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

Abstract

Objective. We developed interferon-␣-kinoid (IFN-K), a drug composed of inactivated IFN␣ coupled to a carrier protein, keyhole limpet hemocyanin. In human IFN␣-transgenic mice, IFN-K induces polyclonal antibodies that neutralize all 13 subtypes of human IFN␣. 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, doubleblind, placebo-controlled, phase I/II dose-escalation study comparing 3 or 4 doses of 30 g, 60 g, 120 g, or 240 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 IFNinduced genes. IFN-K induced anti-IFN␣ antibodies in all immunized patients. Notably, significantly higher anti-IFN␣ 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␣ antibody titer. Serum complement C3 levels were significantly increased in patients with high anti-IFN␣ 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.

Cytokines

“…A novel approach has been to vaccinate patients with SLE with IFN-a-kinoid molecules to induce autoantibodies to IFN-a. All immunized patients returned the IFN-a signature to baseline (62).…”

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…Increased IFNregulated transcripts, including IFIT, IFIT2, and IRF7, in a subset of RA patients were associated with upregulated pathways related to coagulation, complement activation and fatty acid metabolism (110). and their ability to partially inhibit the overexpression of ISGs (128)(129)(130). The inhibition of IFN-/-inducible genes in whole blood was dose-dependent and the expression of genes for BAFF, IL-10, IL-1, GM-CSF were also suppressed (118).…”

Biologic Therapy in Lupus Nephritis

“…Second, at least three LN trials are running: the anti-TWEAK BIIB023 ATLAS trial, the new ABA BMS trial and the anti-BLyS Belimumab LN trial [18,19]. Other potential LN trials are under discussion, awaiting the results of the corresponding nonrenal trials with anti-CD22 epratuzumab [24], blisibimod (fusion protein between Fc portion of IgG and a synthetic peptide sequence that binds to BLyS; PEARL trial) [25], anti-BLyS tabalumab (ILLUMINATE trials) [26], anti-IFNα sifalimumab [27], anti-IFNα AGS-009 [28], anti-IFNα rontalizumab [29], IFN kinoid [30], anti-IFNAR (type I IFN receptor) MEDI-546 [31] or rigerimod, an immunomodulating autoantigenic peptide derived from U1-RNP [32]. The third reason for hope is that cooperation among lupologists is more efficient than ever, as demonstrated by the number of investigator-initiated studies in the field of LN, e.g.…”