Optimization of Fc effector activity of anti-HIV antibodies to target HIV reservoir

优化针对 HIV 储存库的抗 HIV 抗体的 Fc 效应子活性

• 批准号: 9410790
• 负责人: Michel C Nussenzweig
• 金额: $ 84.75万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9410790
• 关键词: Affinity; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Binding; Biological Assay; Biological Models; Cells; Chronic; Clinical; Development; Early treatment; Engineering; Epitopes; Evaluation; Evaluation Studies; Exhibits; Experimental Models; Fc domain; HIV; HIV Antibodies; HIV-1; Half-Life; Human; IgG1; In Vitro; Infection; Infection Control; Interruption; Leukocytes; Macaca mulatta; Mediating; Modeling; Mouse Strains; Pathway interactions; Patients; Pattern; Pharmacology; Plasma; Prevention; Prophylactic treatment; Research; Specificity; Surface; Therapeutic; Variant; Viral; Viremia; Virus Replication; cytotoxic; cytotoxicity; disorder control; experimental study; humanized mouse; improved; in vivo; in vivo Model; mouse model; neonatal Fc receptor; nonhuman primate; particle; pre-clinical; pre-exposure prophylaxis; simian human immunodeficiency virus

ABSTRACT A major barrier to HIV cure is the persistence of HIV-1-infected cells that constitute the HIV reservoir. Although current antiretroviral pharmacologic strategies have no impact on the elimination of the HIV reservoir, anti-HIV- 1 antibodies can specifically target these cells through Fc effector activity, suggesting their potential clinical use for the control of HIV-1 infection. In several pre-clinical evaluation studies, administration of broadly neutralizing anti-HIV-1 antibodies (bNAbs) provided both effective pre-exposure prophylaxis and durable suppression of virus replication in chronically infected models of in vivo HIV-1 infection. More importantly, recent evaluation of the protective activity of these bNAbs in HIV-1-infected patients revealed the capacity of these bNAbs to confer viremic control, as evidenced by the reduction in plasma viremia following bNAb administration. Interactions of the Fc domain of bNAbs with FcγRs expressed on the surface of effector leukocytes contribute to their in vivo antiviral activity by inducing opsonization and clearance of viral particles as well as elimination of HIV-infected cells. Given the importance of Fc effector activity of bNAbs to induce clearance of HIV-infected cells, the proposed studies aim to develop and characterize Fc-optimized bNAbs with improved Fc effector function. The activity of these bNAbs will be evaluated in vitro in well-established cytotoxicity assays, and in vivo in humanized mouse models of HIV-1 infection, as well as in SHIV-infected rhesus monkeys. Fc-optimized bNAbs for enhanced effector activity are expected to specifically target HIV- infected cells, providing sustained disease control and augmented therapeutic potential compared to conventional bNAbs.

摘要 HIV治愈的一个主要障碍是构成HIV库的HIV-1感染细胞的持续存在。虽然 目前的抗逆转录病毒药物策略对消除艾滋病毒储存库没有影响，抗艾滋病毒- 1抗体可以通过Fc效应子活性特异性靶向这些细胞，表明其潜在的临床用途 用于控制HIV-1感染。在几项临床前评价研究中， 中和抗HIV-1抗体（bNAb）提供了有效的暴露前预防和持久的 在体内HIV-1感染的慢性感染模型中抑制病毒复制。更重要的是， 最近对这些bNAb在HIV-1感染患者中的保护活性的评估显示， 这些bNAb提供病毒血症控制，如bNAb后血浆病毒血症减少所证明的 局bNAb的Fc结构域与效应器表面表达的Fcγ R的相互作用 白细胞通过诱导调理作用和病毒颗粒的清除而有助于它们的体内抗病毒活性 以及清除HIV感染细胞。鉴于bNAb的Fc效应子活性对于诱导 HIV感染细胞的清除，所提出的研究旨在开发和表征Fc优化的bNAb 具有改善的Fc效应子功能。这些bNAb的活性将在体外在良好建立的细胞内进行评价。 细胞毒性测定，以及在HIV-1感染的人源化小鼠模型中的体内，以及在SHIV感染的小鼠模型中的体内。 恒河猴预期用于增强效应子活性的Fc优化的bNAb特异性靶向HIV-1。 感染的细胞，提供持续的疾病控制和增强的治疗潜力相比， 常规bNAb。