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.

项目概要 新的治疗方法可以大大减少艾滋病毒感染者的数量 1，从而减少了终生坚持 ART 的需要。然而，解决方案必须包括清除感染 并预防潜在储存库。虽然 ART 是 HIV + 个体的护理标准，但该领域尚未 提出了一种 ART 疗法的替代方案，可以阻止感染并阻止病毒扩散。已被证实的非人类 灵长类动物 (NHP) 感染模型，用于检查可以很快实施的新治疗方案 病毒暴露后，或在 ART 下病毒控制的情况下，需要解决是否有可能 根除艾滋病毒。随着针对多个决定簇的极其有效和广泛的抗体的发现 在 HIV-1 信封上，治愈策略现已被认为是可以实现的目标。本项目的总体目标 是设计Fc功能增强的抗HIV-1人单克隆抗体（mAb）并对其进行病毒检测 在 Clade C、Tier 2、SHIV 暴露后保护模型中根除恒河猴。抗病毒功能 由该分子的 Fc 部分介导的抗体对于对抗 HIV 的抗体保护至关重要，但清除 HIV-1 使用抗体进行感染是抗体的新范例。中和单克隆抗体的特定组合具有 预计具有针对大型跨进化枝 HIV-1 组的中和覆盖潜力 隔离； V2 导向的 mAb 被确定为 RV144 在降低感染风险方面的免疫相关物。我们的 工作假设是单克隆抗体的组合如果增强抗体依赖性细胞毒性 (ADCC)、吞噬作用 (ADCP) 和补体激活，并进行了体内设计和测试以增强 半衰期，对于消除早期急性感染和限制或消除病毒的传播非常有效 水库。该项目提案概述了在体外设计、开发和表征面板的研究计划 具有增强效应功能的人单克隆抗 HIV 单克隆抗体，旨在提高 杀死 HIV-1 感染的细胞。已知效力和广度的单克隆抗体的 Fc 区将通过定点修饰进行修改 诱变以增强效应子功能以及与人类和猕猴 Fc-R 的最佳亲和力。一次 改良的功能测定将用于评估 ADCC、ADCP 和补体的改进 激活。将在 NHP 中进行增加的半衰期评估。修饰的单克隆抗体的组合将是 体外测试以确定中和和效应功能相加效应的最佳分组。 这些单克隆抗体将根据猕猴实验所需的数量和纯度进行大规模生产。 感染后研究的迭代进展将在恒河猴中进行，测试几种 组合并检查剂量和治疗前的不同间隔。实际目标是制定 提供最高程度的病毒和病毒库清除率的最佳单克隆抗体组合。