Medicines based on
vascular endothelial growth factor (
VEGF) neutralising
antibodies such as
bevacizumab have revolutionized the treatment of
age related macular degeneration (AMD), a common blinding disease, and have great potential in preventing
scarring after surgery or accelerating the healing of
corneal injuries. However, at present frequent invasive
injections are required to deliver these
antibodies. Such administration is uncomfortable for patients and expensive for health service providers. Much effort is thus focused on developing
dosage forms that can be administered less frequently. Here we use electrospinning to prepare a solid form of
bevacizumab designed for prolonged release while maintaining antibody stability. Electrospun fibers were prepared with
bevacizumab encapsulated in the core, surrounded by a poly-ε-
caprolactone sheath. The fibers were generated using aqueous
bevacizumab solutions buffered at two different pH values: 6.2 (the pH of the commercial product; Fbeva) and 8.3 (the isoelectric point of
bevacizumab; FbevaP). The fibers had smooth and cylindrical morphologies, with diameters of ca. 500nm. Both sets of
bevacizumab loaded fibers gave sustained release profiles in an in vitro model of the subconjunctival space of the eye. Fbeva displayed first order kinetics with t1/2 of 11.4±4.4 days, while FbevaP comprises a zero-order reservoir type release system with t1/2 of 52.9±14.8 days. Both SDS-PAGE and surface plasmon resonance demonstrate that the
bevacizumab in FbevaP did not undergo degradation during fiber fabrication or release. In contrast, the antibody released from Fbeva had degraded, and failed to bind to
VEGF. Our results demonstrate that pH control is crucial to maintain antibody stability during the fabrication of core/shell fibers and ensure release of functional
protein.
STATEMENT OF SIGNIFICANCE:
Bevacizumab is a potent
protein drug which is highly effective in the treatment of degenerative conditions in the eye. To be effective, frequent
injections into the eye are required, which is deeply unpleasant for patients and expensive for healthcare providers. Alternative methods of administration are thus highly sought after. In our work, we use the electrospinning technique to prepare fiber-based formulations loaded with
bevacizumab. By careful control of the experimental parameters we are able to stabilize the
protein during processing and ensure a constant rate of release over more than two months in vitro. These fibers could thus be used to reduce the frequency of dosing required, reducing cost and improving patient outcomes.