Inhibition of Sema4D in mouse models of choroidal neovascularization reduces lesion volume and vascular leakage to a degree comparable to anti-VEGF therapy, and combination of Sema4D inhibition with anti-VEGF therapy results in significantly greater suppression of lesion volume and vascular leakage than either intervention alone.

When Sema4D binds to PlexinB1 on pericytes, it triggers a chain reaction that makes pericytes contract and produce stiff structural proteins, which destabilizes blood vessels in the eye. This causes leaking and abnormal blood vessel growth. Anti-VEGF therapy alone cannot fully stop this because pericytes shield the vessels. Blocking Sema4D stops pericyte activation, allowing anti-VEGF to work better on the blood vessels themselves, and together they reduce leakage and abnormal vessels more than either alone.