Modifications to improve HIV neutralizing antibodies

改进 HIV 中和抗体的修饰

• 批准号: 8946603
• 负责人: John Mascola
• 金额: $ 180万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8946603
• 关键词: Affinity; Antibodies; Cells; Goals; HIV; HIV Infections; HIV-1; Half-Life; Human; Modification; Monoclonal Antibodies; Mutation; Patients; Relative (related person); Structure; Testing; Treatment Efficacy; Virus; Work; base; design; immunogenicity; improved; in vivo; in vivo Model; neutralizing antibody

This work describes targeted mutations applied to several HIV-1 neutralizing antibodies that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency, which are based on the crystal structures. These modifications are tested against a panel of HIV-1 viruses to determine the breadth and strength of their ability to neutralize. The most potent of these candidates are then selected for testing in in vivo models with the long term goal of testing in humans. In addition, bi-specific antibodies are being developed with the goal of targeting and treating reservoirs of HIV infection in cells.

这项工作描述了几种HIV-1中和抗体的靶向突变，这些抗体是从HIV+供体中分离出来的。这些突变旨在增加宽度、效力和半衰期，以提高治疗应用的潜在功效，并降低免疫原性，以实现更有效和更持久的体内功能。也有基于结构的突变，旨在提高亲和力和中和效力，这是基于晶体结构。这些修饰在一组HIV-1病毒上进行了测试，以确定它们中和能力的广度和强度。然后选择这些候选药物中最有效的药物在体内模型中进行测试，长期目标是在人体中进行测试。此外，正在开发双特异性抗体，目标是靶向和治疗细胞中的HIV感染库。