Novel bNAB-based treatment and prevention of HIV-1

基于 bNAB 的 HIV-1 新型治疗和预防

• 批准号: 10445321
• 负责人: Anthony L DeVico
• 金额: $ 62.91万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445321
• 关键词: AIDS prevention; Adherence; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antibody Therapy; Antibody-mediated protection; Antigens; Antiviral Agents; Binding Sites; CD34 gene; CD4 Antigens; Cell Nucleus; Cells; Characteristics; Chronic; Clinical Trials; Combined Modality Therapy; Data; Development; Disadvantaged; Disease Progression; Dose; Drug Combinations; Drug or chemical Tissue Distribution; Engineering; Ensure; Exhibits; Exposure to; Face; Failure; Family; Fc domain; Generations; Goals; HIV; HIV Antibodies; HIV Infections; HIV-1; Half-Life; Human; Immunoglobulin G; In Vitro; Infection; Lead; Logistics; Macaca mulatta; Methods; Modality; Modeling; Modification; Monkeys; Mus; Mutation; Passive Immunization; Pharmaceutical Preparations; Plasma; Polysaccharides; Positioning Attribute; Prevention; Prevention therapy; Preventive; Prophylactic treatment; Resistance; Risk; SIV; Standardization; Tenofovir; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Variant; Viral Load result; Viremia; Virus; Virus Replication; antiretroviral therapy; base; clinical application; clinical development; experimental study; genotoxicity; humanized mouse; in vivo; interest; mouse model; neonatal Fc receptor; neutralizing antibody; nonhuman primate; novel; pre-exposure prophylaxis; prevent; prophylactic; protective efficacy; reconstitution; recruit; response; side effect; simian human immunodeficiency virus; stem; stem cells; success; transmission process

Background/Rationale: An alternative HIV prophylaxis/treatment modality of growing interest is based on the premise that the disadvantages stemming from cART use for the prevention/treatment of HIV can be mitigated by passive immunization with broadly neutralizing anti-HIV antibodies (bNAbs) against the HIV envelope. A pan- neutralizing antibody could provide a feasible means to treat or prevent HIV infection worldwide. Objectives: Through systematic deconvolution of circulating plasma anti-HIV envelope responses in HIV+ humans, we identified and characterized unique families of extremely broad and potent anti-CD4 receptor binding site (CD4bs) bNAbs with distinct CDR domain structural characteristics. Modifications of these bNAbs generated one iteration, N49P9.6-FR that neutralizes 97% of 117 viruses in a standardized, multi-tier, cross- subtype panel, with an overall potency that surpasses all other anti-CD4bs bNAbs and equals that of anti-glycan bNAbs. Further, because of its breadth, N49P9.6-FR covers viruses that are resistant to other anti-CD4bs bNAbs and is not polyreactive with human antigens in standard tests. Finally, we have generated an “LS” variant (N49P9.6-FR/LS) with mutations in the Fc domain that prolong circulating half-life. As such, N49P9.6-FR/LS provides a new opportunity to fully realize the utility of bNAb-based antivirals. However, the path forward demands demonstrations of efficacy in animal models. Accordingly, the goal of this project is to generate such data. Our hypothesis is that N49P9.6-FR will exhibit potent prevention and suppression of HIV infection, superior to related bNAbs now in clinical development. The specific aims of this proposal are 1) Establish the efficacy of bNAb N49P9.6-FR/LS in humanized mouse models; 2) Establish the protective efficacy of bNAb N49P9.6-FR/LS in the rhesus macaque/SHIV infection model. Methods: We will test the ability of N49P9.6-FR/LS to prevent and treat HIV infection in humanized mouse models and to prevent HIV infection in rhesus macaques. Immunodeficient NSG mice will be reconstituted with either HIV-1 infected human cells (Hu-PBL mice) or human CD34+ stem cells (Hu-CD34 mice) to examine preventive and therapeutic efficacy of the bNAb. Rhesus macaques will be challenged with SHIV to examine the preventive efficacy of the bNAb. In addition, we will complete PK studies with N49P9.6-FR/LS in the mice and rhesus macaques. Impact: Upon completion of the project, we expect to have determined that bNAb N49P9.6-FR has the capacity to provide safe, single-dose, potent, escape-resistant and durable HIV prevention and therapy, superior overall to other bNAbs. Success in this regard should position bNAb N49P9.6-FR for straightforward translational development into clinical applications with significant impact.

背景/理由：人们越来越感兴趣的另一种艾滋病毒预防/治疗方式是基于 前提是可以减轻使用 cART 预防/治疗艾滋病毒所带来的不利影响 通过使用针对 HIV 包膜的广泛中和性抗 HIV 抗体 (bNAb) 进行被动免疫。一个泛- 中和抗体可以为全世界治疗或预防艾滋病毒感染提供可行的手段。 目标：通过对 HIV+ 患者的循环血浆抗 HIV 包膜反应进行系统解卷积 在人类中，我们鉴定并表征了极其广泛和有效的抗 CD4 受体的独特家族 结合位点 (CD4b) bNAb 具有独特的 CDR 结构域结构特征。这些 bNAb 的修饰 生成了一个迭代 N49P9.6-FR，它以标准化、多层、交叉的方式中和了 117 种病毒中的 97% 亚型组合，其整体效力超过所有其他抗 CD4bs bNAb，并与抗聚糖相当 bNAb。此外，由于其广度，N49P9.6-FR 涵盖了对其他抗 CD4b bNAb 具有抗性的病毒 在标准测试中不与人类抗原发生多反应。最后，我们生成了一个“LS”变体 (N49P9.6-FR/LS) Fc 结构域发生突变，可延长循环半衰期。因此，N49P9.6-FR/LS 为充分实现基于 bNAb 的抗病毒药物的效用提供了新的机会。然而，前进的道路 要求在动物模型中证明功效。因此，该项目的目标是产生这样的 数据。我们的假设是 N49P9.6-FR 将表现出有效的预防和抑制 HIV 感染的作用，优于 相关 bNAb 现已进入临床开发阶段。该提案的具体目标是 1) 确定 人源化小鼠模型中的 bNAb N49P9.6-FR/LS； 2) 确定bNAb N49P9.6-FR/LS的保护功效 在恒河猴/SHIV 感染模型中。 方法：我们将测试N49P9.6-FR/LS在人源化小鼠中预防和治疗HIV感染的能力 模型并预防恒河猴的艾滋病毒感染。免疫缺陷 NSG 小鼠将用 HIV-1 感染的人类细胞（Hu-PBL 小鼠）或人类 CD34+ 干细胞（Hu-CD34 小鼠）进行检查 bNAb 的预防和治疗功效。恒河猴将受到 SHIV 的挑战，以检查 bNAb 的预防功效。此外，我们将完成 N49P9.6-FR/LS 在小鼠中的 PK 研究，以及 恒河猴。 影响：项目完成后，我们预计将确定 bNAb N49P9.6-FR 具有以下能力： 提供安全、单剂量、强效、抗逃逸和持久的艾滋病毒预防和治疗，整体优越 至其他 bNAb。在这方面的成功应该使 bNAb N49P9.6-FR 能够直接转化 发展到具有重大影响的临床应用。