Synthekine compositions and methods of use

A synthetic ligand polypeptide comprising:

• at least two binding domains, wherein each binding domain specifically binds to the extracellular domain of a cytokine receptor polypeptide subunit expressed on the surface of a cell;
• wherein:
• the first binding domain is a first monovalent antibody that specifically binds to the extracellular domain of a first cytokine receptor subunit, wherein the first cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence;
• and
• the second binding domain is a second monovalent antibody that specifically binds to the extracellular domain of a second cytokine receptor subunit, wherein the second cytokine receptor subunit has an intracellular domain comprising at least one JAK/STAT binding sequence,
• wherein the first and second cytokine receptor subunits do not naturally multimerize in response to contacting the cell with a naturally occurring cytokine ligand;
• and
• wherein contacting the cell expressing the first and second cytokine receptor subunits results in multimerization of the cytokine receptor subunits and activation of a JAK/STAT-mediated signal in the cell;
• and
• wherein the first and second binding domains are covalently linked through a polypeptide linker.