CXCR5 as a Therapeutic Target in Autoimmune Diseases: Insights from Sjögren’s Syndrome

Introduction CXCR5, a chemokine receptor expressed on B cell and T follicular helper (Tfh) cell, is associated with autoantibody-mediated pathogenesis in multiple autoimmune and chronic inflammatory disorders (I&I) such as SLE, RA, MS, IBD, and Sjögren’s syndrome (SS). The interaction between CXCR5 and its ligand CXCL13 and subsequent formation of ectopic germinal centers have been shown to be key to disease progression. Despite its pivotal role in the CXCR5/CXCL13 signaling axis, CXCR5 remains underexplored as a therapeutic target. In this study, we hypothesize that selective depletion of pathogenic CXCR5+ B and Tfh cells is a promising treatment approach for I&I disorders associated with production of autoantibodies targeting self-antigens. Methods We developed HFB100204, an afucosylated anti-CXCR5 antibody designed to deplete pathogenic CXCR5+ cells through ADCC while blocking CXCL13-dependent signaling. As a case study, we leveraged HiFiBiO Therapeutics’ translational single-cell platform to profile CXCR5+ immune cells in SS patients at different disease stages and evaluated CXCR5+ cell depletion by HFB100204 in vitro and in vivo. Results CXCR5 expression was found to be selectively enriched in autoreactive B cells and hyperactive Tfh cells in SS as the disease progresses. Distinct CXCR5+ B cells populations previously linked to autoreactive phenotypes were overrepresented in SS patients in advanced disease stages. HFB100204 demonstrated robust depletion of CXCR5+ B and Tfh cells in vitro. Notably, HFB100204 selectively depletes CXCR5+ B cells more potently than rituximab and ianalumab from human PBMCs. In vivo, HFB100204 effectively reduced CXCR5+ B and Tfh cells in blood and spleen of hCXCR5-knockin mice, suggesting that this intervention has the potential to disrupt pathological B-Tfh interactions, thus preventing autoantibody formation. Conclusion This study underscores the therapeutic potential of targeting the CXCR5/CXCL13 axis for I&I. Using SS as an example, we show that at a single-cell level, CXCR5 is critical for the disease progression. HFB100204 effectively depletes pathogenic CXCR5+ immune cells, including B cells and Tfh cells, offering a novel strategy for autoimmune diseases. These findings support CXCR5 as an innovative therapeutic target, addressing critical unmet needs in autoimmune disease management.