Targeting interferons in systemic lupus erythematosus: current and future prospects.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown aetiology that can be debilitating and life threatening. As new insights are gained into the underlying pathology of SLE, there have been an unprecedented number of new agents under development to treat the disease via a diverse range of targets. One such class of emerging agents target interferon (IFN) signalling. In this article, we review the preclinical evidence that the inhibition of the secretion and downstream effectors of both IFN-α and IFN-γ may be effective for the treatment of SLE. The primary agents that are currently in clinical development to treat SLE via the targeting of interferon pathways are monoclonal neutralising antibodies (Mab) that bind to and neutralise IFN-γ (AMG 811), IFN-α (sifalimumab, rontalizumab and AGS-009) or its receptor (anifrolumab), and IFN-α kinoid, which is a drug composed of inactivated IFN-α molecules coupled to the keyhole limpet haemocyanin protein. Phase I and II trials have demonstrated acceptable short-term safety with no increase in severe viral infections or reactivation, favourable pharmacokinetic profiles and an inhibition of IFN-associated gene overexpression; however, the impact of these drugs on disease activity must still be assessed in phase III clinical trials. This review concludes with a summary of the challenges that are inherent to this approach to managing SLE.
AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Service de médecine interne 2, Institut E3M, Centre de Référence National pour le Lupus et le Syndrome des Antiphospholipides, 83 boulevard de l'hôpital, 75013, Paris, France.
Alexis
A
Mathian
Miguel
M
Hie
Fleur
F
Cohen-Aubart
Zahir
Z
Amoura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000503:physiopathology; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D016898:Interferon-alpha; D007371:Interferon-gamma