3BNC117 mAb in HIV-infected subjects on combination ART

 描述(申请人提供)：尽管联合抗逆转录病毒疗法(ART)在抑制病毒复制和防止疾病进展方面取得了重大成功，但HIV-1感染仍然存在于潜伏的蓄水池中，主要由长期存活的记忆CD4+T细胞组成。这些潜伏感染的细胞携带有复制能力的HIV-1DNA，因此消除潜伏的病毒库是根除HIV-1感染的关键。目前正在评估几种根除策略，广谱中和抗体(BNAbs)代表着一种很有前途的新模式，特别是如果与潜伏期反转剂结合使用的话。BNAbs与标准ART的不同之处在于，它们可以通过其Fc效应结构域与宿主免疫系统接触。最重要的是，最近的数据显示，bNAbs干扰了人源化小鼠体内储存库的建立和维护。3BNC117是这样一种高效、广泛的NAB，正被开发为HIV-1预防和治疗的临床候选药物。它已被证明在感染HIV-1的人源化小鼠和感染SHV的非人类灵长类动物中导致病毒抑制。我们目前正在对3BNC117进行第一阶段剂量递增研究，研究对象是艾滋病毒感染者和未感染者。现有的临床数据表明，3BNC117总体上是安全的，耐受性良好，在未感染艾滋病毒和感染艾滋病毒的受试者中都具有良好的药代动力学特征。我们现在建议研究3BNC117对人类已建立的HIV-1宿主的影响。设想的临床试验是一项I期开放标签研究，以评估三种3BNC117在仅用ART实现病毒抑制的艾滋病毒感染者中的抗逆转录病毒活性。我们建议通过基于定量聚合酶链式反应的方法来测量与细胞相关的HIV-1DNA和RNA，以及通过功能性病毒生长分析来评估该储存库，该方法测量每百万个静止的CD4+T细胞的感染单位。鉴于这些检测的局限性，这项研究包括一项分析性治疗中断，这是评估艾滋病毒-1持久性和新治疗方式改变宿主能力的更严格工具。此外，我们还将评估3BNC117是否会调节HIV特异性免疫反应，并改变HIV-1感染特有的慢性炎症状态。

 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.