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Abstract Number: 2914

Serum Proteins and Whole Blood Transcripts Suppressed By An Anti-Type I Interferon Receptor Monoclonal Antibody In Subjects With Systemic Sclerosis

Xiang Guo1, Brandon W. Higgs2, Christopher Kane3, Chris, A. Morehouse2, Zheng Liu2, Liangwei Wang4, Stephen Yoo5, Yihong Yao2, Lorin Roskos6 and Wendy White7, 1Translational Sciences, MedImmune LLC, Gaithersburg, MD, 2Translational Sciences, MedImmune, LLC, Gaithersburg, MD, 3MedImmune, LLC, Gaithersburg, MD, 4Biostatistics, MedImmune, LLC, Gaithersburg, MD, 5Clinical Development, MedImmune, LLC, Gaithersburg, MD, 6One MedImmune Way, Medimmune, Gaithersburg, MD, 7Translational Sciences, MedImmune, Gaithersburg, MD

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Biomarkers, interferons and systemic sclerosis

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s-Clinical Aspects and Therapeutics III

Session Type: Abstract Submissions (ACR)

Background/Purpose: To identify serum markers that are modulated by an investigational human IgG1κ monoclonal antibody directed against subunit 1 of the type I interferon receptor (IFNAR1), MEDI-546, in systemic sclerosis (SSc) subjects.

Methods: An open-label single- and multiple-dose phase 1a clinical trial was conducted to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics (PD) of MEDI-546 in SSc patients (NCT00930683). Affymetrix whole genome arrays were used to measure transcript expression in whole blood before and after administration of MEDI-546, and a 5 gene type I IFN signature was used to assess the type I IFN activity and PD effects of MEDI-546 in SSc patients. Serum levels of 93 proteins were measured in 47 SSc patients and compared to 20 healthy controls to determine dysregulated analytes in SSc subjects using a Luminex-based immunoassay platform. Next, this same panel of analytes was used to determine the effects of MEDI-546 by comparing pre- and post-dose samples.

Results: Comparison of serum proteins between SSc subjects and healthy controls identified 35 dysregulated proteins, multiple of which were found to be associated with clinical/laboratory measurements, such as modified Rodnan Total Skin Score (mRTSS) and serum levels of collagen synthesis markers (PINP and PIIINP). Administration of MEDI-546 resulted in suppression of 8 proteins, among which 6 are type I IFN-inducible. Reduction of CXCL10 and soluble CD40L levels were significantly correlated with type I IFN gene signature suppression by MEDI-546. These two proteins are associated with T cell activation and movement, along with CXCL11 and IL2RA that also demonstrated significant down-regulation post-administration of MEDI-546. Furthermore, paired comparison of whole blood microarray data, pre- and post-MEDI-546 administration identified a list of differentially regulated transcripts enriched in regulatory functions by various IFN-related proteins, T cell receptor (TCR), nuclear factor of activated T cells (NFATC2), and CD40L. Thus, both proteomics and transcriptomic results suggest a suppressive effect of MEDI-546 in T cell activation and tissue infiltration. Using serum levels of CXCL10, CXCL11, soluble IL2R, and CD40L, we defined a protein index suppressible by type I IFN blockage. This index exhibited significant correlation with mRTSS and PIIINP levels at baseline, and down-regulation in the index was significantly associated with suppression of type I IFN gene signature post administration.

Conclusion: Our study demonstrated a robust overexpression of multiple serum proteins in SSc patients, particularly those with an elevated type I IFN gene signature score. Type I IFN blockade by MEDI-546 resulted in significant suppression of multiple type I IFN-associated proteins, particularly those related to T cell activation and movement. A protein index suppressible by type I IFN blockage may serve as a responsive or predictive marker for type I IFN-targeted therapy in SSc subjects, which shall be examined in future clinical trials.


Disclosure:

X. Guo,

AstraZeneca,

3,

AstraZeneca,

1;

B. W. Higgs,

MedImmune LLC,

3,

AstraZeneca,

1;

C. Kane,

AstraZeneca,

1,

AstraZeneca,

3;

C. A. Morehouse,

MedImmune LLC,

3;

Z. Liu,

MedImmune LLC,

3,

AstraZeneca,

1;

L. Wang,

AstraZeneca,

1,

MedImmune,

3;

S. Yoo,

AstraZeneca,

1,

MedImmune,

3;

Y. Yao,

MedImmune,

3,

AstraZeneca,

1;

L. Roskos,

AstraZeneca,

3,

AstraZeneca,

1;

W. White,

AstraZeneca,

3,

AstraZeneca,

1.

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