ArticleBioconjugate chemistry2022
Sculpting a Uniquely Reactive Cysteine Residue for Site-Specific Antibody Conjugation.
Article in Bioconjugate chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- DVD-IgG1 antibody-drug conjugates: Expanding the landscape of targeted cancer therapy.Current opinion in chemical biology · 2026Review
- Methods for Conjugating Antibodies with Quantum Dots.Molecules (Basel, Switzerland) · 2025Review
- Modification of Cysteine-Substituted Antibodies Using Enzymatic Oxidative Coupling Reactions.Bioconjugate chemistry · 2023Article
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Authors and funding
6 authors.
Funding
Abstract
Catalytic antibody 38C2 and its humanized version h38C2 harbor a uniquely reactive lysine at the bottom of a 11 Å deep pocket that permits site-specific conjugation of β-diketone-, β-lactam-, and heteroaryl methylsulfonyl-functionalized small and large molecules. Various dual variable domain formats pair a tumor-targeting antibody with h38C2 to enable precise, fast, and stable assembly of antibody-drug conjugates (ADCs). Here, we expand the scope of this ADC assembly strategy by mutating h38C2's reactive lysine to a cysteine. X-ray crystallography of this point mutant, h38C2_K99C, confirmed a deeply buried unpaired cysteine. Probing h38C2_K99C with maleimide, monobromomaleimide, and dibromomaleimide derivatives of a fluorophore revealed highly disparate conjugation efficiencies and stabilities. Dibromomaleimide emerged as a suitable electrophile for the precise, fast, efficient, and stable assembly of ADCs with the h38C2_K99C module. Mass spectrometry indicated the presence of a thio-monobromomaleimide linkage which was further supported by in silico docking studies. Using a dibromomaleimide derivative of the highly potent tubulin polymerization inhibitor monomethyl auristatin F, h38C2_K99C-based ADCs were found to be as potent as h38C2-based ADCs and afford a new assembly route for ADCs with single and dual payloads.
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