Abstract
Purpose :
The complement system is a component of the innate immune system. The alternative pathway of the complement system, in particular, is implicated in the etiology and progression of many ophthalmic diseases, including geographic atrophy (GA) in age related macular degeneration (AMD). Sialic acids, including Poly Sialic Acid (PolySia), may suppress complement associated inflammation by binding siglecs on inflammatory cells and by binding complement inhibitor factor H (CFH). We recently described inhibition of macrophage-mediated inflammation and cytokine release using PolySia Coated Nanoparticles (PolySia-NP) [Krishnan et al., 2023], which reduces pro-inflammatory polarization and promotes resolution. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to incompletely suppress complement activity in complement-associated diseases.
Methods :
We utilized in vitro protein binding assays (ELISA-based and Biacore), human serum based complement hemolytic (AH50 and CH50) and complement deposition assays, and complement multiplex ELISAs of cultured M1 polarized macrophages derived from human peripheral blood mononuclear cells (PBMCs).
Results :
PolySia-NP binds to CFH, which increases CFH binding to C3b, thus interfering with the alternative pathway C3 convertase to decrease complement activity. PolySia-NP treatment of human serum suppresses hemolytic activity, especially for the alternative cascade (AH50), and decreases C3b deposition in response to alternative pathway activator (zymosan). PolySia-NP treatment of human macrophages reduces markers of complement activity (C3a, C5a, C5b-9), especially alternative (Ba, Bb) pathway-specific markers.
Conclusions :
PolySia-NP incompletely suppresses alternative pathway complement activity in human serum and human macrophage cultures. These PolySia-NP developed by Aviceda Therapeutics demonstrate high therapeutic potential for complement mediated diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.