Targeted IgMs agonize ocular targets with extended vitreal exposure
| Autor: | Alberto Estevez, Sharmila Rajan, John Ridgway Brady, Henry Chiu, Phil Hass, Claudio Ciferri, Greg A. Lazar, Amin Famili, Brandon Leonard, Nicholas J. Agard, Julie A. Zorn, Susan Crowell, Yvonne Chen, Marissa L. Matsumoto, Maciej Paluch, Wilson Phung, Minhong Yan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
IgM genetic structures ocular therapeutics Immunology CHO Cells Macular Degeneration 03 medical and health sciences Cricetulus Drug Delivery Systems 0302 clinical medicine agonism Report Ophthalmology Animals Humans Immunology and Allergy Medicine Ocular disease 030304 developmental biology 0303 health sciences antibody engineering business.industry eye diseases Rats Vitreous Body Immunoglobulin M 030220 oncology & carcinogenesis Intravitreal Injections long-acting delivery sense organs business |
| Zdroj: | mAbs article-version (VoR) Version of Record |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | Treatment of ocular disease is hindered by the presence of the blood-retinal barrier, which restricts access of systemic drugs to the eye. Intravitreal injections bypass this barrier, delivering high concentrations of drug to the targeted tissue. However, the recommended dosing interval for approved biologics is typically 6–12 weeks, and frequent travel to the physician’s office poses a substantial burden for elderly patients with poor vision. Real-world data suggest that many patients are under-treated. Here, we investigate IgMs as a novel platform for treating ocular disease. We show that IgMs are well-suited to ocular administration due to moderate viscosity, long ocular exposure, and rapid systemic clearance. The complement-dependent cytotoxicity of IgMs can be readily removed with a P436G mutation, reducing safety liabilities. Furthermore, dodecavalent binding of IgM hexamers can potently activate pathways implicated in the treatment of progressive blindness, including the Tie2 receptor tyrosine kinase signaling pathway for the treatment of diabetic macular edema, or the death receptor 4 tumor necrosis family receptor pathway for the treatment of wet age-related macular degeneration. Collectively, these data demonstrate the promise of IgMs as therapeutic agonists for treating progressive blindness. |
| Databáze: | OpenAIRE |
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