Alternative protein scaffolds for molecular imaging and therapy

Molecular targeting has tremendous potential to enhance the specificity and sensitivity of diagnostics and the safety and potency of therapeutics, as well as to induce unique and precise biological responses. Effective targeting requires specific binding of appropriate affinity, conjugation of effectors (e.g., toxins, radioisotopes, or fusion proteins) as needed, stable maintenance of activity, and effective delivery physiologically. Ideally, solutions to these challenges will be efficiently implemented for a multitude of molecular targets unique to the relevant pathophysiology. Protein scaffolds, molecular frameworks amenable to local diversity to introduce specific binding while retaining favorable biophysical characteristics, offer an intriguing general solution. While antibodies and their derivatives offer viable options, a host of alternative topologies prove superior in stability, size, production, and/or conjugation. Validated scaffolds include the fibronectin domain, knottin, designed ankyrin repeat protein, anticalin, and affibody among others. These scaffolds have demonstrated efficacy in preclinical animal models and, in some cases, clinical trials in therapy or imaging. These translational developments will be reviewed here. The future is bright for both antibodies and their alternatives. Research should be undertaken to identify the most efficacious scaffold for each individual clinical indication and application.