Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117.
Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117.
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DOI：
10.1038/nature14411
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发表时间：
2015-06-25
期刊：
影响因子：
64.8
通讯作者：
Nussenzweig MC
中科院分区：
文献类型：
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作者：
Caskey M;Klein F;Lorenzi JC;Seaman MS;West AP Jr;Buckley N;Kremer G;Nogueira L;Braunschweig M;Scheid JF;Horwitz JA;Shimeliovich I;Ben-Avraham S;Witmer-Pack M;Platten M;Lehmann C;Burke LA;Hawthorne T;Gorelick RJ;Walker BD;Keler T;Gulick RM;Fätkenheuer G;Schlesinger SJ;Nussenzweig MC
结合第一代单克隆抗体的 HIV-1 免疫疗法在临床前和临床环境中基本上无效，因此被放弃。然而，最近开发的基于单细胞的抗体克隆方法已经发现了新一代更有效的 HIV-1 广泛中和抗体 (bNAb)。这些抗体可以在人源化小鼠 (hu-mice) 和非人灵长类动物中预防感染并抑制病毒血症，但它们用于人类 HIV-1 免疫治疗的潜力尚未得到评估。在这里，我们报告了 3BNC117（一种有效的人类 CD4 结合位点抗体）在未感染和 HIV-1 感染个体中进行的首次人体剂量递增 1 期临床试验的结果。 3BNC117 输注耐受性良好，并表现出良好的药代动力学。单次输注 30 mg/kg 3BNC117 可将 HIV-1 感染者的病毒载量 (VL) 降低 0.8 – 2.5 log10，且病毒血症在 28 天内仍显着降低。耐药病毒株的出现情况各不相同，有些个体对 3BNC117 保持敏感达 28 天。我们的结论是，作为单一药物，3BNC117 在减少 HIV-1 病毒血症方面是安全有效的，并且应该探索免疫疗法作为 HIV-1 预防、治疗和治愈的新方式。
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single cell based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies (bNAbs) to HIV-1. These antibodies can prevent infection and suppress viremia in humanized mice (hu-mice) and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favorable pharmacokinetics. A single 30 mg/kg infusion of 3BNC117 reduced the viral load (VL) in HIV-1-infected individuals by 0.8 – 2.5 log10 and viremia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that as a single agent 3BNC117 is safe and effective in reducing HIV-1 viremia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy, and cure.