Tumor inhibitory effect of IRCR201, a novel cross-reactive c-Met antibody targeting the PSI domain

Hyunkyu Park, Donggeon Kim, Eunmi Kim, Jason K. Sa, Hee Won Lee, Suji Yu, Jiwon Oh, Seok Hyung Kim, Yeup Yoon, Do Hyun Nam

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.

Original languageEnglish
Article number1968
JournalInternational journal of molecular sciences
Volume18
Issue number9
DOIs
Publication statusPublished - 2017 Sep 13
Externally publishedYes

Keywords

  • c-Met
  • Cancer
  • Cross-reactivity
  • Fully human antibody
  • IRCR201
  • PSI domain

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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