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Mechanism and engineering of IgG-based monoclonal antibody/receptor interactions

基于 IgG 的单克隆抗体/受体相互作用的机制和工程

基本信息

批准号：
9300976
负责人：
Adam Wesley Barb
金额：
$ 28.74万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9300976
关键词：
Affect Affinity Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antibodies Asparagine Autoimmune Diseases Binding Binding Sites Biochemistry Carbohydrates Cells Development Disease Engineering Fc Receptor Glycoproteins Goals Graft Rejection Hematologic Neoplasms Human Immune Immune system Immunoglobulin G Immunoglobulins Inflammatory Knowledge Laboratories Lead Libraries Link Malignant Neoplasms Mass Spectrum Analysis Measures Modification Molecular Molecular Conformation Monoclonal Antibodies Motion Mutation N-Glycosylation Site NMR Spectroscopy Patients Pharmacologic Substance Polysaccharides Positioning Attribute Preparation Process Production Property Protein Engineering Proteins Public Health Publishing Reporting Resolution Rheumatoid Arthritis Role Sampling Site Solid Neoplasm Stable Isotope Labeling Structure Surface System Systemic Lupus Erythematosus Techniques Testing Therapeutic Monoclonal Antibodies Therapeutic antibodies Transplant-Related Disorder Variant Work X-Ray Crystallography antibody-dependent cell cytotoxicity base cancer therapy design experimental study improved leukemia/lymphoma novel novel drug class novel therapeutics pathogen personalized medicine polypeptide public health relevance receptor receptor binding response therapeutic evaluation tool

项目摘要

DESCRIPTION (provided by applicant): The fragment crystallizable (Fc) region links the dual pathogen identification and destruction properties of immunoglobulin G (IgG). Pathogen opsonization positions Fcs to activate pro-inflammatory Fc¿ receptors (FcgRs) on immune cells. Asparagine-linked (N)-glycan attached to Fc is required for productive engagement of the low-affinity FcgRs, though it is not known how the Fc N-glycan contributes to FcγR binding because the N-glycan does not directly contact the FcgRs. It has been suggested that the N-glycan provides optimal spacing of two Fc domains, stabilizing the Fc quaternary structure to bind the FCγR. Evidence from our laboratory points to a different hypothesis. We determined that Fc N-glycan motion, increased by Fc amino acid mutations far from the FcγR binding site, negatively correlated with Fc¿RIIIa affinity. Only a single region of Fc, the CE polypeptide loop that contains the site of N-glycosylation, was perturbed as a result of these Fc mutations. This result led to the proposal that the N-glycan affects FcγR affinity by pre-organizing the CE loop, and not by optimizing Fc domain orientation. Here we will directly test our hypothesis by measuring the structure and motion of the CE loop, in multiple forms stabilized through glycan or protein engineering, using solution nuclear magnetic resonance spectroscopy. The knowledge of CE loop structure and motion will be applied to redesign the Fc polypeptide to generate aglycosylated Fc variants that maintain high affinity for FcgRs. The molecular details of immune system activation that will emerge from these studies will be important to understand the process of multiple diseases and will be critical to enhance therapeutic monoclonal antibody function through engineering to treat cancer, transplant and autoimmune disease patients.