Abstract Text: RA is a chronic relapsing/remitting disease characterized by synovitis, joint deformity, loss of function and increased mortality. While T-cells are a major component in the pathogenesis, B-cells are also pathogenic. Anti-CD45RC mAb treatment depletes B and T CD45RChigh cells, increasing the ratio of Treg:Tconv and has demonstrated efficacy in experimental models of diseases. Analysis of RA patients showed significantly more CD4+ and less CD8+T cells vs healthy controls (HC), and no differences in the proportions of CD45RChigh/low/neg. Analysis of synovial tissues using IHC demonstrated that non-stabilized patients have more leukocyte infiltration (T and B cells) and more CD45RChigh cells than stabilized or responding patients with methotrexate (MTX) and biologicals. Analysis of the potency of the anti-human CD45RC mAb demonstrated comparable apoptosis in vitro of CD45RChigh T and B from blood cells from RA patients and HC. Treatment with an anti-rat CD45RC mAb in a rat model of collagen induced arthritis efficiently prevented weight loss, mean arthritis severity, maximum score and AUC, similarly to the positive control MTX. Anti-CD45RC mAb completely inhibited anti-collagen antibody and GM-CSF detection in the sera in contrast to MTX and negative control groups. Efficacy of anti-CD45RC mAb correlated with an efficient depletion of CD45RChigh T and B cells as soon as d3 (>94%) and until sacrifice with conserved Treg numbers. Altogether our study demonstrates that anti-CD45RC mAb treatment is a potent immunomodulatory agent to reduce joint inflammation and disease activity in RA and a potential alternative for first line DMARD.
