Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies
In human blood, 1% to 5% of lymphocytes are γδ T cells; they mostly express the γδ T-cell receptor (TCR)Vγ9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-...
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| Published in | Blood Vol. 113; no. 20; pp. 4875 - 4884 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Washington, DC
Elsevier Inc
14.05.2009
Americain Society of Hematology American Society of Hematology |
| Subjects | |
| Online Access | Get full text |
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| Abstract | In human blood, 1% to 5% of lymphocytes are γδ T cells; they mostly express the γδ T-cell receptor (TCR)Vγ9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by γδ T cells is unknown. Here we report that, in association with the CD20+-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVγ9+ cell binding to CD20+ lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVγ9+ cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20+ cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by γδ T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVγ9+ lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs. |
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| AbstractList | In human blood, 1% to 5% of lymphocytes are gammadelta T cells; they mostly express the gammadelta T-cell receptor (TCR)Vgamma9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by gammadelta T cells is unknown. Here we report that, in association with the CD20(+)-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVgamma9(+) cell binding to CD20(+) lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20(+) cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by gammadelta T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVgamma9(+) lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs. In human blood, 1% to 5% of lymphocytes are gammadelta T cells; they mostly express the gammadelta T-cell receptor (TCR)Vgamma9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by gammadelta T cells is unknown. Here we report that, in association with the CD20(+)-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVgamma9(+) cell binding to CD20(+) lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20(+) cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by gammadelta T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVgamma9(+) lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs.In human blood, 1% to 5% of lymphocytes are gammadelta T cells; they mostly express the gammadelta T-cell receptor (TCR)Vgamma9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by gammadelta T cells is unknown. Here we report that, in association with the CD20(+)-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVgamma9(+) cell binding to CD20(+) lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20(+) cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by gammadelta T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVgamma9(+) lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs. In human blood, 1% to 5% of lymphocytes are γδ T cells; they mostly express the γδ T-cell receptor (TCR)Vγ9, recognize nonpeptide phosphoantigens (PAgs) produced by microbes and tumor cells, and mediate different modes of lytic activities directed against tumor target cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by cytolytic lymphoid cells is essential for the clinical activity of anticancer monoclonal antibodies (mAbs), but whether PAgs affect ADCC by γδ T cells is unknown. Here we report that, in association with the CD20+-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRVγ9+ cell binding to CD20+ lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVγ9+ cells and strongly enhanced their ADCC activity. We obtained similar results with BrHPP in the context of the mAbs alemtuzumab and trastuzumab. Furthermore, BrHPP enhanced RTX-mediated depletion of CD20+ cells in vitro from peripheral blood mononuclear cells of healthy subjects and enhanced ADCC by γδ T cells from patients with chronic lymphocytic leukemia. In cynomolgus macaques, a regimen combining RTX, BrHPP, and IL2 activated TCRVγ9+ lymphocytes and enhanced B-cell depletion from blood and lymph nodes. Thus, the combination with BrHPP PAg is able to improve the efficacy of cancer immunotherapy by therapeutic mAbs. |
| Author | Bonnafous, Cecile Cendron, Delphine Lepage, Jean-François Bezombes, Christine Ysebaert, Loîc Fournié, Jean-Jacques Capietto, Aude-Hélène Scaglione, Virginie Quillet-Mary, Anne Gertner-Dardenne, Julie Ingoure, Sophie Gross, Emilie Laurent, Guy Sicard, Hélène |
| Author_xml | – sequence: 1 givenname: Julie surname: Gertner-Dardenne fullname: Gertner-Dardenne, Julie organization: Inserm U563, Toulouse – sequence: 2 givenname: Cecile surname: Bonnafous fullname: Bonnafous, Cecile organization: Innate Pharma SA, Marseilles – sequence: 3 givenname: Christine surname: Bezombes fullname: Bezombes, Christine organization: Inserm U563, Toulouse – sequence: 4 givenname: Aude-Hélène surname: Capietto fullname: Capietto, Aude-Hélène organization: Inserm U563, Toulouse – sequence: 5 givenname: Virginie surname: Scaglione fullname: Scaglione, Virginie organization: Innate Pharma SA, Marseilles – sequence: 6 givenname: Sophie surname: Ingoure fullname: Ingoure, Sophie organization: Innate Pharma SA, Marseilles – sequence: 7 givenname: Delphine surname: Cendron fullname: Cendron, Delphine organization: Inserm U563, Toulouse – sequence: 8 givenname: Emilie surname: Gross fullname: Gross, Emilie organization: Inserm U563, Toulouse – sequence: 9 givenname: Jean-François surname: Lepage fullname: Lepage, Jean-François organization: Innate Pharma SA, Marseilles – sequence: 10 givenname: Anne surname: Quillet-Mary fullname: Quillet-Mary, Anne organization: Inserm U563, Toulouse – sequence: 11 givenname: Loîc surname: Ysebaert fullname: Ysebaert, Loîc organization: Inserm U563, Toulouse – sequence: 12 givenname: Guy surname: Laurent fullname: Laurent, Guy organization: Inserm U563, Toulouse – sequence: 13 givenname: Hélène surname: Sicard fullname: Sicard, Hélène organization: Innate Pharma SA, Marseilles – sequence: 14 givenname: Jean-Jacques surname: Fournié fullname: Fournié, Jean-Jacques email: jean-jacques.fournie@inserm.fr organization: Inserm U563, Toulouse |
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| Keywords | Treatment Hematology Antibody Antibody-dependent cell cytotoxicity |
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| Snippet | In human blood, 1% to 5% of lymphocytes are γδ T cells; they mostly express the γδ T-cell receptor (TCR)Vγ9, recognize nonpeptide phosphoantigens (PAgs)... In human blood, 1% to 5% of lymphocytes are gammadelta T cells; they mostly express the gammadelta T-cell receptor (TCR)Vgamma9, recognize nonpeptide... |
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| SubjectTerms | Adult Animals Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Murine-Derived Antibody-Dependent Cell Cytotoxicity - drug effects Antineoplastic Combined Chemotherapy Protocols - chemistry Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use B-Lymphocytes - immunology B-Lymphocytes - metabolism Biological and medical sciences Cancer Cells, Cultured Diphosphates - administration & dosage Diphosphates - immunology Diphosphates - pharmacology Drug Screening Assays, Antitumor Female Hematologic and hematopoietic diseases Humans Immunology Interleukin-2 - administration & dosage Leukemia, Lymphocytic, Chronic, B-Cell - blood Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - immunology Life Sciences Macaca fascicularis Male Medical sciences Phosphates - immunology Receptors, Antigen, T-Cell, gamma-delta - metabolism Rituximab T-Lymphocytes - immunology T-Lymphocytes - metabolism Up-Regulation - drug effects Up-Regulation - immunology |
| Title | Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies |
| URI | https://dx.doi.org/10.1182/blood-2008-08-172296 https://www.ncbi.nlm.nih.gov/pubmed/19278954 https://www.proquest.com/docview/67243656 https://hal.science/hal-02348974 |
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