Down‐regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon α–kinoid

• Published in: Arthritis and rheumatism 2013-02, Vol.65 (2), p.447-456
• Main Authors: Lauwerys, Bernard R., Hachulla, Eric, Spertini, François, Lazaro, Estibaliz, Jorgensen, Christian, Mariette, Xavier, Haelterman, Edwige, Grouard‐Vogel, Géraldine, Fanget, Bernard, Dhellin, Olivier, Vandepapelière, Pierre, Houssiau, Frédéric A.
• Format: Article
• Language: English
• Subjects: Adult; Double-Blind Method; Down-Regulation - drug effects; Female; Gene Expression; Hemocyanins - immunology; Humans; Interferon-alpha - genetics; Interferon-alpha - immunology; Interferon-alpha - therapeutic use; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Middle Aged; Severity of Illness Index; Treatment Outcome; Vaccination - methods
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.37785

Objective We developed interferon‐α–kinoid (IFN‐K), a drug composed of inactivated IFNα coupled to a carrier protein, keyhole limpet hemocyanin. In human IFNα–transgenic mice, IFN‐K induces polyclonal antibodies that neutralize all 13 subtypes of human IFNα. 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 μg, 60 μg, 120 μg, or 240 μg 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‐IFNα antibodies in all immunized patients. Notably, significantly higher anti‐IFNα 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‐IFNα antibody titer. Serum complement C3 levels were significantly increased in patients with high anti‐IFNα 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.