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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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疾病进展，但它不能根除 HIV-1 感染，也不能加速消除被感染的细胞。 HIV-1 在静息记忆 CD4+ T 细胞中作为整合原病毒持续处于潜伏状态，无法通过 ART 访问。目前正在评估几种根除策略，并广泛消除抗体（bNAb）代表了一种有前途的新模式，特别是与潜伏期逆转剂结合使用时。抗体与 ART 的不同之处在于，它们可以通过其 Fc 结构域招募免疫效应子功能加速病毒和受感染细胞的清除。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。早期抗 HIV-1 bNAb 的被动给药已已在人体中进行评估，发现通常是安全的且耐受性良好。虽然这些第一代中和抗体在临床前和临床环境中基本上无效，选择了新一代 bNAb 可以预防人源化小鼠 (hu-mice) 和非人类感染并抑制主动感染灵长类动物（NHP）。 3BNC117 和 10-1074 是目前两种最有效的广泛中和抗体可用的。 3BNC117 靶向 CD4 结合位点，10-1074 靶向 HIV-1 gp120 V3 环的碱基。在 1 期临床研究中，3BNC117 和 10-1074 迄今为止总体上是安全的。单次输注 3BNC117 抑制 HIV-1 病毒血症平均为 1.48 log 拷贝/ml，而 10-1074 抑制 HIV-1 当剂量为 30 mg/kg 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估时在 ART (ATI) 分析中断期间，3BNC117 有效延迟了抗体敏感的反弹来自 HIV-1 储存库的病毒。与临床前发现类似，出现了耐药病毒株的选择当单独施用任一抗体时。 3BNC117与10-1074组合有相加效果并提供更广泛的病毒株覆盖范围。我们现在建议研究是否可以 3BNC117 和 10-1074 可以通过参与宿主免疫来抑制复制并减少储存库系统。设想的临床试验是一项 I 期、开放标签、随机研究，旨在评估抗逆转录病毒药物的疗效向已获得病毒感染的 HIV 感染受试者 6 个月输注 3BNC117 和 10-1074 的活性无论是否存在 ART，仅用 ART 进行抑制。我们将对储层进行定量评价以及确定具有复制能力的病毒库的遗传组成的定性方法。在此外，我们将评估 3BNC117 和 10-1074 是否调节 HIV-1 特异性免疫反应。