Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai, 201210, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Shijingshan District, Beijing, 100049, China.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai, 201210, China.
Eur J Med Chem. 2020 Mar 15;190:112080. doi: 10.1016/j.ejmech.2020.112080. Epub 2020 Jan 22.
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.
二硫键重桥接策略在均一抗体药物偶联物（ADC）的构建中具有显著优势。然而，对于许多重桥接连接子，抗体铰链区域中二硫键的错配会导致“半抗体”的形成，这是一个主要问题。我们提出双（乙烯砜基）哌嗪（BVP）作为有效的连接子，以选择性地在抗原结合片段（Fab）区域重新桥接二硫键，并在没有二硫键错配的情况下产生具有两个药物载量的高度均一的缀合物。我们还发现，与（R）构型相比，光学活性（S）构型的连接子导致更充分的缀合。BVP 连接的 ADC 在体外细胞毒性方面表现出更好的疗效和抗原选择性。
