HIV-1 Therapy with CCR5 mAB PRO 140-Overview

使用 CCR5 mAB PRO 140 治疗 HIV-1 - 概述

• 批准号: 7394493
• 负责人: WILLIAM C OLSON
• 金额: $ 298.79万
• 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 2011-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394493
• 关键词: HIV; Therapy; CCR5; mAB; PRO

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.

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.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 的自然活性。 In addition, PRO 140 has demonstrated favorable tolerability and pharmacokinetic profiles in an ongoing Phase la clinical trial in healthy volunteers. 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 可能定义了一个独特的 CCR5 抑制剂子类。目前还没有任何 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，这一事实进一步强调了这种治疗方法的高度创新性。 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. IPCP 包括由两个行政和技术核心支持的三个相互关联的项目，以开发、评估和优化 PRO 140。IPCP 包括病毒、宿主和组合对 PRO 140 活性和体外和体内耐药性影响的体外和离体研究（项目 1）、首次 HIV 临床试验（项目 2）以及使用 尖端技术（项目3）。 The Cores provide overall project management as well as scientific, medical, regulatory, manufacturing, quality, bioanalytical, and biometrics support. IPCP 包括病毒侵入领域（Olson、Maddon、Moore 和 Petropoulos 博士）和 HIV-1 治疗（Jacobson、Gulick 和 Hammer 博士）领域的杰出研究人员。 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.