Characterization of CCX282-B, an Orally Bioavailable Antagonist of the CCR9 Chemokine Receptor, for Treatment of Inflammatory Bowel Disease

Walters, Matthew J.; Wang, Yu; Lai, Nu L.; Baumgart, Trageen; Zhao, Bin; Dairaghi, Daniel J.; Bekker, Pirow; Ertl, Linda; Penfold, Mark E.T.; Jaén, Juan C.; Keshav, Satish; Wendt, Emily; Pennell, Andrew M. K.; Ungashe, S; Wei, Zheng; Wright, John J.; Schall, Thomas J.

doi:10.1124/jpet.110.169714

Cited by 141 publications

(122 citation statements)

References 33 publications

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“…Response to human C5a of hC5aR knock-in mouse leukocytes was tested in vitro using a previously described chemotaxis assay. 22 In brief, migration of cells from the upper to the lower ChemoTX chamber (NeuroProbe, Gaithersburg, MD) in response to different concentrations of human C5a was determined by adding CyQUANT solution (Invitrogen) to each lower chamber and measuring the intensity of fluorescence (Migration Signal) of the DNA-binding fluorescent CyQUANT after 120 minutes, which is a relative measure of cell numbers. In vitro, human C5aR responds equally well to murine C5a and human C5a (data not shown), which is in accord with previously reported results.…”

Section: Humanization Of Mice With Human C5armentioning

confidence: 99%

C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN

Xiao

Dairaghi

Powers

et al. 2014

Journal of the American Society of Nephrology

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Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.

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Section: Humanization Of Mice With Human C5armentioning

confidence: 99%

C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN

Xiao

Dairaghi

Powers

et al. 2014

Journal of the American Society of Nephrology

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282

226

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“…CCX282-B is a small molecule inhibitor of CCR9 that blocks migration of gut-specific T-cells [177]. In a recent, double-blind and placebo-controlled phase II study in patients with moderated to severe CD, CCX282-B was well tolerated and safe, since no drug related adverse events, particularly no serious or opportunistic infections, were detected during the 36-week maintenance study period.…”

Section: Ccx282-bmentioning

confidence: 99%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

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“…29,30 In vitro assays Chemotaxis, cytoplasmic calcium release, and radioligand binding assays were conducted as previously described. 25,31 The OC formation assays were conducted as described, 3 using freshly isolated monocytes from human blood. The MTT cell proliferation assay (ATCC) was carried out per the manufacturer's instructions.…”

Section: Cells and Reagentsmentioning

confidence: 99%

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

Dairaghi

Oyajobi

Gupta³

et al. 2012

Blood

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The chemokine CCL3/MIP-1␣ 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. (Blood. 2012;120(7):1449-1457) IntroductionEstablishment of multiple myeloma (MM) in the bone marrow niche is highly dependent on bone resorption and proximity to active osteoclasts (OCs). 1,2 OC and MM cells support and nourish each other in vitro and in vivo. 1,3,4 MM-associated osteolytic bone disease (OBD), which affects Ͼ 80% of patients, results from heightened bone catabolism and decreased bone formation and is characterized by severe bone pain and high rates of fractures, greatly impacting their quality and length of life. 5,6 The chemokine CCL3/MIP-1␣ is one of the most important OC-activating factors produced by MM cells and is generally thought to contribute significantly to MM-associated OBD. 7 In cell culture, CCL3 is among the most consistently identified OC-activating factors produced by primary and immortalized MM cells. 8 The extent of CCL3 secretion by MM cells has been correlated with the extent of lytic bone lesions in patients. 9 Serum levels of CCL3 are elevated in newly diagnosed MM patients and correlate with the extent of bone disease, bone resorption, and disease prognosis. 10 High levels of CCL3 in bone marrow also correlate with MM disease stage and activity. [11][12][13] Other chemokines that have been implicated in the pathogenesis of MM include CCL5/RANTES, which, like CCL3, is a potent activator of chemokine CCR1 and CCR5 receptors. 14 We and others have shown that the pathogenic interplay between MM cells and the bone marrow environment is mediated, in part, by a paracrine mechanism whereby CCL3, secreted by MM cells, stimulates OC activity. 15 At the same time, CCL3 also inhibits osteoblast (OB) formation, further contributing to the imbalance between bone resorption and bone formation. 16 On th...

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Characterization of CCX282-B, an Orally Bioavailable Antagonist of the CCR9 Chemokine Receptor, for Treatment of Inflammatory Bowel Disease

Cited by 141 publications

References 33 publications

C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN

C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

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