Fusion Proteins: Current Status and Future Perspectives

Fusion proteins, consisting of the joined peptide chains of two or more proteins that are naturally not connected, are popular and highly successful recombinant protein drugs with a wide range of different functionalities and therapeutic applications. This chapter summarizes the main features of this protein class and explains the general design principles. Typical building blocks comprise the constant domain of immunoglobulins, linkers with specific properties, and a second protein module that carries some extra functionality such as an enzyme for instance. In some cases, the inherent ability to form higher order complexes is utilized to generate oligomers with novel characteristics. As the artificially combined protein subunits not necessarily share the same physicochemical characteristics, manufacturing becomes challenging. Often even the orientation of the fusion partners has an effect on activity and yield. Therefore, some efforts were undertaken to optimize the constructs through protein engineering. These unnatural proteins are unknown to the human body and immune system, although their components are derived from existing proteins. This can lead to immunogenic reactions particularly through novel epitopes at the junction positions between linkers and fusion partners. The different therapeutic concepts rely on some specific features such as half-life extension by either enlarging the diameter of the proteins to protect them from rapid kidney clearance or through recycling by Fc gamma receptor (FcRn). Both approaches have successfully been used to generate so-called biobetters with enhanced functions. The other important category of fusion proteins contains targeting abilities often conferred trough antibody derivatives. Some proteins from that subtype are immunocytokines that deliver cytokines to specific cell types or organs to exert the corresponding pharmaceutical effect. Overall fusion proteins represent a highly successful but heterogeneous class of recombinant therapeutic.