Preclinical development of a humanized neutralizing antibody targeting HGF.
- Author:
Hyori KIM
1
;
Sung Hee HONG
;
Jung Yong KIM
;
In Chull KIM
;
Young Whan PARK
;
Song Jae LEE
;
Seong Won SONG
;
Jung Ju KIM
;
Gunwoo PARK
;
Tae Min KIM
;
Yun Hee KIM
;
Jong Bae PARK
;
Junho CHUNG
;
In Hoo KIM
Author Information
- Publication Type:Original Article
- MeSH: Animals; Antibodies, Neutralizing*; Cell Line; Cell Proliferation; Glioblastoma; Half-Life; Hepatocyte Growth Factor; Heterografts; Humans*; In Vitro Techniques; Macaca fascicularis; Mice; Mice, Nude; Pharmacokinetics; Phosphorylation; Phosphotransferases; Toxicokinetics
- From:Experimental & Molecular Medicine 2017;49(3):e309-
- CountryRepublic of Korea
- Language:English
- Abstract: 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.
