Antitumor activity, pharmacokinetics, tumor-homing effect, and hepatotoxicity of a species cross-reactive c-Met antibody

Hyunkyu Park, Donggeon Kim, Eunju Son, Sunhwa Shin, Jason K. Sa, Seok Hyung Kim, Yeup Yoon, Do Hyun Nam

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models.

Original languageEnglish
Pages (from-to)409-415
Number of pages7
JournalBiochemical and biophysical research communications
Volume494
Issue number1-2
DOIs
Publication statusPublished - 2017 Dec 9
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) ( HI14C3418 ), funded by the Ministry of Health & Welfare, Republic of Korea . ( HI14C3418 ).

Publisher Copyright:
© 2017

Keywords

  • Antitumor activity
  • c-Met
  • Cancer
  • Cross-reactivity
  • Fully human antibody

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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