Targeted erythropoietin selectively stimulates red blood cell expansion in vivo
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Burrill-2016-Targeted erythropoie.pdf
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Author(s)
Burrill, Devin R.
Vernet, Andyna
Collins, James J.
Silver, Pamela A.
Way, Jeffrey C.
Date Issued
April 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Burrill, Devin R. et al. “Targeted Erythropoietin Selectively Stimulates Red Blood Cell Expansion in Vivo.” Proceedings of the National Academy of Sciences 113.19 (2016): 5245–5250. © 2016 National Academy of Sciences
Version
Final published version
Abstract
The design of cell-targeted protein therapeutics can be informed by natural protein–protein interactions that use cooperative physical contacts to achieve cell type specificity. Here we applied this approach in vivo to the anemia drug erythropoietin (EPO), to direct its activity to EPO receptors (EPO-Rs) on red blood cell (RBC) precursors and prevent interaction with EPO-Rs on nonerythroid cells, such as platelets. Our engineered EPO molecule was mutated to weaken its affinity for EPO-R, but its avidity for RBC precursors was rescued via tethering to an antibody fragment that specifically binds the human RBC marker glycophorin A (huGYPA). We systematically tested the impact of these engineering steps on in vivo markers of efficacy, side effects, and pharmacokinetics. huGYPA transgenic mice dosed with targeted EPO exhibited elevated RBC levels, with only minimal platelet effects. This in vivo selectivity depended on the weakening EPO mutation, fusion to the RBC-specific antibody, and expression of huGYPA. The terminal plasma half-life of targeted EPO was ∼28.3 h in transgenic mice vs. ∼15.5 h in nontransgenic mice, indicating that huGYPA on mature RBCs acted as a significant drug sink but did not inhibit efficacy. In a therapeutic context, our targeting approach may allow higher restorative doses of EPO without platelet-mediated side effects, and also may improve drug pharmacokinetics. These results demonstrate how rational drug design can improve in vivo specificity, with potential application to diverse protein therapeutics.
MIT Department
Institute for Medical Engineering and Science
MIT Synthetic Biology Center
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1073/pnas.1525388113
