Active Immunization Against IFNα with IFN-Kinoid in SLE Patients Is Safe, Immunogenic and Induces Down-Regulation of IFN-Mediated Genes

Background/Purpose: Interferon alpha (IFNα) is associated with the severity and disease activity of SLE. Active immunization against IFNα induces polyclonal antibodies against all IFNα subtypes in vivo and prevents severe renal lupus disease in NZW/NZB SLE-prone mice. We evaluate IFNα-Kinoid in a first clinical study in SLE patients. Method: IFNα-Kinoid (IFNα-K, Neovacs SA, Paris, France) is an immunotherapeutic agent composed of recombinant human IFNα conjugated to KLH as a carrier protein, inactivated and adjuvanted with ISA-51 emulsion. Twenty-eight patients with mild to moderate, seropositive lupus (SLEDAI 4-10) were enrolled in a double-blind, placebo-controlled, phase 1-2, dose escalation study to evaluate the safety and the immunogenicity of four doses of IFNα-K (30, 60, 120 or 240 mg) administered intramuscularly on Days 0, 7 and 28 with an optional fourth dose on Day 84. Safety evaluation included recording of adverse events and monitoring of haematological and biochemical parameters. Immune responses were measured through titration of anti-IFNα and anti-KLH antibodies, and cellular lymphoproliferation assays. Clinical response was assessed by evaluation of BILAG, SLEDAI, PGA, SRI and titration of serum auto-antibodies, and of IFNα regulated chemokines. PBMC were harvested at several time-points and transcriptomic studies were performed on total RNA using Genechip HGU133 Plus 2.0 arrays. Results: The safety profile is very favourable. Few minor and transient local and systemic reactions have been observed following immunization. Only minor and transient infections were reported. Two lupus flares were reported as related serious adverse events, one in the active group in a patient who had spontaneously stopped glucocorticoid therapy after the first IFNα-K dose, the other in the placebo group. A dose-related anti-IFNα antibody response was measured in all immunized patients. Antibodies peak after the last dose and decline afterwards. Transcriptomic studies performed on baseline PBMC samples indicated that the patients cluster into two groups, characterized by the presence or absence of an IFNα signature. Patients with a positive signature have significantly higher dsDNA Ab titers and significantly lower C3 and C4 levels. In the patients with a baseline IFN signature, follow-up transcriptomic studies, performed as early as 38 days after the first IFNα-K injection, showed a significant down-regulation of the expression of IFN-induced genes in the IFNα-K group as compared to the placebo recipients, and, more generally, of SLE over-expressed genes as a whole. Conclusion: This is the first study to show positive immune and pharmacodynamic results with active immunotherapy against Interferon-α in the treatment of Systemic Lupus Erythematosus. These results are promising and further studies are planned in order to expand upon these observations