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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 (B27 2 ) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B27 2  can be detected on leukocytes of  HLA-B27 + Ankylosing spondylitis (AS) patients and  HLA-B27  transgenic rats. We characterized a novel B27 2 –specific monoclonal antibody to study its therapeutic use in  HLA-B27  associated disorders.    Methods  The monoclonal HD5 antibody was selected from a phage library to target cell-surface B27 2  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 B27 2  and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry.    Results  HD5 bound B27 2  with high specificity and affinity (K d  = 0.32 nM). HD5 blocked cell-surface interaction of B27 2  with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B27 2  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 B27 2  molecules.    Conclusion  HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in  HLA-B27  transgenic rats. Monoclonal antibodies targeting cell-surface B27 2  propose a new concept for the modulation of inflammatory responses in  HLA-B27  related disorders.

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