Novel bNAB-based treatment and prevention of HIV-1

基于 bNAB 的 HIV-1 新型治疗和预防

基本信息

批准号：
10653146
负责人：
Anthony L DeVico
金额：
$ 76.69万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/10653146
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 envelope protein HIV therapy HIV-1 Half-Life Human Immunoglobulin G Immunologic Deficiency Syndromes In Vitro Infection Lead Logistics Macaca mulatta Methods Modality Modeling Modification Monkeys Mus Mutation Passive Immunization Pharmaceutical Preparations Plasma Polysaccharides Positioning Attribute Prevention 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 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

项目摘要

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/基本原理：一种替代性HIV预防/兴趣的治疗方式是基于可以减轻因购物车的灾难而造成的灾难的前提。通过被动免疫抑制，对HIV包膜具有广泛中和抗HIV抗体（BNAB）。一个锅中和抗体可以提供可行的手段，以治疗或预防全世界的艾滋病毒感染。目的：通过系统的反向循环血浆抗HIV信封反应在HIV+中的反应人类，我们确定并表征了极宽和潜在抗CD4受体的独特家族具有不同CDR结构特征的结合位点（CD4BS）BNAB。这些bnabs的修改产生了一种迭代，N49P9.6-FR中和标准化，多层，交叉的117个病毒中的97％亚型面板，总体效力超过了所有其他抗CD4BS bnabs，并等于反聚糖 bnabs。此外，由于其广度，N49P9.6-FR涵盖了对其他抗CD4BS BNAB具有抗性的病毒在标准测试中，与人类抗原没有多反应性。最后，我们生成了一个“ LS”变体（N49P9.6-FR/LS）在FC结构域中具有突变，延长了半衰期的循环。因此，N49P9.6-FR/LS 提供了一个新的机会，以充分实现基于BNAB的抗病毒药的实用性。但是，前进的道路需要证明动物模型效率。彼此之间，该项目的目标是生成这样的数据。我们的假设是N49P9.6-FR将表现出潜在的预防和抑制HIV感染，上等现在在临床开发领域的相关BNAB。该提案的具体目的是1）确定人源化小鼠模型中的bnab n49p9.6-fr/ls； 2）建立BNAB N49P9.6-FR/LS的受保护效率在恒河猴/湿暴感染模型中。方法：我们将测试N49P9.6-FR/LS预防和治疗人源化小鼠中HIV感染的能力模型并预防恒河猕猴中的艾滋病毒感染。免疫缺陷的NSG小鼠将与 HIV-1感染了人类细胞（HU-PBL小鼠）或人CD34+干细胞（HU-CD34小鼠）以检查 BNAB的预防和治疗效率。 Shiv将挑战Rhesus猕猴，以检查 BNAB的预防效率。此外，我们将在小鼠中使用N49P9.6-FR/LS完成PK研究，并恒河猕猴。影响：项目完成后，我们希望确定BNAB N49P9.6-FR具有能力提供安全，单剂量，潜在，抗逃避和耐用的HIV预防和治疗，总体上到其他bnabs。在这方面的成功应定位BNAB N49P9.6-FR，以进行直接翻译开发到具有重大影响的临床应用中。