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. 2024 Jun 22.
doi: 10.1007/s10585-024-10297-z. Online ahead of print.

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

Levent Mutlu #  1 , Blair McNamara #  1 , Stefania Bellone  1 , Diego D Manavella  1 , Cem Demirkiran  1 , Michelle Greenman  1 , Miguel Skyler Z Verzosa  1 , Natalia Buza  2 , Pei Hui  2 , Tobias Max Philipp Hartwich  1 , Justin Harold  1 , Yang Yang-Hartwich  1 , Margherita Zipponi  1 , Gary Altwerger  1 , Elena Ratner  1 , Gloria S Huang  1 , Mitchell Clark  1 , Vaagn Andikyan  1 , Masoud Azodi  1 , Peter E Schwartz  1 , Alessandro D Santin  3
Affiliations

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

Levent Mutlu et al. Clin Exp Metastasis. .

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.

Keywords: Antibody-drug conjugate; Clear cell ovarian cancer; DS-8201a; HER2; High-grade serous ovarian cancer; Ovarian cancer; T-DXd; Trastuzumab deruxtecan.

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References

    1. Siegel RL, Giaquinto AN, Jemal A, Cancer statistics, CA, Cancer JC (2024) 2024 Jan-Feb;74(1):12–49. doi: 10.3322/caac.21820. Epub 2024 Jan 17. Erratum in: CA Cancer J Clin. 2024 Mar-Apr;74(2):203. PMID: 38230766
    1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) (2017) SEER Cancer Statistics Review, 1975–2014, National Cancer Institute, Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/
    1. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R (2003) Gynecologic Oncology Group, Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21:3194–3200. https://doi.org/10.1200/JCO.2003.02.153 - DOI - PubMed
    1. du Bois A, Lück H-J, Meier W, Adams H-P, Möbus V, Costa S, Bauknecht T, Richter B, Warm M, Schröder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J (2003) Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group, a randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320–1329. https://doi.org/10.1093/jnci/djg036 - DOI - PubMed
    1. Cannistra SA (1993) Cancer of the ovary. N Engl J Med 329:1550–1559. https://doi.org/10.1056/NEJM199311183292108 - DOI - PubMed

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