Ligands Modified by Circular Permutation as Agonists and Antagonists

A fusion polypeptide comprising, a first polypeptide fusion partner linked to a modified ligand corresponding to all or a portion of a native ligand of a target receptor, wherein the modified ligand has been circularly permuted to create a new N-terminus and a new C-terminus as compared to the native ligand, and wherein the new N-terminus or the new C-terminus of the modified ligand is linked to a first polypeptide fusion partner to form a fusion polypeptide wherein the new C-terminus and the new N-terminus of the modified ligand do not disrupt any binding domain of the modified ligand for the target receptor and wherein the modified ligand optionally has increased affinity for the target receptor as compared to the native ligand for the receptor, wherein the target receptor functions by stepwise formation of a multimeric activation complex to trigger signal transduction of a signaling cellular pathway and wherein when the fusion polypeptide binds the receptor it enhances the stepwise formation of the multimeric activation complex thereby super agonizing signal transduction by the target receptor wherein the modified ligand is circularly permuted IL-2 or IL-15 and wherein the fusion polypeptide has higher selectivity for IL-2 or IL-15 cytokine receptors lacking an alpha chain as compared to the selectivity of the native IL-2 or IL-15 cytokines to their respective receptors lacking an alpha chain.