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Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine
Vincent Chen1,2, Shigeki Umemura1, Yumin Han3
1Georgetown University Medical Center, Washington, DC, USA.
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.
Insights
A novel antibody-drug conjugate, anetumab ravtansine (ARav), shows promise in treating thymic carcinoma by targeting mesothelin (MSLN). This therapy effectively inhibited tumor growth in preclinical models, offering a potential new treatment avenue for this rare cancer.
Area of Science:
- Oncology
- Cancer Biology
- Drug Development
Background:
- Thymic epithelial tumours (TETs), including thymomas and thymic carcinoma, are rare neoplasms requiring novel therapeutic strategies.
- Thymic carcinoma has a poor prognosis, with a 5-year survival rate of approximately 30%.
- Mesothelin (MSLN) is a surface glycoprotein overexpressed in 79% of thymic carcinoma cases, making it a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of the mesothelin-targeting antibody-drug conjugate, anetumab ravtansine (ARav), in inhibiting thymic carcinoma growth.
- To assess ARav's activity both in vitro and in vivo.
Main Methods:
- Utilized flow cytometry to confirm MSLN expression and antibody binding.
- Conducted in vitro cytotoxicity assays to determine ARav's effect on thymic carcinoma cell lines.
- Employed an in vivo xenograft model to evaluate ARav's anti-tumour activity and its combination with cisplatin.
Main Results:
- Anetumab, the antibody component of ARav, successfully bound to and was internalized by MSLN-expressing thymic carcinoma cells.
- ARav demonstrated significant inhibition of thymic carcinoma cell growth in vitro.
- In vivo, ARav treatment reduced tumour growth in a xenograft model, with a combination of lower-dose ARav and cisplatin showing an additive inhibitory effect.
Conclusions:
- Anetumab ravtansine effectively inhibits the growth of mesothelin-positive thymic carcinoma cells.
- These findings support ARav as a potential therapeutic agent for thymic carcinoma.
- Further investigation into ARav, potentially in combination therapies, is warranted for thymic malignancies.
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