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: 8546145
• 负责人: JEFFREY M. JACOBSON
• 金额: $ 260.03万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546145
• 关键词: Address; Adherence; Anti-Retroviral Agents; Antibodies; Antiviral Agents; CCR5 gene; Cell Count; Cells; Chemokine (C-C Motif) Receptor 5; Clinical; Complement; Development; Devices; Drug resistance; Drug toxicity; HIV; HIV Infections; HIV therapy; Host Defense; Immune; Individual; Infection; Injection Site Reaction; Instruction; Life; Medical; Monoclonal Antibodies; Morbidity - disease rate; PRO 140; Pharmaceutical Preparations; Property; RNA; Randomized; Resistance; Safety; Self-Administered; Staging; T-Lymphocyte; Testing; Toxic effect; Treatment Failure; Virus; antiretroviral therapy; double-blind placebo controlled trial; immune function; improved; inhibitor/antagonist; innovation; novel; prevent; research clinical testing; small molecule; success; treatment duration; treatment effect; treatment strategy

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 CCRS'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 eariy-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 Thi7 and other relevant subsets of CCRS"^ 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 Thi7 cell numbers function and CCR5 occupancy. Success requires that treatment demonstrate potent and long-lived antiviral effects (^1.5 logio 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 Thi7 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. RELEVANCE (See instructions): Antiretroviral therapy has dramatically improved the lives of many HIV-infected individuals; however, there remains a need for new treatment strategies to address drug resistance, long-term toxicities and other challenges. This project seeks to obtain proof of concept for an innovative CCR5 antibody used as the first long-acting, self-administered HIV drug. Success would represent a major advance towards the introduction of long-acting HIV therapies as a complement to the current paradigm of daily lifetime adherence to treatment.

抗逆转录病毒疗法（ART）代表了与现代相似之处的医学成功。 但是，ART不会消除HIV，预防长期病毒或完全恢复免疫功能。在 此外，艺术需要终生遵守，并且由于次优的治疗失败是常见的 依从性，耐药性或毒性。弥合这些治疗差距的一种方法是 新型长效疗法的发展是对当前日常治疗范式的补充。 Pro 140是一种人源化抗CCR5单克隆抗体（MAB），表现出有效的长期 在初始临床测试中，抗逆转录病毒活性和令人鼓舞的安全性。 Pro 140有 潜力成为第一个长效（每周或每隔一周），自我管理的艾滋病毒药物。与小型 分子CCR5拮抗剂，Pro 140通过直接而不是变构抑制CCR5-循环（R5）HIV 机制和保留CCR的自然活动。 Pro 140还广泛抑制耐药的R5病毒， 包括那些对小分子CCR5拮抗剂的抗药性。总体而言，Pro 140代表一个独特的类 CCR5抑制剂具有独特的病毒学和免疫学特性。 该项目旨在获得长效，自我管理的艾滋病毒的第一个原理临床证明 药品。拟议的研究是一项随机，双盲的安慰剂对照试验，以探索抗病毒药 Pro 140的活动，安全性，PK和免疫学作用在HIV感染的短期单一疗法中测试 具有耳阶段感染的人。受试者（n = 40）将使用A自我注射Pro 140使用 简单的按钮设备。我们的主要假设是可以有效抑制艾滋病毒的复制 通过不常见的长效HIV药物的自我使用。此外，该研究为 探索治疗对THI7和其他相关子集的影响，这些细胞对 正常的宿主防御，被艾滋病毒严重耗尽，并被现有艺术降低。这 研究将是第一个检查使用任何HIV药物对THI7细胞数量启动治疗的影响的研究 功能和CCR5占用率。 成功要求治疗表现出有效且长期寿命的抗病毒作用（^1.5 Logio平均值 降低HIV RNA），最小注射位点的反应以及易于使用。在我们的免疫学分析中 在整个处理过程中，成功定义为Thi7细胞上的高级（> 90％）CCR5受体占用率 这些细胞没有耗尽的时期。如果成功，该项目将进步创新的治疗 在HIV感染和治疗期间，范式和阐明免疫动力学的基本方面。 相关性（请参阅说明）： 抗逆转录病毒疗法已大大改善了许多HIV感染者的生活。但是，那里 仍然需要采取新的治疗策略来解决耐药性，长期毒性和其他 挑战。该项目旨在获得创新的CCR5抗体的概念证明 长效，自我管理的艾滋病毒药物。成功将代表介绍的重大进步 长期艾滋病毒疗法作为对当前每日终身遵守范式的补充 治疗。