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。此外，抗逆转录病毒治疗需要终生每日坚持，治疗失败的情况很常见，原因是依从性不佳、耐药性或毒性。弥合这些治疗差距的一种方法是开发新的长效疗法，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单抗(MAb)，在最初的临床试验中显示出强大的、长期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)、自我给药的艾滋病毒药物。与小分子CCR5拮抗剂不同，PRO140通过直接而不是变构机制抑制CCR5嗜性(R5)HIV，并保留CCR5的S天然活性。PRO 140还广泛地抑制耐药的R5病毒，包括那些对小分子CCR5拮抗剂具有耐药性的病毒。总体而言，PRO 140代表了一类独特的CCR5抑制剂，具有独特的病毒学和免疫学特性。 该项目寻求获得长效、自我给药的艾滋病毒药物的第一个临床原则证明。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PRO 140作为短期单一疗法在早期感染的艾滋病毒感染者中的抗病毒活性、安全性、PK和免疫学效果。受试者(n=40)将使用简单的按钮装置自我注射PRO 140。我们的主要假设是，通过不频繁地自我使用一种长效艾滋病毒药物，可以有效地抑制艾滋病毒的复制。此外，这项研究提供了一个理想的环境来探索治疗对Th17和其他相关的CCR5[+]T细胞亚群的影响，这些细胞对正常的宿主防御至关重要，被艾滋病毒严重耗尽，并通过现有的ART进行次优恢复。这项研究将首次检测任何HIV药物开始治疗对Th17细胞数量、功能和CCR5占有率的影响。 成功的治疗需要表现出强大和持久的抗病毒效果(&gt；/=1.5log{10}意味着艾滋病毒RNA的减少)、最小的注射部位反应和易用性。在我们的免疫学分析中，成功被定义为在整个治疗期间高水平(90%)CCR5受体在Th17细胞上占据而不耗尽这些细胞。如果成功，该项目将推进一种创新的治疗范例，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。

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.