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活动中起作用。骨关节炎（OA）是一种关节炎症性疾病，在老年人中相当普遍，导致55岁以上人口中近10%的人残疾。目前的药物只能控制疾病，不能治愈或阻止疾病。骨性关节炎的流行加上疾病修饰性骨关节炎药物（DMOADs）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的发生和发展中起重要作用。据推测，中和IL-12或TNF-1可能对OA患者有益，因此，正在研究中和这些细胞因子的生物制剂或药物。抗tnf -1抗体的临床试验目前正在进行中。补体的替代途径（AP）最近被认为与OA的病因有关。我们开发了一组专有的抗体，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的发生和发展中起着重要作用，我们的目标抗体在OA的兔模型中显示出高度有效的解决OA。目前的应用建议开发人源化IgG1作为阻止和阻止人类OA进展的有效治疗方法。在第一阶段，我们进一步在幼兔OA模型中测试了一种特异性中和抗补体单克隆抗体。在二期阶段，我们将研究靶向人源抗体对老龄兔的疗效，评估多种给药方式下该生物制剂的疗效，并建立规模化制备人源抗体的方案。我们的研究将为OA治疗的新疗法的发展提供新的见解。总的来说，这项工作是朝着开发一种经济、有效和安全的治疗药物来预防OA引起的关节损伤的方向迈出的关键一步。

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. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) is a disease which targets the elderly population, and affects a large number of people worldwide. Despite tremendous efforts, no effective and safe treatment is currently available. The treatment of OA is focused on managing pain and swelling, improving quality of life, and minimizing disability. There are no disease-modifying drugs (DMOADs) available at this time, so the disease management is primarily with acetaminophen, non-steroidal antiinflammatory drugs (ibuprofen, naproxen, indomethacin, etc), cyclooxygenase-2 selective inhibitors (celecoxib, etoricoxib, etc), and other non-opiate and opiate analgesics. Intra-articular corticosteroid injections provide benefit in some patients. NovelMed intends to develop a Disease Modifying Treatment for Osteoarthritis. We have developed a humanized monoclonal antibody that displays exciting results in resolving OA in the rabbit model. This application proposes to further evaluate the use of this antibody in juvenile and aged rabbits.