Table 3.
Drugs targeting the CXCR3 chemokine system evaluated in the context of experimentally induced arthritis and rheumatoid arthritis
| Target | Drug type | Drug name | Type of study | Demonstrated (pre)clinical efficacy | Arthritis-related findings | References |
|---|---|---|---|---|---|---|
| CXCR3 | Small-molecule CXCR3 antagonist | AMG 487 | Preclinical | N.D |
↓ invasion of FLS of RA patients in Matrigel by 60% ↓ invasion of FLS of Dark Agouti rats with pristane-induced arthritis in Matrigel by 77% ↓ production of active MMP-1 by FLS of Dark Agouti rats with pristane-induced arthritis ↓ CXCL10-induced Ca2+i mobilization in FLS of Dark Agouti rats and RA patients ↓ number of thick actin filaments, ↓ number of elongated cells, ↓ formation of polarized lamellipodia, ↓ co-localization of phospho-FAK with lamellipodia in FLS of Dark Agouti rats and RA patients |
[214] |
| Preclinical | Yes | Ameliorated severity of CIA | [174, 177, 178] | |||
| Preclinical | N.D. | ↓ invasion of RA patient-derived B cells towards synovial biopsy suspensions of RA patients in Matrigel-filled microchamber | [83] | |||
| Phase IIa | Unknown | Status of the trial for use of AMG 487 in patients with moderate to severe RA is unknown | [212] | |||
| JN-2 | Preclinical | Yes |
Ameliorated systemic inflammation and severity of CIA in CIA-developing mice ↓ CXCL10 mRNA expression, CXCL10 secretion and CXCL10-induced chemotaxis of mouse breast cancer 4T1 cells ↓ CXCR3 ligand-induced cell migration and CXCL10-mediated pro-inflammatory cytokine expression of CD4 + T cells and BMMs |
[176, 181] | ||
| SCH 546738 | Preclinical | Yes | Ameliorated severity of CIA | [175] | ||
| TAK-779 | Preclinical | Yes |
↓ incidence of CIA and ameliorated severity of CIA = IL-12 production and proliferation rate in presence of collagen by co-cultures of LN T cells and LN APC (isolated from of CIA-mice treated with TAK-799 or with vehicle) |
[179] | ||
| Small-molecule CXCR3 agonist | PS372424 | Preclinical | N.D. |
↓ migration of activated CXCR3+ human T cells towards CCL5, CXCL12, CXCL11 or RA SF in vitro ↓ migration of CD45+ human leukocytes towards air pouch filled with RA SF, CCL5, CXCL11 or CXCL12 in humanized mice |
[149] | |
| CXCL10 | Neutralizing mAb | MDX-1100 | Preclinical | Unknown |
Prevented in vitro actions of CXCL10: Inhibits CXCL10-induced cell migration Blocks CXCL10-induced Ca2+i mobilization Inhibits induction of CXCL10-responsive genes |
[230, 231] |
| Phase I | Unknown | Properly tolerated at different dose levels (0.1–10 mg/kg) and favorable half-life (10 days) in HC and patients with ulcerative colitis | ||||
| Phase II | Yes |
ACR20 response at day 85 in MDX-1100- and MTX-treated group (54%) > placebo and MTX-treated group (17%) = ACR-50 response, ACR-70 response, and DAS28 in MDX-1100- and MTX-treated group compared to placebo- and MTX-treated group |
ACR American College of Rheumatology improvement criteria, APC antigen-presenting cells, BMMs bone marrow-derived macrophages, CIA type II collagen-induced arthritis, CCL CC chemokine ligand, CXCL CXC chemokine ligand, CXCR CXC chemokine receptor, DAS28 Disease Activity Score in 28 joints, DMSO dimethyl sulfoxide, ERK extracellular-signal-regulated kinases, FLS fibroblast-like synoviocytes, HC healthy controls, IL interleukin, LN lymph nodes, mAb monoclonal antibody, MMP matrix metalloproteinase, MTX methotrexate, N.D. not determined, phospho-FAK phosphorylated Focal Adhesion Kinase (FAK), PKC Protein Kinase C, RA rheumatoid arthritis, SF synovial fluid