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

IMPC - 探索 C7 阻断作为补体介导的肾脏疾病免疫治疗靶点的潜力

• 批准号: MR/R014248/1
• 负责人: Kevin Marchbank
• 金额: $ 4.89万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR014248%2F1
• 关键词: IMPC; Exploration; potential; C7; blockade

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.

非典型溶血性尿毒综合征（阿胡斯）是一种肾脏疾病，如果不治疗，会迅速进展为肾衰竭。在纽卡斯尔的研究中，阿胡斯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，旨在标记和破坏细菌/病原体。基于补体因子H突变的广泛实验室和比较模型分析已经确定了它们在许多阿胡斯病例中的直接作用。因子H调节C3活化，C3活化是补体完全活化的中心。H因子功能的丧失会导致补体过度活跃和阿胡斯。随后，我们鉴定了与阿胡斯相关的C3中的功能获得性（GOF）突变。为了继续我们的分析，我们基于这些突变产生了几种独特的重组小鼠C3分子，并将C3高活性转移到小鼠C3。然后，我们成功地产生了一个复杂的小鼠模型的基础上的C3突变，C3 GOF小鼠模型。我们的分析表明，这种新的小鼠模型是高度相似的人类阿胡斯，因此提供了一个完美的测试床，以开发和测试新的抗补体疗法。我们在国家肾脏补体治疗中心（NRCTC）认识到，依库珠单抗（一种阻断补体破坏细胞能力的药物）是许多阿胡斯患者（超过80%）的高效治疗方法。依库珠单抗靶向补体的末端途径的功能，并且已经发现依库珠单抗的小鼠版本保护C3 GOF小鼠免于疾病。然而，依库珠单抗并不是一种完美的药物，它价格昂贵，长期使用的效果还不完全清楚，由于其靶蛋白（C5）的快速转化和可变表达，它也可能变得无效。最后，它的使用也使患者容易受到某些细菌的感染。由于依库珠单抗的潜在问题，许多药物正在开发中，但迄今为止还没有一种药物在这些疾病中进行成功的临床试验。补体成分C7是补体的末端途径的另一个关键成员，并且在末端途径中几乎是独特的，因为它在感染期间不被显著上调，它是稳定的并且以相对低的水平表达，使其成为抗补体治疗剂的良好靶标。在这里，我们将确定C7的去除是否保护C3 GOF小鼠免受阿胡斯。我们还将使用C7缺陷小鼠开发抗C7单克隆抗体，以研究这些试剂在C3 GOF小鼠中逆转疾病的能力。我们的输出将更清楚地了解补体末端途径在罕见肾脏疾病阿胡斯中的作用。我们还将产生许多新的末端通路试剂，包括功能性阻断单克隆抗体。该项目将提供关于C7阻断抗体在该模型中作为抗补体治疗的有效性的详细数据，以及与C5阻断相比，这种新的补体治疗剂是否可以在未来提供更好的保护，以防止这种类型的肾脏疾病。最后，由于补体系统的激活涉及大多数（如果不是全部的话）炎性疾病（如年龄相关性黄斑变性和癌症控制），并且与许多自身免疫性疾病（如类风湿性关节炎和狼疮）有关，因此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性疾病/病症。

项目成果

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

• DOI: 10.1093/hmg/ddab086
• 发表时间: 2021-06-17
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: McMahon O;Hallam TM;Patel S;Harris CL;Menny A;Zelek WM;Widjajahakim R;Java A;Cox TE;Tzoumas N;Steel DHW;Shuttleworth VG;Smith-Jackson K;Brocklebank V;Griffiths H;Cree AJ;Atkinson JP;Lotery AJ;Bubeck D;Morgan BP;Marchbank KJ;Seddon JM;Kavanagh D
• 通讯作者: Kavanagh D

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

• DOI: 10.3389/fimmu.2021.752916
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kamala O;Malik TH;Hallam TM;Cox TE;Yang Y;Vyas F;Luli S;Connelly C;Gibson B;Smith-Jackson K;Denton H;Pappworth IY;Huang L;Kavanagh D;Pickering MC;Marchbank KJ
• 通讯作者: Marchbank KJ

82 Using the C3 gain-of-function mouse model of aHUS as a complement therapeutic testbed to enable precision medicine for complement mediated atypical haemolytic uraemic syndrome

82 使用 aHUS 的 C3 功能获得小鼠模型作为补体治疗试验台，以实现补体介导的非典型溶血性尿毒综合征的精准医疗

• DOI: 10.1016/j.imbio.2023.152533
• 发表时间: 2023
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Smith-Jackson K