Strategic design to create HER2-targeting proteins with target-binding peptides immobilized on a fibronectin type III domain scaffold

Wanaporn Yimchuen, Tetsuya Kadonosono, Yumi Ota, Shinichi Sato, Maika Kitazawa, Tadashi Shiozawa, Takahiro Kuchimaru, Masumi Taki, Yuji Ito, Hiroyuki Nakamura, Shinae Kizaka-Kondoh

研究成果: Article査読

5 被引用数 (Scopus)

抄録

Tumor-binding peptides such as human epidermal growth factor receptor 2 (HER2)-binding peptides are attractive therapeutic and diagnostic options for cancer. However, the HER2-binding peptides (HBPs) developed thus far are susceptible to proteolysis and lose their affinity to HER2 in vivo. In this report, a method to create a HER2-binding fluctuation-regulated affinity protein (HBP-FLAP) consisting of a fibronectin type III domain (FN3) scaffold with a structurally immobilized HBP is presented. HBPs were selected by phage-library screening and grafted onto FN3 to create FN3-HBPs, and the HBP-FLAP with the highest affinity (HBP sequence: YCAHNM) was identified after affinity maturation of the grafted HBP. HBP-FLAP containing the YCAHNM peptide showed increased proteolysis-resistance, binding to HER2 with a dissociation constant (KD) of 58 nM in ELISA and 287 nM in biolayer interferometry and specifically detects HER2-expressing cancer cells. In addition, HBP-FLAP clearly delineated HER2-expressing tumors with a half-life of 6 h after intravenous injection into tumor-bearing mice. FN3-based FLAP is an excellent platform for developing target-binding small proteins for clinical applications.

本文言語English
ページ(範囲)15154-15162
ページ数9
ジャーナルRSC Advances
10
26
DOI
出版ステータスPublished - 2020 4月 17
外部発表はい

ASJC Scopus subject areas

  • 化学 (全般)
  • 化学工学(全般)

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