dc.contributor.author | Evans, RJ | |
dc.contributor.author | Perkins, DW | |
dc.contributor.author | Selfe, J | |
dc.contributor.author | Kelsey, A | |
dc.contributor.author | Birch, GP | |
dc.contributor.author | Shipley, JM | |
dc.contributor.author | Schipper, K | |
dc.contributor.author | Isacke, CM | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-01-24T14:42:37Z | |
dc.date.available | 2023-01-24T14:42:37Z | |
dc.date.issued | 2023-02-01 | |
dc.identifier | 711074 | |
dc.identifier.citation | Molecular Cancer Therapeutics, 2022, pp. MCT-22-0312 - | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5665 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.MCT-22-0312 | |
dc.description.abstract | Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first-line treatment remains high, and the 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 the IHC 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 data sets showing a significantly increased expression in both soft-tissue and bone sarcomas compared with 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 antimitotic 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 preclinical 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.format | Print-Electronic | |
dc.format.extent | MCT-22-0312 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Molecular Cancer Therapeutics | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | Endo180 (MRC2) Antibody-Drug Conjugate for the Treatment of Sarcoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-11-02 | |
dc.date.updated | 2023-01-24T13:52:23Z | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1158/1535-7163.MCT-22-0312 | |
rioxxterms.licenseref.startdate | 2022-11-18 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://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-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1158/1535-7163.mct-22-0312 | |
icr.researchteam | Molecular Cell Biology | |
icr.researchteam | Sarcoma Mol Pathol | |
dc.contributor.icrauthor | Evans, Rachel | |
dc.contributor.icrauthor | Selfe, Joanna | |
dc.contributor.icrauthor | Shipley, Janet | |
dc.contributor.icrauthor | Isacke, Clare | |
icr.provenance | Deposited by Prof Clare Isacke on 2023-01-24. Deposit type is initial. No. of files: 1. Files: 221026 Evans merged file.pdf | |