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.

项目摘要 新的治疗方法可以大大减少艾滋病毒感染者的人数， 1，从而减少了终身坚持ART的必要性。然而，解决方案必须包括清除感染 并防止潜在的水库。虽然抗逆转录病毒疗法是艾滋病毒阳性个体的护理标准，但该领域尚未 提出了一种替代ART治疗的方法，可以阻止感染和病毒扩散。一个被证实的非人类 灵长类动物（NHP）感染模型，检查可以很快制定的新治疗方案 在病毒暴露后，或在ART控制病毒的情况下，需要解决是否有可能 根除艾滋病毒。随着针对多个决定因素的极其有效和广泛的抗体的发现， 在艾滋病毒-1信封上，治愈战略现在被认为是一个可以实现的目标。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）， 在进化枝C，第2层，SHIV暴露后保护模型中的恒河猴中的根除。抗病毒功能 由分子的Fc部分介导的免疫应答对于抗体保护抗HIV至关重要，但清除HIV-1 使用抗体的感染是抗体的新范例。中和mAb的特定组合具有 据预测，该疫苗有可能对HIV-1的大型交叉进化枝组进行中和， 分离株;针对V2的mAb被确定为与RV 144在降低感染风险方面的免疫相关性。我们 工作假设是，如果增强了抗体依赖性细胞毒性， 在一些实施方案中，本发明提供了一种用于增加ADCC（ADCC）、吞噬作用（ADCP）和补体激活的细胞因子，并且针对增加的ADCC（ADCC）、吞噬作用（ADCP）和补体激活进行了工程化和体内测试。 半衰期，将是非常有效的消融早期急性感染和限制或消除播种的病毒 水库该项目建议书概述了一项研究计划，以工程师，开发和体外表征面板 具有增强的效应子功能的人单克隆抗HIV mAb，旨在增加 杀死HIV-1感染细胞。具有已知效力和宽度的mAb的Fc区将通过位点定向修饰来修饰。 诱变以增加效应子功能和对人和猕猴Fc γ R的最佳亲和力。一旦 将使用改良的功能测定来评价ADCC、ADCP和补体的改善。 activation.将在NHP中进行半衰期延长评价。修饰的mAb的组合将是 在体外进行测试，以确定中和和效应子功能的累加效应的最佳分组。 将选择这些mAb用于大规模生产，其数量和纯度满足猕猴实验的要求。 将在恒河猴中进行感染后研究的迭代进展，测试几种 联合用药和检查剂量以及治疗前的不同间隔。实际目标是制定 提供最高程度的病毒和储库清除的mAb的最佳组合。