Fc-based cytokines: prospects for engineering superior therapeutics.

The application of Fc (fragment crystallizable)-based cytokines (the fusion of the constant region of IgG to acytokine of interest) as biotherapeutic agents to modulate inflammatory and immune responses has becomeincreasingly popular in recent years. This is because in their monomeric form, cytokines are relatively smallmolecules with short serum half-lives, which necessitates frequent administration and thus limits their clinical12 Jazayeri & Carrollutility. To rectify the problem, attempts have been made to improve the stability of these agents in vivo. This hasbeen achieved through diverse strategies such as modification with polyethylene glycol (PEGylation) or byligating the cytokine to protein moieties such as the constant heavy chain of IgG, known as the Fc fragment. Theconstruction of Fc chimeric proteins has been shown to improve pharmacokinetics. However, since there is aninverse relationship between the size of molecules and the rate at which they diffuse through mucus, Fc fusionconstructs potentially have a lower rate of diffusion. Consequently, a compromise is reached whereby Fcconstructs are engineered to incorporate ligated cytokines in a monomeric form (one molecule of cytokine fusedto a single Fc dimer) rather than in a dimeric form (two molecules of cytokine fused to a single Fc dimer). Arecent and novel approach to improve stability in serum is a procedure that involves sheathing cytokines inprotective protein covers called latency peptides. The enclosed cytokine is protected from degradation andallowed to act where needed when the outer peptide cover is removed. For some applications, a reduced serumhalf-life is desirable; for example, where there is a need to reduce IgG levels in antibody-mediated diseases. Toachieve this goal, a strategy called AbDeg, which involves enhanced Ig degradation, has been devised.This article provides anoverview of the design and construction of Fc-based cytokines, in both dimeric andmonomeric forms. Several examples of recent applications of such constructs, which include cytokine antagonism,cytokine traps, gene therapy and drug delivery, are also discussed. Other antibody-engineeredconstructs such as Fab (fragment, antigen binding) and single chain Fv (fragment, variable) fusions are alsobriefly covered.