Summary And Future Directions

In this chapter, we have focused on approaches for improving the half-life of therapeutic peptides and proteins through direct modulation of their interaction with FcRn, through engineered association with serum albumin (whose clearance properties are also modulated through binding to FcRn), and through chemical manipulation that serves to increase the hydrodynamic radius of the drug through PEGylation or other chemical modification. These approaches may significantly increase the circulating half-life of an injected drug, thereby providing improved drug exposure and patient compliance with the treatment regimen as a result of the increased convenience of fewer office visits to physicians or fewer self-administered injections. Both components have the potential to improve treatment outcomes and patient quality of life.

Looking ahead, it seems likely that the modular elements of these approaches will be combined, for example, by engineering immunoadhesins with even longer half-life through engineering of higher-affinity FcRn binding. In addition, new conjugation chemistry (187) may provide further opportunities to enhance chemical modification techniques for larger hydrodynamic volume and nanoparticle approaches.

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