6U85

Site-specific lysine arylation as an alternative bioconjugation strategy for chemically programmed antibodies and antibody-drug conjugates

Summary for 6U85

• Entry DOI: 10.2210/pdb6u85/pdb
• Descriptor: Antibody Fab heavy chain, antibody Fab Light chain, GLYCEROL, ... (4 entities in total)
• Functional Keywords: single chain fv, scfv, antibody, ror2, kringle domain, receptor tyrosine kinase-like orphan receptor, phage display, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 48077.60

Authors

Park, H.,Rader, C. (deposition date: 2019-09-04, release date: 2019-11-13, Last modification date: 2024-10-30)

Primary citation

Hwang, D.,Tsuji, K.,Park, H.,Burke Jr., T.R.,Rader, C.
Site-Specific Lysine Arylation as an Alternative Bioconjugation Strategy for Chemically Programmed Antibodies and Antibody-Drug Conjugates.
Bioconjug.Chem., 30:2889-2896, 2019

PubMed Abstract: 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.

PubMed: 31675216
DOI: 10.1021/acs.bioconjchem.9b00609

Experimental method

X-RAY DIFFRACTION (2.78 Å)