Measurement of Whole Body Interleukin-6 (IL-6) Production: Prediction of the Efficacy of Anti-IL-6 Treatments

• Published in: Blood 1995-10, Vol.86 (8), p.3123-3131
• Main Authors: Lu, Zhao Yang, Brailly, Hervέ, Wijdenes, John, Bataille, Rέgis, Rossi, Jean-François, Klein, Bernard
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antigen-Antibody Complex - blood; Antineoplastic agents; Biological and medical sciences; C-Reactive Protein - biosynthesis; C-Reactive Protein - genetics; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma - therapy; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunotherapy; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Interleukin-6 - immunology; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidney Neoplasms - therapy; Medical sciences; Models, Biological; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Multiple Myeloma - therapy; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Pharmacology. Drug treatments; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V86.8.3123.3123

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 μg/d (median, 5.7 μg/d; range, 0.5 to 17.5 μg/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 μg/d; range, 18 to 358 μg/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.