Alternative Scaffolds as Bispecific Antibody Mimetics
The use of non-immunoglobulin-based protein scaffolds for engineering of specific recognition was first described some 15 years ago and has matured as a discipline in parallel with the rapidly expanding monoclonal antibody field. As bispecific antibodies and antibody fragments have come into focus lately, the corresponding development of bispecific alternative scaffolds is also emerging. Here, the concept of alternative scaffold proteins is introduced along with comparisons to the antibody and antibody derivatives counterparts. Although the field of bispecifics is anticipated to grow rapidly in the near future, relatively few examples of bispecific binders based on alternative protein scaffolds are reported in the literature. This chapter will present an overview of work that have been published, including a brief introduction to the particular molecular scaffolds with the structural basis and some of the biophysical and biochemical properties before describing the bispecific application.
KeywordsEpidermal Growth Factor Receptor Phage Display Diabetic Macular Edema Bispecific Antibody Affibody Molecule
- Ahlgren S, Orlova A, Wållberg H, Hansson M, Sandström M, Lewsley R, Wennborg A, Abrahmsén L, Tolmachev V, Feldwisch J (2010) Targeting of HER2-expressing tumors using 111In-ABY-025, a second-generation affibody molecule with a fundamentally reengineered scaffold. J Nucl Med 51:1131–1138PubMedCrossRefGoogle Scholar
- Engfeldt T, Orlova A, Tran T, Bruskin A, Widstrom C, Karlström AE, Tolmachev V (2007) Imaging of HER2-expressing tumours using a synthetic affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence. Eur J Nucl Med Mol Imaging 34:722–733PubMedCrossRefGoogle Scholar
- Friedman M, Nordberg E, Höidén-Guthenberg I, Brismar H, Adams GP, Nilsson FY, Carlsson J, Ståhl S (2007) Phage display selection of affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor. Protein Eng Des Sel 20:189–199PubMedCrossRefGoogle Scholar
- Lipovsek D, Lippow SM, Hackel BJ, Gregson MW, Cheng P, Kapila A, Wittrup KD (2007) Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast surface display: molecular convergence with single-domain camelid and shark antibodies. J Mol Biol 368:1024–1041PubMedCrossRefGoogle Scholar
- Wållberg H et al. (2010) Bi-specific affibody molecules for targeting of EGFR and HER2. Sixth annual protein engineering summit PEGS, May 17–21, Boston. Poster Abstract 78Google Scholar