Complement Inhibitors as DMOADs

作为 DMOAD 的补体抑制剂

基本信息

批准号：
8252300
负责人：
Rekha Bansal
金额：
$ 29.48万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8252300
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

项目摘要

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.

描述（由申请人提供）：补体系统在防止炎症和关节固定性方面发挥作用。骨关节炎（OA）是一种关节的炎症性疾病，在老年人中非常普遍，在55年内近10％的人口导致残疾。当前的药物仅管理疾病，不能治愈或停止疾病。 OA的患病率与缺乏改变骨关节炎药物（DMOADS）的疾病的患病率增加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的发育和发展中很重要。已经假设中和IL-12或TNF-1可能会为OA患者提供好处，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。补体的替代途径（AP）最近与OA的病因有关。我们已经开发了专有的抗体组，该抗体有选择地靶向AP，而不会影响经典途径（CP）介导的宿主防御。我们的初步结果表明，AP在OA的开发和发展中起重要作用，并且我们的靶抗体在解决OA方面非常有效，如OA的兔模型所示。当前的应用建议开发人性化的IgG1作为停止和阻止人类OA进展的有效治疗方法。在I期段中，我们进一步测试了年轻的兔OA模型中特定的中和抗补充单克隆抗体。在II期段中，我们将研究靶向人源化抗体对老年兔子的疗效，评估生物学在多种给药模式下的疗效，并建立规程以扩大人性化抗体的制备。我们的研究将为OA治疗的新疗法开发提供新的见解。总体而言，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的方向的关键一步，以防止OA造成的关节损害。公共卫生相关性：骨关节炎（OA）是一种针对老年人口的疾病，影响了全球大量人。尽管做出了巨大的努力，但目前尚无有效且安全的治疗。 OA的治疗重点是管理疼痛和肿胀，改善生活质量并最大程度地减少残疾。目前尚无疾病调整药物（DMOADS），因此疾病管理主要与对乙酰氨基酚，非甾体类抗炎药（ibuprofen，naproxen，inaproxen，indomethacin等），环氧酶-2选择性抑制剂（celecoxib等）（Etecoxib等），以及其他不合格。关节内皮质类固醇注射可为某些患者提供好处。新颖的打算开发一种修饰骨关节炎的疾病。我们已经开发了一种人源化的单克隆抗体，该抗体在兔模型中显示出令人兴奋的结果。该应用建议进一步评估该抗体在少年和老化的兔子中的使用。