Abstract
The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma – CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor - Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.
Highlights
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia and is characterized by accumulation of aberrant B-lymphocytes [1]
CXCR4 is a G protein coupled receptor consisting of 7 transmembrane domains, [2] that is expressed in different cell types, including B cells, monocytes, T cells, neutrophils, macrophages, natural killer (NK) cells, endothelial, epithelial, CD34+ hematopoietic stem cells, and dendritic cells [3,4,5,6]
We observed that the level of expression of CXCR4 was higher in chronic lymphocytic leukemia (CLL) by at least 8 fold when compared to normal B cells
Summary
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia and is characterized by accumulation of aberrant B-lymphocytes [1]. CXCR4 has a single ligand, CXCL12 (chemokine C-X-C motif ligand 12), [8] which is a homeostatic chemokine known as stromal cell-derived factor 1 (SDF-1). Ulocuplumab (BMS-936564, Bristol-Myers Squibb) is a novel IgG4 fully human monoclonal antibody that binds to the second extracellular loop of CXCR4. Ulocuplumab (BMS-936564) binds to CXCR4 at low nanomolar concentrations compared to other commercially available antibodies (e.g. 1D9). This antibody prevents the binding of CXCL12 and inhibits calcium flux mediated cell motility and migration [17]. The Ulocuplumab (BMS-936564) antibody is an IgG4 [17], that lacks complement-dependent cytotoxicity activity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity as confirmed in the current study in primary CLL and Ramos cell lines. We present our studies with primary leukemia cells from CLL patients using Ulocuplumab (BMS-936564) in culture conditions that resemble the leukemia microenvironment
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