MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival.
The hepatocyte growth factor (HGF) and its receptor, c-Met, have been implicated in driving proliferation, invasion, and poor prognosis in pancreatic cancer. Here, we investigated the expression of HGF and c-Met in primary pancreatic cancers and described in vitro and in vivo models in which MetMAb, a monovalent antibody against c-Met, was evaluated. First, expression of HGF and MET mRNA was analyzed in 59 primary pancreatic cancers and 51 normal samples, showing that both factors are highly expressed in pancreatic cancer. We next examined HGF responsiveness in pancreatic cancer lines to select lines that proliferate in response to HGF. Based on these studies, two lines were selected for further in vivo model development: BxPC-3 (c-Met(+), HGF(-)) and KP4 (c-Met(+), HGF(+)) cells. As BxPC-3 cells are responsive to exogenous HGF, s.c. tumor xenografts were grown in a paracrine manner with purified human HGF provided by osmotic pumps, wherein MetMAb treatment significantly inhibited tumor growth. KP4 cells are autocrine for HGF and c-Met, and MetMAb strongly inhibited s.c. tumor growth. To better model pancreatic cancer and to enable long-term survival studies, an orthotopic model of KP4 was established. MetMAb significantly inhibited orthotopic KP4 tumor growth in 4-week studies monitored by ultrasound and also improved survival in 90-day studies. MetMAb significantly reduced c-Met phosphorylation in orthotopic KP4 tumors with a concomitant decrease in Ki-67 staining. These data suggest that the HGF/c-Met axis plays an important role in the progression of pancreatic cancer and that targeting c-Met therein may have therapeutic value.
Jin
Hongkui
H
Department of Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA. hkj@gene.com
Yang
Renhui
R
Zheng
Zhong
Z
Romero
Mally
M
Ross
Jed
J
Bou-Reslan
Hani
H
Carano
Richard A D
RA
Kasman
Ian
I
Mai
Elaine
E
Young
Judy
J
Zha
Jiping
J
Zhang
Zemin
Z
Ross
Sarajane
S
Schwall
Ralph
R
Colbern
Gail
G
Merchant
Mark
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D015398:Signal Transduction; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases