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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-proteins-and-whole-blood-transcripts-suppressed-by-an-anti-type-i-interferon-receptor-monoclonal-antibody-in-subjects-with-systemic-sclerosis/