Ianalumab, an ADCC-Enhanced Anti-BAFF-Receptor Antibody, Has Beneficial Effects in an Active Mouse Model of Immune Thrombocytopenia (ITP)

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by lower-than-normal platelet numbers with increased risk of bleeding. The loss of platelets is primarily driven by autoantibodies directed against platelet glycoproteins that mediate FcR-mediated phagocytosis in the spleen and liver. Recent evidence suggests that blockade of the B-cell activating factor receptor (BAFF-R) signaling pathway as well as direct lysis and depletion of BAFF-R-expressing B-cells may provide a significant clinical benefit to patients with ITP. Ianalumab (VAY736), is a glycoengineered (afucosylated), fully human IgG1 monoclonal antibody directed against BAFF-R operating through this dual mode of action, that also cross-reacts against mouse BAFF-R. Ianalumab was studied in a well-established active murine model of ITP to evaluate its effects on anti-platelet antibodies, platelet counts, bleeding scores, and disease-related mortality. The adoptive transfer of pathogenic splenocytes collected from BALB/c CD61 (GPIIIa) knockout (KO) mice immunized with CD61+ platelets into mice with severe combined immunodeficiency (SCID, CD61+) induces the development of an antibody- and T cell-mediated thrombocytopenia within 3 weeks post-transfer (Chow L et al Blood. 115:1247-1253, 2010). The advantage of this model is that the antibody-mediated ITP is responsive to several clinical ITP therapies (e.g. IVIg, anti-CD20, and TPO-Ras). Here, SCID mice induced to develop ITP were treated with ianalumab at a dose of 100 mg/kg, administered intraperitoneally (i.p.) weekly over 5 weeks. Results from two separate studies were pooled and analyzed. The combined negative control (naïve spleen cell transfer) group (n=11) showed no mortality, no thrombocytopenia or bleeding, undetectable anti-platelet antibodies nor any moribund symptoms. In contrast, SCID mice with ITP exhibited mortality, high antiplatelet antibody levels, thrombocytopenia with bleeding and significantly reduced morbidity scores (e.g. change in movement, eye squinting, piloerection, weight loss etc.). SCID mice with ITP treated with ianalumab (n=13) had significantly reduced blood B-cell counts, and a trend towards reduced ITP-related mortality, with a reduction in the risk of death by 57% compared to the control group. Additionally, ianalumab treatment resulted in a significant reduction in anti-platelet antibody levels compared with the ITP control group at the peak of ITP-related mortality (week 2-3). Compared with the ITP control, Ianalumab treatment resulted in less thrombocytopenia with an earlier time to recovery, and improved morbidity scores. These findings provide evidence that ianalumab is effective in our murine model of active ITP and represents a strong pre-clinical basis for expecting the drug to be effective in patients with ITP.