| Project/Area Number |
12671717
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Ophthalmology
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| Research Institution | Nagoya City University |
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Principal Investigator |
KIMURA Hideya Nagoya City University Medical School, Associate Professor, 医学部, 講師 (50252440)
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| Co-Investigator(Kenkyū-buntansha) |
OGURA Yuichiro Nagoya City University Medical School, Professor, 医学部, 教授 (70191963)
尾関 年則 名古屋市立大学, 医学部, 講師 (60254299)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | choroidal neovascularization / age-related macular degeneration / vascular endotelial cell / monoclonal antibody / targeting / immunoconjugate / integrin α v β 3 / intergrinαvβ3 / integrinαvβ3 |
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| Research Abstract |
Integrin α v β 3 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 monoclonal antibody-mediated drug targeting of choroidal neovascularization (CNV). The objective of this study was to evaluate the efficacy of drug targeting mediated by anti-integrin α v β monoclonal antibody (mAb) in a laser-induced CNV rat model.
The mitomycin C (MMC)-dextran conjugate (MMCD) was synthesized with a carbodiimide-catalyzed reaction. The mAb was conjugated with MMCD (MMCD-mAv). To evaluate the feasibility of mAb-mediated drug targeting in vitro, we investigated the effect of the immunoconjugates involving dextran-binding mitomycin C (MMC) on the proliferation of human umbilical vein endothelial cells (HUVECs). CNV was induced by laser photocoagulation in rats. Immunolocalization of integrin α v β 3 in CNV lesions was assessed immunohistochemically. Intravenous administration of saline (n=7), 1 mg per day of mAb (n=7), 100 μg/kg per day of free MMC (n=7), MMCD-irrelevant Av (n=7), unconjugated MMCD with unconjugated mAb (MMCD+mAv)(n=7)m ir NNCD-mAb(n=8) with an equal amount of free MMC was performed daily for 3 days from day 14 after CNV induction. CNV was assessed by fluorescein angiography two weeks after treatmentand histologically.
The inhibition of immunoconjugates on the proliferation of HUVECs was enhanced specifically by the mediatory effect of mAb. Endothelial cells demonstrated strong imunoreactivity of integrin α v β 3 in the CNV. MMCD-mAb significantly reduced in the MMCD-mAb treated group (P < 0.01). Moreover, the thickness of the lesions was significantly reduced in the MMCD-mAb treated group (P < 0.01).
Immunoconjugates effectively inhibited progression of CNV in this model. The results suggest that monoclonal antibody-mediated drug targeting may be beneficial in the treatment of CNV.
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