IMPC - Exploration of the potential of C7 blockade as a target for immune therapy in complement mediated kidney disease

非典型溶血性尿毒症综合征(AHUS)是一种肾脏疾病，如不治疗可迅速进展为肾功能衰竭。在纽卡斯尔发起的研究中，aHUS与补体系统成员基因的突变有关。补体是我们免疫系统的一部分，旨在标记和摧毁细菌/病原体。广泛的实验室和基于比较模型的补体因子H突变分析已经确定了它们在许多aHUS病例中的直接作用。因子H调节C3的激活，而C3的激活是补体充分激活的中心。因子H功能的丧失会导致补体过度活跃和aHUS。随后，我们确定了C3中与aHUS相关的功能增益(GOF)突变。为了继续我们的分析，我们根据这些突变产生了几个独特的重组小鼠C3分子，并将C3过度活跃转移到小鼠C3。然后，我们成功地基于C3突变之一生成了一个复杂的小鼠模型，即C3GOF小鼠模型。我们的分析表明，这个新的小鼠模型与人类的aHUS高度相似，因此为开发和测试新的抗补体疗法提供了一个完美的试验台。我们国家肾脏补体治疗中心(NRCTC)认识到，eculizumab(一种阻断补体破坏细胞能力的药物)对许多aHUS患者(超过80%)是一种非常有效的治疗方法。Eculizumab针对补体末端途径的功能，已经发现一种小鼠版本的Eulizumab可以保护C3GOF小鼠免受疾病的侵袭。然而，eculizumab并不是一种完美的药物，它的价格昂贵，长期使用的效果尚不完全清楚，还可能由于其靶蛋白(C5)的快速翻转和可变表达而无效。最后，它的使用也使患者容易受到某些细菌的感染。由于eculizumab的潜在问题，许多药物正在开发中，但到目前为止还没有一种药物在这些疾病中进行了成功的临床试验。补体成分C7是补体末端途径的另一个关键成员，在末端途径中几乎是独一无二的，因为它在感染过程中不会显著上调，它是稳定的，并且表达水平相对较低，使其成为抗补体治疗的良好靶点。在这里，我们将确定去除C7是否能保护C3GOF小鼠免受AHUS的伤害。我们还将利用C7缺陷小鼠开发抗C7单抗，以研究这些试剂逆转C3GOF小鼠疾病的能力。我们的成果将是对补体末端途径在罕见肾脏疾病aHUS中的作用有更清晰的理解。我们还将产生许多新的末端途径试剂，包括功能封闭的单抗。该项目将提供关于C7阻断抗体在该模型中作为抗补体疗法的有效性的详细数据，以及与C5阻断相比，这种新的补体疗法是否能在未来提供更好的保护，防止这种类型的肾脏疾病。最后，由于补体系统的激活参与了大多数(如果不是全部)炎症性疾病(如老年性黄斑变性和癌症控制)，并与许多自身免疫性疾病(如类风湿性关节炎和狼疮)有关，这种比较模型和它可能有助于验证的抗C7药物最终可能导致治疗广泛的炎症性疾病/条件。

Atypical haemolytic uraemic syndrome (aHUS) is a kidney disorder which without treatment rapidly progresses to kidney failure. In work instigated in Newcastle, aHUS was linked to mutations in genes that are members of the complement system. Complement is part of our immune system and is designed to label and destroy bacteria/pathogens. Extensive laboratory and comparative model based analysis of mutations in complement factor H have established their direct role in many cases of aHUS. Factor H regulates C3 activation and C3 activation is central to full activation of complement. Loss of factor H function leads to over active complement and aHUS. Subsequently, we identified gain-of-function (GOF) mutations in C3 that associated with aHUS. To continue our analysis, we generated several unique recombinant mouse C3 molecules based on these mutations and transferred C3 hyperactivity to mouse C3. We then successfully generated a sophisticated mouse model based on one of the C3 mutations, a C3 GOF mouse model.Our analysis suggests that this new mouse model is highly similar to aHUS in man and therefore offers a perfect test bed to develop and test new anti-complement therapeutics. We at the National Renal Complement Therapeutic Centre (NRCTC) recognise that eculizumab (a drug that blocks the ability of complement to destroy cells) is a highly effective treatment in many patients with aHUS (greater than 80%). Eculizumab targets the function of the terminal pathway of complement and a mouse version of eculizumab has been found to protect the C3 GOF mice from disease. However, eculizumab is not a perfect drug, it is expensive and the effects of long term use are not yet fully known, it can also be made ineffective due to the quick turn over and variable expression of its target protein (C5). Finally, it's use also makes patients susceptible to infection by certain bacteria.Because of the potential problems with eculizumab, many drugs are being developed but none so far have undergone successful clinical trails in these diseases. Complement component C7 is an another key member of the terminal pathway of complement and is almost unique in the terminal pathway in that it does not get significantly up regulated during infection, it is stable and expressed at relatively low levels making it a good target to for an anti-complement therapeutic. Here, we will establish whether removal of C7 protects C3 GOF mice from aHUS. We will also use the C7 deficient mice to develop anti-C7 monoclonal antibodies to investigate the ability of these reagents to reverse disease in the C3 GOF mice.Our output will be a much clearer understanding of the role of the terminal pathway of complement in the rare kidney disease aHUS. We will also generate many new terminal pathway reagents including functionally blocking monoclonal antibodies. The project will provide detailed data regarding the efficacy of C7 blocking antibodies as an anti-complement therapy in this model, and whether this new complement therapeutic can provide better protection from this type of kidney disease in the future, compared to C5 blockade. Finally, as activation of the complement system is involved in most, if not all, inflammatory conditions (such as age-related macular degeneration and control of cancer) and is linked to many autoimmune diseases (such as rheumatoid arthritis and lupus) this comparative model and the anti-C7 drug it may help validate, could eventually lead to the treatment of a wide range of inflammatory diseases/conditions.