Antigen-independent suppression of ocular angiogenesis via the Fc receptor

通过 Fc 受体对眼部血管生成进行抗原非依赖性抑制

• 批准号: 10003425
• 负责人: Jayakrishna Ambati
• 金额: $ 16.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10003425
• 关键词: Address; Affect; Affinity; Antibodies; Antibody Suppression; Antibody Therapy; Antigens; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Biology; Blood; Blood Vessels; Bone Marrow; Cells; Choroidal Neovascularization; Complement Activation; Corneal Neovascularization; Disease; Dose; Endothelial Cells; Event; Exhibits; Fab Immunoglobulins; Fc Receptor; Fc domain; Future; Goals; Growth; Human; IgG1; Immune system; Immunoglobulin G; Immunologics; Immunology; Laboratories; Length; Ligation; Mediating; Medicine; Microglia; Modality; Modeling; Molecular; Mus; Ocular Pathology; Pathway interactions; Pharmacology; Phenotype; Population; Process; Property; Proteins; Receptor Signaling; Retinal; Retinal Diseases; Route; Signal Pathway; Signal Transduction; Strategic Planning; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic Uses; Transgenic Mice; Treatment Efficacy; VEGFA gene; Vascular Endothelial Growth Factors; Vascular System; Vision research; Work; adaptive immunity; angiogenesis; antigen binding; bevacizumab; blood vessel development; cell type; clinical effect; cytokine; design; human monoclonal antibodies; humanized mouse; immune function; improved; innovation; insight; macrophage; mouse model; novel; novel therapeutics; ocular angiogenesis; programs; ranibizumab; therapeutic candidate

Abstract Aberrant angiogenesis, a process of new blood vessel formation, is implicated in a variety of diseases that affect nearly 10% of the world’s population. In new and exciting work, we made the surprising observation that human IgG1, as a class, suppresses multiple models of ocular and non-ocular angiogenesis in mice and cells independent of their actual target. This target- independent angiostatic effect is mediated through FcγRI receptor signaling. Given the abundance of IgG1 proteins in the blood, as well as their widespread therapeutic use, our findings assume broad importance in better understanding the full range of the biological effects of antibodies. The extent and precise mechanisms of IgG/Fc receptor modulation of the vasculature remain to be deciphered. Therefore, it is critical to define the immunological molecular signaling pathways responsible for mediating the angioinhibitory effects of human IgG1/FcγRI ligation. It is also important to delineate the influence of therapeutic FcγRI-binding proteins on the cell types and molecular pathways involved in aberrant angiogenesis. In addition to advancing the fundamental biology of IgG/Fc-mediated angiosuppression, our findings may also address a significant ophthalmic need by improving existing IgG1-containing medicines. To that end, we will determine whether a rationally guided re-dosing or reformulation of bevacizumab, a full-length humanized IgG1 antibody, can substantially improve its therapeutic efficacy by exploiting this newly discovered anti-angiogenic activity, which is separate from VEGFA neutralization. In order to accomplish these goals, we propose to perform detailed studies in models that better mimic the human vascular and immune systems. We will utilize mouse (including humanized) models of corneal and choroidal neovascularization to provide novel functional and molecular insights into how IgG1/FcγRI signaling contributes to modulation of angiogenesis. Findings from this project will help illuminate innovative molecular basis of the vasculature that can be targeted in the multitude of ocular pathologies caused by abnormal vessel growth. As such, this proposal is aligned with the dual goals of the Retinal Diseases and Immunology Programs of NEI's Vision Research: Needs, Gaps, and Opportunities Strategic Plan.

摘要 异常血管生成是一种新血管形成的过程，与多种血管生成相关。 这些疾病影响了世界上近10%的人口。在新的和令人兴奋的工作，我们取得了 令人惊讶的观察结果是，人IgG 1作为一类，抑制多种眼和 小鼠和细胞中的非眼部血管生成与其实际靶点无关。这个目标- 通过FcγRI受体信号传导介导独立的血管生成抑制作用。鉴于 我们的研究结果表明，血液中存在大量的IgG 1蛋白，以及它们广泛的治疗用途， 在更好地理解生物学效应的全方位方面具有广泛的重要性， 抗体的IgG/Fc受体调节血管系统的程度和精确机制 还有待破解因此，明确免疫分子信号传导机制至关重要 负责介导人IgG 1/FcγRI连接的血管抑制作用的途径。是 描述治疗性Fcγ RI结合蛋白对细胞类型的影响也很重要， 以及参与异常血管生成的分子途径。除了推进 IgG/Fc介导的血管抑制的基础生物学，我们的研究结果也可能解决一个问题， 通过改进现有的含IgG 1的药物来满足眼科的显著需求。为此，我们将 确定是否合理指导贝伐珠单抗的重新给药或重新配制，全长 人源化IgG 1抗体，可以通过利用这一点显著提高其治疗功效。 新发现的抗血管生成活性，这是从VEGFA中和分离。为了 为了实现这些目标，我们建议在模型中进行详细的研究， 人体血管和免疫系统。我们将利用小鼠（包括人源化）模型 角膜和脉络膜新生血管，以提供新的功能和分子见解 IgG 1/FcγRI信号传导如何促进血管生成的调节。时发现的问题 该项目将有助于阐明血管系统的创新分子基础， 由异常血管生长引起的多种眼部病变。因此，这项建议是 与NEI愿景的视网膜疾病和免疫学计划的双重目标保持一致 研究：需求，差距和机会战略计划。