Suppression of soluble T cell-associated proteins by an anti-interferon-α monoclonal antibody in adult patients with dermatomyositis or polymyositis.
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.
['Guo|Xiang|X|', 'Higgs|Brandon W|BW|', 'Rebelatto|Marlon|M|', 'Zhu|Wei|W|', 'Greth|Warren|W|', 'Yao|Yihong|Y|', 'Roskos|Lorin K|LK|', 'White|Wendy I|WI|']
D042702:Angiopoietin-2 D000911:Antibodies, Monoclonal D061067:Antibodies, Monoclonal, Humanized D003882:Dermatomyositis D004311:Double-Blind Method D015536:Down-Regulation D005260:Female D006801:Humans D016898:Interferon-alpha D020382:Interleukin-18 D053645:Interleukin-2 Receptor alpha Subunit D008297:Male D008875:Middle Aged D018482:Muscle, Skeletal D017285:Polymyositis D047889:Receptors, Tumor Necrosis Factor, Type II D012720:Severity of Illness Index D013601:T-Lymphocytes D016896:Treatment Outcome
dermatomyositis polymyositis T cell infiltration soluble interleukin-2 receptor type I interferon