000117982 001__ 117982
000117982 005__ 20240319081013.0
000117982 0247_ $$2doi$$a10.3390/biomedicines10061223
000117982 0248_ $$2sideral$$a129139
000117982 037__ $$aART-2022-129139
000117982 041__ $$aeng
000117982 100__ $$0(orcid)0000-0002-1657-4792$$aGuerrero-Ochoa, Patricia$$uUniversidad de Zaragoza
000117982 245__ $$aPreclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
000117982 260__ $$c2022
000117982 5060_ $$aAccess copy available to the general public$$fUnrestricted
000117982 5203_ $$aTwo 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.
000117982 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B31-20R$$9info:eu-repo/grantAgreement/ES/DGA/E34-17R$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/Construyendo Europa desde Aragón$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-75633-P$$9info:eu-repo/grantAgreement/ES/MINECO/CTQ2013-44367-C2-2-P$$9info:eu-repo/grantAgreement/ES/MINECO/RTI2018-099592-B-C21
000117982 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000117982 590__ $$a4.7$$b2022
000117982 592__ $$a0.897$$b2022
000117982 591__ $$aPHARMACOLOGY & PHARMACY$$b68 / 278 = 0.245$$c2022$$dQ1$$eT1
000117982 593__ $$aMedicine (miscellaneous)$$c2022$$dQ1
000117982 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b92 / 285 = 0.323$$c2022$$dQ2$$eT1
000117982 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2022$$dQ2
000117982 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b54 / 136 = 0.397$$c2022$$dQ2$$eT2
000117982 594__ $$a3.7$$b2022
000117982 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000117982 700__ $$aIbáñez-Pérez, Raquel
000117982 700__ $$aBerbegal-Pinilla, Germán
000117982 700__ $$aAguilar, Diederich
000117982 700__ $$aMarzo, Isabel$$uUniversidad de Zaragoza
000117982 700__ $$aCorzana, Francisco
000117982 700__ $$0(orcid)0000-0001-7947-8813$$aMinjárez-Sáenz, Martha$$uUniversidad de Zaragoza
000117982 700__ $$0(orcid)0000-0001-6815-6720$$aMacías-León, Javier$$uUniversidad de Zaragoza
000117982 700__ $$0(orcid)0000-0003-4115-9766$$aConde, Blanca$$uUniversidad de Zaragoza
000117982 700__ $$0(orcid)0000-0003-3957-9091$$aRaso, Javier$$uUniversidad de Zaragoza
000117982 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, Ramón
000117982 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, Alberto$$uUniversidad de Zaragoza
000117982 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología
000117982 7102_ $$12008$$2700$$aUniversidad de Zaragoza$$bDpto. Produc.Animal Cienc.Ali.$$cÁrea Producción Animal
000117982 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000117982 7102_ $$12008$$2780$$aUniversidad de Zaragoza$$bDpto. Produc.Animal Cienc.Ali.$$cÁrea Tecnología de Alimentos
000117982 773__ $$g10, 6 (2022), 1223$$tBiomedicines$$x2227-9059
000117982 8564_ $$s6808039$$uhttps://zaguan.unizar.es/record/117982/files/texto_completo.pdf$$yVersión publicada
000117982 8564_ $$s2741631$$uhttps://zaguan.unizar.es/record/117982/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000117982 909CO $$ooai:zaguan.unizar.es:117982$$particulos$$pdriver
000117982 951__ $$a2024-03-18-15:23:10
000117982 980__ $$aARTICLE