Olson William C, Jacobson Jeffrey M
Progenics Pharmaceuticals Inc, Tarrytown, NY 10591, USA.
Curr Opin HIV AIDS. 2009 Mar;4(2):104-11. doi: 10.1097/COH.0b013e3283224015.
To summarize emerging clinical and preclinical data pertaining to the use of CCR5 monoclonal antibodies (mAbs) as therapies for HIV-1 infection. The epitope specificity of CCR5 mAbs is discussed in relation to its critical impact on antiviral activity and CCR5 antagonism. We compare and contrast mAbs and small-molecule CCR5 antagonists in terms of their binding and antiviral properties. Two CCR5 mAbs have entered clinical testing and have successfully completed proof-of-concept studies in HIV-infected individuals, providing initial information on the potential therapeutic utility of these agents.
New studies support the view that the most potent antiviral CCR5 mAbs recognize the second extracellular loop of CCR5 either exclusively or in combination with the amino terminus. Studies have revealed fundamental differences in how mAbs and small molecules bind CCR5 and inhibit HIV-1. CCR5 mAbs and small-molecule CCR5 antagonists have demonstrated consistent antiviral synergy and limited or no viral cross-resistance in independent studies. Single intravenous infusions of CCR5 mAbs significantly reduced HIV-1 RNA levels in infected individuals for 2-3 weeks without appreciable toxicity.
CCR5 mAbs have demonstrated broad and potent antiviral activity in vitro. Clinical studies have established CCR5 mAbs as potent antiretroviral agents with prolonged activity following a single dose. CCR5 mAbs represent both a distinct class of CCR5 inhibitor and a novel approach to HIV-1 therapy.
总结与使用CCR5单克隆抗体（mAb）治疗HIV-1感染相关的新出现的临床和临床前数据。讨论CCR5 mAb的表位特异性及其对抗病毒活性和CCR5拮抗作用的关键影响。我们比较并对比了mAb与小分子CCR5拮抗剂在结合和抗病毒特性方面的差异。两种CCR5 mAb已进入临床试验，并在HIV感染个体中成功完成概念验证研究，提供了这些药物潜在治疗效用的初步信息。
新研究支持这样一种观点，即最有效的抗病毒CCR5 mAb仅识别CCR5的第二个细胞外环，或与氨基末端结合识别。研究揭示了mAb和小分子结合CCR5并抑制HIV-1方式的根本差异。在独立研究中，CCR5 mAb和小分子CCR5拮抗剂已证明具有一致的抗病毒协同作用，且病毒交叉耐药性有限或不存在。单次静脉输注CCR5 mAb可使感染个体的HIV-1 RNA水平在2至3周内显著降低，且无明显毒性。
CCR5 mAb在体外已证明具有广泛而有效的抗病毒活性。临床研究已证实CCR5 mAb是强效抗逆转录病毒药物，单次给药后活性持久。CCR5 mAb既是一类独特的CCR5抑制剂，也是一种治疗HIV-1的新方法。
