HIV Entry Inhibitor Therapy with the CCR5 mAb PRO 140

迫切需要针对病毒复制周期的不同阶段的新的艾滋病毒-1疗法，以抗击日益普遍的多药耐药病毒，并减少治疗毒性。趋化因子受体CCR5通过与HIV-1的主要受体CD4共同作用，作为HIV-1进入的关键门户。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与小分子的明显区别在于它缺乏CCR5拮抗作用、病毒耐药模式不重叠、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。项目2建议首次在艾滋病毒感染者中使用PRO 140。我们的临床研究还代表了首次使用CCR5单抗，首次使用不阻断CCR5自然活性的CCR5抑制剂，以及首次使用潜在的长效CCR5抑制剂治疗HFV-1感染。我们的研究旨在通过两个随机临床试验建立PRO 140在单剂量和多剂量环境下的初步概念验证，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患者中单次静脉注射PRO 140的剂量不断增加。第二个(2a阶段)试验将检查每月输注PRO 140与现有抗逆转录病毒药物联合使用16周的情况。这项临床研究与项目1和项目3的实验室研究紧密结合，合作项目共同寻求确定有效的CCR5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的临床概念验证，作为HIV-1感染的一种新的、长效和无毒的治疗策略。更广泛地说，这些整合的临床前/临床研究将为如何最好地部署CCR5抑制剂以最大限度地造福患者提供新的分子水平的见解。

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.