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Natural immunoglobulin M-based delivery of a complement alternative pathway inhibitor in mouse models of retinal degeneration.
- Source :
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Experimental eye research [Exp Eye Res] 2021 Jun; Vol. 207, pp. 108583. Date of Electronic Publication: 2021 Apr 18. - Publication Year :
- 2021
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Abstract
- Purpose: Age-related macular degeneration is a slowly progressing disease. Studies have tied disease risk to an overactive complement system. We have previously demonstrated that pathology in two mouse models, the choroidal neovascularization (CNV) model and the smoke-induced ocular pathology (SIOP) model, can be reduced by specifically inhibiting the alternative complement pathway (AP). Here we report on the development of a novel injury-site targeted inhibitor of the alternative pathway, and its characterization in models of retinal degeneration.<br />Methods: Expression of the danger associated molecular pattern, a modified annexin IV, in injured ARPE-19 cells was confirmed by immunohistochemistry and complementation assays using B4 IgM mAb. Subsequently, a construct was prepared consisting of B4 single chain antibody (scFv) linked to a fragment of the alternative pathway inhibitor, fH (B4-scFv-fH). ARPE-19 cells stably expressing B4-scFv-fH were microencapsulated and administered intravitreally or subcutaneously into C57BL/6 J mice, followed by CNV induction or smoke exposure. Progression of CNV was analyzed using optical coherence tomography, and SIOP using structure-function analyses. B4-scFv-fH targeting and AP specificity was assessed by Western blot and binding experiments.<br />Results: B4-scFv-fH was secreted from encapsulated RPE and inhibited complement in RPE monolayers. B4-scFv-fH capsules reduced CNV and SIOP, and western blotting for breakdown products of C3α, IgM and IgG confirmed a reduction in complement activation and antibody binding in RPE/choroid.<br />Conclusions: Data supports a role for natural antibodies and neoepitope expression in ocular disease, and describes a novel strategy to target AP-specific complement inhibition to diseased tissue in the eye.<br />Precis: AMD risk is tied to an overactive complement system, and ocular injury is reduced by alternative pathway (AP) inhibition in experimental models. We developed a novel inhibitor of the AP that targets an injury-specific danger associated molecular pattern, and characterized it in disease models.<br /> (Copyright © 2021. Published by Elsevier Ltd.)
- Subjects :
- Animals
Blotting, Western
Cell Line
Cell- and Tissue-Based Therapy methods
Choroidal Neovascularization diagnostic imaging
Choroidal Neovascularization immunology
Choroidal Neovascularization therapy
Complement C3 antagonists & inhibitors
Complement C3 genetics
Drug Delivery Systems
Male
Mice
Mice, Inbred C57BL
Recombinant Fusion Proteins
Retinal Degeneration diagnostic imaging
Retinal Degeneration immunology
Tomography, Optical Coherence
Transfection
Antibodies, Monoclonal therapeutic use
Complement Inactivating Agents therapeutic use
Complement Pathway, Alternative drug effects
Disease Models, Animal
Immunoglobulin M immunology
Retinal Degeneration therapy
Retinal Pigment Epithelium metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0007
- Volume :
- 207
- Database :
- MEDLINE
- Journal :
- Experimental eye research
- Publication Type :
- Academic Journal
- Accession number :
- 33878326
- Full Text :
- https://doi.org/10.1016/j.exer.2021.108583