HIV-1 Therapy with CCR5 mAB PRO 140-Overview

描述(申请人提供)：迫切需要针对病毒复制周期的不同步骤的新的艾滋病毒-1疗法，以抗击日益普遍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通过与HIV-1的主要受体CD4一起作为融合辅助受体，发挥着HIV-1进入的关键门户的作用。CCR5在病毒传播和发病机制中发挥核心作用，因此是HIV-1新疗法的一个有吸引力的靶点。PRO 140是一种独特的人源化CCR5单抗(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的自然活动。此外，PRO 140在健康志愿者身上进行的1a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明显区别于小分子，因为它缺乏CCR5拮抗作用、病毒耐药性的非重叠模式、抗病毒协同作用、出色的耐受性以及可能不频繁(例如，每月)给药。因此，PRO 140可以定义唯一的CCR5抑制器子类。没有CCR5抑制剂和针对任何靶点的mAb被批准用于艾滋病毒-1治疗，这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集成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景的新研究试剂。IPCP由三个相互关联的项目组成，由两个行政和技术核心提供支持，以开发、评估和优化PRO 140。IPCP包括体外和体外研究，包括病毒、宿主和组合对体内和体外PRO 140活性和耐药性的影响(项目1)，首例艾滋病毒临床试验(项目2)，以及利用尖端技术对病毒嗜性和易感性的综合分析(项目3)。这些核心提供整体项目管理以及科学、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、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。这项IPCP的成功将为PRO 140作为HIV-1感染的一种新的、长效和无毒的治疗策略建立临床概念验证，并将确定有效的CCR5靶向治疗的关键病毒和宿主决定因素。

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.