Long-acting, self-administered HIV therapy with th CCR5 antibody PRO 140

使用 CCR5 抗体 PRO 140 进行长效、自我管理的 HIV 治疗

• 批准号: 8541374
• 负责人: JEFFREY M. JACOBSON
• 金额: $ 302.63万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-18 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541374
• 关键词: Long; acting; self; administered; HIV

Combination antiretroviral therapy (ART) represents a medical success with few contemporary parallels. However, ART does not eradicate HIV, prevent long-term morbidities, or fully restore immune function. In addition, ART requires lifelong daily adherence, and treatment failure is common due to suboptimal adherence, drug resistance or toxicity. One approach to bridging these treatment gaps is through the development of novel, long-acting therapies as a complement to the current paradigm of daily treatment. PRO 140 is a humanized anti-CCR5 monoclonal antibody (mAb) that has demonstrated potent, long-lived antiretroviral activity and an encouraging safety profile in initial clinical testing. PRO 140 has the potential to be the first long-acting (weekly or every other week), self-administered HIV drug. Unlike small-molecule CCR5 antagonists, PRO 140 inhibits CCR5-tropic (R5) HIV through a direct rather than allosteric mechanism and preserves CCR5's natural activity. PRO 140 also broadly inhibits drug-resistant R5 viruses, including those resistant to small-molecule CCR5 antagonists. Overall, PRO 140 represents a distinct class of CCR5 inhibitor with unique virological and immunological properties. This project seeks to obtain the first clinical proof of principle for a long-acting, self-administered HIV drug. The proposed study is a randomized, double-blind, placebo-controlled trial to explore the antiviral activity, safety, PK and immunological effects of PRO 140 tested as short-term monotherapy in HIV-infected individuals with early-stage infection. Subjects (n=40) will self-inject PRO 140 subcutaneously using a simple push-button device. Our primary hypothesis is that HIV replication can be potently suppressed through infrequent self-use of a long-acting HIV drug. In addition, the study provides an ideal setting to explore the effects of treatment on Th17 and other relevant subsets of CCR5[+] T cells that are critical for normal host defense, are severely depleted by HIV, and are suboptimally restored by existing ART. This study will be the first to examine the effects of initiating treatment with any HIV drug on Th17 cell numbers function and CCR5 occupancy. Success requires that treatment demonstrate potent and long-lived antiviral effects (>/=1.5 log{10} mean decrease in HIV RNA), minimal injection-site reactions, and ease of use. In our immunological analyses, success is defined as high-level (>90%) CCR5 receptor occupancy on Th17 cells throughout the treatment period without depletion of these cells. If successful, this project will advance an innovative treatment paradigm and elucidate fundamental aspects of immune dynamics during HIV infection and therapy.

联合抗逆转录病毒疗法（ART）是一种当代少有的医学成功。然而，ART并不能根除艾滋病毒，预防长期发病，或完全恢复免疫功能。此外，ART需要终身每日坚持，由于次优坚持、耐药性或毒性，治疗失败是常见的。弥合这些治疗差距的一种方法是开发新型长效疗法，作为当前日常治疗模式的补充。 PRO 140是一种人源化的抗CCR 5单克隆抗体（mAb），在最初的临床试验中已证明具有强效、长寿命的抗逆转录病毒活性和令人鼓舞的安全性。PRO 140有可能成为第一个长效（每周或每隔一周），自我管理的艾滋病毒药物。与小分子CCR 5拮抗剂不同，PRO 140通过直接而非变构机制抑制CCR 5嗜性（R5）HIV，并保留CCR 5的天然活性。PRO 140还广泛抑制耐药R5病毒，包括对小分子CCR 5拮抗剂耐药的病毒。总的来说，PRO 140代表了一类独特的CCR 5抑制剂，具有独特的病毒学和免疫学特性。 该项目旨在获得第一个临床证明的原则，长效，自我管理的艾滋病毒药物。拟议的研究是一项随机、双盲、安慰剂对照试验，旨在探索PRO 140作为短期单药治疗在早期感染的HIV感染者中的抗病毒活性、安全性、PK和免疫学效应。受试者（n=40）将使用简单的按钮装置自我皮下注射PRO 140。我们的主要假设是，艾滋病毒复制可以通过不频繁地自我使用长效艾滋病毒药物来有效抑制。此外，该研究提供了一个理想的环境，以探索治疗对Th 17和其他相关的CCR 5 [+] T细胞亚群的影响，这些亚群对正常的宿主防御至关重要，被HIV严重耗尽，并通过现有的ART进行次优恢复。 成功的治疗需要证明有效和长期的抗病毒效果（HIV RNA平均减少>/=1.5 log{10}），最小的注射部位反应和易于使用。在我们的免疫学分析中，成功被定义为在整个治疗期间在Th 17细胞上的高水平（>90%）CCR 5受体占有率，而没有耗尽这些细胞。如果成功，该项目将推进一种创新的治疗模式，并阐明艾滋病毒感染和治疗过程中免疫动力学的基本方面。