Glycoengineering of antibodies to modulate immune functions

抗体糖工程调节免疫功能

• 批准号: 10265519
• 负责人: LAI-XI WANG
• 金额: $ 62.64万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265519
• 关键词: Address; Affect; Animals; Anti-Inflammatory Agents; Antibodies; Antibody Affinity; Antibody Therapy; Antigens; Apoptosis; Autoimmune Diseases; Azides; Biological Assay; Blood Circulation; Cleaved cell; Communicable Diseases; Complement-Dependent Cytotoxicity; Coupled; Data; Development; Disease; Endoglycosidases; Engineering; Fc Receptor; Fluorides; Fucose; Fucosidase; Glycoproteins; Heterogeneity; Hydrolysis; Immunoglobulin G; Immunoglobulin M; Immunology; Knowledge; Lactobacillus casei; Malignant Neoplasms; Methods; Modification; Pathway interactions; Polysaccharides; Research; Rhamnose; Role; Site; Structure; Substrate Specificity; System; Technology; Therapeutic; Therapeutic antibodies; Treatment Efficacy; antibody conjugate; antibody-dependent cell cytotoxicity; cancer therapy; design; genetic approach; glycosylation; immune function; improved; mutant; novel; receptor binding; recruit; sialylation

Project Summary Antibodies are an important class of therapeutics that are widely used for treatment of cancer, autoimmune diseases, and infectious diseases. Compelling experimental data have demonstrated that Fc glycosylation is a critical structural determinant for modulating antibody’s effector functions, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), activation of apoptosis, and anti- inflammatory activities. However, progress in understanding the functional roles of antibody glycosylation is hampered by the tremendous structural heterogeneity of Fc glycosylation. To address this problem, we have developed a chemoenzymatic method that permits site-specific Fc and Fab glycan remodeling to generate homogeneous antibody glycoforms. In ths application, we propose to exploit the site-specific chemoenzymatic glycan remodeling method as a key platform technology to address three important questions related to antibody functions, as highlighted in the following three specific aims. Aim 1 is to understand how Fc glycosylation modulate Fc receptor binding and ADCC activity by selective modification of the core fucose, by performing structural studies, and by synthesizing novel glycoforms, coupled with Fc receptor binding and ADCC assays. Aim 2 is to evaluate how site-specific sialylation of Fc glycans affects antibody’s anti- inflammatory activity by constructing asymmetrically sialylated or multiply sialylated glycoforms, coupled with animal studies. Aim 3 is to augment antibody’s complement-dependent cytotoxicity (CDC) by constructing structurally well-defined Gal/rhamnose antigen-antibody conjugates to recruit natural IgG and IgM antibodies in circulation. These studies will yield important new knowledge in glyco-immunology, which will facilitate the development of more effective antibody-based therapeutics.

项目摘要 抗体是一种重要的治疗类别，可广泛用于癌症治疗，自身免疫性 疾病和传染病。令人信服的实验数据表明，FC糖基化是一个 调节抗体效应函数的关键结构确定剂，包括抗体依赖性 细胞细胞毒性（ADCC），补体依赖性细胞毒性（CDC），凋亡的激活和抗 - 炎症活动。但是，了解抗体糖基化的功能作用的进展是 FC糖基化的巨大结构异质性阻碍了。为了解决这个问题，我们有 开发了一种化学酶方法，该方法允许特异性FC和Fab Glycan重塑产生 均质抗体糖型。在THS应用中，我们建议探索特定地点的化学酶 聚糖改建方法是一种关键平台技术，可以解决与 抗体功能，如以下三个特定目的所强调。目标1是了解FC 糖基化调节FC受体结合和ADCC活性，通过选择性修饰核心岩藻糖，通过 进行结构研究，并通过合成新型糖型，并与FC受体结合和 ADCC分析。 AIM 2是评估FC聚糖特定地点特异性溶解如何影响抗体的抗体 通过构建不对称的脱糖或多重糖糖型，与炎症活性，并与 动物研究。 AIM 3是通过构造抗体完全依赖的细胞毒性（CDC） 结构明确定义的gal/rhamnose抗原抗体有助于募集天然IgG和IgM抗体 在循环中。这些研究将在Glyco-免疫学方面产生重要的新知识，这将促进 开发更有效的基于抗体的治疗。