Interaction of epitopic missense variants of VEGFA with therapeutic monoclonal antibodies

Vascular Endothelial Growth Factor A (VEGFA) is a glycoprotein that mediates various biological processes, including angiogenesis, vascular permeability, and cellular migration. Aberrant VEGFA signaling is also one of the hallmarks of many types of cancer and has been implicated in various ophthalmological conditions such as diabetic macular edema and age-related macular degeneration. Consequently, a number of therapeutic monoclonal antibodies (mAb) targeting VEGFA have been developed and are widely used to treat these conditions. Bevacizumab (BVZ) and Ranibizumab (RBZ) are two such antibodies that are commercially available and used to treat various cancers and ophthalmological conditions. Nevertheless, a very high rate of non-responsiveness to these mAb treatments has been reported. Therefore, it is important to predict the response to these therapeutic mAb treatments in patients in a personalized approach. This study was aimed at analyzing the impacts of missense variants in the respective VEGFA epitopes for these two therapeutic anti-VEGFA mAbs (BVZ and RBZ) on their interaction with VEGFA through the use of multiple in silico tools. Three missense variants (VEGFAR82W, VEGFAR82Q, and VEGFAG92R) in VEGFA epitopes appear to significantly destabilize VEGFA-BVZ interaction, while only two variants (VEGFAR82W and VEGFAR82Q) affect the interaction of VEGFA with RBZ. The VEGFAR82W variant may be pathogenic as well. These missense variants may play roles in the observed heterogeneous response to anti-VEGFA mAb treatments in patients and, therefore, may be used as pharmacogenetic markers for the prediction of responses before administration, and thus for the improvement of therapeutic outcomes.