IANALUMAB’S DUAL MODE OF ACTION: TARGETING B CELLS THROUGH ENHANCED B CELL DEPLETION AND BLOCKADE OF B CELL-ACTIVATING FACTOR RECEPTOR SIGNALING

PV262 / #104 Poster Topic: AS24 - SLE-Treatment Background/Purpose B cells are key players in the pathogenesis of systemic lupus erythematosus (SLE), Lupus Nephritis (LN) and other systemic autoimmune diseases, supporting B cell depletion as an attractive therapeutic strategy in these patients. However, survival signals mediated by high level of B cell-activating factor (BAFF) may interfere with B cell depletion, as well as drive disease flares. Ianalumab, an investigational afucosylated monoclonal antibody targeting BAFF-receptor (BAFF-R), has been shown to deplete B cells through enhanced antibody-dependent cellular cytotoxicity (ADCC) with concurrent blockade of BAFF:BAFF-R mediated signals.[1] Here, we extensively characterize the properties of ianalumab on B cells in vitro , as well as its ability to deplete circulating and tissue B cells in B6 mice and in the spontaneous non-obese diabetic (NOD) mouse model of Sjögren’s disease (SjD). Methods The binding affinity and specificity of ianalumab were evaluated using Biacore and flow cytometry. In vitro B cell killing was assessed using peripheral blood mononuclear cells or isolated NK cells and B cells from healthy volunteers (HVs) and patients with SLE or SjD. In vitro blockade of BAFF stimulation was evaluated through competition assays with labeled BAFF, Western blots of Nuclear Factor Kappa B Subunit 2 (NF- k B2) intact and cleaved forms, B cell proliferation measured by thymidine incorporation, and quantification of IgG secretion. The efficacy of B cell depletion following administration of ianalumab in B6 and NOD mice was investigated using flow cytometry and/or histology in blood and relevant organs. Results Ianalumab demonstrated high affinity and selectivity for BAFF-R. In an ADCC assay co-culturing purified NK cells with B cells from HVs, ianalumab showed a 44-fold increased potency compared to rituximab (Figure 1A). This increased potency was also observed when NK cells from patients with SjD and SLE were tested (Figure 1B). Additionally, ianalumab effectively prevented BAFF from binding to BAFF-R expressing cells. This blockade of BAFF-R on human B cells correlated with effective inhibition of BAFF-induced cleavage of NF-κB2 (p100), proliferation and IgG production. Notably, ianalumab was able to inhibit B cell proliferation with the same potency, when induced by a BAFF trimer or 60-mer (Figure 2). In vivo , ianalumab induced a significant reduction of B cell subpopulations in blood and lymphoid organs of B6 mice. In addition, ianalumab was able to reduce B cells in the salivary glands of NOD mice, showing its ability to reduce B cells in the target organs of mice suffering from systemic autoimmunity. Figure 1. Ianalumab shows superior potency to rituximab in ADCC. A. B cells and NK cells from HVs (N=7 donors) where cocultured in the presence of ianalumab, rituximab or an irrelevant afucosylated antibody, and B cell lysis was evaluated after 60 min. B. NK cells from patients with SjD (N=3 donors) were cocultured with RI-1 cells in the presence of ianalumab or rituximab and RI-1 cell lysis was evaluated after 60 min. Figure 2. Ianalumab inhibits proliferation of human B cells from HVs (N=7 donors) stimulated by BAFF in combination with anti-IgM. Purified B cells were stimulated with BAFF 3-mer or BAFF 60-mer, in the presence of anti-IgM. Cell proliferation was measured by 3H-thymidine incorporation. Conclusions Ianalumab, through its dual mechanism of action, addresses limitations of first-generation B cell targeting therapies for autoimmune diseases by providing more potent B cell depletion and additional BAFF-R blockade on remaining B cells. Accordingly, patients with SLE ( NCT03656562 ) or SjD ( NCT02962895 ) treated with ianalumab for up to 52 weeks showed sustained reduction in disease activity in phase 2 trials.[2,3] Ongoing phase 3 studies in SjD, SLE and LN will provide further evidence on the efficacy and safety of ianalumab in larger patient populations. References: [1.] McWilliams EM. Blood Adv. 2019;3:447-60. [2.] Shen N [abstract]. Arthritis Rheumatol 2023;75 (suppl 9). [3.] Bowman SJ. Lancet 2022;399:161-71.

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