Efficacy of novel bispecific antibody targeting TNF-α/CXCL10 in the treatment of experimental arthritis.

This study was aimed at generating and investigating the efficacy of a novel monoclonal bispecific antibody (BsAb) for the combined inhibition of tumor necrosis factor-α (TNF-α) and CXCL10 as a treatment option for rheumatoid arthritis (RA). A novel BsAb targeting TNF-α and CXCL10 was generated by conjugating a single-chain variable fragment (scFv) of the anti-CXCL10 monoclonal antibody to the Fc region of adalimumab (ADA). The effects of the BsAb on the inflammatory response in the in vitro and in vivo development of arthritis and joint destruction were evaluated in human TNF transgenic (hTNF-Tg) mice, and K/BxN serum transfer arthritis models. The BsAb inhibited CXCL10-mediated CD8+ T cell migration. The binding affinity of the BsAb to TNF-α was comparable to that of ADA and suppressed TNF-α induced cell death and inhibited TNF-α induced ICAM-1 and VCAM-1 in RA fibroblast-like synoviocytes (FLSs). The BsAb decreased the expression of TNFSF11 and the production of IL-6 in RA-FLS cells stimulated with TNF-α and CXCL10. Treatment with the BsAb attenuated the development of arthritis in hTNF-Tg mice and suppressed LPS-induced bone erosion. In the K/BxN serum transfer model, BsAb effectively attenuated ankle swelling, synovial inflammation, cartilage damage, and bone destruction, reducing the activation of osteoclasts. The additional neutralization of TNF-α and CXCL10 from treatment with the novel BsAb was more effective than TNF-α inhibition alone in the in vitro and in vivo models of RA. Thus, the BsAb, targeting both TNF-α and CXCL10, may provide a new therapeutic opportunity for RA patients who fail to respond to the blockade of a single cytokine.

CXCL10/CXCR3 axis is associated with disease activity and the development of mucocutaneous lesions in patients with Behçet's disease.

The objective of this study was to investigate CXC chemokines and its receptor in patients with Behcet's disease (BD) and their associations with disease activity. Blood samples were collected from 109 BD patients and 36 age- and sex-matched healthy controls (HCs). Twenty-two follow-up blood samples were collected in BD patients. Serum CXC chemokines (CXCL1, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13 and CXCL16) and cell surface marker expression (CD3, CD4 and CXCR3) in peripheral blood mononuclear cells (PBMCs) were assayed. Clinical features including disease activity were evaluated at the time of blood collection. CXCR3 expression in skin and intestinal lesions from BD patients and HCs was assessed via immunohistochemistry. Serum CXCL10 levels were correlated with disease activity in terms of Behçet's Disease Current Activity Form (BDCAF) (p < 0.001). In follow-up BD patients, changes in serum CXCL10 levels tended to be correlated with those of BDCAF. The percentage of CXCR3 expression in CD3-positive cells in PBMCs was inversely correlated with serum CXCL10 levels in BD patients (p = 0.022). By immunohistochemistry, the number of CXCR3-positive mononuclear cells was higher in skin and intestinal lesions of BD patients than in those of HCs. These results suggest that the CXCL10/CXCR3 axis may contribute to the pathogenesis of BD.

Serum levels of IgG antibodies against alpha-enolase are increased in patients with Behçet's disease and are associated with the severity of oral ulcer, erythrocyte sedimentation rates, and C-reactive protein.

OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory disease of unknown etiology, characterised by recurrent oral and genital ulcers, skin lesions, uveitis, and arthritis. It is regarded as vasculitis and anti-endothelial cell antibodies (AECA) are found in patients with BD. One of the endothelial cell antibodies was reported to recognise alpha-enolase. This study aimed to investigate expression of alpha-enolase in the surface of peripheral blood cells and serum anti-alpha-enolase antibody (AEA), and their association with clinical manifestations or disease activity of BD. METHODS: Cell surface alpha-enolase expression was examined from several cell types of peripheral blood, including lymphocytes, monocytes, and neutrophils using flow cytometry in patients with BD and healthy controls (HCs). IgG AEA levels were measured by enzyme-linked immunosorbent assay (ELISA) in sera from 110 patients with BD, and age/sex matched 110 HCs. Association of alpha-enolase or AEA with clinical manifestation was analysed. RESULTS: The frequency of surface alpha-enolase-expressing cells was increased in BD in lymphocytes and monocytes. Serum AEA levels were in- creased in BD patients (median [IQR], 0.360 [0.268-0.482], p < 0.0001), particularly with mucocutaneous involvement (0.367 [0.273-0.490], p < 0.0001) compared to HCs (0.274 [0.231-0.357]). The levels of AEA were correlated with the number of oral ulcer, ESR, and CRP. There was no association between serum levels of AEA and other clinical manifestations. CONCLUSIONS: Serum AEA was increased in BD patients and correlated with oral ulcer, ESR and CRP.