Abstract
Purpose :
Tissue factor (TF) is a 46 kD transmembrane receptor found on vascular endothelial cells (EC). In addition to its role as initiator of coagulation, TF plays an important role in angiogenesis and inflammation. TF is elevated in the retina of Age-related Macular Degeneration (AMD) patients and in the neovascularization (NV). TF inhibition has the potential to affect these processes and modify disease progression by halting formation and growth of macular NV. A clinical proof of concept for the benefit of TF inhibition was achieved in a Phase 2 trial where ICON-1 (an immunoconjugate targeting TF) was given to patients with neovascular AMD. Intravitreal (IVT) ICON-1 administration at 300 ug/eye every month for 6 months, resulted in a decrease in both retinal thickness and NV lesion growth/activity with subsequent decreased need for anti-VEGF therapy. The objective of these studies is to characterize the pharmacology and pharmacokinetics of a new TF inhibitor, ICON-4, with optimized properties for IVT administration.
Methods :
ICON-4, a human IgG1, was characterized with a series of in vitro assays. Characterization included affinity measurements (Biacore), ADCC with either a reporter cell line or PBMCs as effector cells, CDC activity, and ADCP. ICON-4 anti-inflammatory effects were characterized using MDA-231 cells to measure the effect on release of GM-CSF and IL-8. ICON-4 effect on coagulation was assessed using Factor X (FX) conversion assay and thrombin generation assays. ICON-4 pharmacokinetics were characterized in NZW rabbits following single IVT administration of 0.6 and 3.6 mg and ocular concentrations quantified by ELISA.
Results :
In all in vitro assays, ICON-4 had better activity compared to ICON-1 with improvement in activity ranging from 3 to 20-fold across the different assays. While ICON-4 was more active in all the assays, it still was inert on coagulation, as it did not impact FXa conversion or thrombin generation. Following IVT administration, ICON-4 had a long vitreous t1/2 of 6 days, which was about 2X longer than previously observed for ICON-1.
Conclusions :
ICON-4 is a potent TF inhibitor with optimized properties well suited and formulated for IVT administration. ICON-4 high affinity is expected to result in more complete TF inhibition with potential for higher efficacy and/or longer duration of action without enhanced risks of bleeding compared to ICON-1.
This is a 2021 ARVO Annual Meeting abstract.