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Identifying Agonist MAbs against GPCRs

识别 GPCR 激动剂单克隆抗体

基本信息

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
项目类别：
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

项目摘要

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.

摘要靶向G蛋白偶联受体（GPCR）的单克隆抗体（MAb）难以分离和激动剂单克隆抗体（激活GPCR）甚至更难发现。隔离针对GPCR的功能性单克隆抗体需要靶蛋白以其天然的形式呈递，由于GPCR是疏水性的，因此很难进行构象和取向，其具有跨膜结构，并且难以纯化。此外，鉴定激动剂单克隆抗体需要产生大量不同的MAb，其全面覆盖表位靶GPCR的表面。一个可以筛选数百万个单个B细胞的平台，鉴定稀有活化单克隆抗体将使一种全新的治疗方法能够被用于市场，针对GPCR的激动剂MAb。