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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/21140
Ver los metadatos del registro completo
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 Técnicas2025-09-29T09:35:51Zoai: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:34982025-09-29 09:35:51.975CONICET 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_ |
1844613120884998144 |
score |
13.070432 |