HIV-1 Therapy with CCR5 mAB PRO 140-Overview

使用 CCR5 mAB PRO 140 治疗 HIV-1 - 概述

• 批准号: 7874949
• 负责人: WILLIAM C OLSON
• 金额: $ 58.07万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-18 至 2011-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874949
• 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.

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HIV-1疗法，以对抗日益流行的多药耐药病毒并降低治疗毒性。我们证明了趋化因子受体CCR 5作为HIV-1进入的关键门户，与HIV-1的主要受体CD 4一起作为融合辅助受体。CCR 5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疗法的有吸引力的靶点。PRO 140是一种独特的人源化CCR 5单克隆抗体（mAb），提供了一种新的治疗特征。与正在开发的小分子CCR 5拮抗剂不同，PRO 140广泛有效地抑制CCR 5介导的HIV-1进入，而不会阻断或以其他方式失调CCR 5的天然活性。此外，PRO 140在健康志愿者中正在进行的Ia期临床试验中显示出良好的耐受性和药代动力学特征。PRO 140在缺乏CCR 5拮抗作用、病毒耐药性的非重叠模式、抗病毒协同作用、优异的耐受性特征和罕见（例如，每月）给药。因此，PRO 140可以定义独特的CCR 5抑制剂亚类。这种治疗方法的高度创新性进一步强调了没有CCR 5抑制剂和针对任何靶点的mAb被批准用于HIV-1治疗的事实。该IPCP的总体目标是通过一系列综合的临床前和临床研究，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的研究药物。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包括病毒、宿主和组合对PRO 140体外和体内活性和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）以及使用尖端技术对病毒嗜性和易感性的综合分析（项目3）。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（Olson，Maddon，摩尔和Petropoulos博士）和HIV-1治疗（Jacobson，Gulick和Hammer博士）领域的杰出研究人员。该IPCP的成功将确立PRO 140作为HIV-1感染的新型、长效、无毒治疗策略的临床概念验证，并将确定有效CCR 5靶向治疗的关键病毒和宿主决定因素。