Using monoclonal antibody Fc variants in strategies to eliminate HIV reservoirs

在消除 HIV 病毒库的策略中使用单克隆抗体 Fc 变体

• 批准号: 10203753
• 负责人: Ann Jones Hessell
• 金额: $ 85.94万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203753
• 关键词: Address; Adherence; Adopted; Affinity; Amino Acids; Animal Model; Antibodies; Antibody-Dependent Enhancement; Antibody-mediated protection; Antiviral Agents; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Cloning; Complement Activation; Development; Dose; Drug Kinetics; Effectiveness; Engineering; Evaluation; Fc Receptor; Goals; Grouping; HIV; HIV Antibodies; HIV Infections; HIV-1; Half-Life; Human; Immune; In Vitro; Individual; Infection; Institutes; Interruption; Investigation; Lead; Life; Lymphoid Cell; Macaca; Macaca mulatta; Mediating; Mission; Modeling; Modification; Molecular; Monoclonal Antibodies; Mucous Membrane; Mutation; National Institute of Allergy and Infectious Disease; Outcome; Phagocytosis; Prevention; Protocols documentation; Public Health; Regimen; Research; Site; Site-Directed Mutagenesis; Testing; Therapeutic antibodies; Tissues; Variant; Viral; Viral Antibodies; Viral Physiology; Viral reservoir; Virus; Virus Diseases; Virus Latency; Work; acute infection; antibody engineering; antibody test; antibody-dependent cell cytotoxicity; antiretroviral therapy; cell killing; curative treatments; design; experience; experimental study; human monoclonal antibodies; improved; in vitro testing; in vivo; infection risk; large scale production; neutralizing monoclonal antibodies; nonhuman primate; novel strategies; novel therapeutics; pandemic disease; pre-clinical; prevent; prototype; purge; research clinical testing; simian human immunodeficiency virus; standard of care; treatment strategy

PROJECT SUMMARY New approaches for curative treatments could substantially reduce the numbers of individuals living with HIV- 1, thus diminishing the need for life-long adherence to ART. However, solutions must include clearing infection and preventing latent reservoirs. While ART is the standard of care for HIV+ individuals, the field has not yet addressed an alternative to ART therapy that could halt infection and halt virus expansion. A proven nonhuman primate (NHP) model for infection that examines new therapeutic regimens that can be instituted very soon after virus exposure, or in cases of viral control under ART, is needed to address whether it is possible to eradicate HIV. With the discoveries of extremely potent and broad antibodies that target multiple determinants on the HIV-1 Envelope, a cure strategy is now recognized as an attainable goal. The overall goal of this project is to design Fc function-enhanced anti-HIV-1 human monoclonal antibodies (mAbs) and test them for virus eradication in rhesus macaques in a Clade C, Tier 2, SHIV post-exposure protection model. Anti-viral functions mediated by the Fc part of the molecule are crucial to antibody protection against HIV, but clearing HIV-1 infection using antibodies is a new paradigm for antibodies. Specific combinations of neutralizing mAbs have been predicted to have the potential for neutralization coverage against large cross-clade panels of HIV-1 isolates; V2-directed mAbs were identified as an immune correlate of RV144 in reducing infection risk. Our working hypothesis is that combinations of mAbs, if enhanced for antibody-dependent cellular cytotoxicity (ADCC), phagocytosis (ADCP), and complement activation, and engineered and tested in vivo for increased half-life, would be extremely effective in ablating early acute infection and limiting or eliminating seeding of viral reservoirs. The project proposal outlines a research plan to engineer, develop and characterize in vitro a panel of human monoclonal anti-HIV mAbs with enhanced effector function designed to increase the effectiveness of killing HIV-1 infected cells. Fc regions of mAbs of known potency and breadth will be modified by site directed mutagenesis for increased effector functions and for optimal affinity to human and macaque FcRs. Once modified, functional assays will be used to evaluate the improvements in ADCC, ADCP and complement activation. Increased half-life evaluations will be performed in NHP. Combinations of modified mAbs will be tested in vitro to identify the most optimal groupings for additive effect of neutralization and effector functions. These mAbs will be chosen for large-scale production in amounts and purity needed for macaque experiments. An iterative progression of post-infection studies will be conducted in rhesus macaques, testing several combinations and examining doses and varying intervals before treatment. The practical goal is to formulate the most optimal combinations of mAbs that provide the highest degree of viral and reservoir clearance.

项目总结 新的治疗方法可以大幅减少艾滋病毒携带者的数量- 1，从而减少了终身坚持艺术的需要。然而，解决方案必须包括清除感染。 预防潜伏油气藏。虽然抗逆转录病毒治疗是艾滋病毒携带者的标准护理，但该领域还没有 提出了一种替代ART疗法的方法，可以阻止感染和阻止病毒传播。一个已被证实的非人类 灵长类(NHP)感染模型，研究即将推出的新治疗方案 在病毒暴露后，或在抗逆转录病毒疗法下进行病毒控制的情况下，需要解决是否可能 根除艾滋病毒。随着针对多个决定因素的极其有效和广泛的抗体的发现 在HIV-1信封上，治愈战略现在被认为是一个可以实现的目标。这个项目的总体目标是 目的是设计Fc功能增强的抗HIV-1人源单抗，并对其进行病毒检测 在暴露后保护模式C，Tier 2，SIV中根除恒河猴。抗病毒功能 由分子的Fc部分介导的是对HIV抗体保护至关重要的，但清除HIV-1 利用抗体进行感染是一种新的抗体研究范式。中和单抗的特定组合具有 被预测有可能中和覆盖HIV-1的大范围交叉小组 V2导向的单抗被确认为RV144在降低感染风险方面的免疫相关性。我们的 工作假说是，单抗的组合，如果增强抗体依赖的细胞细胞毒性 (ADCC)、吞噬(ADCP)和补体激活，并在体内设计和测试增加 半衰期，将在消融早期急性感染和限制或消除病毒播种方面极其有效 水库。该项目提案概述了一项研究计划，该计划旨在设计、开发和表征体外培养板 具有增强效应器功能的人源性抗HIV单抗旨在提高抗HIV单抗的疗效 杀死感染HIV-1的细胞。已知效价和广度的单抗的Fc区将由位点定向修饰 突变以增强效应器功能，并优化与人类和猕猴FcRs的亲和力。一次 将使用改良的功能分析来评估ADCC、ADCP和补体的改善 激活。将在国家卫生计划中进行增加的半衰期评估。修改后的单抗的组合将是 体外测试，以确定中和和效应器功能的相加效应的最优分组。 这些单抗将被选择用于大规模生产，其数量和纯度是猕猴实验所需的。 感染后研究的迭代进展将在恒河猴身上进行，测试几个 并在治疗前检查剂量和不同的间隔。实践的目标是制定 最理想的单抗组合，可提供最高程度的病毒和宿主清除。