Evaluate the therapeutic potential of the elimination of ACPA positive B cells to cure RA – ACPA4CURE

Restoring immune tolerance without inducing global immunosuppression using innovative antigen-specific therapeutic molecules is the main challenge of the Cure RA consortium (2018-2025), a collaborative project between 4 academic teams and the Arthritis R&D Company. As a proof of concept, we have demonstrated over the last 5 years that an innovative hybrid molecule, composed of a recombinant Fc region of an antibody (Ab) "clicked" with a citrullinated peptide, is able to specifically eliminate anti-citrullinated protein antibodies (ACPA)-positive B cells in vitro and in vivo, using Ab-dependent cell-mediated cytotoxicity (ADCC) and Ab-dependent cellular phagocytosis (ADCP) mechanisms. These unpublished results have allowed us to file 3 patents. This innovative approach makes it possible to eliminate specifically autoreactive ACPA+ B cells in rheumatoid arthritis (RA) patients. More importantly, our work opens up a new field for the targeted treatment of systemic autoAb-mediated autoimmune diseases. However, the main limitation of our pilot study is that it clearly showed both in vitro and in vivo the specific elimination of ACPA+ B cells, but lacked substantial evidence to prove the therapeutic effects of the approach on arthritis in vivo. Today, the ACPA4CURE aims is to advance the understanding of the role of ACPA+ B cells in the pathophysiology of RA and to validate our innovative therapeutic approach to cure RA in relevant experimental models.

Our project objectives are the following:

1- To address the safety of the therapeutic molecule in immunocompetent mice, first, and in humanized mouse model. The toxicity of the therapeutic molecule will be evaluated in the experimental model of HLA-DR4 transgenic mice. The rationale of using these mice is because following the immunization protocol with PAD4, these mice develop ACPA with some specificities similar to the human ones, therefore the therapeutic drug will be biologically active in this model (Task 1). In parallel, we will also assess the safety, evaluating serious adverse events and in particular the cytokine release syndrome in humanized mice following injection of the drug (Task 2).

2- To develop a relevant ACPA-dependent experimental model of arthritis, refining the model in HLA-DR4 transgenic mice, to advance the understanding of the role of ACPA+ B cells in the pathophysiology of RA. Two strategies will be investigated, triggering toll-like receptors via LPS (Task 1) or dampening immune check point inhibitors via anti-PD1 and anti CTLA-4 Abs (Task 2). Once established, this ACPA-dependent model of arthritis will be relevant to validate the therapeutic potential of the molecule that specifically depletes ACPA+ B cells (Task 3).

3- To determine the efficacy and specificity of the therapeutic approach in a human PBMC-engrafted humanized mouse, which provides an attractive model for tracking the frequency of ACPA-specific B cells following a vaccination protocol. This model could be a powerful one to validate the efficacy and specificity of the therapeutic molecules according to the ACPA reactivity of the RA patients.

Our working strategy is to directly eliminate autoantigenic B cells expressing high levels of a specific BCR and to indirectly target short- or long-lived autoAb-secreting plasma cells replenished from the memory B cell pool. Our project will validate the therapeutic potential of our innovative drug in relevant experimental models. Although developed to test our biomolecules, the murine models will be available to the scientific community to evaluate other treatment efficacy in RA and could be extended to other autoAb-mediated systemic autoimmune diseases.