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High throughput approach for generating human monoclonal antibodies

产生人单克隆抗体的高通量方法

基本信息

批准号：
8904621
负责人：
Hiep T Tran
金额：
$ 22.48万
依托单位：
ABZYME THERAPEUTICS, LLC
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：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904621
关键词：
Affinity Animals Antibodies Antibody Formation Autoantigens Binding Biological Assay Biological Models Cell surface Cells Cholesterol DNA Development Diagnosis Diploidy Engineering Enzyme-Linked Immunosorbent Assay Enzymes Evolution Fluorescence-Activated Cell Sorting Galactose Generations Genes Genetic Models Human IL2RA gene Immunization Immunoassay Immunoglobulin Somatic Hypermutation In Vitro Individual Interstitial Collagenase Libraries Light Malignant Neoplasms Mammalian Cell Measures Medical Methodology Monoclonal Antibodies National Institute of General Medical Sciences Nature Partner in relationship Petromyzon marinus Phase Process Productivity Proteins Reagent Regulatory T-Lymphocyte Research Rheumatoid Arthritis Saccharomyces cerevisiae Sensitivity and Specificity Specificity Surface Surface Plasmon Resonance System Therapeutic Therapeutic antibodies Time TimeLine Toxin Yeasts activation-induced cytidine deaminase analog base cross reactivity density disulfide bond expression vector human disease human monoclonal antibodies immunogenic improved in vivo innovation interest novel pathogen public health relevance response screening small molecule success therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Thanks to their exquisite specificity and sensitivity, monoclonal antibodies (Mab) have found a broad application in research, diagnosis and therapy. For treatment of human diseases, fully human antibodies are the most desirable as they are generally not immunogenic and well-tolerated. While there are several existing approaches for generation of antibodies, the processes are still time-consuming, labor-intensive, and unpredictable of success. To simplify and to accelerate the generation of fully human antibodies, a novel non-animal approach for antibody production is proposed. The objective will be achieved by using a Self-Diversifying Human Antibody Library (SHALib) effectively displayed on yeast cell surface. SHALib will provide a diverse array of antibodies in vitro, without the need of animal immunization and potential necessary humanization of the antibody. Starting from a naive antibody library from healthy human donors, antibodies with high-affinity and specificity to various targets will be generated and selected through repeated rounds of systematic evolution by somatic hypermutation, target-specific enrichment and fluorescence-activated cell sorting. Since this is a non-animal system, the platform can generate human antibodies against toxins, pathogens, self-antigens, and the like which are by nature difficult to obtain. As a proof-of-principle, in phase I, we will develop human antibodies to five selected targets of therapeutic importance. The targets are for the treatment of high cholesterol (PCSK9), rheumatoid arthritis (MMP1 and MMP13) and cancer (MMP7 and regulatory T cell protein CD25). In Phase II, the platform will be used to develop human monoclonal antibodies to at least 50 targets that are involved in different human diseases. The platform will allow generating quickly human monoclonal antibodies that are of therapeutic potential.