Identification of natural antibodies to interleukin-18 in the sera of normal humans and three nonhuman primate species

• Published in: Clinical immunology (Orlando, Fla.) Vol. 109; no. 2; pp. 188 - 196
• Main Authors: Soos, Jeanne M, Polsky, Rodd M, Keegan, Sean P, Bugelski, Peter, Herzyk, Danuta J
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.11.2003; Elsevier
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Antibodies - blood; Antibodies - immunology; Antibody production; Biological and medical sciences; Cynomolgus; Electrochemiluminescence assay; Enzyme-Linked Immunosorbent Assay; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Interferon-gamma - immunology; Interleukin-18; Interleukin-18 - immunology; Interleukin-18 - pharmacokinetics; Luminescent Measurements; Macaca fascicularis; Macaca mulatta; Male; Natural antibodies; Neopterin; Neopterin - immunology; Neopterin - metabolism; Nonhuman primates; Pan troglodytes; Primates; Recombinant Proteins - immunology; Recombinant Proteins - pharmacokinetics; Natural antibodies; Neopterin; Interleukin-18; Electrochemiluminescence assay; Nonhuman primates; Human; Cytokine; Electrochemiluminescence; Interleukin 18; Natural antibody; Vertebrata; Mammalia; Immunology; Primates
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/S1521-6616(03)00180-3

Natural antibodies to cytokines can be found in the sera of normal healthy individuals in the absence of specific immunostimulation. However, the function, impact, and purpose of natural antibody development have yet to be fully elucidated. Interleukin (IL)-18 is a cytokine that exerts proinflammatory activities and induces natural killer (NK) cell activity. Recombinant human IL-18 (rHuIL-18) is currently in development as a cancer immunotherapy. In this study, the presence of natural antibodies to IL-18 in the sera of normal humans and three nonhuman primate species was evaluated by electrochemiluminescence immunoassay (ECLIA). Of the human sera tested, 6 of 47 samples were positive for natural antibodies to IL-18. Of the nonhuman primate sera tested, 22 of 80 cynomolgus monkey samples, 4 of 31 rhesus monkey samples, and 2 of 20 chimpanzee samples were positive for natural antibodies to IL-18. Natural anti-IL-18 antibodies were neutralizing in 5 of 22 cynomolgus and 2 of 4 rhesus sera. None of the chimpanzee or human sera were able to neutralize IL-18 induction of interferon (IFN)-γ in vitro. In vivo activity of rHuIL-18 was compared in IL-18 natural antibody-positive and -negative cynomolgus monkeys. The presence of natural antibodies to IL-18 did not alter rHuIL-18 systemic exposure levels, induction of neopterin, or induction of treatment-induced antibodies following intravenous administration of rHuIL-18. In conclusion, our data indicate that, as has been found with other cytokines, natural anti-IL-18 antibodies are relatively common. Moreover, natural anti-IL-18 antibodies do not appear to influence rHuIL-18 activity in vivo and are not predictive of a heightened immune response, suggesting that natural anti-IL-18 antibodies do not impact IL-18 therapy. Finally, our data suggest that the ability to detect natural anti-cytokine antibodies may be a useful measure of the adequacy of an assay for deployment in clinical trials.