HIV Entry Inhibitor Therapy with the CCR5 mAb PRO 140

使用 CCR5 mAb PRO 140 进行 HIV 进入抑制剂治疗

• 批准号: 6998059
• 负责人: JEFFREY M. JACOBSON
• 金额: $ 31.15万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998059
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; chemokine receptor; clinical trial phase I; clinical trial phase II; combination chemotherapy; cooperative study; dosage; human subject; human therapy evaluation; immunotherapy; monoclonal antibody; patient oriented research; virus infection mechanism

There is an urgent need for new HIV-1 therapies targeting different steps of the viral replicative cycle to combat the growing prevalence of multidrug-resistant viruses and to reduce treatment toxicities. The chemokine receptor CCR5 serves as a critical portal of HIV-1 entry by acting as a fusion coreceptor in conjunction with CD4, the primary receptor for HIV-1. CCR5 plays a central role in virus transmission and pathogenesis, and therefore represents an attractive target for new HIV-1 therapies. PRO 140 is a unique humanized CCR5 monoclonal antibody (mAb) that offers a novel therapeutic profile. Unlike small-molecule CCR5 antagonists under development, PRO 140 broadly and potently inhibits CCRS-mediated HIV-1 entry without blocking or otherwise dysregulating the natural activities of CCR5. In addition, PRO 140 has demonstrated favorable tolerability and pharmacokinetic profiles in an ongoing Phase la clinical trial in healthy volunteers. PRO 140 is clearly differentiated from small molecules in terms of its lack of CCR5 antagonism, nonoverlapping patterns of viral resistance, antiviral synergy, excellent tolerability profile, and potential for infrequent (e.g., monthly) dosing. PRO 140 may therefore define a unique CCR5 inhibitor subclass. The highly innovative nature of this therapeutic approach is further underscored by the fact that no CCR5 inhibitor and no mAb to any target have been approved for HIV-1 therapy. Project 2 proposes the first use of PRO 140 in HIV-infected individuals. Our clinical research also represents the first use of a CCR5 mAb, the first use of a CCR5 inhibitor that doesn't block the natural activity of CCR5 and the first use of a potentially long-acting CCR5 inhibitor in HFV-1 infection. Our studies are designed to establish initial proof-of-concept for PRO 140 in single- and multi-dose settings via two randomized clinical trials, and these studies will provide new insights into the effects of CCR5 inhibitor therapy on immune parameters. The first (Phase 1b) study will explore escalating single intravenous doses of PRO 140 in subjects with early-stage disease. The second (Phase 2a) trial will examine monthly infusions of PRO 140 administered for 16 weeks in combination with existing antiretrovirals. This clinical research is closely integrated with the laboratory studies of Projects 1 and 3, and collectively the collaborative Projects seek to identify critical viral and host determinants of effective CCR5-targeted therapy. Success in Project 2 would establish clinical proof-of-concept for PRO 140 as a novel, long-acting, and non-toxic treatment strategy for HIV-1 infection. More broadly, these integrated preclinical/clinical studies will provide new molecular-level insight into how to best deploy CCR5 inhibitors for maximum patient benefit.

迫切需要针对病毒复制周期不同步骤的新型HIV-1疗法，以应对多药耐药病毒的日益普遍性并降低治疗毒性。趋化因子受体CCR5通过与CD4（HIV-1的主要受体CD4）结合起到HIV-1进入的关键门户。 CCR5在病毒传播和发病机理中起着核心作用，因此代表了新型HIV-1疗法的有吸引力的靶标。 Pro 140是一种独特的人源化CCR5单克隆抗体（MAB），可提供新颖的治疗特征。与正在开发的小分子CCR5拮抗剂不同，Pro 140广泛，有效地抑制CCRS介导的HIV-1进入，而不会阻止或以其他方式调节CCR5的自然活性。此外，在健康志愿者中，Pro 140在正在进行的LA临床试验中证明了有利的耐受性和药代动力学特征。在缺乏CCR5拮抗作用，病毒抗性，抗病毒协同作用，出色的耐受性和潜力（例如每月一次）剂量的潜力方面，Pro 140与小分子显然与小分子区分开。因此，Pro 140可以定义独特的CCR5抑制剂亚类。这种治疗方法的高度创新性质进一步强调了CCR5抑制剂和任何目标均未批准用于HIV-1治疗的事实。项目2提议在感染HIV感染的个体中首次使用Pro 140。我们的临床研究还代表了CCR5 MAB的首次使用，CCR5 mAB是CCR5抑制剂的首次使用，该抑制剂不会阻止CCR5的自然活性，也是首次使用潜在的长效CCR5抑制剂在HFV-1感染中。我们的研究旨在通过两项随机临床试验在单剂量和多剂量设置中为Pro 140建立初始概念验证，这些研究 将为CCR5抑制剂治疗对免疫参数的影响提供新的见解。第一项（第1B期）研究将探索早期疾病受试者中的单次静脉注射剂量140。第二次（第2A期）试验将检查16周施用的Pro 140的每月输注，并结合现有的抗逆转录病毒。这项临床研究与项目1和3的实验室研究密切相结合，共同项目旨在识别有效的CCR5靶向疗法的关键病毒和宿主决定因素。项目2中的成功将建立Pro 140的临床概念证明，作为一种新型，长效和无毒治疗策略，用于HIV-1感染。更广泛地说，这些综合的临床前/临床研究将为如何最佳部署CCR5抑制剂提供新的分子水平洞察力，以获得最大的患者益处。