The CCR1 Antagonist BX470 Inhibits the Growth of Multiple Myeloma (MM) Cells That Produce MIP-1α.

Abstract Macrophage inflammatory protein-1alpha (MIP-1α) is a key factor in the pathogenesis of MM. MIP-1α is a growth and survival factor for MM (Lentzsch et al., Blood 2003), stimulates osteoclast formation, increases adhesion of MM cells to stromal cells and induces bone resorption and lytic lesions in patients with MM (Choi et al., JCI 2001). High levels of MIP-1α are present in the marrow of 70% of MM patients, and MIP-1α levels correlate with increased bone destruction, tumor burden and a poor prognosis in MM patients (Uneda et al., Br J Haematol 2003). MIP-1α binds to the chemokine receptors CCR1 and CCR5, which are expressed on myeloma cells as well as on osteoclasts. Therefore, targeting MIP-1α mediated effects on myeloma cells as well as on osteoclasts by blocking its receptors is a novel target for treating the majority of MM patients. BX471 is a potent and selective antagonist of CCR1 that inhibits the binding of MIP-1α to CCR1. BX471 inhibits OCL formation (Oba et al., Exp. Hematology 2005) and is currently being studied in phase II trials for multiple sclerosis. However it is unknown if BX471 effects all MM cells or only those MM cells that produce MIP-1α. Secretion of MIP-1α of the MM cell lines (MM.1S, OPM 2, RPMI 8226) was measured by Bio-Plex Cytokine Assay. All cell lines were exposed to serial dilutions of BX 471 (10–1000 nM) for 48 hours and thymidine uptake was measured to assess inhibition of proliferation. CCR1 expression on MM cell lines was detected by PCR. All MM cell lines expressed CCR1. OPM 2 and MM.1S secreted high amounts of MIP-1α within 48hours (2,032 pg/mL and 4,388 pg/mL, respectively). Secretion of MIP-1α by RPMI 8226 MM cells was not detectable. Significant dose-dependent inhibition of proliferation by BX471 was seen with MM.1S and OPM 2 MM cells (40% and 46%, respectively). In contrast RPMI 8226, which did not secret MIP-1α was not inhibited by BX 471 up to 1000 nM. These data show that blocking CCR1 induces significant growth inhibition of MIP-1α producing MM cells and underscore the relevance of MIP-1α as an important autocrine growth and survival factor in MM. This study provides the framework for clinical evaluation of BX 471 in a phase II trial for patients with MM and supports the hypothesis that BX471 targets both the tumor and osteoclastic activity in MIP-1α producing MM cells and suggests that BX471 should be an effective treatment for the majority of MM patients.