Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cisplatin
/ administration & dosage
Drug Synergism
Female
Gene Expression Regulation, Neoplastic
/ drug effects
HT29 Cells
Humans
Immunoconjugates
/ administration & dosage
Maytansine
/ administration & dosage
Mesothelin
/ genetics
Mice
Neoplasms, Glandular and Epithelial
/ drug therapy
Thymoma
/ drug therapy
Thymus Neoplasms
/ drug therapy
Up-Regulation
/ drug effects
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
14
04
2021
accepted:
24
11
2021
revised:
30
10
2021
pubmed:
9
12
2021
medline:
11
3
2022
entrez:
8
12
2021
Statut:
ppublish
Résumé
Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma. Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth. These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.
Sections du résumé
BACKGROUND
Thymic epithelial tumours (TETs) are rare tumours comprised of thymomas and thymic carcinoma. Novel therapies are needed, especially in thymic carcinoma where the 5-year survival rate hovers at 30%. Mesothelin (MSLN), a surface glycoprotein that is cleaved to produce mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF), is expressed in limited tissues. However, its expression is present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases.
METHODS
We utilised flow cytometry, in vitro cytotoxicity assays, and an in vivo xenograft model in order to demonstrate the ability of the MSLN targeting antibody-drug conjugate (ADC) anetumab ravtansine (ARav) in inhibiting the growth of thymic carcinoma.
RESULTS
Thymoma and thymic carcinoma cell lines express MSLN, and anetumab, the antibody moiety of ARav, was capable of binding MSLN expressing thymic carcinoma cells and internalising. ARav was effective at inhibiting the growth of thymic carcinoma cells stably transfected with mMSLN in vitro. In vivo, 15 mg/kg ARav inhibited T1889 xenograft tumour growth, while combining 7.5 mg/kg ARav with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumour growth.
CONCLUSIONS
These data demonstrate that anetumab ravtansine inhibits the growth of MSLN positive thymic carcinoma cells in vitro and in vivo.
Identifiants
pubmed: 34876673
doi: 10.1038/s41416-021-01658-6
pii: 10.1038/s41416-021-01658-6
pmc: PMC8888701
doi:
Substances chimiques
Immunoconjugates
0
MSLN protein, human
0
Maytansine
14083FR882
Mesothelin
J27WDC343N
anetumab ravtansine
M170940PMI
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
754-763Subventions
Organisme : NCI NIH HHS
ID : P30 CA051008
Pays : United States
Organisme : DH | NIHR | Programme Development Grants (NIHR Programme Development Grants)
ID : P30CA051008
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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