S95021, a Novel Selective and Pan-Neutralizing Anti Interferon Alpha (Ifn-Α) Monoclonal Antibody As a Candidate Treatment for Selected Autoimmune Rheumatic Diseases.
Journal of translational autoimmunity(2021)
摘要
Increased interferon-alpha (IFN-alpha) production is a critical component in the pathophysiology of systemic lupus erythematosus (SLE) and other rheumatic autoimmune diseases. Herein, we report the characterization of S95021, a fully human IgG1 anti-IFN-alpha monoclonal antibody (mAb) as a novel therapeutic candidate for targeted patient populations. S95021 was expressed in CHOZN GS-/- cells, purified by chromatography and characterized by using electrophoresis, size exclusion chromatography and liquid chromatography-mass spectrometry. High purity S95021 was obtained as a monomeric entity comprising different charge variants mainly due to N-glycosylation. Surface plasmon resonance kinetics experiments showed strong association rates with all IFN-alpha subtypes and estimated KDs below picomolar values. Pan-IFN-alpha-binding properties were confirmed by immunoprecipitation assays and neutralization capacity with reporter HEK-Blue IFN-alpha/beta cells. S95021 was IFN-alpha-selective and exhibited superior potency and broader neutralization profile when compared with the benchmark anti-IFN-alpha mAbs rontalizumab and sifalimumab. STAT-1 phosphorylation and the type I IFN gene signature induced in human peripheral blood mononuclear cells by recombinant IFN-alpha subtypes or plasmas from selected autoimmune patients were efficiently reduced by S95021 in a dose-dependent manner. Together, our results show that S95021 is a new potent, selective and pan IFN-alpha-neutralizing mAb. It is currently further evaluated as a valid therapeutic candidate in selected autoimmune diseases in which the IFN-alpha pro-inflammatory pathway is dysregulated.
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关键词
Interferon-alpha,Biological therapy,Autoimmune diseases,Systemic lupus erythematosus,Primary Sjogren syndrome
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