The Interleukin-1 (IL-1) family consists of a group of cytokines with potent immuno-stimulatory
activities. Several studies indicate that activation of leukocyte subsets by IL-1 is essential for
protective immunity against a variety of pathogens and for elimination of cancer cells. IL-1 could
have therapeutic value, for instance as vaccine adjuvant, yet its clinical application is hampered by
the undesired side-effects that are associated with IL-1 administration. To allow targeted activity of
cytokines with toxic properties, we recently devised the AcTakine (for Activated by Targeting)
concept. AcTakines are mutant cytokines, with reduced affinity for their receptor, which are coupled
to a heavy chain only antibody (VHH) recognizing a cell surface-expressed marker. The VHH will act
as cytokine guide, concentrating the mutant cytokine at the surface of selected target cells.
Importantly, AcTakines are inactive whilst "en route" through the body and only reveal their activity
through avidity effects at the VHH-targeted cells. We hypothesize that IL-1 AcTakines will allow safe
exploitation of agonistic IL-1 activity, for instance as adjuvant in therapeutic vaccines. In this project
we will develop IL-1 AcTakines (AcTaleukins) that allow targeting of IL-1 cytotoxic T lymphocytes
and cross-presenting dendritic cells. We will test the adjuvant efficacy of the AcTaleukins in vitro
and in vivo, in mouse models of cancer.