Development of MASP-2 MoAbs for the treatment of diabetic nephropathy

描述(申请人提供)：本申请的长期目标是开发一种MASP-2阻断的单抗，作为一种治疗药物，用于预防和治疗糖尿病并发症，即糖尿病肾病(DN)。糖尿病肾病是终末期肾脏疾病的主要原因，导致严重的发病率和死亡率，并造成重大的卫生保健负担，预计2010年医疗费用将达到每年120亿美元。考虑到糖尿病发病率的稳步上升和缺乏有效的治疗，糖尿病肾病是一种具有巨大商业潜力的未得到满足的主要医疗需求。糖尿病肾病的发病机制尚不完全清楚。临床研究表明，补体系统的凝集素途径在糖尿病肾病中起着关键作用。与凝集素途径活性高的糖尿病患者相比，凝集素途径活性低的糖尿病患者具有更好的临床预后和长期生存，提示抑制凝集素途径的治疗药物可能预防或减缓糖尿病肾病的进展。MBL相关蛋白酶2(MASP-2)是凝集素途径所特有的一种酶，是其功能所必需的，目前已成为治疗干预的靶点。利用MASP-2基因敲除小鼠或用抗MASP-2单抗处理的小鼠，已经在体内实现了选择性凝集素途径的阻断。这些治疗方法在小鼠的再灌注损伤、移植和黄斑变性模型中显示出了有益的效果。我们现在建议检验治疗假说，即MASP-2阻断在糖尿病肾脏并发症的治疗中可能也是有用的。这一假设将在db/db小鼠身上进行验证，db/db小鼠是一种已建立的II型糖尿病模型，具有良好的肾脏并发症特征。小鼠将接受抗MASP-2抗体或同型对照治疗，并将评估抗体治疗对蛋白尿、肾功能和糖尿病肾病组织学特征的影响。抗MASP-2抗体对eNOS缺陷db/db小鼠的治疗效果将进一步研究，这些db/db小鼠出现糖尿病、高血压和更严重的糖尿病肾病的病理特征。这些糖尿病肾病模型的有效性的成功证明将为探索抗MASP-2抗体作为糖尿病肾病患者的新治疗方法提供令人信服的理论基础。 公共卫生相关性：糖尿病肾病是终末期肾功能衰竭的主要原因，导致显著的发病率和死亡率，每年的医疗费用接近120亿美元。目前还没有有效的治疗方法。本研究的目的是开发特异性阻断补体系统凝集素途径的抗MASP-2单抗，作为防治糖尿病肾脏并发症的一种新的治疗方法。

DESCRIPTION (provided by applicant): The long-term objective of this application is to develop a MASP-2 blocking monoclonal antibody as a therapeutic agent to prevent and treat complications of diabetes, namely diabetic nephropathy (DN). DN is the leading cause of end stage renal disease, resulting in significant morbidity and mortality and in a major health care burden with medical costs projected to reach $12 billion per year in 2010. Considering a steadily increasing incidence of diabetes and the absence of an effective treatment, DN represents a major unmet medical need of significant commercial potential. The pathogenesis of DN is incompletely understood. Clinical studies suggest a critical role for the lectin pathway of the complement system in DN. Diabetics with low lectin pathway activity have better clinical outcomes and increased long-term survival compared to diabetics with high lectin pathway activity, suggesting that therapeutics that inhibit the lectin pathway may prevent or slow the progression of DN. The MBL- associated protease 2 (MASP-2), an enzyme unique to the lectin pathway and required for its function, has been targeted for therapeutic intervention in the current application. Selective lectin pathway blockade in vivo has been accomplished using MASP-2 knockout mice or mice treated with anti-MASP-2 monoclonal antibody. These treatments have revealed beneficial effects in mouse models of reperfusion injury, transplantation and macular degeneration. We now propose to examine the therapeutic hypothesis that MASP-2 blockade may also be useful in the treatment of renal complications of diabetes. This hypothesis will be tested using db/db mice, an established model of type II diabetes with well-characterized renal complications. Mice will be treated with anti-MASP-2 antibody or isotype control, and effects of antibody treatment on albuminuria, renal function and histological features of DN will be assessed. The therapeutic effects of anti- MASP-2 antibody treatment will be further studied in eNos deficient db/db mice which develop diabetes, hypertension and more advanced pathological features of DN. Successful demonstration of efficacy in these models of diabetic kidney disease will provide compelling rationale to explore anti-MASP-2 antibodies as a novel therapeutic in patients with diabetic kidney disease. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy is the leading cause of end stage renal failure, resulting in significant morbidity and mortality and costs for medical care approaching $12 billion per year. Currently there is no effective treatment available. The objective of this proposal is to develop anti-MASP-2 monoclonal antibodies which specifically block the lectin pathway of the complement system as a novel therapeutic to prevent and treat the renal complications of diabetes.