Introduction: Endostatin is an endogenous angiogenic inhibitor derived from type XVIII collagen. Unexpectedly, human endostatin had a limited response in phase I and II clinical trials due in large part to a short, 42.3min, half-life. Fc-endostatin (FcE) is a recombinant form of human endostatin bound to the Fc domain of IgG antibody, which increases its half-life to several weeks. We assessed the antiangiogenic effects of subconjunctival injected FcE compared to bevacizumab (Avastin®) (BV) using a rabbit VEGF-induced angiogenesis assay.
Methods: Angiogenesis was induced in rabbit corneas through two intrastromal implantations of VEGF polymer 2mm from the limbus. 32 polymers were placed in the 16 eyes of 8 rabbits. Rabbits were randomized to 1 of 4 groups, each receiving subconjunctival injections in both eyes on Days 0, 5, 8, and 12 of: 1) 0.1mL saline, 2) 0.1mL BV 25mg/mL, 3) 0.125mL FcE 2mg/mL (FcE 2), or 4) 0.125mL of FcE 20mg/mL (FcE 20). Corneas were then digitally-imaged at 5 timepoints. An angiogenesis index (AI) was calculated [vessel length (mm) x vessel number] for each polymer observation.
Results: All treatment groups showed a significant decrease in the AI compared to saline on all observation days (p<0.001). BV was a significantly better inhibitor than FcE 20 by Day 8 (p<0.01). By Day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (p<0.01)(please see attached figure).
Conclusions: FcE at both 2mg/mL and 20mg/mL doses significantly inhibited angiogenesis. Lower concentration FcE 2 exhibited better inhibition than FcE 20 – consistent with previous FcE studies referencing a biphasic dose-response curve. FcE 20 was found to be a less potent VEGF inhibitor than BV. Since VEGF is but one stimulator of angiogenesis, FcE should be further investigated as a potent angiogenic inhibitor with an extended half-life.
Patient Care: Fc endostatin is a powerful anti-angiogenic agent with a longer half life than currently used other anti-angiongenic agents.
Learning Objectives: That Fc endostatin significantly inhibits angiogenesis in the VEGF cornea model.
That Fc endostatin should be further investigated as a potent angiogenic inhibitor with an extended half-life.