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dc.contributor.authorEvans, RJ
dc.contributor.authorPerkins, DW
dc.contributor.authorSelfe, J
dc.contributor.authorKelsey, A
dc.contributor.authorBirch, GP
dc.contributor.authorShipley, JM
dc.contributor.authorSchipper, K
dc.contributor.authorIsacke, CM
dc.coverage.spatialUnited States
dc.date.accessioned2023-01-24T14:42:37Z
dc.date.available2023-01-24T14:42:37Z
dc.date.issued2022-11-18
dc.identifier711074
dc.identifier.citationMolecular Cancer Therapeutics, 2022, pp. MCT-22-0312 -en_US
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5665
dc.identifier.eissn1538-8514
dc.identifier.eissn1538-8514
dc.identifier.doi10.1158/1535-7163.MCT-22-0312
dc.identifier.doi10.1158/1535-7163.MCT-22-0312
dc.description.abstractAlthough the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first line treatment remains high and survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From immunohistochemical staining of a large set of 625 human soft tissue sarcomas we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene expression datasets showing a significantly increased expression in both soft tissue and bone sarcomas compared to normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180 expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an Isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide pre-clinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease.
dc.formatPrint-Electronic
dc.format.extentMCT-22-0312 -
dc.languageeng
dc.language.isoengen_US
dc.publisherAmerican Association for Cancer Research (AACR)en_US
dc.relation.ispartofMolecular Cancer Therapeutics
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleEndo180 (MRC2) antibody-drug conjugate for the treatment of sarcoma.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-11-02
dc.date.updated2023-01-24T13:52:23Z
rioxxterms.versionAMen_US
rioxxterms.versionofrecord10.1158/1535-7163.MCT-22-0312en_US
rioxxterms.licenseref.startdate2022-11-18
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/36399638
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Cell Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1158/1535-7163.mct-22-0312
icr.researchteamMolecular Cell Biologyen_US
icr.researchteamSarcoma Mol Patholen_US
dc.contributor.icrauthorEvans, Rachel
dc.contributor.icrauthorSelfe, Joanna
dc.contributor.icrauthorShipley, Janet
dc.contributor.icrauthorIsacke, Clare
icr.provenanceDeposited by Prof Clare Isacke on 2023-01-24. Deposit type is initial. No. of files: 1. Files: 221026 Evans merged file.pdf


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