HIV Entry Inhibitor Therapy with the CCR5 mAb PRO 140

使用 CCR5 mAb PRO 140 进行 HIV 进入抑制剂治疗

基本信息

批准号：
7575211
负责人：
JEFFREY M. JACOBSON
金额：
$ 40.24万
依托单位：
PROGENICS PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575211
关键词：
AIDS clinical trial group Academic Medical Centers Achievement Acquired Immunodeficiency Syndrome Adult Adverse effects Affinity Anti-Retroviral Agents Antiviral Agents Antiviral resistance Award Binding Biology CXCR4 gene Cells Chemokine (C-C Motif) Receptor 5 Chronic Clinical Clinical Research Clinical Trials Collaborations Development Disease Dose Double-Blind Method Drug Kinetics Family Foundations Goals HIV Entry Inhibitors HIV Receptors HIV therapy HIV-1 Human Immune Immunologics Individual Infection Infusion procedures Instruction Intravenous Israel Laboratories Laboratory Study Letters Logic Lymphocyte Marketing Mediating Medical Medical center Molecular Monitor Monoclonal Antibodies Multi-Drug Resistance NIH Program Announcements Nature Oral PRO 140 Pathogenesis Patient Care Patients Pattern Phase Phase III Clinical Trials Placebo Control Placebos Play Prevalence Proteins RNA Randomized Randomized Clinical Trials Research Research Design Role Staging Testing Therapeutic Toxic effect Translating Treatment Protocols Universities Viral Viral Load result Virus Week chemokine receptor clinically relevant clinically significant cohort college concept cost healthy volunteer humanized monoclonal antibodies inhibitor/antagonist innovation insight intravenous administration neutralizing antibody novel novel therapeutics pre-clinical preclinical study programs randomized placebo controlled trial receptor small molecule success therapy development transmission process treatment duration

项目摘要

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 CCRS-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. 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. Project 2 proposes the first use of PRO 140 in HIV-infected individuals. Our clinical research also represents the first use of a CCR5 mAb, the first use of a CCR5 inhibitor that doesn't block the natural activity of CCR5 and the first use of a potentially long-acting CCR5 inhibitor in HFV-1 infection. Our studies are designed to establish initial proof-of-concept for PRO 140 in single- and multi-dose settings via two randomized clinical trials, and these studies will provide new insights into the effects of CCR5 inhibitor therapy on immune parameters. The first (Phase 1b) study will explore escalating single intravenous doses of PRO 140 in subjects with early-stage disease. The second (Phase 2a) trial will examine monthly infusions of PRO 140 administered for 16 weeks in combination with existing antiretrovirals. This clinical research is closely integrated with the laboratory studies of Projects 1 and 3, and collectively the collaborative Projects seek to identify critical viral and host determinants of effective CCR5-targeted therapy. Success in Project 2 would establish clinical proof-of-concept for PRO 140 as a novel, long-acting, and non-toxic treatment strategy for HIV-1 infection. More broadly, these integrated preclinical/clinical studies will provide new molecular-level insight into how to best deploy CCR5 inhibitors for maximum patient benefit.

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重耐药病毒并减少治疗毒性。趋化因子受体 CCR5 与 HIV-1 的主要受体 CD4 一起充当融合辅助受体，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 CCRS 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。此外，PRO 140 在健康志愿者中正在进行的 1a 期临床试验中表现出良好的耐受性和药代动力学特征。 PRO 140 与小分子的明显区别在于它缺乏 CCR5 拮抗作用、病毒耐药性的非重叠模式、抗病毒协同作用、优异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。项目 2 提议首次在 HIV 感染者中使用 PRO 140。我们的临床研究还代表了 CCR5 mAb 的首次使用、不阻断 CCR5 天然活性的 CCR5 抑制剂的首次使用以及潜在长效 CCR5 抑制剂在 HFV-1 感染中的首次使用。我们的研究旨在通过两项随机临床试验在单剂量和多剂量设置中建立 PRO 140 的初步概念验证，这些研究将为 CCR5 抑制剂治疗对免疫参数的影响提供新的见解。第一项（1b 期）研究将探索在早期疾病受试者中逐步增加单次静脉注射 PRO 140 剂量。第二项（2a 期）试验将检查每月输注 PRO 140 与现有抗逆转录病毒药物的组合，持续 16 周。这项临床研究与项目 1 和 3 的实验室研究紧密结合，这些合作项目共同寻求确定有效 CCR5 靶向治疗的关键病毒和宿主决定因素。项目 2 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验证。更广泛地说，这些综合的临床前/临床研究将为如何最好地部署 CCR5 抑制剂以获得最大的患者利益提供新的分子水平见解。