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

我们的免疫系统已经进化成复杂的、多层次的过程，能够区分“自我”和“非自我”，确保我们免受外部环境，特别是感染的影响。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，它们以协调的方式行动，首先检测、确定威胁(例如病原体)，然后立即对感染进行报复；然后是针对未来攻击的长期防御机制。在正常情况下，这个系统是非常有效的，然而，像其他多因素、复杂的机制一样，故障可能会发生，当正常组织被误认为是异物时，就会导致不良结果，并启动一个自我破坏的过程。这种自身免疫反应(或自身损害)是许多疾病的根本问题，如类风湿性关节炎、牛皮癣、炎症性肠道疾病，并影响相当数量的人(约.占人口的20%)，目前观察到的流行率和发病率每年都有净增长，预计随着全球人口老龄化，这种趋势将持续下去。抗体是我们体内长期的抗病原保护者分子，现在也是用于治疗自身免疫性疾病的主要药物类别。抗体可以在实验室中进行筛选和选择，并分离出识别癌症或炎症药物靶点的克隆。在实施生物(大分子)疗法时，他们针对并清除引起炎症的信号分子，抑制反应并控制疾病。它们在许多患者中都很有效，然而，长期使用会导致反应降低，有些人根本就没有反应。这种难治性患者亚群的原因(在某些适应症中高达80%)主要是由于“天然”治疗性抗体的设计和作用模式。它们在与靶点的高亲和力和选择性结合方面非常有效，但它们仅限于一个靶点，而且考虑到自身免疫性疾病的复杂性，移除一个成分可能只会导致另一个成分上调，这种代偿反应最终会绕过药物的作用。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”外来的。这会导致药物迅速从体内排出，这可能在一定程度上解释了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。生物制剂被限制在肠外给药途径可能会导致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。这项提议将提供一种新型的抗体样疗法，以克服这些限制。Elasmogen已经开发出被称为soloMERs的小型蛋白质药物，这种药物比抗体(1/12大小)更简单，并且可以很容易地格式化以识别并结合多个疾病靶点。此外，它们本质上是非免疫原性的，即它们不在我们免疫系统的雷达范围内，使它们能够多次给药，而不会产生抗soloMER抗体。作为这项研究计划的开始材料，现有的一种以炎症关键激活物为靶点的“超有效”候选抗炎SoloMERs将与其他靶向SoloMERs(和/或小分子)的疾病结合起来，创造出以多种方式发挥作用的简单药物，以阻断自身免疫性疾病的自毁途径。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的靶标。我们相信，多特效药物有可能带来新的治疗方案，希望能为那些有重大医疗需求而未得到满足的患者带来希望。

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