Complement Inhibitors as DMOADs

作为 DMOAD 的补体抑制剂

• 批准号: 8730337
• 负责人: Rekha Bansal
• 金额: $ 7.88万
• 依托单位: NOVELMED THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730337
• 关键词: Acetaminophen; Adolescent; Adrenal Cortex Hormones; Affect; Age; Age-Months; Alternative Complement Pathway; Analgesics; Anterior Cruciate Ligament; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Area; Arthritis; Bolus Infusion; Cartilage; Categories; Cell Culture Techniques; Chronic; Clinic; Clinical Trials; Complement; Complement 3a; Complement 5a; Complement Factor B; Complement Inactivators; Complex; Coupled; Data; Degenerative polyarthritis; Development; Diagnostic radiologic examination; Disease; Disease Management; Disease Progression; Dose; Drug Kinetics; Effectiveness; Elderly; Etiology; Evaluation; Feedback; Functional disorder; Histology; Host Defense; Human; Humanities; Hyaluronic Acid; IL8 gene; Ibuprofen; IgG1; Indomethacin; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Interleukin-12; Interleukin-17; Interleukin-6; Investigation; Joints; Knockout Mice; Legal patent; Mammalian Cell; Mediating; Messenger RNA; Modeling; Monitor; Monoclonal Antibodies; Mus; Naproxen; Opiates; Oryctolagus cuniculus; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Population; Preparation; Prevalence; Process; Production; Properdin; Proteins; Protocols documentation; Quality of life; Regimen; Research; Role; Route; Swelling; Symptoms; Synovial Fluid; TNF gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Time; Tissues; United States National Institutes of Health; Variant; Work; aged; arthropathies; bone loss; celecoxib; complement system; cost effective; cyclooxygenase 2; cytokine; disability; etoricoxib; experience; humanized antibody; humanized monoclonal antibodies; improved; inhibiting antibody; inhibitor/antagonist; innovation; insight; joint injury; neutralizing antibody; novel; prevent; scale up; soluble complement C5b-9; success

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.

描述（申请人提供）：补体系统在预防炎症和关节不活动方面发挥作用。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% 致残。目前的药物只能控制疾病，不能治愈或阻止疾病。 OA 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 的发生和进展中很重要。据推测，中和 IL-12 或 TNF-1 可能会给 OA 患者带来益处，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。最近，补体替代途径 (AP) 与 OA 的病因学有关。我们开发了一组专有的抗体，可以选择性地靶向 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 的发生和进展中发挥着重要作用，并且我们的目标抗体在解决 OA 方面非常有效，如兔 OA 模型所示。 目前的申请建议开发人源化 IgG1 作为阻止和阻止人类 OA 进展的有效治疗方法。在第一阶段阶段，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期阶段，我们将研究靶向人源化抗体对老年兔的功效，评估生物制剂在多种给药模式下的功效，并建立人源化抗体的放大制备方案。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，这项工作是开发一种具有成本效益、有效且安全的治疗剂来预防 OA 引起的关节损伤的关键一步。