Treatment of lupus

Abstract

The present disclosure relates to methods and compositions for treating SLE. In particular, the disclosure relates to methods comprising administering a type I IFN receptor inhibitor to a subject.

Description

1. BACKGROUND

[0001] Systemic lupus erythematosus (SLE) is a chronic, multisystem, and disabling autoimmune rheumatic disease of unknown etiology. There is a large unmet medical need in the treatment of SLE, particularly in subjects with moderate or severe disease. Long-term prognosis remains poor for many subjects. SLE remains a disease with a highly variable course and considerable inter-individual variability [1]. There is a continuous need for more targeted approaches to treat SLE [1].

[0002] A significant problem associated with SLE treatment is the heterogeneous clinical presentation of SLE [2]. Any organ can be affected in SLE, with the skin, joints, and kidneys being the most commonly involved [3-5]. Incomplete disease control leads to progressive organ damage, poor quality of life, and increased mortality, with approximately half of all SLE patients developing organ damage within 10 years of diagnosis [6, 7]. There remains a need for medical interventions that improve SLE disease activity across multiple systems.

[0003] The difficulty in developing effective therapeutics for SLE compared to therapeutics for other indications leads to an even higher failure rate of therapeutics in clinical trials in this area. It has therefore proven extremely difficult to develop new therapeutics for the treatment of SLE. There are many examples of clinical candidates that show promise in Phase II but fail to show efficacy and / or safety in subsequent Phase III or Phase III trials.

[0004] Type I interferons (IFNs) play a central role in the pathogenesis and course of SLE. While these cytokines are secreted by innate immune cells to activate the immune system and defend against viral and bacterial infections, overexpression of Type I IFNs occurs in patients with SLE and other autoimmune diseases, and activation of the IFN pathway is associated with increased SLE disease activity.

[0005] The present invention addresses one or more of the above-mentioned problems. 2. SUMMARY

[0006] The present invention relates to an improved treatment of SLE. The present invention particularly relates to a method of treating lupus in a subject in need thereof, the method comprising administering an inhibitor of Type I IFN signaling, wherein the subject is diagnosed with SLE at an age of less than (<) 50 years. The present invention also relates to a method of treating lupus in a subject in need thereof, the method comprising administering an inhibitor of Type I IFN signaling, the subject experiencing their first manifestation of SLE at an age of about 30 years or less.

[0007] The present invention is especially supported by data presented herein for the first time from the SLE Prospective Observational Cohort Study (SPOCS; NCT03189875). SPOCS is the first real-world study to longitudinally evaluate patients’ IFNGS status. Data from SPOCS surprisingly demonstrate that high Type I IFN gene signature (IFNGS) is associated with early SLE diagnosis and lower age at first SLE manifestation. These insights provide an opportunity for better targeting of therapies against pathological Type I IFN gene signature in lupus patients, such as anifrolumab. In particular, these data demonstrate that patients with early diagnosis and onset of SLE can be targeted with, e.g., anifrolumab treatment based on their medical history, without the need for additional testing. 3. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 : IFN score distribution

[0009] Figure 2 : Baseline clinical manifestations by organ system involvement in the SPOCS population by IFNGS quartile

[0010] CNS, central nervous system; IFNGS, Type I Interferon Gene Signature; SLE, systemic lupus erythematosus; SPOCS, SLE Prospective Observational Cohort Study.

[0011] Figure 3 : IFNGS status at baseline by country

[0012] Number of patients classified as low and high IFNGS by country, presented in order of countries by minimum to maximum percentage of low IFNGS patients. IFNGS, Type I Interferon Gene Signature; UK, United Kingdom; USA, United States of America.

[0013] Figure 4 : Age at SLE diagnosis by high and low IFNGS patient subgroups

[0014] Figure 5: Baseline clinical manifestations by organ system involvement in the SPOCS population

[0015] Figure 5A : Total by baseline; Figure 5B : SLEDAI-2K; Figure 5C : Onset. CNS, central nervous system; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SPOCS, SLE Prospective Observational Cohort Study. 4. DETAILED DESCRIPTION

[0016] 4.1. Methods of treating lupus

[0017] The present application relates to a method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising administering to the subject an inhibitor of Type I IFN, wherein the method reduces SLE disease activity in the subject.

[0018] The present application relates to a method of treating SLE in a subject in need thereof, the method comprising administering a therapeutically effective amount of an inhibitor of Type I IFN signaling, wherein a) the subject was diagnosed with SLE at an age of less than (<) 50 years, and / or b) the subject experienced their first manifestation of SLE at an age of about 30 years or less. The method can comprise determining the age at which the patient was diagnosed with SLE and / or the subject experienced their first manifestation of SLE.

[0019] The subject can have been diagnosed with SLE at an age of < 30 years. The subject can have been diagnosed with SLE at an age of 18 to 29 years. The subject can have been diagnosed with SLE at an age of < 18 years.

[0020] The inhibitor of Type I IFN signaling can be a human monoclonal antibody specific for IFNAR1. The monoclonal antibody can be a modified IgG1 class human monoclonal antibody. The inhibitor of Type I IFN signaling can be sifalimumab. The inhibitor of Type I IFN signaling can be QX006N.

[0021] The antibody specific for IFNAR1 can comprise:

[0022] (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3;

[0023] (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4;

[0024] (c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5;

[0025] (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6;

[0026] (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and

[0027] (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0028] An IFNAR1 -specific antibody can comprise: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. An IFNAR1 -specific antibody can comprise an amino acid substitution of L234F in the Fc region, as numbered by the EU index as shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. An IFNAR1 -specific antibody can comprise: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0029] The Type I IFN signaling inhibitor can be anifrolumab or a functional variant thereof.

[0030] The method of treatment can comprise administering to the subject an intravenous dose of anifrolumab or a functional variant thereof. The intravenous dose can be > 300 mg of anifrolumab or a functional variant thereof. The intravenous dose can be < 1000 mg. The intravenous dose can be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose can be administered once every four weeks (Q4W).

[0031] The method of treatment can comprise administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose can be > 105 mg and < 150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose can be < 135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose can be about 120 mg. The subcutaneous dose can be administered in a single administration step. The subcutaneous dose can be administered at intervals of 6-8 days. The subcutaneous dose can be administered once a week. The subcutaneous dose can have a volume of about 0.5 ml to about 1 ml. The subcutaneous dose can have a volume of about 0.8 ml.

[0032] The method can comprise identifying the subject as a pre-treatment IFNGS test high patient.

[0033] The present invention also relates to a pharmaceutical composition for use in the method of the present invention. The pharmaceutical composition can comprise anifrolumab or a functional variant thereof.

[0034] The present invention also relates to an injection device comprising the pharmaceutical composition of the present invention. The injection device can be a pre-filled syringe (PFS). The injection device can be an accessory- fitted pre-filled syringe (AFPS). The injection device can be an auto-injector.

[0035] The present application also relates to a kit comprising the pharmaceutical composition of the present application and instructions for use. The instructions for use specify the subject, i.e. a subject diagnosed with SLE at an age of less than (<) 50 years, and / or a subject who experienced their first SLE manifestation at an age of about 30 years or less. The instructions for use can specify an injection device for use according to any method of the present application.

[0036] 4.2. Inhibitors of Type I IFN signaling

[0037] An "Type I Interferon Receptor Inhibitor" refers to a molecule that antagonizes the receptor for Type I Interferon ligands, such as Interferon-alpha and Interferon-beta. Such an inhibitor can provide, upon administration to a patient, a reduction in the expression of at least one (preferably at least four) pharmacodynamic (PD) marker genes selected from the group consisting of IFI6, RSAD2, IFI44, IFI44L, IFI27, MX1, IFIT1, HERC5, ISG15, LAMP3, OAS3, OAS1, EPST1, IFIT3, LY6E, OAS2, PLSCR1, SIGLEC1, USP18, RTP4, and DNAPTP6. The at least four genes can suitably be IFI27, IFI44, IFI44L, and RSAD2. The "Type I Interferon Receptor" is preferably the Interferon-alpha / beta receptor (IFNAR).

[0038] For example, the Type I Interferon Receptor Inhibitor can be an antibody or antigen-binding fragment thereof that inhibits Type I IFN activity (by inhibiting the receptor). An example of a suitable antibody or antigen-binding fragment thereof that inhibits Type I IFN activity is an Interferon-alpha / beta receptor (IFNAR) antagonist. The Type I Interferon Receptor Inhibitor can be an antibody or antigen-binding fragment thereof that inhibits Type I IFN activity. Additionally or alternatively, the Type I Interferon Receptor Inhibitor can be a small molecule inhibitor of the Type I Interferon Receptor (e.g., for pharmacologically inhibiting Type I Interferon Receptor activity).

[0039] The IFNAR1 inhibitor can be a human monoclonal antibody specific for IFNAR1. The IFNAR1 inhibitor can be a modified IgGl class human monoclonal antibody specific for IFNAR1.

[0040] The antibody can comprise a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3. The antibody can comprise a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4. The antibody can comprise a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5. The antibody can comprise a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6. The antibody can comprise a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7. The antibody can comprise a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0041] The antibody can comprise a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1. The antibody can comprise a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The antibody can comprise a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9. The antibody can comprise a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 10. The antibody can comprise an amino acid substitution of L234F in the Fc region, as numbered by the EU index as shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The antibody can comprise a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11. The antibody can comprise a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0042] The antibody can comprise: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (b) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; c) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0043] The antibody can comprise (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0044] The IFNAR1 inhibitor can be Anifrolumab or a functional variant thereof.

[0045] 4.3. Dosing and methods of administration

[0046] The method can comprise administering to the subject an intravenous dose of anifrolumab or a functional variant thereof. The intravenous dose can be > 300 mg of anifrolumab or a functional variant thereof. The intravenous dose can be < 1000 mg. The intravenous dose can be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose can be administered once every four weeks (Q4W).

[0047] The method can comprise administering a subcutaneous dose of anifrolumab or a functional variant thereof. The subcutaneous dose can be > 105 mg and < 150 mg of anifrolumab or a functional variant thereof. The subcutaneous dose can be < 135 mg of anifrolumab or a functional variant thereof. The subcutaneous dose can be about 120 mg. The subcutaneous dose can be administered in a single administration step. The subcutaneous dose can be administered at 6-8 day intervals. The subcutaneous dose can be administered once a week. The subcutaneous dose can have a volume of about 0.5 ml to about 1 ml. The subcutaneous dose can have a volume of about 0.8 ml.

[0048] The subject can have moderate to severe SLE prior to treatment.

[0049] The subject can be a patient who is high for the Type I interferon stimulated gene signature (IFNGS) test prior to treatment. The method can comprise identifying the subject as a patient who is high for the IFNGS test prior to treatment.

[0050] Many patients with SLE receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anifrolumab allows for tapering of corticosteroids (glucocorticoids) in SLE patients (steroid tapering). The method or method of treatment can comprise administering a corticosteroid to the subject, optionally wherein the corticosteroid is an oral corticosteroid. The method can comprise gradually reducing the dose of corticosteroid administered to the subject (steroid tapering). The method can comprise administering a first dose of corticosteroid and subsequently administering a second dose of corticosteroid, wherein the second dose of corticosteroid is lower than the first dose of corticosteroid. The second dose of corticosteroid can be about 7.5 mg prednisone equivalent or less. The second dose of corticosteroid can be 5 mg prednisone equivalent or less. The method or method of treatment can comprise administering the second dose of corticosteroid once a day. The first dose of corticosteroid can be about 10 mg prednisone equivalent. The method can comprise gradually reducing the dose of corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. The method or method of treatment can comprise administering the second dose of corticosteroid once a day. The method can allow for administration of a reduced dose of corticosteroid for a number of weeks. The second dose of corticosteroid can be administered for at least 24 weeks. The second dose of corticosteroid can be administered for at least 28 weeks.

[0051] The method can comprise steroid tapering of the subject, wherein the dose of the steroid administered to the subject is gradually reduced from a pre-taper dose at baseline to a post-taper dose. The post-taper dose can be < 7.5 mg / day prednisone or prednisone equivalent dose. The pre-taper dose can be 20 mg / day prednisone or prednisone equivalent dose. The steroid can comprise a glucocorticoid. The steroid can comprise an oral glucocorticoid. The steroid can be selected from the group consisting of hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flurandrenolone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, clocortolone, dihydroxycortisone, alclometasone, amcinonide, diflucortolone valerate, fluocinolone acetonide, fluocinolone, fluocinonide, fluocortolone, fluocortolone pivalate, fluocortolone valerate, flurandrenolide, flurandrenolone acetonide, halcinonide, halomethasone, halopredone acetohydroxide, hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone cypionate, hydrocortisone phosphate, hydrocortisone probutate, hydrocortisone suleptate, hydrocortisone valerate, medrysone, paramethasone, tixocortol, triamcinolone acetonide, triamcinolone hexacetonide, and combinations thereof.valerate), flucortolone, fluprednidene, fluandrenolone, fluorometholone, halcinonide, halobetasol, desonide, diflorasone, flurandrenolide, fluocinonide, prednicarbate, desoximetasone, fluprednisolone, prednisone, azelastine, dexamethasone 21 -phosphate, fludrocortisone, flumethasone, fluocinolone, halopredone, hydrocortisone 17-valerate, hydrocortisone 17- butyrate, hydrocortisone 21 -acetate, paramethasone, paramethasone 21 - phosphate, clobetasol propionate, triamcinolone acetonide, or mixtures thereof. The steroid can be prednisone.

[0052] The present application also relates to a unit dose for use in the method of the present application, wherein the unit dose comprises > 105 mg and < 150 mg anifrolumab or a functional variant thereof. Unit doses of anifrolumab suitable for use in the method of the present application are described in WO2022223714 Al [8], which is incorporated herein by reference in its entirety.

[0053] A unit dose can comprise < 135 mg (i.e. 135 mg or less) of anifrolumab or a functional variant thereof. A unit dose can comprise about 120 mg of anifrolumab or a functional variant thereof. A unit dose can comprise 120 mg of anifrolumab or a functional variant thereof. A unit dose can consist essentially of > 105 mg and < 150 mg of anifrolumab or a functional variant thereof. A unit dose can consist essentially of < 135 mg of anifrolumab or a functional variant thereof. A unit dose can consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in a unit dose can be about 150 mg / ml. The volume of a unit dose can be less than 1 ml. The dose or unit dose can have a volume of about 0.5 ml to about 1 ml. The concentration of a unit dose can be about 0.8 ml. The volume of a unit dose can be 0.8 ml. A unit dose can comprise a formulation of about 150 mg / ml to 200 mg / ml anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine, and uncharged excipients. A unit dose can comprise a formulation of 150 mg / ml to 200 mg / ml anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine, and uncharged excipients. A unit dose comprises a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation can have a pH of about 5.9.

[0054] In another aspect, the present application relates to a method of treating SLE in a subject, the method comprising subcutaneously administering a dose of anifrolumab or a functional variant thereof, wherein the dose administered weekly in the subject provides a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose administered weekly in the subject can provide a plasma concentration that is greater than the plasma concentration provided by intravenously administering 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose administered weekly in the subject can provide a plasma concentration that is at least equivalent to the plasma concentration provided by intravenously administering 400 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose can be administered in a single administration step. The dose administered to the subject can be < 150 mg (i.e. less than 150 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be > 105 mg (i.e. greater than 105 mg) of anifrolumab or a functional variant thereof. The dose administered to the subject can be < 135 mg (i.e. 135 mg or less) of anifrolumab or a functional variant thereof. The dose administered to the subject can be about 120 mg of anifrolumab or a functional variant thereof.

[0055] The administration of the dose or unit dose can provide a plasma concentration of anifrolumab or a functional variant thereof in the patient of > 10 pg (i.e., 10 pg or more) of anifrolumab or a functional variant thereof per milliliter of plasma (i.e., a plasma concentration of > 10 pg / ml). The administration of the dose or unit dose can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 10 pg / ml to 100 pg / ml. The administration of the dose or unit dose can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 20 pg / ml to 80 pg / ml. The administration of the dose or unit dose can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 30 pg / ml to 70 pg / ml. The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 20 pg / ml (i.e., 20 pg / ml or more). The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 30 pg / ml (i.e., 30 pg / ml or more). The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 40 pg / ml (i.e., 40 pg / ml or more). The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 20 pg / ml to 100 pg / ml. The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 30 pg / ml to 80 pg / ml. The administration of the dose or unit dose can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 40 pg / ml to 70 pg / ml.

[0056] 4.4. Subjects

[0057] The subject can have been diagnosed with SLE at an age of 60 years or younger. The subject can have been diagnosed with SLE at an age of 59 years or younger. The subject can have been diagnosed with SLE at an age of 58 years or younger. The subject can have been diagnosed with SLE at an age of 57 years or younger. The subject can have been diagnosed with SLE at an age of 56 years or younger. The subject can have been diagnosed with SLE at an age of 55 years or younger. The subject can have been diagnosed with SLE at an age of 54 years or younger. The subject can have been diagnosed with SLE at an age of 53 years or younger. The subject can have been diagnosed with SLE at an age of 52 years or younger. The subject can have been diagnosed with SLE at an age of 51 years or younger. The subject can have been diagnosed with SLE at an age of 50 years or younger. The subject can have been diagnosed with SLE at an age of 49 years or younger. The subject can have been diagnosed with SLE at an age of 48 years or younger. The subject can have been diagnosed with SLE at an age of 47 years or younger. The subject can have been diagnosed with SLE at an age of 46 years or younger. The subject can have been diagnosed with SLE at an age of 45 years or younger. The subject can have been diagnosed with SLE at an age of 44 years or younger. The subject can have been diagnosed with SLE at an age of 43 years or younger. The subject can have been diagnosed with SLE at an age of 42 years or younger. The subject can have been diagnosed with SLE at an age of 41 years or younger. The subject can have been diagnosed with SLE at an age of 40 years or younger. The subject can have been diagnosed with SLE at an age of 39 years or younger. The subject can have been diagnosed with SLE at an age of 38 years or younger. The subject can have been diagnosed with SLE at an age of 37 years or younger. The subject can have been diagnosed with SLE at an age of 36 years or younger. The subject can have been diagnosed with SLE at an age of 35 years or younger. The subject can have been diagnosed with SLE at an age of 34 years or younger. The subject can have been diagnosed with SLE at an age of 33 years or younger. The subject can have been diagnosed with SLE at an age of 32 years or younger. The subject can have been diagnosed with SLE at an age of 31 years or younger. The subject can have been diagnosed with SLE at an age of 30 years or younger.

[0058] The subject can have experienced their first manifestation of SLE at an age of about 30 years or younger, e.g., at age 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20. The subject can have early-onset SLE.

[0059] The subject can be a human subject. The subject can be an adult. The subject can be a patient having an elevated Type I IFN gene signature. The subject can be a patient who tests high for Type I interferon stimulated gene signature (IFNGS) prior to administration with the dose or unit dose. The subject can have elevated genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. The method can comprise identifying the subject as a patient who tests high for IFNGS prior to treatment with the dose or unit dose. The method can comprise measuring expression of genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood of the subject. The method can comprise measuring expression of genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood of the subject by RT-PCR.

[0060] The dose or unit dose can provide a therapeutic effect in the subject that is at least equivalent to the therapeutic effect provided by administration of an intravenous dose of 300 mg anifrolumab or functional variant thereof administered once every four weeks (Q4W). The dose or unit dose can provide a trough concentration of anifrolumab or functional variant thereof in the subject that is greater than the trough concentration of anifrolumab or functional variant thereof provided by an intravenous dose of 300 mg anifrolumab or functional variant thereof administered once every 4 weeks (Q4W). The anifrolumab or functional variant thereof can be comprised within a pharmaceutical composition. The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise 0.05% polysorbate 80. The pharmaceutical composition can comprise 25 mM histidine / histidine HC1. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof, 50 mM lysine HC1, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HC1.

[0061] The methods of the invention can comprise administering the dose or unit dose at intervals of 6 days to 8 days. The dose or unit dose can be administered once weekly (QW). The dose or unit dose can be 120 mg anifrolumab or functional variant thereof, and the method comprises administering the dose once weekly (QW) in a single administration step. In other words, the method comprises administering 120 mg QW of anifrolumab or functional variant thereof. The dose or unit dose can be administered once weekly for at least about 4 weeks. The dose or unit dose can be administered once weekly for at least about 8 weeks. The dose or unit dose can be administered once weekly for at least about 12 weeks. The dose or unit dose can be administered once weekly for at least about 16 weeks. The dose or unit dose can be administered once weekly for at least about 20 weeks. The dose or unit dose can be administered once weekly for at least about 24 weeks. The dose or unit dose can be administered once weekly for at least about 28 weeks. The dose or unit dose can be administered once weekly for at least about 32 weeks. The dose or unit dose can be administered once weekly for about 8 weeks. The dose or unit dose can have a volume that allows it to be suitably delivered in a single subcutaneous administration step. The dose or unit dose can have a volume of about 0.5 ml to about 1 ml. The dose or unit dose can have a volume of less than 1 ml. The dose or unit dose can have a volume of about 0.8 ml.

[0062] 4.5. Pharmaceutical compositions

[0063] The invention also relates to a pharmaceutical composition for use in a method of treating SLE in a subject, the method comprising subcutaneously administering to the subject the pharmaceutical composition, wherein the pharmaceutical composition comprises a dose of anifrolumab or functional variant thereof, wherein the dose is > 105 mg and < 150 mg. The dose of anifrolumab or functional variant thereof can be a unit amount (unit dosage form, pharmaceutical unit dosage form, pharmaceutical unit dose). Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab.

[0064] In another aspect, the application relates to a pharmaceutical composition for use in a method of treating CLE in a subject, the method comprising subcutaneously administering to the subject the pharmaceutical composition, wherein the pharmaceutical composition comprises a dose of anifrolumab or a functional variant thereof, wherein the weekly administration of the pharmaceutical composition provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by the intravenous administration of 300 mg of anifrolumab or a functional variant thereof every 4 weeks. The dose can be < 150 mg (i.e., less than 150 mg) of anifrolumab or a functional variant thereof. The dose can be > 105 mg (i.e., greater than 105 mg) of anifrolumab or a functional variant thereof. The dose can be < 135 mg (i.e., 135 mg or less) of anifrolumab or a functional variant thereof. The dose can be about 120 mg of anifrolumab or a functional variant thereof. The dose can be 120 mg of anifrolumab or a functional variant thereof.

[0065] The pharmaceutical composition can be administered at 6-8 day intervals. The pharmaceutical composition can be administered once a week (QW). The pharmaceutical composition can be administered in a single administration step. The dose can be 120 mg of anifrolumab or a functional variant thereof, and the method of treatment can comprise administering the dose once a week (QW) in a single administration step. The pharmaceutical composition can be administered once a week for at least about 4 weeks. The pharmaceutical composition can be administered once a week for at least about 8 weeks. The dose or unit dose can be administered once a week for at least about 12 weeks. The pharmaceutical composition can be administered once a week for at least about 16 weeks. The pharmaceutical composition can be administered once a week for at least about 20 weeks. The pharmaceutical composition can be administered once a week for at least about 24 weeks. The pharmaceutical composition can be administered once a week for at least about 28 weeks. The pharmaceutical composition can be administered once a week for at least about 32 weeks. The pharmaceutical composition can be administered once a week for about 8 weeks. The pharmaceutical composition can have a volume that allows it to be suitably delivered in a single subcutaneous administration step. The pharmaceutical composition can have a volume of about 0.5 ml to about 1 ml. The pharmaceutical composition can have a volume of less than 1 ml. The pharmaceutical composition can have a volume of about 0.8 ml.

[0066] The administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof in the patient of > 10 pg per ml of plasma (i.e., 10 pg or more) anifrolumab or a functional variant thereof. The administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 10 pg / ml to 100 pg / ml. The administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 20 pg / ml to 80 pg / ml. The administration of the pharmaceutical composition can provide a plasma concentration of anifrolumab or a functional variant thereof in the subject of about 30 pg / ml to 70 pg / ml. The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 20 pg / ml (i.e., 20 pg / ml or more). The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 30 pg / ml (i.e., 30 pg / ml or more). The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of > 40 pg / ml (i.e., 40 pg / ml or more). The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 20 pg / ml to 100 pg / ml. The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 30 pg / ml to 80 pg / ml. The administration of the pharmaceutical composition can provide a trough concentration of anifrolumab or a functional variant thereof in the subject of about 40 pg / ml to 70 pg / ml.

[0067] The therapeutic effect provided by the pharmaceutical composition in a subject can be at least equivalent to the therapeutic effect provided by administering an intravenous dose of 300 mg anifrolumab or functional variant thereof administered every four weeks (Q4W). The trough concentration of anifrolumab or functional variant thereof provided by the pharmaceutical composition in a subject can be greater than the trough concentration of anifrolumab or functional variant thereof provided by administering an intravenous dose of 300 mg anifrolumab or functional variant thereof administered every four weeks (Q4W). Anifrolumab or functional variant thereof can be included within the pharmaceutical composition. The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise 0.05% polysorbate 80. The pharmaceutical composition can comprise 25 mM histidine / histidine HC1. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof, 50 mM lysine HC1, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HC1.

[0068] The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise 0.05% polysorbate 80. The pharmaceutical composition can comprise 25 mM histidine / histidine HC1. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or functional variant thereof, 50 mM lysine HC1, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HC1.

[0069] 4.6. Devices

[0070] The present application also relates to an injection device comprising the unit dose of the present application or the pharmaceutical composition for use in any of the uses of the present application.

[0071] The drug in the injection device can comprise > 105 mg (i.e. greater than 105 mg) and < 150 mg (i.e. less than 150 mg) of anifrolumab or a functional variant thereof. The drug composition in the injection device can comprise about 120 mg of anifrolumab or a functional variant thereof. The drug composition in the injection device can comprise 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the drug composition in the injection device can be 150 mg / ml. The volume of the drug composition in the injection device can be at least about 0.8 ml. The volume of the drug composition can be about 0.8 ml.

[0072] The drug composition in the injection device can comprise about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine, and uncharged excipients. The drug composition in the injection device can comprise 150 mg / mL of anifrolumab or a functional variant thereof. The drug composition in the injection device can comprise 50 mM lysine HC1. The drug composition can comprise 130 mM trehalose dihydrate. The drug composition in the injection device can comprise about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine, and uncharged excipients. The drug composition in the injection device can comprise 150 mg / mL of anifrolumab or a functional variant thereof. The drug composition can comprise 50 mM lysine HC1. The drug composition in the injection device can comprise 130 mM trehalose dihydrate. The drug composition in the injection device can comprise 0.05% polysorbate 80. The drug composition in the injection device can comprise 25 mM histidine / histidine HC1. The drug composition in the injection device can comprise 150 mg / mL of anifrolumab or a functional variant thereof, 50 mM lysine HC1, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HC1.

[0073] In another aspect, the present application relates to an injection device comprising a unit dose. The unit dose can comprise > 105 mg (i.e. at least 105 mg) and < 150 mg (i.e. less than 150 mg) of anifrolumab or a functional variant thereof. The unit dose can comprise < 135 mg (i.e. 135 mg or less) of anifrolumab or a functional variant thereof. The unit dose can comprise about 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device can comprise 120 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of > 105 mg and < 150 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of < 135 mg of anifrolumab or a functional variant thereof. The unit dose in the injection device can consist essentially of about 120 mg of anifrolumab or a functional variant thereof. The concentration of anifrolumab or a functional variant thereof in the unit dose in the injection device can be about 150 mg / ml. The volume of the unit dose in the injection device can be less than 1 ml. The unit dose in the injection device can have a volume of about 0.5 ml to about 1 ml. The concentration of the unit dose can be about 0.8 ml. The volume of the unit dose can be 0.8 ml. The unit dose in the injection device can comprise a formulation of about 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine, and uncharged excipients. The unit dose in the injection device can comprise a formulation of 150 mg / ml to 200 mg / ml of anifrolumab or a functional variant thereof, 25 mM to 150 mM lysine, and uncharged excipients. The unit dose comprises a formulation of 25 mM histidine-HCL, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation can have a pH of about 5.9.

[0074] The injection device can be a pre-filled syringe (PFS). The injection device can be an accessory- fitted pre-filled syringe (AFPS). The injection device can be an auto-injector (AI).

[0075] 4.7. Kits

[0076] In another aspect, the present application relates to a kit comprising a unit dose of the present application and instructions for use, wherein the instructions for use include instructions for subcutaneously administering the unit dose to a subject.

[0077] In another aspect, the present application relates to a kit comprising a pharmaceutical composition for use according to the present application, wherein the instructions for use include instructions for subcutaneously administering the pharmaceutical composition to a subject.

[0078] In another aspect, the present application relates to a kit comprising the injection device of any one of the present application and instructions for use, wherein the instructions for use include instructions for use of the injection device to administer a unit dose or a pharmaceutical composition subcutaneously to a subject.

[0079] The kit of the present application can comprise a package, wherein the package is suitable for containing the injection device and the instructions for use. The instructions for use can be attached to the injection device. The instructions for use can include instructions for administration of > 105 mg and < 150 mg anifrolumab or a functional variant thereof. The instructions for use can include instructions for administration of < 135 mg anifrolumab or a functional variant thereof. The instructions for use can include instructions for administration of 120 mg anifrolumab or a functional variant thereof. The instructions for use can include instructions for administration of 120 mg anifrolumab or a functional variant thereof every 4 weeks. The instructions for use can define the subject as having a type I IFN-mediated disease. The instructions can define the subject as having SLE. The instructions can define the subject as having moderate to severe SLE. The instructions for use can be written instructions.

[0080] The instructions for use can specify the injection device, the unit dose, and / or the pharmaceutical composition for use in treating SLE. The instructions for use include instructions for administration of 120 mg anifrolumab or a functional variant thereof every week.

[0081] The instructions for use can specify the injection device, the unit dose, and / or the pharmaceutical composition for use in treating SLE in a subject who is a subject diagnosed with SLE at an age of less than (<) 50 years, and / or a subject who experienced their first SLE manifestation at an age of about 30 years or less.

[0082] 4.8. Formulations

[0083] Anifrolumab or a functional variant thereof can be comprised within a pharmaceutical composition. The pharmaceutical composition can comprise about 150 mg / ml to 200 mg / ml anifrolumab or a functional variant thereof, about 25 mM to 150 mM lysine salt, and an uncharged excipient. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or a functional variant thereof. The pharmaceutical composition can comprise 50 mM lysine HC1. The pharmaceutical composition can comprise 130 mM trehalose dihydrate. The pharmaceutical composition can comprise 0.05% polysorbate 80. The pharmaceutical composition can comprise 25 mM histidine / histidine HC1. The pharmaceutical composition can comprise 150 mg / mL anifrolumab or a functional variant thereof, 50 mM lysine HC1, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HC1.

[0084] Stable formulations suitable for administration to a subject and comprising anifrolumab are described in detail in U.S. Patent 10125195 B1, which is incorporated herein in its entirety.

[0085] 5. Definitions

[0086] 5.1. Inhibitors of Type I IFN signaling

[0087] 5.1.1. Anifroilumab

[0088] Anifrolumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibody (mAb) directed against subunit 1 of the type I interferon receptor (IFNAR1). Anifrolumab downregulates IFNAR signaling and inhibits expression of IFN-inducible genes. Disclosure related to anifrolumab can be found in U.S. Patent No. 7662381 and U.S. Patent No. 9988459, which are incorporated by reference herein in their entirety. Sequence information for anifrolumab is provided in Error! Reference source not found.

[0089] Table 1: Anifroilumab sequences

[0090]

[0091]

[0092] Anifrolumab is an immunoglobulin comprising the HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively (or functional variants thereof); and the LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively (or functional variants thereof). Anifrolumab is an immunoglobulin comprising the VH of SEQ ID NO: 1 and the VL of SEQ ID NO: 2.

[0093] The constant region of anifrolumab has been modified such that anifrolumab exhibits reduced affinity for at least one Fc ligand compared to the unmodified antibody. Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that comprises an amino acid substitution of L234F in the Fc region, as numbered in the EU as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is a modified IgG class monoclonal antibody specific for IFNAR1 that comprises an amino acid substitution of L234F, L235E, and / or P331S in the Fc region, as numbered in the EU as set forth in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.). Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9. Anifrolumab is an antibody comprising a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a light chain constant region of SEQ ID NO: 9 and a heavy chain constant region of SEQ ID NO: 10. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11. Anifrolumab is an antibody comprising a light chain of SEQ ID NO: 12. Anifrolumab is an antibody comprising a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0094] A functional variant of anifrolumab is a sequence variant that performs the same function as anifrolumab. A functional variant of anifrolumab is a variant that binds to the same target as anifrolumab and has the same effector function as anifrolumab. Functional anifrolumab variants include antigen-binding fragments of anifrolumab and antibodies and immunoglobulin derivatives of anifrolumab. Functional variants include biosimilars and interchangeable products. The terms biosimilar and interchangeable product are defined by the FDA and EMA. The term biosimilar refers to a biological product that has a high degree of structural similarity, both in structure and in pharmacokinetics, safety, and efficacy, to an approved (e.g., FDA-approved) biological product (reference product, e.g., anifrolumab) and that does not have clinically meaningful differences from the reference product. The presence of clinically meaningful differences of a biosimilar can be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies, as well as in the assessment of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical result as the reference product in any given patient.

[0095] For example, a variant of the reference (anifrolumab) antibody can comprise: a heavy chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 3; a heavy chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 4; a heavy chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 5; a light chain CDR1 having at most 2 amino acid differences when compared to SEQ ID NO: 6; a light chain CDR2 having at most 2 amino acid differences when compared to SEQ ID NO: 7; and a light chain CDR3 having at most 2 amino acid differences when compared to SEQ ID NO: 8; wherein the variant antibody binds to the target of anifrolumab (e.g., IFNAR) and preferably binds with the same affinity.

[0096] A variant of the reference (anifrolumab) antibody can comprise: a heavy chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO: 3; a heavy chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO: 4; a heavy chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 5; a light chain CDR1 having at most 1 amino acid difference when compared to SEQ ID NO: 6; a light chain CDR2 having at most 1 amino acid difference when compared to SEQ ID NO: 7; and a light chain CDR3 having at most 1 amino acid difference when compared to SEQ ID NO: 8; wherein the variant antibody optionally binds to the target of anifrolumab (e.g., IFNAR) with the same affinity.

[0097] A variant antibody can have at most 5, 4, or 3 amino acid differences in total across its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there are at most 2 (optionally at most 1) amino acid differences per CDR. A variant antibody can have at most 2 (optionally at most 1) amino acid differences in total across its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there are at most 2 amino acid differences per CDR. A variant antibody can have at most 2 (optionally at most 1) amino acid differences in total across its CDRs when compared to the corresponding reference (anifrolumab) antibody, provided that there are at most 1 amino acid difference per CDR.

[0098] A variant antibody can comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has up to 14 amino acid differences when compared to the heavy chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); the light chain has up to 14 amino acid differences when compared to the light chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g., IFNAR), and preferably binds with the same affinity.

[0099] A variant antibody can comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has up to 14 amino acid differences when compared to the heavy chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); the light chain has up to 14 amino acid differences when compared to the light chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g., IFNAR), and preferably binds with the same affinity.

[0100] A variant antibody can comprise a variable heavy chain and a variable light chain as described herein, wherein: the heavy chain has up to 14 amino acid differences when compared to the heavy chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); the light chain has up to 14 amino acid differences when compared to the light chain sequences herein (up to 2 amino acid differences in each CDR and up to 2 amino acid differences in each framework region); wherein the variant antibody binds to the same target antigen as the reference (anifrolumab) antibody (e.g., IFNAR), and preferably binds with the same affinity.

[0101] Functional variants of anifrolumab include antibodies described in WO 2018 / 023976 Al, which is incorporated by reference herein (Table 2).

[0102] Table 2: Anti-IFNAR antibody sequences

[0103]

[0104] Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 13. Functional variants include antibodies comprising the VH amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 14. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies comprising the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0105] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 13. The anti-IFNAR antibody can comprise the VH amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 14. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody can comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. The anti-IFNAR antibody can comprise the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody can comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. The anti-IFNAR antibody can comprise the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0106] 5.1.2. QX006N

[0107] Functional variants of anifrolumab and anti-IFNAR antibodies include the QX006N antibody described in CN 11327807, which is incorporated by reference herein.

[0108] Table 3: QX006N antibody sequences

[0109]

[0110] The IFNAR inhibitor can be a monoclonal antibody comprising the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody can comprise the VL amino acid sequence of SEQ ID NO: 18.

[0111] QX006N is an immunoglobulin comprising the HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively (or functional variants thereof); the LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively (or functional variants thereof). QX006N is an immunoglobulin comprising the VH amino acid sequence of SEQ ID NO: 17 and the VL amino acid sequence of SEQ ID NO: 18.

[0112] 5.1.3. Sifalimumab

[0113] Sifalimumab (MEDI-545) is a fully human immunoglobulin Gl kappa monoclonal antibody that binds to and neutralizes most IFN-alpha subtypes [9]. Sifalimumab is described in U.S. Patent 7,741,449, which is incorporated by reference herein in its entirety. The efficacy and safety of sifalimumab were evaluated in a Phase lib, randomized, double-blind, placebo-controlled study (NCT01283139) in adults with moderate to severe active systemic lupus erythematosus (SLE). Four hundred thirty-one patients were randomized and received intravenous sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo monthly in addition to standard of care medications. The primary efficacy endpoint was the percentage of patients achieving an SLE Responder Index response at Week 52. A greater percentage of patients receiving sifalimumab (all doses) achieved the primary endpoint compared with placebo (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg, 59.8%).

[0114] 5.1.4. Inhibitors of Type I IFN signaling in the clinic

[0115] Anifrolumab safety has been evaluated in 8 blinded or open-label intravenous (IV) and subcutaneous (SC) studies: 6 studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), 1 study in patients with systemic sclerosis (SSc) (Study MI-CP180), and 1 study in healthy volunteers (Study 06) (Table 4). Of these studies, two (Study 08 and 06) employed SC anifrolumab administration. Two studies are ongoing: 1 study in SLE patients (Study 09) and 1 study in patients with lupus nephritis (LN) (Study 07).

[0116] Table 4: Clinical studies

[0117]

[0118]

[0119] Study MI-CP151 is described in more detail in Higgs et al. 2013

[11] . Study 1013 is described in more detail in Furie et al. 2017

[12] , which is incorporated by reference herein in its entirety. Study 04 is described in more detail in Furie et al. 2019

[13] , which is incorporated by reference herein in its entirety. Results of Study 05 are presented in Morand et al. 2020

[14] , which is incorporated by reference herein in its entirety. A complete overview of evidence of intravenous anifrolumab clinical efficacy in SLE is provided in Tanaka et al., 2020

[15] , which is incorporated by reference herein in its entirety.

[0120] 5.2. Formulations

[0121] Stable formulations suitable for administration to a subject and comprising anifrolumab are described in detail in U.S. Patent 10125195 B1, which is incorporated herein in its entirety.

[0122] The following examples are illustrative of specific embodiments of the present disclosure and various uses thereof. They are shown for illustrative purposes only and should not be construed as limiting the scope of the present disclosure in any way.

[0123] 5.3. Steroids

[0124] Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone. Examples of equivalent doses of oral prednisone are shown in Table 5.

[0125] Table 5: Examples of equivalent doses of oral prednisone

[0126]

[0127] 5.4. Dosage forms

[0128] A unit dose (also referred to as unit dosage, pharmaceutical unit dose, or pharmaceutical unit dosage) is a dose formed by a single unit. The unit dose (unit dosage) is suitable for administration to a subject in a single administration step. The unit dose (unit dosage) can be packaged in a single unit container, for example, packaged in a single-use pre-filled syringe or auto-injector. The advantage provided by unit doses is that they can be ordered, packaged, handled and administered as single dose units containing a predetermined amount of drug. Unit doses reduce administration errors and reduce waste. Unit doses suitable for use of anifrolumab in the treatment of SLE are described in WO2022223714 Al [8].

[0129] 5.5. Delivery devices

[0130] In addition to providing subcutaneous administration of the antibody, the ability for self-administration (e.g., for home use) can be further enhanced via an accessory-borne pre-filled syringe (APFS), an auto-injector (AI), or a combination thereof, for subcutaneous administration. Such devices have been found to be well-tolerated and reliable for administering subcutaneous doses of antibodies and provide a further option for optimizing patient care. Indeed, such devices can alleviate the burden of frequent clinical visits for patients. An example of a suitable APFS device is described in Ferguson et al.

[16] , which is incorporated herein by reference in its entirety.

[0131] The doses elucidated by the present inventors provide additional advantages in the context of APFS administration, as APFS devices typically administer a maximum volume of 1 ml. Doses in the range of >105mg to <155mg can easily be accommodated by a volume of about 0.8 ml, such that the doses of the present invention are uniquely suitable for APFS and AI administration. By comparison, due to the viscosity of anifrolumab, larger doses (in particular doses of >150mg) would need to be administered in a volume of >1 ml, requiring at least two SC injections, which is inconvenient for the patient, and would require multiple pre-filled devices.

[0132] The delivery device can be a single-use disposable system designed to enable manual, SC administration of the dose.

[0133] 5.6. Endpoints

[0134] 5.6.1. Patient reported outcomes

[0135] Physician's global assessment (PGA and MDGA) refers to assessments in which the physician evaluates the subject's status of psoriatic arthritis (PsA) with the aid of a visual analog scale (VAS). The subject is assessed in terms of their current arthritic condition. The VAS is defined in terms of descriptive words ranging from "very good" to "very bad".

[0136] 5.6.2. BILAG-2004 (British Isles Lupus Assessment Group-2004)

[0137] BILAG-2004 is a transformational index with 9 organ systems (general, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, eye, kidney, and blood) that captures the severity of change in clinical manifestations. It has ordinal scales by design and no overall score; rather it records disease activity across different organ systems at a glance by comparing the just past 4 weeks with their previous 4 weeks. It is based on the principle of physician's therapeutic intent and classifies disease activity into 5 different levels from A to E:

[0138] • Grade A indicates very active disease requiring immunosuppressive drugs and / or prednisone doses of >20 mg / day or equivalent

[0139] • Grade B indicates moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressives, antimalarials, or NSAIDs

[0140] • Grade C indicates mild stable disease

[0141] • Grade D implies no disease activity but the system has been affected previously

[0142] • Grade E indicates no current or past disease activity

[0143] Although BILAG-2004 was developed based on the principle of therapeutic intent, treatment is independent of the score index. Only the presence of active manifestations affects the score.

[0144] Improvement in the mucocutaneous or musculoskeletal organ systems as defined by BILAG represents a rash or arthritis, respectively.

[0145] 5.6.3. BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment)

[0146] BICLA is a composite index originally derived from expert consensus of disease activity indices. BICLA response is defined as (1) at least one grade improvement in baseline BILAG score in all body systems with moderate or severe disease activity at entry (e.g., all A (severe disease) scores decreased to B (moderate), C (mild), or D (no activity), and all B scores decreased to C or D); (2) no new BILAG A or more than one new BILAG B score; (3) no worsening in total SLEDAI score from baseline; (4) no significant deterioration in physician global assessment (<10%); and (5) no treatment failure (initiation of non-protocol treatment).

[0147] In particular, a subject is a BICLA responder if the following criteria are met:

[0148] a) all baseline BILAG-2004 A decreased to B / C / D and baseline BILAG-2004 B decreased to C / D, and no BILAG-2004 worsening in other organ systems as defined by 1 new BILAG-2004 A or more than 1 new BILAG-2004 B item;

[0149] b) no worsening in SLEDAI-2K from baseline, worsening defined as an increase >0 points in SLEDAI-2K from baseline;

[0150] c) no worsening in subject's lupus disease activity from baseline, worsening defined by an increase >0.30 points in 3-point PGA VAS;

[0151] d) no discontinuation of study product or use of restricted medications beyond protocol-allowed thresholds prior to assessment

[0152] 5.6.4. SRI (Systemic Lupus Erythematosus Responder Index >4)

[0153] A subject achieves SRI (4) if all the following criteria are met:

[0154] • a decrease >4 points in SLEDAI-2K from baseline;

[0155] • no new organ system affected as defined by 1 or more BILAG-2004 A or 2 or more BILAG-2004 B items

[0156] • use of BILAG-2004 B items compared to baseline;

[0157] • no worsening in subject's lupus disease activity from baseline, worsening defined by an increase >0.30 points in 3-point PGA VAS.

[0158] SRI (X) (X = 5, 6, 7, or 8) is defined by the proportion of subjects meeting the following criteria:

[0159] • Reduction of > X points in SLEDAI-2K from baseline;

[0160] • No new organ systems affected as defined by 1 or more BILAG-2004 A or 2 or more BILAG-2004 B

[0161] • BILAG-2004 B item from baseline using BILAG-2004;

[0162] • No worsening of subject's lupus disease activity from baseline,

[0163] • Worsening defined by an increase of > 0.30 points in 3-point PGA VAS

[0164] 5.6.5. SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000)

[0165] The SLEDAI-2K disease activity index consists of a series of organ manifestations, each of which is defined. The certified investigator or designee physician will complete the SLEDAI-2K assessment and determine whether each manifestation was "present" or "not present" in the most recent 4 weeks. The assessment also includes collection of blood and urine to assess the laboratory categories of SLEDAI-2K.

[0166] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted tool in which descriptors are multiplied by a "weight" specific to the organ. For example, the kidney descriptors are multiplied by 4 and the central nervous system descriptors are multiplied by 8, and these weighted organ manifestations are summed to a final score. The SLEDAI-2K score ranges from 0 to 105 points, with 0 points indicating inactive disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity. The SLEDAI-2K calculated using a 30-day time frame prior to the visit has been shown to be similar to the SLEDAI-2K with a 10-day window

[17] .

[0167] Resolution of rash as defined by SLEDAI-2K is defined as those with a rash score > 2 at baseline with a score of 0 at Week 52.

[0168] 5.7. Systemic lupus erythematosus

[0169] Multiple lines of evidence indicate a role for type I interferons (IFNs) in the pathogenesis of SLE:

[0170] • Genetic polymorphisms associated with type I IFNs are associated with susceptibility to SLE [18-20].

[0171] • High IFN-a levels and type I IFN activity have been reported in SLE [21, 22].

[0172] • In approximately 60% of SLE patients, an increase in messenger ribonucleic acid (mRNA) levels of transcripts induced by type I IFN (type I interferon signature) in peripheral blood mononuclear cells and whole blood is prominent and associated with higher disease activity [23-28].

[0173] • Transcripts induced by type I IFN are the most overexpressed transcripts in SLE

[29] .

[0174] • IFN-induced proteins are increased in SLE patients [30-32].

[0175] • Overexpression of type I IFN, type I IFN signature, and IFN-induced proteins has been associated with higher disease activity and organ system involvement in SLE.

[0176] Patients with high anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody titers, lupus nephritis, and progressive skin rash have high type I IFN serum levels

[21] . Furthermore, patients with acute skin involvement tend to have elevated IFN in blood and skin

[22] . Skin biopsies of SLE patients also show an increase in type I IFN signature

[29] . IFN-induced proteins are increased in patients with active central nervous system (CNS) symptoms

[32] .

[0177] Immune complexes containing SLE autoantibodies, such as anti-dsDNA or anti-ribonucleoprotein (anti-RNP) antibodies, can activate type I IFN production

[21] . After internalization through Fc receptors, immune complexes containing autoantibodies bind endosomal toll-like receptor 7 and toll-like receptor 9, stimulating production of type I IFN. Type I IFN stimulates maturation of monocyte-derived dendritic cells, promoting loss of tolerance and generation of autoreactive T and B cells, autoantibody production, immune complex formation, and further production of type I IFN, leading to an autoimmune self-sustaining cycle.

[0178] Anifrolumab is a human immunoglobulin Gl kappa (IgGl kappa) monoclonal antibody (mAb) directed against type I interferon receptor (IFNAR1). Anifrolumab inhibits the binding of type I IFNs to IFNAR and inhibits the biological activity of all type I IFNs. Two phase 3 studies (TULIP-1 and TULIP-2) and one phase 2b study (MUSE) have provided substantial evidence for the efficacy and safety of anifrolumab in moderate-to-severe active SLE. In all three studies, treatment with anifrolumab was associated with a treatment difference of >16% in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response rate at week 52 compared with placebo. The combined data across a range of other clinically significant endpoints (e.g., oral corticosteroid reduction, cutaneous disease improvement, flare reduction) further support the efficacy of anifrolumab for the treatment of SLE

[33] .

[0179] 5.8. Type I IFN gene signature (IFNGS)

[0180] Type I IFNs are thought to play an important role in SLE pathogenesis, and anifrolumab targets inhibition of this pathway. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether a subject’s disease is driven by type I IFN activation. However, direct measurement of type I IFNs remains a challenge. Therefore, a transcript-based signature was developed to assess the impact of overexpression of the target proteins on a specific set of mRNA markers. Expression of these markers is readily detectable in whole blood and is demonstrated to correlate with expression in diseased tissues, such as skin of SLE. The bimodal distribution of transcriptional scores in SLE subjects supports the definition of IFN test high and low subgroups. The type I IFN test is described in WO2011028933 Al, which is incorporated by reference in its entirety. The type I IFN gene signature can be used to identify whether a subject is a type I IFN gene signature (IFNGS) test high patient or an IFNGS test low patient. The IFNGS test measures the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood of a subject compared to 3 reference genes 18S, ACTB, and GAPDH. The test result is a score compared to a pre-established cutoff that divides patients into 2 groups with low or high levels of IFN inducible gene expression.

[0181] Expression of genes can be measured by RT-PCR. Suitable primers and probes for detection of the genes can be found in WO2011028933. A suitable kit for measuring gene expression for the IFNGS test is QIAGEN therascreen ®The IFIGx RGQ RT-PCR kit (IFIGx kit) was used as described in Brohawn et al.

[34] , which is incorporated by reference in its entirety. The Type I IFN gene signature test measures mRNA expression of 4 Type I IFN inducible genes (IFI27, IFI44, IFI44L, and RSAD2) relative to 3 housekeeping genes (ACTB, 18S, and GAPDH).

[0182] The Type I IFN GS test can be performed at a designated central laboratory using the QIAGEN therascreen IFN inducible gene expression (IFIGx) Rotor-Gene Q (RGQ) Reverse Transcriptase PCR (RT-PCR) system. The expression system consists of a collection tube and

[0183] The above RNA isolation kit, and the therascreen IFIGx RGQ RT-PCR kit for use with the RGQ molecular diagnostic platform with IFIGx software, make up the IFIGx kit. The IFIGx kit measures the expression of four Type I IFN inducible genes (IFI27, IFI44, IFI44L, and RSAD2) relative to three housekeeping genes (ACTB, 18S, and GAPDH) and produces a qualitative diagnostic score as positive or negative. Results are expressed as a score compared to a pre-established cutoff based on ΔCt in the valley of a bimodal distribution and patients are classified into one of two groups representing low or high IFIGx

[35] (Table 1). Figure 1

[0184] Analytical validation of the four-gene test as the IFIGx measurement has been reported and is in two phase III studies of anifrolumab for the treatment of SLE (NCT02446899 and NCT02446912)

[36] . SLE patients presenting with heterogeneous disease activity and symptoms are often stratified by low or high levels of IFIGx [37, 38].

[0185] 6. Example: Burden of systemic lupus erythematosus in clinical practice: baseline data from the interferon presentation cohort study (SPOCS) 6.1. Introduction

[0186] 6.2. Methods

[0187] SLE is a very heterogeneous disease. Better understanding of the differences between patients can reveal insights into the disease pathogenesis, allow for better targeted treatments, and ultimately will result in improved clinical outcomes.

[0188] ​The SLE Prospective Observational Cohort Study (SPOCS; NCT03189875) was designed to systematically describe the patient journey in terms of clinical characteristics, disease activity and progression, treatment patterns, clinical outcomes, patient-reported health outcomes (PROs), and healthcare resource utilization (HCRU) in patients with moderate-to-severe systemic lupus erythematosus (SLE) according to IFNGS status

[35] . SPOCS is the first real-world study to longitudinally evaluate patients’ IFNGS status. Type I IFN inducible (IFI) gene expression, measured using the IFN gene signature (IFNGS), provides a means to assess activation of the type I IFN pathway in individual patients.

[0189] 6.2.1. Study design and patients

[0190] 6.2.2. Data collection

[0191] SPOCS (NCT03189875) is an international, multicenter, prospective, observational cohort of patients with moderate-to-severe SLE. Patients were enrolled from June 2017 to December 2019, and followed for up to 3 years, with planned biannual study visits ending in November 2022. All treatment was based on patient and treating physician decisions only, and was not influenced by the SPOCS protocol. Demographic, clinical, and laboratory data were collected from patients enrolled in 8 countries in North America (Canada and the United States), Europe (France, Germany, Italy, Spain, United Kingdom), and Australia. The study design was broad in terms of enrollment. To be included in the study, patients had to be >18 years of age and provide written informed consent. All patients met American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria, had a current or past serological profile of antinuclear antibodies (ANA) or anti-double stranded DNA antibodies, received systemic treatment for active SLE for at least 6 months (except for nonsteroidal anti-inflammatory drugs [NSAIDs] and analgesics), and were classified as having moderate-to-severe SLE (modified Systemic Lupus Erythematosus Disease Activity Index 2000 [modified SLEDAI-2K, excluding urine or laboratory results including immunology measures and lupus headache] score >4 or SLEDAI-2K score >6 points). Patients were excluded if they had active severe lupus nephritis, were enrolled in an interventional trial involving study medication, or were unable to complete study measures. Due to slow accrual of eligible patients, the planned sample size of 1500 patients was modified to 900; therefore, in 25% of patients, the endpoint precision estimate of incidence was adjusted to 2.1 (95% confidence interval: 0.30-2.44) using an event rate of interest of 1 event per 100 person-years in the 2-year follow-up.

[0192] SPOCS is conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the International Council for Harmonization Good Clinical Practices, Good Pharmacoepidemiology Practice, and applicable regulations according to the study classification in each country. Written informed consent is provided by all patients enrolled in SPOCS.

[0193] 6.2.3. IFNGS testing

[0194] To understand baseline characteristics and identify any differences in the cohort, data were collected at study entry, defined as the routine visit at which the consent form was signed. Baseline data included patient demographics (e.g., age, sex, and race [American Indian or Alaska Native, Asian, Black or African American, Native American, Native Hawaiian or Other Pacific Islander, White, or Other Race] or ethnicity [Hispanic or Latino, Non-Hispanic or Latino], as allowed by local regulations), body mass index, SLE disease characteristics (including date of first diagnosis, SLEDAI-2K and modified SLEDAI-2K scores), organ system involvement and organ damage according to the SLICC / ACR Damage Index (SDI) score, number and severity of SLE flares (mild / moderate or severe) according to the Systemic Lupus Erythematosus Responder Index (SRI)-4, physician global assessment (PGA) of disease activity, comorbidities, and SLE treatments and concomitant medications. Blood samples were collected to determine baseline IFNGS.

[0195] Statistical analysis

[0196] Blood samples were collected in PAXgene ™ tubes and sent to a central laboratory for processing. The QIAGEN therascreen ® IFN-IFI gene expression Rotor-Gene ® Q reverse transcriptase PCR system determined baseline mRNA expression of 4 type I IFN inducible genes (IFI27, IFI44, IFI44L, and RSAD2) relative to 3 housekeeping genes (ACTB, 18S, and GAPDH) for each patient. This expression score was compared to pre-established cutoffs to classify each patient as high or low IFNGS [29, 39].

[0197] 6.2.4. Patient and public involvement

[0198] Demographics, clinical characteristics, and SLE medications were summarized by the overall SPOCS population, SLEDAI-2K category (<10 vs. >10)

[18] , IFNGS status (high vs. low), and country. Continuous variables were reported as arithmetic mean and standard deviation, median, first and third quartile, and range, as appropriate. Categorical variables were summarized as the number and percentage of patients with non-missing values in each category. Mann-Whitney U test, chi-square test, Kruskal-Wallis test, or Fisher’s exact test were used to compare patient subgroups. All P values were nominal. All calculations and analyses were performed in R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

[0199] 6.3. Results

[0200] No patients or members of the public were involved in the design of this trial.

[0201] 6.3.1. Baseline patient characteristics and demographics

[0202] Table 6: Baseline demographics and patient characteristics of the SPOCS population by SLEDAI-2K and IFNGS category presentation

[0203] Between June 2017 and December 2019, 1050 patients were screened; 823 patients were enrolled from North America (n = 389) and Europe or Australia (n = 434). The majority of enrolled patients [93.2%, 767 / 823] were female, and the mean (SD) age at study entry was 45.3 (13.9) years (Table 6). Overall, 9.1% (71 / 779) of enrolled patients were Asian, 16.4% (128 / 779) were Black, 69.5% (541 / 779) were White, and 5.0% (39 / 779) of patients were identified as a different race. The mean (SD) number of years since SLE diagnosis was 11.1 (9.2) years (Table 7).

[0204] When stratified by baseline disease activity score, 241 patients had SLEDAI-2K > 10 and 343 patients had SLEDAI-2K < 10. Patients with SLEDAI-2K > 10 were younger than those with SLEDAI-2K < 10 (mean [SD]: 42.8 [13.7] vs 46.6 [14.2] years; P = 0.001) (Table 6). No difference in mean age of first SLE manifestation was observed between patients with SLEDAI-2K > 10 and < 10. Ethnicity distribution was similar in patients with SLEDAI-2K > 10 and < 10 (white: 69.4% (159 / 229) vs 67.6% (217 / 321), black: 17.0% (39 / 229) vs 16.5% (53 / 321), and Asian: 8.7% (20 / 229) vs 10.6% (34 / 321); P = 0.89). At baseline, the mean [SD] duration of SLE was shorter in patients with SLEDAI-2K > 10 than in those with SLEDAI-2K < 10 (10.4 [8.6] vs 12.4 [9.6] years; P = 0.012) (Table 7).

[0205] Figure 4

[0206]

[0207] All P values are nominal; no adjustment for multiplicity has been made. Subgroups were not included in the total population n due to missing data.

[0208] BMI, body mass index; SD, standard deviation; IFNGS, type I interferon gene signature; IQR, interquartile range; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SPOCS, Systemic Lupus Erythematosus Prospective Observational Cohort Study.

[0209] Approximately two-thirds of the patients were classified as high IFNGS, while one-third were classified as low IFNGS (70.6% [522 / 739] vs. 29.4% [217 / 739]) (Table 6). The proportion of patients in each IFNGS category differed between ethnic groups (P<0.001); the percentages of Asian, Black, and White patients in the high IFNGS group were 10.4%, 19.9%, and 64.4%, respectively, while the percentages in the low IFNGS group were 4.7%, 7.0%, and 84.0%, respectively. Within the Asian group, 83.3% (50 / 60) of patients had high IFNGS and 16.7% (10 / 60) had low IFNGS; within the Black group, 86.5% (96 / 111) of patients had high IFNGS and 13.5% (15 / 111) had low IFNGS; and within the White group, 63.5% (311 / 490) of patients had high IFNGS and 36.5% (179 / 490) had low IFNGS. At baseline, the high IFNGS group was younger (mean [SD] age: 43.1 [13.6] years vs. 50.7 [12.9] years; P<0.001) (Table 6). Compared with the low IFNGS group, a greater percentage of patients in the high IFNGS group were <30 years old at SLE diagnosis (50.5% vs. 22.7%) (Table 7). Patients in the high-IFNGS group were younger at first presentation of SLE than those in the low-IFNGS group (mean [SD]: 30.0 [12.7] years vs. 36.8 [14.6] years; P < 0.001) (Table 7), with 53.7% of patients being < 30 years old at first presentation, compared to 32.3% in the low-IFNGS group. Figure 4 Surprisingly, while approximately 50% of patients diagnosed in their 50s and older had low IFNGS, less than 20% of patients diagnosed in their 29s and younger had low IFNGS. 6.3.2. Baseline SLE disease activity and damage ).

[0210] Figure 5A

[0211] In the entire SpOCS cohort, patients most commonly had musculoskeletal involvement (75.3%), dermal involvement (67.6%), or immune system involvement at baseline (66.4%). Table 7: Clinical characteristics of the SPOCS population at baseline by SLEDAI-2K and IFNGS category presentation The mean (SD) SLEDAI-2K score was 9.8 (4.6) and the median (interquartile range [IQR]: 25th to 75th percentile) score was 8.0 (6.0–12.0) (Table 7).

[0212] Figure 5B

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] All P values are nominal; no adjustment for multiplicity has been made. Subgroups were not included in the total population n due to missing data.

[0219] aModified SLEDAI-2K score defined as SLEDAI-2K assessment score excluding scores attributable to any urine or laboratory results including immunologic measures and lupus headache.

[0220] bSystemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index > 0.

[0221] cAnnualized flare rate was calculated by dividing the number of flares by the follow-up time in days and multiplying by 365.25.

[0222] dWithin 6 months of entering the study.

[0223] ACR, American College of Rheumatology SLE classification criteria; CNS, central nervous system; CVD, cardiovascular disease; ESRD, end-stage renal disease; IFNGS, type I interferon gene signature; IQR, interquartile range; PGA, physician global assessment; SD, standard deviation; SDI, SLICC / ACR Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SLICC, Systemic Lupus International Collaborating Clinics; SPOCS, SLE Prospective Observational Cohort Study.

[0224] The percentage of patients with baseline SLEDAI-2K organ domain involvement was higher in patients with baseline SLEDAI-2K score > 10 than in patients with baseline score < 10 for CNS domain (18.7% vs. 0.9%), kidney domain (32.0% vs. 7.3%), immune domain (83.0% vs. 56.6%), and dermal domain (74.3% vs. 58.3%) ( Figure 2 ).

[0225] On average, modified SLEDAI-2K scores, SLEDAI-2K scores, and the percentage of patients with SLEDAI-2K scores >10 did not differ between high IFNGS patients and low IFNGS patients. There were more patients in the high IFNGS group with blood (12.6% vs. 4.1%), immune (74.4% vs. 45.6%), or dermal (69.7% vs. 62.2%) SLEDAI-2K domain involvement compared to the low IFNGS group (all P<0.05). 6.3.3. Flares Conversely, high IFNGS patients had less CNS (5.8% vs. 11.1%; P=0.012) and musculoskeletal (72.6% vs. 81.6%; P=0.010) involvement than patients in the low IFNGS group. Renal domain involvement was 20.2% in patients in the high IFNGS group compared to 16.3% in the low IFNGS group.

[0226] The mean (SD) SDI score was 1.2 (1.6), and about half of all patients had organ damage (52.4%, 425 / 811) (Table 7). The percentage of patients with organ damage was slightly higher in the low IFNGS group than in the high IFNGS group (57.6% vs. 49.6%; P=0.048).

[0227] Figure 5C

[0228] About half of all patients (54.1%, 445 / 822) had experienced >1 flare in the 6 months prior to the baseline visit (Table 7); organ system involvement was generally similar between patients who had experienced and had not experienced flares 6.3.4. SLE treatment Patients with SLEDAI-2K scores >10 had a higher mean [SD] annual flare rate in the year prior to enrollment (1.9 [2.4] vs. 1.3 [2.0], P=0.005) and severe flares (as assessed by physicians) were more common (12.9% vs. 5.3%; P=0.001) than patients with SLEDAI-2K scores <10 at baseline. Flares did not vary by IFNGS status, however; the annual flare rate or flare severity (all P=NS) and percentage (high vs. low IFNGS: 55.0%, 287 / 522 vs. 52.3%, 113 / 216; P=0.51) did not differ between the high and low IFNGS groups in patients who experienced >1 flare in the 6 months prior to the baseline visit.

[0229] Table 8: SLE medications of the SPOCS population at baseline by SLEDAI-2K and IFNGS category presentation

[0230] At baseline, 80.4% (662 / 823) of patients were receiving an antimalarial (53.8% (443 / 823) were receiving an immunosuppressant, and 20.2% (166 / 823) were receiving a biologic (Table 3). Sixty-one percent (506 / 823) of patients had used or were using oral glucocorticoids in the past year. Among patients receiving oral glucocorticoids, the mean cumulative and daily doses were similar, irrespective of SLEDAI-2K or IFNGS group.

[0231] There were no differences in any other baseline therapies between SLEDAI-2K groups at baseline (all P > 0.5) (Table 8). More patients classified as high IFNGS were receiving immunosuppressants (58.0% [303 / 522] vs 43.8% [95 / 217]; P < 0.001) and oral glucocorticoids (67.8% [354 / 522] vs 49.3% [107 / 217]; P < 0.001) relative to low IFNGS, and fewer patients in the high IFNGS group were receiving antimalarials (78.0% [407 / 522] vs 87.1% [189 / 217]; P = 0.004) relative to low IFNGS. A higher percentage of patients in the high IFNGS group were receiving immunosuppressants relative to low IFNGS, irrespective of concurrent antimalarial use (Table 9).

[0232] Table 9: Baseline immunosuppressant and antimalarial use by IFNGS status presentation

[0233]

[0234]

[0235] All P values are nominal; no adjustment for multiplicity has been made. Subgroups were not included in the total population n due to missing data.

[0236] a Cytotoxic or immunosuppressive agents, including cyclophosphamide, methotrexate, mycophenolate mofetil / mycophenolic acid (MMF / MPA), azathioprine, tacrolimus, mizoribine, leflunomide, or cyclosporine; b Belimumab or rituximab; c Number of patients with at least one ongoing glucocorticoid prescription or at least one prescription recorded in the previous year; d Sum of all glucocorticoids received in the past 365 days, standardized to g / year; e Cumulative glucocorticoids were divided by 365 to convert to daily dose and patients were grouped into daily dose groups.

[0237] AM, antimalarial; biologic, belimumab or rituximab; IFNGS, type I interferon gene signature; IQR, interquartile range; SD, standard deviation; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SLICC, Systemic Lupus International Collaborating Clinics; SPOCS, SLE Prospective Observational Cohort Study.

[0238] 6.3.5. Characteristics by country presentation

[0239]

[0240] a cytotoxic or immunosuppressive agent, including cyclophosphamide, methotrexate, mycophenolate mofetil / mycophenolic acid, azathioprine, tacrolimus, mizoribine, leflunomide, or cyclosporine.

[0241] IFNGS, type I interferon gene signature.

[0242] Figure 3

[0243] The percentage of patients with high IFNGS ranged from 64% to 83% across countries ( Table 10: Baseline demographics and patient characteristics of the SPOCS population by country Overall baseline data presented by country are provided in the online supplement (Tables 10-12).

[0244] Table 11: Baseline demographics and patient characteristics of the SPOCS population by country

[0245]

[0246]

[0247] All P values are nominal; no adjustment for multiplicity has been made. Subgroups were not included in the total population n due to missing data.

[0248] BMI, body mass index; IQR, interquartile range; SD, standard deviation; SLE, systemic lupus erythematosus; SPOCS, SLE Prospective Observational Cohort Study; UK, United Kingdom; USA, United States of America.

[0249] Table 12: Clinical characteristics of the SPOCS population at baseline by country

[0250]

[0251]

[0252]

[0253]

[0254] All P values are nominal; multiple testing has not been adjusted. Subgroups are not included in the overall population n due to missing data.

[0255] a Modified SLEDAI-2K score defined as SLEDAI-2K assessment score excluding scores attributable to any urine or laboratory results including immunologic measures and lupus headache.

[0256] b Annualized flare rate was calculated by dividing the number of flares by the follow-up time in days and multiplying by 365.25.

[0257] c Within 6 months of entering the study.

[0258] ACR, American College of Rheumatology classification criteria for SLE; CVD, cardiovascular disease; ESRD, end-stage renal disease; IQR, interquartile range; SD, standard deviation; SDI, SLICC / ACR Damage Index; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SLICC, Systemic Lupus International Collaborating Clinics; SPOCS, SLE Prospective Observational Cohort Study; UK, United Kingdom; USA, United States of America.

[0259] 6.4. Discussion

[0260]

[0261]

[0262] All P values are nominal; multiple testing has not been adjusted. Subgroups are not included in the overall population n due to missing data.

[0263] a Cytotoxic or immunosuppressive agents including cyclophosphamide, methotrexate, mycophenolate mofetil / mycophenolic acid (MMF / MPA), azathioprine, tacrolimus, mizoribine, leflunomide, or cyclosporine; b Belimumab or rituximab; c Number of patients with at least one ongoing prescription for glucocorticoids or at least one prescription recorded in the previous year; d Sum of all glucocorticoids received in the past 365 days, standardized to g / year; e Cumulative glucocorticoids were converted to daily doses by dividing by 365 and patients were grouped into daily dose groups.

[0264] AM, antimalarial; biologic, belimumab or rituximab; IFNGS, type I interferon gene signature; IQR, interquartile range; SD, standard deviation; SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SLICC, Systemic Lupus International Collaborating Clinics; SPOCS, SLE Prospective Observational Cohort Study.

[0265] References

[0266] SPOCS is a prospective observational study designed to systematically describe the patient journey in terms of clinical outcomes over time in a large real-world patient cohort with moderate to severe SLE. Overall, SPOCS identified a substantial clinical burden in a broadly representative group of moderate to severe SLE patients in a real-world setting; the mean SLE duration in SPOCS patients was 11 years, with about half experiencing at least 1 flare in the 6 months prior to study enrollment and over half having evidence of organ damage at baseline. In addition, the inventors characterized patients with high disease activity and elevated IFN signaling based on high IFNGS status to gain insight into two patient subgroups with higher medical need.

[0267] Patients with higher SLE disease activity tend to experience greater clinical, social, and economic burden than patients with low disease activity. In the SPOCS SLE cohort, approximately 41% of patients had high disease activity at baseline based on SLEDAI-2K score > 10. Patients with SLEDAI-2K > 10 were younger and had shorter SLE duration than patients with SLEDAI-2K < 10. At baseline, the percentage of patients with organ-specific manifestations in the immune, cutaneous mucous membrane, kidney, vascular, blood, and serosal systems was significantly higher in the SLEDAI-2K > 10 group compared to the SLEDAI < 10 group. Consistent with other real-world studies, SPOCS patients with higher baseline SLEDAI-2K scores (> 10) experienced more flares and more severe flares than patients with lower baseline scores. There were no differences in treatment between the baseline SLEDAI-2K groups, which will facilitate examination of the impact of treatment in these two groups longitudinally in the study.

[0268] SPOCS is the first real-world study to evaluate IFNGS levels in patients and found that baseline IFNGS status was associated with differences in patient characteristics. Patients in the high IFNGS group were younger at the time of first manifestation of SLE than patients in the low IFNGS group, with twice as many patients in the high IFNGS group being under 30 years of age at the time of SLE diagnosis as in the low IFNGS group. Conversely, the proportion of patients in the low IFNGS group who had "late-onset" SLE (i.e., patients who were diagnosed with SLE at > 50 years of age) was twice as high. Age of onset, referred to here as "age at SLE diagnosis," has been associated with differences in clinical outcomes and disease progression. For example, late-onset SLE less frequently presents with organ-specific manifestations and tends to be more indolent. This is consistent with the pattern observed in this cohort, as high IFNGS patients were more likely than low IFNGS patients to have blood, immune, and dermal involvement. In our real-world study, we identified less musculoskeletal involvement in high IFNGS patients compared to low IFNGS patients; in a clinical trial setting, similar findings were identified in high IFNGS patients with moderate to severe SLE compared to low IFNGS patients. In our study, according to the SDI, slightly more low IFNGS patients had organ damage compared to high IFNGS patients, which can be due to the older age of low IFNGS patients, as evidenced by their more frequent comorbidities. There were more patients in the high IFNGS group than in the low IFNGS group who received immunosuppressants and / or oral glucocorticoids, likely due to differences in disease activity and manifestations at baseline.

[0269] Notably, the relative proportion of high IFNGS to low IFNGS patients was higher in black and Asian patients compared to white patients, supporting the findings in other moderate to severe SLE populations. Three of the four genes included in the SPOCS IFNGS assay (IFI27, IFI44L, and RSAD2) have been associated with African ancestry; in the same meta-analysis (which adjusted for the presence of LN and HCQ use), only IFI27 expression was associated with disease activity.

[0270] SPOCS is a prospective study designed to systematically describe the patient journey in clinical practice for patients enrolled from multiple centers in a range of countries. The study was designed to broadly represent the moderate to severe SLE population. Unlike many real-world studies related to SLE that rely on existing electronic health records in insurance claims databases, this study began with the collection of very detailed baseline data, followed by longitudinal collection according to the same procedures.

[0271] ​

[0272] All publications mentioned in this specification are herein incorporated by reference in their entirety.

[0273] [1] E. Lever, M. R. Alves, and D. A. Isenberg, Pharmacogenomics Pers. Med. 13, 39 (2020).

[0274] [2] G. J. Pons-Estel et al., Semin. Arthritis Rheum. 39, 257 (2010).

[0275] [3] D. P. McCauliffe, Semin. Cutan. Med. Surg. 20, 14 (2001).

[0276] [4] L. Uva et al., Autoimmune Dis. 2012, 834291 (2012).

[0277] [5] A. S. Zayat et al., Rheumatol. Oxf. Engl. 55, 485 (2016).

[0278] [6] C. Sa et al., Rheumatology (Oxford, England) 48, (2009).

[0279] [7] I. B. Murimi-Worstell et al., BMJ Open 10, e031850 (2020).

[0280] [8] C. LINDHOLM et al., WO2022223714A1 (27 October 2022).

[0281] [9] M. Khamashta et al., Ann. Rheum. Dis. 75, 1909 (2016).

[0282]

[10] R. Tummala et al., Lupus Sci. Med. 5, e000252 (2018).

[0283]

[11] B. W. Higgs et al., Ann. Rheum. Dis. 73, 256 (2014).

[0284]

[12] R. Furie et al., Arthritis Rheumatol. Hoboken Nj 69, 376 (2017).

[0285]

[13] R. A. Furie et al., Lancet Rheumatol. 1, e208 (2019).

[0286]

[14] E. F. Morand et al., N. Engl. J. Med. 382, 211 (2020).

[0287]

[15] Y. Tanaka and R. Tummala, Mod. Rheumatol. 0, 1 (2020).

[0288]

[16] G. T. Ferguson et al., J. Asthma Allergy 11, 63 (2018).

[0289]

[17] Z. Touma, M. Urowitz, and D. Gladman, Lupus 19, 49 (2010).

[0290]

[18] L. A. Criswell, Bull. NYU Hosp. Jt. Dis. 66, 176 (2008).

[0291]

[19] S. Sigurdsson et al., Hum. Mol. Genet. 17, 872 (2008).

[0292]

[20] S. Sigurdsson et al., Hum. Mol. Genet. 17, 2868 (2008).

[0293]

[21] A. A. Bengtsson et al., Lupus 9, 664 (2000).

[0294]

[22] M. C. Dall’era et al., Ann. Rheum. Dis. 64, 1692 (2005).

[0295]

[23] E. C. Baechler et al., Proc. Natl. Acad. Sci. U. S. A. 100, 2610 (2003).

[0296]

[24] L. Bennett et al., J. Exp. Med. 197, 711 (2003).

[0297]

[25] M. K. Crow and J. Wohlgemuth, Arthritis Res. Ther. 5, 279 (2003).

[0298]

[26] X. Feng et al., Arthritis Rheum. 54, 2951 (2006).

[0299]

[27] K. A. Kirou et al., Arthritis Rheum. 50, 3958 (2004).

[0300]

[28] K. A. Kirou et al., Arthritis Rheum. 52, 1491 (2005).

[0301]

[29] Y. Yao et al., Hum. Genomics Proteomics HGP 2009, 374312 (2009).

[0302]

[30] X. Huang et al., Cell. Signal. 20, 112 (2008).

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[31] W. Hylton et al., Ann. Rheum. Dis. 45, 220 (1986).

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[32] H. Okamoto et al., Arthritis Rheum. 50, 3731 (2004).

[0305]

[33] Y. Tanaka and R. Tummala, Mod. Rheumatol. 31, 1 (2021).

[0306]

[34] ACR Meeting Abstracts (n.d.).

[0307]

[35] E. R. Hammond et al., BMJ Open 10, e036563 (2020).

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[36] P. K. Brohawn et al., Ann. Rheum. Dis. 77, 1704 (2018).

[0309]

[37] L. Chiche et al., Arthritis Rheumatol. 66, 1583 (2014).

[0310]

[38] W. P. Kennedy et al., Lupus Sci. Med. 2, e000080 (2015).

[0311]

[39] E. F. Morand et al., N. Engl. J. Med. 382, 211 (2020).

Claims

1. A method of treating systemic lupus erythematosus (SLE) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of Type I IFN signaling, wherein: a) the subject is diagnosed with SLE at an age of less than (<) 50 years, and / or b) the subject experiences their first manifestation of SLE at an age of about 30 years or less.

2. The method of claim 1, wherein the subject is diagnosed with SLE at an age of < 30 years.

3. The method of claim 1 or 2, wherein the subject is diagnosed with SLE at an age of 18 to 29 years.

4. The method of claim 1 or 2, wherein the subject is diagnosed with SLE at an age of < 18 years.

5. The method of any preceding claim, wherein the inhibitor of Type I IFN signaling is a human monoclonal antibody specific for IFNAR1.

6. The method of claim 5, wherein the antibody comprises: (a) a heavy chain variable region complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and (f) a light chain variable region complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO:

8.

7. The method of claim 5-6, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; and (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO:

2.

8. The method of any one of claims 5-7, wherein the antibody comprises an amino acid substitution of L234F in the Fc region, as numbered by the EU index as shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody.

9. The method of any one of claims 5-7, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:

12.

10. The method of any one of claims 5-7, wherein the inhibitor of IFNAR1 is anifrolumab or a functional variant thereof.

11. The method of claim 10, comprising administering to the subject an intravenous dose of anifrolumab or a functional variant thereof. ​ ​ ​ ​ ​ ​ ​ ​ 12. The method of claim 11, wherein the intravenous dose is > 300 mg anifrolumab or functional variant thereof.

13. The method of claim 10 or 11, wherein the intravenous dose is < 1000 mg.

14. The method of claim 13, wherein the intravenous dose is about 300 mg, about 900 mg, or about 1000 mg.

15. The method of any one of claims 11 to 14, wherein the intravenous dose is administered once every four weeks (Q4W).

16. The method of claim 10, comprising administering a subcutaneous dose of anifrolumab or functional variant thereof.

17. The method of claim 16, wherein the subcutaneous dose is > 105 mg and < 150 mg anifrolumab or functional variant thereof.

18. The method of claim 16, wherein the subcutaneous dose is < 135 mg anifrolumab or functional variant thereof.

19. The method of claim 16, wherein the subcutaneous dose is about 120 mg.

20. The method of any one of claims 16 to 19, wherein the subcutaneous dose is administered in a single administration step.

21. The method of any one of claims 16 to 19, wherein the subcutaneous dose is administered at intervals of 6 days to 8 days.

22. The method of any one of claims 16 to 19, wherein the subcutaneous dose is administered once a week.

23. The method of any one of claims 16 to 19, wherein the subcutaneous dose has a volume of about 0.5 ml to about 1 ml.

24. The method of claim 23, wherein the subcutaneous dose has a volume of about 0.8 ml.

25. The method of any preceding claim, wherein the subject is a patient who is high in the pre-treatment Interferon Type I Stimulated Gene Signature (IFNGS) test.

26. The method of any preceding claim, comprising identifying the subject as a patient who is high in the pre-treatment IFNGS test.

27. A pharmaceutical composition for use in the method of any one of claims 1 to 26, wherein the pharmaceutical composition comprises anifrolumab or functional variant thereof.

28. An injection device comprising the pharmaceutical composition of claim 27.

29. The injection device of claim 28, wherein the injection device is a pre-filled syringe (PFS).

30. The injection device of claim 28, wherein the injection device is an accessory- fitted pre-filled syringe (AFPS).

31. The injection device of claim 28, wherein the injection device is an auto-injector.

32. A kit comprising the injection device of any one of claims 29 to 31, and instructions for use.

33. The kit of claim 32, wherein the instructions for use include instructions for use specifying the subject, i.e., a subject diagnosed with SLE at an age of less than (<) 50 years, and / or a subject who experienced their first manifestation of SLE at an age of about 30 years or less.

34. The kit of claim 32, wherein the instructions for use include instructions for use specifying the subject, i.e., a subject diagnosed with SLE at an age of less than (<) 40 years, and / or a subject who experienced their first manifestation of SLE at an age of about 30 years or less.

35. The kit of claim 32, wherein the instructions for use include instructions for use specifying the subject, i.e

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