Choroidal consequences differ between anti-VEGF therapies

Aflibercept’s possession of a fragment crystallisable (Fc) region may make it more likely to induce unwanted effects in retinal and choroidal vessels than other anti-vascular endothelial growth factor (VEGF) therapies, say researchers.

Anti-VEGF therapies have become the standard treatment for wet age-related macular degeneration, but they differ in their sites and modes of activity.

Aflibercept, a newer agent, is a fully human, recombinant fusion protein composed of the second immunoglobulin (Ig)-binding domain of VEGF receptor (VEGFR)1 and the third Ig-binding domain of the VEGFR2 fused to the Fc region of human IgG1 and works by binding to all VEGF-A isoforms, VEGF-B and placental growth factor.

By contrast, ranibizumab is an affinity-matured, humanised, monoclonal antibody fragment that works by blocking the receptor-binding domain of all isoforms of VEGF-A.

Researcher Ulrich Schraermeyer (Centre for Ophthalmology, Tuebingen, Germany) and colleagues compared the effects of these two anti-VEGF therapies on both eyes of eight cynomolgus monkeys intravitreally injected with either ranibizumab or aflibercept. Two untreated monkeys served as controls.

Immunohistochemistry showed that ranibizumab permeated the retina through intercellular spaces, whereas aflibercept was taken up by neuronal and retinal pigment epithelium (RPE) cells.

Both anti-VEGF therapies were associated with a reduction of the choriocapillaris area compared with no treatment, and eryptosis was observed after both treatments.

Stasis and haemolysis were observed occasionally in the choriocapillaris 7 days after ranibizumab injection, but by this time, aflibercept had already caused stasis and haemolysis in most parts of the choriocapillaris and in deeper choroidal vessels. And the RPE was hypertrophic at this time after afilbercept compared with after ranibizumab injection or no treatment. There was also evidence of extracellular haemoglobin, known to be toxic, and individual RPE cell death following aflibercept treatment only.

The mean thickness of the choriocapillaris endothelium and the number of fenestrations were reduced after anti-VEGF treatment compared with no treatment, but significantly more so following aflibercept than ranibizumab.

The researchers conclude in the British Journal of Ophthalmology that, “[f]rom a theoretical point of view, it is not an advantage that aflibercept has an Fc fragment because it may cause unpredictable reactions with other molecules and cells.”

They add that the clinical significance of their findings and the relation to the Fc domain specifically remain to be determined.




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