Background/Purpose: CD45RC is an isoform of CD45, a transmembrane tyrosine phosphatase, essential regulator of T and B cells antigen receptor signaling, expressed by most blood B cells and some T cell subsets (Th1 and precursors, TEMRA cells). We demonstrated that administration of an anti-CD45RC mAb in preclinical models of transplant rejection, graft versus host disease (GvHD), Duchene dystrophy or APECED leads to prevention or control of the disease. 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.

In this study, we deciphered the mechanism of action of the anti-human CD45RC mAb and assessed its effect in vitro and in vivo on human immune cell populations. We then assessed the potential of the anti-CD45RC mAb in an experimental model of rheumatoid arthritis.

Methods: Cells were isolated from peripheral blood. Apoptosis, antibody-Dependent Cellular Cytotoxicity (ADCC), antibody-Dependent Cellular Phagocytosis (ADCP) and Complement-Dependent Cytotoxicity (CDC) were assessed by Annexin V/DAPI staining and cell count. In vivo studies were performed in CD34+ immune-humanized NSG mice, in a model of xenogeneic GVHD in human PBMC-reconstituted immunodeficient NSG mice or in a model of collagen-induced arthritis (CIA) in rat.

Results: We demonstrated that the humanized anti-human CD45RC mAb induced CD45RChigh T and B cell death mainly by direct apoptosis of CD45RChigh cells, inducing signaling but not cytokine release. We demonstrated contribution of cross linking and ADCP. Using in vivo studies in CD34+ immune-humanized NSG mice, we showed that a single iv administration of anti-CD45RC mAb induced an efficient killing of CD45RChigh T and B cells as soon as day 1, this effect was dose and time-dependent and targeted cells recovered by day 24. We also showed a dose dependent efficacy in a model of xenogeneic GVHD in human PBMC-reconstituted immunodeficient NSG mice.

Treatment with an anti-rat CD45RC mAb in a rat model of CIA efficiently prevented the disease, completely inhibited anti-collagen antibody production, inflammation of the paws and GM-CSF secretion in the sera. Efficacy of the anti-CD45RC mAb correlated with depletion of CD45RChigh T and B cells by d3 ( >94%) and until sacrifice with conserved Treg numbers. Analysis of RA patients showed a strong infiltration by CD45RChigh cells of synovial tissues using IHC.

Conclusion: Altogether our study demonstrates the mechanisms by which anti-human CD45RC mAb mediates CD45RChigh T and B cell death to control immune responses and that anti-CD45RC mAb treatment is a potent immunomodulatory agent rebalancing the Treg/teff ratio to reduce joint inflammation and disease activity in RA and a potential alternative for first line DMARD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elimination-of-cd45rchigh-t-and-b-cells-by-anti-cd45rc-mab-lead-to-efficient-control-of-experimental-rheumatoid-arthritis/