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) 代表了当代罕见的医学成功。 然而，ART 并不能根除 HIV、预防长期发病或完全恢复免疫功能。在 此外，ART 需要终生每日坚持，治疗失败很常见，因为效果不佳 依从性、耐药性或毒性。弥补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范例的补充。 PRO 140 是一种人源化抗 CCR5 单克隆抗体 (mAb)，已被证明是有效的、长效的。 在初步临床测试中具有抗逆转录病毒活性和令人鼓舞的安全性。 PRO 140 具有 有潜力成为第一个长效（每周或每隔一周）自行给药的艾滋病毒药物。与小不同的是—— 分子 CCR5 拮抗剂，PRO 140 通过直接而非变构抑制 CCR5 亲性 (R5) HIV 机制并保留 CCRS 的自然活性。 PRO 140 还广泛抑制耐药 R5 病毒， 包括那些对小分子 CCR5 拮抗剂耐药的药物。总体而言，PRO 140 代表了一个独特的类别 具有独特病毒学和免疫学特性的 CCR5 抑制剂。 该项目旨在获得长效、自我管理的艾滋病毒的第一个临床原理证明 药品。拟议的研究是一项随机、双盲、安慰剂对照试验，旨在探索抗病毒药物 PRO 140 作为 HIV 感染者的短期单一疗法的活性、安全性、PK 和免疫学效果经过测试 早期感染者。受试者 (n=40) 将使用注射器自行皮下注射 PRO 140 简单的按钮装置。我们的主要假设是 HIV 复制可以被有效抑制 通过不经常自行使用长效艾滋病毒药物。此外，该研究还提供了一个理想的环境 探索治疗对 Thi7 和其他相关 CCRS”^ T 细胞亚群的影响，这些细胞对于 正常的宿主防御，被 HIV 严重削弱，并且通过现有的 ART 恢复效果不佳。这 这项研究将是第一个检查开始使用任何 HIV 药物治疗对 Thi7 细胞数量的影响的研究 功能和 CCR5 占用。 成功需要治疗表现出有效且持久的抗病毒作用（^1.5 logio 均值 HIV RNA 减少）、注射部位反应最小且易于使用。在我们的免疫学分析中， 成功定义为在整个治疗过程中 Thi7 细胞上 CCR5 受体的高水平 (>90%) 占据 没有耗尽这些细胞的时期。如果成功，该项目将推进创新治疗 范式并阐明艾滋病毒感染和治疗期间免疫动态的基本方面。 相关性（参见说明）： 抗逆转录病毒治疗极大地改善了许多艾滋病毒感染者的生活；然而，有 仍然需要新的治疗策略来解决耐药性、长期毒性和其他问题 挑战。该项目旨在获得用作第一个创新 CCR5 抗体的概念证明 长效、自行给药的艾滋病毒药物。成功将代表着在引进方面取得了重大进展 长效艾滋病毒疗法作为当前日常生活坚持模式的补充 治疗。