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 Blood, 14 May 2009, Vol. 113, No. 20, pp. 4875-4884.
Prepublished online as a Blood First Edition Paper on March 10, 2009; DOI 10.1182/blood-2008-08-172296.

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Submitted August 5, 2008
Accepted February 22, 2009

Bromohydrin pyrophosphate enhances ADCC induced by therapeutic antibodies

Julie Gertner-Dardenne, Cecile Bonnafous, Christine Bezombes, Aude-Helene Capietto, Virginie Scaglione, Sophie Ingoure, Delphine Cendron, Emilie Gross, Jean-Francois Lepage, Anne Quillet-Mary, Loic Ysebaert, Guy Laurent, Helene Sicard, and Jean-Jacques Fournie*

INSERM, U563, Toulouse, France
Innate Pharma SA, Marseilles, France
Universite Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
Service d'Hematologie, Centre Hospitalier Universitaire Toulouse, Hopital Purpan, Toulouse, France

* Corresponding author; email: jean-jacques.fournie{at}inserm.fr.

In human blood, 1-5 % of lymphocytes are {gamma}{delta} T cells; they mostly express the {gamma}{delta} T cell receptor (TCR)V{gamma}9, recognize non-peptide 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 {gamma}{delta} T cells is unknown. Here we report that, in association with the CD20+-specific mAb rituximab (RTX), the synthetic PAg bromohydrin pyrophosphate (BrHPP) increased TCRV{gamma}9+ cell binding to CD20+ lymphoma cells in vitro. This combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRV{gamma}9+ 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 PBMCs of healthy individuals and enhanced ADCC by {gamma}{delta} T cells from patients with chronic lymphocytic leukaemia (CLL). In cynomolgus macaques, a regimen combining RTX, BrHPP and IL2 activated TCRV{gamma}9+ 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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