A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients.
Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoid proliferative disease that exists under diverse clinical forms ranging from chronic to acute. Although leukemic cells from patients with ATL exhibit an intrinsic resistance to chemotherapy, monoclonal antibodies directed against CD25 (interleukin 2 receptor alpha [IL-2Ralpha] antibody) have been used as specific therapeutic agents. However, significant clinical results with these antibodies have been demonstrated only in chronic forms of ATL. In contrast to resting T cells, human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells constitutively express high levels of surface transferrin receptor (TfR). Herein, we report the characterization of a new monoclonal antibody (mAb A24) directed against the human TfR and the evaluation of its capacity to block the proliferation of ATL cells ex vivo. We determined that A24 binds TfR with an equilibrium constant (K'd) of 2.7 nM and competes with transferrin for binding to TfR. A24 also inhibited [55Fe]-transferrin uptake in activated T cells and blocked T-cell proliferation. Moreover, A24 reduced and impaired TfR expression and recycling, respectively. Most important, we showed that A24 blocked the ex vivo proliferation of malignant T cells from both acute and chronic forms of ATL, through induction of programmed cell death. Therefore efficient therapeutic tools to treat acute forms of ATL might be derived from A24.
Institut National de la Santé et de la Recherche Médicale (INSERM) E-0225, Faculté de Médecine Xavier Bichat, Paris, France.
Ivan C
IC
Moura
Yves
Y
Lepelletier
Bertrand
B
Arnulf
Patrick
P
England
Cedric
C
Baude
Carole
C
Beaumont
Ali
A
Bazarbachi
Marc
M
Benhamou
Renato C
RC
Monteiro
Olivier
O
Hermine
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D016923:Cell Death; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D018613:Microscopy, Confocal; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011990:Receptors, Transferrin / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014168:Transferrin / Q000378:metabolism / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron