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- Title
Bis‐ethynylphosphonamidates as an Modular Conjugation Platform to Generate Multi‐Functional Protein‐ and Antibody‐Drug‐Conjugates.
- Authors
Kasper, Marc‐André; Lassak, Lukas; Vogl, Annette M.; Mai, Isabelle; Helma, Jonas; Schumacher, Dominik; Hackenberger, Christian P. R.
- Abstract
Bis‐ethynylphosphonamidates allow for a simple chemoselective addition of two thiol‐containing modules in a row. We describe four such bis‐electrophiles that carry different functional O‐substituents with tunable hydrophilicity and enable further subsequent conjugations, thus facilitating a simple protocol for constructing protein‐protein conjugates. An increased spacer length between the two ethynylphosphonamidates simplifies the formation of a conjugate from two bulky proteins. We apply these reagents to obtain homogeneous Antibody‐Drug‐Conjugates (ADCs) from DM1 and trastuzumab with excellent cytotoxicity and selectivity for the targeted cell line. Moreover, a bis‐ethynylphosphonamidate, carrying an additional alkyne for a chemoselective triple conjugation, has been subjected to fluorescent labeling of an ADC specifically at the drug site give an Antibody‐Drug‐Fluorophore‐Conjugate (ADFC), allowing for the observation of intracellular trafficking after ADC uptake into the targeted cell.
- Subjects
TRASTUZUMAB; CELL lines
- Publication
European Journal of Organic Chemistry, 2022, Vol 2022, Issue 10, p1
- ISSN
1434-193X
- Publication type
Article
- DOI
10.1002/ejoc.202101389