Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates. While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive dynamic covalent linker, we devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate mimics key features of antibody-drug conjugates such as (1) a multipartite structure, (2) peptide recognition sites arranged at distinct locations and at defined distances, (3) a high molecular weight protein scaffold, and (4) an attached drug molecule. These antibody-inspired protein-drug conjugates target cancer cells that overexpress somatostatin receptors, enable controlled release in the microenvironment of cancer cells through an entirely new dynamic covalent biotin linker and exhibit stability in biological media.