Glycoantigen evolution targeting antibodies of the PGT 128 lineage

糖抗原进化靶向 PGT 128 谱系抗体

基本信息

批准号：
10062844
负责人：
Isaac Jonathan Krauss
金额：
$ 56.08万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062844
关键词：
Affinity Amino Acids Animal Model Antibodies Antibody Response Antigens Award B cell repertoire B-Lymphocytes Binding Biophysics Cell Culture Techniques Cells Collaborations Complex Directed Molecular Evolution Elements Epitopes Evaluation Event Evolution Glycopeptides Goals HIV HIV Envelope Protein gp120 HIV Infections Health Human Hybridomas Immune response Immunization Individual Infection Knock-in Knock-in Mouse Libraries Macaca mulatta Mannose Messenger RNA Methods Monitor Monoclonal Antibodies Mus Oryctolagus cuniculus Patients Peptides Phase Polysaccharides Protocols documentation Regimen Site Specificity Structure Surface Techniques Testing Vaccines Variant Viral Virus cohort deep sequencing design experimental study immunogenicity neutralizing antibody polypeptide reconstitution response scaffold tool vaccine development

项目摘要

Project Summary/Abstract Extensive study of HIV+ individuals in recent years has brought to light many examples of antibodies that can neutralize a broad range of HIV strains and protect against viral challenge in animal models of infection. The portion of viral surface most commonly targeted by such antibodies is now known to be the “high-mannose patch”: among patients producing broadly-neutralizing antibodies, 38% target this one region of the virus. One of the most potent high mannose patch antibodies, PGT128, binds to a particular arrangement of high-mannose glycans and conserved peptide residues. Our goal is to develop vaccine immunogens which mimic this arrangement precisely and be used to elicit PGT128-like antibodies. Our approach will utilize unique directed evolution methods to develop glycoimmunogens in which PGT128 epitope elements are correctly reconstituted. It is also possible that additional immunogens will be required to correctly prime the immune response by stimulating germline precursors of PGT128. Therefore, we will develop glycopeptides targeting both mature and germline PGT128 antibodies. In collaboration with David Nemazee at Scripps, we will investigate the ability of these glycopeptides in combination, to activate a germline PGT128 response that can mature into a response with broadly- neutralizing PGT128-like specificity.

项目概要/摘要近年来对 HIV+ 个体的广泛研究揭示了许多抗体的例子可以中和多种 HIV 病毒株并保护动物模型免受病毒攻击现在已知这种抗体最常靶向的病毒表面部分是。 “高甘露糖贴片”：在产生广泛中和抗体的患者中，38% 的患者以此为目标最有效的高甘露糖补丁抗体之一 PGT128 与病毒的一个区域结合。我们的目标是开发高甘露糖聚糖和保守肽残基的特殊排列。精确模仿这种排列并用于引发 PGT128 样的疫苗免疫原抗体。我们的方法将利用独特的定向进化方法来开发糖免疫原，其中 PGT128 表位元件也可能被正确重组。需要通过刺激 PGT128 的种系前体来正确启动免疫反应。因此，我们将开发针对成熟和种系 PGT128 抗体的糖肽。与斯克里普斯的 David Nemazee 合作，我们将研究这些糖肽在组合，以激活种系 PGT128 反应，该反应可以成熟为具有广泛- 中和 PGT128 样特异性。