Preclinical development of a humanized neutralizing antibody targeting HGF
Experimental & Molecular Medicine
;
: e309-2017.
Artículo
en Inglés
| WPRIM
| ID: wpr-198940
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.
Texto completo:
Disponible
Índice:
WPRIM (Pacífico Occidental)
Asunto principal:
Fosforilación
/
Fosfotransferasas
/
Técnicas In Vitro
/
Farmacocinética
/
Línea Celular
/
Factor de Crecimiento de Hepatocito
/
Glioblastoma
/
Proliferación Celular
/
Anticuerpos Neutralizantes
/
Xenoinjertos
Tipo de estudio:
Estudio pronóstico
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
Experimental & Molecular Medicine
Año:
2017
Tipo del documento:
Artículo
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