Examining IgG4 sialylation as a gain of function post-translation modification in IgG4-related diseases

检查 IgG4 唾液酸化作为 IgG4 相关疾病中翻译后修饰的功能获得

• 批准号: 10032974
• 负责人: Robert McCullough Anthony
• 金额: $ 84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10032974
• 关键词: Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Autoantigens; Autoimmune Process; B-Lymphocytes; Binding; Biological; Biological Assay; Biology; Biophysics; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell-Mediated Cytolysis; Cells; Clinical; Communicable Diseases; Complement 1q; Complement-Dependent Cytotoxicity; Complex; Data; Development; Disease; Dose; Effector Cell; Family; Galectin 3; Goals; Human; Hypersensitivity; IgG1; IgG2; IgG3; IgG4; Immune checkpoint inhibitor; Immunoglobulin G; Immunology; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Intravenous Immunoglobulins; Knowledge; Laminin; Lead; Lesion; MS4A1 gene; Malignant Neoplasms; Mediating; Mission; Modification; Mus; Pathology; Patients; Phagocytosis; Plasma Cells; Polysaccharides; Public Health; Recombinant Immune Globulin; Regulation; Research; Resolution; Role; Signal Transduction; Testing; Therapeutic Uses; Therapeutic antibodies; Translations; Transplantation; United States National Institutes of Health; anti-CD20; antibody-dependent cell cytotoxicity; autoinflammatory; cytotoxic; defined contribution; design; experimental study; gain of function; glycosylation; immunoregulation; in vivo; innovation; insight; neoplasm immunotherapy; programmed cell death protein 1; receptor; receptor binding; sialylation; standard of care; success; translational impact

Project Summary/Abstract. IgG4-related diseases (IgG4-RDs) are a family of related autoinflammatory diseases characterized by fibrotic lesions comprised of CD4+ T cells and IgG4+ plasma cells, and markedly elevated oligoclonal IgG4. However, whether IgG4 antibodies contribute to IgG4-RD pathology remains unclear. Despite the tremendous clinical success of immunotheraputics, little is known regarding IgG4 biology relative to IgG1. Our long-term goals are to understand the role and regulation of glycosylation to antibody biology, to ultimately modulate antibody effector functions in vitro and in vivo. The overall objective of this application is to comprehensively dissect cytotoxic activity of sialylated IgG4. Our central hypothesis is autoantigen-specific IgG4 in IgG4-RD is sialylated, and contributes to the pathology Of IgG4-RD. Our approach combines characterizing IgG from the sera of IgG4-RD and healthy patients, while examining precisely glycoengineered IgG4 in receptor binding and effector function assays. Our hypothesis is informed by preliminary data shown here in the Approach subsection of the Research Strategy section. The rationale that underlies the proposed research is understanding how IgG4 mediate cytotoxic effector function will enable new insights into IgG biology, and may lead to development of innovative antibody-based therapies. We will test our central hypothesis and, thereby, attain the objective of this application by pursuing the following three specific aims using a combination of biophysical experiments, and in vitro and in vivo functional assays. 1) Define the glycosylation and FcγRs-binding profiles of total and autoantigen-specific IgG in IgG4-RD. Hypothesis: Sialylation enables FcγR binding by IgG4. 2) Examine the effector functions of sialylated IgG4 in vitro. Hypothesis: Sialylated IgG4 mediates effector cell-specific pro-inflammatory effector functions. 3) Determine the in vivo effector functions of sialylated IgG4. Hypothesis: Sialylated IgG4 exerts pro- inflammatory effector functions in vivo. This proposal is expected to have broad clinical implications, ranging from diseases where elevated IgG4 titers are associated in the pathology or resolution, as well as to design of immunotherapeutics, and represents a substantive departure from the status quo by underscoring the cytotoxic capacity of IgG4.

项目摘要/摘要。 IgG4相关疾病（IgG4-RDS）是一个相关自身炎症性疾病的家族，其特征是纤维化 病变包括CD4+ T细胞和IgG4+浆细胞，并显着升高寡克隆IgG4。然而， IgG4抗体是否有助于IgG4-RD病理学尚不清楚。尽管有巨大的临床 关于IgG4生物学相对于IgG1，免疫疗法的成功鲜为人知。我们的长期目标是 了解糖基化对抗体生物学的作用和调节，以最终调节抗体效应子 体外和体内功能。该应用的总体目的是全面剖析细胞毒性 溶解的IgG4的活性。我们的中心假设是IgG4-RD中的自身抗原特异性IgG4，并且是囊化的，并且 有助于IgG4-RD的病理。我们的方法结合了来自IgG4-RD血清IgG的特征 和健康的患者，同时在受体结合和效应子功能中检查精确糖化的IgG4 测定。 我们的假设通过研究策略的方法小节中所示的初步数据告知 部分。拟议的研究基础的基本原理是了解IgG4的中值细胞毒性效应子如何 功能将使新见解对IgG生物学有新的见解，并可能导致基于创新抗体的发展 疗法。我们将检验我们的中心假设，从而通过追求 遵循三个特定目标，结合了生物物理实验，体外和体内功能 测定。 1）定义IgG4-RD中总和特异性IgG的糖基化和FcγRS结合曲线。 假设：溶解作用使IgG4结合FcγR。 2）在体外检查溶解的IgG4的效应函数。假设：溶解的IgG4介导效应子 细胞特异性促炎作用子功能。 3）确定溶解的IgG4的体内效应子函数。假设：溶解的IgG4执行pro- 炎症效应子在体内功能。 预计该建议将具有广泛的临床意义，包括升高IgG4滴度的疾病 在病理或分辨率以及免疫治疗剂的设计中相关，并代表 通过强调IgG4的细胞毒性能力，与现状相去甚远。