2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation.
2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation.
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DOI：
10.1038/srep30835
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发表时间：
2016-08-09
影响因子：
4.6
通讯作者：
Wagner A
中科院分区：
文献类型：
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作者：
Dovgan I;Kolodych S;Koniev O;Wagner A
绝大多数抗体-药物缀合物（ADC）通过胺-巯基缀合制备。迄今为止，N-琥珀酰亚胺基-4-（马来酰亚胺甲基）环己烷羧酸酯（SMCC）已成为用于制备ADC和其它功能缀合物的最常用试剂之一。然而，基于SMCC的缀合物在血液循环中的稳定性有限，并且接头具有疏水特性，这可能引起主要的药代动力学影响。为了解决这个问题，我们开发了SMCC试剂的异双功能类似物，即，4-（马来酰亚胺基甲基）-1，3-二氧杂环己烷-5-羰基）氧基）-2，3，5，6-四氟苯磺酸钠（MDTF）用于胺-硫醇缀合。通过用1，3-二氧六环取代SMCC结构中的环己基环，我们增加了连接体的亲水性。制备了基于MD接头的FRET探针，与MCC接头相比，其在人血浆以及各种水性缓冲液中显示出上级稳定性。详细的研究证明了MD接头的加速琥珀酰亚胺开环，产生稳定的缀合物。最后，将MDTF试剂用于制备血清稳定的抗体-染料偶联物。
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.