Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia.
To date, chronic lymphocytic leukemia (CLL) remains incurable with current treatments, which include the monoclonal antibodies (mAbs) rituximab and alemtuzumab. The efficacy of rituximab is modest when used as single agent, and alemtuzumab induces severe immunosuppression. To develop more potent and specific therapies, we propose the CC chemokine receptor 7 (CCR7) as an attractive target molecule to treat CLL, as it not only fulfills the requirements of a high-surface expression and a good level of tissue specificity, but it also plays a crucial role in mediating the migration of the tumor cells to lymph nodes (LNs) and thus, in the development of clinical lymphadenopathy. In the current work, murine anti-human CCR7 mAb mediated a potent, complement-dependent cytotoxicity (CDC) against CLL cells while sparing normal T lymphocytes from the same patients. The sensitivity to CDC was related to the antigenic density of CCR7. Moreover, these mAb blocked the in vitro migration of CLL cells in response to CC chemokine ligand 19 (CCL19), one of the physiological ligands of CCR7. Conversely, CLL cells were poorly lysed through antibody-dependent, cell-mediated cytotoxicity (ADCC), probably as a result of the murine origin and the isotype of the anti-CCR7 mAb used. Molecular engineering techniques will allow us to obtain chimeric or humanized anti-CCR7 mAb to reach the best clinical response for this common and yet incurable leukemia.
Alfonso-Pérez
Manuel
M
Department of Immunology, Hospital Universitario de La Princesa, C/Diego de León 62, 28006 Madrid, Spain.
López-Giral
Sonia
S
Quintana
Nuria E
NE
Loscertales
Javier
J
Martín-Jiménez
Patricia
P
Muñoz
Cecilia
C
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor / Q000276:immunology / Q000473:pathology; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004354:Drug Screening Assays, Antitumor; D004705:Endocytosis; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000276:immunology; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C515460:CCL19 protein, human; C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D054400:Receptors, CCR7; D019707:Receptors, Chemokine