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.

说明(申请人提供)：补体系统起到预防炎症和关节不动的作用。骨关节炎(OA)是一种关节炎症性疾病，在老年人中相当普遍，在55岁以上的人口中导致近10%的人残疾。目前的药物只能治疗这种疾病，而不能治愈或阻止这种疾病。骨性关节炎的流行，加上缺乏治疗疾病的骨关节炎药物(DMOADs)，加剧了这种疾病对人类的负面影响。最近的研究表明，细胞因子在骨性关节炎的发生发展中起着重要作用。据推测，中和IL-12或肿瘤坏死因子-1可能对骨关节炎患者有好处，因此，中和这些细胞因子的生物制剂或药物正在研究中。抗肿瘤坏死因子-1抗体的临床试验目前正在进行中。补体的替代途径(AP)最近被认为与骨性关节炎的病因有关。我们已经开发了一组专有的抗体，这些抗体可以选择性地针对AP，而不会影响通过经典途径(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，并且我们的靶抗体在解决OA方面是高效的，正如兔OA模型所表明的那样。目前的应用建议开发人源化的IgG1作为一种有效的治疗方法来阻止和阻止人类骨性关节炎的进展。在I相片段中，我们进一步在幼兔OA模型中检测了一种特异性的中和抗补体单抗。在第二阶段，我们将研究靶向人源化抗体对老龄兔的效果，评价多种给药模式下的生物效果，并建立放大制备人源化抗体的方案。我们的研究将为开发治疗骨性关节炎的新疗法提供新的见解。总体而言，拟议的工作是朝着开发成本效益高、有效和安全的治疗药物的方向迈出的关键一步，以防止骨关节炎造成的关节损害。