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Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2

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Abstract

High-grade serous ovarian cancer (HGSOC) and ovarian clear cell carcinoma (CC), are biologically aggressive tumors endowed with the ability to rapidly metastasize to the abdominal cavity and distant organs. About 10% of HGSOC and 30% of CC demonstrate HER2 IHC 3 + receptor over-expression. We evaluated the efficacy of trastuzumab deruxtecan (T-DXd; DS-8201a), a novel HER2-targeting antibody-drug conjugate (ADC) to an ADC isotype control (CTL ADC) against multiple HGSOC and CC tumor models. Eleven ovarian cancer cell lines including a matched primary and metastatic cell line established from the same patient, were evaluated for HER2 expression by immunohistochemistry and flow cytometry, and gene amplification by fluorescence in situ hybridization assays. In vitro experiments demonstrated T-DXd to be significantly more effective against HER2 3 + HGSOC and CC cell lines when compared to CTL ADC (p < 0.0001). T-DXd induced efficient bystander killing of HER2 non-expressing tumor cells when admixed with HER2 3 + cells. In vivo activity of T-DXd was studied in HER2 IHC 3 + HGSOC and CC mouse xenograft models. We found T-DXd to be significantly more effective than CTL ADC against HER2 3 + HGSOC (KR(CH)31) and CC (OVA10) xenografts with a significant difference in tumor growth starting at day 8 (p = 0.0003 for KR(CH)31, p < 0.0001 for OVA10). T-DXd also conferred a survival advantage in both xenograft models. T-DXd may represent an effective ADC against primary and metastatic HER2-overexpressing HGSOC and CC.

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Funding

This work was supported in part by grants from NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Domenic Cicchetti Foundation, the Discovery to Cure Foundation, the Guido Berlucchi Foundation, and Gilead Sciences Inc., Foster City, CA to A.D.S. This investigation was also supported by NIH Research Grant CA-16,359 from NCI and Standup-to-cancer (SU2C) convergence grant 2.0 to A.D.S.

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Author notes

  1. Levent Mutlu and Blair McNamara contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics, Gynecology, and Reproductive Sciences, 333 Cedar Street, LSOG 305, PO Box 208063, New Haven, CT, 06520, USA

    Levent Mutlu, Blair McNamara, Stefania Bellone, Diego D. Manavella, Cem Demirkiran, Michelle Greenman, Miguel Skyler Z. Verzosa, Tobias Max Philipp Hartwich, Justin Harold, Yang Yang-Hartwich, Margherita Zipponi, Gary Altwerger, Elena Ratner, Gloria S. Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. Schwartz & Alessandro D. Santin

  2. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Natalia Buza & Pei Hui

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  1. Levent Mutlu
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Contributions

Conception and design: B. M, L.M, S.B, L.M, A.S. Development and methodology: S.B, D.M, A.S. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S.B, L.M, D.M, J.H, M.Z, V.A, M.A. Analysis and interpretation of data (e.g., statistical analysis, pathology, biostatistics, computational analysis): S.B, L.M, B.M, N.B, P.H, D.M, A.S. Writing, review, and/or revision of the manuscript: S.B, B.M, D.M, C.M, M.G, T.V, T.H, M.Z, G.A, E.R, G.H, M.C, V.A, M.A, P.S, A.D.S. Administrative, technical, or material support (e.g., reporting or organizing data, constructing databases): S.B, L.M, B.M, D.M, M.Z. Study supervision: B.M, S.B, M.A, P.S, A.D.S.

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Correspondence to Alessandro D. Santin.

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Conflict of interest

A.D.S. reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO and grants and personal fees from EISAI and R-Pharm USA. The other authors declare no conflict of interest. G.S.H reports consulting fees from GlaxoSmithKline and AstraZeneca.

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Mutlu, L., McNamara, B., Bellone, S. et al. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2. Clin Exp Metastasis (2024). https://doi.org/10.1007/s10585-024-10297-z

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