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

描述（由申请人提供）：风湿性关节炎（RA）是一种严重的衰弱性疾病，影响约0.5-1%的人口。 目前，对这种疾病最有效的治疗包括单独使用几种抗TNF药物之一或与甲氨蝶呤联合使用。然而，这种治疗会产生显著的副作用，最明显的是增加感染的风险，这是一些患者无法忍受的。因此，需要一种针对炎症级联反应中新靶点的有效替代治疗方法。本研究的目的是确定MBL相关丝氨酸蛋白酶（MASP-2），凝集素激活补体途径的一个重要组成部分，是否可能是这样的。 一个目标Omeros已经开发了一个强大的专有计划，围绕使用MASP-2拮抗剂治疗各种急性和慢性炎症。Omeros与William Schwaeble博士（英国莱斯特大学）建立了持续的合作关系。他是第一个与其他研究同事合作克隆人类MASP-2的人。Schwaeble博士随后与人合著了许多出版物，重点关注MASP-2和其他凝集素途径组分的分子生物学和生物化学。作为我们联合合作的一部分，已向Schwaeble博士和Omeros提交了关于MASP-2抑制剂对各种急性和慢性炎症性疾病的治疗效用的专利申请。 我们已经开始开发针对MASP-2的阻断抗体，其可用于在适当的炎症动物模型中进行原理研究的证据。该计划的长期目标是开发能够阻断人MASP-2功能的单克隆抗体（MoAb）作为潜在的治疗剂。 我们提出了初步数据，其表明在抗体诱导的RA模型中，C57 B1/6背景的MASP-2 -/-小鼠比其野生型同窝对照对发展炎症不太敏感，从而表明MASP-2拮抗剂用于治疗RA的潜在效用。在MASP-2 -/-小鼠中，临床和组织学评分均存在明显且一致的降低。然而，在野生型动物中仅观察到轻微的关节炎反应，并且已知C57 BL/6小鼠在这方面表现出较差的反应。 RA疾病模型。我们目前正在将MASP-2 -/-小鼠回交到DBA/1背景中，DBA/1背景对抗体诱导的关节炎以及胶原诱导的关节炎高度易感。因此，本文提出的研究的目标是确定在抗体诱导的或胶原蛋白诱导的关节炎模型中，已经回交到DBA/1背景中的MASP-2 -/-小鼠是否比其野生型同窝对照发展更不严重的疾病。这些研究的结果应证明MASP-2是否是治疗RA的有希望的新靶点。

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.