CCR1 blockade and myeloma bone disease

In this issue of Blood, Dairaghi and colleagues demonstrate the efficacy of a potent and orally bioavailable inhibitor of CCR1, one of the receptors for the chemokine CCL3/MIP-1α, in a mouse model of multiple myeloma (MM) and MM bone disease. They show CCX721 to be a highly selective and efficient inhibitor of CCR1 and in turn a suppressor of osteoclastic activity, osteolytic lesions, and disease burden in a preclinical MM model.¹ 

More than 70% of patients with MM either present or eventually develop osteolytic bone disease and despite recent advances in the treatment of MM, osteolytic bone disease remains a tremendous source of morbidity.²  Bisphosphonates remain a mainstay of therapy and while they reduce, but do not eliminate, the progression of MM bone disease, they are inconvenient to administer and are associated with some serious complications including jaw osteonecrosis, microfractures, and renal injury.³  Clearly there is room for improvement in our therapeutic arsenal for this devastating complication. To design better therapeutics for MM bone disease, one must dissect the intricate interplay between key cellular elements of the bone marrow microenvironment on which malignant plasma cells depend for their survival. This bone marrow milieu is composed of bone marrow stromal cells, osteoblasts, osteoclasts, and endothelial cells as well as extracellular matrix proteins, all of which enable the survival of MM cells as well as their cellular homing, growth, and drug resistance.²  Of all the osteoclast-stimulating factors secreted by MM cells, CCL3/MIP-1α is believed to play one of the most crucial roles. CCL3/MIP-1α, a small protein of the chemokine family, enables leukocyte homing to sites of inflammation or tissue injury by binding to several membrane-bound G-coupled receptors, in particular CCR1 and CCR5.⁴  While several chemokines can bind to CCR1 and CCR5, CCL3/MIP-1α is the only chemokine that has been consistently observed to be expressed and secreted in most MM cell cultures, primary MM bone marrow, and even patient serum samples where it correlates with the extent of lytic bone lesions.⁵  MM cells produce CCL3/MIP-1α under the control of the fibroblast growth factor receptor (FGFR3) and downstream RAS-MAPK signaling, making CCL3 and its effectors tantalizing targets in patients who harbor either the t(4;14) translocation, resulting in FGFR3 overexpression, or the more commonly found activating RAS mutations.⁶  But even in the absence of these genetic changes, CLL3/MIP-1α can also be produced by other cells in the MM bone marrow microenvironment, such as osteoclasts, osteoblasts, and stromal cells.⁵  CCL3/MIP-1α induces osteolysis through the activation of specific receptors such as CCR1 and CCR5 found on osteoclastic precusors as well as mature osteoclasts. Previous attempts at blockade have included the use of cumbersome neutralizing antibodies to CCL3/MIP-1α as well as pharmacologic inhibitors of CCR1 and CCR5.⁷  Before the current study, it was generally believed that for complete CCL3/MIP-1α blockade, both receptors would have to be targeted. Furthermore, exclusive CCR1 or CCR5 blockade in preclinical models showed that while both appear to have profound antiosteolytic activities, only CCR1 inhibition could reduce tumor burden.⁸ 

Here, Dairaghi and colleagues counter the notion that to achieve clinical efficacy, both CCR1 and CCR5 need to be inhibited. They use a mouse-active orally bioavailable structural analog of a CCR1-inhibiting compound already in clinical trials for inflammatory diseases. They demonstrate that CCX721 is an extremely potent and highly selective inhibitor of CCR1 function in both mouse and primary human monocytes. After PK studies, an optimal oral-dose regimen was determined and used on a mouse model that has shown therapeutic fidelity in MM bone disease. CCX721, administered either prophylactically or therapeutically, reduced tumor burden in their model, as demonstrated by a reduction in a monoclonal immunoglobulin biomarker and by green fluorescent protein–tagged cell imaging. Interestingly, the reduction of tumor burden was not due to a direct cytotoxic effect on MM cells, as CCX721 had no effect on the viability of cultured mouse and human MM cell lines, no effect on subcutaneously implanted plasmacytomas and no effect on splenic MM cells in their mice. The effect of CCX721 on MM tumor burden is therefore entirely dependent on the bone marrow microenvironment. Within this environment, the authors demonstrate a marked reduction of osteoclasts and this translates into a reduction in the number osteolytic bone lesions. To suggest potential clinical efficacy in humans, they note that nanomolar concentrations of CCX721 were sufficient to effectively inhibit osteoclastogenesis from normal human mononuclear precursors. These results represent a clear improvement over those seen with other CCL3/MIP-1α inhibitors and use a molecule that is orally bioavailable and whose parent compound is already in clinical trials for inflammatory diseases.

While CCR1 inhibition may seem like an excellent idea in mouse models of diseases, human clinical trials have not been so successful. In the inflammatory diseases, 3 trials of 3 separate CCR1 inhibitors did not show much therapeutic benefit, possibly because of chemokine family cross-talk or low levels of CCR1 inhibition.⁷  In MM, Dairaghi and colleagues have shown that exclusive, but profound, CCR1 inhibition is enough to achieve clinical efficacy in their model, suggesting that any chemokine redundancy may not matter. Their work paves the way for human clinical trials of their compound, or its parent, in treating MM bone disease. However, given recent reports that the standard-of-care bisphosphonate, zoledronic acid, not only reduces skeletal-related events but also may contribute to improving overall survival in MM, the clinical bar has been set very high.⁹