Preclinical development of a humanized neutralizing antibody targeting HGF.
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.
Asan Institute for Life Sciences, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea.
Hyori
H
Kim
National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Sung Hee
SH
Hong
National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Jung Yong
JY
Kim
National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
In-Chull
IC
Kim
National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Young-Whan
YW
Park
Yooyoung Central Research Institute, Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea.
Song-Jae
SJ
Lee
Yooyoung Central Research Institute, Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea.
Seong-Won
SW
Song
Yooyoung Central Research Institute, Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea.
Jung Ju
JJ
Kim
Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Gunwoo
G
Park
Department of Internal Medicine, Seoul National University Hospital, Jongno-gu, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea.
Tae Min
TM
Kim
Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.|Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Yun-Hee
YH
Kim
Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
Jong Bae
JB
Park
Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea.
Junho
J
Chung
Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
In-Hoo
IH
Kim
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy*; D004285:Dogs; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D008252:Macaca fascicularis; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000276:immunology
D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000074322:Antineoplastic Agents, Immunological; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met