Induction of anti-recombinant human granulocyte-macrophage colony- stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients

Abstract

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.

Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy

“…In total, 19 of the 20 patients in the study had produced GM-CSF-reactive anti-bodies at the completion of therapy (Table 1). Detectable GM-CSF antibody disappeared at about 30 weeks after the last injection [25].…”

“…Twenty patients with a median age of 65 years (range 14-78 years) entered the phase II trial [25]. All had metastatic colorectal carcinoma and a Karnofsky index of 5 80%.…”

“…A solid-phase indirect ELISA was used to detect GM-CSF binding antibodies in the serum samples from patients [25]. Briefly, roundbottomed microtitre plates were incubated at room temperature overnight with 125 l/well of rhGM-CSF (1 .…”

“…Clinical data from studies using different forms of GM-CSF to support myeloregeneration suggest that very few patients develop GM-CSF antibodies during the course of treatment [22][23][24]. However, in a recent study [25], patients with metastatic colorectal carcinoma receiving a combination therapy of E. coli-derived GM-CSF and a colon carcinoma-reactive MoAb in the absence of any concomitant chemotherapy developed antibodies which compromised the clinical efficacy of GM-CSF. However, it was not clear whether the diminished effects of GM-CSF were a consequence of antibody-mediated accelerated plasma clearance of the administered GM-CSF or of the occurrence of GM-CSF neutralizing antibodies [25].…”

“…However, in a recent study [25], patients with metastatic colorectal carcinoma receiving a combination therapy of E. coli-derived GM-CSF and a colon carcinoma-reactive MoAb in the absence of any concomitant chemotherapy developed antibodies which compromised the clinical efficacy of GM-CSF. However, it was not clear whether the diminished effects of GM-CSF were a consequence of antibody-mediated accelerated plasma clearance of the administered GM-CSF or of the occurrence of GM-CSF neutralizing antibodies [25]. Here, we report the development of neutralizing and non-neutralizing GM-CSF antibodies and the clinical consequences related to the induction of these antibodies in this group of non-immunocompromised carcinoma patients.…”