| Autor: |
Breanna S. Vollmar, Mingjian Fei, Wei-Ching Liang, Daniel D. Bravo, Joy Wang, Lanlan Yu, Nick Corr, Gu Zhang, Erin McNamara, Shabkhaiz Masih, Elin Chee, Gawon Shin, Rachana Ohri, Douglas D. Leipold, Cong Wu, Edward Dere, Jianyong Wang, Haochu Huang, Yan Wu, Minhong Yan |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Bioconjugate chemistry. 33(10) |
| ISSN: |
1520-4812 |
| Popis: |
Here, we explore whether PEGylation of antibodies can modulate their biodistribution to the eye, an organ once thought to be immune privileged but has recently been shown to be accessible to IV-administered large molecules, such as antibodies. We chose to PEGylate an anti-MerTK antibody, a target with known potential for ocular toxicity, to minimize biodistribution to retinal pigment epithelial cells (RPEs) in the eye by increasing the hydrodynamic volume of the antibody. We used site-specific conjugation to an engineered cysteine on anti-MerTK antibody to chemically attach 40-kDa branched or linear PEG polymers. Despite reduced binding to MerTK on cells, site-specifically PEGylated anti-MerTK retained similar potency in inhibiting MerTK-mediated macrophage efferocytosis of apoptotic cells. Importantly, we found that PEGylation of anti-MerTK significantly reduced MerTK receptor occupancy in RPE cells in both naïve mice and MC-38 tumor-bearing mice, with the branched PEG exhibiting a greater effect than linear PEG. Furthermore, similar to unconjugated anti-MerTK, PEGylated anti-MerTK antibody triggered type I IFN response and exhibited antitumor effect in syngeneic mouse tumor studies. Our results demonstrate the potential of PEGylation to control ocular biodistribution of antibodies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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