Abstract
Purpose :
Patients with neovascular age-related macular degeneration (nAMD) are currently treated with anti-vascular endothelial growth factor (anti-VEGF). However, the benefit of the anti-VEGF treatment is diminished in the long-term due to appearance of atrophy. We tested whether KNP-301, a dual inhibitor of C3b of the complement system and VEGF, could reduce the formation of choroidal neovascularization (CNV) and retinal degeneration using mouse models of nAMD and dry-AMD.
Methods :
The binding kinetics of KNP-301 with C3b and VEGF165 were tested using surface plasmon resonance assay. The activation of the alternative complement pathway and the classical complement pathway was evaluated with human C1q-depleted serum and human factor B-depleted serum, respectively. Three laser lesions were executed on the right eye of C57BL/6JRj mice to induce CNV. Test compounds were administrated by intravitreal (IVT) injection (2 µl/eye) immediately after lasering. The CNV lesions were monitored using fluorescein angiography and spectral domain optical coherence tomography. NaIO3 was injected intravenously to induce retinal degeneration in C57BL/6 mice. Test compounds were administrated by IVT injection (1.5 µl/eye). The outer nuclear layer (ONL) thickness was determined by immunofluorescent staining. The ocular pharmacokinetics (PK) of KNP-301 was determined in vitreous humor of New Zealand White Rabbits.
Results :
KNP-301 demonstrated binding to both C3b (KD = 4.34 nM) and human VEGF165 (KD = 6.28 pM). KNP-301 selectively inhibited the alternative pathway in a dose-dependent manner (EC50 = 330 nM), whereas the classical pathway was not inhibited. Mice treated with either a mouse surrogate of KNP-301 (n=14) or aflibercept (n=10) had a significantly lower grading of CNV leak compared to vehicle treatment group (n=13; Fisher’s exact test, p≤0.0045 for all). Moreover, mice treated with the mouse surrogate of KNP-301 (n=10) showed reduced ONL thickness compared to mice treated with vehicle control (n=10). Lastly, the half-life of KNP-301 in vitreous humor was 2.5 fold greater than aflibercept.
Conclusions :
Our study showed that KNP-301 binds to C3b and VEGF, and selectively inhibits the alternative pathway of the complement system. Moreover, the mouse surrogate of KNP-301 significantly inhibits the formation of CNV and prevents retinal degeneration in mouse models of n-AMD and dry-AMD.
This is a 2021 ARVO Annual Meeting abstract.