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Characterisation of Anifrolumab, a Fully Human Anti-Interferon Receptor

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Characterisation of Anifrolumab, a Fully Human Anti-Interferon Receptor Clinical trials and drug discovery Characterisation of anifrolumab, a Lupus Sci Med: first published as 10.1136/lupus-2018-000261 on 5 April 2018. Downloaded from fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus Jeffrey M Riggs,1 Richard N Hanna,1 Bhargavi Rajan,2 Kamelia Zerrouki,1 Jodi L Karnell,1 Divya Sagar,1 Inna Vainshtein,2 Erika Farmer,3 Kimberly Rosenthal,4 Chris Morehouse,5 Melissa de los Reyes,5 Kevin Schifferli,1 Meina Liang,2 Miguel A Sanjuan,1 Gary P Sims,1 Roland Kolbeck1 To cite: Riggs JM, Hanna RN, ABSTRACT morbidity as well as pathogenic secondary Rajan B, et al. Characterisation Objective We investigated the mechanistic and complications.2 Numerous environmental of anifrolumab, a fully human pharmacological properties of anifrolumab, a fully human, and genetic factors trigger SLE in predisposed anti-interferon receptor effector-null, anti-type I interferon (IFN) alpha receptor 1 antagonist antibody for individuals, contributing to the complex epide- (IFNAR1) monoclonal antibody in development for SLE. 3 the treatment of systemic miology of affected populations. A previous Methods IFNAR1 surface expression and internalisation lupus erythematosus. review examined the immunopathogenesis of on human monocytes before and after exposure to Lupus Science & Medicine SLE in detail.4 An important serological hall- 2018;5:e000261. doi:10.1136/ anifrolumab were assessed using confocal microscopy and lupus-2018-000261 flow cytometry. The effects of anifrolumab on type I IFN mark of the disease is the presence of autoan- pathway activation were assessed using signal transducer tibodies that bind to circulating nuclear anti- and activator of transcription 1 (STAT1) phosphorylation, gens. A strong association also exists between JMR and RNH contributed IFN-stimulated response element–luciferase reporter cell the presence of anti-double-stranded DNA equally. assays and type I IFN gene signature induction. The ability (anti-dsDNA), anti-Ro and anti-ribonucleop- of anifrolumab to inhibit plasmacytoid dendritic cell (pDC) Some of the data have been rotein, and type I interferon (IFN) activity in function and plasma cell differentiation was assessed 5 6 published in abstract form autoimmune patients. The primary source by flow cytometry and ELISA. Effector-null properties of following presentation at of type I IFNs appears to be plasmacytoid anifrolumab were assessed in antibody-dependent cell- http://lupus.bmj.com/ the 2017 Annual Meeting dendritic cells (pDCs), which uptake immune of the American College of mediated cytotoxicity (ADCC) and complement-dependent Rheumatology (Sims GP, Riggs cytotoxicity (CDC) assays with B cells. complexes containing DNA/RNA through J, Hanna R, et al. Arthritis Results Anifrolumab reduced cell surface IFNAR1 by Fcγ receptor (FcγR) IIA (CD32A). DNA/RNA Rheumatol 2017; 69 (Suppl 10)). eliciting IFNAR1 internalisation. Anifrolumab blocked type I uptake, in turn, activates intracellular nucleic IFN-dependent STAT1 phosphorylation and IFN-dependent acid-sensing toll-like receptors (TLRs), which Received 24 January 2018 7 8 signalling induced by recombinant and pDC-derived trigger the induction of type I IFNs. Revised 2 March 2018 type I IFNs and serum of patients with SLE . Anifrolumab In murine models of lupus and scleroderma, Accepted 8 March 2018 suppressed type I IFN production by blocking the type I on October 1, 2021 by guest. Protected copyright. targeted deletion or transcriptional impairment IFN autoamplification loop and inhibited proinflammatory cytokine induction and the upregulation of costimulatory of pDCs reduces the autoimmune pathology 1Respiratory, Inflammation and molecules on stimulated pDCs. Blockade of IFNAR1 observed in vivo. Additionally, depletion of Autoimmunity, MedImmune LLC, suppressed plasma cell differentiation in pDC/B cell co- pDCs in a pre-established model of scleroderma Gaithersburg, Maryland, USA cultures. Anifrolumab did not exhibit CDC or ADCC activity. attenuates skin fibrosis, emphasising the role for 2Clinical Pharmacology and Conclusions Anifrolumab potently inhibits type I pDCs in both the establishment and the mainte- DMPK, MedImmune LLC, IFN-dependent signalling, including the type I IFN 9–11 Mountain View, California, USA nance of autoimmune disease. autoamplification loop, and is a promising therapeutic for 3Analytical Sciences, A growing body of evidence supports the patients with SLE and other diseases that exhibit chronic MedImmune LLC, Gaithersburg, roles of type I IFNs in the immunopathogen- Maryland, USA dysfunctional type I IFN signalling. 12–14 4 esis of SLE and other interferonopathies. Antibody Discovery and Protein Multiple genetic polymorphisms increase Engineering, MedImmune LLC, Gaithersburg, Maryland, USA INTRODUCTION type I IFN signalling and are associated with 15 5Translational Medicine, Systemic lupus erythematosus (SLE) is a increased susceptibility to SLE. Increased MedImmune LLC, Gaithersburg, chronic, multisystem autoimmune disease type I IFN expression and type I IFN-induced Maryland, USA 16 17 characterised by reoccurring flares and remis- cell signalling correlate with SLE severity, 1 Correspondence to sions. Clinical manifestations of SLE range and therapeutic use of type I IFNs for patients Dr Gary P Sims; simsg@ in severity and presentation and include with viral hepatitis can induce a lupus-like medimmune. com life-threatening renal and neuropsychiatric syndrome.18 Riggs JM, et al. Lupus Science & Medicine 2018;5:e000261. doi:10.1136/lupus-2018-000261 1 Lupus Science & Medicine The family of type I IFNs includes 13 IFN-α subtypes, H3K1 (molecule derived from patent sequence of Lupus Sci Med: first published as 10.1136/lupus-2018-000261 on 5 April 2018. Downloaded from IFN-β, IFN-δ, IFN-ε, IFN-κ and IFN-ω. Type I IFN and Medarex/Bristol-Myers Squibb, New York, New York, the IFN alpha receptors 1 (IFNAR1) and 2 (IFNAR2) USA), along with an allophycocyanin-conjugated anti- form a functional IFNAR complex, leading to tyrosine body against CD11b (ICRF44, BioLegend, San Diego, phosphorylation of signal transducer and activator of California, USA). Cells were washed twice and then either transcription 1 (STAT1) and 2 (STAT2).19 20 Phosphory- imaged immediately or incubated at 37°C in culture lated STAT1 and STAT2 translocate with IFN regulatory media (X-Vivo; Lonza, Basel, Switzerland) with 5% factor 9 (IRF9) to the nucleus and drive IFN-stimulated carbon dioxide (CO2) for 30–60 min to examine IFNAR1 response element (ISRE) activation. ISRE promotes tran- internalisation. H3K1 binds to IFNAR1 at an epitope that scription of multiple IFN-stimulated genes, which leads is different from the epitope for anifrolumab. To deter- to the production of hundreds of proinflammatory and mine surface expression of IFNAR1 after internalisation, immunomodulatory proteins involved in the host innate cells were incubated with 5 µg/mL of A594-labelled H3K1 immune response to viral infection.21 22 IFNAR activation antibody for 30 min at 4°C, washed twice and then imaged also mediates cell-intrinsic induction of ISRE to produce immediately using a Leica SP5 confocal microscope more type I IFN and thereby autoamplify the IFN (Leica Microsystems Inc., Buffalo Grove, Illinois, USA). response.23–25 Thus, in autoimmune diseases, immune Surface IFNAR1 expression was quantified at 30 min after cells can rapidly produce large amounts of IFN at local- anifrolumab treatment using Imaris (Bitplane, Belfast, ised sites that ultimately can lead to tissue damage and UK) image analysis software. For image quantification of disease exacerbation.26 Medicines targeting the type I IFN IFNAR1 internalisation, a membrane mask was created pathway may provide a therapeutic benefit in SLE and using CD11b-APC fluorescence to define individual other diseases with a prominent type I IFN gene signature. cell membranes, and the amount of IFNAR1-A488-la- Anifrolumab (also known as MEDI546) is a fully human, belled or CD11b-APC‒labelled spots detected at the cell membrane, and inside individual cells, was assessed using effector-null, Ig G1 κ monoclonal antibody that binds to IFNAR1 and blocks type I IFN signalling. Anifrolumab is Imaris. currently in clinical development for treatment of SLE To assess surface IFNAR1 expression after treatment and lupus nephritis. Crystal structure and docking anal- with anifrolumab by flow cytometry, monocytes were incu- yses confirm that anifrolumab sterically inhibits type I IFN bated without (untreated control) and with 20 µg/mL of binding to IFNAR1.27 Anifrolumab was engineered with a unlabelled anifrolumab at 37°C for 0.5, 1, 4 or 24 hours. triple mutation L234F/L235E/P331S in the heavy chain Cells were then chilled on ice to stop internalisation and to reduce engagement with the cell surface receptor FcγR acid washed (500 mM of glycine HCl, pH 2.7) to remove and potential Fc-mediated effector functions (ie, effector residual surface-bound anifrolumab. To detect surface null), such as antibody-dependent cell-mediated cytotox- IFNAR1, cells were Fc blocked and then stained with 1 µg/ icity (ADCC) and complement-dependent cytotoxicity mL of A647-labelled anifrolumab at 4°C for 60 min. For http://lupus.bmj.com/ (CDC).28 the background control, identical aliquots were prein- In this study, we profiled the mechanistic and pharma- cubated with excess anifrolumab (100 µg/mL) prior to cological characteristics of anifrolumab. To this end, we staining with 1 µg/mL of A647-labelled anifrolumab.
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