GMCSF-interleukin fusion cytokines induce novel immune effectors that can serve as biopharmaceuticals for treatment of autoimmunity and cancer

Abstract

We created the GIFTs, fusions of granulocyte-colony macrophage-stimulating-factor with IL-2, or IL-15 or IL-21, in order to stimulate distinct, but complimentary elements of the immune response. We found that the physical coupling of two functionally distinct cytokines as a bifunctional hybrid allowed for synergistic bioactivity not seen by the simple combined use of parent components. Indeed, despite how these interleukins are pro-inflammatory cytokines that serve essential roles in the maturation of CD8(+) T cells and NK cells, the GIFTs were remarkably different from one another, with GIFT-2 and GIFT-21 promoting and GIFT-15 downregulating inflammation. The common denominator to the biochemistry of these fusokines was their ability to hijack the signalling machinery associated with common to their respective γ-chain interleukin receptors, radically altering the activation status of responding lymphomyeloid cells. By studying the GIFTs, we found that both secreted and cell surface factors presented by GIFT-activated lymphomyeloid cells were required to modulate the immune responses in murine models of multiple sclerosis and cancer. The ability of GIFTs to co-opt the normal signalling machinery of interleukin receptors leads to the acquisition of functional responder cell phenotypes unparalleled in nature. These novel properties provide opportunities to alter maladapted immune responses in health and disease.