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是通过凝集素途径进行补体活化所独特需要的血浆丝氨酸蛋白酶，并且可能是开发用于炎性病症的新型治疗剂的有吸引力的靶标。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可引发强烈的炎症反应，其被认为在许多疾病状态中显著促成不期望的组织损伤。最近的结果暗示了补体激活在AMD的发病机制中的中心作用，特别是脉络膜新生血管（CNV），AMD的最严重形式。为了治疗AMD，期望开发仅靶向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的途径特异性抑制剂。人类供体组织的免疫组织学研究表明经典途径在AMD中触发补体激活中不起主要作用。来自I期研究的结果已经显示MASP-2 MoAb对CNV的抑制，并且现在已经为MASP-2在介导由视网膜激光损伤引起的CNV中的重要作用提供了明确的证据。此外，我们已经证实，在凝集素途径缺陷型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，证明MASP-2是该适应症的有吸引力的治疗靶标。第1年的具体目的包括：1）通过评估对脉络膜/ RPE组织中的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，建立抗MASP-2 MoAb在AMD小鼠模型中的药理学和保护机制。第1年的其他具体目标包括：2）评价抗MASP-2 MoAb临床候选物在非人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）确定抗MASP-2 MoAb临床候选物在非人灵长类动物AMD模型中的功效和4）评价单剂量施用抗MASP-2 MoAb的局部眼部和整体安全性和毒性。 公共卫生相关性：视网膜相关性黄斑变性（AMD）是55岁以后失明的主要原因。据估计，在美国有175万人患有这种疾病，另有700万人处于“危险之中”。在这项SBIR资助中，研究将评估一种名为MASP-2的治疗AMD的潜在新靶点。将用抗MASP- 2单克隆抗体进行研究以确定其作为AMD模型中的新型治疗剂的潜力。

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.