Identifying Agonist MAbs against GPCRs

识别 GPCR 激动剂单克隆抗体

• 批准号: 9756430
• 负责人: JOSEPH Benjamin RUCKER
• 金额: $ 13.22万
• 依托单位: INTEGRAL MOLECULAR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756430
• 关键词: Abbreviations; Adverse event; Affinity; Agonist; Amino Acids; Animals; Antibodies; Antibody-drug conjugates; B-Lymphocytes; Binding; Biochemical; Biological Assay; Biological Response Modifier Therapy; Biophysics; Blood - brain barrier anatomy; Brain; Cell surface; Clinical Trials; Clone Cells; Complex; DNA; Drug Delivery Systems; Epitopes; G-Protein-Coupled Receptors; Health; Human; Hydrophobicity; Immunize; Individual; Industry; Infiltration; Irritable Bowel Syndrome; Kinetics; Membrane; Membrane Proteins; Metabolic Diseases; Microfluidics; Molecular; Molecular Conformation; Monoclonal Antibodies; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Orthologous Gene; Pharmaceutical Preparations; Positioning Attribute; Property; Proteins; Proteome; Receptor Activation; Role; Serotonin Receptors 5-HT4; Serum; Specificity; Structure; Surface; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; TimeLine; Virus-like particle; Work; base; biophysical properties; clinical application; drug candidate; experimental study; extracellular; lead candidate; preclinical development; receptor binding; response; screening; small molecule; therapeutic target

ABSTRACT Monoclonal antibodies (MAbs) that target G protein-coupled receptors (GPCRs) are difficult to isolate, and agonist MAbs (that activate GPCRs) are even more difficult to discover. Isolating functional MAbs against GPCRs requires that the target protein be presented in its native conformation and orientation, which is difficult because GPCRs are hydrophobic, form complex transmembrane structures, and are difficult to purify. Moreover, identifying agonist MAbs requires generating a large number of diverse MAbs that comprehensively cover the epitope surface of the target GPCR. A platform that could screen through millions of individual B cells to identify rare activating MAbs would enable an entirely new class of therapeutics to be brought to market, agonist MAbs against GPCRs.

抽象的 靶G蛋白偶联受体（GPCR）的单克隆抗体（mAb）难以 分离株和激动剂mAb（激活GPCR）更难发现。隔离 针对GPCRS的功能性mAB要求将靶蛋白呈现在其本地 构象和方向，这很困难，因为GPCR是疏水，形成复杂的 跨膜结构，难以纯化。而且，识别激动剂mabs 需要产生大量的不同单元单元，以全面覆盖表位 目标GPCR的表面。一个可以筛选数百万个单独的B单元的平台 识别罕见的激活mAB将使一类全新的治疗剂带入 市场，针对GPCR的激动剂mab。