Characterization of the in vitro and in vivo activity of monoclonal antibodies to human IL-18.
IL-18 is a cytokine with potent IFN-gamma inducing activities as well as an important mediator of Th1 polarized immune responses. In this study we demonstrated that IL-18 induces the concentration-dependent production of the proinflammatory mediators IFN-gamma, IL-6, and GM-CSF, but not the anti-inflammatory cytokine, IL-10 from peripheral blood lymphocytes in the presence of mitogen. Three neutralizing IL-18 monoclonal antibodies (MAbs) were investigated, one of which (2C10) inhibited IL-18 bioactivity with an IC50 of 0.1 nM and had a K(D) of 3.9 x 10(-11) M. A NOD/SCID mouse model engrafted with human peripheral blood lymphocytes was developed to test the in vivo efficacy of this MAb. The IFN-gamma production induced by LPS administration was inhibited approximately 90% by prior dosing of MAb 2C10. The therapeutic utility of a high-affinity IL-18 MAb may be of benefit in Th1-driven autoimmune diseases such as rheumatoid arthritis and Crohn's Disease, where elevated levels of IL-18 have been observed.
Holmes
S
S
Department of MCCS, SmithKline Beecham, Harlow, Essex, UK. Stephen_D_Holmes@sbphrd.com
Abrahamson
J A
JA
Al-Mahdi
N
N
Abdel-Meguid
S S
SS
Ho
Y S
YS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009500:Neutralization Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D020382:Interleukin-18