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

• 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
• 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

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的不同步骤开发新的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。趋化因子受体CCR5通过与CD4 （HIV-1的主要受体）结合作为融合共受体，作为HIV-1进入的关键门户。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ccrs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。项目2建议在艾滋病毒感染者中首次使用PRO 140。我们的临床研究也是首次使用CCR5单抗，首次使用不阻断CCR5天然活性的CCR5抑制剂，以及首次在HFV-1感染中使用潜在长效CCR5抑制剂。我们的研究旨在通过两项随机临床试验建立PRO 140在单剂量和多剂量环境下的初步概念验证