MASP-2: A Potential New Target for Treatment of Rheumatoid Arthritis

MASP-2：治疗类风湿关节炎的潜在新靶点

基本信息

批准号：
7392873
负责人：
Emma E. Moore
金额：
$ 14.66万
依托单位：
OMEROS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392873
关键词：
Acute Adverse effects Affect Animal Model Animals Antibodies Arthritis Backcrossings Biochemistry Blocking Antibodies Bone and Cartilage Funding C57BL/6 Mouse Chronic Clinical Collaborations Collagen Collagen Arthritis Complement Activation Condition Daily Data Development Disease Disease model End Point Etanercept Evaluation Goals Grant Host Defense Mechanism Human Human Cloning Infection Inflammation Inflammatory Joints Knee joint Lectin Legal patent Licensing Methotrexate Modeling Molecular Biology Monoclonal Antibodies Mus Partner in relationship Pathway interactions Patients Phase Pilot Projects Plasma Play Population Publications Reporting Research Rheumatoid Arthritis Risk Role Score Serine Protease Symptoms Therapeutic Therapeutic Agents Universities Wild Type Mouse adalimumab complement pathway day infliximab inhibitor/antagonist mannose-binding protein-associated serine proteases novel programs response

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a severely debilitating disease that affects approximately 0.5-1% of the population. Currently, the most effective treatment for this disease involves the use of one of several anti-TNF agents either alone or in combination with methotrexate. However, significant side effects are associated with this treatment, most notably the risk of increased infections which cannot be tolerated by some patients. Therefore, there is a need for an effective alternative treatment for this disease with an agent directed at a novel target in the flammatory cascade. The goal of the research proposed here is to determine whether MBL-associated serine protease (MASP-2), an essential component of the lectin-activated complement pathway, may be such a target. Omeros has developed a strong proprietary program around the use of MASP-2 antagonists for the treatment of a variety of acute and chronic inflammatory conditions. Omeros has established an ongoing collaboration with Dr. William Schwaeble (University of Leister, U.K.) who was the first to clone human MASP-2 in collaboration with other research colleagues. .Dr. Schwaeble has subsequently co-authored many publications focused on the molecular biology and biochemistry of MASP-2 and other lectin pathway components. As part of our joint collaboration, patent applications have been filed with Dr. Schwaeble and Omeros on the therapeutic utility of inhibitors of MASP-2 for various acute and chronic inflammatory conditions. We have initiated the development of blocking antibodies to MASP-2 that can be used for proof of principle studies in appropriate inflammatory animal models. The long-term goal of this program is to develop monoclonal antibodies (MoAbs) capable of blocking human MASP-2 function as potential therapeutic agents. We present preliminary data that suggest that MASP-2 -/- mice on a C57Bl/6 background are less susceptible than their wild-type litter mate controls to developing inflammation in an antibody-induced model of RA, thereby indicating the potential utility of MASP-2 antagonists for the treatment of RA. There was a clear and consistent reduction in both the clinical and histological scores in the MASP-2 -/- mice. However, only a mild arthritic response was observed in the wild-type animals and C57BL/6 mice are known to show a poor response in this RA disease model. We are currently backcrossing the MASP-2 -/- mice into the DBA/1 background which is highly susceptible to both the antibody-induced arthritis as well as collagen-induced arthritis. Therefore, the goal of the research proposed here is to determine whether MASP-2 -/- mice that have been backcrossed into the DBA/1 background develop less severe disease than their wild-type litter mate controls in either the antibody-induced or the collagen-induced arthritis models. Results from these studies should demonstrate whether MASP-2 is a promising novel target for the treatment of RA.

描述（由申请人提供）：类风湿关节炎（RA）是一种严重使人衰弱的疾病，影响约0.5-1％的人口。目前，对该疾病的最有效治疗方法涉及单独或与甲氨蝶呤结合使用几种抗TNF剂之一。但是，这种疗法的显着副作用与某些患者无法忍受的感染的风险相关。因此，需要对这种疾病的有效替代治疗方法，该疾病针对燃料级联的一种新型靶标。这里提出的研究的目的是确定MBL相关的丝氨酸蛋白酶（MASP-2）是凝集素激活的补体途径的重要组成部分，可能是这样的目标。 Omeros围绕使用MASP-2拮抗剂来治疗各种急性和慢性炎症条件的强大专有计划。 Omeros与William Schwaeble博士（英国利斯特大学）建立了一项持续的合作，他是第一个与其他研究同事合作克隆人Masp-2的人。 .dr。 Schwaeble随后共同撰写了许多专注于MASP-2和其他凝集素途径成分的分子生物学和生物化学的出版物。作为我们共同合作的一部分，已与Schwaeble博士和Omeros博士提交了专利申请，以针对MASP-2抑制剂的治疗效用，以针对各种急性和慢性炎症条件。我们已经开发了对MASP-2的阻断抗体的开发，该抗体可用于在适当的炎症动物模型中进行原则研究证明。该程序的长期目标是开发能够阻止人MASP-2作为潜在治疗剂的单克隆抗体（MOAB）。我们提供的初步数据表明，在C57BL/6背景上的MASP-2 - / - 小鼠比其野生型垃圾伴侣控制不太容易受到影响，而在抗体诱导的RA模型中发育炎症，从而表明MASP的潜在实用性-2拮抗剂治疗RA。 MASP-2 - / - 小鼠的临床和组织学评分都明显降低。但是，众所周知，在野生型动物和C57BL/6小鼠中仅观察到温和的关节炎反应，在此中显示出较差的反应 RA病模型。我们目前正在将MASP-2 - / - 小鼠反向DBA/1背景，该背景高度容易受到抗体诱导的关节炎以及胶原蛋白诱导的关节炎的影响。因此，此处提出的研究的目的是确定已反向DBA/1背景的MASP-2 - / - 小鼠是否比其抗体诱导的野生型垃圾对照组的严重疾病较差或胶原蛋白引起的关节炎模型。这些研究的结果应证明MASP-2是否是RA治疗的有前途的新目标。