Patterson James T, Isaacson Jason, Kerwin Lisa, Atassi Ghazi, Duggal Rohit, Bresson Damien, Zhu Tong, Zhou Heyue, Fu Yanwen, Kaufmann Gunnar F
Sorrento Therapeutics, Inc., 4955 Directors Place, San Diego, CA 92121, USA.
Sorrento Therapeutics, Inc., 4955 Directors Place, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2017 Dec 15;27(24):5490-5495. doi: 10.1016/j.bmcl.2017.09.065. Epub 2017 Oct 6.
Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity.
生物偶联物形式为双特异性抗体的抗原靶向提供了替代策略。在此，使用不同的双特异性形式生成了靶向前列腺特异性膜抗原（PSMA）的Fab缀合物。αCD3 Fab的链间二硫键桥接使得能够通过共价连接安装靶向PSMA的小分子二氟甲基鸟氨酸（DUPA）（合成Fab）或连接αPSMA Fab（双特异性Fab）。还原条件的优化对于选择性链间二硫键还原和良好的生物偶联物产率至关重要。使用前列腺癌细胞系通过体外细胞毒性试验测试了αPSMA/CD3 Fab缀合物的活性。两种双特异性形式均表现出优异的效力和抗原选择性。
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