PEGylation of anti-MerTK Antibody Modulates Ocular Biodistribution.
|
| Abstract |
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.
|
|---|---|
| Authors | 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 |
| Journal | Bioconjugate chemistry (Bioconjug Chem) Vol. 33 Issue 10 Pg. 1837-1851 (10 19 2022) ISSN: 1520-4812 [Electronic] United States |
| PMID | 36153839 (Publication Type: Journal Article) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!