Anti-PDGF-B monoclonal antibody reduces liver fibrosis development.
OBJECTIVE
To evaluate the usefulness of a platelet-derived growth factor (PDGF)-B specific monoclonal antibody (mAb) as a therapeutic agent to treat chronic liver fibrosis.


METHODS
Liver fibrosis was induced in ICR mice by bile duct ligation (BDL) or BALB/c mice by weekly injection of concanavalin A (ConA) for 4 or 8 weeks. A mAb specific for mouse and human PDGF-B chain, AbyD3263, was generated, tested in vitro and administered twice a week throughout the experimental period.


RESULTS
AbyD3263 showed neutralizing activity against mouse and human PDGF-B chain in cell-based assays, as measured in vitro by inhibition of phosphorylation of PDGF receptor β and proliferation of hepatic stellate cells induced by PDGF-BB. The half life of AbyD3263 in mice exceeded 7 days and dosing of animals twice a week resulted in constant plasma levels of the mAb. Induction of liver fibrosis by BDL and ConA resulted in elevated levels of alanine aminotransferase (ALT) in plasma and hydroxyproline in the liver. Treatment with AbyD3263 did not modify ALT levels, but significantly reduced hydroxyproline content in the liver with a maximum reduction of 39% and 54% in the BDL and ConA models, respectively, compared to controls. Conclusios:  Consistent with the notion that PDGF-BB plays an important role in the progression of liver fibrosis, AbyD3263 exhibits efficacy in pre-clinical disease models suggesting that pharmacological inhibition of PDGF-B chain may be a therapeutic approach to treat liver fibrosis.
Ogawa
Shinji
S
Inflammation Research Unit Pharmaceutical Sciences Biotherapeutics CoE, St. Louis Laboratories, Pfizer Global Research and Development Asia Research, Pfizer Worldwide Research and Development, Chesterfield Parkway West, Chesterfield, Missouri, USA Discovery Biology Drug Safety Research & Development, Nagoya Laboratories, Pfizer Global Research and Development, Taketoyo, Aichi, Japan.
Ochi
Takashi
T
Shimada
Hideaki
H
Inagaki
Kazuyuki
K
Fujita
Isami
I
Nii
Aisuke
A
Moffat
Mark A
MA
Katragadda
Madan
M
Violand
Bernard N
BN
Arch
Robert H
RH
Masferrer
Jaime L
JL