POS1432 MECHANISMS OF CD45RChigh T AND B CELL DEPLETION BY AN ANTI-CD45RC mAb IN EXPERIMENTAL RHEUMATOID ARTHRITIS

Abstract

Background:

CD45RC, an isoform of the transmembrane tyrosine phosphatase CD45, plays a pivotal role in T and B cell receptor signaling. It is expressed by most blood B cells and subsets of T cells (e.g., Th1, precursors, and TEMRA cells). Anti-CD45RC monoclonal antibodies (mAbs) have demonstrated efficacy in preventing or controlling diseases such as transplant rejection, graft-versus-host disease (GvHD), Duchenne muscular dystrophy, and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in preclinical models. However, the precise mechanism of action (MoA) remained unclear. Rheumatoid arthritis (RA) is a chronic autoimmune disease where both T and B cells contribute to the pathogenesis, leading to synovitis, joint deformity, and increased mortality.

Objectives:

To elucidate the MoA of humanized anti-human CD45RC mAb, assess its impact on human immune cell populations in vitro and in vivo, and evaluate its therapeutic potential in an experimental model of RA.

Methods:

Peripheral blood cells were analyzed for apoptosis, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) using Annexin V/DAPI staining and cell counts. In vivo studies were performed in CD34⁺ immune-humanized NSG mice and xenogeneic GvHD models. Efficacy in RA was assessed by means of a collagen-induced arthritis (CIA) rat model.

Results:

The anti-CD45RC mAb selectively induced cell death in CD45RC^high T and B cells through direct cytotoxicity, triggered by binding to cells expressing >45 CD45RC molecules/µm². This interaction initiated intracellular signaling without cytokine release. Cytotoxicity was enhanced through cross-linking and ADCP mediated by monocyte-derived macrophages, but not by ADCC or CDC due to the structural properties of CD45RC. In vivo, a single intravenous administration of anti-CD45RC mAb in CD34⁺ humanized NSG mice resulted in dose- and time-dependent depletion of CD45RC^high cells, with recovery by day 24. The minimal effective dose (MED) was determined for preventing xenogeneic GvHD in human PBMC-reconstituted mice. In the CIA rat model, anti-CD45RC mAb efficiently prevented disease onset, inhibited anti-collagen antibody production, reduced paw inflammation, and decreased serum GM-CSF. These effects correlated with sustained depletion of CD45RC^high T and B cells (>94%) and preservation of Tregs. Synovial tissue from RA patients exhibited strong infiltration of CD45RC^high cells, supporting clinical relevance.

Conclusion:

Our findings reveal that the first-in-class anti-CD45RC mAb mediates the targeted depletion of CD45RC^high T and B cells by inducing direct apoptosis and ADCP. This rebalances the Treg/Teff ratio, reduces joint inflammation, and suppresses disease activity in RA. These results establish anti-CD45RC mAb as a potent immunomodulatory agent with broad potential for managing transplant rejection and autoimmune diseases, including RA, and as a promising alternative to first-line Disease-modifying antirheumatic drugs (DMARDs).

REFERENCES:

[1] Besnard M et al. Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. J Clin Invest. 2022 Apr 1;132(7):e156507. doi: 10.1172/JCI156507. [2] Boucault L et al. Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease. Blood Adv. 2020 Jun 9;4(11):2501-2515. doi: 10.1182/bloodadvances.2020001688. [3] Picarda E et al. Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells. JCI Insight. 2017 Feb 9;2(3):e90088. doi: 10.1172/jci.insight.90088.

Acknowledgements:

This work was funded by AbolerIS Pharma, the Labex IGO (ANR-11-LABX-0016-01), the Agence Nationale de la Recherche PRC (18-CE18-0024-02), the I-SITE NExT (ANR-16-IDEX-0007), and the Agence de la Biomedecine. AbolerIS Pharma was further supported by the iLab program (DOS0162058) and the REACT-EU initiative (PL0032023).

Disclosure of Interests:

Cecile Bergua AbolerIS Pharma, Marine Besnard AbolerIS Pharma, Ghenima Ahmil: None declared, Laure-Helene Ouisse: None declared, Nadege Vimond AbolerIS Pharma, Elise Brisebard: None declared, Frederic Blanchard: None declared, Thibaut Larcher: None declared, Ronald Van Brempt AbolerIS Pharma, Benoit Le Goff: None declared, Ignacio Anegon AbolerIS Pharma, AbolerIS Pharma, Carole Guillonneau AbolerIS Pharma, AbolerIS Pharma, AbolerIS Pharma. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.