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Abstract Number: 218

Proteomics Study of a Phase 1b Trial with an Anti-IFN-α Monoclonal Antibody Indicates Association of Soluble Interleukin 2 Receptor with Type I Interferon Activity in Patients with Dermatomyositis or Polymyositis

Xiang Guo1, Brandon W. Higgs1, Wei Zhu2, Yihong Yao1 and Wendy White3, 1Translational Sciences, MedImmune, LLC, Gaithersburg, MD, 2Translational Science, MedImmune, LLC, Gaithersburg, MD, 3Translational Sciences, MedImmune, Gaithersburg, MD

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: cytokines, interferons and myositis

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Session Information

Session Title: Muscle Biology, Myositis and Myopathies: Clinical and Therapuetic Aspects of Idiopathic Inflammatory Myopathies

Session Type: Abstract Submissions (ACR)

Background/Purpose: To evaluate downstream effects of an anti-IFN-α monoclonal antibody (mAb) in adult dermatomyositis (DM) and polymyositis (PM) patients using serum proteomics and gene expression profiling from patient blood and muscle samples.

Methods: A phase 1b randomized, double-blinded, placebo-controlled, multicenter clinical trial was conducted in adult patients with DM or PM. Whole blood, serum, and muscle specimens were procured both pre and 98 days post administration with an anti-IFN-α mAb, sifalimumab. Affymetrix whole genome arrays were used to measure transcript expression in whole blood and muscle, while a multiplex luminex immunoassay was used to measure serum levels of more than 130 proteins. Target modulation of type I IFN activity was measured using a 13 gene type I IFN gene signature in patients following administration with either sifalimumab or placebo.

Results: Serum levels of soluble interleukin-2 receptor (sIL-2R) were significantly higher at baseline in 19 DM and 18 PM patients showing an elevated blood type I IFN signature than in 6 DM and 5 PM patients without an elevated signature and 20 normal controls. Among patients with high baseline type I IFN gene signature, those expressing high levels of sIL-2R had lower manual muscle testing (MMT8) scores at baseline, compared to patients with only an elevated baseline type I IFN gene signature. Following administration with sifalimumab, whole genome transcript profiling identified the IL2 signaling pathway as among the top ten most suppressed pathway, along with several T cell-related signaling pathways.  This result was not identified in placebo-dosed patients.  Sifalimumab also down-regulated sIL-2R levels by more than 30% in 3 DM and 4 PM patients, with no significant change in 11 placebo dosed patients. Further, patients showing strong sIL-2R down-regulation post dosing of sifalimumab, also exhibited suppression of the type I IFN gene signature (target suppression > 80% in the blood). 

Conclusion: Our results demonstrate that sIL-2R levels in the serum of myositis patients, in combination with a blood type I IFN gene signature, may correlate with disease activity in a patient subset better than a type I IFN gene signature alone. Sifalimumab down-regulated serum sIL-2R levels in a subset of myositis patients that also showed strong suppression of the type I IFN gene signature in blood. These results suggest the possibility to combine sIL-2R and type I IFN gene signature as a prognostic marker for myositis patients.


Disclosure:

X. Guo,

AstraZeneca,

1,

MedImmune,

3;

B. W. Higgs,

AstraZeneca,

1,

MedImmune,

3;

W. Zhu,

AstraZeneca,

1,

MedImmune,

3;

Y. Yao,

AstraZeneca,

1,

MedImmune,

3;

W. White,

AstraZeneca,

1,

MedImmune,

3.

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