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Rational engineering of an erythropoietin fusion protein to treat hypoxia

View ORCID ProfileJungmin Lee, Andyna Vernet, Nathalie G. Gruber, Kasia M. Kready, Devin R. Burrill, Jeffrey C. Way, View ORCID ProfilePamela A. Silver
doi: https://doi.org/10.1101/2021.06.24.449789
Jungmin Lee
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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  • ORCID record for Jungmin Lee
Andyna Vernet
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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Nathalie G. Gruber
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
4Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria
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Kasia M. Kready
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
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Devin R. Burrill
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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Jeffrey C. Way
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
3Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: Jeffrey_Way@hms.harvard.edu
Pamela A. Silver
1Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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  • ORCID record for Pamela A. Silver
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Abstract

Erythropoietin enhances oxygen delivery and reduces hypoxia-induced cell death, but its pro-thrombotic activity is problematic for use of erythropoietin in treating hypoxia. We constructed a fusion protein that stimulates red blood cell production and neuroprotection without triggering platelet production, a marker for thrombosis. The protein consists of an anti-glycophorin A nanobody and an erythropoietin mutant (L108A). The mutation reduces activation of erythropoietin receptor homodimers that induce erythropoiesis and thrombosis, but maintains the tissue-protective signaling. The binding of the nanobody element to glycophorin A rescues homodimeric erythropoietin receptor activation on red blood cell precursors. In a cell proliferation assay, the fusion protein is active at 10−14 M, allowing an estimate of the number of receptor–ligand complexes needed for signaling. This fusion protein stimulates erythroid cell proliferation in vitro and in mice, and shows neuroprotective activity in vitro. Our erythropoietin fusion protein presents a novel molecule for treating hypoxia.

Competing Interest Statement

J.C.W., D.R.B. and P.A.S. are shareholders in a company that has a license to the IH4 antibody element described in this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 24, 2021.
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Rational engineering of an erythropoietin fusion protein to treat hypoxia
Jungmin Lee, Andyna Vernet, Nathalie G. Gruber, Kasia M. Kready, Devin R. Burrill, Jeffrey C. Way, Pamela A. Silver
bioRxiv 2021.06.24.449789; doi: https://doi.org/10.1101/2021.06.24.449789
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Rational engineering of an erythropoietin fusion protein to treat hypoxia
Jungmin Lee, Andyna Vernet, Nathalie G. Gruber, Kasia M. Kready, Devin R. Burrill, Jeffrey C. Way, Pamela A. Silver
bioRxiv 2021.06.24.449789; doi: https://doi.org/10.1101/2021.06.24.449789

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