MASP-2 Therapy for Macular Degeneration

MASP-2 治疗黄斑变性

• 批准号: 8035293
• 负责人: Thomas Anton Dudler
• 金额: $ 17.37万
• 依托单位: OMEROS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035293
• 关键词: Accounting; Affect; Age; Age related macular degeneration; Animals; Antibodies; Applications Grants; Area; Automobile Driving; Biological Markers; Blindness; Bruch' s basal membrane structure; Choroid; Choroidal Neovascularization; Cicatrix; Clinical; Complement; Complement Activation; Complement Inactivators; Complex; Country; Development; Diabetic Retinopathy; Disease; Dose; Elderly; Emotional; Evaluation; Food; Foundations; Glaucoma; Goals; Government; Grant; Growth Factor; Host Defense Mechanism; Human; Immune; Impairment; Individual; Inflammatory; Inflammatory Response; Injury; Investigation; Kentucky; Knockout Mice; Laboratories; Laser injury; Lasers; Lectin; Left; Licensing; Lucentis; Macular degeneration; Mediating; Medicine; Modeling; Monoclonal Antibodies; Mus; National Eye Institute; Nonexudative age-related macular degeneration; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Play; Population; Reading; Recovery; Regulation; Reperfusion Injury; Reporting; Research; Research Personnel; Retina; Risk; Rodent; Role; Safety; Serine Protease; Side; Small Business Innovation Research Grant; Solid; Strategic Planning; Structure of retinal pigment epithelium; Subgroup; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Tissue Donors; Tissues; Toxic effect; United States; Universities; Validation; Vascular Endothelial Growth Factors; Vision; Wild Type Mouse; Work; base; body system; clinical effect; college; complement pathway; complement system; design; drug development; effective therapy; human MASP2 protein; human disease; in vivo; inhibitor/antagonist; interest; macula; mannose-binding protein-associated serine proteases; mouse Masp2 protein; mouse model; neovascular; nonhuman primate; novel therapeutics; ophthalmic drug; pathogen; phase 1 study; pre-clinical; preclinical study; prevent; programs; public health relevance; research clinical testing; socioeconomics; therapeutic target; tool; web site

DESCRIPTION (provided by applicant): The overall goal is to develop monoclonal antibody (MoAb)-based compounds capable of blocking human MASP-2 function as potential therapeutic agents for the treatment of age-related macular degeneration (AMD). MASP-2 is a plasma serine protease uniquely required for complement activation via the lectin pathway and may be an attractive target for the development of novel therapeutics for inflammatory disorders. The complement system is an important host defense mechanism, however excessive or uncontrolled complement activation can trigger an intense inflammatory response that is thought to significantly contribute to undesired tissue damage in many disease states. Recent results implicate a central role for complement activation in the pathogenesis of AMD, and especially of choroidal neovascularization (CNV), the most serious form of AMD. To treat AMD it would be desirable to develop pathway-specific inhibitors which would target only the complement pathway causing the particular pathology without completely shutting down the immune defense capabilities of complement. Immunohistological studies of human donor tissues indicate that the classical pathway does not play a major role in triggering complement activation in AMD. Results from the Phase I studies have shown inhibition of CNV by MASP-2 MoAbs and now have provided definitive proof for an important role of MASP-2 in mediating CNV caused by laser injury to the retina. In addition, we have confirmed that laser injury-induced increases in VEGF are prevented in the lectin pathway deficient MASP-2 (-/-) mice. These findings further provide very convincing evidence that MASP-2 is an attractive therapeutic target for this indication. The Specific Aims for year 1 include: 1) Establishment of the pharmacology and protective mechanisms of anti-MASP-2 MoAb in the mouse model of AMD by evaluating the therapeutic effects on CNV, lectin pathway biomarkers and the disease-relevant growth factor, VEGF, in choroid/ RPE tissue. The other specific aim for year 1 includes: 2) Evaluation of an anti-MASP-2 MoAb clinical candidate on local and systemic pharmacodynamics in the non-human primate. The specific aims for year 2 include: 3) Establishment of the efficacy of the anti-MASP-2 MoAb clinical candidate in a non-human primate AMD model and 4) Evaluation of the local ocular and global safety and toxicity of a single dose administration of the anti- MASP-2 MoAb. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness after age 55. It is estimated that 1.75 million individuals suffer from this disease in the United States, with another 7 million "at risk". In this SBIR grant, studies will evaluate a potential new target called MASP-2 for treatment of AMD. Studies will be conducted with anti-MASP- 2 monoclonal antibodies to determine their potential as novel therapeutic agents in models of AMD.

描述(申请人提供)：总体目标是开发能够阻断人类MASP-2功能的基于单抗(MOAB)的化合物，作为治疗年龄相关性黄斑变性(AMD)的潜在治疗剂。MASP-2是一种血浆丝氨酸蛋白酶，通过凝集素途径激活补体是唯一必需的，可能成为炎症性疾病新疗法开发的一个有吸引力的靶点。补体系统是一种重要的宿主防御机制，然而过度或不受控制的补体激活可引发强烈的炎症反应，在许多疾病状态下被认为是导致不必要的组织损伤的重要因素。最近的研究结果表明，补体激活在AMD的发病机制中起中心作用，特别是在AMD最严重的形式--脉络膜新生血管(CNV)中。为了治疗AMD，人们希望开发针对补体途径的特异性抑制剂，它只针对导致特定病理的补体途径，而不完全关闭补体的免疫防御能力。对人类供体组织的免疫组织学研究表明，经典途径在AMD的补体激活中不起主要作用。I期研究结果表明，MASP-2MoAbs对CNV有抑制作用，并为MASP-2在介导激光损伤视网膜CNV中的重要作用提供了确凿的证据。此外，我们已经证实，在凝集素途径缺陷的MASP-2(-/-)小鼠中，激光损伤诱导的血管内皮生长因子的增加是可以防止的。这些发现进一步提供了非常令人信服的证据，表明MASP-2是这一适应症的一个有吸引力的治疗靶点。第一年的具体目标包括：1)通过评价抗MASP-2单抗对脉络膜/RPE组织中CNV、凝集素途径生物标志物和疾病相关生长因子VEGF的治疗作用，建立抗MASP-2单抗在AMD小鼠模型中的药理和保护机制。第一年的另一个具体目标包括：2)评估一种抗MASP-2单抗临床候选药物在非人类灵长类动物中的局部和系统药效学。第二年的具体目标包括：3)在非人类灵长类AMD模型中建立抗MASP-2单抗临床候选药物的有效性，以及4)评估单次注射抗MASP-2单抗的局部和全球安全性和毒性。 公共卫生相关性：老年性黄斑变性(AMD)是55岁后致盲的主要原因。据估计，美国有175万人患有这种疾病，另有700万人面临风险。在这项SBIR拨款中，研究将评估一种名为MASP-2的潜在新靶点，用于治疗AMD。将用抗MASP-2的单抗进行研究，以确定它们在AMD模型中作为新的治疗药物的潜力。