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.