Journal
CHEMBIOCHEM
Volume 21, Issue 1-2, Pages 113-119Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201900587
Keywords
antibody-drug conjugates; bioconjugation; cysteine-selective linkers; protein conjugation; synthesis design
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SPP1623, HA4468/9-1, LE721/13-2, SFB1243/A01]
- Einstein Foundation Berlin (Leibniz-Humboldt Professorship)
- Boehringer-Ingelheim Foundation (Plus 3 award)
- Fonds der Chemischen Industrie
- Leibniz Association
- Leibniz Wettbewerb
- German Federal Ministry for Economic Affairs and Energy
- European Social Fund
- Bavarian Ministry of Economic Affairs, Regional Development and Energy
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Herein, the application of N-hydroxysuccinimide-modified phosphonamidate building blocks for the incorporation of cysteine-selective ethynylphosphonamidates into lysine residues of proteins, followed by thiol addition with small molecules and proteins, is reported. It is demonstrated that the building blocks significantly lower undesired homo-crosslinking side products that can occur with commonly applied succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of subsequent thiol addition. Furthermore, a method to separate the phosphonamidate enantiomers to be able to synthesize protein conjugates in a defined configuration has been developed. Finally, the building blocks are applied to the construction of functional antibody-drug conjugates, analogously to FDA-approved, SMCC-linked Kadcyla, and to the synthesis of a functional antibody-protein conjugate.
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