3BNC117 and 10-1074 to suppress HIV-1 replication and reduce the reservoir

3BNC117 和 10-1074 抑制 HIV-1 复制并减少病毒库

• 批准号: 9897465
• 负责人: Marina Caskey
• 金额: $ 81.49万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897465
• 关键词: Acceleration; Anti-Retroviral Agents; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Antiviral Agents; Binding; Binding Sites; Biological Assay; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Clinical; Clinical Research; Clinical Trials; Coupled; Dendritic Cells; Development; Disease Progression; Dose; Drug Kinetics; Effector Cell; Fc domain; Fostering; Generations; Genetic; Genetic Transcription; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Health; Human; Immune; Immune response; Immune system; Immunotherapy; Impaired cognition; In Vitro; Individual; Infection; Infection prevention; Infusion procedures; Interruption; Intravenous infusion procedures; Kinetics; Long-Term Effects; Maintenance; Mathematics; Measures; Mediating; Modality; Natural Killer Cells; Nucleic Acids; Phase; Phenotype; Plasma; Property; Proviruses; Qualitative Methods; RNA; Randomized; Regimen; Resistance; Rest; Safety; Serological; Surface; T-Lymphocyte; Testing; V3 Loop; Viral; Viral reservoir; Viremia; Virus; Virus Latency; Virus Replication; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; comorbidity; experimental study; gp-120 Antigen; humanized mouse; immunological status; in vivo; memory CD4 T lymphocyte; mouse model; neutralizing antibody; nonhuman primate; open label; phase 1 study; pre-clinical; prevent; recruit; success; viral rebound; virology

Project Summary Combination antiretroviral therapy (ART) is highly successful in suppressing viral replication and preventing disease progression, however it cannot eradicate HIV-1 infection, and it does not accelerate the elimination of infected cells. HIV-1 persists in a latent state as integrated proviruses in resting memory CD4+ T cells that are not accessible to ART. Several eradication strategies are currently being evaluated, and broadly neutralizing antibodies (bNAbs) represent a promising new modality, particularly if coupled with latency reversing agents. Antibodies differ from ART in that they can recruit immune effector functions through their Fc domains to accelerate clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster development of host immune responses. Passive administration of earlier anti-HIV-1 bNAbs has been evaluated in humans and found to be generally safe and well tolerated. While these first generation neutralizing antibodies were largely ineffective in preclinical and clinical settings, selected newer generation bNAbs can prevent infection and suppress active infection in humanized mice (hu-mice) and non-human primates (NHP). 3BNC117 and 10-1074 are two of most potent broadly neutralizing antibodies currently available. 3BNC117 targets the CD4 binding site and 10-1074 targets the base of the V3 loop of HIV-1 gp120. In phase 1 clinical studies, 3BNC117 and 10-1074 have been generally safe to date. A single infusion of 3BNC117 suppressed HIV-1 viremia by an average of 1.48 log copies/ml, while 10-1074 suppressed HIV-1 viremia by an average of 1.34 copies/ml when dosed at 30 mg/kg. When evaluated in ART-treated individuals during an analytical interruption of ART (ATI), 3BNC117 effectively delayed rebound of antibody sensitive viruses from the HIV-1 reservoir. Similar to preclinical findings, selection of resistant viral strains occurred when either antibody was administered alone. The combination of 3BNC117 and 10-1074 have additive effects and provide broader coverage of viral strains. We now propose to study whether the administration of 3BNC117 and 10-1074 can suppress replication and reduce the reservoir by engaging the host immune system. The envisioned clinical trial is a phase I, open label, randomized study to evaluate the antiretroviral activity of 6 monthly infusions of 3BNC117 and 10-1074 to HIV-infected subjects who have achieved viral suppression with ART alone, in the presence or absence of ART. We will evaluate the reservoir by quantitative and qualitative methods to determine the genetic composition of the replication-competent viral reservoir. In addition, we will evaluate if 3BNC117 and 10-1074 modulate HIV-1-specific immune responses.

项目摘要 联合抗逆转录病毒疗法（ART）在抑制病毒复制和预防病毒感染方面非常成功 然而，它不能根除HIV-1感染，也不能加速消除 被感染的细胞HIV-1作为整合的前病毒在静息记忆CD 4 + T细胞中以潜伏状态持续存在， 目前正在评估几种根除战略， 抗体（bNAb）代表了一种有前途的新形式，特别是如果与潜伏期逆转剂偶联。 抗体与ART的不同之处在于它们可以通过其Fc结构域募集免疫效应子功能， 加速病毒和感染细胞的清除。此外，免疫复合物是有效的免疫原， 可以促进宿主免疫反应的发展。被动给予早期抗HIV-1 bNAb， 在人类中进行了评估，发现通常是安全的，耐受性良好。虽然这些第一代 中和抗体在临床前和临床环境中基本无效，选择新一代 bNAb可以在人源化小鼠（hu-小鼠）和非人中预防感染和抑制活动性感染。 灵长类动物（NHP）。3BNC 117和10-1074是目前最有效的两种广泛中和抗体 available. 3BNC 117靶向CD 4结合位点，10-1074靶向HIV-1 gp 120的V3环的碱基。 在I期临床研究中，3BNC 117和10-1074迄今为止基本安全。单次输注 3BNC 117抑制HIV-1病毒血症的平均值为1.48 log拷贝/ml，而10-1074抑制HIV-1 当以30 mg/kg剂量给药时，病毒血症平均降低1.34拷贝/ml。在接受ART治疗的个体中进行评价时 在ART的分析中断期间（ATI），3BNC 117有效地延迟了抗体敏感性的反弹， HIV-1病毒库中的病毒。与临床前研究结果相似， 当任一抗体单独施用时。3BNC 117与10-1074的组合具有加性效应 并提供更广泛的病毒株覆盖范围。我们现在建议研究是否 3BNC 117和10-1074可以通过接合宿主免疫抑制剂来抑制复制并减少储库。 系统设想的临床试验是一项I期，开放标签，随机研究，以评估抗逆转录病毒药物 对已实现病毒感染的HIV感染受试者每月输注3BNC 117和10-1074 6次的活性 在有或没有ART的情况下，单独使用ART进行抑制。我们将通过定量分析来评估水库。 和定性方法来确定可复制病毒库的遗传组成。在 此外，我们将评估3BNC 117和10-1074是否调节HIV-1特异性免疫应答。