Abstract
The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer.
Keywords:
C-Met; Hepatocyte growth factor (HGF); Prostate cancer; Rabbit monoclonal antibody.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Monoclonal / biosynthesis
-
Antibodies, Monoclonal / isolation & purification
-
Antibodies, Monoclonal / pharmacology*
-
Antibodies, Neutralizing / biosynthesis
-
Antibodies, Neutralizing / isolation & purification
-
Antibodies, Neutralizing / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Gene Expression Regulation, Neoplastic*
-
Hepatocyte Growth Factor / antagonists & inhibitors*
-
Hepatocyte Growth Factor / genetics
-
Hepatocyte Growth Factor / metabolism
-
Human Umbilical Vein Endothelial Cells / cytology
-
Human Umbilical Vein Endothelial Cells / drug effects
-
Human Umbilical Vein Endothelial Cells / metabolism
-
Humans
-
Male
-
Mice
-
Mice, Nude
-
Phosphorylation / drug effects
-
Prostate / drug effects
-
Prostate / metabolism
-
Prostate / pathology
-
Prostatic Neoplasms / drug therapy*
-
Prostatic Neoplasms / genetics
-
Prostatic Neoplasms / metabolism
-
Prostatic Neoplasms / pathology
-
Protein Binding / drug effects
-
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-met / genetics
-
Proto-Oncogene Proteins c-met / metabolism
-
Rabbits
-
Signal Transduction
-
Structure-Activity Relationship
-
Xenograft Model Antitumor Assays
Substances
-
Antibodies, Monoclonal
-
Antibodies, Neutralizing
-
Hepatocyte Growth Factor
-
Proto-Oncogene Proteins c-met