Murga Jose D, Franti Michael, Pevear Daniel C, Maddon Paul J, Olson William C
Progenics Pharmaceuticals, Inc, Tarrytown, NY 10591, USA.
Antimicrob Agents Chemother. 2006 Oct;50(10):3289-96. doi: 10.1128/AAC.00699-06.
The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.
趋化因子受体CCR5为1型人类免疫缺陷病毒（HIV-1）进入易感CD4(+)细胞提供了一个入口。单克隆抗体（MAb）和小分子CCR5抑制剂均已进入人体临床试验，但对于它们之间潜在的相互作用却知之甚少。我们在体外评估了CCR5单克隆抗体、小分子CCR5拮抗剂以及HIV-1 gp120、gp41和逆转录酶抑制剂之间的相互作用。使用联合指数（CI）方法和严格的统计标准对抑制数据进行协同效应分析。在CCR5单克隆抗体PRO 140与小分子CCR5拮抗剂马拉维若（UK-427,857）、维立瑞若（SCH-D）和TAK-779之间观察到了强效且具有统计学意义的抗病毒协同作用。在各种检测系统、HIV-1包膜、CCR5靶细胞以及抑制水平中均一致观察到了高水平的协同作用。CI值范围为0.18至0.64，相当于体外剂量降低高达14倍。竞争性结合研究揭示了单克隆抗体和小分子CCR5抑制剂对CCR5的结合存在非互易模式，这表明协同作用发生在受体结合水平。此外，PRO 140和马拉维若均与趋化因子RANTES（CCR5的天然配体）产生协同作用；然而，小分子CCR5拮抗剂和PRO 140与其他类别的HIV-1抑制剂联合使用时均表现为相加效应。这些发现为在HIV-1治疗的新型双CCR5治疗方案中对单克隆抗体和小分子CCR5抑制剂进行临床探索提供了理论依据。
