Chicken-Derived Humanized Antibody Targeting a Novel Epitope F2pep of Fibroblast Growth Factor Receptor 2: Potential Cancer Therapeutic Agent

Keng Chang Tsai, Chao Di Chang, Ming Hui Cheng, Tsai Yu Lin, Yan Ni Lo, Tz Wen Yang, Fu Ling Chang, Chen Wei Chiang, Yu Ching Lee, Yun Yen

研究成果: 雜誌貢獻文章同行評審

6 引文 斯高帕斯(Scopus)

摘要

Fibroblast growth factors (FGFs) and their receptors control various biological functions. Dysregulated FGF signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling caused by FGFR2 overexpression has been observed in various human cancers, such as gastric cancer. Antibodies are highly suitable for target therapy because of their specificity toward FGFR2. Patients with cancer and aberrantly activated FGFR2 signaling can benefit from therapeutic intervention with FGFR2-targeting antibodies. In this study, we produced the anti-FGFR2 single-chain variable fragment (scFv) from immunized chickens through the phage display method. The isolated scFv S3 targeted designed epitope F2pep of FGFR2 and prevented the access of FGFs; thus, it exhibited the ability to inhibit cell growth in gastric cancer. Furthermore, scFv S3 recognized endogenous FGFR2 on the cancer cells and inhibited downstream cell signaling. To study the inhibition effect of the humanized immunoglobulin G (IgG) hS3 in vivo, nonobese diabetic/severe combined immunodeficiency mice were inoculated with SUN16 cancer cells. An intravenous injection of hS3 inhibited tumor growth in the mice. Moreover, the hS3 also inhibited angiogenesis in the matrix gel-assisted angiogenesis model. After using site-directed mutagenesis to identify the key residue on the hS3-targeting site of FGFR2, molecular modeling was used to determine the interaction between hS3 and FGFR2. Rational molecular docking analysis results revealed that two ionic interactions caused the interaction between scFv hS3 and the peptide F2pep of FGFR2. The results showed that antibody hS3 has high potential in cancer therapy in the future.

原文英語
頁(從 - 到)2387-2397
頁數11
期刊ACS Omega
4
發行號1
DOIs
出版狀態已發佈 - 1月 31 2019

ASJC Scopus subject areas

  • 一般化學
  • 一般化學工程

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