Viral Host And Combinational Influences on PRO 140

PRO 140 上的病毒宿主和组合影响

• 批准号: 6998057
• 负责人: JOHN P MOORE
• 金额: $ 13.56万
• 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/6998057
• 关键词: HIV infections; antiAIDS agent; antireceptor antibody; antiviral agents; cell line; chemokine receptor; clinical research; cooperative study; cross immunity; drug resistance; drug screening /evaluation; genetic strain; human immunodeficiency virus 1; human tissue; immunologic substance development /preparation; monoclonal antibody; tissue /cell culture; virus genetics; virus infection mechanism; virus receptors

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. We demonstrated that 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 CCR5-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, non-overlapping 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, an issue that we will explore in Project 1. 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. The primary objective of Project 1 is to identify viral and host determinants of the antiviral activity of PRO 140 and small-molecule CCR5 antagonists, addressing issues of forced resistance, cross-resistance, and potential synergistic effects. Initial studies will compare PRO 140 and small molecules for their potency and breadth of antiviral activity in vitro. We will endeavor to correlate variations in potency with relevant viral and host factors. We will compare the evolution of HIV-1 resistance to PRO 140 and small molecules and determine the degree of cross-resistance. We will also examine whether PRO 140 can be usefully combined with small molecules and with HIV-1 inhibitors that have other mechanisms of action, and we will explore the molecular basis for any synergies observed. An important aspect of Project 1 is to correlate our in vitro findings with the clinical responses observed in the same patients treated with PRO 140 in Project 2. We will therefore perform a series of in vitro and ex vivo studies that are integrated with the PRO 140 clinical trials. This will enable us to directly test our hypotheses about the potential viral and host factors that influence the outcome of CCR5 therapy in humans. Our findings will be augmented by tropism, susceptibility and other analyses performed using complementary technologies in Project 3. Overall, Project 1 will provide basic insights into CCR5 inhibitor function and will lay the groundwork for deploying PRO 140 and small-molecule CCR5 antagonists in a manner that provides maximum therapeutic benefit to HIV-1 infected individuals.

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。我们证明，趋化因子受体CCR5通过与HIV-1的主要受体CD4结合起到融合融合的融合感受体来作为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广泛而有效地抑制CCR5介导的HIV-1 进入不阻止或以其他方式调节CCR5的自然活动。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，病毒抗性的非重叠模式，抗病毒协同作用，出色的耐受性和潜在的（例如每月一次）剂量的潜力方面，Pro 140显然与小分子区分开。因此，Pro 140可以定义一个独特的CCR5抑制剂子类，这是我们将在项目1中探讨的问题。这种治疗方法的高度创新性质进一步强调了以下事实。 没有CCR5抑制剂，并且没有对任何靶标的MAB进行HIV-1治疗。项目1的主要目的是识别Pro 140抗病毒活性的病毒和宿主决定因素 和小分子CCR5拮抗剂，解决了强迫抗性，越野抗性和潜在协同作用的问题。最初的研究将比较Pro 140和小分子的体外抗病毒活性的效力和广度。我们将努力将效力的变化与相关病毒和宿主因素相关联。我们将比较HIV-1抗性对Pro 140和小分子的演变，并确定程度 越野抗性。我们还将检查Pro 140是否可以与小分子和具有其他作用机理的HIV-1抑制剂结合在一起，我们将探索观察到的任何协同作用的分子基础。项目1的一个重要方面是将我们的体外发现与在项目2中用Pro 140治疗的同一患者中观察到的临床反应相关联。因此，我们将进行一系列与Pro 140临床试验集成的体外和实体研究。这将使我们能够直接检验有关影响人类CCR5治疗结果的潜在病毒和宿主因素的假设。我们的发现将通过项目3中使用补充技术进行的向流主义，易感性和其他分析来增强。总体而言，项目1将对CCR5抑制剂功能提供基本见解，并将为部署Pro 140和小分子CCR5拮抗剂提供最大程度的治疗益处，从而为HIV-1提供最大的治疗益处。