Modified recombinant human erythropoietin with potentially reduced immunogenicity

Abstract Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of...

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Autores principales:	Thanutsorn Susantad, Mayuree Fuangthong, Kannan Tharakaraman, Phanthakarn Tit-oon, Mathuros Ruchirawat, Ram Sasisekharan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/18ae4af54d95460894f2257d68c11d8a
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spelling	oai:doaj.org-article:18ae4af54d95460894f2257d68c11d8a2021-12-02T14:12:46ZModified recombinant human erythropoietin with potentially reduced immunogenicity10.1038/s41598-020-80402-12045-2322https://doaj.org/article/18ae4af54d95460894f2257d68c11d8a2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80402-1https://doaj.org/toc/2045-2322Abstract Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB109 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB109, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.Thanutsorn SusantadMayuree FuangthongKannan TharakaramanPhanthakarn Tit-oonMathuros RuchirawatRam SasisekharanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thanutsorn Susantad Mayuree Fuangthong Kannan Tharakaraman Phanthakarn Tit-oon Mathuros Ruchirawat Ram Sasisekharan Modified recombinant human erythropoietin with potentially reduced immunogenicity
description	Abstract Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB109 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB109, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.
format	article
author	Thanutsorn Susantad Mayuree Fuangthong Kannan Tharakaraman Phanthakarn Tit-oon Mathuros Ruchirawat Ram Sasisekharan
author_facet	Thanutsorn Susantad Mayuree Fuangthong Kannan Tharakaraman Phanthakarn Tit-oon Mathuros Ruchirawat Ram Sasisekharan
author_sort	Thanutsorn Susantad
title	Modified recombinant human erythropoietin with potentially reduced immunogenicity
title_short	Modified recombinant human erythropoietin with potentially reduced immunogenicity
title_full	Modified recombinant human erythropoietin with potentially reduced immunogenicity
title_fullStr	Modified recombinant human erythropoietin with potentially reduced immunogenicity
title_full_unstemmed	Modified recombinant human erythropoietin with potentially reduced immunogenicity
title_sort	modified recombinant human erythropoietin with potentially reduced immunogenicity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/18ae4af54d95460894f2257d68c11d8a
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Modified recombinant human erythropoietin with potentially reduced immunogenicity

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