Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein

Autores
Ochoa, María C.; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas Stubbs, Sandra; Azpilikueta, Arantza; Mazzolini Rizzo, Guillermo Daniel; Gúrpide, Alfonso; Prieto, Jesús; Pardo, Julián; Berraondo, Pedro; Melero, Ignacio
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα−/− mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.
Fil: Ochoa, María C.. Universidad de Navarra; España
Fil: Fioravanti, Jessica. Universidad de Navarra; España
Fil: Rodriguez, Inmaculada. Universidad de Navarra; España
Fil: Hervas Stubbs, Sandra. Universidad de Navarra; España
Fil: Azpilikueta, Arantza. Universidad de Navarra; España
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gúrpide, Alfonso. Universidad de Navarra; España
Fil: Prieto, Jesús. Universidad de Navarra; España
Fil: Pardo, Julián. Universidad de Zaragoza; España
Fil: Berraondo, Pedro. Universidad de Navarra; España
Fil: Melero, Ignacio. Universidad de Navarra; España
Materia
Il-15
Hdl-Conjugated
Cancer
Toxicity
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/21140
Acceder
id CONICETDig_f025a86eee23518748720497aa430a58
oai_identifier_str oai:ri.conicet.gov.ar:11336/21140
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion proteinOchoa, María C.Fioravanti, JessicaRodriguez, InmaculadaHervas Stubbs, SandraAzpilikueta, ArantzaMazzolini Rizzo, Guillermo DanielGúrpide, AlfonsoPrieto, JesúsPardo, JuliánBerraondo, PedroMelero, IgnacioIl-15Hdl-ConjugatedCancerToxicityhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα−/− mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.Fil: Ochoa, María C.. Universidad de Navarra; EspañaFil: Fioravanti, Jessica. Universidad de Navarra; EspañaFil: Rodriguez, Inmaculada. Universidad de Navarra; EspañaFil: Hervas Stubbs, Sandra. Universidad de Navarra; EspañaFil: Azpilikueta, Arantza. Universidad de Navarra; EspañaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gúrpide, Alfonso. Universidad de Navarra; EspañaFil: Prieto, Jesús. Universidad de Navarra; EspañaFil: Pardo, Julián. Universidad de Zaragoza; EspañaFil: Berraondo, Pedro. Universidad de Navarra; EspañaFil: Melero, Ignacio. Universidad de Navarra; EspañaAmerican Association for Cancer Research2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/21140Ochoa, María C.; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas Stubbs, Sandra; Azpilikueta, Arantza; et al.; Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein; American Association for Cancer Research; Cancer Research; 73; 1; 1-2013; 139-1490008-5472CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/73/1/139info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-12-2660info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:03:56Zoai:ri.conicet.gov.ar:11336/21140instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:03:56.715CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
title Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
spellingShingle Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
Ochoa, María C.
Il-15
Hdl-Conjugated
Cancer
Toxicity
title_short Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
title_full Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
title_fullStr Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
title_full_unstemmed Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
title_sort Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein
dc.creator.none.fl_str_mv Ochoa, María C.
Fioravanti, Jessica
Rodriguez, Inmaculada
Hervas Stubbs, Sandra
Azpilikueta, Arantza
Mazzolini Rizzo, Guillermo Daniel
Gúrpide, Alfonso
Prieto, Jesús
Pardo, Julián
Berraondo, Pedro
Melero, Ignacio
author Ochoa, María C.
author_facet Ochoa, María C.
Fioravanti, Jessica
Rodriguez, Inmaculada
Hervas Stubbs, Sandra
Azpilikueta, Arantza
Mazzolini Rizzo, Guillermo Daniel
Gúrpide, Alfonso
Prieto, Jesús
Pardo, Julián
Berraondo, Pedro
Melero, Ignacio
author_role author
author2 Fioravanti, Jessica
Rodriguez, Inmaculada
Hervas Stubbs, Sandra
Azpilikueta, Arantza
Mazzolini Rizzo, Guillermo Daniel
Gúrpide, Alfonso
Prieto, Jesús
Pardo, Julián
Berraondo, Pedro
Melero, Ignacio
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Il-15
Hdl-Conjugated
Cancer
Toxicity
topic Il-15
Hdl-Conjugated
Cancer
Toxicity
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα−/− mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.
Fil: Ochoa, María C.. Universidad de Navarra; España
Fil: Fioravanti, Jessica. Universidad de Navarra; España
Fil: Rodriguez, Inmaculada. Universidad de Navarra; España
Fil: Hervas Stubbs, Sandra. Universidad de Navarra; España
Fil: Azpilikueta, Arantza. Universidad de Navarra; España
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gúrpide, Alfonso. Universidad de Navarra; España
Fil: Prieto, Jesús. Universidad de Navarra; España
Fil: Pardo, Julián. Universidad de Zaragoza; España
Fil: Berraondo, Pedro. Universidad de Navarra; España
Fil: Melero, Ignacio. Universidad de Navarra; España
description Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα−/− mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/21140
Ochoa, María C.; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas Stubbs, Sandra; Azpilikueta, Arantza; et al.; Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein; American Association for Cancer Research; Cancer Research; 73; 1; 1-2013; 139-149
0008-5472
CONICET Digital
CONICET
url http://hdl.handle.net/11336/21140
identifier_str_mv Ochoa, María C.; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas Stubbs, Sandra; Azpilikueta, Arantza; et al.; Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein; American Association for Cancer Research; Cancer Research; 73; 1; 1-2013; 139-149
0008-5472
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/73/1/139
info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-12-2660
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781283766632448
score 12.982451

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