3BNC117 mAb in HIV-infected subjects on combination ART

3BNC117 mAb 用于接受联合 ART 治疗的 HIV 感染受试者

• 批准号: 9232973
• 负责人: Marina Caskey
• 金额: $ 69.77万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232973
• 关键词: Animals; Anti-Retroviral Agents; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Area; Binding Sites; Biological Assay; Cardiovascular Diseases; Cells; Characteristics; Chronic; Clinical; Clinical Data; Clinical Trials; Comorbidity; Coupled; Cyclic GMP; DNA; Data; Dendritic Cells; Disabled Persons; Disease Progression; Dose; Drug Kinetics; Gold; HIV; HIV-1; Health; Human; Immune response; Immune system; Impaired cognition; Individual; Infection; Inflammation; Infusion procedures; Interruption; Intravenous infusion procedures; Laboratories; Lead; Lymphoid Tissue; Maintenance; Measures; Methods; Modality; Pharmaceutical Preparations; Phase; Plasma; Population; Prevention therapy; Proviruses; RNA; Regimen; Rest; Safety; T-Lymphocyte; Testing; Therapeutic; University Hospitals; Viral; Viral reservoir; Viremia; Virus; Virus Latency; Virus Replication; antiretroviral therapy; base; clinical candidate; cytotoxicity; experimental study; gp-120 Antigen; humanized mouse; immunological status; in vivo; killings; member; memory CD4 T lymphocyte; neutralizing antibody; nonhuman primate; novel therapeutics; open label; prevent; public health relevance; simian human immunodeficiency virus; small molecule; success; tool; transmission process; viral rebound

 DESCRIPTION (provided by applicant): Despite the major success of combination antiretroviral therapy (ART) in suppressing viral replication and preventing disease progression, HIV-1 infection persists in a latent reservoir, composed primarily of a long- lived population of resting memory CD4+ T cells. These latently infected cells harbor replication competent HIV-1 DNA, therefore the elimination of the latent viral reservoir is essential to eradicating HIV-1 infection. Several eradication strategies are currently being evaluated, and broadly neutralizing antibodies (bNAbs) represent a promising new modality, particularly if coupled with latency reversing agents. BNAbs differ from standard ART in that they can engage the host immune system by virtue of their Fc effector domains. Most importantly, recent data shows that bNAbs interfere with the establishment and maintenance of the reservoir in humanized mice. 3BNC117 is one of such highly potent and broad NAbs and is being developed as a clinical candidate for HIV-1 prevention and therapy. It has been shown to lead to viral suppression in HIV-1 infected humanized mice and in SHIV-infected non-human primates. We are currently testing 3BNC117 in a phase 1 dose-escalation study in HIV-infected and uninfected individuals. The available clinical data shows that 3BNC117 is generally safe and well tolerated, and has a favorable pharmacokinetic profile in both HIV- uninfected and HIV-infected subjects. We now propose to study the effects of 3BNC117 on established HIV-1 reservoirs in humans. The envisioned clinical trial is a phase I, open label study to evaluate the antiretroviral activity of three infuions of 3BNC117 in HIV-infected subjects who have achieved viral suppression with ART alone. We propose to evaluate the reservoir by quantitative PCR-based assays to measure cell-associated HIV-1 DNA and RNA and by functional viral outgrowth assays that measure infectious units per million CD4+ resting T cells. Given the limitations of these assays, the study includes an analytical treatment interruption which is a more stringent tool to evaluate HIV-1 persistence and the ability of new therapeutic modalities to alter the reservoir. In addition we will evaluate if 3BNC117 will modulate HIV-specific immune responses and modify the state of chronic inflammation characteristic of HIV-1 infection.

 描述（由申请人提供）：尽管联合抗逆转录病毒治疗（ART）在抑制病毒复制和预防疾病进展方面取得了重大成功，但HIV-1感染仍存在于潜伏库中，主要由长寿的静息记忆CD 4 + T细胞群组成。这些潜伏感染的细胞携带有复制能力的HIV-1 DNA，因此消除潜伏的病毒储存库对根除HIV-1感染至关重要。目前正在评估几种根除策略，广泛中和抗体（bNAb）代表了一种有前途的新模式，特别是如果与潜伏期逆转剂结合。BNAb与标准ART的不同之处在于它们可以凭借其Fc效应结构域参与宿主免疫系统。最重要的是，最近的数据显示，bNAb干扰人源化小鼠中储库的建立和维持。3BNC 117是这样一种高效和广泛的NAb之一，并且正在被开发为用于HIV-1预防和治疗的临床候选物。它已显示在HIV-1感染的人源化小鼠和SHIV感染的非人灵长类动物中导致病毒抑制。我们目前正在HIV感染者和未感染者中进行1期剂量递增研究，以测试3BNC 117。可用的临床数据显示，3BNC 117通常是安全的且耐受性良好，并且在HIV未感染和HIV感染的受试者中具有有利的药代动力学特征。我们现在建议研究3BNC 117对人类中已建立的HIV-1储库的影响。所设想的临床试验是I期、开放标签研究，以评价在已经单独用ART实现病毒抑制的HIV感染受试者中三次输注3BNC 117的抗逆转录病毒活性。我们建议通过基于定量PCR的测定来评估水库，以测量细胞相关的HIV-1 DNA和RNA，并通过功能性病毒生长测定来测量每百万CD 4+静息T细胞的感染单位。鉴于这些检测的局限性，该研究包括分析治疗中断，这是一种更严格的工具，用于评估HIV-1的持久性和新治疗方式改变储库的能力。此外，我们将评估3BNC 117是否会调节HIV特异性免疫应答并改变HIV-1感染的慢性炎症特征状态。