Bristol-Myers Squibb, Pennington, New Jersey, USA.
PLoS One. 2013 May 22;8(5):e63818. doi: 10.1371/journal.pone.0063818. Print 2013.
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.
探究 BMS-936558（一种完全人源抗 PD-1 单克隆免疫球蛋白 G4，可阻断配体结合）在慢性丙型肝炎病毒（HCV）感染患者中的抗病毒潜力。
在这项概念验证、安慰剂对照、单次递增剂量研究中，招募了 54 名慢性 HCV 感染患者（N=54）。干扰素-α治疗经验丰富的患者（n=42）按照 5∶1 的比例随机接受 BMS-936558（0.03、0.1、0.3、1.0、3.0 mg/kg[每组各 5 例]或 10 mg/kg[10 例]）或安慰剂（n=7）单次输注。另外 12 名 HCV 初治患者按照 10 mg/kg BMS-936558（n=10）或安慰剂（n=2）的顺序随机分组。患者在给药后 85 天内接受随访。接受 BMS-936558（0.1[1 例]或 10 mg/kg）和 1 例安慰剂的 5 例患者达到了主要研究终点，即在至少 2 次连续访视时 HCV RNA 降低≥0.5 log10 IU/mL；3 例（10 mg/kg）实现了>4 log10 的降低。2 例（10 mg/kg）患者的 HCV RNA 降至定量下限以下（25 IU/mL），其中 1 例（先前的无应答者）在研究后 1 年仍无法检测到 RNA。在没有证据表明免疫缺陷的情况下，在第 2 天观察到 CD4+、CD8+和 CD19+细胞的短暂减少，包括幼稚和记忆 CD4+和 CD8+亚群。未观察到免疫球蛋白亚群的临床相关变化或与治疗相关的循环细胞因子的趋势。BMS-936558 表现出剂量相关性暴露增加，半衰期为 20-24 天。BMS-936558 大多具有良好的耐受性。1 例患者（10 mg/kg）在发生 4 对数病毒载量下降的同时出现无症状的 4 级 ALT 升高。6 例患者发生轻度至中度免疫相关不良事件，包括 2 例符合自身免疫性甲状腺炎的甲状腺功能亢进症。需要进一步研究 PD-1 通路阻断在慢性病毒疾病中的作用。
BMS-936558 具有良好的抗病毒活性，在 HCV 感染患者中安全且耐受性良好。
