Mol Ther. 2026 Sep 2:S1525-0016(26)00773-2. doi: 10.1016/j.ymthe.2026.08.047. Online ahead of print.
ABSTRACT
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.
PMID:42687384 | DOI:10.1016/j.ymthe.2026.08.047