[Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti–CTLA-4 antibody in a mouse model

Autoři: Tomomi Nakayama Iwata aff001;  Kiyoshi Sugihara aff001;  Teiji Wada aff001;  Toshinori Agatsuma aff001
Působiště autorů: Oncology Research Laboratories I, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan aff001
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222280


[Fam-] trastuzumab deruxtecan (DS-8201a) is a HER2 (ERBB2)-targeting antibody-drug conjugate, composed of a HER2-targeting antibody and a topoisomerase I inhibitor, exatecan derivative, that has antitumor effects in preclinical xenograft models and clinical trials. Recently, [fam-] trastuzumab deruxtecan was reported to enhance antitumor immunity and was beneficial in combination with an anti–PD-1 antibody in a mouse model. In this study, the antitumor effect of [fam-] trastuzumab deruxtecan in combination with an anti–CTLA-4 antibody was evaluated. [Fam-] trastuzumab deruxtecan monotherapy had antitumor activity in an immunocompetent mouse model with EMT6 human HER2-expressing mouse breast cancer cells (EMT6-hHER2). [Fam-] trastuzumab deruxtecan in combination with the anti–CTLA-4 antibody induced more potent antitumor activity than that by monotherapy with either agent. The combination therapy increased tumor-infiltrating CD4+ and CD8+ T cells in vivo. Mechanistically, cured mice with treatment of [fam-] trastuzumab deruxtecan and an anti–CTLA-4 antibody completely rejected EMT6-mock cells similar to EMT6-hHER2 cells, and splenocytes from the cured mice responded to both EMT6-hHER2 and EMT6-mock cells as measured by interferon-gamma release. Taken together, these results indicate that antitumor immunity is induced by [fam-] trastuzumab deruxtecan and is facilitated in combination with anti–CTLA-4 antibody.

Klíčová slova:

Antibodies – Cancer treatment – Cytotoxic T cells – Enzyme-linked immunoassays – Flow cytometry – Immunohistochemistry techniques – Mouse models – T cells


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2019 Číslo 10
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