Immunomodulatory mechanisms of anifrolumab: A transcriptomic and proteomic analysis of phase III trials

Anifrolumab, a type I interferon receptor 1 (IFNAR1) is approved for treatment of adults with moderate to severe systemic lupus erythematosus (SLE). It acts by blocking type I interferon (IFN) signaling that plays a key role in the pathogenesis of SLE.

Below, we summarize an article published by Baker et al. in Annals of the Rheumatic Diseases investigating the immunomodulatory mechanisms underlying IFNAR1 blockade by anifrolumab using longitudinal transcriptomic and proteomic analyses of the phase III TULIP-1 and TULIP-2 trials.

Methods

• Patients with moderate-to-severe SLE receiving intravenous anifrolumab or placebo alongside standard therapy in the TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials were assessed.
• Whole-blood expression of 18,017 genes and 184 plasma protein analytes were assessed.
• Treatment groups were compared for gene counts and protein levels via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA sequencing, and longitudinal linear mixed effect models.

Key findings¹

• A total of 726 patients were analyzed.
  • 502 patients comprised the transcriptomic dataset (244 received anifrolumab and 258 received placebo).
  • 256 patients from TULIP-1 comprised the proteomics dataset (124 patients received anifrolumab and 132 received placebo).

Differentially expressed genes

• At Week 24 and 52, anifrolumab resulted in downregulation of 1,681 and 2,092 genes, respectively, and upregulation of 1,170 and 1,645 genes, respectively vs placebo.
• The most significantly downregulated genes at Weeks 24 and 52 are shown in Figure 1.

*Data from Baker, et al.¹

 Differentially regulated pathways

• Several MetaBase intracellular signaling pathways were downregulated including
  • IFN-α/-β29 via:
    • Janus kinases/signal transducer and activator of transcription (normalized enrichment score [NES] −2.84);
    • phosphoinositide 3-kinases and nuclear factor kappa light chain enhancer of activated B cells (NES −2.13); and
    • mitogen-activated protein kinase pathways (NES −2.21).
  •  IFN-γ29 via:
    • IFN-γ mediated apoptosis induction and inhibition of proliferation (NES −2.32)
    • IFN-γ actions on extracellular matrix and cell differentiation (NES −2.13).
  • NETosis-associated pathways (NES −2.21).
• Several MetaBase pathways associated with protein synthesis were upregulated, including regulation of translation initiation (NES 3.59).

Blood transcriptome modules

• Anifrolumab downregulated modules associated with IFN activity compared with placebo at Week 52 (false discovery rate p value [P_FDR] ≤0.01).
• Anifrolumab also downregulated modules for non-IFN pathways including modules for antigen presentation (NES −2.03), neutrophils (NES −1.88), and monocytes (NES −1.86).
• Several modules were upregulated including those associated with lymphocytes and T cells, as well as protein modification and synthesis (P_FDR ≤0.01).

Proteins longitudinally modulated

• Anifrolumab significantly downregulated 34 and upregulated 7 proteins (P_FDR ≤0.05, each).

Key learnings

Anifrolumab resulted in modulation of multiple inflammatory pathways downstream of type I IFN signaling, including apoptotic, innate, and adaptive immune system, pivotal in the immunopathogenesis of SLE. The findings support that IFNAR1 blockade with anifrolumab yields broad anti-inflammatory effects and may aid in reversing the immune cell composition imbalances seen in patients with SLE.