HIV-1 Therapy with CCR5 mAB PRO 140-Overview

使用 CCR5 mAB PRO 140 治疗 HIV-1 - 概述

• 批准号: 7119534
• 负责人: WILLIAM C OLSON
• 金额: $ 302.85万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119534
• 关键词: antiAIDS agent; chemokine receptor; clinical research; cooperative study; monoclonal antibody

DESCRIPTION (provided by applicant): 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. 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 overall goal of this IPCP is to optimally translate PRO 140 from a novel treatment concept into a promising new investigational agent via an integrated series of preclinical and clinical studies. The IPCP comprises three interrelated Projects supported by two administrative and technical Cores to develop, evaluate, and optimize PRO 140. The IPCP encompasses in vitro and ex vivo studies of the viral, host and combinatorial influences on PRO 140 activity and resistance in vitro and in vivo (Project 1), first-in-HIV clinical trials (Project 2), and integrated analyses of viral tropism and susceptibility using cutting-edge technology (Project 3). The Cores provide overall project management as well as scientific, medical, regulatory, manufacturing, quality, bioanalytical, and biometrics support. The IPCP includes distinguished investigators in the fields of viral entry (Drs. Olson, Maddon, Moore, and Petropoulos) and HIV-1 therapy (Drs. Jacobson, Gulick, and Hammer). Success in this IPCP would establish clinical proof-of-concept for PRO 140 as a novel, long acting, and non-toxic treatment strategy for HIV-1 infection and would identify the critical viral and host determinants of effective CCR5- targeted therapy.

描述（由申请人提供）：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药耐药病毒并减少治疗毒性。我们证明趋化因子受体CCR5作为HIV-1进入的关键门户，与CD4 （HIV-1的主要受体）结合作为融合共受体。CCR5在病毒传播和发病机制中起着核心作用，因此代表了新的HIV-1治疗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），提供了一种新的治疗方案。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，而不会阻断或以其他方式失调CCR5的自然活性。此外，在一项正在进行的健康志愿者临床试验中，PRO 140显示出良好的耐受性和药代动力学特征。PRO 140在缺乏CCR5拮抗剂、病毒耐药无重叠模式、抗病毒协同作用、出色的耐受性以及不频繁（例如每月）给药方面明显区别于小分子。因此，pro140可以定义一个独特的CCR5抑制剂亚类。没有CCR5抑制剂和针对任何靶点的单抗被批准用于HIV-1治疗，这一事实进一步强调了这种治疗方法的高度创新性。该IPCP的总体目标是通过一系列临床前和临床研究，将PRO 140从一种新的治疗概念最佳地转化为一种有前途的新研究药物。IPCP包括三个相互关联的项目，由两个行政和技术核心支持，以开发、评估和优化PRO 140。IPCP包括体外和离体研究，研究病毒、宿主和组合对PRO 140活性和体内和体外耐药性的影响（项目1），首次hiv临床试验（项目2），以及利用尖端技术对病毒的趋向性和易感性进行综合分析（项目3）。这些核心提供全面的项目管理以及科学、医疗、监管、制造、质量、生物分析和生物识别支持。IPCP包括病毒进入领域的杰出研究人员(dr。Olson, Maddon， Moore和Petropoulos)和HIV-1治疗(dr。Jacobson, Gulick, and Hammer)。该IPCP的成功将为PRO 140作为一种新型、长效、无毒的HIV-1感染治疗策略建立临床概念证明，并将确定有效的CCR5靶向治疗的关键病毒和宿主决定因素。