Dhainaut J F, Vincent J L, Richard C, Lejeune P, Martin C, Fierobe L, Stephens S, Ney U M, Sopwith M
Intensive Care Units, Cochin Port-Royal University Hospital, Paris, France.
Crit Care Med. 1995 Sep;23(9):1461-9. doi: 10.1097/00003246-199509000-00004.
To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group.
Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571).
Seven academic intensive care units in Europe.
Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care.
Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg.
The humanized anti-TNF-alpha antibody was well tolerated. The overall all-cause 28-day mortality rate was 62%. Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days. This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately with the dose. The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels. While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group.
The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis.
确定一种“人源化”抗人肿瘤坏死因子-α（TNF-α）抗体在感染性休克患者中的安全性，并研究该抗体在此患者群体中的药代动力学、免疫反应以及对细胞因子浓度的影响。
前瞻性、随机、安慰剂对照的II期多中心临床试验，使用递增剂量的全人源化抗TNF-α抗体（CDP571）。
欧洲的7个学术重症监护病房。
42例迅速进展的感染性休克患者，除接受标准支持治疗外还接受了CDP571治疗。
患者静脉注射安慰剂或4种单剂量CDP571之一：0.1、0.3、1.0或3.0mg/kg。
人源化抗TNF-α抗体耐受性良好。28天全因死亡率为62%。安慰剂组和治疗组的死亡率相似，不过所有接受0.3mg/kg CDP571的6例患者均在7天内死亡。这一结果与剂量无关，与该组患者基线时较差的预后特征相符。CDP571的峰值浓度和曲线下面积随剂量成比例增加。检测到的低水平免疫反应对循环中的CDP571结合TNF-α的能力及抗体的药代动力学影响很小。在所有活性剂量水平下，CDP571给药30分钟后观察到循环TNF-α浓度突然降低。虽然所有剂量组中白细胞介素-1β和白细胞介素-6的血浆浓度均随时间下降，但治疗组在最初24小时内这些细胞因子浓度下降得比安慰剂组更快。
人源化抗TNF-α抗体CDP571耐受性良好，能够使感染性休克患者循环中的TNF-α浓度呈剂量依赖性降低。需要进一步研究以确定该抗体改善严重脓毒症重症患者生存率的疗效。
