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Fusokine Interleukin-2/Interleukin-18, a Novel Potent Innate and Adaptive Immune Stimulator with Decreased Toxicity

¹ Division of Medical and Regulatory Affairs, ² Molecular Immunology Laboratory, ³ Histology and Animal Facilities Laboratory, Transgene SA; and ⁴ Immunologie et Chimie Thérapeutiques, Centre National de la Recherche Scientifique/Institut de Biologie Molécullaire et Cellulaire, Strasbourg, France

Requests for reprints: Stephane Paul, Molecular Immunology Laboratory, Transgene SA, 11 rue de Holsheim, 67082, Strasbourg, France. E-mail: paul{at}transgene.fr.

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.

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