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Development of Dl1.72, a novel anti-DLL1 antibody with anti-tumor efficacy against estrogen receptor-positive breast cancer

2021-08-02Artigo científico Acesso aberto
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dc.contributor.authorSilva, Gabriela
dc.contributor.authorSales-Dias, Joana
dc.contributor.authorCasal, Diogo B.
dc.contributor.authorAlves, Sara
dc.contributor.authorDomenici, Giacomo
dc.contributor.authorBarreto, Clara
dc.contributor.authorMatos, Carolina
dc.contributor.authorLemos, Ana R.
dc.contributor.authorMatias, Ana T.
dc.contributor.authorKucheryava, Khrystyna
dc.contributor.authorFerreira, Andreia
dc.contributor.authorMoita, Maria Raquel
dc.contributor.authorBraga, Sofia
dc.contributor.authorBrito, Catarina
dc.contributor.authorCabral, M. Guadalupe
dc.contributor.authorCabral, MG
dc.contributor.authorCasalou, Cristina
dc.contributor.authorBarral, Duarte C.
dc.contributor.authorC. Barral, Duarte
dc.contributor.authorSousa, Pedro M. F.
dc.contributor.authorVideira, Paula A.
dc.contributor.authorBandeiras, Tiago M.
dc.contributor.authorBarbas, Ana
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.institutionInstituto de Tecnologia Química e Biológica António Xavier (ITQB)
dc.contributor.institutionDCV - Departamento de Ciências da Vida
dc.contributor.institutionUCIBIO - Applied Molecular Biosciences Unit
dc.contributor.pblMDPI - Multidisciplinary Digital Publishing Institute
dc.date.accessioned2023-01-12T22:16:47Z
dc.date.available2023-01-12T22:16:47Z
dc.date.issued2021-08-02
dc.descriptionFunding Information: Funding: This research was funded by Fundação para a Ciência e Tecnologia, Portugal, grants PTDC/BBB-BMD/4497/2014 (to A.B.) and PD/BD/113987/2015 (to J.S.-D.), iBETXplore grants 3D-ABC-PI-717 (to G.D.) and BiACaT-HER2:JAG1 (to G.S.). iNOVA4Health—UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Fundação para a Ciência e Tecnolo-gia/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds is acknowledged. Funding from the INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), is gratefully acknowledged. Support was also provided by the Applied Molecular Biosciences Unit—UCIBIO, which is financed by national funds from Fundação para a Ciência e Tecnologia (UIDP/04378/2020 and UIDB/04378/2020). Funding Information: This research was funded by Funda??o para a Ci?ncia e Tecnologia, Portugal, grants PTDC/BBB-BMD/4497/20141 (to A.B.) and PD/BD/113987/2015 (to J.S.-D.), iBETXplore grants 3D-ABC-PI-717 (to G.D.) and BiACaT-HER2:JAG1 (to G.S.). iNOVA4Health?UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Funda??o para a Ci?ncia e Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds is acknowledged. Funding from the INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC), is gratefully acknowledged. Support was also provided by the Applied Molecular Biosciences Unit?UCIBIO, which is financed by national funds from Funda??o para a Ci?ncia e Tecnologia (UIDP/04378/2020 and UIDB/04378/2020). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
dc.description.abstractThe Notch-signaling ligand DLL1 has emerged as an important player and promising therapeutic target in breast cancer (BC). DLL1-induced Notch activation promotes tumor cell proliferation, survival, migration, angiogenesis and BC stem cell maintenance. In BC, DLL1 overexpression is associated with poor prognosis, particularly in estrogen receptor-positive (ER+) subtypes. Directed therapy in early and advanced BC has dramatically changed the natural course of ER+ BC; however, relapse is a major clinical issue, and new therapeutic strategies are needed. Here, we report the development and characterization of a novel monoclonal antibody specific to DLL1. Using phage display technology, we selected an anti-DLL1 antibody fragment, which was converted into a full human IgG1 (Dl1.72). The Dl1.72 antibody exhibited DLL1 specificity and affinity in the low nanomolar range and significantly impaired DLL1-Notch signaling and expression of Notch target genes in ER+ BC cells. Functionally, in vitro treatment with Dl1.72 reduced MCF-7 cell proliferation, migration, mammosphere formation and endothelial tube formation. In vivo, Dl1.72 significantly inhibited tumor growth, reducing both tumor cell proliferation and liver metastases in a xenograft mouse model, without apparent toxicity. These findings suggest that anti-DLL1 Dl1.72 could be an attractive agent against ER+ BC, warranting further preclinical investigation.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent4225871
dc.identifier.doi10.3390/cancers13164074
dc.identifier.issn2072-6694
dc.identifier.otherPURE: 33310345
dc.identifier.otherPURE UUID: dfdc825e-1538-4c9d-9c62-37ceff9b5ee9
dc.identifier.otherScopus: 85112348312
dc.identifier.otherPubMed: 34439228
dc.identifier.otherPubMedCentral: PMC8392387
dc.identifier.otherORCID: /0000-0001-5987-2485/work/100976789
dc.identifier.otherORCID: /0000-0001-8867-2407/work/123561666
dc.identifier.otherWOS: 000689049500001
dc.identifier.urihttp://hdl.handle.net/10362/147438
dc.identifier.urlhttps://www.scopus.com/pages/publications/85112348312
dc.language.isoeng
dc.peerreviewedyes
dc.subjectAngiogenesis
dc.subjectCell proliferation
dc.subjectDLL1
dc.subjectER breast cancer
dc.subjectMonoclonal antibody
dc.subjectNotch signaling
dc.subjectTumor growth
dc.subjectOncology
dc.subjectCancer Research
dc.subjectSDG 3 - Good Health and Well-being
dc.titleDevelopment of Dl1.72, a novel anti-DLL1 antibody with anti-tumor efficacy against estrogen receptor-positive breast canceren
dc.typejournal article
degois.publication.issue16
degois.publication.titleCancers
degois.publication.volume13
dspace.entity.typePublication
person.familyNameCabral
person.familyNameBarral
person.givenNameMaria de Guadalupe
person.givenNameDuarte
person.identifier.ciencia-idCB1B-C82A-D84A
person.identifier.ciencia-id8810-DEBC-025E
person.identifier.orcid0000-0001-9016-9173
person.identifier.orcid0000-0001-8867-2407
person.identifier.ridN-4029-2016
person.identifier.ridE-7548-2013
person.identifier.scopus-author-id55412398200
person.identifier.scopus-author-id6602513159
rcaap.rightsopenAccess
relation.isAuthorOfPublication08736bca-6978-4566-858b-b2edac1b2618
relation.isAuthorOfPublicatione8205a0a-7fb2-450a-9917-417ec75d88b3
relation.isAuthorOfPublication.latestForDiscovery08736bca-6978-4566-858b-b2edac1b2618

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