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不同阶段的新的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CCR 5通过与HIV-1的主要受体CD 4结合作为融合辅助受体而充当HIV-1进入的关键门户。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。项目2建议在艾滋病毒感染者中首次使用PRO 140。我们的临床研究还代表了CCR 5 mAb的首次使用，不阻断CCR 5天然活性的CCR 5抑制剂的首次使用，以及HFV-1感染中潜在长效CCR 5抑制剂的首次使用。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中的初步概念验证，这些研究 将为CCR 5抑制剂治疗对免疫参数的影响提供新的见解。第一项（1b期）研究将在早期疾病受试者中探索PRO 140单次静脉给药递增。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联合给药16周。这项临床研究与项目1和3的实验室研究紧密结合，共同合作的项目旨在确定有效的CCR 5靶向治疗的关键病毒和宿主决定因素。项目2的成功将建立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。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CCR 5抑制剂以获得最大的患者获益提供新的分子水平的见解。