A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.
A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.
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BMS-936558的随机，双盲，安慰剂对照的评估，一种完全人类的单克隆抗体，对慢性丙型肝炎病毒感染的患者，对程序性死亡-1（PD-1）。
DOI：
10.1371/journal.pone.0063818
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lowy I
中科院分区：
文献类型：
--
作者：
Gardiner D;Lalezari J;Lawitz E;DiMicco M;Ghalib R;Reddy KR;Chang KM;Sulkowski M;Marro SO;Anderson J;He B;Kansra V;McPhee F;Wind-Rotolo M;Grasela D;Selby M;Korman AJ;Lowy I
程序性死亡1（PD-1）受体及其配体的表达与T细胞耗竭表型有关，T细胞耗竭表型导致几种慢性病毒感染（包括人丙型肝炎病毒（HCV））持续存在。在慢性HCV感染患者（N = 54）中进行的一项概念验证、安慰剂对照单次给药剂量递增研究中，探索了BMS-936558（MDX-1106）（一种阻断配体结合的全人源抗PD-1单克隆免疫球蛋白-G4）的抗病毒潜力。 干扰素-α治疗经历的患者（n = 42）以5：1的比例随机接受BMS-936558（0.03、0.1、0.3、1.0、3.0 mg/kg [n = 5]或10 mg/kg [n = 10]）或安慰剂（n = 7）单次输注。 另外12例HCV初治患者随机接受10 mg/kg BMS-936558（n = 10）或安慰剂（n = 2）。 患者在给药后随访85天。接受BMS-936558（0.1 [n = 1]或10 mg/kg）的5例患者和1例安慰剂患者在至少2次连续访视中达到了HCV RNA降低≥ 0.5 log10 IU/mL的主要研究终点; 3例（10 mg/kg）达到了> 4 log10降低。 2例患者（10 mg/kg）的HCV RNA低于定量下限（25 IU/mL），其中1例患者（既往无效应答者）在研究后1年仍无法检测到RNA。在第2天观察到CD4+、CD8+和CD19+细胞（包括初始和记忆性CD4+和CD8+亚群）一过性减少，无免疫缺陷证据。未观察到免疫球蛋白亚群的临床相关变化或循环细胞因子的治疗相关趋势。BMS-936558表现出剂量相关的暴露量增加，半衰期为20 - 24天。BMS-936558大部分耐受性良好。1例患者（10 mg/kg）发生无症状4级ALT升高，与4-log病毒载量降低同时发生。6例患者表现出轻度至中度强度的免疫相关不良事件，包括2例与自身免疫性甲状腺炎一致的甲状腺功能亢进症。需要进一步研究慢性病毒性疾病中的PD-1通路阻断。ClinicalTrials.gov
Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) – a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding – was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4+, CD8+ and CD19+ cells, including both naïve and memory CD4+ and CD8+ subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20–24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted. ClinicalTrials.gov NCT00703469 NCT00703469
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影响因子：
4.4
作者：
Burke KP;Cox AL
通讯作者：
Cox AL
DOI：
10.1086/655653
发表时间：
2010-10-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Boutwell CL;Rolland MM;Herbeck JT;Mullins JI;Allen TM
通讯作者：
Allen TM
DOI：
10.4049/jimmunol.1102885
发表时间：
2012-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Good-Jacobson KL;Song E;Anderson S;Sharpe AH;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1084/jem.20090847
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Francisco LM;Salinas VH;Brown KE;Vanguri VK;Freeman GJ;Kuchroo VK;Sharpe AH
通讯作者：
Sharpe AH