Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.

Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these...

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Autores principales:	Daniela Verthelyi, Vivian Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c3ec014292b45969bf0a541655eb57a
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spelling	oai:doaj.org-article:2c3ec014292b45969bf0a541655eb57a2021-11-18T07:01:18ZTrace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.1932-620310.1371/journal.pone.0015252https://doaj.org/article/2c3ec014292b45969bf0a541655eb57a2010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21203556/?tool=EBIhttps://doaj.org/toc/1932-6203Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs) that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS) and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1(st) dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins.Daniela VerthelyiVivian WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e15252 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daniela Verthelyi Vivian Wang Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
description	Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs) that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS) and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1(st) dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins.
format	article
author	Daniela Verthelyi Vivian Wang
author_facet	Daniela Verthelyi Vivian Wang
author_sort	Daniela Verthelyi
title	Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
title_short	Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
title_full	Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
title_fullStr	Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
title_full_unstemmed	Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.
title_sort	trace levels of innate immune response modulating impurities (iirmis) synergize to break tolerance to therapeutic proteins.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/2c3ec014292b45969bf0a541655eb57a
work_keys_str_mv	AT danielaverthelyi tracelevelsofinnateimmuneresponsemodulatingimpuritiesiirmissynergizetobreaktolerancetotherapeuticproteins AT vivianwang tracelevelsofinnateimmuneresponsemodulatingimpuritiesiirmissynergizetobreaktolerancetotherapeuticproteins
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Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.

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