A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients

Abstract

IntroductionAdult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disorder associated with the human T-cell lymphotropic virus type 1 (HTLV-1). 1 HTLV-1 infection is endemic mainly in Japan and in the Caribbean, affecting 20 to 30 million individuals worldwide. HTLV-1 was the first human retrovirus in which monoclonal provirus integration in the host cellular DNA was observed. ATL occurs in only 2% to 4% of people infected with HTLV-1. The tumor syndrome comprises a proliferation of tumor CD4 ϩ T cells in peripheral blood, lytic bone lesions, and multiple visceral lesions with skin and lung infiltration. 2 It exhibits diverse clinical features ranging from chronic to acute forms.Smoldering and chronic forms exhibit a relatively good prognosis with an indefinite or 36-month median survival time, respectively. In these forms it is not yet demonstrated that treatment may improve prognosis and reduce the risk of evolution toward an acute form. In contrast, acute leukemic and lymphomatous forms of ATL have a very bad prognosis with a median survival of only 6 and 10 months, respectively, and a projected 4-year survival of about 5%. This is principally due to a severe immunodeficiency associated in some cases with opportunistic infections 3 and to an intrinsic resistance to high doses of chemotherapy. Novel treatments, such as the association of interferon ␣ (IFN-␣) and zidovudine (AZT), produced a high response rate in ATL patients with minimal side effects and seemed to prolong survival. [4][5][6][7] Yet, only a small percentage of patients achieve long-lasting remissions.HTLV-1-infected T cells overexpress markers of T-cell activation such as interleukin 2 receptor ␣ (IL-2R␣) when compared with uninfected stimulated T cells from the same donors. 8,9 Immunotherapy, using unlabeled or radiolabeled humanized antibodies directed against IL-2R␣, 10,11 have exploited the difference in IL-2R␣ expression between normal and malignant cells. However, clinical trials have shown that T cells derived from patients with acute ATL were in most cases resistant to anti-IL-2R␣ treatment. 10,12 The transferrin receptor (TfR) is another inducible receptor that is overexpressed in ATL cells, 13 whereas its background level in resting cells is very low. TfR is a disulfide-linked homodimeric transmembrane glycoprotein consisting of two 760-amino acid monomers of approximately 90 kDa each. TfR plays a crucial role in the regulation of iron uptake and cell growth. 14,15 When diferric transferrin binds to its cell surface receptor, it is internalized via clathrin-coated pits to acidic vesicles where the iron-transferrin complex is dissociated. 16,17 After release, the receptor and apotransferrin recycle back to the cell surface.TfR is constitutively expressed in cells of tissues that are constantly renewed, such as precursors of blood cells in the bone marrow, hepatocytes in the liver, keratinocytes in the epidermis, [17][18][19][20] More importantly, several studies have shown that TfR is expressed more abundantly in m...

The IgA1 immune complex–mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy

“…After exploring the biochemical pathways involved in IgA1-induced HMC activation, we assessed the possible involvement of TfR1 in IgA1-induced stimulation of these pathways in HMC. We have previously characterized a monoclonal antibody (mAb) A24 specific for TfR1 that targets proliferating cells, blocks cellular division, and induces cellular apoptosis 30, 31 . Pre-incubation of HMC with mAb A24 blocked pIgA1 (Dou)-induced IL-6 secretion (Figure 7A) as well as cellular proliferation (Figure 7B).…”

Microarrays of 41 Human Tumor Cell Lines for the Characterization of New Molecular Targets: Expression Patterns of Cathepsin B and the Transferrin Receptor

“…One of these agents, a diphtheria toxin linked to human transferrin, is being evaluated in a phase II clinical trial [11], while others have recently been developed, e.g. artemisinin-tagged holotransferrin [12], an avidin-linked anti-CD71 antibody [13], immunoliposomes [14] or neutralizing antibodies [15, 16]. …”

SDF-1 Chemokine Signalling Modulates the Apoptotic Responses to Iron Deprivation of Clathrin-Depleted DT40 Cells

“…In particular, iron restriction is known to induce apoptosis in activated T-lymphocytes and the promyelocytic cell-line HL60 [42]. Furthermore, a monoclonal antibody that blocks transferrin binding to its receptor induced apoptosis in adult T-cell leukaemia cells [43]. As with DT40, these are all fast growing lymphocyte-derived cells, suggesting that a relatively high apoptotic sensitivity to iron deficiency may be a common feature of this type of cell-line.…”

“…A number of therapeutic strategies for the treatment of leukaemia and other lymphocyte-derived tumours have been proposed and are currently undergoing clinical trials. Several of these aim to stimulate apoptosis by blocking transferrin endocytosis [43], [56], or prevent iron uptake using chelating agents [57]. Moreover, the up-regulation of SDF-1/CXCR4 expression is a known mechanism used by some tumour cells that contributes to chemotherapy resistance [30].…”