Novel bNAB-based treatment and prevention of HIV-1

背景/理论：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购物车预防/治疗艾滋病毒所产生的不利因素 通过使用针对艾滋病毒包膜的广谱中和抗艾滋病毒抗体(BNAbs)进行被动免疫。平底锅- 中和抗体为世界范围内治疗或预防HIV感染提供了一种可行的手段。 目的：通过对HIV+中循环血浆抗HIV包膜反应的系统去卷积 人类，我们鉴定并鉴定了非常广泛和有效的抗CD4受体的独特家族 结合部位(CD4bs)具有明显CDR结构域结构特征的bNAbs。这些bNAbs的修饰 生成了一次迭代N49P9.6-FR，在标准化、多层、交叉的 亚型面板，总体效力超过所有其他抗CD4b bNAbs，与抗多糖相当 BNAbs。此外，由于其广泛性，N49P9.6-FR涵盖了对其他抗CD4b bNAbs具有抵抗力的病毒 在标准测试中与人类抗原不发生多反应。最后，我们生成了一个“LS”变量 (N49P9.6-FR/LS)，Fc结构域突变延长循环半衰期。因此，N49P9.6-FR/LS 为全面实现基于bNAb的抗病毒药物的应用提供了新的契机。然而，前进的道路 要求在动物模型中展示疗效。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将显示出有效的预防和抑制艾滋病毒感染，优越 相关的bNAbs目前正在临床开发中。这项建议的具体目标是：1)建立 BNAb N49P9.6-FR/LS人源化小鼠模型；2)建立bNAb N49P9.6-FR/LS的保护作用 在恒河猴/希沃克病毒感染模型中。 方法：在人源化小鼠体内检测N49P9.6-FR/LS对HIV感染的防治作用 模型，并防止恒河猴感染艾滋病毒。免疫缺陷的NSG小鼠将用 HIV-1感染的人细胞(Hu-PBL小鼠)或人CD34+干细胞(Hu-CD34小鼠)检测 BNAb的预防和治疗作用。猕猴将接受SIV病毒的挑战，以检查 BNAb的预防效果。此外，我们还将完成N49P9.6-FR/LS在小鼠和 恒河猴。 影响：项目完成后，我们预计已确定bNAb N49P9.6-FR具有 提供安全、单剂、有效、防逃逸和持久的艾滋病毒预防和治疗，总体上优越 到其他bNAb。这方面的成功将使bNAb N49P9.6-FR成为直截了当的翻译 发展为临床应用具有重大影响。

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.