Glycopeptide evolution targeting antibodies of the PGT128 lineage.

糖肽进化靶向 PGT128 谱系的抗体。

• 批准号: 9392707
• 负责人: Isaac Jonathan Krauss
• 金额: $ 52.34万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2018-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392707
• 关键词: Address; Affinity; 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; Human; Hybridomas; Immune response; Immunization; Individual; Infection; Knock-in; Knock-in Mouse; Libraries; Macaca mulatta; Mannose; Messenger RNA; Methods; Monitor; Mus; Mutate; Oryctolagus cuniculus; Patients; Peptides; Phase; Polysaccharides; Protocols documentation; Regimen; Site; Specificity; Structure; Surface; Techniques; Testing; Vaccines; Variant; Vertebral column; Viral; Virus; cohort; deep sequencing; design; experimental study; immunogenicity; neutralizing antibody; polypeptide; reconstitution; response; scaffold; tool; vaccine evaluation

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 glycopeptide immunogens 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肽免疫原 哪些PGT128表位元件被正确重构也可能是额外的。 需要免疫原通过刺激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的糖肽。 我们将与斯克里普斯的 David Nemazee 合作研究这些抗体的能力。 糖肽组合，激活种系 PGT128 反应，该反应可以成熟为反应 具有广泛中和 PGT128 样特异性。