Protein-based masks to unlock conditional activation of therapeutics

Protein therapeutic binders provide targeted treatment options for autoimmune, cardiovascular, and neurodegenerative diseases, as well as cancer. However, these therapies can cause off-site toxicities when they bind to healthy tissue that also expresses their target. One method to combat this issue is through the addition of a masking moiety that prevents binding until released by a particular stimulus. Both protein and peptide-derived masks can inhibit binding, either via steric hinderance using large domains or by affinity-based direct competition. In diseased tissue, protease expression levels and pH are often altered, which can be leveraged for site-specific removal or deactivation of a masking moiety. Therefore, emergent strategies have been used to design conditionally activated, disease-targeted, protein-based therapeutics. This review will focus on the design, effectiveness, and mechanism of masks for cytokines, antibodies, and their derivatives, and further discuss strategies for future therapeutic avenues.