Cargando…

Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation

Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for β cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinic...

Descripción completa

Detalles Bibliográficos
Autores principales: Pellegrini, Silvia, Zamarian, Valentina, Landi, Elisa, Cospito, Alessandro, Lombardo, Marta Tiffany, Manenti, Fabio, Citro, Antonio, Schiavo Lena, Marco, Piemonti, Lorenzo, Sordi, Valeria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456216/
https://www.ncbi.nlm.nih.gov/pubmed/36077097
http://dx.doi.org/10.3390/ijms23179699
_version_ 1784785759404818432
author Pellegrini, Silvia
Zamarian, Valentina
Landi, Elisa
Cospito, Alessandro
Lombardo, Marta Tiffany
Manenti, Fabio
Citro, Antonio
Schiavo Lena, Marco
Piemonti, Lorenzo
Sordi, Valeria
author_facet Pellegrini, Silvia
Zamarian, Valentina
Landi, Elisa
Cospito, Alessandro
Lombardo, Marta Tiffany
Manenti, Fabio
Citro, Antonio
Schiavo Lena, Marco
Piemonti, Lorenzo
Sordi, Valeria
author_sort Pellegrini, Silvia
collection PubMed
description Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for β cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody–drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived β cells (iβs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill iβs nor had an impact on iβ identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iβ transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived β cells, potentially providing enhanced safety for iPSC-based β cell replacement therapy in clinical scenarios.
format Online
Article
Text
id pubmed-9456216
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-94562162022-09-09 Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation Pellegrini, Silvia Zamarian, Valentina Landi, Elisa Cospito, Alessandro Lombardo, Marta Tiffany Manenti, Fabio Citro, Antonio Schiavo Lena, Marco Piemonti, Lorenzo Sordi, Valeria Int J Mol Sci Article Insulin-producing cells derived from induced pluripotent stem cells (iPSCs) are promising candidates for β cell replacement in type 1 diabetes. However, the risk of teratoma formation due to residual undifferentiated iPSCs contaminating the differentiated cells is still a critical concern for clinical application. Here, we hypothesized that pretreatment of iPSC-derived insulin-producing cells with an anti-CD30 antibody–drug conjugate could prevent in vivo teratoma formation by selectively killing residual undifferentiated cells. CD30 is expressed in all human iPSCs clones tested by flow cytometry (n = 7) but not in iPSC-derived β cells (iβs). Concordantly, anti-CD30 treatment in vitro for 24 h induced a dose-dependent cell death (up to 90%) in human iPSCs while it did not kill iβs nor had an impact on iβ identity and function, including capacity to secrete insulin in response to stimuli. In a model of teratoma assay associated with iβ transplantation, the pretreatment of cells with anti-CD30 for 24 h before the implantation into NOD-SCID mice completely eliminated teratoma development (0/10 vs. 8/8, p < 0.01). These findings suggest that short-term in vitro treatment with clinical-grade anti-CD30, targeting residual undifferentiated cells, eliminates the tumorigenicity of iPSC-derived β cells, potentially providing enhanced safety for iPSC-based β cell replacement therapy in clinical scenarios. MDPI 2022-08-26 /pmc/articles/PMC9456216/ /pubmed/36077097 http://dx.doi.org/10.3390/ijms23179699 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pellegrini, Silvia
Zamarian, Valentina
Landi, Elisa
Cospito, Alessandro
Lombardo, Marta Tiffany
Manenti, Fabio
Citro, Antonio
Schiavo Lena, Marco
Piemonti, Lorenzo
Sordi, Valeria
Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title_full Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title_fullStr Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title_full_unstemmed Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title_short Treating iPSC-Derived β Cells with an Anti-CD30 Antibody–Drug Conjugate Eliminates the Risk of Teratoma Development upon Transplantation
title_sort treating ipsc-derived β cells with an anti-cd30 antibody–drug conjugate eliminates the risk of teratoma development upon transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456216/
https://www.ncbi.nlm.nih.gov/pubmed/36077097
http://dx.doi.org/10.3390/ijms23179699
work_keys_str_mv AT pellegrinisilvia treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT zamarianvalentina treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT landielisa treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT cospitoalessandro treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT lombardomartatiffany treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT manentifabio treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT citroantonio treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT schiavolenamarco treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT piemontilorenzo treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation
AT sordivaleria treatingipscderivedbcellswithananticd30antibodydrugconjugateeliminatestheriskofteratomadevelopmentupontransplantation