‘Engineered protein scaffolds: have they lived up to expectations?’

Abstract

Monoclonal antibodies are currently the most successful class of therapeutic agents. However, the conventional immunoglobulin (Ig) format is not always optimally suited to meet clinical demands. First, immunological effector functions mediated by the Fc region can evoke undesired side effects. Second, poor tissue penetration due to the large molecular size hampers successful treatment of solid tumors. Also, the long circulation in blood resulting from both the large size and FcRn-mediated endosomal recycling is unfavorable both for therapies that require flexible adjustment of dosing and for in vivo imaging applications. Finally, due to their complex biomolecular architecture, including four polypeptide chains with around 1500 amino acids and at least two glycosylation sites, the production of full size antibodies is costly and requires mammalian expression systems. As a consequence, during the last two decades more than 50 alternative types of binding proteins have been proposed with the intention to overcome some of the inherent limitations of antibodies. However, only a minority of these ‘alternative scaffolds’ have reached the clinic so far, which can be seen as the ultimate success in pharmaceutical biotechnology. According to recent reviews, ten drug candidates based on seven different protein scaffolds have been tested in clinical trials while one biological received market approval (the engineered Kunitz domain/protease inhibitor ecallantide) [1,2]. At present, the biopharmaceutical development is dominated by the following protein scaffolds: • Affibodies based on the Z-domain of Staphylococcal protein A [3];