Ragnhammar P, Friesen H J, Frödin J E, Lefvert A K, Hassan M, Osterborg A, Mellstedt H
Department of Oncology (Radiumhemmet), Karolinska Hospital, Stockholm, Sweden.
Blood. 1994 Dec 15;84(12):4078-87.
The pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), induction of anti-GM-CSF antibodies, and clinical effects related to the induction of the antibodies were analyzed in patients with metastatic colorectal carcinoma (CRC) who were not on chemotherapy (n = 20, nonimmunocompromised patients). rhGM-CSF (250 micrograms/m2/d; Escherichia coli-derived) was administered subcutaneously for 10 days every month for 4 months. Eight patients with multiple myeloma (MM) on intensive chemotherapy followed by rhGM-CSF treatment were also included (immunocompromised patients). After a single injection of GM-CSF at the first cycle in CRC patients, the maximum calculated concentration (Cmax) was 5.24 +/- 0.56 ng/mL; the half life (T1/2) was 2.91 +/- 0.8 hours; and the area under the concentration curve (AUC) was 30.86 +/- 6.03 hours x ng/mL (mean +/- SE). No anti-GM-CSF antibodies were detected. During the subsequent cycles, 95% of the CRC patients developed anti-GM-CSF IgG antibodies, which significantly altered the pharmacokinetics of rhGM-CSF at the third and fourth cycles with decreased Cmax (2.87 +/- 0.57 ng/mL; P < .05), T1/2 (1.57 +/- 0.2 hours; P < .05), and AUC (14.90 +/- 4.10 hours x ng/mL; P < .005). The presence of anti-GM-CSF antibodies significantly reduced the GM-CSF-induced enhancement of granulocytes, and there was a clear tendency for a decreased increment of monocytes. Antibodies diminished systemic side effects of rhGM-CSF. Only 1 of 8 MM patients showed a very low anti-GM-CSF antibody titer after GM-CSF therapy, as shown by enzyme-linked immunosorbent assay and Western blot. Therefore, in nonimmunocompromised patients, exogenous nonglycosylated GM-CSF induced an anti-GM-CSF IgG antibody response in practically all patients, which seemed to be of clinical significance. In immunocompromised patients, virtually no significant antibody response was shown.
对未接受化疗的转移性结直肠癌（CRC）患者（n = 20，非免疫受损患者）分析了重组人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）的药代动力学、抗GM-CSF抗体的诱导以及与抗体诱导相关的临床效果。rhGM-CSF（250微克/平方米/天；大肠杆菌来源）每月皮下注射10天，共4个月。还纳入了8例接受强化化疗后接受rhGM-CSF治疗的多发性骨髓瘤（MM）患者（免疫受损患者）。在CRC患者的第一个周期单次注射GM-CSF后，计算得出的最大浓度（Cmax）为5.24±0.56纳克/毫升；半衰期（T1/2）为2.91±0.8小时；浓度曲线下面积（AUC）为30.86±6.03小时×纳克/毫升（平均值±标准误）。未检测到抗GM-CSF抗体。在随后的周期中，95%的CRC患者产生了抗GM-CSF IgG抗体，这在第三个和第四个周期显著改变了rhGM-CSF的药代动力学，Cmax降低（2.87±0.57纳克/毫升；P <.05），T1/2降低（1.57±0.2小时；P <.05），AUC降低（14.90±4.10小时×纳克/毫升；P <.005）。抗GM-CSF抗体的存在显著降低了GM-CSF诱导的粒细胞增加，并明显有单核细胞增加减少的趋势。抗体减少了rhGM-CSF的全身副作用。如酶联免疫吸附测定和蛋白质印迹所示，8例MM患者中只有1例在GM-CSF治疗后显示出非常低的抗GM-CSF抗体滴度。因此，在非免疫受损患者中，外源性非糖基化GM-CSF几乎在所有患者中诱导了抗GM-CSF IgG抗体反应，这似乎具有临床意义。在免疫受损患者中，几乎未显示出明显的抗体反应。
