title: CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease.
abstract: The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.
authors.affiliation: ChemoCentryx Inc., 850 Maude Ave., Mountain View, CA 94043, USA. ddairaghi@chemocentryx.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dairaghi
authors.forename: Babatunde O
authors.initials: BO
authors.lastname: Oyajobi
authors.forename: Anjana
authors.initials: A
authors.lastname: Gupta
authors.forename: Brandon
authors.initials: B
authors.lastname: McCluskey
authors.forename: Shichang
authors.initials: S
authors.lastname: Miao
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Seitz
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Yibin
authors.initials: Y
authors.lastname: Zeng
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D018925:Chemokines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D018925:Chemokines; D054389:Receptors, CCR1