Exp Mol Med.
2017 Mar;49(3):e309. 10.1038/emm.2017.21.
Preclinical development of a humanized neutralizing antibody targeting HGF
- Affiliations
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- 1Asan Institute for Life Sciences, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
- 2National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
- 3Yooyoung Central Research Institute, Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea.
- 4Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
- 5Department of Internal Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Republic of Korea.
- 6Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea.
- 7Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. ikim@ncc.re.kr
- 8Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
- 9Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea. jjhchung@snu.ac.kr
- KMID: 2375796
- DOI: http://doi.org/10.1038/emm.2017.21
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.
MeSH Terms
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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
Antibodies, Neutralizing
Hepatocyte Growth Factor
Phosphotransferases
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