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Prevention of Mantle Lymphoma Tumor Establishment by Routing Transferrin Receptor toward Lysosomal Compartments

¹ Centre National de la Recherche Scientifique UMR 8147, Université Paris V, Hôpital Necker; ² Institut National de la Santé et de la Recherche Médicale U520, Institut Curie; ³ Institut National de la Santé et de la Recherche Médicale U699, Faculté de Médecine Xavier Bichat; ⁴ Service d'Anatomo-pathologie and ⁵ Service d'Hématologie, Hôpital Necker, Paris, France; and ⁶ Institut National de la Santé et de la Recherche Médicale, Institut Gustave Roussy, Villejuif, France

Requests for reprints: Olivier Hermine, Centre National de la Recherche Scientifique UMR 8147, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. Phone: 33-1-44-49-53-86; Fax: 33-1-44-49-06-76; E-mail: hermine{at}necker.fr or Ivan C. Moura, INSERM U699, Immunopathologie rénale, récepteurs et inflammation, Faculté de Médecine Xavier Bichat, 16 Rue Henri Huchard, F-75870 Paris Cedex 18, France. Phone: 33-1-44-85-62-61; Fax: 33-1-44-85-62-60; E-mail: moura72@gmail.com.

Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC₅₀ = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases. [Cancer Res 2007;67(3):1145–54]

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