Site-Specific Lysine Arylation as an Alternative Bioconjugation Strategy for Chemically Programmed Antibodies and Antibody–Drug Conjugates

• Published in: Bioconjugate chemistry Vol. 30; no. 11; pp. 2889 - 2896
• Main Authors: Hwang, Dobeen, Tsuji, Kohei, Park, HaJeung, Burke, Terrence R, Rader, Christoph
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.11.2019; Amer Chemical Soc
• Subjects: Amides; Antibodies; Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Conjugates; Conjugation; Immunoglobulins; Life Sciences & Biomedicine; Lysine; Organic chemistry; Physical Sciences; Science & Technology; Strategy; β-Lactam antibiotics; CHEMISTRY; INTEGRIN
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.9b00609

By exploiting a uniquely reactive lysine residue (Lys99) for site-specific attachment of small molecules, the humanized catalytic antibody h38C2 has been used as bioconjugation module in the assembly of chemically programmed antibodies and antibody–drug conjugates. Treatment of h38C2 with β-lactam-functionalized small molecules has been previously shown to result in covalent conjugation by selective formation of a stable amide bond with the ε-amino group of the Lys99 residue. Here we report that heteroaryl methylsulfonyl (MS-PODA)-functionalized small molecules represent an alternative bioconjugation strategy through highly efficient, site-specific, and stable arylation of the Lys99 residue. A set of chemically programmed antibodies and antibody–drug conjugates assembled by Lys99 arylation provided proof-of-concept for the therapeutic utility of this alternative bioconjugation strategy. While being equally effective as β-lactam-functionalized ligands for bioconjugation with catalytic antibody h38C2, the MS-PODA moiety offers distinct synthetic advantages, making it highly attractive.