Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies

• Published in: Blood Vol. 113; no. 20; pp. 4875 - 4884
• Main Authors: Gertner-Dardenne, Julie, Bonnafous, Cecile, Bezombes, Christine, Capietto, Aude-Hélène, Scaglione, Virginie, Ingoure, Sophie, Cendron, Delphine, Gross, Emilie, Lepage, Jean-François, Quillet-Mary, Anne, Ysebaert, Loîc, Laurent, Guy, Sicard, Hélène, Fournié, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.05.2009; Americain Society of Hematology; American Society of Hematology
• Subjects: 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; Treatment; Hematology; Antibody; Antibody-dependent cell cytotoxicity
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2008-08-172296

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.