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.

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。在 此外，ART需要终身每日坚持，由于次优治疗，治疗失败是常见的。 粘附、耐药性或毒性。弥合这些治疗差距的一种方法是通过 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），已证明其具有强效、长效、 在最初的临床试验中，抗逆转录病毒活性和令人鼓舞的安全性。PRO 140具有 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。不像小- 分子CCR 5拮抗剂，PRO 140通过直接而不是变构抑制CCR 5-嗜性（R5）HIV 保持CCRS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拮抗剂有抗性的那些。总的来说，PRO 140代表了一个独特的类别 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 药这项研究是一项随机、双盲、安慰剂对照试验，旨在探索抗病毒药物 PRO 140作为HIV感染者短期单药治疗的活性、安全性、PK和免疫学效应 早期感染的人。受试者（n=40）将使用 简单按钮装置。我们的主要假设是艾滋病毒的复制可以被有效地抑制 通过不频繁地自我使用一种长效艾滋病毒药物。此外，该研究提供了一个理想的环境， 探索治疗对Th 17和CCRS + T细胞的其他相关亚群的影响，这些亚群对于 正常的宿主防御能力被艾滋病毒严重耗尽，并且通过现有的抗逆转录病毒疗法得到了次优的恢复。这 这项研究将是第一个检查任何艾滋病毒药物治疗对Thi 7细胞数量的影响的研究 功能和CCR 5占用。 成功需要治疗显示出有效和长期的抗病毒作用（平均值为1.5 log 10 减少HIV RNA）、最小的注射部位反应和易用性。在我们的免疫分析中， 成功定义为在整个治疗过程中Thi 7细胞上的高水平（>90%）CCR 5受体占有率 这些细胞没有耗尽。如果成功，该项目将推进一种创新的治疗方法， 范例和阐明在HIV感染和治疗免疫动力学的基本方面。 相关性（参见说明）： 抗逆转录病毒疗法极大地改善了许多艾滋病毒感染者的生活;然而， 仍然需要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CCR 5抗体的概念证明，该抗体用作第一个 长效的自我管理的艾滋病毒药物。如果成功， 长效艾滋病毒疗法作为补充，以目前的范式，每天坚持 治疗