Bauerschlag Dirk, Meinhold-Heerlein Ivo, Maass Nicolai, Bleilevens Andreas, Bräutigam Karen, Al Rawashdeh Wa'el, Di Fiore Stefano, Haugg Anke Maria, Gremse Felix, Steitz Julia, Fischer Rainer, Stickeler Elmar, Barth Stefan, Hussain Ahmad Fawzi
Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, 24105, Kiel, Germany.
Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
Pharm Res. 2017 Apr;34(4):696-703. doi: 10.1007/s11095-017-2096-4. Epub 2017 Jan 10.
Targeted theranostics is an alternative strategy in cancer management that aims to improve cancer detection and treatment simultaneously. This approach combines potent therapeutic and diagnostic agents with the specificity of different cell receptor ligands in one product. The success of antibody drug conjugates (ADCs) in clinical practice has encouraged the development of antibody theranostics conjugates (ATCs). However, the generation of homogeneous and pharmaceutically-acceptable ATCs remains a major challenge. The aim of this study is to detect and eliminate ovarian cancer cells on-demand using an ATC directed to EGFR.
An ATC with a defined drug-to-antibody ratio was generated by the site-directed conjugation of IRDye®700 to a self-labeling protein (SNAP-tag) fused to an EGFR-specific antibody fragment (scFv-425).
In vitro and ex vivo imaging showed that the ATC based on scFv-425 is suitable for the highly specific detection of EGFR ovarian cancer cell, human tissues and ascites samples. The construct was also able to eliminate EGFR cells and human ascites cells with IC values of 45-66 nM and 40-90 nM, respectively.
Our experiments provide a framework to create a versatile technology platform for the development of ATCs for precise detection and treatment of ovarian cancer cells.
靶向治疗诊断是癌症管理中的一种替代策略,旨在同时改善癌症检测和治疗。这种方法将强效治疗和诊断剂与一种产品中不同细胞受体配体的特异性相结合。抗体药物偶联物(ADC)在临床实践中的成功推动了抗体治疗诊断偶联物(ATC)的发展。然而,生成均一且符合药学要求的ATC仍然是一项重大挑战。本研究的目的是使用一种针对表皮生长因子受体(EGFR)的ATC按需检测和消除卵巢癌细胞。
通过将IRDye®700定点偶联到与EGFR特异性抗体片段(单链抗体片段-425,scFv-425)融合的自标记蛋白(SNAP-tag)上,生成具有确定药物与抗体比例的ATC。
体外和离体成像显示,基于scFv-425的ATC适用于EGFR卵巢癌细胞、人体组织和腹水样本的高特异性检测。该构建体还能够消除EGFR细胞和人腹水细胞,其半数抑制浓度(IC)值分别为45 - 66 nM和40 - 90 nM。
我们的实验提供了一个框架,用于创建一个通用技术平台,以开发用于精确检测和治疗卵巢癌细胞的ATC。