Abstract
Purpose :
Anti-VEGF therapies are now the standard of care for patients with neovascular age-related macular degeneration (nAMD). Whilst VEGF is known to play a significant role in the pathology, other factors such as connective tissue growth factor (CTGF) have been reported to be elevated in patients. We have examined a novel bi-cistronic vector (IKC151V) which neutralizes both VEGF and CTGF in two rodent models of nAMD, and compared the efficacy to a vector expressing aflibercept only.
Methods :
The affinity of recombinant VEGF capture protein-2 (VC2) and aflibercept to Fc proteins was determined by the use of luminescence-based assays. Null control vector, mono-cistronic aflibercept (IKC163V) vector and anti-VEGF/anti-CTGF bi-cistronic (IKC151V) vector were examined in a murine model of laser-induced CNV and a transgenic model of subretinal neovascularisation (Vldlr-/-).
Results :
The VC2 component in IKC151V has a reduced affinity for human FcRn (IC50: aflibercept= 34 nM, VC2= 24 μM) and FcgammaRI (IC50: aflibercept= 20 pM, VC2= 63 μM). In the laser-induced CNV model, IKC151V significantly reduced the mean lesion severity score and lesion volume versus Null control vector at day 7, and performed better than the mono-cistronic aflibercept (IKC163V) 14 days after laser treatment (Lesion volume (107 μm3): Null= 1.66 ± 0.33, IKC163V= 0.80 ± 0.12*, IKC151V= 0.36 ± 0.08*; *p ≤0.001). This reduced lesion size was despite significantly lower vitreous levels of anti-VEGF protein in the IKC151V treated eye versus IKC163V (IKC163V= 7.1 ± 3.2 μg/mL, IKC151V= 4.9 ± 1.7 μg/mL*; *p ≤0.01). Similarly, IKC151V-treated Vldlr-/- mice demonstrated a reduced lesion severity score compared to IKC163V-treated eyes (IKC163V= 0.79 ± 0.86, IKC151V= 0.35 ± 0.42) and a reduced total number of lesions (IKC163V= 0.39 ± 0.62, IKC151V= 0.0 ± 0.0).
Conclusions :
In two models of nAMD, IKC151V was able to attenuate developing and existing neovascularisation to a greater extent than expressing aflibercept alone. These data support the hypothesis that in addition to VEGF, CTGF plays an important contributing factor to disease pathology and that IKC151V has the potential to prevent and even reverse the vascular changes associated with nAMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.