Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes.
BACKGROUND
Since there is evidence that the Fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept on monkey eyes were investigated.


METHODS
Four cynomolgus monkeys were intravitreally injected with 0.5 mg of ranibizumab and another four with 2 mg of aflibercept. Two untreated monkeys served as controls. Funduscopy, fluorescein angiography (FA), spectral-domain-optical coherence tomography (SD-OCT) and measurement of intraocular pressure (IOP) were performed. The eyes were inspected by light, fluorescence and electron microscopy. The diameter of the choriocapillaris (CC) was measured by morphometry, and the areas of the CC with free haemoglobin, CC fenestrations and endothelial thickness were quantified.


RESULTS
Analysis showed ranibizumab permeated the retina via intercellular clefts, whereas aflibercept was taken up by ganglion cells, cells of the inner and outer retinal layers and the retinal pigment epithelium (RPE). Stasis and haemolysis in the choriocapillaris and choroidal vessels were more frequent after aflibercept treatment, which caused hypertrophy and death of individual RPE cells. The area of the CC was significantly reduced after both drugs compared with controls, but the reduction of the CC endothelium thickness, number of fenestrations and the areas with haemolysis were more pronounced after aflibercept.


CONCLUSIONS
Ranibizumab permeated the retina through intercellular spaces, whereas aflibercept was taken up by neuronal and RPE cells. Aflibercept induced protein complex formation and more haemolysis in the choriocapillaris, leading to individual RPE cell death. The clinical significance and relation of these findings to the Fc domain or to other characteristics of aflibercept remain to be investigated.
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany Preclinical Drug Assessment, STZ OcuTox, Tübingen, Germany.
Sylvie
S
Julien
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany.
Antje
A
Biesemeier
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany Preclinical Drug Assessment, STZ OcuTox, Tübingen, Germany.
Tatjana
T
Taubitz
Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany Preclinical Drug Assessment, STZ OcuTox, Tübingen, Germany.
Ulrich
U
Schraermeyer
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects; D002829:Choroid / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005451:Fluorescein Angiography; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000187:drug effects; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D008840:Microfilament Proteins / Q000378:metabolism; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D012171:Retinal Vessels / Q000187:drug effects; D041623:Tomography, Optical Coherence; D014746:Vimentin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D005904:Glial Fibrillary Acidic Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008840:Microfilament Proteins; D011993:Recombinant Fusion Proteins; D014746:Vimentin; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab
Choroid; Drugs; Neovascularisation; Retina