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Targeting the pathogenic Th17 cell axis in autoimmunity:developing a portfolio of novel, rationally designed and innovatively delivered biologics

靶向自身免疫中的致病性 Th17 细胞轴：开发一系列新颖、合理设计和创新交付的生物制剂

基本信息

批准号：
MR/V026283/1
负责人：
Obinna Ubah
金额：
$ 200.73万
依托单位：
Elasmogen Ltd
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV026283%2F1
关键词：
Targeting pathogenic Th17 cell axis

项目摘要

Our immune systems have evolved into complex, multi-layered processes that are capable of differentiating between "self" and "non-self" ensuring that we are protected from the external environment, and in particular infections. Each of us contains a sophisticated tool-box that consists of specialised cells, tissues and signalling molecules that act in a co-ordinated fashion to first detect, determine a threat (e.g. pathogen) and then muster an immediate retaliation to an infection; followed by a long-term defence mechanism against future attacks. Under normal circumstances, this system is highly effective, however, like other multi-factorial, complex mechanisms, failures can happen, and undesirable outcomes result where normal tissue is mistaken for foreign and a process of self-destruction is initiated. This auto-immune response (or self-damage) is the underlying issue in many diseases such as Rheumatoid arthritis, Psoriasis, Inflammatory bowel diseases, and affects a significant number of people (approx. 20% of the population) with the currently observed net increase in prevalence and incidence recorded each year predicted to continue, as the global population ages. Antibodies, which are the long-term anti-pathogenic protector molecules within our bodies are now also the leading class of drugs used to treat autoimmune diseases. Antibodies can be screened and selected in the lab and clones isolated that recognise for example cancer or inflammation drug targets. As administered biologic (large molecule) therapies, they target and clear the signalling molecules that cause inflammation, dampening down the response and keeping the disease under control. They have been effective in many patients, however, long-term use results in a decreased response and some people simply do not respond at all. The reasons for this refractory sub-set of patients (up to 80% in some indications) primarily lies in the design and mode of action of "natural" therapeutic antibodies. They are incredibly effective at binding with high affinity and selectivity to target, but they are limited to only one target and given the complexity of auto-immune disease, removal of one component may simply result in another being upregulated, with this compensatory response eventually bypassing the effect of the drug. Furthermore, the large and complex nature of the antibody may mean that the drug itself is "seen" by the patient's immune system as foreign. This results in the rapid removal of the drug from the body, which, in part, may explain why some patients require higher and higher effective dosing over time and eventually stop responding completely. The parenteral route of administration which the biologics are restricted to can causes severe injection site reactions and even infections, thereby complicating and worsening treatment outcomes.This proposal will deliver a new type of antibody-like therapy that overcomes these limitations. Elasmogen, has developed small protein drugs called soloMERs that are simpler than antibodies (1/12 th size) and can be readily formatted to recognise and bind to more than one disease target. In addition, they are inherently non-immunogenic, i.e. they fall below the radar of our immune systems, enabling them to be dosed multiple times without generating anti-soloMER antibodies. As starting material for this research program, an existing "super-potent" candidate anti-inflammatory soloMERs, which targets a key activator of inflammation, will be combined with other disease targeting soloMERs (and/or small molecules) to create simple drugs that act in multiple ways to block the self-destruct pathways in autoimmune diseases. These first-in class drug formats will be capable of simultaneously neutralising targets in the blood, on the cell surface or even inside the cell. We believe that multi-specific drugs have the potential to bring new treatment regimens & hope to those patients with significant medical unmet needs

我们的免疫系统已经进化成复杂的多层过程，能够区分“自我”和“非自我”，确保我们免受外部环境的影响，特别是感染。我们每个人都有一个复杂的工具箱，由专门的细胞，组织和信号分子组成，它们以协调的方式首先检测，确定威胁（例如病原体），然后立即对感染进行报复;其次是对未来攻击的长期防御机制。在正常情况下，该系统是非常有效的，然而，像其他多因素，复杂的机制，失败可能会发生，并导致不希望的结果，其中正常组织被误认为是外来的，并启动自毁过程。这种自身免疫反应（或自我损伤）是许多疾病的潜在问题，如风湿性关节炎，牛皮癣，炎症性肠病，并影响了相当多的人（约100万人）。20%的人口），随着全球人口老龄化，预计目前观察到的每年记录的患病率和发病率的净增加将继续下去。抗体是我们体内长期抗病原体的保护分子，现在也是用于治疗自身免疫性疾病的主要药物。可以在实验室中筛选和选择抗体，并分离出识别例如癌症或炎症药物靶标的克隆。作为生物（大分子）疗法，它们靶向并清除引起炎症的信号分子，抑制反应并控制疾病。它们对许多患者有效，然而，长期使用会导致反应降低，有些人根本没有反应。这种难治性患者亚组（在某些适应症中高达80%）的原因主要在于“天然”治疗性抗体的设计和作用模式。它们在以高亲和力和选择性结合靶点方面非常有效，但它们仅限于一个靶点，并且鉴于自身免疫疾病的复杂性，去除一种组分可能会简单地导致另一种组分上调，这种补偿反应最终绕过药物的作用。此外，抗体的大而复杂的性质可能意味着药物本身被患者的免疫系统“视为”外来物。这导致药物从体内迅速清除，这在一定程度上可以解释为什么一些患者随着时间的推移需要越来越高的有效剂量，最终完全停止反应。生物制剂局限于非肠道给药途径，可引起严重的注射部位反应，甚至感染，从而使治疗结果复杂化和恶化。该提案将提供一种克服这些限制的新型抗体样治疗。Elasmogen开发了一种称为soloMER的小蛋白质药物，它比抗体（1/12大小）更简单，并且可以很容易地识别和结合一种以上的疾病靶标。此外，它们本质上是非免疫原性的，即它们低于我们免疫系统的雷达，使它们能够多次给药而不产生抗soloMER抗体。作为这项研究计划的起始材料，现有的“超级强效”候选抗炎soloMER，靶向炎症的关键激活剂，将与其他疾病靶向soloMER（和/或小分子）组合，以创造简单的药物，以多种方式发挥作用，阻断自身免疫性疾病中的自毁途径。这些一流的药物形式将能够同时中和血液中，细胞表面甚至细胞内部的靶点。我们相信，多特异性药物有可能为那些有重大医疗需求未得到满足的患者带来新的治疗方案和希望