Assembly of pH‐Responsive Antibody‐Drug‐Inspired Conjugates

• Published in: Macromolecular bioscience Vol. 22; no. 2; pp. e2100299 - n/a
• Main Authors: Raabe, Marco, Heck, Astrid Johanna, Führer, Siska, Schauenburg, Dominik, Pieszka, Michaela, Wang, Tao, Zegota, Maksymilian Marek, Nuhn, Lutz, Ng, David Y. W., Kuan, Seah Ling, Weil, Tanja
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.02.2022
• Subjects: Antibodies; Antibodies, Monoclonal - chemistry; antibody‐inspired conjugates; Antigens; Antineoplastic Agents - chemistry; Assembly; avidin–biotin; Bioavailability; Biotin; boronic acid–salicylhydroxamate; Cancer; Conjugates; Controlled release; Drug development; Hydrogen-Ion Concentration; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Low molecular weights; Microenvironments; Molecular weight; Peptides; pH effects; pH‐responsive linkers; Proteins; protein‐drug conjugates; Receptors; Somatostatin; Somatostatin receptors; antibody-inspired conjugates; boronic acid-salicylhydroxamate; protein-drug conjugates; avidin-biotin; pH-responsive linkers
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.202100299

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 (ADCs). 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 linker, the authors devise herein the convenient assembly of a trivalent protein‐drug conjugate. The conjugate should ideally possess distinct features of ADCs such as 1) recognition sites that recognize cell receptor and are arranged on 2) distinct locations on a high molecular weight protein scaffold, 3) a stimuli‐responsive linker, as well as 4) an attached payload such as a drug molecule. These AD‐like conjugates target cancer cells that overexpress somatostatin receptors, can enable controlled release in the microenvironment of cancer cells through a new pH‐responsive biotin linker, and exhibit stability in biological media. An antibody‐drug‐inspired conjugate is assembled on a protein scaffold with a linker, based on boronic acid–salicylhydroxamate interactions, to allow for controlled release of the cytotoxic drug in acidic or oxidative conditions.