Fisher C J, Opal S M, Dhainaut J F, Stephens S, Zimmerman J L, Nightingale P, Harris S J, Schein R M, Panacek E A, Vincent J L
Department of Pulmonary, Cleveland Clinic Foundation 44195.
Crit Care Med. 1993 Mar;21(3):318-27. doi: 10.1097/00003246-199303000-00006.
To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody in severe sepsis.
Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006).
Twelve academic medical center intensive care units in the United States and Europe.
Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti-TNF antibody.
Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart.
The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock.
The murine anti-TNF-alpha monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.
确定一种抗肿瘤坏死因子（TNF）-α单克隆抗体在严重脓毒症中的安全性、药代动力学及活性。
开放标签、前瞻性、II期多中心试验，使用递增剂量的鼠单克隆抗体（CB0006）。
美国和欧洲的12个学术医疗中心重症监护病房。
80例严重脓毒症或脓毒性休克患者，除接受抗TNF抗体治疗外，还接受标准支持治疗和抗菌治疗。
患者静脉注射CB0006四种给药方案之一：0.1mg/kg、1.0mg/kg、10mg/kg或两剂1mg/kg，间隔24小时。
尽管98%的患者产生了抗鼠抗体，但该鼠单克隆抗TNF抗体耐受性良好。整个研究人群未发现生存获益，但研究开始时循环TNF浓度升高的患者似乎从高剂量抗TNF抗体治疗中获益。白细胞介素（IL）-6水平升高预示着致命结局（p = 0.003），但未发现TNF水平是一个预后指标。与未处于休克状态的脓毒症患者相比，研究开始时处于休克状态的患者TNF水平更高（206.7±60.7 vs. 85.9±26.1 pg/mL；p < 0.001），且结局较差（生存率分别为41% vs. 71%；p = 0.007）。
在该临床试验中，鼠抗TNF-α单克隆抗体CB0006已被证明是安全的，可能对循环TNF浓度升高的脓毒症患者有用。需要进一步研究以确定这种免疫治疗药物在脓毒症中的疗效及最终临床应用价值。
