Complement Inhibitors as DMOADs

描述（由申请人提供）：补体系统在预防炎症和关节不动中发挥作用。骨关节炎（OA）是一种关节炎性疾病，在老年人中相当普遍，并导致55岁以上人口中近10%的残疾。目前的药物只能控制疾病，不能治愈或阻止疾病。骨关节炎的流行加上疾病修饰骨关节炎药物（DMOAD）的缺乏加剧了这种疾病对人类的负面影响。 最近的研究表明，细胞因子在OA的发生和发展中是重要的。据推测，中和IL-12或TNF-1可能为OA患者提供益处，因此，正在研究中和这些细胞因子的生物制剂或药物。目前正在进行抗TNF-1抗体的临床试验。补体的旁路途径（AP）最近被认为与OA的病因有关。我们已经开发了一组专有的抗体，它们选择性地靶向AP，而不影响通过经典途径（CP）介导的宿主防御。我们的初步结果表明，AP在OA的发展和进展中起着重要作用，并且我们的靶抗体在解决OA方面非常有效，如兔OA模型所示。 本申请提出开发人源化IgG 1作为用于停止和阻止人类OA进展的有效治疗。在I期部分，我们进一步在幼兔OA模型中测试特异性中和抗补体单克隆抗体。在II期部分，我们将研究靶向人源化抗体对老年兔的有效性，评估生物制剂在多种给药模式下的有效性，并建立人源化抗体规模化制备的方案。我们的研究将为开发治疗OA的新疗法提供新的见解。总的来说，拟议的工作是开发一种具有成本效益，有效和安全的治疗剂，以预防由OA引起的关节损伤的方向的关键一步。

DESCRIPTION (provided by applicant): Complement system play a role in preventing inflammation and joint immobility. Osteoarthritis (OA), an inflammatory disease of the joints, is quite prevalent among the elderly and causes disability in nearly 10% of the population over 55 years. Current medications only manage the disease and do not cure or halt the disease. The prevalence of OA coupled with the absence of Disease Modifying Osteoarthritis Drugs (DMOADs) heightens the negative impact of this disease on humanity. Recent studies have shown that cytokines are important in the development and progression of OA. It has been hypothesized that neutralizing IL-12 or TNF-1 may provide benefit to OA patients, hence, biologics or drugs that neutralize these cytokines are being investigated. Clinical trials with an anti-TNF-1 antibody are currently ongoing. The alternative pathway (AP) of complement has recently been implicated in the etiology of OA. We have developed a proprietary group of antibodies that selectively target the AP without affecting the host defense mediated via the classical pathway (CP). Our preliminary results suggest that the AP plays an important role in the development and progression of OA and that our target antibody is highly effective in resolving OA as indicated by rabbit models of OA. The current application proposes development of a humanized IgG1 as a potent treatment for halting and arresting the progression of OA in humans. In the Phase I segment, we further test a specific neutralizing anti-complement monoclonal antibody in the young rabbit OA model. In the Phase II segment, we will study the efficacy of the targeted humanized antibody to aged rabbits, evaluate the efficacy of the biologic in multiple modes of administration, and establish protocol for scaled up preparation of the humanized antibody. Our studies will provide new insight into the development of novel therapies for the treatment of OA. Overall, the proposed work is a critical step in the direction of developing a cost-effective, efficacious and safe therapeutic agent for preventing joint damage caused by OA.