Anifrolumab (also known as MEDI546) is a fully human, effector-null, IgG1κ monoclonal antibody (mAb) developed by MedImmune. It binds to interferon (IFN) alpha receptors 1 (IFNAR1) and blocks type I IFN signalling. Anifrolumab is currently in clinical development for treatment of systemic lupus erythematosus (SLE) and lupus nephritis. In the Phase IIb MUSE trial (NCT01438489), anifrolumab 300 mg every 4 weeks intravenously plus standard of care significantly decreased SLE disease activity across a range of endpoints, especially for patients with type I IFN gene signature test high results at baseline. Two Phase III trials (TULIP-I/II; NCT02446899/NCT02446912) are currently ongoing to further evaluate the efficacy and safety of intravenous anifrolumab for patients with moderate to severe SLE. Of the three novel anti-type type I IFN pathway antibodies (rontalizumab, sifalimumab and anifrolumab) evaluated in Phase II clinical trials for SLE, the intravenous formulation of anifrolumab had the highest efficacy relative to placebo.
SLE is a chronic, multisystem autoimmune disease characterized by reoccurring flares and remissions. A growing body of evidence supports the roles of type I IFNs in the immunopathogenesis of SLE and other interferonopathies. Multiple genetic polymorphisms increase type I IFN signalling and are associated with increased susceptibility to SLE. Increased type I IFN expression and type I IFN-induced cell signalling correlate with SLE severity, and therapeutic use of type I IFNs for patients with viral hepatitis can induce a lupus-like syndrome. The family of type I IFNs includes IFN-α subtypes, IFN-β, IFN-δ, IFN-ε, IFN-κ and IFN-ω. type I IFN and the IFN alpha receptors 1 (IFNAR1) and 2 (IFNAR2) form a functional IFNAR complex, leading to tyrosine phosphorylation of signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2). Phosphorylated STAT1 and STAT2 translocate with IFN regulatory factor 9 (IRF9) to the nucleus and drive IFN-stimulated response element (ISRE) activation. ISRE promotes transcription of multiple IFN-stimulated genes, which leads to the production of hundreds of proinflammatory and immunomodulatory proteins involved in the host innate immune response to viral infection. IFNAR activation also mediates cell-intrinsic induction of ISRE to produce more type I IFN and thereby autoamplify the IFN response. Thus, in autoimmune diseases, immune cells can rapidly produce large amounts of IFN at localized sites that ultimately can lead to tissue damage and disease exacerbation. Medicines targeting the type I IFN pathway may provide a therapeutic benefit in SLE and other diseases with a prominent type I IFN gene signature. Anifrolumab was designed to target IFNAR1 and blocks the type I IFN signalling. On the other, anifrolumab was engineered with a triple mutation L234F/L235E/P331S in the heavy chain to reduce engagement with the cell surface Fc gamma receptor (FcγR) and potential Fc-mediated effector function, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Fig.1 Mechanism of action of anifrolumab
|NCT ID||Status||Conditions||Lead Sponsor||Update Time|
|NCT02547922||Recruiting||Lupus Nephritis||AstraZeneca||September 14, 2015|
|NCT03435601||Recruiting||Rheumatoid Arthritis||Josef Smolen, Univ. Prof. Dr.||February 16, 2018|
|NCT02794285||Recruiting||Active Systemic Lupus Erythematosus||AstraZeneca||June 9, 2016|
|NCT02446899||Active, not recruiting||Active Systemic Lupus Erythematosus||AstraZeneca||May 18, 2015|
|NCT02446912||Active, not recruiting||Active Systemic Lupus Erythematosus||AstraZeneca||May 18, 2015|
|NCT02962960||Active, not recruiting||Systemic Lupus Erythematosus||AstraZeneca||November 15, 2016|
* The table was excerpted from the following website