Understanding the Properdin Paradox using C3 D1115N (gain-of-function) knock-in mice

我们在国家肾脏补体治疗中心（NRCTC）是最早认识到eculizumab（Soliris，一种阻断我们免疫系统部分补体的药物）是许多罕见血液和肾脏疾病患者的高效治疗方法之一，特别是阵发性睡眠性血红蛋白尿症（PNH）和非典型溶血性尿毒综合征（阿胡斯）。然而，我们也很容易接受依库珠单抗是令人难以置信的昂贵，它确实对所有患有阿胡斯的患者有效（或者实际上在许多患有相关疾病的患者中称为C3肾小球病），并且因为它完全关闭了我们免疫系统的一个重要组成部分，它使接受药物治疗的患者对可能导致脑膜炎的感染高度敏感（>1000倍）。因此，需要更好的抗补体药物是明确的。许多这样的药物正在开发中，靶向补体成分C3。C3是补体系统的核心，是补体激活的旁路途径的重要部分，其是自激活扩增环并驱动补体的大部分抗菌功能。使用靶向补体系统的这一部分的药物可能有显着的副作用，相对于感染的易感性和不良反应的vaccine.Models系统，以全面，现实的方式测试药物靶向C3，相对于阿胡斯，通常缺乏。在过去的十年中，我们已经成功地产生了几个独特的拷贝的小鼠C3分子的基础上发现的变化（或突变）在人类C3与阿胡斯。在这样做的过程中，我们证明了我们可以将患者的功能变化转移到小鼠模型中。在这种情况下，我们产生了一个过度活跃的C3分子。在C3的两个基因拷贝上都有这种变化的小鼠迅速发展为阿胡斯。我们的分析证实，以等同于在人体中使用依库珠单抗的方式阻断补体系统完全保护小鼠免受阿胡斯，因此验证了用于测试其他抗补体药物的模型。我们的同事最近的工作表明，阻断补体系统中另一种蛋白质（称为备解素）功能的药物可能会预防阿胡斯的某些方面，而且确实可能对PNH有用。然而，其他研究的封锁备解素在C3肾小球疾病是灾难性的。这留下了关于在阿胡斯中使用抗备解素药物的适用性的重要问题有待解决。此外，解决这些问题可能对我们对备解素功能的整体知识产生重大影响，并允许在更一般的情况下更好地选择抗补体药物使用，例如常见的自身免疫性疾病，如类风湿性关节炎和系统性红斑狼疮，或者甚至在器官移植期间。本研究的目的是提供关于使用抗备解素药物治疗aHUS的功效的详细数据，所述治疗使用最复杂的阿胡斯小动物模型。将这些发现与目前的一线抗补体药物进行比较。评估新的抗补体药物是否可以提供比现有药物更好的保护，无论导致疾病的补体蛋白变体如何，即确定未来治疗阿胡斯患者的个性化药物的详细框架的需求或提供理由。最后，由于补体系统的激活涉及大多数（如果不是全部）炎性病症，（如年龄相关性黄斑变性和控制癌症），并与许多自身免疫性疾病有关（如类风湿性关节炎和狼疮），进一步验证这种比较模型，其核心是过度活跃的C3，将巩固其作为首要模型的地位，以分析补体激活在各种炎症性疾病/病症的进展和治疗中的作用。

We at the National Renal Complement Therapeutic Centre (NRCTC) were one of the first to recognise that eculizumab (Soliris, a drug that blocks part of our immune system known as complement) is a highly effective treatment in many patients with rare blood and kidney diseases, particularly paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). However, we also readily accept that eculizumab is incredibly expensive, it does work on all patients with aHUS (or indeed in many patients with a related disease known as C3 glomerulopathy) and because it completely switches off an important component of our immune system, it leaves patients treated with the drug highly susceptible (>1000 fold more so) to infections that can cause meningitis. Therefore, the need for better anti-complement drugs is clear. Many such drugs are in development that target complement component C3. C3 is at heart of the complement system, an important part of the alternative pathway of complement activation which is a self-activating amplification loop and drives much of the anti-bacterial function of complement. Use of drugs that target this part of the complement system may have significant side effects with respect to susceptibility to infection and poor response to vaccines.Models systems to test drugs that target C3 in a comprehensive, realistic manner, with respect to aHUS, are generally lacking. Over the last decade we have successfully generated several unique copies of mouse C3 molecules based on changes (or mutations) found in human C3 that associated with aHUS. In doing so, we demonstrated that we could transfer functional changes from patients to a mouse model. In this case, we generated a C3 molecule which was hyperactive. Mice with this change on both gene copies of C3 rapidly develop aHUS. Our analysis confirms that blockade of the complement system in a manner equivalent to use of eculizumab in man completely protects mice from aHUS and therefore validates the model for testing of other anti-complement drugs. Recent work by our colleagues has suggested that drugs that block the function of another protein in the complement system, known as properdin, may prevent aspects of aHUS and indeed, may be useful in PNH. However, other studies examining the blockade of properdin in C3 glomerulopathy were catastrophic. This leaves important questions around the suitability of use of anti-properdin drugs in aHUS to be resolved. Furthermore, addressing these questions may have significant impact on our knowledge of properdin function overall and allow better choice of anti-complement drug use in more general conditions such as common autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus or indeed during organ transplantation.Therefore, the aim of this study is to provide detailed data regarding the efficacy of using anti-properdin drugs in the treatment of aHUS using the most sophisticated small animal model of aHUS available. To compare these findings to the current front line anti-complement drugs. To assess whether new anti-complement drugs can provide better protection than existing drugs regardless of the complement protein variant that caused the disease, i.e. establish the need or provide the rationale for a detailed framework for personalised medicine in the treatment of aHUS patients for the future. 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), the further validation of this comparative model, which has hyperactive C3 at its heart, will cement its place as the premier model to analyse the role of complement activation in the progression, and the treatment, of a wide range of inflammatory diseases/conditions.