Subcutaneous administration of recombinant glycosylated interleukin 6 in patients with cancer: Pharmacokinetics, pharmacodynamics and immunomodulatory effects

TY - JOUR

T1 - Subcutaneous administration of recombinant glycosylated interleukin 6 in patients with cancer

T2 - Pharmacokinetics, pharmacodynamics and immunomodulatory effects

AU - Banks, Rosamonde E.

AU - Forbes, Mary A.

AU - Patel, Poulam M.

AU - Storr, Mark

AU - Hallam, Susan

AU - Clarke, Deborah

AU - Novick, Daniela

AU - Ingham, Eileen

AU - Bowmer, Christopher

AU - Southgate, Jennifer

AU - Trejdosiewicz, Ludwik K.

AU - Illingworth, John

AU - Perren, Timothy J.

AU - Selby, Peter J.

PY - 2000/4/1

Y1 - 2000/4/1

N2 - This is the first report of the serum profile of a glycosylated recombinant form of human IL-6 (rhIL-6) administered subcutaneously (1-10 μg/kg/day) in a phase I/II trial as a thrombopoietic agent in patients with advanced cancer. The pharmacodynamic effects of IL-6 were also examined. Detailed pharmacokinetic measurements were made in four patients. Peak concentrations at 5-8 h and a median t0.5 of ca. 5 h were similar to those previously reported for non-glycosylated IL-6. However, higher peak concentrations and apparent differences in effective dose levels to those previously reported with the non-glycosylated form were seen. Indications of an apparent attenuation in circulating IL-6 concentrations with continuing injections were seen in eight of 10 patients examined but anti-IL-6 antibody generation was seen in only two patients. Soluble interleukin 6 receptor concentrations generally decreased. No major changes in T cell subsets were seen but expression of CD25 and CD54 by T lymphocytes significantly increased, accompanied by marked increases in soluble CD25 (sIL-2R) and CD54 (sICAM-1). No consistent change in B cells, monocytes or NK cells were seen. No evidence for induction of TNF-α was found. This study demonstrates similar biological effects of glycosylated rhIL-6 to those reported for the non-glycosylated form but illustrates several apparent differences which are discussed further. (C) 2000 Academic Press.

AB - This is the first report of the serum profile of a glycosylated recombinant form of human IL-6 (rhIL-6) administered subcutaneously (1-10 μg/kg/day) in a phase I/II trial as a thrombopoietic agent in patients with advanced cancer. The pharmacodynamic effects of IL-6 were also examined. Detailed pharmacokinetic measurements were made in four patients. Peak concentrations at 5-8 h and a median t0.5 of ca. 5 h were similar to those previously reported for non-glycosylated IL-6. However, higher peak concentrations and apparent differences in effective dose levels to those previously reported with the non-glycosylated form were seen. Indications of an apparent attenuation in circulating IL-6 concentrations with continuing injections were seen in eight of 10 patients examined but anti-IL-6 antibody generation was seen in only two patients. Soluble interleukin 6 receptor concentrations generally decreased. No major changes in T cell subsets were seen but expression of CD25 and CD54 by T lymphocytes significantly increased, accompanied by marked increases in soluble CD25 (sIL-2R) and CD54 (sICAM-1). No consistent change in B cells, monocytes or NK cells were seen. No evidence for induction of TNF-α was found. This study demonstrates similar biological effects of glycosylated rhIL-6 to those reported for the non-glycosylated form but illustrates several apparent differences which are discussed further. (C) 2000 Academic Press.

KW - Clinical trial

KW - Glycosylated

KW - Immunomodulation

KW - Interleukin 6

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=0033939175&partnerID=8YFLogxK

U2 - 10.1006/cyto.1999.0556

DO - 10.1006/cyto.1999.0556

M3 - Article

C2 - 10805221

AN - SCOPUS:0033939175

SN - 1043-4666

VL - 12

SP - 388

EP - 396

JO - Cytokine

JF - Cytokine

IS - 4

ER -