Rational design of environmentally responsive antibodies with pH-sensing synthetic amino acids.

ABSTRACT: Antibodies are widely used as therapeutic agents to tackle various diseases. In the present study, to enhance their clinical values, we rationally designed pH-responsivity by exploiting the idiosyncratic protonation/deprotonation profiles of non-natural amino acids. 3-Nitro-L-tyrosine, 3-cyano-L-tyrosine, and 3, 5-halogenated-L-tyrosine, each with near neutral pK_a, were thus incorporated into Fab fragments in place of tyrosines and other residues in the variable regions. Cell-based assays showed that these modifications achieved up to 140-fold tighter binding to antigens and several-fold tighter cytotoxicity to antigen-expressing cell at pH 6.0 than pH 7.4. The pH-dependent binding effect was retained in full-length antibodies. In silico structural analyses revealed electrostati

SUBMITTER: Isoda Y 

PROVIDER: S-EPMC11339442 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature