title: 2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation.
abstract: The vast majority of antibody-drug conjugates (ADC) are prepared through amine-to-thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the preparation of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analogue of a SMCC reagent, i.e., sodium 4-(maleimidomethyl)-1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine-to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepared and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aqueous buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the preparation of serum stable antibody-dye conjugate.
authors: Laboratory of Functional ChemoSystems (UMR 7199), LabEx Medalis, University of Strasbourg, France.
authors: Igor
authors: I
authors: Dovgan
authors: Syndivia SAS, 650 Boulevard Gonthier d'Andernach, 67400 Illkirch, France.
authors: Sergii
authors: S
authors: Kolodych
authors: Syndivia SAS, 650 Boulevard Gonthier d'Andernach, 67400 Illkirch, France.
authors: Oleksandr
authors: O
authors: Koniev
authors: Laboratory of Functional ChemoSystems (UMR 7199), LabEx Medalis, University of Strasbourg, France.|Syndivia SAS, 650 Boulevard Gonthier d'Andernach, 67400 Illkirch, France.
authors: Alain
authors: A
authors: Wagner