The effects of VEGF-A-inhibitors aflibercept and ranibizumab on the ciliary body and iris of monkeys.
OBJECTIVE
To investigate the effects of intravitreal ranibizumab (Lucentis®) and aflibercept (Eylea®) on the ciliary body and the iris of 12 cynomolgus monkeys with regard to the fenestrations of their blood vessels.


METHODS
Structural changes in the ciliary body and in the iris were investigated with light, fluorescent, and transmission electron microscopy (TEM). The latter was used to specifically quantify fenestrations of the endothelium of blood vessels after treatment with aflibercept and ranibizumab. Each of the two ciliary bodies treated with aflibercept and the two treated with ranibizumab and their controls were examined after 1 and 7 days respectively. Ophthalmological investigations including funduscopy and intraocular pressure measurements were also applied.


RESULTS
Ophthalmological investigations did not reveal any changes within the groups. Both drugs reduced the VEGF concentration in the ciliary body pigmented epithelium. The structure of the ciliary body was not influenced, while the posterior pigmented epithelium of the iris showed vacuoles after aflibercept treatment. Ranibizumab was mainly concentrated on the surface layer of the ciliary epithelium, in the blood vessel walls and the lumen of some of the blood vessels, and in the cells of the epithelium of the ciliary body. Aflibercept was more concentrated in the stroma and not in the cells of the epithelium, but as with ranibizumab, also in the blood vessel walls and some of their lumina, and again on the surface layer of the epithelium. Both aflibercept-and ranibizumab-treated eyes showed a decreased number of fenestrations of the capillaries in the ciliary body compared to the untreated controls. On day 1 and day 7, aflibercept had fewer fenestrations than the ranibizumab samples of the same day.


CONCLUSIONS
Both aflibercept and ranibizumab were found to reach the blood vessel walls of the ciliary body, and effectively reduced their fenestrations. Aflibercept might eliminate VEGF to a greater extent, possibly due to a higher elimination of fenestrations in a shorter time. Moreover, the vacuoles found in the iris need further research, in order to evaluate whether they carry a possible pathological potential.
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Maximilian
M
Ludinsky
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Sarah
S
Christner
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Nan
N
Su
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Tatjana
T
Taubitz
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Alexander
A
Tschulakow
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Antje
A
Biesemeier
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany.
Sylvie
S
Julien-Schraermeyer
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Schleichstrasse 12/1, 72076, Tuebingen, Germany. ulrich.schraermeyer@med.uni-tuebingen.de.|STZ OcuTox Preclinical Drug Assessment, Hechingen, Germany. ulrich.schraermeyer@med.uni-tuebingen.de.
Ulrich
U
Schraermeyer
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D002924:Ciliary Body / Q000098:blood supply / Q000187:drug effects* / Q000648:ultrastructure; D005451:Fluorescein Angiography; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D007498:Iris / Q000098:blood supply / Q000187:drug effects* / Q000648:ultrastructure; D008252:Macaca fascicularis; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D000069579:Ranibizumab / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab
Aflibercept; Anti-VEGF therapy; Blood vessels; Ciliary body; Electron microscopy; Fenestration; Iris; Ranibizumab