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

描述（由申请人提供）：本申请的长期目标是开发一种MASP-2阻断单克隆抗体作为治疗药物，以预防和治疗糖尿病并发症，即糖尿病肾病（DN）。肾病是导致终末期肾病的主要原因，发病率和死亡率高，是医疗保健的主要负担，预计2010年每年的医疗费用将达到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方法，DN代表了一个具有巨大商业潜力的未满足的主要医疗需求。DN的发病机制尚不完全清楚。临床研究表明，补体系统的凝集素通路在DN中起关键作用。与具有高凝集素途径活性的糖尿病患者相比，具有低凝集素途径活性的糖尿病患者具有更好的临床结果和更高的长期生存率，这表明抑制凝集素途径的治疗方法可以预防或减缓DN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，也是其功能所必需的，在目前的应用中已成为治疗干预的目标。通过敲除MASP-2或用抗MASP-2单克隆抗体处理小鼠，在体内实现了选择性凝集素通路阻断。这些治疗在小鼠再灌注损伤、移植和黄斑变性模型中显示出有益的效果。我们现在建议检查治疗假设，即MASP-2阻断也可能有助于治疗糖尿病的肾脏并发症。这一假设将通过db/db小鼠进行验证，db/db小鼠是一种具有明确特征的肾脏并发症的II型糖尿病模型。用抗masp -2抗体或同型对照治疗小鼠，评估抗体治疗对蛋白尿、肾功能和DN组织学特征的影响。我们将进一步研究抗MASP-2抗体治疗eNos缺陷db/db小鼠的治疗效果，这些小鼠出现糖尿病、高血压和DN的更晚期病理特征。在这些糖尿病肾病模型中成功证明其疗效将为探索抗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依据。

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.