Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment

Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, expressed in a varie...

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Autores: Guerrero-Ochoa, Patricia, Ibáñez-Pérez, Raquel, Berbegal-Pinilla, Germán, Aguilar, Diederich, Marzo, Isabel, Corzana, Francisco, Minjárez-Sáenz, Martha, Macías-León, Javier, Conde, Blanca, Raso, Javier, Hurtado-Guerrero, Ramón, Anel, Alberto
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:117982
Acesso em linha:http://zaguan.unizar.es/record/117982
Access Level:acceso abierto
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spelling Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral TreatmentGuerrero-Ochoa, PatriciaIbáñez-Pérez, RaquelBerbegal-Pinilla, GermánAguilar, DiederichMarzo, IsabelCorzana, FranciscoMinjárez-Sáenz, MarthaMacías-León, JavierConde, BlancaRaso, JavierHurtado-Guerrero, RamónAnel, AlbertoTwo granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers.2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://zaguan.unizar.es/record/117982reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/ES/DGA/B31-20Rinfo:eu-repo/grantAgreement/ES/DGA/E34-17Rinfo:eu-repo/grantAgreement/ES/DGA-FEDER/Construyendo Europa desde Aragóninfo:eu-repo/grantAgreement/ES/MINECO/BFU2016-75633-Pinfo:eu-repo/grantAgreement/ES/MINECO/CTQ2013-44367-C2-2-Pinfo:eu-repo/grantAgreement/ES/MINECO/RTI2018-099592-B-C21info:eu-repo/semantics/openAccessoai:zaguan.unizar.es:1179822026-05-29T13:59:51Z
dc.title.none.fl_str_mv Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
title Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
spellingShingle Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
Guerrero-Ochoa, Patricia
title_short Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
title_full Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
title_fullStr Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
title_full_unstemmed Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
title_sort Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
dc.creator.none.fl_str_mv Guerrero-Ochoa, Patricia
Ibáñez-Pérez, Raquel
Berbegal-Pinilla, Germán
Aguilar, Diederich
Marzo, Isabel
Corzana, Francisco
Minjárez-Sáenz, Martha
Macías-León, Javier
Conde, Blanca
Raso, Javier
Hurtado-Guerrero, Ramón
Anel, Alberto
author Guerrero-Ochoa, Patricia
author_facet Guerrero-Ochoa, Patricia
Ibáñez-Pérez, Raquel
Berbegal-Pinilla, Germán
Aguilar, Diederich
Marzo, Isabel
Corzana, Francisco
Minjárez-Sáenz, Martha
Macías-León, Javier
Conde, Blanca
Raso, Javier
Hurtado-Guerrero, Ramón
Anel, Alberto
author_role author
author2 Ibáñez-Pérez, Raquel
Berbegal-Pinilla, Germán
Aguilar, Diederich
Marzo, Isabel
Corzana, Francisco
Minjárez-Sáenz, Martha
Macías-León, Javier
Conde, Blanca
Raso, Javier
Hurtado-Guerrero, Ramón
Anel, Alberto
author2_role author
author
author
author
author
author
author
author
author
author
author
description Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/117982
url http://zaguan.unizar.es/record/117982
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/DGA/B31-20R
info:eu-repo/grantAgreement/ES/DGA/E34-17R
info:eu-repo/grantAgreement/ES/DGA-FEDER/Construyendo Europa desde Aragón
info:eu-repo/grantAgreement/ES/MINECO/BFU2016-75633-P
info:eu-repo/grantAgreement/ES/MINECO/CTQ2013-44367-C2-2-P
info:eu-repo/grantAgreement/ES/MINECO/RTI2018-099592-B-C21
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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