Argx-113, a Novel Fc-Based Approach for Antibody-Induced Pathologies Such As Primary Immune Thrombocytopenia (2016)

Abstract The neonatal Fc Receptor (FcRn) is a key player in the maintenance of high serum levels of immunoglobulin G (IgG) antibodies. IgGs enter cells by pinocytic uptake and bind FcRn in acidic endosomal compartments. FcRn then recycles IgGs back to the cell surface where they are released into circulation at physiological pH. This half-life prolonging salvage pathway has obvious advantages in IgG-mediated pathogen clearance, but also leads to persistence of disease-causing autoantibodies present in various autoimmune indications like immune thrombocytopenia (ITP). Indeed, the principal characteristic of ITP is autoantibody-mediated peripheral platelet destruction and impaired platelet production in bone marrow which leads to an increased risk of bleeding. Functional inhibition of the FcRn receptor could therefore be a novel therapeutic modality in the treatment of ITP as standard treatment options, like immunomodulatory drugs, typically suffer from a high risk of comorbidities. ARGX-113 is a proprietary antibody Fc-fragment based on argenx' ABDEG™ technology. ABDEG™ mutations dramatically increase the Fc/FcRn binding both at neutral and acidic pH. This results in constitutive blockage of FcRn function by ARGX-113, and concomitantly leads to fast clearance of pathogenic antibodies in an autoimmune setting. The ABDEG™ concept was validated in various mouse models for IgG-induced autoimmune indications. In all models, a significant reduction of disease severity is observed upon ARGX-113 administration, which parallels with markedly reduced disease-causing antibody levels. Follow-up studies in cynomolgus monkeys demonstrated a highly effective and rapid elimination of immunoglobulins, which outperformed by far the pharmacodynamic effects of a 50-fold higher dose of intravenous immunoglobulin (IVIg), a standard-of-care therapy in many IgG-driven autoimmune indications. A first-in-human Phase I study was initiated to evaluate safety, tolerability, efficacy (reduction in IgG levels), pharmacokinetics and immunogenicity of ARGX-113 following single or multiple intravenous administration(s). Up to 68 healthy volunteers will be enrolled in this double-blind placebo-controlled study (48 active, 20 placebo). At present, the compound showed favorable safety and tolerability across multiple doses and dosing regimens with promising pharmacodynamics effects relating to speed, depth and duration of IgG reduction. Upon multiple dosing, IgG reduction of up to 85% is observed and IgG levels slowly return to baseline when dosing is terminated. Full study results, covering all planned doses and dosing regimens, will be presented focusing on safety, PK/PD relationship, IgG subset response, anti-drug antibody formation and dose/dosing regimen selection for future studies. In addition, the study design and outcome measures of a Phase II study evaluating safety, tolerability and efficacy of ARGX-113 in an ITP setting is being prepared and will be presented. Disclosures Ulrichts: argenx: Employment. Cousin:argenx: Employment. Dreier:argenx: Employment. de Haard:argenx: Employment. Leupin:argenx: Employment.