Down-Regulation of Interferon Signature in Systemic Lupus Erythematosus Patients by Active Immunization With Interferon α-Kinoid

Objective. We developed interferon-alpha-kinoid (IFN-K), a drug composed of inactivated IFN alpha coupled to a carrier protein, keyhole limpet hemocyanin. In human IFN alpha-transgenic mice, IFN-K induces polyclonal antibodies that neutralize all 13 subtypes of human IFN alpha. We also previously demonstrated that IFN-K slows disease progression in a mouse model of systemic lupus erythematosus (SLE). This study was undertaken to examine the safety, immunogenicity, and biologic effects of active immunization with IFN-K in patients with SLE. Methods. We performed a randomized, double-blind, placebo-controlled, phase I/II dose-escalation study comparing 3 or 4 doses of 30 mu g, 60 mu g, 120 mu g, or 240 mu g of IFN-K or placebo in 28 women with mild to moderate SLE. Results. IFN-K was well tolerated. Two SLE flares were reported as serious adverse events, one in the placebo group and the other in a patient who concomitantly stopped corticosteroids 2 days after the first IFN-K dose, due to mild fever not related to infection. Transcriptome analysis was used to separate patients at baseline into IFN signature-positive and -negative groups, based on the spontaneous expression of IFN-induced genes. IFN-K induced anti-IFN alpha antibodies in all immunized patients. Notably, significantly higher anti-IFN alpha titers were found in signature-positive patients than in signature-negative patients. In IFN signature-positive patients, IFN-K significantly reduced the expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFN alpha antibody titer. Serum complement C3 levels were significantly increased in patients with high anti-IFN alpha antibody titers. Conclusion. These results show that IFN-K is well tolerated, immunogenic, and significantly improves disease biomarkers in SLE patients, indicating that further studies of its clinical efficacy are warranted.