bc9b00475_si_001.pdf (269.05 kB)
Hyaluronic Acid–Antibody Fragment Bioconjugates for Extended Ocular Pharmacokinetics
journal contribution
posted on 2019-10-11, 15:38 authored by Amin Famili, Susan R. Crowell, Kelly M. Loyet, Danielle Mandikian, C. Andrew Boswell, David Cain, Joyce Chan, Laetitia Comps-Agrar, Amrita Kamath, Karthikan RajagopalTreatment of ocular diseases associated
with neovascularization
currently requires frequent intravitreal injections of antivascular
endothelial growth factor (anti-VEGF) therapies. Reducing the required
frequency of anti-VEGF injections and associated clinical visits may
improve patient adherence to the prescribed treatment regimen and
improve outcomes. Herein, we explore conjugation of rabbit and fragment
antibodies (Fab) to the biopolymer hyaluronic acid (HA) as a half-life
modifying strategy, and assess the impact on Fab biophysical properties
and vitreal pharmacokinetics. HA-Fab conjugates of three distinct
molecular weights and hydrodynamic radii (RH) were assessed for in vivo pharmacokinetic performance
relative to unconjugated Fab after intravitreal injection in rabbits.
Covalent conjugation to HA did not significantly alter the thermal
stability or secondary or tertiary structure, or diminish the potency
of the Fab, thereby preserving its pharmacological properties. Conjugation
to HA did significantly slow the in vivo clearance
of Fab from the rabbit vitreous in an RH-dependent manner. Compared to free Fab (observed vitreal half-life
of 2.8 days), HA-Fab conjugates cleared with observed half-lives of
7.6, 10.2, and 18.3 days for 40 kDa, 200 kDa, and 600 kDa HA conjugates,
respectively. This work elucidates a possible strategy for long-acting
delivery of proteins intended for the treatment of chronic posterior
ocular diseases.