Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments.
A major limitation on the therapeutic use of cytokine antagonists is that the amount of cytokine to be neutralized in vivo is not presently known. We previously reported that anti-interleukin-6 (IL-6) monoclonal antibody (MoAb) administered to a patient with multiple myeloma (MM) induced high amounts of IL-6 to circulate in the form of monomeric immune complexes. Based on this observation, the present study developed a new methodology to estimate daily IL-6 production in 13 patients with MM or renal cancer who received anti-IL-6 MoAb. Treatment was considered effective when the production of C-reactive protein (CRP) was inhibited. The production of this acute-phase protein by hepatocytes is dependent on the activation of IL-6 gp130 transducer. Inhibition of tumor proliferation was also evaluated in patients with MM. In 7 of 13 patients whose CRP production was completely inhibited (> 96%) and who showed some antitumoral effects, whole-body IL-6 production in vivo was less than 18 micrograms/d (median, 5.7 micrograms/d; range, 0.5 to 17.5 micrograms/d). In the other 6 patients, subtotal inhibition of CRP production and a lack of antitumoral response were associated with high IL-6 production (median, 180 micrograms/d; range, 18 to 358 micrograms/d). These in vivo observations were consistent with mathematical modeling that predicted that anti-IL-6 MoAb treatment would be efficient only in low IL-6 producers. These data indicate the difficulty of neutralizing IL-6 with a single anti-IL-6 MoAb in vivo and call for new strategies to avoid accumulation of IL-6 in the form of stable immune complexes.
Lu
Z Y
ZY
Institute for Molecular Genetics, CNRS BP5051, Montpellier, France.
Brailly
H
H
Wijdenes
J
J
Bataille
R
R
Rossi
J F
JF
Klein
B
B
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000097:blood; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002097:C-Reactive Protein; D015850:Interleukin-6; D009363:Neoplasm Proteins; D000093242:Interleukin-6 Inhibitors