Wee S, Pascual M, Eason J D, Schoenfeld D A, Phelan J, Boskovic S, Blosch C, Mohler K, Cosimi A B
Transplantation Unit, Massachusetts General Hospital, Boston 02114, USA.
Transplantation. 1997 Feb 27;63(4):570-7. doi: 10.1097/00007890-199702270-00015.
A preliminary clinical study of renal allograft recipients revealed that a dimeric form of the human 80 kDa soluble receptor (sTNFR:Fc) for tumor necrosis factor (TNF) is well tolerated and attenuates the OKT3-induced acute clinical syndrome. The current study determined the in vivo biological effects and fate of sTNFR:Fc in these patients. Serial assessment of both antigenic and biological activities of circulating TNF and sTNFR:Fc have led to the following observations. (1) Although control patients typically responded to the first OKT3 injection with a rapid increase of biologically active TNFalpha, patients on sTNFR:Fc therapy had markedly higher serum TNFalpha antigenic levels, but no detectable bioactivity. Thus, sTNFR:Fc functioned as a potent antagonist, despite its cytokine-carrier effect. (2) Peak sTNFR:Fc levels averaging 800 and 2500 ng/ml were routinely achieved in vivo, using the low-dose (0.05 mg/kg) and high-dose (0.15 mg/kg) protocols. (3) The half-life of circulating sTNFR:Fc was estimated to be approximately 4.4 days, and levels of p80 receptors in treated patients remained significantly above those in control patients for at least 20 days. (4) In vitro blocking studies demonstrated that circulating sTNFR:Fc remained biologically active for 2 weeks. These results demonstrate that under current protocols, significant serum levels of sTNFR:Fc, capable of effectively neutralizing TNF activity over prolonged periods, can be achieved. The persistent OKT3 side effects observed, despite sTNFR:Fc therapy, are therefore likely to be caused by factors other than TNF.
一项针对肾移植受者的初步临床研究表明，人肿瘤坏死因子（TNF）80 kDa可溶性受体的二聚体形式（sTNFR:Fc）耐受性良好，并可减轻OKT3诱导的急性临床综合征。本研究确定了sTNFR:Fc在这些患者体内的生物学效应和转归。对循环TNF和sTNFR:Fc的抗原活性和生物学活性进行系列评估后得出以下观察结果。（1）尽管对照患者通常在首次注射OKT3后生物活性TNFα迅速升高，但接受sTNFR:Fc治疗的患者血清TNFα抗原水平明显更高，但未检测到生物活性。因此，尽管sTNFR:Fc具有细胞因子载体作用，但其仍发挥了强效拮抗剂的功能。（2）使用低剂量（0.05 mg/kg）和高剂量（0.15 mg/kg）方案时，体内sTNFR:Fc水平通常分别达到平均800和2500 ng/ml的峰值。（3）循环sTNFR:Fc的半衰期估计约为4.4天，治疗患者的p80受体水平在至少20天内显著高于对照患者。（4）体外阻断研究表明，循环sTNFR:Fc在2周内仍具有生物学活性。这些结果表明，按照目前的方案，可以实现能够长时间有效中和TNF活性的显著血清sTNFR:Fc水平。因此，尽管进行了sTNFR:Fc治疗，但观察到的持续OKT3副作用可能是由TNF以外的因素引起的。
