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

开发用于治疗糖尿病肾病的 MASP-2 MoAb

基本信息

批准号：
8007238
负责人：
Thomas Anton Dudler
金额：
$ 19.84万
依托单位：
OMEROS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007238
关键词：
Ablation Affinity Albumins Albuminuria Antibodies Architecture Area Blocking Antibodies Body Weight Cardiac Characteristics Clinical Clinical Research Collaborations Complications of Diabetes Mellitus Consensus Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Dialysis procedure Disease Dose End stage renal failure Enzymes Evaluation Exhibits Extracellular Matrix Gene Expression Genetic Polymorphism Genotype Glomerular Filtration Rate Glucose Goals Government Healthcare Human Hyperglycemia Hypertension Incidence Inflammatory Response Invaded Kidney Kidney Diseases Kidney Transplantation Knockout Mice Lead Lectin Legal patent Link Macular degeneration Measures Medical Medical Care Costs Metabolic Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Nature Non-Insulin-Dependent Diabetes Mellitus Outcome Oxidative Stress Pathogenesis Pathway interactions Patient Care Patients Pattern Recognition Systems Peptide Hydrolases Persons Pharmaceutical Preparations Phase Phenotype Population Positioning Attribute Process Progressive Disease Prospective Studies Proteinuria Renal function Reperfusion Injury Research Design Risk Rodent Role Schedule Small Business Innovation Research Grant Societies Staging Structure Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Intervention Tissues Translations Transplantation base carbohydrate structure care burden clinical practice complement pathway complement system cost db/db mouse diabetic effective therapy glomerular basement membrane hemodynamics human disease improved in vivo manufacturing scale-up mortality mouse model novel novel therapeutic intervention novel therapeutics pathogen pre-clinical prevent programs protective effect public health relevance renal ischemia treatment effect type I diabetic urinary

项目摘要

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.

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一种治疗剂，以预防和治疗糖尿病并发症，即糖尿病性肾病（DN）。 DN是最终阶段肾脏疾病的主要原因，导致了明显的发病率和死亡率，并承担了重大的医疗保健负担，医疗费用预计在2010年将达到120亿美元。考虑到糖尿病发生率稳步增加，并且缺乏有效的糖尿病。治疗，DN代表着具有巨大商业潜力的主要未满足医疗需求。 DN的发病机理尚不完全理解。临床研究表明，DN中补体系统的凝集素途径的关键作用。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局和长期存活率，这表明抑制凝集素途径的治疗剂可能会预防或减慢DN的进展。 MBL相关的蛋白酶2（MASP-2）是凝集素途径独有的酶，其功能所需的酶已被针对当前应用中的治疗干预。使用MASP-2基因敲除小鼠或用抗MASP-2单克隆抗体治疗的小鼠，已经完成了体内选择性凝集素途径阻滞。这些处理揭示了在再灌注损伤，移植和黄斑变性的小鼠模型中的有益作用。现在，我们建议检查治疗性假设，即MASP-2阻断也可能在治疗糖尿病的肾脏并发症中有用。该假设将使用DB/DB小鼠进行检验，DB/DB小鼠是具有良好特征肾脏并发症的II型糖尿病型模型。将通过抗MASP-2抗体或同种型对照治疗小鼠，并评估抗体治疗对蛋白尿，肾功能和DN的组织学特征的影响。抗MASP-2抗体治疗的治疗作用将在eNOS缺乏DB/DB小鼠中进一步研究，DB/DB小鼠会发展出DN的糖尿病，高血压和更先进的病理特征。在这些糖尿病肾脏疾病模型中，成功证明了功效，将为探索抗MASP-2抗体作为糖尿病肾脏疾病患者的一种新型治疗性提供令人信服的理由。公共卫生相关性：糖尿病性肾病是末期肾脏衰竭的主要原因，导致每年120亿美元的医疗服务的发病率和死亡率和成本显着。目前尚无有效的治疗方法。该建议的目的是开发抗MASP-2单克隆抗体，该抗体特异性地阻止了补体系统的凝集素途径，作为一种新型治疗，以预防和治疗糖尿病的肾脏并发症。