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的 HIV-1 疗法，以对抗日益流行的多重耐药病毒并减少治疗毒性。我们证明趋化因子受体 CCR5 通过与 HIV-1 的主要受体 CD4 结合作为融合辅助受体，成为 HIV-1 进入的关键门户。 CCR5 在病毒传播和发病机制中发挥着核心作用，因此代表了新的 HIV-1 疗法的一个有吸引力的靶点。 PRO 140 是一种独特的人源化 CCR5 单克隆抗体 (mAb)，提供新颖的治疗方案。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 进入而不阻断或以其他方式失调 CCR5 的自然活动。此外，PRO 140 在健康志愿者中正在进行的 1a 期临床试验中表现出良好的耐受性和药代动力学特征。 PRO 140 与小分子的明显区别在于它缺乏 CCR5 拮抗作用、不重叠的病毒耐药模式、抗病毒协同作用、出色的耐受性以及不频繁（例如每月）给药的潜力。因此，PRO 140 可能定义一个独特的 CCR5 抑制剂子类，我们将在项目 1 中探讨这个问题。以下事实进一步强调了这种治疗方法的高度创新性： 目前还没有 CCR5 抑制剂和针对任何靶点的单克隆抗体被批准用于 HIV-1 治疗。项目 1 的主要目标是确定 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，解决强制耐药、交叉耐药和潜在协同效应的问题。初步研究将比较 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联系起来。我们将比较 HIV-1 对 PRO 140 和小分子的耐药性的演变，并确定耐药程度 交叉耐药性。我们还将研究 PRO 140 是否可以有效地与小分子和具有其他作用机制的 HIV-1 抑制剂组合，并且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研究结果与项目 2 中使用 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 相结合的体外和离体研究临床试验。这将使我们能够直接测试我们关于影响人类 CCR5 治疗结果的潜在病毒和宿主因素的假设。我们的研究结果将通过项目 3 中使用补充技术进行的趋向性、敏感性和其他分析得到增强。总体而言，项目 1 将提供对 CCR5 抑制剂功能的基本见解，并将为以某种方式部署 PRO 140 和小分子 CCR5 拮抗剂奠定基础为 HIV-1 感染者提供最大的治疗益处。