Abstract
Purpose :
Anti-VEGF biologics are important for effective management of neovascular ocular diseases, including wet age-related macular degeneration (AMD). Despite recent advances in improving the durability of these treatments, the current generation of anti-VEGF biologics still fall short of the long-standing goal of twice-yearly administration. Valitor has developed a platform technology based on multivalent protein (MVP) conjugation to enable sustained anti-VEGF biologic therapy after intravitreal (ITV) injection, thereby substantially reducing the required dosing frequency compared to current treatments. The objective of our studies was to assess the toxicology and immune responses of our long-acting multivalent conjugated biologics.
Methods :
MVP conjugates were made by covalently binding a hyaluronic acid (HyA) backbone to multiple copies of single-domain anti-VEGF antibodies (VHH) that have been engineered with humanization and in vivo stability motifs. We characterized the MVPs using biolayer interferometry to measure binding affinity and a cell bioassay to measure anti-VEGF bioactivity (IC50). The ITV half-life of the MVPs was measured using rabbit and non-human primate models with radiolabeling and mass spectrometry detection methods. Safety observations, including anti-drug antibody titers were assessed in non-human primates receiving 2 doses spaced 45 days apart.
Results :
We generated MVPs with approximately 75 anti-VEGF VHH molecules per HyA, sub-picomolar binding affinity to VEGF, and IC50s that were equivalent to clincally-validated anti-VEGF biologics. The ITV half-life of the anti-VEGF MVPs was approximately 15.5 days in the rabbit model, and serum level anti-VEGF concentrations were ~10,000X lower than the ocular tissues. Toxicology findings were consistent with the preclinical reports for licensed anti-VEGF biologics and ADAs were not detected in the aqueous fluid of treated eyes at any time point after the first or second dose.
Conclusions :
MVP conjugation appears to be a promising strategy to develop long-acting biologic drugs for ITV administration. Based on our preclinical findings, an anti-VEGF MVP has the potential to safely enable a reliable 6-month clinical dosing frequency for most if not all patients. This platform could also be used to develop additional long-acting therapies for other ophthalmic indications, such as geographic atrophy.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.