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: 10212190
• 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/10212190
• 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; antiretroviral therapy; cytotoxic; cytotoxicity; disorder control; experimental study; humanized mouse; improved; in vivo; in vivo Model; in vivo evaluation; mouse model; neonatal Fc receptor; nonhuman primate; particle; pre-exposure prophylaxis; preclinical evaluation; 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 艾滋病毒治愈的一个主要障碍是构成艾滋病毒储存库的艾滋病毒-1感染细胞的持久性。虽然 目前的抗逆转录病毒药物策略对消除艾滋病毒宿主没有影响，抗艾滋病毒- 1抗体可通过Fc效应器活性特异性靶向这些细胞，提示其潜在的临床应用。 用于控制HIV-1感染。在几项临床前评估研究中，给药广泛 中和抗HIV-1抗体(BNAbs)提供了有效的暴露前预防和持久的 在体内感染HIV-1的慢性感染模型中抑制病毒复制。更重要的是， 最近对这些bNAbs在HIV-1感染患者中的保护活性的评估表明，它们具有 这些bNAb提供病毒控制，正如bNAb后血浆病毒血症的减少所证明的那样。 行政管理。BNAb的Fc结构域与效应器表面表达的Fcγ受体的相互作用 白细胞通过诱导病毒颗粒的调离和清除而参与体内的抗病毒活性 以及消除感染艾滋病毒的细胞。鉴于bNAbs的Fc效应活性对诱导 清除HIV感染细胞，拟议的研究旨在开发和表征Fc优化的bNAbs 具有改进的FC效应器功能。这些bNAbs的活性将在体外进行评估。 在人源化的HIV-1感染小鼠模型中以及在SHV感染的体内进行细胞毒性试验 恒河猴。针对增强效应器活性的FC优化的bNAbs有望专门针对HIV- 感染细胞，提供持续的疾病控制和增强的治疗潜力 常规bNAbs。