Background/Purpose: The type I interferon (IFN-I) family of cytokines signal through a ubiquitously expressed heterodimeric receptor (IFNAR) composed of IFNAR1 and the high-affinity binding chain IFNAR2 eliciting antiviral, antiproliferative, and immunomodulatory effects. IFN-I is thought to play a central role in the pathogenesis of systemic lupus erythematosus (SLE) and therapeutic approaches to down-modulate this pathway have demonstrated efficacy in SLE clinical trials. The IFN-I pathway is composed of multiple closely related IFN-α subtypes and single functional molecules for IFN-β, IFN-ε, IFN-κ and IFN-ω. Some members of the IFN-I family are thought to contribute to SLE pathogenesis, while others may be more relevant for host defense. We developed a fully-human monoclonal antibody (CNTO 6358) to selectively neutralize the most prevalent soluble IFN-Is expressed in SLE, while retaining the functions of IFN-β, including critical antiviral contributions to host defense. Here we illustrate in vitro bioactivity using endogenous SLE patient-derived IFN-I preparations, including immune complexes and serum/plasma from racially diverse SLE populations, providing evidence that the neutralization and potency profile of CNTO 6358 may enable potent suppression of IFN-Is prevalent in SLE without suppression of other IFN-Is more essential for other host defense processes. We further describe an in vitro assay that may enable the prediction of responders and non-responders with CNTO 6358, providing a transformational framework for SLE precision medicine.

Methods: Pooled SLE serum and plasma or conditioned media from cells exposed to pooled SLE patient immune complexes or recombinant human IFN-Is were utilized as stimuli in an ISRE reporter gene assay (RGA) in the presence of CNTO 6358 or control. SLE patient whole blood was incubated in vitro for 24 hours in the presence or absence of CNTO 6358 and the impact of inhibitor treatment on gene expression was determined by RNA-Seq relative to untreated healthy donor samples. All patient samples were collected under informed consent.

Results: IFN-I activity present in plasma and serum preparations from multiple SLE cohorts and activity present in conditioned media from PBMCs exposed to SLE patient immune complexes was neutralized to levels seen in healthy control samples. The in vitro addition of CNTO 6358 to blood from individual SLE patients enabled the identification of donors having robust normalization of baseline elevated IFN-I signature gene expression and those having moderate to minimal transcriptional changes.

Conclusion: Our SLE IFN-I inhibitor CNTO 6358 exhibited potent neutralization of multiple SLE patient-derived IFN-I preparations, demonstrating a bioactivity profile targeting the most prevalent IFN-I subtypes elevated in SLE patients, while preserving the functionality of other IFN-Is which may be more important for host defense. Furthermore, our in vitro assay and in silico methodologies may enable prediction of responders to our treatment, providing a transformational framework for SLE precision medicine.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/introducing-a-novel-sle-specific-ifn-i-inhibitor-cnto-6358-laying-the-groundwork-for-precision-medicine-in-lupus/