Sustained high levels of circulating chaperoned interleukin-6 after active specific cancer immunotherapy.
In a phase 1 study of recombinant interleukin-6 (rIL-6) in patients with advanced solid tumors (n = 15), we discovered that the endogenous IL-6 levels, in pretreatment plasma or serum samples, were distributed into two groups. One set of patients (designated "type 1"; n = 9) was characterized by low plasma IL-6 levels (48 to 1,700 pg/mL) as measured using enzyme-linked immunosorbent assays (ELISA) for IL-6. In the second set of patients (designated "type 2"; n = 6), IL-6 ELISAs showed high levels of plasma IL-6 (50 to 600 ng/mL). Neither group had detectable B9 hybridoma cell growth factor activity associated with the IL-6 in their pretreatment plasma or serum. Plasma C-reactive protein (CRP) levels were markedly elevated in type II patients suggesting that the circulating IL-6 was biologically active in vivo. In both groups of patients there was a small but significant increase in B9 activity in the plasma within three hours after rIL-6 administration (n = 5). Gel filtration profiles showed that circulating IL-6 in type 1 patients, 15 to 120 minutes after rIL-6 administration was of approximate mass 20 to 40 kD, whereas in type 2 patients, the IL-6 before and after exogenous rIL-6 administration was indistinguishable and was of an approximate mass of 200 kD. IL-6 immunoaffinity purification of the 200 kD complexes showed these to contain multiple isoforms of IL-6 (14 to 31 kD) and the soluble IL-6 receptor (sIL-6R; 50 to 55 kD). A distinguishing clinical history was that all of the type 2 patients had been actively immunized with an anti-idiotypic monoclonal antibody (MoAb) (MK2-23) 3 to 12 months before initiation of this study for advanced melanoma. An analysis of the plasma IL-6 content in other melanoma patients (n = 16) during antiidiotypic MoAb immunization indicated that marked (up to 600 ng/mL) and sustained (several months) elevations of circulating "chaperoned" IL-6 were induced by active immunization regimens.
May
L T
LT
Department of Microbiology and Immunology, New York Medical College, Valhalla 10595.
Patel
K
K
García
D
D
Ndubuisi
M I
MI
Ferrone
S
S
Mittelman
A
A
Mackiewicz
A
A
Sehgal
P B
PB
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D002850:Chromatography, Gel; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D006433:Hemocyanins / Q000627:therapeutic use; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D016233:Immunotherapy, Active; D015850:Interleukin-6 / Q000097:blood* / Q000627:therapeutic use*; D008545:Melanoma / Q000097:blood / Q000628:therapy*; D009163:Mycobacterium bovis / Q000276:immunology; D011994:Recombinant Proteins
D000911:Antibodies, Monoclonal; D007130:Immunoglobulin Idiotypes; D015850:Interleukin-6; D011994:Recombinant Proteins; D002097:C-Reactive Protein; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin