Mannosidase-stabilized glycan immunogens for elicitation of high mannose patch antibodies

甘露糖苷酶稳定的聚糖免疫原，用于引发高甘露糖贴片抗体

• 批准号: 10619737
• 负责人: Isaac Jonathan Krauss
• 金额: $ 24.38万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619737
• 关键词: Affinity; Antibodies; Antibody Response; Antigens; Binding; Carbohydrates; Carrier Proteins; Collaborations; Disaccharides; Enzyme-Linked Immunosorbent Assay; Epitopes; Family; Family member; Glycoconjugates; Glycopeptides; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; Hydrophobicity; Immunization; Immunize; Infection; Laboratories; Length; Macaca mulatta; Mannose; Mannosidase; Memory B-Lymphocyte; Methods; Modification; Oryctolagus cuniculus; Oxygen; Patients; Peptides; Polysaccharides; Proteins; Serum; Structure; Structure of germinal center of lymph node; Sulfur; Surface; Testing; V3 Loop; Vaccination; Vaccines; Variant; Virus; X-Ray Crystallography; analog; arm; cross reacting material 197; glycosylation; immunogenicity; improved; in vivo; man; mannosyl(9)-N-acetylglucosamine2; neutralizing antibody; prevent; response

Project Summary/Abstract HIV broadly neutralizing antibodies (bnAbs) most commonly target the High Mannose Patch (HMP), a mannose-rich region of HIV Env in the vicinity of the V3 loop and the N332 glycan. HMP bnAbs (e.g., 2G12, PGT128, BG18) tend to recognize non-reducing-terminal Man1α-2Man moieties within oligomannose glycans; however, in immunizations with oligomannose glycoconjugates, antibodies are rarely raised against Man1a-2Man, and instead bind to core motifs of the glycan. We hypothesize that in vivo mannosidase trimming of Man1a-2Man termini is a major reason why antibodies do not develop against this motif. In Aim 1, we will prepare stabilized oligomannose glycans, in which a sulfur linkage prevents mannosidase cleavage of the Man1α-2Man, but structurally mimics the natural glycan and is recognized by bnAbs. In Aim 2, we will immunize rabbits with CRM197 glycoconjugates containing the stabilized or unstabilized glycans and compare the resulting antibodies’ HIV Env binding and neutralization activity. We will also intensively characterize the ability of these antibodies to bind Man1a- 2Man using an oligomannose-focused glycan array.

项目摘要/摘要 HIV广泛中和抗体（BNAB）最常见的是靶向高甘露糖贴（HMP），A V3环和N332 Glycan附近的HIV环境富含甘露糖的区域（例如 2G12，PGT128，BG18）倾向于识别非还原末端MAN1α-2MAN部分部分 但是，在用少突糖糖缀合物的免疫中，抗体是抗体 很少对Man1a-2人提出，而是与聚糖的核心图案结合。 MAN1A-2MAN TERMINI的体内甘露糖苷酶修剪是抗体不发展的主要原因 在AIM 1中，我们将准备稳定的寡头糖糖。 防止MAN1α-2MAN的甘露糖苷酶切割，但结构性模仿天然聚糖和IS是IS是IS。 在AIM 2中被BNAB识别。 稳定或不稳定的聚糖，并比较产生的抗体的HIV env结合和 中和活性。 2MAN使用以少突糖为重点的聚糖阵列。