Tropism, Susceptibility and Resistance Deteminants

趋向性、敏感性和耐药性决定因素

• 批准号: 6998065
• 负责人: CHRISTOS J PETROPOULOS
• 金额: $ 11.73万
• 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/6998065
• 关键词: HIV infections; antiAIDS agent; cooperative study; drug resistance; drug screening /evaluation; genetic strain; human tissue; monoclonal antibody; patient oriented research; 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. 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, 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, 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. In Project 3, we will utilize novel phenotypic and genotypic technologies to examine viral tropism, susceptibility and resistance to PRO 140. Initial studies will explore the natural variation in PRO 140 susceptibility using a broad panel of viruses selected from the 6000-member ViroLogic library with an emphasis on potential key controlling parameters. A primary focus of this Project is to monitor coreceptor usage and PRO 140 susceptibility in patients treated with PRO 140 in the clinical trials of Project 2. In this capacity, we will identify eligible study patients who present with pure R5 viruses, and we will monitor study participants for any change in coreceptor usage or PRO 140 susceptibility. We will examine whether any resistant variants represent outgrowth of pre-existing minor species or are the result of sequence evolution in response to therapy. The variants will be analyzed in vitro to determine their molecular mechanisms and genetic determinants of resistance, patterns of cross-resistance to HIV-1 entry and enzyme inhibitors, and intrinsic fusogenicity. Our laboratory research will be carried out in collaboration with Dr. Moore (Project 1), and we will address a complementary set of issues using distinct research methodologies. Project 3 is essential to the conduct of the first-in-HIV clinical studies of Project 2 and to the overall IPCP goal of optimally translating PRO 140 from an innovative treatment concept into a promising new investigational agent via an integrated series of preclinical and clinical proof-of-concept studies.

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。与正在发育中的小分子CCR5拮抗剂不同，Pro 140广泛，有效地抑制CCR5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可能会定义一个独特的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CCR5抑制剂和任何对任何目标均未批准进行HIV-1治疗的事实。在项目3中，我们将利用新型的表型和基因型技术来检查病毒性侵入性，对Pro 140的敏感性和抵抗力。最初的研究将探索Pro 140易感性的自然变化，使用从6000多名成员的病毒中选择的广泛病毒，并强调潜在的关键控制参数。该项目的主要重点是在项目2的临床试验中监测受PRO 140治疗的患者的肌肉受体使用和Pro 140的敏感性。以这种能力，我们将确定符合条件的研究患者，这些患者呈现出纯R5病毒，我们将监测研究参与者的colectoraptor用法或Pro 140敏感性的任何变化。我们将检查是否有任何抗性变体代表现有的次要物种的生长或 是响应治疗的序列进化的结果。这些变体将在体外进行分析，以确定其分子机制和耐药性的遗传决定因素，对HIV-1进入的交叉耐药性和酶抑制剂的模式以及内在的融合性。我们的实验室研究将与摩尔博士（项目1）合作进行，我们将使用不同的研究方法解决一系列互补的问题。项目3对于项目2的首次HIV临床研究以及IPCP的总体目标是将Pro 140从创新的治疗概念最佳地转化为有希望的新研究代理的总体IPCP目标至关重要的。