IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1alpha, IL-1beta, IL-33, IL-36alpha, IL-36beta and IL-36gamma). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.

• Hojen, J. F.
• Kristensen, M. L. V.
• McKee, A. S.
• Wade, M. T.
• Azam, T.
• Lunding, L. P.
• de Graaf, D. M.
• Swartzwelter, B. J.
• Wegmann, M.
• Tolstrup, M.
• Beckman, K.
• Fujita, M.
• Fischer, S.
• Dinarello, C. A.