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dc.contributor.authorDomínguez, Juan Manuel
dc.contributor.authorPérez-Chacón, Gema
dc.contributor.authorGuillén, María José
dc.contributor.authorMuñoz-Alonso, María José
dc.contributor.authorSomovilla-Crespo, Beatriz
dc.contributor.authorCibrian, Danay 
dc.contributor.authorAcosta-Iborra, Bárbara
dc.contributor.authorAdrados, Magdalena
dc.contributor.authorMuñoz-Calleja, Cecilia
dc.contributor.authorCuevas, Carmen
dc.contributor.authorSanchez-Madrid, Francisco 
dc.contributor.authorAvilés, Pablo
dc.contributor.authorZapata, Juan M
dc.date.accessioned2020-04-20T14:16:41Z
dc.date.available2020-04-20T14:16:41Z
dc.date.issued2020-04
dc.identifier.citationJ Hematol Oncol. 2020; 13(1):32es_ES
dc.identifier.issn1756-8722es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9633
dc.description.abstractBACKGROUND: In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. METHODS: Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. RESULTS: CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. CONCLUSION: Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.es_ES
dc.description.sponsorshipThis work was partially supported by grant IPT-2012-0198-090000 (“MARINMAB” project) from Ministerio de Economía y Competitividad (MINECO) and European Regional Development’s funds (ERDF) and by CSIC grant 2019AEP146.es_ES
dc.language.isoenges_ES
dc.publisherBMCes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectADCes_ES
dc.subjectAminopeptidase-Nes_ES
dc.subjectAntibody-drug conjugatees_ES
dc.subjectCD13es_ES
dc.subjectEndocytosises_ES
dc.subjectFibrosarcomaes_ES
dc.subjectMI130110es_ES
dc.titleCD13 as a new tumor target for antibody-drug conjugates: validation with the conjugate MI130110es_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID32264921es_ES
dc.format.volume13es_ES
dc.format.number1es_ES
dc.format.page32es_ES
dc.identifier.doi10.1186/s13045-020-00865-7es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1756-8722es_ES
dc.relation.publisherversionhttps://doi.org/10.1186/s13045-020-00865-7es_ES
dc.identifier.journalJournal of hematology & oncologyes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Comunicación Intercelular en la Respuesta Inflamatoriaes_ES
dc.repisalud.institucionCNICes_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución 4.0 Internacional
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