April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
The Anti-plgf Antibody (5d11d4) Specifically Reduces Choroidal Neovascularization in vivo on a Mouse Model
Author Affiliations & Notes
  • S. van de veire
    Ophthalmology, Universitaire Ziekenhuizen Leuven (UZLeuven), Leuven, Belgium
    Laboratory of Ophthalmology,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • T. Van Bergen
    Laboratory of Ophthalmology,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • M. Mazzone
    Vesalius Research Center,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • B. Jonckx
    Vesalius Research Center,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • S. A. Vinores
    Vesalius Research Center,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
    Johns Hopkins University School of Medicine, Wilmer Eye Instutute, Baltimore, Maryland
  • L. Moons
    Biology,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • I. Stalmans
    Ophthalmology, Universitaire Ziekenhuizen Leuven (UZLeuven), Leuven, Belgium
    Laboratory of Ophthalmology,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • P. Carmeliet
    Vesalius Research Center,
    Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium
  • Footnotes
    Commercial Relationships  S. van de veire, None; T. Van Bergen, None; M. Mazzone, None; B. Jonckx, None; S.A. Vinores, None; L. Moons, None; I. Stalmans, None; P. Carmeliet, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 4510. doi:
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      S. van de veire, T. Van Bergen, M. Mazzone, B. Jonckx, S. A. Vinores, L. Moons, I. Stalmans, P. Carmeliet; The Anti-plgf Antibody (5d11d4) Specifically Reduces Choroidal Neovascularization in vivo on a Mouse Model. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4510.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : We previously showed that an anti-PlGF antibody (5D11D4) inhibits choroidal neovascularization (CNV) in a mouse model of AMD. An additive effect was shown in combination therapy with an anti-VEGFR antibody. Specificity of this antibody was assessed in this study.

Methods: : CNV was induced in mice by placing 3 Argon laser burns on the choroid. Mice with a genetic loss of PlGF (PlGF-/- mice), with a lacking tyrosin kinase domain of the Flt-1 receptor (Flt1:TK-/- mice) and with a knock-down of the monocytes chemoattractive protein (CCl2-/- mice) were generated. The optimal dose of 25mg/kg of 5D11D4 was injected ip. for 3 times a week.

Results: : In a first experiment, confirming previous findings, loss of PlGF inhibited CNV; however, administration of 5D11D4 to PlGF-/- mice did not inhibit CNV further than in control-treated PlGF-/- mice, indicating that 5D11D4 did not have off-target effects in this model. Second, Ccl2-/- mice, a known model for AMD, developed a CNV lesion that was slightly larger than in WT mice within 14 days after laser-injury. Notably, 5D11D4 was able to inhibit CNV by 53%. Third, we investigated whether PlGF signaling through Flt1 is essential in CNV. FITC-dextran perfused flatmounts revealed that CNV lesions were indeed reduced by 70% in Flt1-TK-/- mice, comparably as observed in PlGF-/- mice. 5D11D4 was unable to inhibit CNV in Flt1-TK-/- mice any further, suggesting that Flt1 mediates the activity of PlGF. Fourth, intravitreal injection of a 5D11D4 Fab fragment every 2 days in WT mice inhibited CNV, comparable to the inhibition, achieved with systemic injection of the full length 5D11D4 mAb. Fifth, we also tested the high-affinity murine anti-human PlGF mAb 16D3 in humanized PlGF-/- mice. Human PlGF-2 enhanced CNV, but this increase was again blocked by 16D3. And finally, of two other high-affinity binding anti-mPlGF mAbs, 3C7A8 and 12H6B6, the first one inhibited CNV, while 12H6B6 was ineffective, showing that anti-PlGF mAb clones with proven efficacy in vitro are not necessarily effective in blocking PlGF-driven processes in vivo.

Conclusions: : We have proved that 5D11D4 specifically inhibits laser-induced CNV formation, in different transgenic models and that this effect is mediated via the Flt1 receptor.

Keywords: choroid: neovascularization • growth factors/growth factor receptors • drug toxicity/drug effects 
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