Purchase this article with an account.
Hiroshi Kamizuru, Hideya Kimura, Tsutomu Yasukawa, Yasuhiko Tabata, Yoshihito Honda, Yuichiro Ogura; Monoclonal Antibody-Mediated Drug Targeting to Choroidal Neovascularization in the Rat. Invest. Ophthalmol. Vis. Sci. 2001;42(11):2664-2672.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
purpose. Active drug targeting mediated by monoclonal antibodies (mAbs)
of vascular endothelial cells in tumors is a new concept in cancer
therapy. Integrin αvβ3 has been reported to be strongly expressed
in vascular endothelial cells of surgically excised choroidal
neovascular membranes and is thought to be a potential antigen for
mAb-mediated drug targeting of choroidal neovascularization (CNV). The
objective of this study was to evaluate the efficacy of drug targeting
mediated by anti-integrin αvβ3 mAbs in a laser-induced CNV rat
methods. The mitomycin C (MMC)-dextran (MMCD) conjugate was synthesized with a
carbodiimide-catalyzed reaction. The mAb was conjugated with MMCD
(MMCD-mAb). To evaluate the feasibility of mAb-mediated drug targeting
in vitro, we investigated the effect of the immunoconjugates involving
dextran-binding MMC on the proliferation of human umbilical vein
endothelial cells (HUVECs). CNV was induced by laser photocoagulation
in male Brown Norway rats. Immunolocalization of integrin αvβ3 in
CNV lesions was assessed immunohistochemically with the anti-von
Willebrand factor antibody as an endothelial cell marker. Intravenous
administration of saline (n = 7), 1 mg/day mAb (n= 7), 100 μg/kg per day free MMC (n = 7), MMCD
with irrelevant Ab (n = 7), unconjugated MMCD with
unconjugated mAb (MMCD+mAb; n = 7), or MMCD with mAb
(MMCD-mAb; n = 8) containing an equal amount of free
MMC, was performed daily for 3 days from day 14 after CNV induction.
CNV was assessed by fluorescein angiography 2 weeks after treatment.
Fluorescein leakage was scored on a four-grade scale. The animals were
killed 2 weeks after treatment, and the lesions were evaluated
results. The inhibition of immunoconjugates on the proliferation of HUVECs was
enhanced specifically by the mediatory effect of the mAb. Endothelial
cells demonstrated strong immunoreactivity of integrin αvβ3 in the
CNV. In the vehicle-treated group, fluorescein leakage equal to that
before treatment was observed 2 weeks after treatment, with an average
score of 2.00 ± 0.17 (mean ± SEM). MMCD-mAb significantly
inhibited the development of CNV in rats (P <
0.01). Moreover, the thickness of the lesions was significantly reduced
in the MMCD-mAb–treated group (P < 0.01).
conclusions. Immunoconjugates effectively inhibited progression of CNV in this
model. The results suggest that mAb-mediated drug targeting may be
beneficial in the treatment of CNV.
This PDF is available to Subscribers Only