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Translational Therapeutics

Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine

Abstract

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.

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Fig. 1: MSLN expression in TET cell lines and MSLN transfected MP57 cells.
Fig. 2: Anetumab binds with and is internalised by MSLN expressing thymic carcinoma cells.
Fig. 3: Anetumab ravtansine specifically inhibits mMSLN transfected MP57 thymic carcinoma cells.
Fig. 4: Anetumab ravtansine inhibits T1889 thymic carcinoma xenografts in a nude mouse model.
Fig. 5: Anetumab ravtansine treated T1889 xenografts have decreased MSLN levels and increased cleaved caspase 3 levels.
Fig. 6: MSLN in thymic carcinoma increases drug resistance against cytotoxic compounds.

Data availability

All data analysed in this manuscript is available in the figures or supplemental material.

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Acknowledgements

Tapan Bera, PhD and Ira Pastan, MD provided us mesothelin expression plasmids for our transfections.

Funding

This work was funded by Bayer AG and the National Institutes of Health’s Cancer Center Support Grant (P30CA051008).

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Authors and Affiliations

Authors

Contributions

Vincent Chen, PhD conceptualised, designed, and executed the experiments. Vincent Chen, PhD also wrote the manuscript and generated the figures. Shigeki Umemura, MD assisted with in vitro work. Robin Tucker, DVM assisted with in vivo work. Joeffrey Chahine, MD read and scored all IHC slides. In-Kyu Kim, PhD assisted with conceptualisation and execution of experiments. Masanori Onda, MD, PhD provided MPF antibody for immunoblotting. Anette Sommer, PhD; Sabine Zitzmann-Kolbe, PhD; and Christoph Schatz, PhD assisted with conceptualisation of the experiments. Yumin Han, PhD; Renuka Raman, PhD; Yongfeng He, PhD; and Trevor Lee provided technical support and/or generated figures for the supplemental. Giuseppe Giaccone, MD, PhD oversaw the work.

Corresponding author

Correspondence to Giuseppe Giaccone.

Ethics declarations

Ethics approval and consent to participate

This study did not utilise human subjects. All mouse work was approved by the Georgetown Institutional Animal Care and Use Committee (Protocol number: 2016-1169).

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Not applicable.

Competing interests

Anette Sommer, PhD is a shareholder of Bayer AG. Christoph Schatz, PhD is a shareholder of Bayer AG. All other authors declare no conflicts of interests.

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Chen, V., Umemura, S., Han, Y. et al. Exploiting mesothelin in thymic carcinoma as a drug delivery target for anetumab ravtansine. Br J Cancer 126, 754–763 (2022). https://doi.org/10.1038/s41416-021-01658-6

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