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

Abstract

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.

• Authors: Silvia Pellegrini, Valentina Zamarian, Elisa Landi, Alessandro Cospito, Marta Tiffany Lombardo, Fabio Manenti, Antonio Citro, Marco Schiavo Lena, Lorenzo Piemonti, Valeria Sordi
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 17 (Aug 26 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36077097 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Immunoconjugates
• Insulin
• Ki-1 Antigen

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Differentiation
• Humans
• Immunoconjugates (pharmacology)
• Induced Pluripotent Stem Cells
• Insulin (metabolism)
• Ki-1 Antigen (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Teratoma (etiology, metabolism, prevention & control)