Background MEDI-546 is an investigational human IgG1κ monoclonal antibody directed against subunit 1 of the type I interferon receptor (IFNAR1). An open-label single- and multiple-dose phase 1a clinical trial has been conducted for MEDI-546 in adult systemic sclerosis (SSc) subjects (NCT00930683).
Objectives To identify serum markers and pathophysiological pathways modulated by MEDI-546 in SSc subjects.
Methods Affymetrix whole genome arrays were used to measure transcript expression in whole blood and skin biopsies of SSc subjects, and a 5 gene type I IFN signature was used to determine the pharmacodynamics effects of MEDI-546. Serum levels of 93 proteins, two collagen synthesis markers, along with 6 novel collagen degradation and tissue damage markers were measured in 47 SSc subjects and 30 healthy controls. These serum markers were then used to assess the down-stream biological effects of MEDI-546 by comparing pre- and post-dose samples.
Results Whole blood gene expression study demonstrated down-regulation of type I IFN-inducible transcripts across various time points post-administration of MEDI-546. The most extensive down-stream effects after type I IFN neutralization were seen at day 56, and upstream regulator analysis suggested the suppression of T cell receptor, nuclear factor of activated T cells (NFATC2), and CD40L by MEDI-546 administration. The proteomics study identified 8 proteins with decreased serum levels at day 56 among which 6 are type I IFN-inducible and 4 (CXCL10, CD40L, CXCL11, IL2RA) are associated with T cell activation and movement. Reduction of CXCL10 and CD40L levels were significantly correlated with type I IFN gene signature suppression. Furthermore, our results showed that C3M, a novel serum marker of matrix metalloproteinase-degraded type III collagen, is significantly lower in SSc subjects than normal controls, while the classic type III collagen synthesis marker (PIIINP) is significantly higher in SSc subjects. The ratio of PIIINP/C3M showed trends of correlation with SSc disease index MRTSS and HAQDI. MEDI-546 administration significantly decreased serum PIIINP/C3M ratio, suggesting a suppressive effects of MEDI-546 on collagen accumulation of SSc subjects. Skin microarray data also demonstrated the suppression of multiple collagen transcripts, tissue inhibitor of metalloproteinase, and other extracellular matrix-related transcripts by MEDI-546 administration. The down-regulation of PIIINP/C3M ratio was significantly correlated with the suppression of a T cell-associated composite index defined by serum levels of CXCL10, CD40L, CXCL11, and IL2R. Two SSc subjects with the highest decrease of MRTSS score demonstrated high suppression of both T cell-associated protein index and PIIINP/C3M ratio after MEDI-546 administration.
Conclusions Our study demonstrated suppressive effects of MEDI-546 on T cell activation and collagen accumulation through which tissue fibrosis may be alleviated. A T cell-associated protein index and a novel type III collagen turnover marker may serve as early response or predictive markers for type I IFN-targeted therapy in SSc subjects in future clinical trials.
Disclosure of Interest None declared
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