Figure 5. Engineering strategies are being explored preclinically to enhance the drug-like properties of cytokines.

(A) Both site-specific and non-specific polymer conjugation methods have been explored to extend the serum half-lives of cytokines or to create a drug depot for controllable sustained release. (B) The bivalent (Top) and monovalent (Bottom) formats of Fc-fused cytokines have been engineered. (C) Cytokines are conjugated to human serum albumin (HSA) directly via covalent or genetic fusions (Top). Alternatively, they are fused to the albumin-binding domain (ABD) (Middle) or fatty acid moieties (Bottom) that can non-covalently bind to endogenous HSA upon administration. (D) Cytokine mimetics such as peptides, bispecific antibodies, zipper-like coiled-coil constructs, and other engineered protein scaffolds have been studied as potential therapeutics.