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Bis(vinylsulfonyl)piperazines as efficient linkers for highly homogeneous antibody-drug conjugates.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.ejmech.2020.112080
Rong Huang 1 , Yao Sheng 2 , Ding Wei 1 , Jianghui Yu 1 , Hongli Chen 2 , Biao Jiang 2
Affiliation  

Disulfide re-bridging strategy has demonstrated significant advantages in the construction of homogeneous antibody drug conjugates (ADCs). However, a major issue that disulfide scrambling at the hinge region of antibody leads to the formation of "half-antibody" has appeared for many re-bridging linkers. We present bis(vinylsulfonyl)piperazines (BVP) as efficient linkers to selectively re-bridge disulfides at the antigen-binding fragment (Fab) regions and produce highly homogeneous conjugates with a loading of two drugs without disulfide scrambling. We also found that optically active (S)-configuration linkers led to more sufficient conjugation compared with (R)-configuration. The BVP-linked ADCs demonstrated superior efficacy and antigen-selectivity in vitro cytotoxicity.

中文翻译:

双(乙烯基磺酰基)哌嗪作为高度均一的抗体-药物偶联物的有效连接子。

二硫键的再桥策略已证明在构建均相抗体药物偶联物(ADC)中具有显着优势。然而,对于许多重新桥连的接头,已经出现了一个主要问题,即二硫键在抗体的铰链区上的加扰导致“半抗体”的形成。我们提出双(乙烯基磺酰基)哌嗪(BVP)作为有效的接头,以选择性地在抗原结合片段(Fab)区域重新桥联二硫键,并产生高度均质的结合物,其中两种药物的负载均不加扰二硫键。我们还发现,与(R)-构型相比,光学活性的(S)-构型接头导致更充分的共轭。与BVP相连的ADC在体外细胞毒性方面显示出优异的功效和抗原选择性。
更新日期:2020-01-22
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