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

联合抗逆转录病毒疗法(ART)代表了医学上的成功，几乎没有当代可与之媲美的药物。 然而，抗逆转录病毒疗法不能根除艾滋病毒、预防长期疾病或完全恢复免疫功能。在……里面 此外，抗逆转录病毒治疗需要终生坚持，治疗失败的情况很常见，因为治疗效果不佳。 粘附性、耐药性或毒性。弥合这些治疗差距的一种方法是通过 开发新的长效疗法，作为对当前日常治疗范例的补充。 PRO 140是一种人源化的抗CCR5的单抗，已证明是有效的，长期的 活的抗逆转录病毒活性和在初步临床测试中令人鼓舞的安全性。Pro 140拥有 有可能成为第一个长效(每周或每隔一周)、自我给药的艾滋病毒药物。不像小的- 分子CCR5拮抗剂，PRO 140通过直接而不是变构抑制CCR5嗜性(R5)HIV 机制，并保留了CCRs的自然活性。PRO 140还广泛地抑制耐药的R5病毒， 包括对小分子CCR5拮抗剂耐药的那些。总体而言，PRO 140代表了一个不同的类别 具有独特病毒学和免疫学特性的CCR5抑制剂。 该项目寻求获得长效、自我给药的艾滋病毒的第一个临床原则证据。 毒品。这项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感染者短期单一疗法的活性、安全性、PK和免疫学效应 早期感染的个体。受试者(n=40)将自身皮下注射PRO 140。 简单的按钮装置。我们的主要假设是艾滋病毒的复制可以被有效地抑制 通过不频繁地自行使用一种长效艾滋病毒药物。此外，这项研究提供了一个理想的环境 探讨治疗对Thi7和其他相关的CCR“^T细胞亚群的影响 正常的宿主防御，被艾滋病毒严重耗尽，并通过现有的ART进行次优恢复。这 这项研究将首次检查任何HIV药物开始治疗对Thi7细胞数量的影响 功能和CCR5占有率。 成功要求治疗显示出有效和持久的抗病毒效果(^1.5卢吉奥意味着 减少HIV RNA)，最小的注射部位反应，以及使用的方便性。在我们的免疫分析中， 成功定义为在整个治疗过程中高水平(90%)CCR5受体在Thi7细胞上的占据 这些细胞不会耗尽的时期。如果成功，这个项目将推进一种创新的治疗方法 范例和阐明艾滋病毒感染和治疗过程中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。该项目寻求获得作为第一个使用的创新的CCR5抗体的概念证明 长效、自我给药的艾滋病毒药物。成功将代表着朝着引入的方向迈进了一大步 长效艾滋病毒疗法作为对目前日常生活中坚持的 治疗。

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.