Haeckel, A.
[Author];
Ascher, Lena
[Author];
Beindorff, N.
[Author];
Prasad, S.
[Author];
Garczynska, K.
[Author];
Guo, J.
[Author];
Schellenberger, E.
[Author]
Long‑circulating XTEN864‑annexin A5 fusion protein for phosphatidylserine‑related therapeutic applications
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Media type:
E-Article
Title:
Long‑circulating XTEN864‑annexin A5 fusion protein for phosphatidylserine‑related therapeutic applications
Contributor:
Haeckel, A.
[Author];
Ascher, Lena
[Author];
Beindorff, N.
[Author];
Prasad, S.
[Author];
Garczynska, K.
[Author];
Guo, J.
[Author];
Schellenberger, E.
[Author]
Published:
BAM-Publica - Publikationsserver der Bundesanstalt für Materialforschung und -prüfung (BAM), 2021
Language:
English
DOI:
https://doi.org/10.1007/s10495-021-01686-w
Origination:
Footnote:
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Description:
Annexin A5 (anxA5) is a marker for apoptosis, but has also therapeutic potential in cardiovascular diseases, cancer, and, due to apoptotic mimicry, against dangerous viruses, which is limited by the short blood circulation. An 864-amino-acid XTEN polypeptide was fused to anxA5. XTEN864-anxA5 was expressed in Escherichia coli and purified using XTEN as tag. XTEN864-anxA5 was coupled with DTPA and indium-111. After intravenous or subcutaneous injection of 111In-XTEN864-anxA5, mouse blood samples were collected for blood half-life determination and organ samples for biodistribution using a gamma counter. XTEN864-anxA5 was labeled with 6S-IDCC to confirm binding to apoptotic cells using flow cytometry. To demonstrate targeting of atherosclerotic plaques, XTEN864-anxA5 was labeled with MeCAT(Ho) and administered intravenously to atherosclerotic ApoE−/−mice. MeCAT(Ho)-XTEN864-anxA5 was detected together with MeCAT(Tm)-MAC-2 macrophage antibodies by imaging mass cytometry (CyTOF) of aortic root sections. The ability of anxA5 to bind apoptotic cells was not affected by XTEN864. The blood half-life of XTEN864-anxA5 was 13 h in mice after IV injection, markedly longer than the 7-min half-life of anxA5. 96 h after injection, highest amounts of XTEN864-anxA5 were found in liver, spleen, and kidney. XTEN864-anxA5 was found to target the adventitia adjacent to atherosclerotic plaques. XTEN864-anxA5 is a long-circulating fusion protein that can be efficiently produced in E. coli and potentially circulates in humans for several days, making it a promising therapeutic drug.