Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia

Abstract

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.

CCR7 Signaling Inhibits T Cell Proliferation

“…CCR7 targeting might work not only by interfering with tumor cell homing, and thereby metastases, but also by reducing the growth of these tumors. Alfonso-Perez and colleagues (49) have demonstrated a largely specific lysis of CCR7-positive lymphoma cells in vitro by using Ab-mediated complement cytotoxicity. Although we used another approach, this work shows that the high expression of CCR7 in tumor cells makes them an easy target for CCR7-directed therapy.…”

The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

“…By inhibition of these pathways, B-CLL cells were no longer protected from undergoing apoptosis. Due to the high surface expression and tissue specificity of CCR7 in B-CLL cells, Alfonso-Perez et al [13] proposed a murine anti-CCR7 monoclonal antibody as a new therapeutical agent. They report on a potent, complement-dependent cytotoxicity against B-CLL cells whilst sparing normal T lymphocytes from the same patient.…”

“…For this reason, therapeutic targeting of chemokine activity has become the focus of extensive pharmaceutical research [10][11][12]. B-CLL cells possess a characteristic chemokine receptor profile; hence, receptor inhibition could function as a promising tool for treatment [13]. In addition, since the expression of some chemokines and chemokine receptors correlates with important and well-established predictive clinical parameters, they might be implemented as new diagnostic markers [14][15][16][17][18].…”

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

“…In addition, it has been reported a strong correlation between the expression of CCR7 by solid tumor cells and the presence of LN metastases (2). These findings prompted us to investigate a possible role of CCR7 as therapeutic target for CLL and demonstrated that anti-CCR7 monoclonal antibodies (mAbs) efficiently eliminated CLL cells in vitro (18).…”