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Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys.

Zhang M, Zhang J, Yan M, Li H, Yang C, Yu D - Mol. Vis. (2008)

Bottom Line: The reduction of experimental CNV was greater in eyes treated with 300 microg and 500 microg KH902 than in eyes treated with 0.1 mg KH902 and the control eyes.The results of mf-ERG demonstrated that there was greater improvement in the 300 microg and 500 microg KH902-treated eyes than in the 100 microg KH902-treated eyes and control eyes.This study suggests that KH902 has promise as a local antiangiogenic treatment of CNV.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, West China Hospital, Sichuan University, China.

ABSTRACT

Purpose: KH902 is a fusion protein which combines ligand binding elements taken from the extracellular domains of vascular endothelial growth factor (VEGF) receptors 1 and 2 and the Fc portion of IgG1. This study is designed to examine the inhibitory effect of KH902 in the choroidal neovascularization (CNV) monkey model.

Methods: The binding affinity with VEGF was measured by using the human VEGF ELISA kit, and the biological activity effect of KH902 was assayed by an in vitro inhibition experiment on human umbilical vein endothelial cell proliferation that was induced by VEGF. The experimental CNV was induced by causing perimacular laser injury in the eyes of rhesus monkeys and confirmed by fluorescence fundus angiography (FFA), optical coherence tomography (OCT), and multifocal electroretinograms (mf-ERG) 20 days after the infliction of the laser injury. KH902 was delivered to the animals through intravitreal injection at various doses. Monkeys were observed four weeks after injection by ophthalmic examination, FFA, OCT, mf-ERG, histopathology, and immunohistochemistry analysis.

Results: KH902 binds VEGF at a high affinity with a mean of IC(50) of 10 pM. KH902 at 41 nM can completely block VEGF-induced cell proliferation and KH902 at 10.7 nM can block 82.6% of cell growth. In the eyes of the treatment group, which received 300 microg and 500 microg KH902, choroidal neovascularization leakage was obviously less than before injection, and no leakage was observed at the end of the observation after injection. No high reflect light echogenic mass was detected by OCT. However, in the 0.1 mg KH902-treated and control eyes, the leakage and high reflect light echogenic mass still existed. The reduction of experimental CNV was greater in eyes treated with 300 microg and 500 microg KH902 than in eyes treated with 0.1 mg KH902 and the control eyes. There were fiber-vasculosa membrane proliferation in the 100 microg KH902-treated eyes and control eyes but not in the 300 microg and 500 microg KH902-treated eyes under histopathologic observation. The results of mf-ERG demonstrated that there was greater improvement in the 300 microg and 500 microg KH902-treated eyes than in the 100 microg KH902-treated eyes and control eyes.

Conclusions: KH902 presents high affinity with VEGF and inhibitory activity on the proliferation of human umbilical vein endothelial cells (HUVECs) induced by VEGF. A single 300 microg or 500 microg KH902 intravitreal injection effectively inhibited leakage and growth of the CNV in rhesus monkeys without evidence of toxicity. This study suggests that KH902 has promise as a local antiangiogenic treatment of CNV.

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Related in: MedlinePlus

Local multifocal electroretinogram measurements on day 20 after laser and on day 28 after intravitreal injection. On day 20 after laser burn, the peak of the macular and the amplitudes of the retina that corresponded to those involved in CNV was markedly cut down. On day 28 after injection, the amplitudes increased and the function of locally involved retina improved compared to the results on day 20 after laser burn in the KH902-treated eyes, especially in the 300 μg and 500 μg KH902-treated one. But, there was no marked change in the control eye.
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f11: Local multifocal electroretinogram measurements on day 20 after laser and on day 28 after intravitreal injection. On day 20 after laser burn, the peak of the macular and the amplitudes of the retina that corresponded to those involved in CNV was markedly cut down. On day 28 after injection, the amplitudes increased and the function of locally involved retina improved compared to the results on day 20 after laser burn in the KH902-treated eyes, especially in the 300 μg and 500 μg KH902-treated one. But, there was no marked change in the control eye.

Mentions: Local mf-ERG measurement allows for mapping of retinal function, and the location of dysfunction in the retina can be indicative of its future potential impact on vision. On day 20 after laser burn, the three dimensional map of mf-ERG demonstrated that the peak of the macular and the amplitudes of the retina corresponding to those involved in CNV cut down markedly. Local dysfunction in the macular retina could be presented clearly. In the control eyes, the abnormality presented no change on days 14 and 28 after intravitreal injection. However, in treated eyes on day 20 after laser, the amplitudes increased and the function of locally involved retina improved. Especially on day 28, the peak of the macular recovered and the map of the macular retina improved in those that received 300 μg and 500 μg KH902 (Figure 11).


Recombinant anti-vascular endothelial growth factor fusion protein efficiently suppresses choridal neovasularization in monkeys.

Zhang M, Zhang J, Yan M, Li H, Yang C, Yu D - Mol. Vis. (2008)

Local multifocal electroretinogram measurements on day 20 after laser and on day 28 after intravitreal injection. On day 20 after laser burn, the peak of the macular and the amplitudes of the retina that corresponded to those involved in CNV was markedly cut down. On day 28 after injection, the amplitudes increased and the function of locally involved retina improved compared to the results on day 20 after laser burn in the KH902-treated eyes, especially in the 300 μg and 500 μg KH902-treated one. But, there was no marked change in the control eye.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2267739&req=5

f11: Local multifocal electroretinogram measurements on day 20 after laser and on day 28 after intravitreal injection. On day 20 after laser burn, the peak of the macular and the amplitudes of the retina that corresponded to those involved in CNV was markedly cut down. On day 28 after injection, the amplitudes increased and the function of locally involved retina improved compared to the results on day 20 after laser burn in the KH902-treated eyes, especially in the 300 μg and 500 μg KH902-treated one. But, there was no marked change in the control eye.
Mentions: Local mf-ERG measurement allows for mapping of retinal function, and the location of dysfunction in the retina can be indicative of its future potential impact on vision. On day 20 after laser burn, the three dimensional map of mf-ERG demonstrated that the peak of the macular and the amplitudes of the retina corresponding to those involved in CNV cut down markedly. Local dysfunction in the macular retina could be presented clearly. In the control eyes, the abnormality presented no change on days 14 and 28 after intravitreal injection. However, in treated eyes on day 20 after laser, the amplitudes increased and the function of locally involved retina improved. Especially on day 28, the peak of the macular recovered and the map of the macular retina improved in those that received 300 μg and 500 μg KH902 (Figure 11).

Bottom Line: The reduction of experimental CNV was greater in eyes treated with 300 microg and 500 microg KH902 than in eyes treated with 0.1 mg KH902 and the control eyes.The results of mf-ERG demonstrated that there was greater improvement in the 300 microg and 500 microg KH902-treated eyes than in the 100 microg KH902-treated eyes and control eyes.This study suggests that KH902 has promise as a local antiangiogenic treatment of CNV.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, West China Hospital, Sichuan University, China.

ABSTRACT

Purpose: KH902 is a fusion protein which combines ligand binding elements taken from the extracellular domains of vascular endothelial growth factor (VEGF) receptors 1 and 2 and the Fc portion of IgG1. This study is designed to examine the inhibitory effect of KH902 in the choroidal neovascularization (CNV) monkey model.

Methods: The binding affinity with VEGF was measured by using the human VEGF ELISA kit, and the biological activity effect of KH902 was assayed by an in vitro inhibition experiment on human umbilical vein endothelial cell proliferation that was induced by VEGF. The experimental CNV was induced by causing perimacular laser injury in the eyes of rhesus monkeys and confirmed by fluorescence fundus angiography (FFA), optical coherence tomography (OCT), and multifocal electroretinograms (mf-ERG) 20 days after the infliction of the laser injury. KH902 was delivered to the animals through intravitreal injection at various doses. Monkeys were observed four weeks after injection by ophthalmic examination, FFA, OCT, mf-ERG, histopathology, and immunohistochemistry analysis.

Results: KH902 binds VEGF at a high affinity with a mean of IC(50) of 10 pM. KH902 at 41 nM can completely block VEGF-induced cell proliferation and KH902 at 10.7 nM can block 82.6% of cell growth. In the eyes of the treatment group, which received 300 microg and 500 microg KH902, choroidal neovascularization leakage was obviously less than before injection, and no leakage was observed at the end of the observation after injection. No high reflect light echogenic mass was detected by OCT. However, in the 0.1 mg KH902-treated and control eyes, the leakage and high reflect light echogenic mass still existed. The reduction of experimental CNV was greater in eyes treated with 300 microg and 500 microg KH902 than in eyes treated with 0.1 mg KH902 and the control eyes. There were fiber-vasculosa membrane proliferation in the 100 microg KH902-treated eyes and control eyes but not in the 300 microg and 500 microg KH902-treated eyes under histopathologic observation. The results of mf-ERG demonstrated that there was greater improvement in the 300 microg and 500 microg KH902-treated eyes than in the 100 microg KH902-treated eyes and control eyes.

Conclusions: KH902 presents high affinity with VEGF and inhibitory activity on the proliferation of human umbilical vein endothelial cells (HUVECs) induced by VEGF. A single 300 microg or 500 microg KH902 intravitreal injection effectively inhibited leakage and growth of the CNV in rhesus monkeys without evidence of toxicity. This study suggests that KH902 has promise as a local antiangiogenic treatment of CNV.

Show MeSH
Related in: MedlinePlus