Fusokine interleukin-2/interleukin-18, a novel potent innate and adaptive immune stimulator with decreased toxicity.
To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity.
Acres
Bruce
B
Division of Medical and Regulatory Affairs, Molecular Immunology Laboratory, Histology and Animal Facilities Laboratory, Transgene SA, Strasbourg, France.
Gantzer
Murielle
M
Remy
Christelle
C
Futin
Nicolas
N
Accart
Nathalie
N
Chaloin
Olivier
O
Hoebeke
Johan
J
Balloul
Jean-Marc
JM
Paul
Stéphane
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016233:Immunotherapy, Active / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D006023:Glycoproteins; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; C118370:interleukin-18 binding protein