Abstract
Purpose :
Brolucizumab, a single-chain variable fragment, effectively inhibits VEGF and suppresses vascular permeability and angiogenesis in patients with wet age-related macular degeneration. However, a few patients experienced adverse effects, such as retinal vasculitis or vascular occlusion, following intravitreal injection of brolucizumab. To elucidate the association between brolucizumab and retinal vascular inflammation, we evaluated how brolucizumab induces inflammation in retinal endothelial cells (RECs) and monocytes under high VEGF conditions and compared with various anti-VEGF agents.
Methods :
RECs were isolated from human donor eyes, and THP-1 cells, the monocytes, were utilized. These cells were exposed to VEGF to mimic the patients requiring the treatments of anti-VEGF therapy. Ranibizumab, brolucizumab, and sequential switching were compared. There were various conditions, including individual drug treatments and sequential administration of ranibizumab and brolucizumab. Experimental results were measured and analyzed by qPCR to assess changes in mRNA expression levels within each cell.
Results :
Unlike the sole treatment of brolucizumab or ranibizumab, switching from ranibizumab to brolucizumab increased the expression of the inflammatory signaling molecules, such as IL-1B and TGFB in RECs. Despite the decreased CCL2 secretion in RECs when switching to brolucizumab from ranibizumab, the increased expression of CCR2 in THP-1 cells suggests the direct augmentation in monocyte activation by anti-VEGF switching. THP-1 cells also expressed increased MMP2 and MMP9 gene expression to facilitate the monocyte infiltration by degrading ECM.
Conclusions :
The transition from ranibizumab to brolucizumab appears to have a higher propensity to induce retinal vascular inflammation than individual treatments. In this context, RECs secrete inflammatory signaling molecules, and inflammatory cells, mainly monocytes, exhibit increased activation in response to the drug-switching environment.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.