Non-immunoglobulin scaffolds: a focus on their targets

• Non-immunoglobulin (non-Ig) scaffolds are small antibody alternatives.
• 139 binders of 20 different non-Ig scaffold types have been developed against 102 different targets.
• Their main application is in the treatment and diagnosis of cancer and inflammatory diseases.
• They can also be used in structural studies and post-translational modification monitoring.

Non-immunoglobulin (non-Ig) scaffolds are, in contrast to antibodies, small single-domain proteins that require no post-translational modification, often lack disulfide bonds, and can undergo straightforward multimerization. Among the 20 different types of non-Ig scaffolds, Adhirons, Alphabodies, Centyrins, Pronectins, Repebodies, Affimers, and Obodies have been introduced in the past 4 years. 102 proteins have been specifically targeted by 139 different non-Ig scaffold binders. The most frequent application of non-Ig scaffolds is in the treatment and diagnosis of cancer and inflammatory diseases, and 10 non-Ig scaffolds have already been tested in clinical trials. Recently, non-Ig scaffolds have often been used in research as structure determination chaperones, for intracellular monitoring of post-translational modifications, and as antibody alternatives for microscopy, flow cytometry, and Western blotting.