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Evidence for the efficacy of PlGF inhibition in age‐related macular degeneration
Author(s) -
VAN DE VEIRE S,
CARMELIET P,
VAN BERGEN T,
MOONS L,
STALMANS I
Publication year - 2010
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2010.3215.x
Subject(s) - choroidal neovascularization , macular degeneration , medicine , antibody , cancer research , placental growth factor , immunology , endocrinology , pharmacology , vascular endothelial growth factor , vegf receptors , ophthalmology
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 5D11D4 was assessed in this study. Methods CNV was induced in mice by placing 3 laser burns on the choroid. Mice with a PlGF deficiency or a lacking tyrosin kinase domain of the Flt‐1R or with a knock‐down of the monocyte chemoattractive protein were generated. The optimal dose of 25mg/kg of 5D11D4 was injected in all mice ip. 3 times a week. Results In a first experiment, 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. Second, Ccl2‐/‐ mice 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 again by 53%. Third, we investigated whether PlGF signaling works specifically through Flt1 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. Fourth, we also tested the murine anti‐human PlGF mAb 16D3 in humanized PlGF‐/‐ mice. Human PlGF‐2 increased laser‐induced CNV after 5 days, but this increase was again blocked by 16D3. And finally, of two other anti‐mPlGF mAbs, 3C7A8 and 12H6B6, the first one inhibited CNV, while 12H6B6 was ineffective Conclusion We have proven that 5D11D4 specifically inhibits laser‐induced CNV formation, in different transgenic models and that this effect is mediated via the Flt1 receptor.