Suppression of soluble T cell-associated proteins by an anti-interferon-  monoclonal antibody in adult patients with dermatomyositis or polymyositis

Abstract

Objective. The aim of this study was to identify serum markers that are modulated by an investigational anti-IFN-α mAb, sifalimumab, in adult DM or PM patients.Methods. In a phase 1b clinical trial, sera were collected from a total of 48 DM or PM adult patients receiving either placebo for 3 months or sifalimumab for 6 months. Samples were tested for 128 selected proteins using a multiplex luminex immunoassay. Muscle biopsies from selected patients were stained for T cell infiltration using an anti-CD3 antibody.Results. A robust overexpression of multiple serum proteins in DM or PM patients was observed, particularly in patients with an elevated baseline type I IFN gene signature in the blood or muscle. Neutralization of the type I IFN gene signature by sifalimumab resulted in coordinated suppression of T cell-related proteins such as soluble IL-2RA, TNF receptor 2 (TNFR2) and IL-18. Muscle biopsies from two patients with the highest serum protein suppression were selected and found to have a pronounced reduction of muscle T cell infiltration. Down-regulation of IL-2RA correlated with favourable manual muscle test 8 (MMT-8) alterations in sifalimumab-dosed patients.Conclusion. A reduced level of multiple T cell-associated proteins after sifalimumab but not placebo administration suggests a suppressive effect of blocking type I IFN signalling on T cell activation and chemoattraction that may lead to a reduction of T cell infiltration in the muscle of myositis patients. Further, soluble IL-2RA changes from baseline may serve as a responsive and/or predictive marker for type I IFN-targeted therapy in adult DM or PM patients.

Current pharmacological treatment of idiopathic inflammatory myopathies

“…Positive correlation between gene neutralization and improvement of muscle strength by MMT8 was also recorded. A follow-up study [92] reported a suppressive effect on T cell-related proteins and a reduction of T cells infiltration in the muscle of these patients by blocking type I IFN.…”

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

“…However, expression of IFN-α and IFN-β and their inducible genes is not exclusively specific to DM and also occurs in PM [1,78], and PM patients have shown responsiveness to anti-IFN-α therapy [73,79]. Furthermore pDCs, a major source of IFN-α, have been identified in the muscle tissue of patients with PM and IBM in addition to DM [77].…”

Interferons as components of the complex web of reactions sustaining inflammation in idiopathic inflammatory myopathies

“…CCL2 protein was found increased in part of 22 tested IBM sera [16]. In addition, CCL2 and CCL3 mRNA and protein levels have repeatedly been shown significantly increased in serum from juvenile and adult DM patients [51,67].…”