MASP-2 Therapy for Macular Degeneration

描述（由申请人提供）：总体目标是开发能够阻断人 MASP-2 功能的基于单克隆抗体 (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，是通过凝集素途径激活补体所必需的，并且可能是开发炎症性疾病新型疗法的一个有吸引力的靶标。补体系统是重要的宿主防御机制，然而，过度或不受控制的补体激活会引发强烈的炎症反应，这被认为在许多疾病状态下会显着导致不良的组织损伤。最近的结果表明，补体激活在 AMD 的发病机制中发挥着核心作用，尤其是脉络膜新生血管 (CNV)（AMD 最严重的形式）的发病机制。为了治疗 AMD，需要开发途径特异性抑制剂，该抑制剂仅针对引起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 中触发补体激活中并不起主要作用。 I 期研究的结果表明 MASP-2 MoAb 可抑制 CNV，现在为 MASP-2 在介导视网膜激光损伤引起的 CNV 中发挥重要作用提供了明确的证据。此外，我们还证实，在凝集素途径缺陷的 MASP-2 (-/-) 小鼠中，激光损伤诱导的 VEGF 增加被阻止。这些发现进一步提供了非常令人信服的证据，表明 MASP-2 是该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) 通过评估对脉络膜/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 的治疗效果，建立 AMD 小鼠模型中抗 MASP-2 MoAb 的药理学和保护机制。第一年的其他具体目标包括：2) 评估抗 MASP-2 MoAb 临床候选药物在非人类灵长类动物中的局部和全身药效学。第 2 年的具体目标包括：3) 在非人灵长类 AMD 模型中确定抗 MASP-2 MoAb 临床候选药物的功效，以及 4) 评估单剂量施用抗 MASP-2 MoAb 的局部眼部和整体安全性和毒性。 公共健康相关性：年龄相关性黄斑变性 (AMD) 是 55 岁以后失明的主要原因。据估计，美国有 175 万人患有这种疾病，另有 700 万人“处于危险之中”。在这笔 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。将使用抗 MASP-2 单克隆抗体进行研究，以确定它们作为 AMD 模型中新型治疗剂的潜力。

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.