新型全人源IgG4抗CCR5单克隆抗体HGS004在HIV-1感染患者中的安全性、药代动力学及抗病毒活性

Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients.

作者信息

Lalezari Jacob, Yadavalli Gopal K, Para Michael, Richmond Gary, Dejesus Edwin, Brown Stephen J, Cai Wendy, Chen Cecil, Zhong John, Novello Lu Anne, Lederman Michael M, Subramanian G Mani

机构信息

Quest Clinical Research, San Francisco, CA 94115, USA.

出版信息

J Infect Dis. 2008 Mar 1;197(5):721-7. doi: 10.1086/527327.

DOI:10.1086/527327

PMID:18266604

Abstract

BACKGROUND

HGS004 is a fully human immunoglobulin (Ig) G4 monoclonal antibody against CC chemokine receptor 5 (CCR5) with robust in vitro activity against a diverse panel of CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates.

METHODS

A single-blind, randomized, placebo-controlled study was conducted in patients infected with CCR5-tropic HIV-1 to evaluate the safety, pharmacokinetics, and antiviral activity of HGS004. Sixty-three subjects were randomized into 5 dose cohorts (0.4, 2, 8, 20, and 40 mg/kg) and received a single intravenous dose of HGS004 or placebo.

RESULTS

HGS004 was well tolerated, and no dose-limiting toxicities were observed. Pharmacokinetics were nonlinear across the 0.4-40-mg/kg dose range, with dose-proportional increases in maximum concentration, although the area under the curve increased more than proportionally to dose. High levels of receptor occupancy were observed for up to 28 days in the higher-dose cohorts. Plasma HIV-1 RNA reductions of >1 log(10) at day 14 were observed in 14 (54%) of 26 subjects in the 8-, 20-, and 40-mg/kg cohorts. In the 40-mg/kg cohort, 4 of 10 subjects had a >1 log(10) HIV-1 RNA reduction at day 28. Drug concentrations relative to isolate sensitivity (the ratio of the concentration at day 14 to IC(90)) predicted antiviral response on day 14.

CONCLUSIONS

HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.

摘要

背景

HGS004是一种全人源免疫球蛋白（Ig）G4单克隆抗体，可靶向C-C趋化因子受体5（CCR5），对多种CCR5嗜性的1型人类免疫缺陷病毒（HIV-1）分离株具有强大的体外活性。

方法

开展了一项单盲、随机、安慰剂对照研究，纳入CCR5嗜性HIV-1感染患者，以评估HGS004的安全性、药代动力学和抗病毒活性。63名受试者被随机分为5个剂量组（0.4、2、8、20和40mg/kg），接受单次静脉注射HGS004或安慰剂。

结果

HGS004耐受性良好，未观察到剂量限制性毒性。在0.4-40mg/kg剂量范围内，药代动力学呈非线性，最大浓度随剂量成比例增加，尽管曲线下面积的增加与剂量不成比例。在高剂量组中，观察到高达28天的高受体占有率。在8、20和40mg/kg剂量组的26名受试者中，14名（54%）在第14天血浆HIV-1 RNA降低>1 log₁₀。在40mg/kg剂量组中，10名受试者中有4名在第28天HIV-1 RNA降低>1 log₁₀。相对于分离株敏感性的药物浓度（第14天的浓度与IC₉₀的比值）可预测第14天的抗病毒反应。