Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin

Granulysin is a protein present in the granules of human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, with cytolytic activity against microbes and tumors. Previous work demonstrated the therapeutic effect of intratumoral injection of recombinant granulysin using in vivo models of bre...

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Main Authors: Raquel Ibáñez-Pérez, Patricia Guerrero-Ochoa, Sameer Al-Wasaby, Rocío Navarro, Antonio Tapia-Galisteo, Diego De Miguel, Oscar Gonzalo, Blanca Conde, Luis Martínez-Lostao, Ramón Hurtado-Guerrero, Laura Sanz, Alberto Anel
Format: Article
Language:English
Published: Taylor & Francis Group 2019-11-01
Series:OncoImmunology
Subjects:
cea
Online Access:http://dx.doi.org/10.1080/2162402X.2019.1641392
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spelling doaj-ddae2382868c4a1a8515e30f3143a05f2020-11-25T03:24:39ZengTaylor & Francis GroupOncoImmunology2162-402X2019-11-0181110.1080/2162402X.2019.16413921641392Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxinRaquel Ibáñez-Pérez0Patricia Guerrero-Ochoa1Sameer Al-Wasaby2Rocío Navarro3Antonio Tapia-Galisteo4Diego De Miguel5Oscar Gonzalo6Blanca Conde7Luis Martínez-Lostao8Ramón Hurtado-Guerrero9Laura Sanz10Alberto Anel11Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)“Puerta de Hierro” University Hospital“Puerta de Hierro” University HospitalImmunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)“Lozano Blesa” University Clinical HospitalBiocomputation and Physics of Complex Systems Institute (BIFI), University of Zaragoza“Puerta de Hierro” University HospitalImmunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón)Granulysin is a protein present in the granules of human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, with cytolytic activity against microbes and tumors. Previous work demonstrated the therapeutic effect of intratumoral injection of recombinant granulysin using in vivo models of breast cancer and multiple myeloma. In the present work we have developed a granulysin gene fusion to the anti-carcinoembryonic antigen (CEA/CEACAM5) single chain Fv antibody fragment MFE23. Both granulysin and the granulysin-based immunotoxin were expressed in Pichia pastoris. The immunotoxin specifically recognized CEA, purified or expressed on the cell surface. Moreover, the bioactivity of the immunotoxin against several CEA+ cell lines was higher than that of granulysin alone. Granulysin and the immunotoxin were tested as a treatment in in vivo xenograft models in athymic mice. When injected intratumorally, both granulysin and the immunotoxin were able to inhibit tumor growth. Furthermore, systemic administration of the immunotoxin demonstrated a decrease in tumor growth in a CEA+ tumor-bearing mouse model, whereas granulysin did not exhibit a therapeutic effect. This is the first granulysin-based immunotoxin and the present work constitutes the proof of concept of its therapeutic potential.http://dx.doi.org/10.1080/2162402X.2019.1641392granulysinscfvimmunotoxinceacolon carcinoma
collection DOAJ
language English
format Article
sources DOAJ
author Raquel Ibáñez-Pérez
Patricia Guerrero-Ochoa
Sameer Al-Wasaby
Rocío Navarro
Antonio Tapia-Galisteo
Diego De Miguel
Oscar Gonzalo
Blanca Conde
Luis Martínez-Lostao
Ramón Hurtado-Guerrero
Laura Sanz
Alberto Anel
spellingShingle Raquel Ibáñez-Pérez
Patricia Guerrero-Ochoa
Sameer Al-Wasaby
Rocío Navarro
Antonio Tapia-Galisteo
Diego De Miguel
Oscar Gonzalo
Blanca Conde
Luis Martínez-Lostao
Ramón Hurtado-Guerrero
Laura Sanz
Alberto Anel
Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
OncoImmunology
granulysin
scfv
immunotoxin
cea
colon carcinoma
author_facet Raquel Ibáñez-Pérez
Patricia Guerrero-Ochoa
Sameer Al-Wasaby
Rocío Navarro
Antonio Tapia-Galisteo
Diego De Miguel
Oscar Gonzalo
Blanca Conde
Luis Martínez-Lostao
Ramón Hurtado-Guerrero
Laura Sanz
Alberto Anel
author_sort Raquel Ibáñez-Pérez
title Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
title_short Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
title_full Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
title_fullStr Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
title_full_unstemmed Anti-tumoral potential of a human granulysin-based, CEA-targeted cytolytic immunotoxin
title_sort anti-tumoral potential of a human granulysin-based, cea-targeted cytolytic immunotoxin
publisher Taylor & Francis Group
series OncoImmunology
issn 2162-402X
publishDate 2019-11-01
description Granulysin is a protein present in the granules of human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, with cytolytic activity against microbes and tumors. Previous work demonstrated the therapeutic effect of intratumoral injection of recombinant granulysin using in vivo models of breast cancer and multiple myeloma. In the present work we have developed a granulysin gene fusion to the anti-carcinoembryonic antigen (CEA/CEACAM5) single chain Fv antibody fragment MFE23. Both granulysin and the granulysin-based immunotoxin were expressed in Pichia pastoris. The immunotoxin specifically recognized CEA, purified or expressed on the cell surface. Moreover, the bioactivity of the immunotoxin against several CEA+ cell lines was higher than that of granulysin alone. Granulysin and the immunotoxin were tested as a treatment in in vivo xenograft models in athymic mice. When injected intratumorally, both granulysin and the immunotoxin were able to inhibit tumor growth. Furthermore, systemic administration of the immunotoxin demonstrated a decrease in tumor growth in a CEA+ tumor-bearing mouse model, whereas granulysin did not exhibit a therapeutic effect. This is the first granulysin-based immunotoxin and the present work constitutes the proof of concept of its therapeutic potential.
topic granulysin
scfv
immunotoxin
cea
colon carcinoma
url http://dx.doi.org/10.1080/2162402X.2019.1641392
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