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: 9765313
• 负责人: Jayakrishna Ambati
• 金额: $ 40.38万
• 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/9765313
• 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.

抽象的 异常血管生成是新血管形成的过程，与多种疾病有关 在这项令人兴奋的新工作中，我们做出了影响世界近 10% 人口的疾病。 令人惊讶的观察结果是，人类 IgG1 作为一类，可抑制眼部和眼部疾病的多种模型。 小鼠和细胞中的非眼部血管生成与其实际目标无关。 独立的血管抑制作用是通过 FcγRI 受体信号传导介导的。 我们的研究结果表明，血液中存在丰富的 IgG1 蛋白，以及它们广泛的治疗用途 在更好地理解其全部生物效应方面具有广泛的重要性 IgG/Fc 受体调节脉管系统的程度和精确机制。 因此，定义免疫分子信号传导至关重要。 介导人 IgG1/FcγRI 连接的血管抑制作用的负责途径。 对于描述治疗性 FcγRI 结合蛋白对细胞类型的影响也很重要 和参与异常血管生成的分子途径。 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 为此，我们将通过改进现有的含 IgG1 药物来满足重大眼科需求。 确定是否合理指导贝伐珠单抗（全长）的重新给药或重新配制 人源化IgG1抗体，利用这一点可以大幅提高其治疗效果 新发现的抗血管生成活性，与 VEGFA 中和作用是分开的。 为了实现这些目标，我们建议在更好地模仿的模型中进行详细研究 我们将利用小鼠（包括人源化）模型。 角膜和脉络膜新生血管形成提供新的功能和分子见解 研究结果显示 IgG1/FcγRI 信号如何促进血管生成的调节。 该项目将有助于阐明脉管系统的创新分子基础，可针对 异常血管生长引起的多种眼部病变因此，该建议是。 符合 NEI Vision 视网膜疾病和免疫学项目的双重目标 研究：需求、差距和机会战略计划。