Treatment of spondyloarthropathy

Her, Minyoung; Kavanaugh, Arthur

doi:10.1097/bor.0b013e3283620177

Cited by 15 publications

(2 citation statements)

References 29 publications

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“…In the clinic, biological treatment of AS relies on TNF inhibitors that have demonstrated to be fairly effective. However, up to 40% of patients do not respond and some patients who initially improve, subsequently lose their response [ 23 – 26 ]. In addition, the efficacy of TNF inhibitors to slow-down structural progression of the disease has revealed conflicting results in different studies [ 24 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, there is still an unmet clinical need for additional therapies. Alternative biological treatments targeting various cytokines, cell-surface molecules, and signaling molecules have been assessed [ 23 , 24 ]. While most biologics have shown little efficacy in SpA, promising early clinical results have been demonstrated with a neutralizing antibody that targets IL-17A in phase II/III development [ 28 ], and a monoclonal antibody targeting IL-12/IL-23 in phase II clinical development [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats

et al. 2015

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Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders.MethodsThe monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry.ResultsHD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules.ConclusionHD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.

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