| Autor: |
Chen Y; Departments of Antibody Engineering, Genentech Inc ., South San Francisco, CA, USA., Paluch M; Departments of Protein Chemistry, Genentech Inc ., South San Francisco, CA, USA., Zorn JA; Departments of Structural Biology, Genentech Inc ., South San Francisco, CA, USA., Rajan S; Departments of Preclinical & Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc ., South San Francisco, CA, USA., Leonard B; Departments of Antibody Engineering, Genentech Inc ., South San Francisco, CA, USA., Estevez A; Departments of Structural Biology, Genentech Inc ., South San Francisco, CA, USA., Brady J; Departments of Molecular Oncology, Genentech Inc ., South San Francisco, CA, USA., Chiu H; Departments of Biochemical and Cellular Physiology, Genentech Inc ., South San Francisco, CA, USA., Phung W; Departments of Microchemistry Proteomics and Lipidomics, Genentech Inc ., South San Francisco, CA, USA., Famili A; Departments of Drug Development, Genentech Inc ., South San Francisco, CA, USA., Yan M; Departments of Molecular Oncology, Genentech Inc ., South San Francisco, CA, USA., Ciferri C; Departments of Structural Biology, Genentech Inc ., South San Francisco, CA, USA., Matsumoto ML; Departments of Structural Biology, Genentech Inc ., South San Francisco, CA, USA., Lazar GA; Departments of Antibody Engineering, Genentech Inc ., South San Francisco, CA, USA., Crowell S; Departments of Preclinical & Translational Pharmacokinetics and Pharmacodynamics, Genentech Inc ., South San Francisco, CA, USA., Hass P; Departments of Protein Chemistry, Genentech Inc ., South San Francisco, CA, USA., Agard NJ; Departments of Antibody Engineering, Genentech Inc ., South San Francisco, CA, USA. |
| Abstrakt: |
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. |
