Treatment for lupus

Abstract

This disclosure relates to methods and compositions for the treatment of SLE. Specifically, this disclosure relates to methods including the administration of type I IFN receptor inhibitors.

Description

[Technical Field]

[0001] background Systemic lupus erythematosus (SLE) is a chronic, multi-organ, autoimmune rheumatic disease of unknown etiology. There is a substantial unmet medical need for the treatment of SLE, particularly in patients with moderate or severe disease. Long-term prognosis remains poor for many patients. SLE remains a disease with a highly variable course and considerable inter-individual variability[1]. More targeted approaches to the treatment of SLE are continuously needed[1].

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

[0003] The difficulty in developing effective treatments for SLE leads to a higher failure rate of therapies in clinical trials in this area compared to therapies for other indications. Thus, the development of novel therapies for the treatment of SLE has proven to be extremely difficult. There are many examples of clinical candidates that showed promise in Phase II but failed to demonstrate efficacy and / or safety in subsequent Phase III studies.

[0004] Type I interferons (IFNs) play a central role in the pathogenesis and disease course of SLE. These cytokines are secreted by innate immune cells to activate the immune system and protect 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 improved SLE disease activity.

[0005] The present invention solves one or more of the above-mentioned problems. [Overview of the Initiative]

[0006] The present invention relates to improved treatments for SLE. In particular, the present invention relates to a method for carrying out the treatment of lupus in a subject who is in need of treatment, comprising administering a type I IFN signaling inhibitor, wherein the subject was diagnosed with SLE at an age of less than 50 years. The present invention also relates to a method for carrying out the treatment of lupus in a subject who is in need of treatment, comprising administering a type I IFN signaling inhibitor, wherein the subject experienced the first signs of SLE at an age of about 30 years or younger.

[0007] This invention is supported, in particular, by data presented herein for the first time, from the SLE Prospective Observation Cohort Study (SPOCS, NCT03189875). SPOCS is the first real-world study to evaluate the IFNGS status of patients over the long term. Surprisingly, data from SPOCS demonstrate that high type I IFN gene signatures (IFNGS) are associated with earlier SLE diagnosis and earlier onset of SLE symptoms. These insights offer opportunities for better targeting of therapies against pathological type I IFN gene signatures in lupus patients, such as aniflorumab. In particular, these data demonstrate that patients with earlier diagnosis and onset of SLE can be targeted with aniflorumab therapy, for example, based on the patient's medical history and without the need for additional trials. [Brief explanation of the drawing]

[0008] [Figure 1] IFN score distribution [Figure 2] Baseline clinical signs of organ system infiltration in the SPOCS population using IFNGS; CNS, central nervous system; IFNGS, type I interferon gene signature; SLE, systemic lupus erythematosus; SPOCS, prospective observational cohort study of SLE. [Figure 3] Country-specific baseline IFNGS status: The number of patients classified as low IFNGS and high IFNGS is presented by country, with countries listed in order from the lowest to the highest percentage of low IFNGS patients. IFNGS, type I interferon gene signature; UK; USA. [Figure 4] Patient subgroups with high and low IFNGS scores, and age at SLE diagnosis. [Figure 5-1] Baseline clinical signs of organ system infiltration in the SPOCS population. Figure 5A: Overall baseline; Figure 5B: SLEDAI-2K; Figure 5C: Flare. CNS, central nervous system; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SPOCS, prospective observational cohort study of SLE. [Figure 5-2] Baseline clinical signs of organ system infiltration in the SPOCS population. Figure 5A: Overall baseline; Figure 5B: SLEDAI-2K; Figure 5C: Flare. CNS, central nervous system; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SPOCS, prospective observational cohort study of SLE. [Figure 5-3] Baseline clinical signs of organ system infiltration in the SPOCS population. Figure 5A: Overall baseline; Figure 5B: SLEDAI-2K; Figure 5C: Flare. CNS, central nervous system; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SPOCS, prospective observational cohort study of SLE. [Modes for carrying out the invention]

[0009] 4.1. How to treat lupus The present invention relates to a method for treating systemic lupus erythematosus (SLE) in a subject requiring treatment, comprising administering a type I IFN inhibitor to the subject, thereby reducing SLE disease activity in the subject.

[0010] The present invention relates to a method for carrying out treatment of SLE in a subject requiring treatment, comprising administering a therapeutically effective dose of a type I IFN signaling inhibitor, wherein a) the subject was diagnosed with SLE at an age of less than 50 years, and / or b) the subject experienced the first symptoms of SLE at an age of approximately 30 years or less. The method may include determining the age at which the patient was diagnosed with SLE, and / or the age at which the subject experienced the first symptoms of SLE.

[0011] The target population may be diagnosed with SLE at age <30. The target population may be diagnosed with SLE at age 18-29. The target population may be diagnosed with SLE at age <18.

[0012] The inhibitor of type I IFN signaling may be a human monoclonal antibody specific to IFNAR1. The monoclonal antibody may be a modified IgG1 class human monoclonal antibody. The inhibitor of type I IFN signaling may be cifalimumab. The inhibitor of type I IFN signaling may be QX006N.

[0013] IFNAR1-specific antibodies are (a) Heavy chain variable region complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3; (b) Heavy chain variable region complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4; (c) Heavy chain variable region complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5; (d) An amino acid sequence, light chain variable region complementarity determining region 1 (LCDR1) containing SEQ ID NO: 6; (e) An amino acid sequence, light chain variable region complementarity determining region 2 (LCDR2) containing SEQ ID NO: 7; and (f) An amino acid sequence, light chain variable region complementarity determining region 3 (LCDR3) containing SEQ ID NO: 8 may be included.

[0014] The IFNAR1-specific antibody may include (a) a human heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1, and (b) a human light chain variable region containing the amino acid sequence of SEQ ID NO: 2. The IFNAR1-specific antibody may contain an amino acid substitution of L234F numbered by the EU index shown in Kabat in the Fc region, and the antibody exhibits a reduced affinity for at least one Fc ligand as compared to the unmodified antibody. The IFNAR1-specific antibody may include (a) a human heavy chain containing the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain containing the amino acid sequence of SEQ ID NO: 12.

[0015] The inhibitor of type I IFN signaling may be anifrolumab or a functional variant thereof.

[0016] The method of treatment may include administering an intravenous dose of anifrolumab or a functional variant thereof to a subject. The intravenous dose may be ≧300 mg of anifrolumab or a functional variant thereof. The intravenous dose may be ≦1000 mg. The intravenous dose may be about 300 mg, about 900 mg, or about 1000 mg. The intravenous dose may be administered every 4 weeks (Q4W).

[0017] The treatment method may include administering a subcutaneous dose of aniflorumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg of aniflorumab or a functional variant thereof. The subcutaneous dose may be ≤135 mg of aniflorumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single dose step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of about 0.5 to about 1 ml. The subcutaneous dose may have a volume of about 0.8 ml.

[0018] This method may include identifying subjects as patients with high IFNGS test scores before treatment.

[0019] The present invention also relates to pharmaceutical compositions for use in the methods of the present invention. The pharmaceutical compositions may include aniflorumab or functional variants thereof.

[0020] The present invention also relates to an injection device comprising the pharmaceutical composition of the present invention. The injection device may be a pre-filled syringe (PFS). The injection device may be a pre-filled syringe with accessories (AFPS). The injection device may be an auto-injector.

[0021] The present invention also relates to an injection device and a kit including instructions for use. The instructions for use may specify that the subjects are those diagnosed with SLE at an age of less than 50 years and / or those who experienced the first signs of SLE at an age of approximately 30 years or younger. The instructions for use may specify that the injection device is for use in accordance with any of the methods of the present invention.

[0022] 4.2. Inhibitors of Type I IFN Signaling A “Type I interferon receptor inhibitor” refers to a molecule that is antagonistic to the receptors of type I interferon ligands such as interferon-α and interferon-β. Such inhibitors may provide 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, SIGLECl, USP18, RTP4, and DNAPTP6 after administration to a patient. The at least four genes may appropriately be IFI27, IFI44, IFI44L, and RSAD2. The “Type I interferon receptor” is preferably an interferon-α / β receptor (IFNAR).

[0023] For example, a type I interferon receptor inhibitor may be an antibody or its antigen-binding fragment that inhibits type I IFN activity (by inhibiting the receptor). An example of a suitable antibody or its antigen-binding fragment (that inhibits type I IFN activity) is an interferon-α / β receptor (IFNAR) antagonist. A type I interferon receptor inhibitor may be an antibody or its antigen-binding fragment that inhibits type I IFN activity. Furthermore, or alternatively, a type I interferon receptor inhibitor may be a small molecule inhibitor of the type I interferon receptor (for example, for pharmacological inhibition of type I interferon receptor activity).

[0024] IFNAR1 inhibitors may be human monoclonal antibodies specific to IFNAR1. IFNAR1 inhibitors may also be modified IgG1 class human monoclonal antibodies specific to IFNAR1.

[0025] The antibody may contain heavy chain variable region complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3. The antibody may contain heavy chain variable region complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4. The antibody may contain heavy chain variable region complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5. The antibody may contain light chain variable region complementarity determination region 1 (LCDR1) containing the amino acid sequence and SEQ ID NO: 7. The antibody may contain light chain variable region complementarity determination region 2 (LCDR2) containing the amino acid sequence and SEQ ID NO: 7. The antibody may contain light chain variable region complementarity determination region 3 (LCDR3) containing the amino acid sequence and SEQ ID NO: 8.

[0026] The antibody may contain a human heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1. The antibody may contain a human light chain variable region containing the amino acid sequence of SEQ ID NO: 2. The antibody may contain a human light chain constant region containing the amino acid sequence of SEQ ID NO: 9. The antibody may contain a human heavy chain constant region containing the amino acid sequence of SEQ ID NO: 10. The antibody may contain the L234F amino acid substitution in the Fc region, numbered by the EU index shown in Kabat, and the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The antibody may contain a human heavy chain containing the amino acid sequence of SEQ ID NO: 11. The antibody may contain a human light chain containing the amino acid sequence of SEQ ID NO: 12.

[0027] The antibody may include: (a) heavy chain variable region complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3; (b) heavy chain variable region complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4; (c) heavy chain variable region complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5; (d) light chain variable region complementarity determination region 1 (LCDR1) containing the amino acid sequence and SEQ ID NO: 6; (b) light chain variable region complementarity determination region 2 (LCDR2) containing the amino acid sequence and SEQ ID NO: 7; (c) light chain variable region complementarity determination region 3 (LCDR3) containing the amino acid sequence and SEQ ID NO: 8.

[0028] The antibody may comprise (a) a human heavy chain containing the amino acid sequence of SEQ ID NO: 11, and (b) a human light chain containing the amino acid sequence of SEQ ID NO: 12.

[0029] The IFNAR1 inhibitor may be aniflorumab or a functional variant thereof.

[0030] 4.3. Dosage and Method of Administration This method may include administering an intravenous dose of aniflorumab or its functional variant. The intravenous dose may be ≥300 mg of aniflorumab or its functional variant. The intravenous dose may be ≤1000 mg. The intravenous dose may be approximately 300 mg, approximately 900 mg, or approximately 1000 mg. The intravenous dose may be administered every four weeks (Q4W).

[0031] This method may include administering a subcutaneous dose of aniflorumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg of aniflorumab or a functional variant thereof. The subcutaneous dose may be ≤135 mg of aniflorumab or a functional variant thereof. The subcutaneous dose may be approximately 120 mg. The subcutaneous dose may be administered in a single dose step. The subcutaneous dose may be administered at intervals of 6 to 8 days. The subcutaneous dose may be administered once a week. The subcutaneous dose may have a volume of approximately 0.5 to approximately 1 m³. The subcutaneous dose may have a volume of approximately 0.8 ml.

[0032] The subjects may have moderate to severe SLE prior to treatment.

[0033] The subjects may be patients with high levels of type I interferon-stimulated gene signature (IFNGS) testing before treatment. This method may include identifying subjects as patients with high levels of IFNGS testing before treatment.

[0034] Many SLE patients are administered corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Aniflorumab enables tapering of corticosteroids (glucocorticoids) in SLE patients (steroid saving). The treatment method or method may include administering corticosteroids to the subject, optionally, being oral corticosteroids. This method may include tapering the dose of corticosteroids administered to the subject (steroid saving). This method may include administering a first dose of corticosteroids followed by a second dose of corticosteroids, the second dose of corticosteroids being lower than the first dose of corticosteroids. The second dose of corticosteroids may be approximately 7.5 mg or less of a dose equivalent to prednisone. The second dose of corticosteroids may be 5 mg or less of a dose equivalent to prednisone. This method or treatment may include administering a second dose of corticosteroid once daily. The first dose of corticosteroid may be equivalent to approximately 10 mg of prednisone. This method may include gradually reducing the dose of corticosteroid administered to the patient from 10 mg or more per day to less than 10 mg per day. This method or treatment may include administering a second dose of corticosteroid once daily. This method may allow for the administration of reduced doses of corticosteroid for several weeks. The second dose of corticosteroid may be administered for at least 24 weeks. The second dose of corticosteroid may be administered for at least 28 weeks.

[0035] This method may include steroid saving in the subjects, in which the dose of steroid administered to the subjects is gradually reduced from the baseline pre-saving dose to the post-saving dose. The post-saving dose may be ≤7.5 mg / day of prednisone or a prednisone equivalent dose. The pre-saving dose may be 20 mg / day of prednisone or a prednisone equivalent dose. The steroid may include glucocorticoids. The steroid may include oral glucocorticoids. Steroids include hydrocortisone, mometasone, fluticasone, fluocinolone acetonide, fluocinolone, flulandrenolonone acetonide, ciclesonide, budesonide, beclomethasone, deflazacort, flunisolide, beclomethasone dipropionate, betamethasone, betamethasone valerate, methylprednisolone, dexamethasone, prednisolone, cortisol, triamcinolone, clobetasol, clobetasol propionate, clobetasol butyrate, cortisone, corticosterone, crocoltolone, dihydroxycortisone, alclomethasone, amcinonide, diflucortolone valerate, flucortolone, and flupredniden. The steroid may be selected from the group consisting of fluandrenolone, fluorometholone, halcinonide, halobetazole, desonide, diflorazone, fluandrenolone, fluocinonide, prednicarbate, desoximethasone, fluprednisolone, prednisone, azelastine, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, halopredone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, prednisolone, prednisolone 21-phosphate, clobetasol propionate, triamcinolone acetonide, or mixtures thereof. The steroid may be prednisone.

[0036] The present invention also relates to unit doses for use in the methods of the present invention, the unit doses comprising aniflorumab or functional variants thereof in >105 mg and ≤150 mg. Unit doses of aniflorumab suitable for use in the methods of the present invention are described in WO2022223714 A1[8], which are incorporated herein by reference in their entirety.

[0037] A unit dose may contain ≤135 mg (i.e., 135 mg or less) of aniflorumab or its functional variant. A unit dose may contain approximately 120 mg of aniflorumab or its functional variant. A unit dose may contain 120 mg of aniflorumab or its functional variant. A unit dose may essentially consist of >105 mg and <150 mg of aniflorumab or its functional variant. A unit dose may essentially consist of ≤135 mg of aniflorumab or its functional variant. A unit dose may essentially consist of approximately 120 mg of aniflorumab or its functional variant. The concentration of aniflorumab or its functional variant in a unit dose may be approximately 150 mg / ml. The volume of a unit dose may be less than 1 ml. A dose or unit dose may have a volume of approximately 0.5 to approximately 1 ml. The concentration of a unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose may include a formulation of aniflorumab or a functional variant thereof at approximately 150–200 mg / ml, a lysine salt at approximately 25–150 mM, and an uncharged excipient. The unit dose may include a formulation of aniflorumab or a functional variant thereof at approximately 150–200 mg / ml, a lysine salt at approximately 25–150 mM, and an uncharged excipient. The unit dose may include a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of approximately 5.9.

[0038] In another aspect, the present invention relates to a method for treating SLE in a subject, the method comprising subcutaneous administration of a dose of aniflorumab or a functional variant thereof, wherein weekly administration of the dose provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by a 4-week intravenous administration of 300 mg of aniflorumab or a functional variant thereof. Weekly administration of the dose may provide a plasma concentration in the subject exceeding the plasma concentration provided by a 4-week intravenous administration of 300 mg of aniflorumab or a functional variant thereof. Weekly administration of the dose may provide a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by a 4-week intravenous administration of 400 mg of aniflorumab or a functional variant thereof. The dose may be administered in a single dose step. The dose administered to the subject may be <150 mg (i.e., less than 150 mg) of aniflorumab or a functional variant thereof. The dose administered to the subjects may be >105 mg (i.e., greater than 105 mg) of aniflorumab or its functional variant. The dose administered to the subjects may be ≤135 mg (i.e., 135 mg or less) of aniflorumab or its functional variant. The dose administered to the subjects may be approximately 120 mg of aniflorumab or its functional variant.

[0039] A dose or unit dose may provide a plasma concentration of aniflorumab or its functional variant in patients with a concentration of ≥10 μg per ml of plasma (i.e., ≥10 μg / ml). A dose or unit dose may provide a plasma concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 10–100 μg / ml. A dose or unit dose may provide a plasma concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 20–80 μg / ml. A dose or unit dose may provide a plasma concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 30–70 μg / ml. A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of ≥20 μg / ml (i.e., ≥20 μg / ml). A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of ≥30 μg / ml (i.e., 30 μg / ml or higher). A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of ≥40 μg / ml (i.e., 40 μg / ml or higher). A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 20–100 μg / ml. A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 30–80 μg / ml. A dose or unit dose may provide a trough concentration of aniflorumab or its functional variant in subjects with a concentration of approximately 40–70 μg / ml.

[0040] 4.4. Target The subjects may be diagnosed with SLE at the age of 60 or younger. The subjects may be diagnosed with SLE at the age of 59 or younger. The subjects may be diagnosed with SLE at the age of 58 or younger. The subjects may be diagnosed with SLE at the age of 57 or younger. The subjects may be diagnosed with SLE at the age of 56 or younger. The subjects may be diagnosed with SLE at the age of 55 or younger. The subjects may be diagnosed with SLE at the age of 54 or younger. The subjects may be diagnosed with SLE at the age of 53 or younger. The subjects may be diagnosed with SLE at the age of 52 or younger. The subjects may be diagnosed with SLE at the age of 51 or younger. The subjects may be diagnosed with SLE at the age of 50 or younger. The subjects may be diagnosed with SLE at the age of 49 or younger. The subjects may be diagnosed with SLE at the age of 48 or younger. The subjects may be diagnosed with SLE at the age of 47 or younger. The subjects may be diagnosed with SLE at the age of 46 or younger. The target population may be diagnosed with SLE at the age of 45 or younger. The target population may be diagnosed with SLE at the age of 44 or younger. The target population may be diagnosed with SLE at the age of 43 or younger. The target population may be diagnosed with SLE at the age of 42 or younger. The target population may be diagnosed with SLE at the age of 41 or younger. The target population may be diagnosed with SLE at the age of 40 or younger. The target population may be diagnosed with SLE at the age of 39 or younger. The target population may be diagnosed with SLE at the age of 38 or younger. The target population may be diagnosed with SLE at the age of 37 or younger. The target population may be diagnosed with SLE at the age of 36 or younger. The target population may be diagnosed with SLE at the age of 35 or younger. The target population may be diagnosed with SLE at the age of 34 or younger. The target population may be diagnosed with SLE at the age of 33 or younger. The target population may be diagnosed with SLE at the age of 32 or younger. The target population may be diagnosed with SLE at the age of 31 or younger. The target group includes individuals aged 30 or younger who have been diagnosed with SLE.

[0041] Participants may be under 30 years of age, for example, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20, and may have experienced their first signs of SLE. Participants may also have early-onset SLE.

[0042] The subjects may be human subjects. The subjects may be adults. The subjects may be patients with elevated type I IFN gene signature. The subjects may be patients with high type I interferon-stimulated gene signature (IFNGS) test scores prior to dose or unit dose administration. The subjects may have elevated levels of the genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood. This method may include identifying subjects as patients with high IFINGS test scores prior to dose or unit dose treatment. This method may include measuring the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subjects' whole blood. This method may include measuring the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the subjects' whole blood by RT-PCR.

[0043] The dose or unit dose may provide a therapeutic effect at least equivalent to that provided by an intravenous dose of 300 mg of aniflorumab or its functional variant administered once every 4 weeks (Q4W). The dose or unit dose may provide a trough concentration of aniflorumab or its functional variant greater than that provided by an intravenous dose of 300 mg of aniflorumab or its functional variant administered once every 4 weeks (Q4W). Aniflorumab or its functional variant may be contained in a pharmaceutical composition. The pharmaceutical composition may contain about 150-200 mg / ml of aniflorumab or its functional variant, about 25-150 mM of lysine salt and an uncharged excipient. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM trehalose dihydrate. The pharmaceutical composition may contain 0.05% polysorbate 80. The pharmaceutical composition may contain 25 mM histidine / histidine HCl. The pharmaceutical composition may contain 150 mg / mL aniflorumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0044] The method of the present invention may include administering a dose or unit dose at intervals of 6 to 8 days. The dose or unit dose may be administered once weekly (QW). The dose or unit dose may be 120 mg aniflorumab or a functional variant thereof, and the method includes administering the dose once weekly (QW) in a single dose step. In other words, the method includes administering 120 mg QW aniflorumab or a functional variant thereof. The dose or unit dose may be administered once weekly for at least about 4 weeks. The dose or unit dose may be administered once weekly for at least about 8 weeks. The dose or unit dose may be administered once weekly for at least about 12 weeks. The dose or unit dose may be administered once weekly for at least about 16 weeks. The dose or unit dose may be administered once weekly for at least about 20 weeks. The dose or unit dose may be administered once weekly for at least about 24 weeks. The dose or unit dose may be administered once weekly for at least about 28 weeks. The dose or unit dose may be administered once a week for at least about 32 weeks. The dose or unit dose may be administered once a week for at least about 8 weeks. The dose or unit dose may have a volume suitable for delivery in a single subcutaneous administration step. The dose or unit dose may have a volume of about 0.5 to about 1 ml. The dose or unit dose may have a volume of less than 1 ml. The dose or unit dose may have a volume of about 0.8 ml.

[0045] 4.5. Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition for use in a method of treating SLE in a subject, the method comprising subcutaneous administration of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of aniflorumab or a functional variant thereof, the dose being >105 mg and <150 mg. The dose of aniflorumab or a functional variant thereof may be a unit dose (unit dose form, pharmaceutical unit dose form, pharmaceutical unit dose). The functional aniflorumab variant comprises an antigen-binding fragment of aniflorumab, as well as an antibody and immunoglobulin derivative of aniflorumab.

[0046] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating CLE in a subject, comprising subcutaneous administration of the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of aniflorumab or a functional variant thereof, and weekly administration of the pharmaceutical composition provides a plasma concentration in the subject that is at least equivalent to the plasma concentration provided by intravenous administration of 300 mg of aniflorumab or a functional variant thereof every four weeks. Weekly administration may provide in the subject a plasma concentration substantially equivalent to the plasma concentration provided by intravenous administration of 400 mg of aniflorumab or a functional variant thereof every four weeks. The dose may be <150 mg (i.e., less than 150 mg) of aniflorumab or a functional variant thereof. The dose may be >105 mg (i.e., greater than 105 mg) of aniflorumab or a functional variant thereof. The dose may be ≤135 mg (i.e., 135 mg or less) of aniflorumab or a functional variant thereof. The dose may be approximately 120 mg of aniflorumab or its functional variant.

[0047] The pharmaceutical composition may be administered at intervals of 6 to 8 days. The pharmaceutical composition may be administered once weekly (QW). The pharmaceutical composition may be administered in a single-dose procedure. The dose may be 120 mg of aniflorumab or a functional variant thereof, and the treatment method may include administering the dose once weekly (QW) in a single-dose procedure. The pharmaceutical composition may be administered once weekly for at least about 4 weeks. The pharmaceutical composition may be administered once weekly for at least about 8 weeks. The dose or unit dose may be administered once weekly for at least about 12 weeks. The pharmaceutical composition may be administered once weekly for at least about 16 weeks. The pharmaceutical composition may be administered once weekly for at least about 20 weeks. The pharmaceutical composition may be administered once weekly for at least about 24 weeks. The pharmaceutical composition may be administered once weekly for at least about 28 weeks. The pharmaceutical composition may be administered once weekly for at least about 32 weeks. The pharmaceutical composition may be administered once weekly for about 8 weeks. The pharmaceutical composition may have a volume that allows for appropriate delivery in a single subcutaneous administration step. The pharmaceutical composition may have a volume of about 0.5 to about 1 ml. The pharmaceutical composition may have a volume of less than 1 ml. The pharmaceutical composition may have a volume of about 0.8 ml.

[0048] Administration of the pharmaceutical composition may provide a plasma concentration of aniflorumab or its functional variant of ≥10 μg per ml of plasma (i.e., ≥10 μg / ml) in the patient. Administration of the pharmaceutical composition may provide a plasma concentration of aniflorumab or its functional variant of approximately 10–100 μg / ml in the subject. Administration of the pharmaceutical composition may provide a plasma concentration of aniflorumab or its functional variant of approximately 20–80 μg / ml in the subject. Administration of the pharmaceutical composition may provide a plasma concentration of aniflorumab or its functional variant of approximately 30–70 μg / ml in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of ≥20 μg / ml (i.e., ≥20 μg / ml) in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of ≥30 μg / ml (i.e., 30 μg / ml or higher) in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of ≥40 μg / ml (i.e., 40 μg / ml or higher) in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of approximately 20 to 100 μg / ml in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of approximately 30 to 80 μg / ml in the subject. Administration of the pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant of approximately 40 to 70 μg / ml in the subject.

[0049] The pharmaceutical composition may provide a therapeutic effect in a subject that is at least equivalent to the therapeutic effect provided by a single (Q4W) intravenous dose of 300 mg of aniflorumab or its functional variant. The pharmaceutical composition may provide a trough concentration of aniflorumab or its functional variant higher than the trough concentration of aniflorumab or its functional variant provided by a 300 mg intravenous dose of aniflorumab or its functional variant administered once every four weeks (Q4W). Aniflorumab or its functional variant may be contained within the pharmaceutical composition. The pharmaceutical composition may contain about 150-200 mg / ml of aniflorumab or its functional variant, about 25-150 mM of lysine salt and an uncharged excipient. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM trehalose dihydrate. The pharmaceutical composition may contain 0.05% polysorbate 80. The pharmaceutical composition may contain 25 mM histidine / histidine HCl. The pharmaceutical composition may contain 150 mg / mL aniflorumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0050] The pharmaceutical composition may contain approximately 150-200 mg / ml of aniflorumab or its functional variant, approximately 25-150 mM of lysine salt, and an uncharged excipient. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM of trehalose dihydrate. The pharmaceutical composition may contain approximately 150-200 mg / ml of aniflorumab or its functional variant, approximately 25-150 mM of lysine salt, and an uncharged excipient. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM of trehalose dihydrate. The pharmaceutical composition may contain 0.05% of polysorbate 80. The pharmaceutical composition may contain 25 mM histidine / histidine HCl. The pharmaceutical composition may contain 150 mg / mL aniflorumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0051] 4.6. Devices The present invention also relates to an injection device comprising a unit dose of the present invention or a pharmaceutical composition for any use of the present invention.

[0052] The pharmaceutical product in the injection device may contain aniflorumab or a functional variant thereof in an amount >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg). The pharmaceutical composition in the injection device may contain about 120 mg of aniflorumab or a functional variant thereof. The pharmaceutical composition in the injection device may contain 120 mg of aniflorumab or a functional variant thereof. The concentration of aniflorumab or a functional variant thereof in the pharmaceutical composition in the injection device may be 150 mg / ml. The volume of the pharmaceutical composition in the injection device may be at least about 0.8 ml. The volume of the pharmaceutical composition may be about 0.8 ml.

[0053] The pharmaceutical composition in the injection device may contain approximately 150-200 mg / ml of aniflorumab or its functional variant, approximately 25-150 mM of lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition in the injection device may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may contain approximately 150-200 mg / ml of aniflorumab or its functional variant, approximately 25-150 mM of lysine salt, and an uncharged excipient. The pharmaceutical composition in the injection device may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition in the injection device may contain 130 mM of trehalose dihydrate. The pharmaceutical composition in the injection device may contain 0.05% polysorbate 80. The pharmaceutical composition in the injection device may contain 25 mM histidine / histidine HCl. The pharmaceutical composition in the injection device may contain 150 mg / mL aniflorumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0054] In another embodiment, the present invention relates to an injection device containing a unit dose. The unit dose may contain an aniflorumab or functional variant thereof in an amount >105 mg (i.e., at least 105 mg) and <150 mg (i.e., less than 150 mg). The unit dose may contain aniflorumab or functional variant thereof in an amount ≤135 mg (i.e., 135 mg or less). The unit dose may contain about 120 mg of aniflorumab or functional variant thereof. The unit dose in the injection device may contain 120 mg of aniflorumab or functional variant thereof. The unit dose in the injection device may essentially consist of >105 mg and <150 mg of florumab or functional variant thereof. The unit dose in the injection device may essentially consist of aniflorumab or functional variant thereof in an amount ≤135 mg. The unit dose in the injection device may essentially consist of about 120 mg of aniflorumab or functional variant thereof. The concentration of aniflorumab or its functional variant in a unit dose within the injection device may be approximately 150 mg / ml. The volume of the unit dose within the injection device may be less than 1 ml. The unit dose within the injection device may have a volume of approximately 0.5 to approximately 1 ml. The concentration of the unit dose may be approximately 0.8 ml. The volume of the unit dose may be 0.8 ml. The unit dose within the injection device may contain a formulation of approximately 150 to 200 mg / ml of aniflorumab or its functional variant, approximately 25 to 150 mM of lysine salt, and an uncharged excipient. The unit dose within the injection device may contain a formulation of 150 to 200 mg / ml of aniflorumab or its functional variant, 25 to 150 mM of lysine salt, and an uncharged excipient. The unit dose includes a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The formulation may have a pH of approximately 5.9.

[0055] The injection device may be a pre-filled syringe (PFS). The injection device may be a pre-filled syringe with accessories (AFPS). The injection device may be an auto-injector (AI).

[0056] 4.7. Kit In another embodiment, the present invention relates to a kit comprising a unit dose and instructions for use, wherein the instructions for use include instructions for subcutaneous administration of the unit dose to a subject.

[0057] In another embodiment, the present invention relates to a kit comprising a pharmaceutical composition for use of the present invention, wherein the instructions for use include instructions for subcutaneous administration of the pharmaceutical composition to a subject.

[0058] In another embodiment, the present invention relates to a kit comprising an injection device and instructions for use, wherein the instructions for use include instructions for use of an injection device for subcutaneous administration of a unit dose or pharmaceutical composition.

[0059] The kit of the present invention may include packaging, which is adapted to hold an injection device and instructions for use. The instructions for use may be attached to the injection device. The instructions for use may include instructions for administration of >105 mg and <150 mg of aniflorumab or its functional variant. The instructions for use may include instructions for administration of ≤135 mg of aniflorumab or its functional variant. The instructions for use may include instructions for administration of 120 mg of aniflorumab or its functional variant. The instructions for use may include instructions for administration of 120 mg of aniflorumab or its functional variant every four weeks. The instructions for use may define a subject as having type I IFN-mediated disease. The instructions may define a subject as having SLE. The instructions may define a subject as having moderate to severe SLE. The instructions for use may be in written form.

[0060] The instructions for use may specify that the injection device, unit dose, and / or pharmaceutical composition are for use in the treatment of SLE. The instructions for use may include instructions for weekly administration of 120 mg of aniflorumab or a functional variant thereof.

[0061] The instructions for use may specify that the injection device, unit dose, and / or pharmaceutical composition are for use in the treatment of SLE in subjects, and that subjects are diagnosed with SLE at an age of less than 50 years and / or that subjects experienced the first signs of SLE at an age of approximately 30 years or younger.

[0062] 4.8. Formulation Aniflorumab or its functional variant may be included in the pharmaceutical composition. The pharmaceutical composition may contain about 150–200 mg / ml of aniflorumab or its functional variant, about 25–150 mM of lysine salt and an uncharged excipient. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant. The pharmaceutical composition may contain 50 mM of lysine HCl. The pharmaceutical composition may contain 130 mM of trehalose dihydrate. The pharmaceutical composition may contain 0.05% of polysorbate 80. The pharmaceutical composition may contain 25 mM of histidine / histidine HCl. The pharmaceutical composition may contain 150 mg / mL of aniflorumab or its functional variant, 50 mM of lysine HCl, 130 mM of trehalose dihydrate, 0.05% of polysorbate 80 and 25 mM of histidine / histidine HCl.

[0063] A stable formulation containing aniflorumab, suitable for administration to the target population, is described in detail in U.S. Patent No. 10125195(B1), which is incorporated herein by reference.

[0064] 5.Definition 5.1. Inhibitors of Type I IFN Signaling 5.1.1. Aniflorumab Aniflorumab (MEDI-546, anifro, ANI) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against subunit 1 of the type I interferon receptor (IFNAR1). Aniflorumab downregulates IFNAR signaling and suppresses the expression of IFN-inducible genes. Disclosures relating to aniflorumab can be found in U.S. Patent No. 7,662,381 and U.S. Patent No. 9,988,459, which are incorporated herein by reference in their entirety. Sequence information for aniflorumab is provided.

[0065] [Table 1]

[0066] Aniflorumab is an immunoglobulin containing HCDR1, HCDR2, and HCDR3 (or their functional variants) of SEQ ID NOs. 3, 4, and 5, respectively, and LCDR1, LCDR2, and LCDR3 (or their functional variants) of SEQ ID NOs. 6, 7, and 8, respectively. Aniflorumab is an immunoglobulin containing VH of SEQ ID NO. 1 and VL of SEQ ID NO. 2.

[0067] The constant region of aniflorumab is modified such that aniflorumab exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. Aniflorumab is an IFNAR1-specific modified IgG class monoclonal antibody containing the L234F amino acid substitution in its Fc region, numbered by the EU index described in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Virginia). Aniflorumab is an IFNAR1-specific modified IgG class monoclonal antibody containing the L234F, L235E and / or P331S amino acid substitutions in its Fc region, numbered by the EU index described in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Virginia). Aniflorumab is an antibody containing the light chain constant region of SEQ ID NO: 9. Aniflorumab is an antibody containing the heavy chain constant region of SEQ ID NO: 10. Aniflorumab is an antibody containing the light chain constant region of SEQ ID NO: 9 and the heavy chain constant region of SEQ ID NO: 10. Aniflorumab is an antibody containing the heavy chain of SEQ ID NO: 11. Aniflorumab is an antibody containing the light chain of SEQ ID NO: 12. Aniflorumab is an antibody containing the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12.

[0068] Functional variants of aniflorumab are sequence variants that perform the same function as aniflorumab. Functional variants of aniflorumab bind to the same target as aniflorumab and have the same effector function as aniflorumab. Functional aniflorumab variants include antigen-binding fragments of aniflorumab, as well as antibodies and immunoglobulin derivatives of aniflorumab. Functional variants include biosimilars and compatible products. The terms biosimilar and compatible product are defined by the FDA and EMA. The term biosimilar refers to a biological product that is structurally very similar to an approved (e.g., FDA-approved) biological product (reference product, e.g., aniflorumab) and does not have clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically significant differences in a biosimilar may be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and evaluations of clinical immunogenicity. Compatible products are biosimilars that are expected to produce the same clinical outcomes as the reference product in any given patient.

[0069] For example, a variant of the reference (aniflorumab) antibody may include a heavy chain CDR1 having at most two amino acid differences compared to SEQ ID NO: 3; a heavy chain CDR2 having at most two amino acid differences compared to SEQ ID NO: 4; a heavy chain CDR3 having at most two amino acid differences compared to SEQ ID NO: 5; a light chain CDR1 having at most two amino acid differences compared to SEQ ID NO: 6; a light chain CDR2 having at most two amino acid differences compared to SEQ ID NO: 7; and a light chain CDR3 having at most two amino acid differences compared to SEQ ID NO: 8. The variant antibody preferably binds to the target of aniflorumab (e.g., IFNAR) with the same affinity.

[0070] Variants of the reference (aniflorumab) antibody may include a heavy chain CDR1 with at most one amino acid difference compared to SEQ ID NO: 3; a heavy chain CDR2 with at most one amino acid difference compared to SEQ ID NO: 4; a heavy chain CDR3 with at most one amino acid difference compared to SEQ ID NO: 5; a light chain CDR1 with at most one amino acid difference compared to SEQ ID NO: 6; a light chain CDR2 with at most one amino acid difference compared to SEQ ID NO: 7; and a light chain CDR3 with at most one amino acid difference compared to SEQ ID NO: 8. The variant antibodies bind to the target of aniflorumab (e.g., IFNAR) with the same affinity at any selection.

[0071] A mutant antibody may have at most 5, 4, or 3 amino acid differences in total in its CDR compared to the corresponding reference (aniflorumab) antibody, provided that there are at most 2 (optionally at most 1) amino acid differences per CDR. A mutant antibody may have at most 2 (optionally at most 1) amino acid differences in total in its CDR compared to the corresponding reference (aniflorumab) antibody, provided that there are at most 2 amino acid differences per CDR. A mutant antibody may have at most 2 (optionally at most 1) amino acid differences in total in its CDR compared to the corresponding reference (aniflorumab) antibody, provided that there is at most 1 amino acid difference per CDR.

[0072] A mutant antibody may have at most 5, 4, or 3 amino acid differences in total within its framework region compared to the corresponding reference (aniflorumab) antibody, provided that there are at most 2 (optionally, at most 1) amino acid differences per framework region. Optionally, a mutant antibody may have at most 2 (optionally, at most 1) amino acid differences in total within its framework region compared to the corresponding reference (aniflorumab) antibody, provided that there are at most 2 amino acid differences per framework region. Optionally, a mutant antibody may have at most 2 (optionally, at most 1) amino acid differences in total within its framework region compared to the corresponding reference (aniflorumab) antibody, provided that there is at most 1 amino acid difference per framework region.

[0073] The mutant antibody may include a variable heavy chain and a variable light chain as described herein, wherein the heavy chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) compared to the heavy chain sequence herein, and the light chain has at most 14 amino acid differences (at most 2 amino acid differences in each CDR and at most 2 amino acid differences in each framework region) compared to the light chain sequence herein, and the mutant antibody preferably binds to the same target antigen (e.g., IFNAR) as the reference (aniflornimab) antibody with the same affinity.

[0074] A variant heavy or light chain may be referred to as a "functional equivalent" of the reference heavy or light chain. The variant antibody may include the variable heavy and variable light chains described herein, wherein the heavy chain has at most seven amino acid differences (at most one amino acid difference in each CDR and at most one amino acid difference in each framework region) compared to the heavy chain sequence herein, and the light chain has at most seven amino acid differences (at most one amino acid difference in each CDR and at most one amino acid difference in each framework region) compared to the light chain sequence herein, and the variant antibody preferably binds to the same target antigen (e.g., IFNAR) as the reference (aniflornimab) antibody with the same affinity.

[0075] Functional variants of aniflorumab include antibodies described in International Publication No. 2018 / 023976(A1), which is incorporated herein by reference (Table 2).

[0076] [Table 2]

[0077] Functional variants include antibodies containing the VH amino acid sequence and SEQ ID NO: 13. Functional variants include antibodies containing the VH amino acid sequence and SEQ ID NO: 16. Functional variants include antibodies containing the VL amino acid sequence and SEQ ID NO: 14. Functional variants include antibodies containing the VL amino acid sequence and SEQ ID NO: 15. Functional variants include antibodies containing the VL amino acid sequence and SEQ ID NO: 16. Functional variants include antibodies containing the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. Functional variants include antibodies containing the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies containing the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. Functional variants include antibodies containing the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0078] An IFNAR inhibitor may be a monoclonal antibody containing the VH amino acid sequence of SEQ ID NO: 13. An anti-IFNAR antibody may contain the VH amino acid sequence of SEQ ID NO: 16. An anti-IFNAR antibody may contain the VL amino acid sequence of SEQ ID NO: 14. An anti-IFNAR antibody may contain the VL amino acid sequence of SEQ ID NO: 15. An anti-IFNAR antibody may contain the VL amino acid sequence of SEQ ID NO: 16. An anti-IFNAR antibody may contain the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 16. An anti-IFNAR antibody may contain the VH sequence of SEQ ID NO: 13 and the VL amino acid sequence of SEQ ID NO: 15. An anti-IFNAR antibody may contain the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 15. An anti-IFNAR antibody may contain the VH sequence of SEQ ID NO: 16 and the VL amino acid sequence of SEQ ID NO: 14.

[0079] 5.1.2.QX006N Functional variants of aniflorumab and anti-IFNAR antibodies include the QX006N antibody described in CN11327807, which is incorporated herein by reference.

[0080] [Table 3]

[0081] The IFNAR inhibitor may be a monoclonal antibody containing the VH amino acid sequence of SEQ ID NO: 17. The anti-IFNAR antibody may also contain the VL amino acid sequence of SEQ ID NO: 18.

[0082] QX006N is an immunoglobulin containing HCDR1, HCDR2, and HCDR3 (or their functional variants) from SEQ ID NOs. 19, 20, and 21, respectively, and LCDR1, LCDR2, and LCDR3 (or their functional variants) from SEQ ID NOs. 22, 23, and 23, respectively. QX006N is an immunoglobulin containing the VH amino acid sequence from SEQ ID NOs. 17 and the VL amino acid sequence from SEQ ID NOs. 18.

[0083] 5.1.3. Sifalimumab Sifarimumab (MEDI-545) is a fully human immunoglobulin G1κ monoclonal antibody that binds to and neutralizes most IFN-α subtypes.[9] Sifarimumab is described in U.S. Patent No. 7,741,449, which is incorporated herein by reference in its entirety. The efficacy and safety of sifarimumab were evaluated in a phase IIb randomized, double-blind, placebo-controlled trial (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). 431 patients were randomized to receive either monthly intravenous sifarimumab (200 mg, 600 mg, or 1200 mg) or placebo, in addition to standard care. The primary efficacy endpoint was the percentage of patients who achieved an SLE responder index response at week 52. Compared to placebo, a greater percentage of patients who received cifalimumab (total dose) met the primary endpoint (placebo: 45.4%, 200 mg: 58.3%, 600 mg: 56.5%, 1200 mg: 59.8%).

[0084] 5.1.4. Inhibitors of type I IFN signaling in clinics The safety of aniflorumab was evaluated in eight blinded or open-label intravenous (IV) and subcutaneous (SC) studies: six studies in patients with SLE (Study 05, Study 04, Study 1013, Study 1145, and Study 08), one study in patients with systemic sclerosis (SSc) (Study MI-CP180), and one study in healthy volunteers (Study 06) (Table 4). Of these studies, two (Studies 08 and 06) used SC aniflorumab administration. Two studies are ongoing: one in patients with SLE (Study 09) and one in patients with lupus nephritis (LN) (Study 07).

[0085] [Table 4]

[0086] 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 in its entirety herein by reference. Study 04 is described in more detail in Furie et al. 2019

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

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

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

[0087] 5.2. Formulations A stable formulation containing aniflorumab, suitable for administration to the target population, is described in detail in U.S. Patent No. 10125195(B1), which is incorporated entirely herein.

[0088] The following embodiments illustrate specific embodiments of the Disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the Disclosure.

[0089] 5.3. Steroids Oral corticosteroids (OCS, glucocorticoids) include prednisone, cortisone, hydrocortisone, methylprednisolone, prednisolone, and triamcinolone. Examples of equivalent doses of oral prednisone are shown in Table 5.

[0090] [Table 5]

[0091] 5.4. Dosage Form A unit dose (also called a unit dose form, pharmaceutical unit dose, or pharmaceutical unit dose form) is a dose formed from a single unit. Unit doses (unit dose forms) are suitable for administration to a subject in a single administration step. Unit doses (unit dose forms) can be packaged in a single-unit container, such as a single-use pre-filled syringe or auto-injector. Unit doses offer the advantage that they can be ordered, packaged, handled, and administered as a single dose unit containing a predetermined amount of drug. Unit doses reduce administration errors and reduce waste. Unit doses of aniflorumab suitable for use in the treatment of SLE are described in WO2022223714 A1[8].

[0092] 5.5. Delivery Devices As with providing subcutaneous administration of antibodies, the ability to self-administer (e.g., for home use) can be further enhanced by subcutaneous administration via pre-filled syringes with accessories (APFS), auto-injectors (AI), or a combination thereof. Such devices have been found to be sufficiently tolerable and reliable for administering subcutaneous doses of antibodies and provide further options for optimizing patient care. In fact, such devices can reduce the burden of frequent clinic visits for patients. An example of a suitable APFS device is described in Ferguson et al.

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

[0093] Since APFS devices typically administer a maximum volume of 1 ml, the doses elucidated by the inventors offer further advantages in the context of APFS administration. Doses in the range of >105 mg to <155 mg can be easily accommodated in a volume of approximately 0.8 ml, and as a result, the doses(s) of the present invention are uniquely suitable for APFS and AI administration. For comparison, due to the viscosity of aniflorumab, larger doses (especially doses >150 mg) would need to be administered in a volume of >1 ml, requiring at least two SC injections, which would be inconvenient for the patient and would require multiple pre-filled devices.

[0094] The delivery device may be a single-use, disposable system designed to allow manual SC administration of the dose.

[0095] 5.6. Endpoints 5.6.1. Patient-reported outcomes The Physician Global Assessment (PGA and MDGA) of Disease Activity refers to an assessment in which a physician evaluates the status of a subject's psoriatic arthritis (PsA) using a visual analog scale (VAS). The subject is assessed according to the current state of their arthritis. The VAS is fixed with verbal descriptors ranging from "very good" to "very bad."

[0096] 5.6.2.BILAG-2004(British Isles Lupus Assessment Group-2004) BILAG-2004 is a translational index across nine organ systems (general, mucocutaneous, neuropsychiatric, musculoskeletal, cardiopulmonary, gastrointestinal, ocular, renal, and hematological) that can capture the changing severity of clinical signs. It has an ordinal scale by design and does not have a comprehensive score; rather, it records disease activity across seemingly different organ systems by comparing the most recent four weeks with the preceding four weeks. It is based on the principle of physician's intent to treat and classifies disease activity into five different levels, A through E. • Grade A represents a highly active disease requiring immunosuppressants and / or a dose of prednisone >20 mg / day or equivalent. Grade B indicates moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarial drugs, or NSAIDs. • Grade C indicates a mild, stable illness. • Grade D indicates no disease activity, but the system has been affected previously. • Grade E indicates no current or past disease activity.

[0097] BILAG-2004 was developed based on the principle of treatment intent, but treatment is not relevant to the scoring index. Only the presence of signs of activity affects the scoring.

[0098] Improvements in the mucocutaneous or musculoskeletal system, according to the BILAG definition, represented rash or arthritis, respectively.

[0099] 5.6.3.BILA(BILAG-Based Composite Lupus Assessment) BICLA is a composite index originally derived by expert consensus on disease activity indices. A BICLA response is defined as (1) improvement of at least one level in baseline BILAG scores in all physical systems with moderate or severe disease activity at the time of enrollment (e.g., all A (severe disease) scores decrease to B (moderate), C (mild), or D (no activity), and all B scores decrease to C or D), (2) no new BILAG A scores or one or more new BILAG B scores, (3) no deterioration in total SLEDAI score from baseline, (4) no significant deterioration in physician's comprehensive assessment (≤10%), and (5) no treatment failure (initiation of non-protocol treatment).

[0100] In particular, the target group is BICLA responders if the following criteria are met. a) Reduction of all baseline BILAG-2004 A items to B / C / D and reduction of baseline BILAG-2004 B items to C / D, as defined by one new BILAG-2004 A item or one or more new BILAG-2004 B items, and no worsening of BILAG-2004 in other organ systems. b) No deterioration from baseline in SLEDAI-2K, defined as an increase of >0 points from baseline in SLEDAI-2K. c) No worsening from baseline in lupus disease activity in the subject, defined as an increase of ≥0.30 points on a 3-point PGA VAS. d) No use of restricted medicines exceeding the protocol's acceptable threshold prior to discontinuation or evaluation of the test product.

[0101] 5.6.4. SRI (Systemic Lupus Erythematosus Response Index ≥ 4) A subject achieves SRI(4) if all of the following criteria are met. • A reduction of ≥4 points from baseline in SLEDAI-2K. • One or more BILAG-2004 A values ​​compared to baseline using BILAG-2004. • No new organ systems were affected as defined by item B of BILAG-2004. • There was no deterioration from baseline in lupus disease activity in the subjects, as defined by an increase of ≥0.30 points on a 3-point PGA VAS.

[0102] SRI(X) (X=5, 6, 7, or 8) is defined by the proportion of subjects that meet the following criteria: • Reduction of ≥X points from baseline in SLEDAI-2K. • One or more BILAG-2004 A values ​​compared to baseline using BILAG-2004. • No new organ systems were affected as defined by the BILAG-2004 B items above. • There was no deterioration from baseline in lupus disease activity in the subjects, as defined by an increase of ≥0.30 points on a 3-point PGA VAS.

[0103] 5.6.5.SLEDAI-2K(Systemic Lupus Erythematosus Disease Activity Index 2000) The SLEDAI-2K disease activity index consists of a list of organ signs, each with its own definition. An accredited or designated physician will complete the SLEDAI-2K assessment and determine whether each sign has been “present” or “absent” in the past four weeks. The assessment will also include blood and urine collection for the evaluation of the SLEDAI-2K laboratory categories.

[0104] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted tool in which descriptors are multiplied by the "weights" of specific organs. For example, the renal descriptor is multiplied by 4, the central nervous system descriptor by 8, and these weighted organ signs are summed up to arrive at the final score. The SLEDAI-2K score ranges from 0 to 105, with 0 indicating inactive disease. The SLEDAI-2K score is a valid, reliable, and highly sensitive clinical assessment of lupus disease activity. SLEDAI-2K calculated using a 30-day time frame prior to visit for clinical and laboratory values ​​has been shown to be similar to SLEDAI-2K with a 10-day window

[17] .

[0105] In SLEDAI-2K, rash resolution is defined as a score of 0 at week 52 for patients who had a rash score of ≥2 at baseline.

[0106] 5.7. Systemic lupus erythematosus Multiple chains of evidence suggest a role for type I interferon (IFN) in the pathogenesis of SLE. • Genetic polymorphisms associated with type I IFN are linked to susceptibility to SLE [18-20] • High IFN-α levels and type I IFN activity have been reported in SLE [21, 22]. Increased levels of messenger ribonucleic acid (mRNA), whose transcription is induced by type I interferon (type I IFN signature), are prominent in peripheral blood mononuclear cells and whole blood in approximately 60% of SLE patients and are associated with greater disease activity [23-28]. • Transcripts induced by type I IFNs are the most overexpressed transcripts in SLE.

[29] • IFN-induced proteins are increased in patients with SLE [30-32]. Overexpression of type I IFN, type I IFN signature, and type I IFN-induced proteins are associated with greater disease activity and organ system invasion in SLE.

[0107] Patients with high anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody titers, lupus nephritis, and progressive skin rashes have high serum levels of type I IFN

[21] . In addition, patients with acute skin infiltrates tend to have elevated IFN in the blood and skin

[22] . Skin biopsies from patients with SLE also show an increased type I IFN signature

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

[32] .

[0108] Immune complexes containing SLE autoantibodies, such as anti-dsDNA or anti-ribonucleoprotein (anti-RNP) antibodies, can activate type I IFN production

[21] . After internalization via Fc receptors, autoantibody-containing immune complexes bind to endosomal Toll-like receptors 7 and 9, stimulating type I IFN production. Type I IFN stimulates monocyte-derived dendritic cell maturation, which promotes loss of tolerance and the generation of autoreactive T and B cells, autoantibody production, immune complex formation, and further production of type I IFN, creating a self-persistent autoimmune cycle.

[0109] Aniflorumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) against the type I interferon receptor (IFNAR1). Aniflorumab inhibits the binding of type I IFNs to IFNARs and inhibits the biological activity of all type I IFNs. Two phase 3 studies (TULIP-1 and TULIP-2) and a phase 2b study (MUSE) have provided substantial evidence of the efficacy and safety of aniflorumab for moderate to severe active SLE. In all three trials, treatment with aniflorumab was associated with a >16% treatment difference compared to placebo at week 52 in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response rate. Combined data across a range of other clinically important endpoints (e.g., reduced oral corticosteroid use, improved skin disease, reduced flare) further support the efficacy of aniflorumab for the treatment of SLE

[33] .

[0110] 5.8. Type I IFN gene signature (IFNGS) Type I IFN is thought to play a central role in the pathogenesis of SLE disease, and inhibition of this pathway is targeted by aniflorumab. To understand the relationship between type I IFN expression and response to anti-IFN treatment, it is necessary to know whether the disease in question is driven by type I IFN activation. However, direct measurement of type I IFN remains challenging. Therefore, we developed transcript-based markers to evaluate the effect of overexpression of target proteins on a specific set of mRNA markers. The expression of these markers is readily detectable in whole blood and correlates with expression in affected tissues such as skin in SLE. The bimodal distribution of transcript scores for SLE subjects supports the definition of high and low subpopulations of IFN testing. Type I IFN testing is described in International Publication No. 2011028933(A1), which is incorporated in its entirety herein by reference. Type I IFN gene signatures can be used to identify subjects who have high or low type I IFN gene signature (IFNGS) testing. The IFNGS trial measures the expression of the genes IFI27, IFI44, IFI44L, and RSAD2 in the whole blood of the subjects, compared to three reference genes: 18S, ACTB, and GAPDH. The results of the trial are scores compared to pre-established cutoffs that classify patients into two groups: those with low or high levels of IFN-induced gene expression.

[0111] Gene expression can be measured by RT-PCR. Suitable primers and probes for gene detection can be found in International Publication No. 2011028933. A suitable kit for measuring gene expression for the IFNGS test is the QIAGEN therascreen® IFIGx RGQ RT-PCR kit (IFIGx kit), as described in Brohawn et al.

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

[0112] Type I IFNGS testing can be performed in a designated central laboratory using the QIAGEN therascreen IFN-inducible gene expression (IFIGx) Rotor-Gene Q (RGQ) reverse transcriptase PCR (RT-PCR) system. This expression system, along with the therascreen IFIGx RGQ RT-PCR kit used with the RGQ molecular diagnostic platform equipped with IFIGx software, includes collection tubes and

[0113] The IFIGx kit consists of the RNA isolation kit described above. The IFIGx kit measures the expression of four type I IFN-inducible genes (IFI27, IFI44, IFI44L, and RSAD2) against three housekeeping genes (ACTB, 18S, and GAPDH) to generate a positive or negative qualitative diagnostic score. The results are expressed as a score compared to a pre-established delta Ct-based cutoff in a bimodal distribution trough, classifying patients into one of two groups representing low or high IFIGx

[35] (Figure 1).

[0114] Analysis and validation of four-gene testing as an IFIGx measure has been reported in two Phase III studies of aniflorumab for the treatment of SLE (NCT02446899 and NCT02446912)

[36] . Patients with SLE exhibiting heterogeneous disease activity and symptoms are generally stratified by low or high levels of IFIGx [37, 38].

[0115] 6. Examples: Burden on systemic lupus erythematosus in clinical practice: Baseline data from the interferon-assisted prospective observational cohort study of SLE (SPOCS) 6.1. Introduction SLE is a highly heterogeneous disease. A better understanding of patient variability could shed light on disease etiology, enable better targeted therapies, and ultimately lead to improved clinical outcomes.

[0116] The SLE Prospective Observational Cohort Study (SPOCS, NCT03189875) was designed to systematically describe the patient journey in patients with moderate to severe systemic lupus erythematosus (SLE) according to IFNGS status, in terms of clinical features, disease activity and progression, treatment patterns, clinical outcomes, patient-reported health outcomes (PROs), and health resource utilization (HCRU)

[35] . SPOCS is the first real-world study to assess patients' IFNGS status over the long term. Type I IFN-inducible (IFI) gene expression, measured using IFN gene signatures (IFNGS), provides a method to assess type I IFN pathway activation in individual patients.

[0117] 6.2. Method 6.2.1. Study Design and Patients 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 three years with planned biannual study visits ending in November 2022. All treatments were based solely on the decisions of the physician treating the patient and were not influenced by the SPOCS protocol. Demographic, clinical, and laboratory data were collected from enrolled patients in eight countries across North America (Canada and the United States), Europe (France, Germany, Italy, Spain, and the United Kingdom), and Australia. The study was designed to be comprehensive in enrollment. To be included in the study, patients had to be ≥18 years of age and provide written informed consent. All patients meet the American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria, have current or previous serological tests for antinuclear antibodies (ANA) or anti-double-stranded DNA antibodies, have received at least 6 months of systemic treatment for active SLE (beyond nonsteroidal anti-inflammatory drugs [NSAIDs] and analgesics), and are classified as having moderate to severe SLE (Modified Systemic Lupus Erythematosus Disease Activity Index). A score of 2000 [excluding modified SLEDAI-2K, urinary or immunological scales, and laboratory results including lupus headache] ≥ 4 or a SLEDAI-2K score ≥ 6 points. Patients were excluded if they had active severe lupus nephritis, were enrolled in an intervention trial including the investigational drug, or were unable to complete the test measurements. The planned sample size of 1500 patients was adjusted to 900 for slow accrual of eligible patients, and thus the endpoint precision estimate for incidence was adjusted to 2.1 (95% confidence interval: 0.30–2.44) using the incidence of the target event of 1 event per 100 person-years in 25% of patients at 2-year follow-up.

[0118] SPOCS is conducted in accordance with the principles of the Declaration of Helsinki and is consistent with the International Council for Harmonization Good Clinical Practices, Good Pharmacoepidemiology Practice, and the application of research classifications in each country. All patients enrolled in SPOCS provided written informed consent.

[0119] 6.2.2. Data Collection To understand baseline characteristics and identify any differences within the cohort, data were collected at study participation, defined as regular visits at the time of signed consent. Baseline data included patient demographics (e.g., age, sex, and race [Native American or Alaskan Native, Asian, Black or African American, Australian Indigenous, Hawaiian or other Pacific Islander, White, or Other], or ethnicity [Hispanic or Latino, Non-Hispanic or Latino], as permitted by local regulations), body mass index, SLE disease characteristics including date of first diagnosis, SLEDAI-2K and modified SLEDAI-2K scores, organ system infiltration and organ injury by SLICC / ACR Injury Index (SDI) score, Safety of Estrogens in Lupus National Assessment (SELENA)-SLEDAI Flare Index (SFI), number and severity (mild / moderate or severe) of SLE flares by Physician Global Assessment of Disease Activity (PGA), comorbidities, and SLE treatments and concomitant medications. Blood samples were collected to determine baseline IFNGS.

[0120] 6.2.3. IFNGS Test Blood samples were collected in PAXgene® tubes and sent to the central laboratory for processing. Baseline mRNA expression of four type I IFN-inducible genes (IFI27, IFI44, IFI44L, and RSAD2) for three housekeeping genes (ACTB, 18S, and GAPDH) was determined for each patient using the QIAGEN therascreen® IFN-IFI gene expression Rotor-Gene® Q reverse transcriptase PCR system. This expression score was compared to a pre-established cutoff to classify each patient as either high or low IFNGS [29, 39].

[0121] statistical analysis Demographics, clinical characteristics, and SLE medications were summarized by the overall SPOCS population, SLEDAI-2K categories (<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 quartiles, and range, where appropriate. Categorical variables were summarized as the number and percentage of patients with non-missing values ​​in each category. Patient subgroups were compared using the Mann-Whitney U test, chi-squared test, Kruskal-Wallis test, or Fisher's exact test. All p-values ​​presented are apparent. All calculations and analyses were performed using R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

[0122] 6.2.4. Patient and citizen involvement Neither patients nor the general public were involved in the design of this trial.

[0123] 6.3.Results 6.3.1. Baseline patient characteristics and demographics 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 vast majority of enrolled patients [93.2%, 767 / 823] were female, and the mean (SD) age at study enrollment 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) were identified as belonging to different races. The mean (SD) time since SLE diagnosis was 11.1 (9.2) years (Table 7).

[0124] When stratified by baseline disease activity score, 241 patients had SLEDAI-2K ≥ 10 and 343 had SLEDAI-2K < 10. Patients with SLEDAI-2K ≥ 10 were younger than those with SLEDAI-2K < 10 (mean [SD]: 42.8 [13.7] years vs. 46.6 [14.2] years; P = 0.001) (Table 6). No difference was observed in mean age at first symptom of SLE between patients with SLEDAI-2K ≥ 10 and those with SLEDAI-2K < 10. The racial distribution was similar in patients with SLEDAI-2K ≥ 10 versus SLEDAI-2K < 10 (Caucasians: 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 versus SLEDAI-2K < 10 (10.4 [8.6] years vs. 12.4 [9.6] years); P=0.012) (Table 7).

[0125] [Table 6] All p-values ​​are nominal and have not been adjusted for multiplicity. Subgroups are not summed for the entire population n due to missing data. 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 (SLE Prospective Observational Cohort Study).

[0126] Approximately two-thirds of patients were classified as having a high IFNGS score, and one-third as having a low IFNGS score (70.6% [522 / 739] vs. 29.4% [217 / 739]) (Table 6). The proportion of patients in each IFNGS category differed among races (P<0.001), with Asian, Black, and White patients accounting for 10.4%, 19.9%, and 64.4% of the high IFNGS group, respectively, compared to 4.7%, 7.0%, and 84.0% of the low IFNGS group. 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. 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). A larger percentage of patients in the high IFNGS group were <30 years old at SLE diagnosis (50.5% vs. 22.7%) compared to the low IFNGS group (Table 7). Patients in the high IFNGS group were younger at the time of first symptom of SLE than patients in the low IFNGS group (mean [SD]: 30.0 [12.7] years vs. 36.8 [14.6] years; P < 0.001) (Table 7), and 53.7% of patients were <30 years at the time of first symptom compared to 32.3% in the low IFNGS group (Figure 4). Surprisingly, about 50% of patients diagnosed at age 50+ were low IFNGS, and less than 20% of patients diagnosed at age 29 or younger were low IFNGS (Figure 4).

[0127] 6.3.2. Baseline SLE disease activity and injury In the SPOCS cohort as a whole, patients most frequently had musculoskeletal (75.3%), cutaneous (67.6%), or immune (66.4%) infiltrations at baseline (Figure 5A). The mean (SD) SLEDAI-2K score was 9.8 (4.6), and the median (interquartile range [IQR]: 25th–75th percentile) score was 8.0 (6.0–12.0) (Table 7).

[0128] [Table 7-1]

[0129] [Table 7-2] All p-values ​​are nominal and have not been adjusted for multiplicity. Subgroups are not summed for the entire population n due to missing data. a The modified SLEDAI-2K score was defined as a SLEDAI-2K assessment score that does not include points resulting from any urinalysis or immunology measures or laboratory results, including lupus headache. b Systemic Lupus International Collaborating Clinics / American College of Rheumatology Damage Index>0. c The annual flare rate is calculated by dividing the number of flares by the daily tracking period and multiplying by 365.25. d Within 6 months of taking the exam. 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 Injury Index; SLE, Systemic Lupus Erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000; SLICC, Systemic Lupus International Collaborating Clinics; SPOCS, SLE Prospective Observational Cohort Study.

[0130] The percentage of patients with baseline SLEDAI-2K organ domain infiltration was higher among patients with a baseline SLEDAI-2K score ≥ 10 compared to patients with a baseline score < 10 for the CNS domain (18.7% vs. 0.9%), renal domain (32.0% vs. 7.3%), immunological domain (83.0% vs. 56.6%), and cutaneous domain (74.3% vs. 58.3%) (Figure 5B).

[0131] On average, the percentage of patients with modified SLEDAI-2K scores, SLEDAI-2K scores, and SLEDAI-2K scores ≥ 10 did not differ between high and low IFNGS patients. More patients in the high IFNGS group than in the low IFNGS group had hematological (12.6% vs. 4.1%), immunological (74.4% vs. 45.6%), or cutaneous (69.7% vs. 62.2%) SLEDAI-2K domain infiltration (all P<0.05) (Figure 2). Conversely, fewer patients in the high IFNGS group than in the low IFNGS group had CNS (5.8% vs. 11.1%, P=0.012) and musculoskeletal (72.6% vs. 81.6%, P=0.010) infiltration. Renal domain infiltration among patients in the high IFNGS group was 20.2% compared to 16.3% in the low IFNGS group.

[0132] The mean (SD) SDI score was 1.2 (1.6), and approximately half of all patients had organ damage (52.4%, 425 / 811) (Table 7). A slightly higher percentage of patients in the low IFNGS group had organ damage than in the high IFNGS group (57.6% vs. 49.6%, P=0.048).

[0133] 6.3.3. Flare Approximately half of all patients (54.1%, 445 / 822) experienced a flare of ≥1 within 6 months prior to the baseline visit (Table 7). Organ system infiltration was generally similar between patients who experienced flares and those who did not (Figure 5C). Compared to patients with a baseline SLEDAI-2K score <10, patients with a SLEDAI-2K score ≥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 a more common severe flare (as assessed by physician) (12.9% vs. 5.3%, P=0.001). In contrast, flares did not vary by IFNGS status, and neither the annual flare rate, flare severity (all P=NS), nor the percentage of patients who experienced a flare of ≥1 in the 6 months prior to baseline visit (IFNGS high vs. low: 55.0%, 287 / 522 vs. 52.3%, 113 / 216, P=0.51) differed between the high and low IFNGS groups.

[0134] 6.3.4.SLE treatment At baseline, 80.4% (662 / 823) of patients were receiving antimalarial agents, 53.8% (443 / 823) were receiving immunosuppressants, and 20.2% (166 / 823) were receiving biologics (Table 3). Oral glucocorticoids were used by 61.5% (506 / 823) of patients or had been used in the past year. Among patients receiving oral glucocorticoids, the mean cumulative dose and daily dose were similar regardless of whether they were in the SLEDAI-2K or IFNGS group.

[0135] There were no differences in any of the other baseline treatments between the baseline SLEDAI-2K groups (all P≥0.5) (Table 8). More patients classified as high for IFNGS compared to low received immunosuppressive agents (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), while fewer patients in the high IFNGS group received antimalarial drugs compared to the low group (78.0% [407 / 522] vs. 87.1% [189 / 217], P = 0.004). A higher percentage of patients in the high IFNGS group compared to the low group were receiving immunosuppressive agents regardless of antimalarial drug use (Table 9).

[0136]

Table 8

[0137] [Table 9] a Cytotoxic agents or immunosuppressants include cyclophosphamide, methotrexate, mycophenolate mofetil / mycophenolate, azathioprine, tacrolimus, mizoribine, leflunomide, or cyclosporine. IFNGS, type I interferon gene signature.

[0138] 6.3.5. Country-Specific Characteristics The percentage of patients with high IFNGS ranged from 64% to 83% across countries (Figure 3). Overall baseline data by country is provided online as supplements (Tables 10-12).

[0139] [Table 10] All p-values ​​are nominal and have not been adjusted for multiplicity. Subgroups are not summed for the entire population n due to missing data. BMI (Body Mass Index); IQR (Interquartile Range); SD (Standard Deviation); SLE (Systemic Lupus Erythematosus); SPOCS (SLE Prospective Observational Cohort Study); UK; USA.

[0140] [Table 11-1]

[0141] [Table 11-2] All p-values ​​are nominal and have not been adjusted for multiplicity. Subgroups are not summed for the entire population n due to missing data. a The modified SLEDAI-2K score was defined as a SLEDAI-2K assessment score that does not include points resulting from any urinalysis or immunology measures or laboratory results, including lupus headache. b The annual flare rate is calculated by dividing the number of flares by the daily tracking period and multiplying by 365.25. c Within 6 months of taking the exam. ACR, American College of Rheumatology SLE classification criteria; 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.

[0142] [Table 12-1]

[0143] [Table 12-2] All p-values ​​are nominal and have not been adjusted for multiplicity. Subgroups are not summed for the entire population n due to missing data. aCytotoxic agents or immunosuppressants include cyclophosphamide, methotrexate, mycophenolate mofetil / mycophenolate (MMF / MPA), azathioprine, tacrolimus, mizoribine, leflunomide, or cyclosporine. b Belimumab or rituximab; c The number of patients with at least one ongoing glucocorticoid prescription or at least one prescription recorded in the previous year; d The total amount of glucocorticoids received in the past 365 days, standardized to g / year; e The cumulative glucocorticoids are divided by 365 to convert them to a daily dose, and patients are grouped into daily dose groups. AM, antimalarial drugs; biologics, 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.

[0144] 6.4. Discussion SPOCS is a prospective observational study designed to systematically describe the patient journey with respect to clinical outcomes over time in a large real-world cohort of patients with moderate to severe SLE. Overall, SPOCS identified substantial clinical burden in a broadly representative group of patients with moderate to severe SLE in a real-world setting. SPOCS patients had a mean duration of SLE of 11 years, approximately half of them experienced at least one flare within 6 months prior to study enrollment, and more than half had evidence of organ damage at baseline. In addition, the inventors gained insights into two subgroups of patients with greater medical needs by characterizing patients with high disease activity and patients with elevated IFN signaling according to high IFNGS status.

[0145] Patients with higher SLE disease activity tend to experience greater clinical, social, and economic burdens than those with lower disease activity. In the SPOCS SLE cohort, approximately 41% of patients had high disease activity at baseline based on a SLEDAI-2K score of ≥10. Patients with SLEDAI-2K ≥10 were younger and had a shorter duration of SLE than those with SLEDAI-2K <10. At baseline, the percentage of patients with organ-specific signs in the immune, mucocutaneous, renal, vascular, hematological, and serosal systems was particularly higher in the SLEDAI-2K ≥10 group compared to the SLEDAI <10 group. SPOCS patients with higher baseline SLEDAI-2K scores (≥10) experienced more flares and more severe flares than patients with lower baseline scores, consistent with other real-world studies. There were no differences in therapy between the baseline SLEDAI-2K groups, which will help in investigating the long-term effects of treatment in these two groups in this study.

[0146] SPOCS, the first real-world study to assess patients' IFNGS levels, found that baseline IFNGS status was associated with differences in patient characteristics. Patients in the high IFNGS group were younger at the time of the first signs of SLE than those in the low IFNGS group, and the percentage of patients in the high IFNGS group under 30 years of age at SLE diagnosis was twice that of the low IFNGS group. Conversely, the low IFNGS group had twice the proportion of patients with “late-onset” SLE (i.e., patients diagnosed with SLE at ≥50 years of age). Age of onset (specified herein as “age at SLE diagnosis”) is associated with differences in clinical outcomes and disease progression. For example, late-onset SLE tends to be less frequent in showing organ-specific signs and is more painless. This is consistent with the pattern observed in this cohort, as patients in the high IFNGS group were more likely to have hematological, immunological, and cutaneous infiltrates than patients in the low IFNGS group. In a real-world study, we identified less musculoskeletal infiltration in high-vs-low IFNGS patients, and similar findings were identified in high-vs-low IFNGS patients with moderate to severe SLE in a clinical trial setting. In our study, according to SDI, slightly more low-vs-high IFNGS patients had organ damage, which is likely a function of higher age in low-IFNGS patients, as evidenced by more frequent comorbidities. More patients in the high-IFNGS group received immunosuppressants and / or oral glucocorticoids than in the low-IFNGS group, possibly due to differences in disease activity and signs at baseline.

[0147] In particular, the relative proportion of patients with high IFNGS versus low IFNGS was higher among Black and Asian patients compared to Caucasian patients, supporting findings in other moderate to severe SLE populations. Three of the four genes included in the SPOCS IFNGS assay (IFI27, IFI44L, and RSAD2) were associated with African ancestry, and in the same meta-analysis (adjusted for the presence of LN and HCQ use), only IFI27 expression was associated with disease activity.

[0148] SPOCS is a prospective study designed to systematically describe the patient journey in clinical practice for patients enrolled from multiple centers across a range of countries. The study was designed to broadly represent the moderate to severe SLE population. In contrast to many SLE-related real-world studies that rely on existing electronic health records in insurance claims databases, this study began with the collection of highly detailed baseline data, which was then collected over the long term following the same procedure.

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Claims

1. A method for treating systemic lupus erythematosus (SLE) in a subject requiring treatment, comprising administering a therapeutically effective dose of a type I IFN signaling inhibitor to the subject, a) The subject was diagnosed with SLE at an age of under 50 years (<), and / or b) A method in which the subject experienced the first signs of SLE at an age of approximately 30 years or younger.

2. The method according to claim 1, wherein the subject is diagnosed with SLE at the age of 30.

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

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

5. The method according to any one of claims 1 to 4, wherein the inhibitor of type I IFN signaling is a human monoclonal antibody specific to IFNAR1.

6. The aforementioned antibody (a) Heavy chain variable region complementarity determination region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3; (b) Heavy chain variable region complementarity determination region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4; (c) Heavy chain variable region complementarity determination region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5; (d) Amino acid sequence, light chain variable region complementarity determination region 1 (LCDR1) including SEQ ID NO: 6; (e) Amino acid sequence, light chain variable region complementarity determination region 2 (LCDR2) including SEQ ID NO: 7; and (f) The method according to claim 5, comprising an amino acid sequence and a light chain variable region complementarity determination region 3 (LCDR3) containing SEQ ID NO:

8.

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

2.

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

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

12.

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

11. The method according to claim 10, comprising administering an intravenous dose of aniflorumab or a functional variant thereof to the subject.

12. The method according to claim 11, wherein the intravenous dose is aniflorumab or a functional variant thereof in an amount of ≥300 mg.

13. The method according to claim 10 or 11, wherein the intravenous dose is ≤ 1000 mg.

14. The method according to claim 13, wherein the intravenous dose is approximately 300 mg, approximately 900 mg, or approximately 1000 mg.

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

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

17. The method according to claim 16, wherein the subcutaneous dose is aniflorumab or a functional variant thereof in doses of >105 mg and <150 mg.

18. The method according to claim 16, wherein the subcutaneous dose is aniflorumab or a functional variant thereof in an amount of ≤135 mg.

19. The method according to claim 16, wherein the subcutaneous dose is approximately 120 mg.

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

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

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

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

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

25. The method according to any one of claims 1 to 24, wherein the subject is a patient with high type I interferon-stimulated gene signature (IFNGS) test scores before treatment.

26. The method according to any one of claims 1 to 25, comprising identifying the subject as a patient with high IFNGS test scores before treatment.

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

28. An injection device comprising the pharmaceutical composition described in claim 27.

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

30. The injection device according to claim 28, wherein the injection device is a pre-filled syringe with accessories (AFPS).

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

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

33. The kit according to claim 32, wherein the instruction manual includes a statement that the subject is a subject diagnosed with SLE at an age of less than 50 years, and / or a subject who experienced the first signs of SLE at an age of approximately 30 years or younger.

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