regulatory and Ob-binding activities. Fusion of these domains to rat IgG2a Fc generated an effective complement inhibitor (rCrry-Ig) with a circulating half-life prolonged from 7 min for Crry alone to 53 h for rCrry-Ig. Systemic administration of rCrry-Ig over 5 weeks generated a weak immune response to the recombinant agent, however this was predominantly IgM in nature and did not neutralise Crry function or cause clearance of the agent from plasma. Administration of rCrry-Ig completely abrogated clinical disease in a rat model of myasthenia gravis whereas soluble Crry lacking the immunoglobulin Fe domain caused a partial response. rCrry-Ig not only ablated clinical disease, but also prevented C3 and C9 deposition at the neuromuscular junction and inhibited cellular infiltration at this site. The long half-life and low immunogenicity of this agent will be useful for therapy in chronic models of inflammatory disease in the rat. (c) 2007 Elsevier Ltd. All rights reserved.