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- 2017.1
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Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.
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참고문헌 (22)
참고문헌 신청
Aune G / 2011 / Increased circulating hepatocyte growth factor(HGF) : a marker of epithelial ovarian cancer and an indicator of poor prognosis / Gynecol Oncol 121 : 402 ~ 406
Birchmeier C / 2003 / Met, metastasis, motility and more / Nat Rev Mol Cell Biol 4 : 915 ~ 925
Burnette WN / 1981 / ‘Western blotting’ : electrophoretic transfer of proteins from sodium dodecyl sulfate?polyacrylamide gels to unmodified nitrocellulose and radiographi
Christensen JG / 2005 / c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention / Cancer Lett 225 : 1 ~ 26
Cunningham DTN / 2015 / Phase III, randomized, doubleblind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as
Birchmeier C / 2003 / Met, metastasis, motility and more / Nat Rev Mol Cell Biol 4 : 915 ~ 925
Burnette WN / 1981 / ‘Western blotting’ : electrophoretic transfer of proteins from sodium dodecyl sulfate?polyacrylamide gels to unmodified nitrocellulose and radiographi
Christensen JG / 2005 / c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention / Cancer Lett 225 : 1 ~ 26
Cunningham DTN / 2015 / Phase III, randomized, doubleblind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as
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