Novel bNAB-based treatment and prevention of HIV-1

背景/原理：一种越来越受关注的替代性HIV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因素 通过使用针对HIV包膜的广泛中和抗HIV抗体（bNAb）进行被动免疫。一个平底锅- 中和抗体可以提供一种可行的手段，以治疗或预防全球艾滋病毒感染。 目的：通过对HIV+患者循环血浆抗HIV包膜应答的系统性去卷积， 在人类中，我们鉴定并表征了极其广泛和有效的抗CD 4受体的独特家族， 具有不同CDR结构域结构特征的结合位点（CD 4 bs）bNAb。这些bNAb的修饰 产生了一个迭代，N49P9.6-FR，在一个标准化的，多层的，交叉的， 亚型组，总体效力超过所有其他抗CD 4 bs bNAb，与抗聚糖相当 bNAb。此外，由于其广泛性，N49P9.6-FR涵盖了对其他抗CD 4 bs bNAb具有抗性的病毒 并且在标准测试中不与人抗原多反应。最后，我们生成了一个“LS”变体 （N49P9.6-FR/LS），其在Fc结构域中具有延长循环半衰期的突变。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 需要在动物模型中证明其功效。因此，该项目的目标是产生这样的 数据我们的假设是N49 P9.6-FR将表现出有效的预防和抑制HIV感染，上级， 相关的bNAb目前在临床开发中。该提案的具体目标是：（1）确定 在人源化小鼠模型中的bNAb N49 P9.6-FR/LS; 2）建立bNAb N49 P9.6-FR/LS的保护功效 在恒河猴/SHIV感染模型中。 方法：在人源化小鼠体内检测N49P9.6-FR/LS对HIV感染的预防和治疗作用 模型和预防恒河猴中的HIV感染。免疫缺陷NSG小鼠将用以下物质重建： HIV-1感染的人细胞（Hu-PBL小鼠）或人CD 34+干细胞（Hu-CD 34小鼠）以检查 bNAb的预防和治疗功效。恒河猴将受到SHIV的挑战，以检查 bNAb的预防效果。此外，我们将在小鼠中完成N49P9.6-FR/LS的PK研究， 恒河猴 影响：项目完成后，我们预计已经确定bNAb N49P9.6-FR具有以下能力： 提供安全、单剂量、有效、不易逃逸和持久的艾滋病毒预防和治疗，总体上具有上级 其他bnab在这方面的成功应该定位bNAb N49P9.6-FR用于直接翻译 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.