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

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  • معلومة اضافية
    • المصدر:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: San Francisco, CA : Public Library of Science
    • الموضوع:
      Antibodies, Monoclonal, Humanized/*pharmacology ; Breast Neoplasms/*drug therapy ; CTLA-4 Antigen/*immunology ; Camptothecin/*analogs & derivatives ; Immunity, Innate/*drug effects ; Immunoconjugates/*pharmacology; Animals ; Antibodies/drug effects ; Antibodies/immunology ; Breast Neoplasms/genetics ; Breast Neoplasms/immunology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen/antagonists & inhibitors ; Camptothecin/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Female ; Humans ; Mice ; Receptor, ErbB-2/genetics ; Trastuzumab
    • نبذة مختصرة :
      [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.
      Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: all of the authors are paid employees of Daiichi Sankyo Co., Ltd. The authors would like to declare the following patent applications associated with this research: combination of antibody-drug conjugate and immune checkpoint inhibitor; PCT/JP2017/044426 [TNI, TW]. [fam-] trastuzumab deruxtecan is in clinical development. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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    • الرقم المعرف:
      0 (Antibodies)
      0 (Antibodies, Monoclonal, Humanized)
      0 (CTLA-4 Antigen)
      0 (Immunoconjugates)
      5384HK7574 (trastuzumab deruxtecan)
      EC 2.7.10.1 (ERBB2 protein, human)
      EC 2.7.10.1 (Receptor, ErbB-2)
      P188ANX8CK (Trastuzumab)
      XT3Z54Z28A (Camptothecin)
    • الموضوع:
      Date Created: 20191002 Date Completed: 20200311 Latest Revision: 20201209
    • الموضوع:
      20240829
    • الرقم المعرف:
      PMC6772042
    • الرقم المعرف:
      10.1371/journal.pone.0222280
    • الرقم المعرف:
      31574081