The
current standard of care for antivascular endothelial growth
factor (VEGF) treatment requires frequent intravitreal (IVT) injections
of protein therapeutics, as a result of limited retention within the
eye. A thorough understanding of the determinants of ocular pharmacokinetics
(PK) and its translation across species is an essential prerequisite
for developing more durable treatments. In this work, we studied the
ocular PK in macaques of the protein formats that comprise today’s
anti-VEGF standard of care. Cynomolgus monkeys received a single IVT
injection of a single-chain variable fragment (scFv, brolucizumab),
antigen-binding fragment (Fab, ranibizumab), fragment crystallizable-fusion
protein (Fc-fusion, aflibercept), or immunoglobulin G monoclonal antibody
(IgG, VA2 CrossMAb). Drug concentrations were determined in aqueous
humor samples collected up to 42 days postinjection using immunoassay
methods. The ocular half-life (t
1/2) was
2.28, 2.62, 3.13, and 3.26 days for scFv, Fab, Fc-fusion, and IgG,
respectively. A correlation with human t
1/2 values from the literature confirmed the translational significance
of the cynomolgus monkey as an animal model for ocular research. The
relation between ocular t
1/2 and molecular
size was also investigated. Size was inferred from the molecular weight
(MW) or determined experimentally by dynamic light scattering. The
MW and hydrodynamic radius were found to be good predictors for the
ocular t
1/2 of globular proteins. The
analysis showed that molecular size is a determinant of ocular disposition
and may be used in lieu of dedicated PK studies in animals.