Aflibercept exhibits VEGF binding stoichiometry distinct from bevacizumab and does not support formation of immune-like complexes Article

Industry Collaboration International Collaboration

cited authors

  • MacDonald, Douglas A., Martin, Joel, Muthusamy, Kathir K., Luo, Jiann-Kae, Pyles, Erica, Rafique, Ashique, Huang, Tammy, Potocky, Terra, Liu, Yang, Cao, Jingtai, Bono, Francoise, Delesque, Nathalie, Savi, Pierre, Francis, John, Amirkhosravi, Ali, Meyer, Todd, Romano, Carmelo, Glinka, Meredith, Yancopoulos, George D., Stahl, Neil, Wiegand, Stanley J., Papadopoulos, Nicholas

abstract

  • Anti-vascular endothelial growth factor (VEGF) therapies have improved clinical outcomes for patients with cancers and retinal vascular diseases. Three anti-VEGF agents, pegaptanib, ranibizumab, and aflibercept, are approved for ophthalmic indications, while bevacizumab is approved to treat colorectal, lung, and renal cancers, but is also used off-label to treat ocular vascular diseases. The efficacy of bevacizumab relative to ranibizumab in treating neovascular age-related macular degeneration has been assessed in several trials. However, questions persist regarding its safety, as bevacizumab can form large complexes with dimeric VEGF(165), resulting in multimerization of the Fc domain and platelet activation. Here, we compare binding stoichiometry, Fc gamma receptor affinity, platelet activation, and binding to epithelial and endothelial cells in vitro for bevacizumab and aflibercept, in the absence or presence of VEGF. In contrast to bevacizumab, aflibercept forms a homogenous 1:1 complex with each VEGF dimer. Unlike multimeric bevacizumab:VEGF complexes, the monomeric aflibercept:VEGF complex does not exhibit increased affinity for low-affinity Fc gamma receptors, does not activate platelets, nor does it bind to the surface of epithelial or endothelial cells to a greater degree than unbound aflibercept or control Fc. The latter finding reflects the fact that aflibercept binds VEGF in a unique manner, distinct from antibodies not only blocking the amino acids necessary for VEGFR1/R2 binding but also occluding the heparin-binding site on VEGF(165).

Publication Date

  • July 1, 2016

webpage

published in

category

start page

  • 389

end page

  • 406

volume

  • 19

issue

  • 3

WoS Citations

  • 7

WoS References

  • 41