内化
成纤维细胞生长因子受体
成纤维细胞生长因子受体1
细胞毒性T细胞
结合
癌症研究
化学
受体
连接器
癌细胞
乳腺癌
癌症
药理学
成纤维细胞生长因子
生物化学
医学
体外
内科学
计算机科学
数学分析
数学
操作系统
作者
Mateusz Adam Krzyścik,Natalia Porębska,Łukasz Opaliński,Jacek Otlewski
标识
DOI:10.1016/j.ijbiomac.2023.127657
摘要
Breast cancer remains a significant global health challenge, necessitating the development of effective targeted therapies. This study aimed to create bispecific targeting molecules against HER2 and FGFR1, two receptors known to play crucial roles in breast cancer progression. By combining the high-affinity Affibody ZHER2:2891 and a modified, stable form of fibroblast growth factor 2 (FGF2), we successfully generated bispecific proteins capable of simultaneously recognizing HER2 and FGFR1. Two variants were designed: AfHER2-sFGF2 with a shorter linker and AfHER2-lFGF2 with a longer linker between the HER2 and FGFR1-recognizing proteins. Both proteins exhibited selective binding to HER2 and FGFR1, with AfHER2-lFGF2 demonstrating simultaneous binding to both receptors. AfHER2-lFGF2 exhibited superior internalization compared to FGF2 in FGFR-positive cells and significantly increased internalization compared to AfHER2 in HER2-positive cells. To enhance their therapeutic potential, highly potent cytotoxic agent MMAE was conjugated to the targeting proteins, resulting in protein-drug conjugates. The bispecific AfHER2-lFGF2-vcMMAE conjugate demonstrated exceptional cytotoxic activity against HER2-positive, FGFR-positive, and dual-positive cancer cell lines that was significantly higher compared to monospecific conjugates. These data indicate the beneficial effect of simultaneous targeting of HER2 and FGFR1 in precise anticancer medicine and contribute valuable insights into the design and potential of bispecific targeting molecules for breast cancer treatment.
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