Background Antibody-cytokine fusion proteins (“immunocytokines”) are innovative biopharmaceutical agents, which are being considered for the therapy of cancer and chronic inflammatory conditions. Immunomodulatory fusion proteins capable of selective localization at the sites of rheumatoid arthritis (RA) are of particular interest, as they may increase the therapeutic index of the cytokine payload. In this study, we investigated the therapeutic potential of F8-IL4 in RA. The F8 antibody recognizes the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis, which is strongly over-expressed at sites of arthritis (Schwager et al, 2009; Villa et al, 2008).
Objectives Recombinant IL4 has previously been investigated in preclinical models of rheumatoid arthritis, showing disease-modifying efficacy (Joosten et al, 1997; Joosten et al, 1999). The antibody-based targeted delivery of IL4 to sites of arthritis in vivo may result in a therapeutic action, which is dramatically more potent, compared to the non-targeted IL4 cytokine.
Methods The targeting and therapeutic activity of F8-IL4 was investigated in the collagen-induced arthritis mouse model. Different combination regimes were tested and evaluated by the analysis of serum and tissue cytokine levels.
Results Here we show that F8-IL4 selectively localizes to neovascular structures at sites of rheumatoid arthritis in the mouse, leading to high local concentrations of IL4. When used in combination with dexamethasone, F8-IL4 was able to cure mice with established collagen-induced arthritis. Response to treatment was associated with an elevation of IL13 levels and decreased IL6 plasma concentrations.
Conclusions The F8-IL4 immunocytokine cures RA in an established mouse model of the disease. A fully human version of F8-IL4 is currently being developed for clinical investigation.
Joosten LA, Lubberts E, Durez P, Helsen MM, Jacobs MJ, Goldman M, van den Berg WB (1997) Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. Arthritis Rheum 40(2): 249-60.
Joosten LA, Lubberts E, Helsen MM, Saxne T, Coenen-de Roo CJ, Heinegard D, van den Berg WB (1999) Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis. Arthritis Res 1(1): 81-91.
Schwager K, Kaspar M, Bootz F, Marcolongo R, Paresce E, Neri D, Trachsel E (2009) Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis. Arthritis Res Ther 11(5): R142.
Villa A, Trachsel E, Kaspar M, Schliemann C, Sommavilla R, Rybak JN, Rosli C, Borsi L, Neri D (2008) A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. Int J Cancer 122(11): 2405-13
Acknowledgements The authors are grateful to ETH Zürich, to the Swiss National Science Foundation, to the Commission for Technology und Innovation (CTI Medtech Award) and to the European Union (FP7 Project PRIAT).
Disclosure of Interest T. Hemmerle Consultant for: Philochem AG, Otelfingen, Switzerland, F. Doll: None declared, D. Neri Shareholder of: Philogen SpA, Siena, Italy
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