Treatment of cutaneous lupus erythematous

Abstract

This disclosure relates to methods and compositions for treating cutaneous lupus erythematosus (CLE). Specifically, this disclosure relates to a method comprising administering a type I IFN receptor inhibitor to a subject.

Description

[Previous Technology]

[0001] Cutaneous lupus erythematosus (CLE) is a rare, chronic, inflammatory, autoimmune, type 1 interferon (IFN) driven skin disease that can occur spontaneously or as part of a broader diagnosis of systemic lupus erythematosus (SLE). The most common treatment is topical corticosteroids, but treatment adherence can decline over time, and continued use can cause side effects.

[0002] CLE involves the skin much more than SLE. CLE may be part of the SLE spectrum or may be a standalone entity without systemic features. When CLE is part of SLE, it may recur or may be part of a multi-organ recurrence without any other systemic deterioration.2

[0003] Belimumab is a monoclonal antibody that reduces B lymphocyte survival by blocking the binding of soluble human B lymphocyte stimulating factor (BLyS) to its B cell receptor. Belimumab is approved by the FDA and EMA for the treatment of SLE, but not for the treatment of CLE. In fact, no drug has been approved for CLE in more than 50 years, highlighting the significant unmet medical need for new treatments with disease-specific mechanisms of action that reduce overall disease activity while also decreasing the risk of relapse and long-term skin damage.

[0004] Anilumab is a human monoclonal antibody targeting the type I IFN receptor subunit 1.3 Two phase 3 randomized controlled trials (TULIP-1 and TULIP-2) demonstrated that anilumab provides therapeutic benefit at clinical endpoints and is well tolerated in patients with moderate to severe SLE. The safety and efficacy of type I IFN receptor inhibitors in CLE patients have not been previously established.

[0005] The present invention solves one or more of the above problems. [Summary of the Invention]

[0006] This invention relates to a treatment for improving cutaneous lupus erythematosus (CLE). Specifically, this invention relates to a method of treating CLE in subjects of need, comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, wherein the method reduces the subject's CLE disease activity. Among other things, this invention is supported for the first time by data presented herein from two phase III, multicenter, multinational, randomized, double-blind, placebo-controlled clinical trials (NCT 02446899 and NCT 02962960) demonstrating that the IFNAR1 inhibitor (anilumab) treats the rash in patients with moderate to severe CLE (i.e., CLASI score ≥ 10) in just 4 weeks.

[0007] The present invention also relates to a method suitable for use in treating subjects with CLE, particularly by subcutaneous administration of a unit dose of aniluromab.

Implementation Method

[0042] Methods for treating cutaneous lupus erythematosus (CLE)

[0043] The present invention relates to a method for treating cutaneous lupus erythematosus (CLE) in a subject in need, the method comprising administering a type I IFN receptor (IFNAR1) inhibitor to the subject, wherein the method reduces the subject’s CLE disease activity.

[0044] Reducing CLE disease activity in the subject may include a reduction in the patient's rash compared to pre-treatment levels. Reducing CLE disease activity in the subject may include rash resolution. Reducing CLE disease activity may include ≥50% improvement in rash compared to pre-treatment levels. Reducing CLE disease activity may include ≥50% improvement in rash compared to pre-treatment levels, as assessed by mCLASI. Prior to treatment, the subject's CLASI or mCLASI score may be ≥6 or ≥10. Reduction in CLE activity may be achieved by week 4 of treatment. This IFNAR1 inhibitor reduces interferon-stimulated skin gene expression. IFNAR1 inhibitor

[0045] "Type I interferon receptor inhibitors" refer to molecules that antagonize receptors of type I interferon ligands such as interferon-α and interferon-β. When administered to a patient, such inhibitors preferably 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, SIGLEC1, USP18, RTP4, and DNAPTP6. At least four genes may suitably be IFI27, IFI44, IFI44L, and RSAD2. The "type I interferon receptor" is preferably the interferon-α / β receptor (IFNAR). IFNAR1 is a subunit of IFNAR. IFNAR1 and IFNAR are used interchangeably in this document.

[0046] 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 (which 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. Alternatively or alternatively, a type I interferon receptor inhibitor may be a small molecule inhibitor of the type I interferon receptor (e.g., for pharmacological inhibition of type I interferon receptor activity).

[0047] The IFNAR1 inhibitor may be a human monoclonal antibody specific to IFNAR1. The IFNAR1 inhibitor may be a modified IgG1-like human monoclonal antibody specific to IFNAR1.

[0048] The antibody may contain a heavy chain variable region complementation-determining region 1 (HCDR1) containing the amino acid sequence of SEQ ID NO: 3. The antibody may contain a heavy chain variable region complementation-determining region 2 (HCDR2) containing the amino acid sequence of SEQ ID NO: 4. The antibody may contain a heavy chain variable region complementation-determining region 3 (HCDR3) containing the amino acid sequence of SEQ ID NO: 5. The antibody may contain a light chain variable region complementation-determining region 1 (LCDR1) containing the amino acid sequence of SEQ ID NO: 6. The antibody may contain a light chain variable region complementation-determining region 2 (LCDR2) containing the amino acid sequence of SEQ ID NO: 7. The antibody may contain a light chain variable region complementation-determining region 3 (LCDR3) containing the amino acid sequence of SEQ ID NO: 8.

[0049] The antibody may comprise a human heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1. The antibody may comprise a human light chain variable region containing the amino acid sequence of SEQ ID NO: 2. The antibody may comprise a human light chain constant region containing the amino acid sequence of SEQ ID NO: 9. The antibody may comprise a human heavy chain constant region containing the amino acid sequence of SEQ ID NO: 10. The antibody may contain an amino acid substitution of L234F in the Fc region, as numbered by the EU index shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody. The antibody may comprise a human heavy chain containing the amino acid sequence of SEQ ID NO: 11. The antibody may comprise a human light chain containing the amino acid sequence of SEQ ID NO: 12.

[0050] The antibody may comprise: (a) a heavy chain variable region complementation-determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementation-determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region complementation-determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementation-determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (b) a light chain variable region complementation-determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and (c) a light chain variable region complementation-determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 8.

[0051] 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.

[0052] This IFNAR1 inhibitor may be aniluzumab or a functional variant thereof. Dosage and method of administration.

[0053] The method may include administering an intravenous dose of anilumab or a functional variant thereof to the subject. The intravenous dose may be ≥ 300 mg of anilumab 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 four weeks (Q4W).

[0054] The method may include administering a subcutaneous dose of anilumab or a functional variant thereof. The subcutaneous dose may be >105 mg and <150 mg of anilumab or a functional variant thereof. The subcutaneous dose may be ≤135 mg of anilumab or a functional variant thereof. The subcutaneous dose may be about 120 mg. The subcutaneous dose may be administered in a single administration step. The subcutaneous dose may be administered at 6-8 day intervals. The subcutaneous dose may be administered once weekly. The volume of the subcutaneous dose may be about 0.5 to about 1 ml. The volume of the subcutaneous dose may be about 0.8 ml.

[0055] The subject may have moderate to severe CLE prior to treatment. The subject may have mild CLE. Moderate to severe CLE is defined as a CLASI score ≥ 10.

[0056] The subject may be a patient with a high pre-treatment type I interferon-stimulated gene marker (IFNGS) test result. The method may include identifying the subject as a patient with a high pre-treatment IHFGS test result.

[0057] Many patients with CLE receive corticosteroids (glucocorticoids, oral corticosteroids, OCS). However, corticosteroids are associated with organ damage. Anilumab allows for the gradual tapering of corticosteroids (glucocorticoids) in CLE patients (steroid control). This treatment or approach may include administering a corticosteroid to the subject, as needed, wherein the corticosteroid is an oral corticosteroid. This approach may include gradually tapering the dose of corticosteroid administered to the subject (steroid control). This approach may include administering a first dose of the corticosteroid and subsequently administering a second dose of the corticosteroid, wherein the second dose of the corticosteroid is lower than the first dose of the corticosteroid. The second dose of the corticosteroid may be an equivalent dose of approximately 7.5 mg of presbyson or less. The second dose of the corticosteroid may be an equivalent dose of 5 mg of presbyson or less. This approach or treatment may include administering a second dose of corticosteroid once daily. The first dose of the corticosteroid may be approximately 10 mg of the equivalent of pressoner. This method may include gradually reducing the dose of corticosteroid administered to the patient from 10 mg or more daily to less than 10 mg daily. This method or treatment may include administering a second dose of corticosteroid once daily. This method may allow administration of a reduced dose 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.

[0058] This method may include steroid control in a subject, wherein the dose of steroid administered to the subject is gradually reduced from the baseline pre-control dose to the post-control dose. The post-control dose may be ≤ 7.5 mg / day of prisson or an equivalent dose of prisson. The pre-control dose may be 20 mg / day of prisson or an equivalent dose of prisson. Steroids may include glucocorticoids. Steroids may include oral glucocorticoids. This steroid can be selected from the group consisting of: hydrocortisone, mometasone, fluticasone, acetone fluocinolone acetonide, fluocinolone acetonide, cyclosporine, budesonide, beclomethasone, deficotinide, flunisolone, beclomethasone dipropionate, betamethasone, beclomethasone valerate, methylpresone, dexamethasone, presone, cortisol, triamcinolone, clobetasol, beclomethasone propionate, beclomethasone butyrate, corticosteroids, clotropone, dihydroxycortisone, aclomethasone, ansine, diflucolide valerate, flucolide, fluprednisolone, fluandrolone, fluandrolone. Nandrolone, fluocinolone, halcinonide, ubetasol, desotinide, difluralasone, fluproxetine, fluronolone corticosteroid, prednisolone, dehydrocorticosteroid, fluprexone, azelastine, dexamethasone 21-phosphate, fluproxetine, flumethasone, fluproxetine corticosteroid, haloprexone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21-acetate, fluprexone, fluprexone 21-phosphate, beclomethasone propionate, acetone corticosteroid, or mixtures thereof. This steroid may be fluprexone.

[0059] The present invention also relates to a unit dose for use in the method of the present invention, wherein the unit dose comprises >105 mg and ≤150 mg of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). The unit dose may comprise 105 mg to 149 mg of an IFNAR inhibitor.

[0060] This unit dose may contain ≤ 135 mg (i.e., 135 mg or less) of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). This unit dose may contain 105 mg to 135 mg of an IFNAR inhibitor. This unit dose may contain approximately 120 mg of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). This unit dose may contain 120 mg of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). This unit dose may consist substantially of > 105 mg and < 150 mg of an IFNAR inhibitor (aniluzumab or a functional variant thereof). This unit dose may consist substantially of ≤ 135 mg of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). This unit dose may consist substantially of approximately 120 mg of an IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof). The concentration of the IFNAR inhibitor (e.g., aniluzumab or a functional variant thereof) in this unit dose may be approximately 150 mg / ml. The volume of this unit dose may be less than 1 ml. The volume of this dose or unit dose may be from about 0.5 ml to about 1 ml. The concentration of this unit dose may be about 0.8 ml. The volume of this unit dose may be 0.8 ml. This unit dose may contain a formulation of about 150 mg / ml to 200 mg / ml anilumab or a functional variant thereof, about 25 mM to 150 mM lysine, and unloaded excipients. This unit dose may contain a formulation of 150 mg / ml to 200 mg / ml anilumab or a functional variant thereof, 25 mM to 150 mM lysine, and unloaded excipients. This unit dose contains a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The pH of this formulation may be about 5.9.

[0061] In another aspect, the present invention relates to a method of treating a subject with CLE, the method comprising subcutaneously administering a dose of anilumab or a functional variant thereof, wherein weekly administration of the dose provides plasma concentrations in the subject that are at least equivalent to plasma concentrations provided by intravenous administration of 300 mg anilumab or a functional variant thereof every 4 weeks. Weekly administration of the dose may provide plasma concentrations in the subject that are greater than plasma concentrations provided by intravenous administration of 300 mg anilumab or a functional variant thereof every 4 weeks. Weekly administration of the dose may provide plasma concentrations in the subject that are at least equivalent to plasma concentrations provided by intravenous administration of 400 mg anilumab or a functional variant thereof every 4 weeks. The dose may be administered in a single administration step. The dose administered to the subject may be < 150 mg (i.e., less than 150 mg) of anilumab or a functional variant thereof. The dose administered to the subject may be > 105 mg (i.e., greater than 105 mg) of anilumab or a functional variant thereof. The dose administered to the subject may be ≤ 135 mg (i.e., 135 mgl or less) of aniluzumab or a functional variant thereof. The dose administered to the subject may be approximately 120 mg of aniluzumab or a functional variant thereof.

[0062] Administration of this dose or unit dose can provide a plasma concentration of anilumab or its functional variant in the patient at a level of ≥ 10 µg (i.e., 10 μg or more) per ml of plasma (i.e., a plasma concentration ≥ 10 µg / ml). Administration of this dose or unit dose can provide a plasma concentration of anilumab or its functional variant in the subject of about 10 µg / ml to 100 µg / ml. Administration of this dose or unit dose can provide a plasma concentration of anilumab or its functional variant in the subject of about 20 µg / ml to 80 µg / ml. Administration of this dose or unit dose can provide a plasma concentration of anilumab or its functional variant in the subject of about 30 µg / ml to 70 µg / ml. Administration of this dose or unit dose can provide a trough concentration of anilumab or its functional variant in the subject of ≥ 20 µg / ml (i.e., 20 μg / ml or higher). This dose or unit dose can provide a trough concentration of ≥ 30 µg / ml (i.e., 30 μg / ml or higher) of anilumab or its functional variant in the subject. This dose or unit dose can provide a trough concentration of ≥ 40 µg / ml (i.e., 40 μg / ml or higher) of anilumab or its functional variant in the subject. This dose or unit dose can provide a trough concentration of approximately 20 µg / ml to 100 µg / ml of anilumab or its functional variant in the subject. This dose or unit dose can provide a trough concentration of approximately 30 µg / ml to 80 µg / ml of anilumab or its functional variant in the subject. This dose or unit dose can provide a trough concentration of approximately 40 µg / ml to 70 µg / ml of anilumab or its functional variant in the subject.

[0063] In another aspect, the present invention relates to a method of treating a subject with CLE, the method comprising subcutaneously administering a dose of aniluzumab or a functional variant thereof, wherein the dose is 105 mg to 149 mg.

[0064] This dose or unit dose may be 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg or 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg or 149 mg. Subject

[0065] The subject may be a human subject. The subject may be an adult. The subject may be a patient with elevated type I IFN gene markers. The subject may be a patient with elevated pre-type I interferon-stimulated gene markers (IFNGS) tests when administered this dose or unit dose. The subject may have elevated IFI27, IFI44, IFI44L, and RSAD2 genes in whole blood. The method may include identifying the subject as a patient with elevated pre-IFNGS tests when treated with this dose or unit dose. The method may include measuring the expression of IFI27, IFI44, IFI44L, and RSAD2 genes in the subject's whole blood. The method may include measuring the expression of IFI27, IFI44, IFI44L, and RSAD2 genes in the subject's whole blood by RT-PCR.

[0066] This dose or unit dose may provide in the subject a therapeutic effect at least equivalent to that provided by an intravenous dose of 300 mg anilumab or a functional variant thereof administered every 4 weeks (Q4W). This dose or unit dose may provide in the subject a trough concentration of anilumab or a functional variant thereof that is greater than the trough concentration of anilumab or a functional variant thereof provided by an intravenous dose of 300 mg anilumab or a functional variant thereof administered every 4 weeks (Q4W). The anilumab or a functional variant thereof may be included in the pharmaceutical composition. The pharmaceutical composition may contain about 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, about 25 mM to 150 mM lysine, and unloaded excipients. The pharmaceutical composition may contain 150 mg / mL anilumab or a functional variant thereof. The pharmaceutical composition may contain 50 mM lysine HCl. The drug composition may contain 130 mM trehalose dihydrate. The drug composition may contain 0.05% polysorbate 80. The drug composition may contain 25 mM histidine / histidine HCl. The drug composition may contain 150 mg / mL aniluzumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0067] The method of the present invention may include administering the 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 of anilumab or a functional variant thereof, wherein the method includes administering the dose once weekly (QW) in a single administration step. In other words, the method includes administering 120 mg QW of anilumab 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. This dose or unit may be administered once weekly for at least approximately 32 weeks. This dose or unit may be administered once weekly for approximately 8 weeks. This dose or unit may have a volume suitable for delivery in a single subcutaneous administration step. The volume of this dose or unit may be from approximately 0.5 ml to approximately 1 ml. The volume of this dose or unit may be less than 1 ml. The volume of this dose or unit may be approximately 0.8 ml. Drug composition.

[0068] The present invention also relates to a pharmaceutical composition for use in a method of treating a subject with CLE, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of anilumab or a functional variant thereof, wherein the dose is > 105 mg and < 150 mg. The dose of anilumab or a functional variant thereof may be a unit dose (unit dose form, drug unit dose form, drug unit dose). Functional anilumab variants include an antigen-binding fragment of anilumab and antibody and immunoglobulin derivatives of anilumab.

[0069] In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating a subject with CLE, the method comprising subcutaneously administering the pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a dose of anilumab or a functional variant thereof, wherein weekly administration of the pharmaceutical composition in the subject provides plasma concentrations at least equivalent to those provided by intravenous administration of 300 mg anilumab or a functional variant thereof every 4 weeks. Weekly administration of this dose may provide plasma concentrations in the subject approximately equivalent to those provided by intravenous administration of 400 mg anilumab or a functional variant thereof every 4 weeks. This dose may be < 150 mg (i.e., less than 150 mg) of anilumab or a functional variant thereof. This dose may be > 105 mg (i.e., greater than 105 mg) of anilumab or a functional variant thereof. This dose may be ≤ 135 mg (i.e., 135 mg or less) of anilumab or a functional variant thereof. The dose may be approximately 120 mg of aniluzumab or a functional variant thereof.

[0070] This drug composition can be administered at intervals of 6 to 8 days. It can be administered once weekly (QW). It can be administered in a single dosing step. The dose can be 120 mg of aniluzumab or a functional variant thereof, and this treatment may include administration of this dose in a single dosing step once weekly (QW). It can be administered once weekly for at least approximately 4 weeks. It can be administered once weekly for at least approximately 8 weeks. It can be administered once weekly or in units for at least approximately 12 weeks. It can be administered once weekly for at least approximately 16 weeks. It can be administered once weekly for at least approximately 20 weeks. It can be administered once weekly for at least approximately 24 weeks. It can be administered once weekly for at least approximately 28 weeks. It can be administered once weekly for at least approximately 32 weeks. The drug composition can be administered once weekly for approximately 8 weeks. The drug composition can have a volume suitable for delivery in a single subcutaneous administration step. The volume of the drug composition can be from approximately 0.5 ml to approximately 1 ml. The volume of the drug composition can be less than 1 ml. The volume of the drug composition can be approximately 0.8 ml.

[0071] Administration of this drug composition can provide a plasma concentration of anilumab or a functional variant thereof in a patient at a level of ≥ 10 µg (i.e., 10 μg or more) per ml of plasma (i.e., a plasma concentration ≥ 10 µg / ml). Administration of this drug composition can provide a plasma concentration of anilumab or a functional variant thereof of about 10 µg / ml to 100 µg / ml in the subject. Administration of this drug composition can provide a plasma concentration of anilumab or a functional variant thereof of about 20 µg / ml to 80 µg / ml in the subject. Administration of this drug composition can provide a plasma concentration of anilumab or a functional variant thereof of about 30 µg / ml to 70 µg / ml in the subject. Administration of this drug composition can provide a trough concentration of anilumab or a functional variant thereof of ≥ 20 µg / ml (i.e., 20 μg / ml or higher) in the subject. Administration of this drug composition may provide in the subject a trough concentration of anilumab or a functional variant thereof of ≥ 30 µg / ml (i.e., 30 μg / ml or higher). Administration of this drug composition may provide in the subject a trough concentration of anilumab or a functional variant thereof of ≥ 40 µg / ml (i.e., 40 μg / ml or higher). Administration of this drug composition may provide in the subject a trough concentration of anilumab or a functional variant thereof of approximately 20 µg / ml to 100 µg / ml. Administration of this drug composition may provide in the subject a trough concentration of anilumab or a functional variant thereof of approximately 30 µg / ml to 80 µg / ml. Administration of this drug composition may provide in the subject a trough concentration of anilumab or a functional variant thereof of approximately 40 µg / ml to 70 µg / ml.

[0072] The pharmaceutical composition can provide in the subject a therapeutic effect at least equivalent to that provided by an intravenous dose of 300 mg anilumab or a functional variant thereof administered once every 4 weeks (Q4W). The pharmaceutical composition can provide in the subject a trough concentration of anilumab or a functional variant thereof that is greater than the trough concentration of anilumab or a functional variant thereof provided by an intravenous dose of 300 mg anilumab or a functional variant thereof administered once every 4 weeks (Q4W). Anilumab or a functional variant thereof may be included in the pharmaceutical composition. The pharmaceutical composition may contain about 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, about 25 mM to 150 mM lysine, and unloaded excipients. The pharmaceutical composition may contain 150 mg / mL anilumab or a functional variant thereof. The pharmaceutical composition may contain 50 mM lysine HCl. The drug composition may contain 130 mM trehalose dihydrate. The drug composition may contain 0.05% polysorbate 80. The drug composition may contain 25 mM histidine / histidine HCl. The drug composition may contain 150 mg / mL aniluzumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0073] The pharmaceutical composition may contain approximately 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition may contain 150 mg / mL anilumab or a functional variant thereof. The pharmaceutical composition may contain 50 mM lysine HCl. The pharmaceutical composition may contain 130 mM trehalose dihydrate. The pharmaceutical composition may contain approximately 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The pharmaceutical composition may contain 150 mg / mL anilumab or a functional variant thereof. The pharmaceutical composition may contain 50 mM lysine HCl. The pharmaceutical composition may contain 130 mM trehalose dihydrate. The pharmaceutical composition may contain 0.05% polysorbate 80. The drug composition may contain 25 mM histidine / histidine HCl. The drug composition may contain 150 mg / mL aniluzumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl. Equipment

[0074] The present invention also relates to an injection device comprising a unit dose of the pharmaceutical composition of the present invention or for any purpose of the present invention.

[0075] The drug in the injection device may contain >105 mg (i.e., greater than 105 mg) and <150 mg (i.e., less than 150 mg) of anilumab or a functional variant thereof. The drug composition in the injection device may contain about 120 mg of anilumab or a functional variant thereof. The concentration of anilumab or a functional variant thereof in the drug composition in the injection device may be about 150 mg / ml. The volume of the drug composition in the injection device may be at least about 0.8 ml. The volume of the drug composition may be about 0.8 ml.

[0076] The drug composition in this injection device may contain approximately 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The drug composition in this injection device may contain 150 mg / mL anilumab or a functional variant thereof. The drug composition in this injection device may contain 50 mM lysine HCl. The drug composition may contain 130 mM trehalose dihydrate. The drug composition in this injection device may contain approximately 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, approximately 25 mM to 150 mM lysine salt, and unloaded excipients. The drug composition in this injection device may contain 150 mg / mL anilumab or a functional variant thereof. The drug composition may contain 50 mM lysine HCl. The drug composition in this injection device may contain 130 mM trehalose dihydrate. The drug composition in this injection device may contain 0.05% polysorbate 80. The drug composition in this injection device may contain 25 mM histidine / histidine HCl. The drug composition in this injection device may contain 150 mg / mL aniluzumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0077] In another aspect, the present invention relates to an injection device comprising a unit dose. The unit dose may contain >105 mg (i.e., at least 105 mg) and <150 mg (i.e., less than 150 mg) of anilumab or a functional variant thereof. The unit dose may contain ≤135 mg (i.e., 135 mg or less) of anilumab or a functional variant thereof. The unit dose may contain about 120 mg of anilumab or a functional variant thereof. The unit dose in the injection device may contain 120 mg of anilumab or a functional variant thereof. The unit dose in the injection device may consist substantially of >105 mg and <150 mg of anilumab or a functional variant thereof. The unit dose in the injection device may consist substantially of ≤135 mg of anilumab or a functional variant thereof. The unit dose in the injection device may consist substantially of about 120 mg of anilumab or a functional variant thereof. The concentration of anilumab or a functional variant thereof in the unit dose in the injection device may be about 150 mg / ml. The volume of a unit dose in this injection device can be less than 1 ml. The volume of a unit dose in this injection device can be from about 0.5 ml to about 1 ml. The concentration of the unit dose can be about 0.8 ml. The volume of the unit dose can be 0.8 ml. The unit dose in this injection device may contain a formulation of about 150 mg / ml to 200 mg / ml anilumab or a functional variant thereof, about 25 mM to 150 mM lysine, and unloaded excipients. The unit dose in this injection device may contain a formulation of 150 mg / ml to 200 mg / ml anilumab or a functional variant thereof, 25 mM to 150 mM lysine, and unloaded excipients. The unit dose contains a formulation of 25 mM histidine-HCl, 130 mM trehalose, and 0.05% w / v polysorbate 80. The pH of the formulation may be about 5.9.

[0078] 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 autoinjector (AI). Kit

[0079] In another aspect, the present invention relates to a kit comprising a unit dose of the present invention and instructions for use, wherein the instructions for use include instructions for administering the unit dose subcutaneously to a subject.

[0080] In another aspect, the present invention relates to a kit containing a pharmaceutical composition for use in the present invention, wherein the instructions for use include instructions for administering the pharmaceutical composition subcutaneously to a subject.

[0081] In another aspect, the present invention relates to a kit comprising an injection device and an instruction manual comprising any of the present invention, wherein the instruction manual comprises an instruction manual for administering the unit dose or pharmaceutical composition subcutaneously to the subject.

[0082] The kit of the present invention may include packaging adapted to contain an injection device and instructions for use. Instructions for use may be attached to the injection device. The instructions for use may include instructions for administering >105 mg and <150 mg of anilumab or a functional variant thereof. The instructions for use may include instructions for administering ≤135 mg of anilumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anilumab or a functional variant thereof. The instructions for use may include instructions for administering 120 mg of anilumab or a functional variant thereof every 4 weeks. The instructions for use may define the subject as having type I IFN-mediated disease. The instructions for use may define the subject as having CLE. The instructions for use may define the subject as having moderate to severe CLE. The instructions for use may be written instructions.

[0083] This instruction manual may specify the injection device, unit dose, and / or drug composition for use in the treatment of CLE. This instruction manual includes instructions for weekly administration of 120 mg aniluzumab or a functional variant thereof. Formulation

[0084] Anilumab or a functional variant thereof may be included in the pharmaceutical composition. The pharmaceutical composition may contain approximately 150 mg / mL to 200 mg / mL anilumab or a functional variant thereof, approximately 25 mM to 150 mM lysine, and unloaded excipients. The pharmaceutical composition may contain 150 mg / mL anilumab or a functional variant thereof. The pharmaceutical composition may contain 50 mM 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 anilumab or a functional variant thereof, 50 mM lysine HCl, 130 mM trehalose dihydrate, 0.05% polysorbate 80, and 25 mM histidine / histidine HCl.

[0085] Stable formulations suitable for administration to subjects containing aniluromab are described in detail in U.S. Patent 10,125,195 B1, the entire contents of which are incorporated herein by reference. Definition of Aniluromab

[0086] Anilumab (MEDI-546, anifro, ANI) is a monoclonal antibody (mAb) targeting subunit 1 of the type I interferon receptor (IFNAR1) of human immunoglobulin G1κ (IgG1κ). Anilumab downregulates IFNAR communication and inhibits the expression of IFN-inducible genes. Disclosures relating to anilumab can be found in U.S. Patent Nos. 7,662,381 and 9,988,459, which are incorporated herein by reference in their entirety. Sequence information for anilumab is provided in Table 5-1: Sequence. [Table 5-1]: Sequence describe SEQ ID sequence Aniluzumab VH 1 EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLESMGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHDIEGFDYWGRGTLVTVSS Aniluzumab VL 2 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFAWYQQKPGQAPRLLIYGASSRATGIPDRLSGSGSGTDFTLTITRLEPEDFAVYYCQQYDSSAITFGQGTRLEIK HCDR1 3 NYWIA HCDR2 4 IIYPGDSDIRYSPSFQG HCDR3 5 HDIEGFDY LCDR1 6 RASQSVSSSFFA LCDR2 7 GASSRAT LCDR3 8 QQYDSSAIT Light chain constant region 9 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Heavy chain constant region 10 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Heavy chain 11 EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLESMGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQWSSLKASD TAMYYCARHD IEGFDYWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYIC NVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPA SIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK Light chain 12 EIVLTQSPGTLSLSPGERATLSCRASQSVS SSFFAWYQQK PGQAPRLLIY GASSRATGIPDRLSGSGSGT DFTLTITRLE PEDFAVYYCQ QYDSSAITFG QGTRLEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0087] "Anilumab" is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively; and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. Anilumab is an immunoglobulin comprising VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2.

[0088] The constant region of aniluzumab has been modified to give it a reduced affinity for at least one Fc ligand compared to the unmodified antibody. Aniluzumab is a modified IgG monoclonal antibody specific to IFNAR1 containing an amino acid substitution of L234F in its Fc region, as indicated in the EU index shown in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Virginia). Aniluzumab is a modified IgG monoclonal antibody specific to IFNAR1 containing amino acid substitutions of L234F, L235E, and / or P331S in its Fc region, as indicated in the EU index shown in Kabat (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Virginia). Aniluma antibody contains the light chain constant region of SEQ ID NO: 9. Aniluma antibody contains the heavy chain constant region of SEQ ID NO: 10. Aniluma antibody contains both the light chain constant region of SEQ ID NO: 9 and the heavy chain constant region of SEQ ID NO: 10. Aniluma antibody contains the heavy chain of SEQ ID NO: 11. Aniluma antibody contains the light chain of SEQ ID NO: 12. Aniluma antibody contains both the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12.

[0089] Functional variants of anilumab perform the same function as anilumab. Functional variants of anilumab bind to the same target and have the same effector function as anilumab. Functional anilumab variants include antigen-binding fragments of anilumab as well as antibody and immunoglobulin derivatives of anilumab. Functional variants include biosimilars and interchangeable products. The terms biosimilars and interchangeable products are defined by the FDA and EMA. The term biosimilar is a biological product that is structurally highly similar to an approved (e.g., FDA-approved) biological product (reference product, such as anilumab) and has no clinically significant differences from the reference product in terms of pharmacokinetics, safety, and efficacy. The presence of clinically significant differences in biosimilars can be assessed in human pharmacokinetic (exposure) and pharmacodynamic (response) studies and in the evaluation of clinical immunogenicity. An interchangeable product is a biosimilar that is expected to produce the same clinical outcomes as the reference product in any given patient.

[0090] For example, a variant of the reference (anilumumab) antibody may comprise: a heavy chain CDR1 having a difference of up to 2 amino acids compared to SEQ ID NO: 3; a heavy chain CDR2 having a difference of up to 2 amino acids compared to SEQ ID NO: 4; a heavy chain CDR3 having a difference of up to 2 amino acids compared to SEQ ID NO: 5; a light chain CDR1 having a difference of up to 2 amino acids compared to SEQ ID NO: 6; a light chain CDR2 having a difference of up to 2 amino acids compared to SEQ ID NO: 7; and a light chain CDR3 having a difference of up to 2 amino acids compared to SEQ ID NO: 8; wherein the variant antibody binds to the target of anililumumab (e.g., IFNAR), and preferably binds with the same affinity.

[0091] A variant of the reference (anilumumab) antibody may include: a heavy chain CDR1 having a difference of up to one amino acid compared to SEQ ID NO: 3; a heavy chain CDR2 having a difference of up to one amino acid compared to SEQ ID NO: 4; a heavy chain CDR3 having a difference of up to one amino acid compared to SEQ ID NO: 5; a light chain CDR1 having a difference of up to one amino acid compared to SEQ ID NO: 6; a light chain CDR2 having a difference of up to one amino acid compared to SEQ ID NO: 7; and a light chain CDR3 having a difference of up to one amino acid compared to SEQ ID NO: 8; wherein the variant antibody binds to the target of anililumumab (e.g., IFNAR) with the same affinity as required.

[0092] When compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 5, 4, or 3 amino acid differences in its CDR, provided that there are at most 2 (up to 1 as needed) amino acid differences per CDR. When compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (up to 1 as needed) amino acid differences in its CDR, provided that there are at most 2 amino acid differences per CDR. When compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (up to 1 as needed) amino acid differences in its CDR, provided that there are at most 1 amino acid difference per CDR.

[0093] When compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 5, 4, or 3 amino acid differences in its frame regions, provided that there are at most 2 (up to 1 if needed) amino acid differences in each frame region. Alternatively, when compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (up to 1 if needed) amino acid differences in its frame regions, provided that there are at most 2 amino acid differences in each frame region. Alternatively, when compared with the corresponding reference (anilumab) antibody, the variant antibody may have a total of up to 2 (up to 1 if needed) amino acid differences in its frame regions, provided that there are at most 1 amino acid difference in each frame region.

[0094] The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: when compared with the heavy chain sequence herein, the heavy chain has a maximum of 14 amino acid differences (a maximum of 2 amino acid differences in each CDR and a maximum of 2 amino acid differences in each frame region); and when compared with the light chain sequence herein, the light chain has a maximum of 14 amino acid differences (a maximum of 2 amino acid differences in each CDR and a maximum of 2 amino acid differences in each frame region); wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anilumumab) antibody, and preferably binds with the same affinity.

[0095] The variant heavy chain or light chain may be referred to as a "functional equivalent" of the reference heavy chain or light chain. The variant antibody may comprise a variable heavy chain and a variable light chain as described herein, wherein: when compared with the heavy chain sequence herein, the heavy chain has a maximum of 7 amino acid differences (a maximum of 1 amino acid difference in each CDR and a maximum of 1 amino acid difference in each frame region); and when compared with the light chain sequence herein, the light chain has a maximum of 7 amino acid differences (a maximum of 1 amino acid difference in each CDR and a maximum of 1 amino acid difference in each frame region); wherein the variant antibody binds to the same target antigen (e.g., IFNAR) as the reference (anilumumab) antibody, and preferably binds with the same affinity.

[0096] Functional variants of aniluromumab include the antibody described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 5-2). [Table 5-2]: Anti-IFNAR antibody sequences describe SEQ ID sequence H15D10 (VH) 13 EVQLVQSGAEVKKPGESLRISCKGSGYTFTNYWVAWVRQMPGKGLESMGIIYPGDSDTRYSPSFQGHVTISADKSISTAY L8C3 (VL) 14 DIQMTQSPSSLSASLGDRVTITCRASQNVGNYLNWYQQKPGKAPKLLIYRASNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQMEHAPPTFGQGTKVEIKR L16C11 (VL) 15 EIVLTQSPGTLSLSPGERATLSCRASQSVIGYYLAWYQQKPGQAPRLLIYSVSTLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYYRFPITFGQGTKVEIK H19B7 (VH) 16 EVQLVQSGAEVKKPGESLRISCKGSGYTFTNYWMAWVRQMPGKGLESMGIIYPSDSDTRYSPSFQGHVTISADKSISTAYLQWSSLKASDTAMYYCARHDVEGYDYWGQGTLVTVSS

[0097] The functional variant comprises an antibody containing the VH amino acid sequence SEQ ID NO: 13. The functional variant comprises an antibody containing the VH amino acid sequence SEQ ID NO: 16. The functional variant comprises an antibody containing the VL amino acid sequence SEQ ID NO: 14. The functional variant comprises an antibody containing the VL amino acid sequence SEQ ID NO: 15. The functional variant comprises an antibody containing the VH amino acid sequence SEQ ID NO: 16. The functional variant comprises an antibody containing both the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 16. The functional variant comprises an antibody containing both the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 15. The functional variant comprises an antibody containing both the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 15. The functional variants include antibodies containing the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 14.

[0098] An IFNAR inhibitor may be a monoclonal antibody containing the VH amino acid sequence SEQ ID NO: 13. An anti-IFNAR antibody may contain the VH amino acid sequence SEQ ID NO: 16. An anti-IFNAR antibody may contain the VL amino acid sequence SEQ ID NO: 14. An anti-IFNAR antibody may contain the VL amino acid sequence SEQ ID NO: 15. An anti-IFNAR antibody may contain the VL amino acid sequence SEQ ID NO: 16. An anti-IFNAR antibody may contain both the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 16. An anti-IFNAR antibody may contain both the VH sequence SEQ ID NO: 13 and the VL amino acid sequence SEQ ID NO: 15. An anti-IFNAR antibody may contain both the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 15. Anti-IFNAR antibodies may contain the VH sequence SEQ ID NO: 16 and the VL amino acid sequence SEQ ID NO: 14.

[0099] Functional variants of aniluzumab and anti-IFNAR antibodies include the QX006N antibody described in CN 11327807, which is incorporated herein by reference. Functional variants of aniluzumab include the antibody described in WO 2018 / 023976 A1, which is incorporated herein by reference (Table 3). [Table 3]: QX006N antibody sequence describe SEQ ID NO sequence QX006N (VH) 17 EVQLVESGGGLVQPGGSLRLSCAASGFSLSSYYMTWVRQAPGKGLEWVSVINVYGGTYYASWAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREDVAVYMAIDLWGQGTLVTVSS QX006N (VL) 18 AIQMTQSPSSSLSASVGDRVTITCQASQSISNQLSWYQQKPGKAPKLLIYDASSLASGVPSRFSGSRSGTKFTLTISSLQPEDFATYYCLGIYGDGADDGIAFGGGTKVEIK QX006N (HCDR1) 19 SYYMT QX006N (HCDR2) 20 VINVYGGTYYASWAKG QX006N (HCDR3) twenty one EDVAVYMAIDL QX006N (LCDR1) twenty two QASQSISNQLS QX006N (LCDR2) twenty three DASSLAS QX006N (LCDR3) twenty four LGIYGDGADDGIA

[0100] IFNAR inhibitors may be monoclonal antibodies containing the VH amino acid sequence SEQ ID NO: 17. Anti-IFNAR antibodies may contain the VL amino acid sequence SEQ ID NO: 18.

[0101] QX006N is an immunoglobulin comprising HCDR1, HCDR2, and HCDR3 (or functional variants thereof) of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively; and LCDR1, LCDR2, and LCDR3 (or functional variants thereof) of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 23, respectively. QX006N is an immunoglobulin comprising the VH amino acid sequence SEQ ID NO: 17 and the VL amino acid sequence SEQ ID NO: 18. (This is related to) cutaneous lupus erythematosus.

[0102] Cutaneous lupus erythematosus (CLE) is a rare, chronic, inflammatory, autoimmune, type 1 interferon (IFN)-driven skin disease that can occur spontaneously or as part of a broader diagnosis of systemic lupus erythematosus (SLE). There are three subtypes of CLE: acute CLE, subacute CLE, and chronic CLE. Chronic CLE is the most diverse category and is further subdivided into discoid CLE, chilblain LE, LE lipoitis, and edematous lupus (also known as intermittent CLE and sometimes classified as a separate subtype). UV exposure, smoking, and certain medications are common triggers that exacerbate CLE. Infections and hormones can also trigger CLE symptoms. Currently, there is no specific treatment for CLE, highlighting a significant unmet medical need for novel treatments with disease-specific mechanisms of action that reduce overall disease activity while also decreasing the risk of relapse and long-term skin damage. The most commonly used treatment is topical corticosteroids, but treatment adherence declines over time, and continued use can cause side effects.1,6 Other "off-label" treatments include systemic therapy with antimalarial drugs (hydroxychloroquine), steroids, methotrexate, azathioprine, mycophenolate mofetil, mycophenolate mofetil, diaminophen, thalidomide, and lenalidomide, as well as topical / external therapy with triamcinolone (intralesional injection), calcineurin inhibitors, salbutamol, retinoids, R333, clindamycin, and Janus kinase inhibitors.1 Prophylactic treatments include UV protection, smoking cessation, elimination of photosensitizing drugs, and vitamin D1 supplementation. Steroids

[0103] Oral corticosteroids (OCS, glucocorticoids) include presoni, cortisone, hydrocortisone, methylpresone, presone, and triamcinolone. Examples of equivalent doses of oral presoni are shown in Table 5-4. Dosage Forms

[0104] A unit dose (also known as a unit dose form, drug unit dose, or drug unit dose form) is a dose consisting of a single unit. Unit doses (unit dose forms) are suitable for administration to a subject in a single dosing. Unit doses (unit dose forms) can be packaged in a single unit container, such as a disposable pre-filled syringe or auto-injector. The advantage of unit doses is that they can be ordered, packaged, handled, and administered as a single dose unit containing a predetermined amount of drug. Unit doses can reduce dosing errors and waste. PK / PD

[0105] Plasma levels obtainable by SC and IV administration can be compared using plasma drug concentration-time curves (AUC), which reflect the body's exposure to antibodies after drug administration. For example, during clinical studies, plasma drug concentration-time curves can be plotted by measuring plasma concentrations at several time points. If computer simulation modeling is used, plasma drug concentration-time for any given dose can be predicted. The AUC (area under the curve) can then be calculated by integrating the plasma drug concentration-time curves. A suitable method is described in Tummala et al. 4, which is incorporated herein by reference in its entirety. In the example described herein, PK parameters were calculated using non-compartmental analysis with Phoenix WinNonlin V / 6.2 (Certara, Princeton, NJ, USA) and included the area under the serum concentration-time curve (AUC), clearance (CL, CL / F), maximum serum concentration (Cmax), and time to reach maximum serum concentration (tmax). All data were analyzed using SAS System V.9.2 (SAS Institute Inc., Cary, North Carolina, USA).

[0106] Conveniently, the ratio of AUC obtained by SC administration to AUC obtained by IV administration (AUCSC / AUCIV) can be calculated, thus providing a numerical comparison of bioavailability provided by the dosing route. The "AUC ratio" mentioned herein refers to the AUCSC / AUCIV ratio. For statistical robustness, the AUC ratio is preferably the mean, median, or pattern (e.g., mean) calculated from multiple replicate experiments (or computer simulations). Reference examples demonstrate this approach. The mean, median, or pattern (preferably the mean) can be derived by aggregating data from multiple patients (or multiple computer simulations). Therefore, the AUC ratio can reflect the mean, median, or pattern (preferably the mean) AUC of multiple patients. Pharmacokinetics Glossary

[0107] Area under curve (AUC): The area under the plasma drug concentration-time curve, which is used as a measure of drug exposure.

[0108] C average: steady-state average concentration.

[0109] Cmax: The maximum (or peak) concentration of the drug in plasma.

[0110] C minimum: minimum plasma drug concentration.

[0111] C-valence: The steady-state drug concentration in plasma prior to the next dose. valence plasma concentration (the concentration measured at the end of the dosing interval at steady state [obtained directly before the next dose]).

[0112] LLOQ: Limit of Quantification, the lowest amount of analyte in a sample that can be quantified with appropriate precision and accuracy.

[0113] Linear pharmacokinetics: A drug is considered to exhibit linear pharmacokinetics when the concentration of a drug in the blood or plasma increases proportionally with increasing dose, and the elimination rate is proportional to the concentration. The clearance and distribution volume of such drugs are dose-independent.

[0114] Nonlinear pharmacokinetics: In contrast to linear pharmacokinetics, the concentration of a drug in the blood or plasma does not increase proportionally with increasing dose. Clearance and volume of distribution may vary with the administered dose. Nonlinearity may relate to any component of the absorption, distribution, and / or elimination processes. Delivery device

[0115] In addition to providing subcutaneous antibody administration, self-administration (e.g., at home) can be further enhanced by using pre-filled syringes with accessories (APFS), automated syringes (AI), or combinations thereof. Such devices have been found to be well-tolerated 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 patient visits. Ferguson et al. [5] describe examples of suitable APFS devices, which are incorporated herein by reference in their entirety.

[0116] The dosages described by the inventors offer advantages in APFS administration because APFS devices typically deliver a maximum volume of 1 ml. Doses in the range of >105 mg to <155 mg can be readily contained in a volume of about 0.8 ml, making one or more dosages of the present invention particularly suitable for APFS and AI administration. For comparison, due to the viscosity of aniluzumab, larger doses (especially >150 mg) need to be delivered in a volume of >1 ml, requiring at least two SC injections, which is inconvenient for patients and necessitates multiple pre-filled devices.

[0117] The delivery device can be a single-use, disposable system designed for manual subcutaneous (SC) administration of the dose. Endpoint BILAG-2004 (British Islands Lupus Assessment Group-2004)

[0118] BILAG-2004 is a transformation index for nine organ systems (general condition, mucocutaneous and dermal, neuropsychiatric, musculoskeletal, cardiopulmonary, gastrointestinal, ocular, renal, and hematologic) that captures the severity of changes in clinical presentation. By design, it has ordinal levels and does not have a global score; more precisely, it provides a clear overview of disease activity across different organ systems by comparing the most recent four weeks with the previous four weeks. It is based on the physician's intention-to-treat principle and classifies disease activity into five different levels from A to E: • Level A indicates very active disease requiring immunosuppressive drugs and / or a dose of >20 mg / day of prisson or its equivalent. • Level B indicates moderate disease activity requiring lower doses of corticosteroids, topical steroids, topical immunosuppressants, antimalarial drugs, or NSAIDs. • Level C indicates mildly stable disease. • Level D indicates no disease activity, but the system has been previously affected. • Level E indicates no current or past disease activity.

[0119] Although BILAG-2004 was developed based on the principles of intention therapy, the treatment is unrelated to the scoring index. Only the presence of activity affects the score.

[0120] Improvements in the mucocutaneous-skin or musculoskeletal system, as defined by BILAG, represent skin rash or arthritis, respectively. BICLA (BILAG-based Comprehensive Lupus Assessment)

[0121] BICLA is a comprehensive index originally derived from expert consensus on the disease activity index. BICLA response is defined as (1) improvement of at least one grade of baseline BILAG score in all body systems with moderate or severe disease activity at the time of participation (e.g., all A (severe disease) scores decreased to B (moderate), C (mild), or D (inactive) and all B scores decreased to C or D); (2) no new BILAG A or more than one new BILAG B score; (3) no deterioration of the total SLEDAI score from baseline; (4) no significant regression (≤ 10%) in physician-wide assessment; and (5) no treatment failure (initiation of non-protocol treatment).

[0122] Specifically, a subject is considered a BICLA responder if the following criteria are met: a) All baseline BILAG-2004 A scores decreased to B / C / D and all baseline BILAG-2004 B scores decreased to C / D, with no worsening of BILAG-2004 in other organ systems, as defined by one new BILAG-2004 A score or more than one new BILAG-2004 B score; b) SLEDAI-2K scores did not worsen from baseline, as defined by an increase of >0 points in SLEDAI-2K scores from baseline; c) Lupus disease activity did not worsen from baseline according to a 3-point PGA VAS score, as defined by an increase of ≥0.30 points; d) The subject did not discontinue the study product or use any restrictive medications beyond the permitted thresholds of the protocol prior to evaluation.

[0123] The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was developed in 2005 as a method specifically for tracking skin activity and lesions in CLE patients.7 CLASI is a simple, single-page tool that individually quantifies skin disease activity and lesions at various sites of the body.8 CLASI is characterized by a Skin Activity Summary Score (CLASI-A) and a Lesion Summary Score (CLASI-D). The index has high inter-rater and intra-rater reliability and responds to changes when used in adults with CLE and SLE. CLASI activity scores are correlated with disease severity: mild, moderate, and severe disease correspond to CLASI activity score ranges of 0-9 (sensitivity 93%, specificity 78%), 10-20, and 21-70 (sensitivity 80%, specificity 95%), respectively (Table 5-5). [Table 5-5]: CLE Disease Severity Based on CLASI Activity Scores CLE disease CLASI Activity Scoring Range Mild 0-9 moderate 10-20 Severe 21-70

[0124] The Disease Area and Severity Index (CLASI) for cutaneous lupus erythematosus quantifies disease activity and lesions in cutaneous lupus erythematosus. It can differentiate between different levels of treatment response; for example, it can detect a specific percentage decrease in the activity score from baseline, or can be reported via mean / median scores. Specifically, the CLASI is an empirically proven index for assessing cutaneous lesions of lupus and consists of two separate scores: the first score summarizes the inflammatory activity of the disease; the second score is a measure of the damage caused by the disease. The activity score takes into account erythema, scaling / hypertrophy, mucosal lesions, recent alopecia, and non-scarring alopecia. The lesion score represents hyperpigmentation, scarring / atrophy / lipoitis, and scalp scarring. Subjects are asked whether their hyperpigmentation has persisted for 12 months or longer; in this case, the hyperpigmentation score is doubled. Each of these parameters is measured in 13 distinct anatomical locations, specifically included because these anatomical locations are most frequently affected in cutaneous lupus erythematosus (CLE). The most severe lesions in each region are measured.

[0125] The modified CLASI (mCLASI) is defined as the active portion of the CLASI describing skin erythema, scaling / hypertrophy, and scalp inflammation. The activity of oral ulcers and alopecia (without scalp inflammation) is excluded from the mCLASI analysis, as are all other measures of lesions. A clinically significant improvement in the rash, as measured using mCLASI, is defined as a decrease in the baseline activity score of ≥50%. SRI (Systemic Lupus Erythematosus Responder Index ≥4)

[0126] A subject achieves SRI(4) if all of the following criteria are met: • A decrease of ≥ 4 points from baseline in SLEDAI-2K; • No new organ system involvement compared to baseline using BILAG-2004, as defined by one or more BILAG-2004 A items or two or more • BILAG-2004 B items; • No worsening of lupus disease activity from baseline according to the 3-point PGA VAS, as defined by an increase of ≥ 0.30 points.

[0127] SRI(X) (X = 5, 6, 7, or 8) is defined by the proportion of subjects meeting the following criteria: • A decrease in SLEDAI-2K score from baseline ≥ X points; • No new organ system involvement compared to baseline using BILAG-2004, as defined by one or more BILAG-2004 A criteria or two or more BILAG-2004 B criteria; • No worsening of lupus disease activity from baseline according to a 3-point PGA VAS score, as defined by an increase in SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) score ≥ 0.30 points.

[0128] The SLEDAI-2K Disease Activity Index consists of a series of organ manifestations, each with its own definition. A certified investigator or designated physician will complete the SLEDAI-2K assessment and determine whether each manifestation is "present" or "absent" over the past 4 weeks. The assessment also includes collecting blood and urine samples to evaluate the laboratory category of SLEDAI-2K.

[0129] The SLEDAI-2K assessment consists of 24 lupus-related items. It is a weighted tool in which descriptors are multiplied by the "weight" of a specific organ. For example, the kidney descriptor is multiplied by 4 and the central nervous system descriptor by 8, and the weighted organ performance is summed to obtain the final score. The SLEDAI-2K score ranges from 0 to 105, with 0 indicating no active disease. The SLEDAI-2K score is a valid, reliable, and sensitive clinical assessment of lupus disease activity. The SLEDAI-2K calculated using a 30-day timeframe prior to clinical and laboratory value visits has been shown to be similar to the SLEDAI-2K with a 10-day window.9

[0130] SLEDAI-2K defined rash resolution as a rash score ≥ 2 at baseline being 0 at week 52. Type I IFN gene markers (IFNGS)

[0131] Type I IFN is believed to play an important role in the pathogenesis of SLE, and inhibition of this pathway is targeted by aniluzumab. To understand the relationship between type I IFN expression and response to anti-IFN therapy, it is necessary to know whether the subject's disease is driven by type I IFN activation. However, directly measuring type I IFN remains challenging. Therefore, transcript-based markers have been developed to evaluate the effect of target protein overexpression on a specific set of mRNA markers. The expression of these markers is readily detectable in whole blood and shows correlation with expression in diseased tissues (e.g., skin) in SLE. The bimodal distribution of transcript scores in SLE subjects supports the definition of high and low IFN test subsets (Figure 1). The type I IFN test is described in WO 2011028933 A1, which is incorporated herein by reference in its entirety. Type I IFN gene markers can be used to identify subjects with high or low type I IFN gene marker (IFNGS) test results. The INFNGS test measures the expression of genes IFI27, IFI44, IFI44L, and RSAD2 in whole blood of subjects compared to three reference genes: 18S, ACTB, and GAPDH. The test results are scores compared to a pre-defined cutoff value that categorizes patients into two groups with low or high levels of IFN-inducible gene expression (Figure 1).

[0132] Gene expression can be measured by RT-PCR. Suitable primers and probes for gene detection can be found in WO 2011028933. A suitable kit for measuring gene expression in INGS testing is the QIAGENtherascreen® IIGx RGQ RT-PCR kit (IFIGx kit), as described by Brohawn et al.10, which is incorporated herein by reference in its entirety.

[0133] IFN 21 gene markers (IFNGS) are validated pharmacodynamic markers of type I IFN communication

[10] , which are elevated in patients with type I IFN-mediated diseases, including CLE.

[0134] The 4-gene INGS score is calculated by measuring the expression of IFI27, IFI44, IFI44L, and RSAD2. The 5-gene INGS score is calculated by measuring the expression of IFI27, RSAD2, IFI44, IFI44L, and IFI6. The 21-gene INGS score is calculated by measuring the genes shown in Figure 28. Gene expression can be measured by detecting mRNA in the whole blood or tissue of the subject. INGS (4-gene, 5-gene, or 21-gene) scores can be detected by measuring the expression of INGS genes (e.g., mRNA) in the blood or tissue of the subject and comparing the expression levels of these genes with the expression of housekeeping genes or control genes (e.g., ACTB, GAPDH, and 18S rRNA) in the blood or tissue. Example 1: MUSE, ClinicalTrial.gov ID: NCT 01438489

[0135] MUSE is a phase 2, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of two intravenous (IV) treatment regimens in adult participants with chronic, moderate to severe active SLE who had an inadequate response to standard care (SOC) SLE. The study product (anilumumab or placebo) was administered at a fixed dose every 4 weeks (28 days) for a total of 13 doses.

[0136] MUSE is described in more detail in Furie et al. 20173, which is incorporated herein by reference in its entirety. Example 2: TULIP I and II, ClinicalTrial.gov Identifiers: NCT 02446912 and NCT 02446899

[0137] TULIP I and TULIP II are phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled studies designed to evaluate the efficacy and safety of two intravenous (IV) regimens of anilumatumab compared to placebo in subjects with moderate to severe active autoantibody-positive systemic lupus erythematosus (SLE) receiving standard of care (SOC). (Restricted Use)

[0138] If a subject accepts one of the following, the subject is considered a non-responder. Sulfasalazine; Danazol; Diaminophen; Azathioprine > 200 mg / day or daily dose greater than the dose in week 0 (day 1); Mycophenolate mofetil > 2.0 g / day or Mycophenolic acid > 1.44 g / day or daily dose greater than the dose in week 0 (day 1); Oral, SC, or intramuscular methotrexate > 25 mg / week or daily dose greater than the dose in week 0 (day 1); Mizoribine > 150 mg / day or daily dose greater than the dose in week 0 (day 1); Any change in the route of administration of oral, SC, or intramuscular methotrexate; Intravenous corticosteroids > 40 mg / day but ≤ 1 gm / day methylpresphone or equivalent; Intramuscular corticosteroids > 80 mg / day methylpresphone or equivalent; Subcutaneous or intramuscular corticosteroid precursors; With OCS > 40 Treatment may be administered with 1 mg / day of pressonin or an equivalent; treatment with an OCS dose higher than that of day 1 for a period > 14 days; corticosteroids with a long biological half-life (e.g., dexamethasone, betamethasone); other immunosuppressants including but not limited to calcineurin inhibitors (e.g., cyclosporine, tacrolimus [including topical]) or leflunomide. Cyclosporine eye drops may be used in this study.

[0139] TULIP is described in more detail by Furie et al. (2019-11), which is incorporated herein by reference in its entirety. Results for TULIP II are presented by Morand et al. (2020-12), which is also incorporated herein by reference in its entirety. Example 3: Assessment of skin relapse and gradual OCS tapering in lupus patients treated with aniluzumab in two phase 3 trials.

[0140] Lupus relapse and treatment with oral corticosteroids (OCS) for lupus are associated with cumulative organ damage. In the phase 3 trials TULIP-1 (NCT 02446912) and TULIP-2 (NCT 02446899), lupus patients receiving aniluzumab (a monoclonal antibody against type I interferon receptor subunit 1) had a lower relapse rate and were able to gradually taper their OCS dose compared to placebo. In the TULIP trial, the inventors evaluated the effect of aniluzumab treatment on cutaneous relapse and the effects of gradual OCS tapering. Methods

[0141] The randomized, double-blind, placebo-controlled TULIP-1 and TULIP-2 trials evaluated the efficacy and safety of anilumab (300 mg IV every 4 weeks for 48 weeks, with the primary endpoint at week 52) in patients with moderate to severe active SLE despite standard care. Relapse was defined as ≥ 1 new BILAG-2004 A or ≥ 2 new BILAG-2004 B domain scores compared to the initial visit. Patients receiving a baseline OCS ≥ 10 mg / day were required to perform a tapering attempt to ≤ 7.5 mg / day between weeks 8 and 40. Maintaining the OCS dose reduction was defined as achieving an OCS dose ≤ 7.5 mg / day by week 40 and maintaining it until week 52. TULIP-1 and TULIP-2 were analyzed separately using restrictive medication rules according to the TULIP-2 protocol, and data from both trials were pooled. The inventors descriptively analyzed relapses in patients with baseline OCS ≥ 10 mg / day and maintained OCS reduction using the organ domain. Results

[0142] Data from 726 patients were summarized; 360 received 300 mg anilumab (180 patients in each trial), and 366 received placebo (184 and 182 patients in TULIP-1 and TULIP-2, respectively). Baseline patient demographics and treatment characteristics were comparable between treatment groups (Figure 5). In the anilumab and placebo groups, most patients had ≥ 1 BILAG A organ domain score (48.3% and 48.9%, respectively) or no A and ≥ 2 B (47.2% and 44.3%, respectively) (Figure 5). The mean (SD) SLEDAI-2K scores were 11.4 (3.8) and 11.5 (3.7) in the anilumab and placebo groups, respectively. At baseline, the most commonly affected organ domains were mucocutaneous skin (BILAG-2004 86.4%, n = 627; SLEDAI-2K 96.3%, n = 699), musculoskeletal (BILAG-2004 88.8%, n = 645; SLEDAI-2K 94.2%, n = 684), and immunological domain (SLEDAI-2K 64.3%, n = 467) (Figures 6A-C). Due to the exclusion of patients with severe active lupus nephritis or severe active CNS manifestations, central nervous system (CNS) / neuropsychiatric system and renal involvement were relatively uncommon at baseline for both BILAG-2004 (< 3%, neuropsychiatric system; < 8%, kidney) and SLEDAI-2K (< 0.6%, CNS; < 10%, kidney). Baseline organ domain involvement assessed by BILAG-2004 and SLEDAI-2K was similar across treatment groups (Figures 6A-C).

[0143] At week 52, patients receiving more aniluzumab treatment showed improvement in the BILAG-2004 mucocutaneous and musculoskeletal domain scores compared to placebo. Improvements were also observed in most less frequently affected domains (Figure 7).

[0144] A total of 360 patients received anilumarub (TULIP-1, n = 180; TULIP-2, n = 180), and 366 patients received placebo (TULIP-1, n = 184; TULIP-2, n = 182). In summary, fewer patients experienced ≥ 1 episode with anilumarub (33.6%, n = 121) compared to placebo (42.9%, n = 157). In both treatment groups, episodes most frequently occurred in the mucocutaneous, musculoskeletal, and renal domains; across all three domains, fewer patients experienced ≥ 1 episode with anilumarub (22.8%, 19.4%, and 5.0%) compared to placebo (26.8%, 25.4%, and 7.4%) (Figure 7 and Table 8-1). [Table 8-1]: Number of relapses by organ domain in the pooled TULIP-1 and TULIP-2 data. Number of recurrences Total, n (%) Mucosal skin, n (%) Musculoskeletal system, n (%) Kidney, n (%) placebo (n = 366) Aniluzumab 300 mg (n = 360) placebo (n = 366) Aniluzumab 300 mg (n = 360) placebo (n = 366) Aniluzumab 300 mg (n = 360) placebo (n = 366) Aniluzumab 300 mg (n = 360) 0 209 (57.1) 239 (66.4) 268 (73.2) 278 (77.2) 273 (74.6) 290 (80.6) 339 (92.6) 342 (95.0) ≥ 1 157 (42.9) 121 (33.6) 98 (26.8) 82 (22.8) 93 (25.4) 70 (19.4) 27 (7.4) 18 (5.0) 1 89 (24.3) 74 (20.6) 68 (18.6) 62 (17.2) 67 (18.3) 48 (13.3) 17 (4.6) 10 (2.8) 2 49 (13.4) 28 (7.8) 26 (7.1) 18 (5.0) 21 (5.7) 14 (3.9) 7 (1.9) 5 (1.4) ≥ 3 19 (5.2) 19 (5.3) 4 (1.1) 2 (0.6) 5 (1.4) 8 (2.2) 3 (0.8) 3 (0.8) BILAG, Great Britain Island Lupus Assessment Group. Recurrence in the entire group was defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B compared to the initial visit. Recurrence in the BILAG organ domain was considered to be present if the corresponding organ was associated with the recurrence. Data for organ domains associated with ≥1 episode were presented in ≥5% of patients in the aniluma group.

[0145] Patients receiving anilumab with maintenance OCS reduction (TULIP-1: 19.6%; TULIP-2: 22.2%) experienced ≥ 1 relapse less frequently than those receiving placebo (TULIP-1: 41.2%; TULIP-2: 52.0%) (Figure 8). Patients receiving anilumab without maintenance OCS reduction (TULIP-1: 53.8%; TULIP-2: 45.2%) experienced a similar percentage of ≥ 1 relapse compared to those receiving placebo (TULIP-1: 54.4%; TULIP-2: 48.3%). Conclusion

[0146] In the phase 3 TULIP-1 and TULIP-2 trials, fewer patients experiencing relapses across the three most commonly affected organ domains (mucocutaneous, musculoskeletal, and renal) were treated with anilitumab compared to placebo. Surprisingly, anilitumab was associated with a >2-fold reduction in relapses among patients with maintenance OCS dose reductions compared to placebo. TULIP data support the ability of anilitumab to reduce SLE skin (mucocutaneous) relapses during OCS tapering, an important attribute for long-term management of SLE patients. Results from the TULIP-1 and TULIP-2 trials previously indicated that patients treated with anilitumab had a higher BICLA responder rate. Both BILAG and SLEDAI were included in the BICLA index. However, BILAG was used to assess improvement and exacerbation, while SLEDAI-2K was used only to assess exacerbation. Evaluations of individual organ domains using the BILAG-2004 and SLEDAI-2K assessments showed that, compared to placebo, aniluzumab treatment was associated with improvements in the mucocutaneous organ domain (skin). Example 4: The effect of aniluzumab on rashes in SLE patients and the impact of interferon information on the pooled data from the phase 3 trial. Background Art

[0147] In the phase 2 MUSE trial (NCT 01438489) and the phase 3 TULIP trial (Figures 4 and 7), aniluzumab treatment was associated with clinical improvement in mucocutaneous disease activity in SLE patients compared to placebo. The inventors examined the symptom-targeting effects of a subset of the biomarker definitions. Target

[0148] In pooled data from the phase 3 TULIP trial, the effects of aniluzumab on skin rash in SLE patients and its influence on IFN gene marker (IFNGS) status were evaluated using disease measures with varying sensitivities. Methods

[0149] TULIP-1 (NCT 02446912) and TULIP-2 (NCT 02446899) ​​were placebo-controlled 52-week trials in which aniluzumab was administered intravenously every 4 weeks in patients with moderate to severe SLE (see Sections 6 and 7). In this post-hoc analysis, rash and arthritis outcomes were assessed using the mucocutaneous domain of the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) (a stringent measure) and the British Isles Lupus Assessment Group (BILAG) index (a more sensitive measure capturing partial improvement). Improvement in rash was also assessed using the Modified Cutaneous Lupus Disease Area and Severity Index (mCLASI) score. Results

[0150] In the pooled data from TULIP-1 and TULIP-2, 600 patients (anilumab 300 mg, n = 298; placebo, n = 302) were classified as high-INGS test patients, and 126 patients (anilumab, n = 62; placebo, n = 64) were classified as low-INGS test patients. In summary, more patients receiving anilumab achieved complete rash resolution as defined by SLEDAI-2K compared to placebo (difference 13.5%, nominal P < 0.001) (Figure 9A). For rash, the more sensitive measure of improvement (≥ Grade 1) using BILAG showed that anilumab was superior to placebo (15.5%, nominal P < 0.001); results were comparable in the high subset of INGS tests (SLEDAI-2K: 17%, nominal P < 0.001; BILAG: 16.1%, nominal P < 0.001) (Figure 9B). A trend toward anilumab-related rash improvement was observed in patients with low INGS scores. In patients with a baseline mCLASI activity score > 0, anilumab resulted in more frequent ≥ 50% improvement from baseline to week 52 as defined by mCLASI compared to placebo (15.6%, nominal P < 0.001) (Figure 9C). Conclusion

[0151] In the pooled data from TULIP-1 and TULIP-2, using measures with varying degrees of stringency, aniluzumab treatment was associated with improvement in rash compared to placebo. Example 5: Efficacy profile of aniluzumab across organ domains in patients with moderate to severe SLE from the pooled data of the TULIP-1 and TULIP-2 trials.

[0152] The similarity in the design of the TULIP-1 and TULIP-2 trials facilitates pooling data to evaluate individual organ systems, which may have greater statistical power than individual trials alone. In this post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials, the inventors evaluated the effects of aniluzumab on disease activity in individual SLE organ domains, particularly the skin. Methods, Patient and Study Design

[0153] This is a post-hoc analysis of pooled data from the 52-week TULIP-1 and TULIP-2 trials, in which patients with moderate to severe SLE who had received standard therapy with oral glucocorticoids, antimalarial drugs and / or immunosuppressants were randomized to receive aniluzumab 300 mg intravenously every 4 weeks or placebo for 48 weeks.

[0154] The study design and methods have been described in detail previously [11,12]. In summary, all patients were 18 to 70 years of age and met the American College of Rheumatology (ACRL) SLE classification criteria. Patients with active severe neuropsychiatric SLE or severe lupus nephritis were excluded. For patients receiving prisone or its equivalent at baseline ≥ 10 mg / day, a mandatory attempt was made to gradually taper oral corticosteroids to ≤ 7.5 mg / day between weeks 8 and 40; gradual tapering was also permitted for patients receiving lower doses at baseline. In all patients, the corticosteroid dose was required to remain stable from week 40 to week 52. Study endpoints and assessments

[0155] Organ domain involvement was assessed using BILAG-200417 and SLEDAI-2K. BILAG-2004 response was defined as a reduction from baseline A (severe disease) to B (moderate), C (mild), or D (no current disease), or from baseline B to C or D. From baseline to week 52, the proportion of patients achieving 1-step (e.g., from A to B or B to C), 2-step (e.g., from A to C or B to D), and up to 3-step (i.e., from A to D) improvement in a given organ domain was assessed. SLEDAI-2K improvement was defined as a reduction in the domain score among patients with a baseline score > 0. For both BILAG-2004 and SLEDAI-2K, patients using restrictive medical therapies beyond the protocol-permitted thresholds or discontinuing the study product were classified as non-responders.

[0156] Cutaneous lupus erythematosus disease area and severity index (CLASI) activity score (CLASI-A) 7 and swollen and tender joint counts were used to further evaluate cutaneous and joint disease. CLASI response was defined as a ≥50% reduction in CLASI-A in patients with a baseline CLASI-A ≥ 10.

[0157] In addition to changes in mean hematologic and serologic values, the percentage of patients with abnormal (low or high) baseline values ​​that converted to normal at week 52 was also assessed. Patients who discontinued study treatment or whose week 52 data were missing were considered not to have normalized.

[0158] The modified CLASI (mCLASI) was defined as the active portion of the CLASI describing skin erythema, scaling / hypertrophy, and scalp inflammation. The activity of oral ulcers and alopecia (without scalp inflammation) was excluded from the mCLASI analysis, as were all other measures of lesions. A clinically significant improvement in the rash, as measured using mCLASI, was defined as a decrease in the baseline activity score of ≥50%. Statistical Analysis

[0159] Similar TULIP-1 and TULIP-2 trial designs allowed for pooling results. Organ domain responder rates for BILAG-2004 and SLEDAI-2K, SLEDAI-2K organ domain responders over time, CLASI-A responders over time, and joint count reductions from baseline ≥ 50% were calculated using a stratified Cochran-Mantel-Haenszel method employing stratification factors (matched to those in the TULIP studies) (SLEDAI-2K score at screening, type I IFN gene marker test status at screening, and oral glucocorticoid dose on day 1). Reported two-sided p-values ​​and 95% confidence intervals (CIs) are based on this method. All reported p-values ​​are nominal. To evaluate pooled TULIP data, TULIP-1 data were analyzed according to the TULIP-2 revised rules for restricted drug analysis. For first visits with missing data, the last observation carryover method was used to estimate missing data; subsequent visits without data estimation were not included. Results: Patient demographics and SLE medications at baseline.

[0160] Data from 726 patients were pooled; 360 patients received 300 mg aniluzumab IV Q4W (180 patients per trial), and 366 patients received placebo (184 patients in the TULIP-1 group and 182 patients in the TULIP-2 group). In the pooled population, 82.6% (600 / 726) of patients were found to have high INGS, and 17.4% (126 / 726) of patients had low INGS (Table 1). The baseline patient demographics were comparable between the treatment groups (Table 10-1). Of the 726 patients enrolled, the mean age was 41.8 years and 92.8% were female. For patients with high and low INGS, the mean ages were 41.1 years and 45.1 years, respectively, and 92.5% and 94.4% were female, respectively.

[0161] SLE-related treatments were similar between the treatment groups (Table 10-1). At baseline, the majority of patients (82.0%) were receiving glucocorticoid therapy, and more than 50% of patients in both treatment groups were receiving ≥ 10 mg / day. Among patients receiving aniluzumab or placebo, a similar proportion also received immunosuppressants (48.1% vs. 48.4%) and antimalarial therapy (67.5% vs. 73.0%). Patients with high INGS were more likely to receive any dose (84.7% vs. 69.0%) and ≥ 10 mg / day (54.7% vs. 37.3%) of glucocorticoids than those with low INGS. The same was true for immunosuppressants (51.0% vs. 34.9%), but fewer patients with high INGS were receiving antimalarial therapy than those with low INGS (68.2% vs. 80.2%).

[0162] Baseline organ domain involvement assessed using BILAG-2004 and SLEDAI-2K was similar across treatment groups (Figures 10A and 10B). The most frequently affected organ domains at baseline were mucocutaneous (BILAG-2004 86.4% [627 / 726]; SLEDAI-2K 96.3% [699 / 726]), musculoskeletal (BILAG-2004 88.8% [645 / 726]; SLEDAI-2K 94.2% [684 / 726]), and immunological domain (SLEDAI-2K 64.3% [467 / 726]) (Figures 10A and 10B); no immunological variables were captured in BILAG-2004. Renal and neuropsychiatric involvement was relatively uncommon at baseline, regardless of whether BILAG-2004 or SLEDAI-2K was used for assessment. In the most frequently affected BILAG-2004 domains (musculoskeletal and mucocutaneous), most patients had severe or moderate disease activity at baseline, as shown by the overall frequency of BILAG A (musculoskeletal 31.5% [229 / 726], mucocutaneous 21.9% [159 / 726]) or BILAG B (musculoskeletal 57.3% [416 / 726]; mucocutaneous 64.5% [468 / 726]) scores. BILAG organ domain scores were balanced across treatment groups (Figure 11); SLEDAI-2K could not distinguish the severity of activity within organ domains. Patient disease characteristics: rash.

[0163] In the aniluma and placebo groups, and in the high and low INGS subgroups, ≥ 85% of patients had a rash at baseline as measured by SLEDAI-2K or BILAG-2004 (Table 10-1). The mean (SD) baseline mCLASI activity scores were 6.2 (7.03) and 5.8 (6.88) in the aniluma and placebo groups, respectively. At baseline, patients with high INGS had higher mCLASI scores than those with low INGS (mean [SD]: 6.6 [7.50] vs. 4.2 [3.5] in the aniluma group and 5.9 [7.06] vs. 5.3 [4.79] in the placebo group). Activity scores > 0 were observed in ≥ 85% of patients in the aniluma and placebo groups, and in the high and low INGS subgroups. In both the anilumab and placebo groups, 20% of patients had an activity score ≥ 10 (Table 10-1). In the subgroups of patients with high INGS versus low INGS, 22.8% and 9.7% in the anilumab group, and 20.9% and 17.2% in the placebo group, respectively, had an activity score ≥ 10. [Table 10-1]: Baseline characteristics of clinical outcome measures feature placebo Aniluzumab 300 mg Total Group (n = 366) INGS high (n = 302) INGS Low (n = 64) Total Group (n = 360) INGS high (n = 298) INGS Low (n = 62) Age, mean (SD), years 41.0 (11.9) 40.7 (11.7) 42.7 (12.6) 42.6 (12.0) 41.5 (11.9) 47.6 (11.3) Females, n (%) 341 (93.2) 280 (92.7) 61 (95.3) 333 (92.5) 275 (92.3) 58 (93.5) Race, n (%) White people Black person Asian other 244 (66.7) 48 (13.1) 35 (9.6) 31 (8.5) 192 (63.6) 40 (13.2) 33 (10.9) 29 (9.6) 52 (81.3) 8 (12.5) 2 (3.1) 2 (3.1) 235 (65.3) 46 (12.8) 41 (11.4) 30 (8.3) 184 (61.7) 41 (13.8) 39 (13.1) 27 (9.1) 51 (82.3) 5 (8.1) 2 (3.2) 3 (4.8) Time from initial SLE diagnosis to randomization, median (range), months 78.5 (4-503) 87.5 (4-503) 52.0 (6-389) 91.0 (0-555) 97.0 (6-555) 77.0 (0-388) Baseline treatment for SLE, n (%) Oral glucocorticoids a < 10 mg / day ≥ 10 mg / day 304 (83.1) 181 (49.5) 185 (50.5) 257 (85.1) 97 (32.1) 160 (53.0) 47 (73.4) 22 (34.4) 25 (39.1) 291 (80.8) 351 (48.3) 375 (51.7) 251 (84.2) 83 (27.9) 168 (56.4) 40 (64.5) 18 (29.0) 22 (35.5) Antimalarial drugs 267 (73.0) 214 (70.9) 53 (82.8) 243 (67.5) 185 (65.4) 48 (77.4) Immunosuppressants b 177 (48.4) 157 (52.0) 20 (31.3) 173 (48.1) 149 (50.0) 24 (31.3) Rash measured using SLEDAI-2K, n (%) current 318 (86.9) 261 (86.4) 57 (89.1) 321 (89.2) 266 (89.3) 55 (88.7) Rash measured using BILAG-2004, n (%) A 75 (20.5) 63 (20.9) 12 (18.8) 84 (23.3) 71 (23.8) 13 (21.0) B 237 (64.8) 196 (64.9) 41 (64.1) 231 (64.2) 190 (63.8) 41 (66.1) C 44 (12.0) 34 (11.3) 10 (15.6) 34 (9.4) 28 (9.4) 6 (9.7) D / E 10 (2.7) 9 (3.0) 1 (1.6) 11 (3.1) 9 (3.0) 2 (3.2) Rash measured using mCLASI, n (%) Activity score > 0 311 (85.0) 256 (84.8) 55 (85.9) 323 (89.7) 268 (89.9) 55 (88.7) Activity score ≥ 10 74 (20.2) 63 (20.9) 11 (17.2) 74 (20.6) 68 (22.8) 6 (9.7) BILAG-2004, British Isles Lupus Assessment Group-2004; mCLASI, Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index; INFNGS, Interferon Gene Marker; Q4W, every 4 weeks; SD, Standard Deviation; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. When measured with SLEDAI-2K, a rash component ≥ 2 is considered present. When measured with SLEDAI-2K, arthritis component ≥ 4 is considered present. A, Severe disease; B, Moderate disease; C, Mild disease; D / E, No disease activity. a. Oral corticosteroids containing prasone or equivalents. b. Immunosuppressants: azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, and imidazolidin. Organ-domain efficacy of BILAG-2004.

[0164] A heatmap was used to illustrate the BILAG-2004 patient-level organ domain scores obtained every 4 weeks throughout the trial (Figure 12). At week 52, 55.5% (176 / 317) of patients treated with anilumab achieved a BILAG-2004 musculoskeletal response compared to 43.6% (143 / 328) of patients receiving placebo (difference 11.9%; 95% CI 4.2, 19.4; nominal P < 0.01) (Figure 13), and 53.3% (168 / 315) of patients treated with anilumab achieved a BILAG-2004 mucocutaneous response compared to 38.1% (119 / 312) of patients receiving placebo (difference 15.5%; 95% CI 7.8, 23.2; nominal P < 0.001) (Figure 13). Improvements in the mucocutaneous-cutaneous BILAG-2004 domain were observed with aniluzumab at weeks 4 and 32, respectively (P < 0.05 for both) (Figure 14). Regarding SLEDAI-2K organ domain efficacy, at week 52, patients treated with aniluzumab showed significantly greater improvements than those receiving placebo in the most affected SLEDAI-2K organ domains at baseline: mucocutaneous-cutaneous (54.7% [190 / 348] vs. 39.4% [138 / 351]; nominal P < 0.001), musculoskeletal (48.8% [164 / 335] vs. 40.4% [141 / 349]; nominal P < 0.05), and immunological domain (18.6% [44 / 237] vs. 11.3% [26 / 230]; nominal P < 0.05) (Figure 15). Starting from week 12, improvements in the mucocutaneous SLEDAI-2K domain, which are beneficial to aniluzumab, were observed (P < 0.05) (Figure 15). Efficacy of aniluzumab in improving rash.

[0165] At week 52, patients treated with anilumab achieved more rash cessation as defined by SLEDAI-2K than those receiving placebo (difference 13.5%; nominal P < 0.001) (Table 10-2, Figure 16). These data were driven by the high subset of INGS (difference 17.0%; nominal P < 0.001), rather than the low subset of INGS (difference -2.8%; nominal P = 0.746) (Table 10-2, Figure 16A). As early as week 12, rash cessation as defined by SLEDAI-2K was more frequent with anilumab compared to placebo, and this difference persisted until week 52 (Figure 17A). The results of the high subset of INGS were comparable (Figure 17B), but there was less separation between treatment groups throughout the study, and patients with low INGS had a higher placebo response (Figure 17C).

[0166] At week 52, patients treated with anilumab achieved more improvement in rash (≥ 1 severity grade reduction) as assessed by BILAG than those treated with placebo (Table 10-2, Figure 16B). Results were similar in the high INGS subset (difference 16.1%; nominal P < 0.001), and there was a trend toward anilumab-related rash improvement in patients with low INGS (difference 12.2%; nominal P = 0.203) (Table 10-2, Figure 16B). As early as week 4, anilumab showed greater improvement in rash as defined by BILAG-2004 than placebo at all time points (Figure 17A). A similar situation was observed in the high INGS subset (Figure 17B), but the separation between treatment groups was less pronounced in patients with low INGS, and the placebo response was higher than in patients with high INGS (Figure 17AC).

[0167] Based on mCLASI assessment, more patients treated with aniluzumab with a baseline score > 0 achieved ≥ 50% rash improvement at week 52 (difference 15.6%; nominal P < 0.001) (Table 10-2, Figure 16C). Outcomes were comparable in patients with high INGS (difference 18.1%; nominal P < 0.001), but not in patients with low INGS (difference 3.6%; nominal P = 0.700) (Table 10-2, Figure 16C). A similar trend was observed in a smaller subset of patients with a baseline mCLASI score ≥ 6 or ≥ 10 (Table 10-2). mCLASI improvement in rash (in patients with mCLASI activity scores > 0) was seen as early as week 4 (Figure 19A). At all time points, the improvement with aniluzumab was greater than that with placebo, and this was also observed in patients with high INGS (Figure 19B), but the improvement was not significant in patients with low INGS due to the high placebo response (Figure 19C). [Table 10-2]: Clinical outcome measures of rash at week 52 Aniluzumab 300 mg placebo total INGS High INGS low total INGS High INGS low SLEDAI-2K n 321 266 55 318 216 57 Responders, n (%) [SE] 123 (38.4) [2.71] 109 (41.2) [3.02] 14 (25.4) [6.07] 79 (24.9) [2.48] 63 (24.2) [2.71] 16 (28.2) [6.10] Difference [SE] (95% CI) 13.5 [3.67] (6.3 to 20.7) 17.0 [4.05] (9.1 to 25.0) -2.8 [8.61] (-19.7 to 14.1) — — — P-value < 0.001 < 0.001 0.746 — — — BILAG-2004 n 315 261 54 312 259 53 Responders, n (%) [SE] 168 (53.6) [2.79] 139 (53.5) [3.06] 29 (53.7) [6.78] 119 (38.1) [2.75] 97 (37.4) [3.01] 22 (41.5) [6.79] Difference [SE] (95% CI) 15.5 [3.92] (7.8 to 23.2) 16.1 [4.29] (7.7 to 24.6) 12.2 [9.59] (6.6 to 31.0) — — — P-value < 0.001 < 0.001 0.203 — — — mCLASI Baseline > 0 n 323 268 55 311 256 55 Responders, n (%) [SE] 186 (57.8) [2.74] 155 (58.1) [3.00] 31 (56.4) [6.70] 131 (42.2) [2.78] 102 (40) [3.07] 29 (52.7) [6.64] Difference [SE] (95% CI) 15.6 [3.91] (8.0 to 23.3) 18.1 [4.29] (9.7 to 26.6) 3.6 [9.43] (-14.8 to 22.1) — — — P-value < 0.001 < 0.001 0.700 — — — ≥6 at baseline n 141 121 20 135 113 twenty two Responders, n (%) [SE] 86 (61.2) [4.14] 73 (60.5) [4.47] 13 (65.0) [10.92] 65 (47.9) [4.25] 50 (44.3) [4.66] 15 (68.1) [10.28] Difference [SE] (95% CI) 13.3 [5.93] (1.6 to 24.9) 16.2 [6.46] (3.6 to 28.9) -3.1 [15.00] (-32.5 to 26.3) — — — P-value 0.025 0.012 0.835 — — — ≥10 at baseline n 74 68 6 74 63 11 Responders, n (%) [SE] 45 (60.9) [5.70] 40 (58.9) [5.99] 5 (85.0) [19.26] 35 (47.4) [5.81] 26 (41.5) [6.21] 9 (80.9) [14.29] Difference [SE] (95% CI) 13.5 [8.14] (-2.4 to 29.5) 17.4 [8.63] (0.5 to 34.3) 4.1 [23.99] (-42.9 to 51.1) — — — P-value 0.097 0.043 0.864 — — — BILAG-2004, British Isles Lupus Assessment Group-2004; mCLASI, Modified Disease Area and Severity Index for Cutaneous Lupus Erythematosus; INFNGS, Interferon Gene Marker; SE, Standard Error; SLEDAI-2K, Disease Activity Index for Systemic Lupus Erythematosus 2000. Laboratory Markers - Hematology and Serology

[0168] Patients in the anilumab group and the placebo group had similar mean hematological values ​​at baseline (Table 10-3). [Table 10-3] Changes in hematological measures from baseline to week 52 Placebo (n = 365) a Aniluma 300 mg (n = 360) Heme Baseline mean (SD), g / L 126.0 (15.2) 125.0 (14.8) Change from baseline, mean (SD), g / L -2.7 (11.33) 0.5 (10.59) Patients with abnormal heme levels at baseline normalized by week 52, n (%) b 0 (0) 0 (0) Hematocrit Baseline mean (SD) 0.4 (0.04) 0.4 (0.04) Change from baseline, mean (SD) -0.005 (0.03) 0.005 (0.03) Patients with abnormal hematocrit at baseline normalized at week 52, n (%) b 0 (0) 0 (0) Lymphocytes Baseline mean (SD), 10 9 / L 1.3 (0.6) 1.3 (0.6) Change from baseline, mean (SD), 10 9 / L -0.03 (0.5) 0.3 (0.6) Patients with baseline lymphocyte abnormalities normalized at week 52, n (%) b 11 (3.0) 23 (6.4) neutrophils Baseline mean (SD), 10 9 / L 4.0 (2.1) 3.8 (1.8) Change from baseline, mean (SD), 10 9 / L 0.1 (2.0) 0.7 (1.8) Patients with baseline neutrophil abnormalities normalized at week 52, n (%) b 0 (0) 1 (0.3) platelets Baseline mean (SD), 10 9 / L 250.2 (79.8) 239.9 (78.2) Change from baseline, mean (SD), 10 9 / L 3.2 (49.8) 24.3 (58.2) Patients with abnormal platelet counts at baseline had their counts normalized by week 52, n (%) b 1 (0.3) 0 (0.0) SD, standard deviation. a) One patient was removed from the analysis after the study was completed; b) Normal ranges for heme (>60 to <200 g / L), hematocrit (>0.18 to <0.64), lymphocytes (>0.5 to <10.0 10⁹ / L), neutrophils (>0.5 to <20.0 10⁹ / L), and platelets (>20 to <600 10⁹ / L).

[0169] At week 52, a therapeutic effect of aniluzumab was observed that increased mean (SD) of heme (0.5 [10.59] vs -2.7 [11.33] g / L) and platelets (24.3 [58.2] vs 3.2 [49.8] x10⁹ / L) compared to placebo. In the aniluzumab group, 6.4% (23 / 360) of patients with leukopenia at baseline showed normalization, compared to 3.0% (11 / 366) of patients receiving placebo.

[0170] Among patients who were anti-dsDNA positive at baseline, the mean (SD) level of anti-dsDNA antibodies decreased with aniluzumab treatment but increased with placebo treatment (-25.0 [238.4] vs. 28.0 [498.5] U / mL). Therefore, by week 52, 7.8% (13 / 167) of patients receiving aniluzumab converted to anti-dsDNA negative, compared to 5.8% (9 / 155) of patients receiving placebo (Table 10-4).

[0171] At week 52, a greater improvement in mean (SD) complement C3 levels from baseline was observed with aniluzumab (0.13 [0.18]) compared to placebo (0.04 [0.16] U / mL) (Table 10-4). Normalization was observed in 16.2% (21 / 130) of patients with low C3 at baseline and in 9.5% (13 / 137) of patients treated with aniluzumab compared to placebo. Similarly, normalization of low baseline C4 occurred in more patients treated with aniluzumab compared to placebo (22.6% [19 / 84] vs. 7.1% [6 / 85]). [Table 10-4]: Changes in laboratory markers from baseline to week 52 Placebo (n = 366) Aniluma 300 mg (n = 360) Anti-dsDNA a,b At baseline, anti-dsDNA was positive, n (%) 155 (42.3) 167 (43.4) Mean (SD), U / mL 211.95 (549.65) 129.34 (261.40) Change from baseline, mean (SD), U / mL 27.96 (498.47) -24.98 (238.39) Patients with abnormal anti-dsDNA at baseline normalized at week 52, n (%) 9 (5.8%) 13 (7.8%) C3 a,c C3 abnormality at baseline, n (%) 137 (37.4) 130 (36.1) Mean (SD), U / mL 0.70 (0.14) 0.69 (0.15) Change from baseline, mean (SD), U / mL 0.04 (0.16) 0.13 (0.18) Patients with abnormal C3 levels at baseline had their levels normalized by week 52, n (%) 13 (9.5) 21 (16.2) C4 a,d C4 abnormality at baseline, n (%) 85 (23.2) 84 (23.3) Mean (SD), U / mL 0.07 (0.02) 0.07 (0.02) Change from baseline, mean (SD), U / mL 0.02 (0.04) 0.02 (0.03) Patients with baseline C4 abnormalities normalized at week 52, n (%) 6 (7.1) 19 (22.6) Anti-dsDNA, anti-double-stranded DNA; C3, complement 3; C4, complement 4; SD, standard deviation. a. Patients with only baseline positive anti-dsDNA or low C3 or C4 were included in the pooled statistics for the corresponding variables; b. "Positive" anti-dsDNA antibody was defined as a result > 15 U / mL; c. "Abnormal" complement C3 level was defined as a result < 0.9 g / L; d. "Abnormal" complement C4 level was defined as a result < 0.1 g / L. Discussion

[0172] In this post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials, aniluzumab treatment, compared with placebo, was associated with greater improvement in the most commonly affected organ domains (mucocutaneous skin and musculoskeletal) in patients with moderate to severe SLE. Aniluzumab treatment also resulted in greater improvement in skin disease and a higher frequency of hematologic and serological normalization compared with placebo.

[0173] Results from the TULIP-1 and TULIP-2 trials previously demonstrated that patients treated with anilumab had a higher BICLA responder rate compared to those receiving placebo. Surprisingly, these analyses of the present invention also demonstrated concordance between the BILAG-2004 and SLEDAI-2K activity assessments for dermatology. For example, >85% of patients measured using BILAG-2004 had baseline mucocutaneous domain involvement, compared to >90% measured using SLEDAI-2K. Using the BILAG-2004 or SLEDAI-2K organ domain responder assessment, greater improvement in the mucocutaneous domain was observed with anilumab compared to placebo, and the improvements within these domains were comparable across indices.

[0174] In addition to the analysis of the BILAG-2004 and SLEDAI-2K mucocutaneous domains, the inventors also used the validated skin-specific tool CLASI to assess skin disease in SLE patients. The inventors evaluated CLASI responses in a subset of patients with a baseline CLASI-A ≥ 10, focusing on patients with moderate to severe skin disease. Using all three skin disease measures, the inventors observed robust early improvement in skin involvement in patients treated with aniluzumab compared to placebo.

[0175] Serological activity indicates immune system activation and is generally associated with SLE disease activity. More patients treated with aniluzumab were able to normalize anti-dsDNA antibody and complement C3 and C4 levels compared to those receiving placebo. These results suggest that the effect of aniluzumab on serological markers is consistent with the greater improvement observed in patients treated with aniluzumab compared to placebo in the SLEDAI-2K immunological domain.

[0176] The Phase 3 TULIP trial found that, using measures of varying stringency, anilumab 300 mg IV Q4W treatment was associated with improvement in rash and arthritis compared to placebo in SLE patients. The SLEDAI-2K definition of rash and arthritis remission is very stringent and requires complete remission of these symptoms. The SLEDAI-2K evaluation of rash and arthritis demonstrated that patients treated with anilumab achieved more remissions compared to placebo. The BILAG definition of rash improvement is detectable as partial improvement and is therefore more sensitive to changes. BILAG detected rash improvement as a result of anilumab treatment. Evaluation of the mCLASI score also detected partial rash improvement. This instrument is very flexible in its ability to detect improvement sensitively or stringently, depending on the severity of the rash at entry and the degree of change as a cutoff point for improvement. Over time, the evaluation of the mCLASI score demonstrated that anilumab treatment was associated with improvement in the early stages of treatment compared to placebo. Evaluation of joint counts can detect partial improvement in arthritis. Similarly, its ability to detect improvement is flexible in terms of sensitivity and strictness because the initial joint count can be modified and the degree of change selected for improvement can be tailored. As a result of aniluzumab treatment, joint tenderness / swelling counts improved.

[0177] The results also indicated that, in terms of improvement in rash and arthritis, patients with high baseline INGS responded better to aniluzumab treatment relative to placebo. Among all disease measures of rash and arthritis, the improvement at week 52 in patients with high INGS was comparable to the overall population outcome, and the time course of these improvements was closely correlated with the outcomes observed in the overall population. Most patients had high INGS at baseline; therefore, the trends seen in the overall population are expected to reflect this majority. The high proportion of patients with high INGS is not surprising, as these patients are more likely to be enrolled in randomized trials, as standard therapy struggles to manage their disease, as shown in patients with high baseline glucocorticoid doses. In patients with low INGS, there appeared to be an increased response to aniluzumab treatment for rash and arthritis when measured with more sensitive instruments, suggesting some benefit in this subgroup.

[0178] These analyses particularly support the hypothesis that type I IFN is a key driver of SLE dermatology. The effect of IFN messaging on mCLASI becomes apparent early in treatment, as a difference exists between aniluzumab and placebo as early as week 4 in patients with high IFNGS. This separation does not occur until week 20 in patients with low IFNGS. However, in patients with low IFNGS, some trends toward rash improvement associated with aniluzumab have emerged after using more sensitive measures. Due to differences in manifestation between tissues and blood, IFN activity may not always reflect the level of IFNGS manifestation measured in the blood at screening. Therefore, if a patient is found to have low IFNGS levels at screening, this may not indicate the completeness of systemic IFN activity and could explain some apparent differences in clinical response improvement between the two subgroups.

[0179] Interestingly, patients with low IFNGS who received placebo consistently showed a higher treatment response compared to those with high IFNGS, which may have masked the benefit of aniluzumab in this subgroup of patients. This high placebo response became more apparent when more sensitive disease measures were used. There are several possible explanations for this high placebo response, including better response to standard therapy in patients with low IFNGS than in those with high IFNGS, differences in baseline disease severity between these subgroups, and / or differences in the underlying mechanisms of the disease.

[0180] In summary, the pooled data from the TULIP trial demonstrate that aniluzumab treatment is associated with improvement in rash. Using measures of varying stringency and sensitivity, the inventors show that the more stringent measure (SLEDAI-2K endpoint) requires complete resolution of any rash and is primarily driven by a subset of patients with high INGS. Conversely, the more sensitive measure was able to detect subtle but clinically important benefits of aniluzumab treatment in a small sample of patients with low INGS. These data further support the use of aniluzumab for the treatment of CLE. Example 6: Subcutaneous administration of aniluzumab versus IV aniluzumab in SSc patients: a Phase I study MI-CP180

[0181] The mean serum concentrations of anilumab following a single weight-based administration are shown in Figure 21A. Following a single dose, anilumab exhibited non-linear-linear PK at lower dose levels (< 10.0 mg / kg) in both high- and low-IFNGS patients. A dose-proportional increase in the maximum C was observed, but the increase in AUC exceeded the dose-proportional range between 0.1 mg / kg and 10.0 mg / kg. In the high-dose cohort, anilumab t1 / 2 was prolonged. At the highest dose level studied (20.0 mg / kg), the terminal t1 / 2 was approximately 12 days. Phase I (Study 06) of IV and SC anilumab in healthy volunteers.

[0182] In this phase I randomized placebo-controlled study, 30 healthy adults were assigned to three treatment cohorts (anilumab 300 mg SC (n = 6), anilumab 300 mg IV (n = 6), and anilumab 600 mg SC (n = 6)) and placebo (n = 4 / cohort). Following SC administration, exposure to anilumab was proportionally increased from 300 mg to 600 mg based on the area under the serum concentration-time curve. The arithmetic mean serum anilumab concentration-time curves after a single IV and SC administration are shown in Figure 21B. As reported by Tummala et al. 20187 (which is incorporated herein by reference in its entirety), this study estimated that the bioavailability of anilumab in healthy volunteers was 87% for IV exposure. Phase II (Study 08) of aniluma SC in SLE patients.

[0183] This study aimed to characterize the pharmacokinetics and pharmacodynamics of subcutaneously administered aniluzumab (Figure 22A).

[0184] This study investigated the clinical pharmacology, safety, and exploratory efficacy of subcutaneous anilumarub. Pharmacokinetics in Study 08 were consistent with high bioavailability in Study 06 (healthy volunteers) and high CL in INGS-positive SLE patients. Subcutaneous administration of anilumarub every 2 weeks to patients with SLE and moderate to severe cutaneous manifestations exhibited non-linear pharmacokinetics exceeding dose proportion and neutralized type I interferon gene markers in a dose-dependent manner (Figures 22B and 22C). In particular, subcutaneous administration of 150 mg or 300 mg anilumarub every 2 weeks for 50 weeks exhibited non-linear pharmacokinetics, thereby achieving C trough concentrations exceeding dose proportion. The number of adverse events with subcutaneous anilumarub was similar to that observed after intravenous administration in large studies of SLE patients.

[0185] The results of the study 08 were fully described by Bruce et al. 14, and are incorporated herein by reference in their entirety.

[0186] Study 08 was limited by its small sample size, preventing the conclusions regarding the biological effects of the investigational drug (e.g., complement C3 or C4 concentrations) or its clinical efficacy (e.g., CLASI score). The inclusion of only patients with high type I interferon gene markers and active skin disease also limited the study's generalization to patients with similar disease characteristics. The increasing frequency of missing values ​​over time further limited the study's scope. Conclusion

[0187] Anilumab's pharmacokinetic profile consistently exhibits target-mediated drug disposition, with concentration or exposure reduction exceeding dose proportion at lower dose levels. High bioavailability of anilumab administered via subcutaneous injection was observed in Study 06 (healthy volunteers); the AUC ratio of anilumab SC to anilumab IV at 300 mg was approximately 87%. Example 7: Determining the optimal subcutaneous unit dose target.

[0188] To determine the optimal dosage regimen for subcutaneous administration of aniluzumab, the inventors developed population PK and PK / PD models, utilizing existing human clinical trials. PK data from Phase III studies 04 and 05 and Phase II study 1013 were used to assist in the development of the population PK model.

[0189] The inventors’ initial goal was to test subcutaneous doses that provided exposure equivalent to the standard 300 mg IV (Q4W) dose, while allowing for more routine dosing at lower doses. This was based on the understanding that 300 mg IV Q4W provided optimal clinical PK curves and clinical efficacy (e.g., achieving a BICLA response), as reported by Furie et al. 201710, which is incorporated herein by reference in its entirety and summarized in Examples 3 and 4. The initial selection of the subcutaneous dose of aniluromab was subsequently determined.

[0190] In the initial analysis, the inventors identified a specific dosing regimen that was predicted to provide equivalent exposure to achievable with 300 mg Q4W IV. Initially, a weekly (QW) subcutaneous 105 mg dosing regimen was found to provide an AUC ratio close to (or slightly greater than) 1 (Figure 23A), even though bioavailability was expected to be reduced by approximately 7% compared to Tummal et al. 20187 (which is incorporated herein by reference in its entirety) (Figure 23B). 105 mg subcutaneous QW showed to provide comparable or improved median trough concentrations and INGS inhibition compared to the contrasting 300 Q4W mg IV dose (Figures 24A and 24B). Based on these initial analyses, it appears that aniluzumab at a SC 105 mg QW dose is equivalent to 300 mg Q4W, thus providing the best efficacy / risk profile for treating SLE patients. Importantly, these analyses assume that the 300 mg IV dose is close to the plateau of the aniluzumab dose-response curve. Correction selection of aniluzumab subcutaneous dose.

[0191] Therefore, based on the data available from the MUSE study, Study 06, and Study 08, the inventors initially considered 105 mg QW to be the optimal SC dose of aniluzumab for the treatment of type I IFN-mediated disease. However, to confirm the choice of the 105 mg SC dose, the inventors further analyzed data from the TULIP I (Study 04) and TULIP II (Study 05) clinical trials.

[0192] Additional data were used to demonstrate a positive correlation between exposure and BICLA in patients with high INGS levels. Surprisingly, this relationship was observed even in the 300 mg IV Q4W group (Figures 25A and 25B). Therefore, BICLA response was variable in the 300 mg IV Q4W patient group. Logistic regression of patients’ BICLA response at week 52 confirmed that PK exposure was a significant covariate in TULIP I and TULIP II. The C-mean was found to be statistically significant in all participants’ analyses and high INGS was found to be significant in both independent TULIP I and TULIP II treatments as well as in pooled analyses of TULIP I and TULIP II. In the pooled data of the TULIP I and TULIP II studies, exposure response demonstrated that higher C-mean was associated with higher BICLA and SRI (4). In other words, there was exposure-dependent variability in the response to aniluzumab in SLE patients given 300 mg Q4W IV (Figures 25A and 25B).

[0193] Surprisingly, the 300 mg IV Q4W dose was found to reside at the beginning of the exposure response plateau, while the suboptimal 150 mg IV dose resided in the step region of the exposure response curve (Figure 26A). As a result of these analyses, the inventors determined that a 105 mg QW subcutaneous dose (previously considered equivalent to a 300 mg IV Q4W dose) did not provide the optimal balance of efficacy and safety for SLE patients. Therefore, the inventors decided to choose an alternative dose of SC administration that would mitigate the impact of population response variability in SLE patients.

[0194] In summary, the initial analysis showed that a subcutaneous dose of 105 mg QW aniluzumab would achieve at least similar efficacy to 300 mg IV Q4W. However, surprisingly, further analysis by the inventors of newly available data from further studies revealed that the concentration at this weekly (QW) dose could be increased, but not to the maximum threshold in terms of bioavailability and efficacy. In other words, the QW dose could be increased beyond 105 mg to provide higher plasma concentrations and INGS inhibition, and to reduce the variability in response observed in SLE patients. Therefore, a dose of 105 mg is suboptimal.

[0195] Surprising additional dose-response data were further validated by demonstrating an increased probability of achieving the relevant BICLA response (in patients with high INGS) with weekly subcutaneous administration of concentrations above 105 mg (Table 12-1: SC efficacy prediction assuming no dose delay / interruption). These data demonstrate an unexpected location of the dose-response plateau (e.g., subcutaneous administration), which shifts to the right as the dose increases above 105 mg (Figure 26B), indicating that the maximum BICLA response can actually be achieved at doses above 105 mg, and that higher doses are preferred (Table 12-1). Aniluzumab bioavailability is highly variable.

[0196] Following further investigation into the bioavailability of aniluma, the inventors clarified that the bioavailability of aniluma can exhibit surprisingly high levels of variability across different patients following subcutaneous administration. This high level of variability in aniluma bioavailability was not adequately addressed in previous studies reporting bioavailability >80% after subcutaneous administration (see Example 3)7. In Study 08 (SLE patients, SC), a population pharmacokinetic model revealed a bioavailability (F1) of 81% in healthy volunteers (Table 12-2).

[0197] The bioavailability of typical monoclonal antibodies administered subcutaneously ranges from 52% to 80%15. The inventors externally validated the study 08 (Ph2 SC in SLE) using a PPK model developed based on healthy volunteers and SLE patients in an IV study to determine bioavailability in the SLE population.

[0198] In-depth analysis of the data from Study 08 revealed that the injection site of SC affects bioavailability. In particular, when estimating the bioavailability of 300 mg via the abdomen relative to IV, the bioavailability (F1) was estimated to be 85.4%, compared to 81% without considering the injection site. Consequently, the C trough after thigh injection showed a decreasing trend compared to abdominal injection (Figures 27A and 27B). Thus, considering the variability attributable to injection site and the greater variability in bioavailability in SLE patients compared to healthy volunteers, it is surprising to conclude that bioavailability may actually be as low as 70%. Importantly, if the bioavailability (F1) is assumed to be 81%–87%, the initial expectation is that 105 mg would provide a C mean comparable to 300 mg IV (Figure 28). In contrast, when the estimated bioavailability is reduced to approximately 70% or lower, the median C mean of a 105 mg QW subcutaneous dose is as low as below 1 (Figures 29A, 29B, and Tables 12–3). [Table 12-3]: Availability of Aniluzumab Biopharmaceuticals

[0155] Bioavailability

[0156] 90 mg SC QW

[0157] 105 mg SC QW

[0158] 120 mg SC QW

[0159] 135 mg SC QW

[0160] 150 mg SC QW

[0161] 82%

[0162] 0.92

[0163] 1.14

[0164] 1.36

[0165] 1.59

[0166] 1.81

[0167] ~70%

[0168] 0.73

[0169] 0.92

[0170] 1.11

[0171] 1.31

[0172] 1.49

[0173] ~ 60%

[0174] 0.57

[0175] 0.73

[0176] 0.89

[0177] 1.06

[0178] 1.22 Value = Median C-mean of 300 mg IV; SC = Subcutaneous

[0199] Furthermore, there was an undesirable 30% overlap in the C-mean between the 105 mg SC QW and the second-best IV dose of 150 mg Q4W, whereas only 16% overlap was observed when bioavailability was assumed to be 81% (Fig. 29A). However, when using the 120 mg SC dose, the C-mean overlap with the 150 mg IV dose was less than the overlap with the optimal IV dose of 300 mg IV, even assuming a low bioavailability of 70% (Fig. 29B). Moreover, the 120 mg SC QW dose had the least overlap with the undesirable 1000 mg IV dose (Fig. 29C), at which the risk of shingles infection was increased (Fig. 31). There was an undesirable overlap between the 150 mg SC QW dose and the 1000 mg IV Q4W dose. Even more surprisingly, SC doses of 120 mg or higher were expected to have better PD suppression than the assumed optimal 300 mg IV dose (Table 12-4) (Table 12-5).

[0200] Therefore, a dose higher than 105 mg (preferably 120 mg or higher) was chosen to optimize the exposure response by minimizing the impact of variability in response onset and bioavailability in SLE patients (Table 12-4, Figures 30A and 30B). SC doses below 150 mg QW also hold promise for reducing the risk of shingles infection. [Table 12-4]: %PD inhibition calculated at week 24, SC dose SC WK24 inhibition (%) Dosage (mg) 75% 80% 90% 90 89.0 84.6 63.8 105 92.9 89.8 69.2 120 94.8 91.9 74.2 135 96.0 93.9 75.8 150 96.5 94.6 80.2 [Table 12-5]: %PD suppression calculated at week 24, IV dose IV WK24 inhibition (%) Dosage (mg) 75% 80% 90% 300 74.2 68.3 42.5 400 82.9 77.9 54.7 450 85.9 80.8 56.4 500 88.7 84.8 62.5 600 92.7 88.8 68.9 1000 96.9 94.5 80.2

[0201] Doses of 120 mg and 135 mg QW specifically provide reasonable benefit-risk profiles. At doses of 150 mg QW or higher, safety risks increase, such as an increased risk of shingles, considering that a 150 mg QW SC dose is equivalent to 1000 mg IV Q4W (Figure 29C, Figure 31). Therefore, subcutaneous doses less than 150 mg QW and greater than 105 mg QW are identified as optimal. Subcutaneous doses less than 150 mg QW and less than or equal to 135 mg are identified as even more optimal. A subcutaneous dose of 120 mg is identified as the optimal dose.

[0202] In summary, the inventors surprisingly found that, considering the previously available preliminary data, the optimal subcutaneous dose of anilumab might initially appear to be 105 mg QW (Figure 12). However, further data and analysis surprisingly showed that doses of 105 mg QW or lower would result in a large proportion of patients being underdosed (Figure 26B, Tables 12-3). Therefore, the inventors demonstrated a particularly advantageous dosing regimen at doses higher than 105 mg QW. Based on estimated bioavailability, a particularly ideal dose was determined to be 120 mg subcutaneously QW, equivalent to approximately 400 mg IV Q4W. Thus, the optimal SC dose is surprisingly >30% higher than the optimal dose considered solely based on a comparison of 300 mg IV Q4W and previously known bioavailability of anilumab.

[0203] Therefore, the inventors have surprisingly demonstrated that doses greater than 105 mg SC-QW and less than 150 mg SC-QW, especially 120 mg QW, (a) maximize efficacy while maintaining an acceptable safety profile, (b) mitigate the effects of bioavailability variability, and (c) mitigate the effects of response onset variability. Thus, doses greater than 105 mg QW are advantageous in taking into account bioavailability variability, thereby improving treatment outcomes. Dose less than 150 mg QW reduces the risk of shingles infection.

[0204] Pharmacokinetic data from healthy volunteers (Study 06 [IV arm only]) and SLE patients (Studies 1013, 02, 04, and 05) were also summarized to evaluate the impact of covariates such as demographics and renal / hepatic function tests on PK exposure. Patients with higher body weight and higher type I IFN test results were found to have significantly higher clearance (CL) and lower concentrations. However, surprisingly, these covariates had no clinically relevant impact on efficacy and safety. Surprisingly, other covariates evaluated in the population PK model were not significant for specific populations, including race / ethnicity / region, age, sex, renal / hepatic function tests, standards of care (e.g., OCS, antimalarial drugs, azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, imidazoribine, and NSAIDs), and medications commonly used in SLE patients (ACE inhibitors and HMG-CoA reductase inhibitors). Conclusion

[0205] The inventors have demonstrated that anilumab doses < 150 mg Q and > 105 mg QW will provide at least similar or even higher C-means than 300 mg IV Q4W over 52 weeks. A 120 mg SC QW dose will specifically provide efficacy at least equivalent to that demonstrated by a 300 mg IV Q4W dose. It is further reasonably demonstrated that a 120 mg SC QW dose will provide efficacy greater than that demonstrated by a 300 mg IV Q4W dose.

[0206] Therefore, based on a combination of PK / PD data, data from the Phase II LN study (Study 7, see Section Error! Citation source not found. Again Error! Citation source not found.), and knowledge of the aniluzumab IV and SC clinical program in SLE as described in Section 12.2, a dosing regimen of 6 doses of 900 mg aniluzumab IV Q4W was selected, followed by 120 mg aniluzumab SC QW.

[0207] Study 07 evaluated two dosing regimens: a basic regimen using the recommended dose for SLE patients (300 mg IV Q4W) and an enhanced regimen that started with three doses of 900 mg IV Q4W, followed by 300 mg IV Q4W for the remainder of the study. The enhanced regimen showed results indicating a greater treatment benefit compared to the basic regimen.

[0208] However, compared to the 300 mg IV Q4W dose in SLE patients without active kidney disease, the initial exposure of both regimens at 300 mg IV Q4W was suboptimal. Therefore, a more intensive dosing regimen was chosen, with an initial dose of 900 mg IV Q4W for 6 doses, followed by 120 mg SC QW. This regimen will provide sustained aniluzumab exposure / PD suppression and improved UPCR results compared to the dosing regimen previously evaluated in Study 07. The 120 mg SC QW dose will provide at least similar or non-inferior exposure and PD suppression in SLE patients compared to 300 mg IV Q4W.

[0209] The IV administration route is primarily used for anilumarub clinical regimens in SLE patients without active kidney disease, but a more convenient SC administration route is also under development. In anilumarub clinical development programs for SLE (IV and SC) and LN (IV) patients, both IV and SC administration routes have proven safe and well-tolerated. The SC anilumarub administration route using aPFS is expected to provide greater convenience and dosing flexibility for patients and / or caregivers, reduce the risk of infection associated with clinical visit dosing (including but not limited to influenza or COVID-19), and improve treatment accessibility and adherence compared to IV dosing. Example 8: Injection Device

[0210] Anilumumab is administered via an injection device [1] [9] such as a pre-filled syringe (PFS) (Fig. 32A) or an auto-injector (AI) (Fig. 32B). Auto-injector

[0211] Anilumab can be administered by an auto-injector[1]. The auto-injector is shown in an exploded view (Fig. 33A) and in its assembled form (Fig. 33B). A label[4] is wrapped around and attached to the auto-injector[1] (Fig. 33C). The auto-injector has an auto-injector housing[3], a cap and a cap remover[2], and a drive mechanism[5]. A unit dose[6] of the liquid anilumab formulation is contained in the auto-injector housing[3]. The unit dose[6] can be observed through the observation window[7]. Prefilled syringe with accessories

[0212] Anilumab can be administered via a prefilled syringe with accessories (APFS)[8]. The APFS[8] contains a unit dose of anilumab[6] contained in a main container[9], as shown in the assembled state in Figure 34A and the exploded view in Figure 34B. The main container[9] has a plunger stopper

[16] . The main container has a nominal fill volume of 0.8 ml

[17] , but may contain slightly more than 0.8 ml. The remaining space in the main container[9] is occupied by air bubbles

[18] . The air bubbles

[18] may have a size of 3-5 mm, or 4 mm if required. The main container[9] has a defined stopper position

[19] .

[0213] The main container [9] of the prefilled syringe with accessories (APFS) is disposed in the PFS assembly [8], which includes a needle protector

[12] , a finger flange

[11] , and a plunger rod

[13] . A label

[14] is provided with the main container [9] in the PFS assembly [8]. The label

[14] is wrapped around the syringe [9] in the label placement position

[15] . Packaging

[0214] The injection device[1] [8] is provided as a kit

[20] (Fig. 35). Labels[4]

[14] are provided with the APFS or auto-injector in the package. The labels include instructions for use of the injection device[1], [8]. The package includes a tamper seal. References All publications mentioned in this specification are incorporated herein by reference. (1) Shi, H.; Gudjonsson, JE; Kahlenberg, JM Treatment of Cutaneous Lupus Erythematosus: Current Approaches and Future Strategies.Curr. Opin. Rheumatol.2020,32(3), 208-214. https: / / doi.org / 10.1097 / BOR.0000000000000704. (2) Jarrett, P.; Werth, VP A Review of Cutaneous Lupus Erythematosus: Improving Outcomes with a Multidisciplinary Approach. VP; Kalunian, K.; Brohawn, P.; Illei, GG; Drappa, J.; Wang, L.; Yoo, S.; Investigators, for the CS Anifrolumab, an Anti-Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus.Arthritis Rheumatol. Hoboken Nj2017,69(2), 376. https: / / doi.org / 10.1002 / art.39962. (4) Tummala, R.; Rouse, T.; Berglind, A.; Santiago, L.Safety, Tolerability and Pharmacokinetics of Subcutaneous and Intravenous Anifrolumab in Healthy Volunteers.Lupus Sci. Med.2018,5(1), e000252. https: / / doi.org / 10.1136 / lupus-2017-000252. (5) Ferguson, G. T.; Mansur, A. H.; Jacobs, J. S.; Hebert, J.; Clawson, C.; Tao, W.; Wu, Y.; Goldman, M. Assessment of an Accessorized Pre-Filled Syringe for Home-Administered Benralizumab in Severe Asthma.J. Asthma Allergy2018,11, 63-72. https: / / doi.org / 10.2147 / JAA.S157762. (6) A Pilot Study Characterizing Factors in Adherence to Cutaneous Lupus Treatment - Teresa Ro, Rechelle Z. Tull, Leah A. Cardwell, Michael E. Farhangian, Farah Moustafa, Irma Richardson, Joseph L. Jorizzo, Steven Feldman, William Huang, 2018 https: / / journals.sagepub.com / doi / abs / 10.1177 / 1203475418770581 (accessed Apr 12, 2021). (7) Albrecht, J.; Taylor, L.; Berlin, J. A.; Dulay, S.; Ang, G.; Fakharzadeh, S.; Kantor, J.; Kim, E.; Militello, G.; McGinnis, K.; Richardson, S.; Treat, J.; Vittorio, C.; Van Voorhees, A.; Werth, V. P.The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): An Outcome Instrument for Cutaneous Lupus Erythematosus.J. Invest. Dermatol.2005,125(5), 889-894. https: / / doi.org / 10.1111 / j.0022-202X.2005.23889.x. (8) Klein, R. S.; Morganroth, P. A.; Werth, V. P. Cutaneous Lupus and the CLASI Instrument.Rheum. Dis. Clin. North Am.2010,36(1), 33-51. https: / / doi.org / 10.1016 / j.rdc.2009.12.001. (9) Touma, Z.; Urowitz, M.; Gladman, D. SLEDAI-2K for a 30-Day Window.Lupus2010,19(1), 49-51. https: / / doi.org / 10.1177 / 0961203309346505. (10) Interferon-Inducible Gene Expression Kit As a Potential Diagnostic Test for Anifrolumab: Analytical Validation for Use in Clinical Trials.ACR Meeting Abstracts. (11) Furie, R. A.; Morand, E. F.; Bruce, I. N.; Manzi, S.; Kalunian, K. C.; Vital, E. M.; Ford, T. L.; Gupta, R.; Hiepe, F.; Santiago, M.; Brohawn, P. Z.; Berglind, A.; Tummala, R.Type I Interferon Inhibitor Anifrolumab in Active Systemic Lupus Erythematosus (TULIP-1): A Randomised, Controlled, Phase 3 Trial.Lancet Rheumatol.2019,1(4), e208-e219. https: / / doi.org / 10.1016 / S2665-9913(19)30076-1. (12) Morand, EF; Furie, R.; Tanaka, Y.; Bruce, IN; Askanase, AD; Richez, C.; Bae, S.-C.; Brohawn, PZ; Pineda, L.; Berglind, A.; 211-221. https: / / doi.org / 10.1056 / NEJMoa1912196. [Simplified Explanation of the Diagram]

[0008] [Figure 1]: IFN score distribution [Figure 2]: MUSE tracking

[0009] Figure 2A: Patients are required to complete a 12-week follow-up period and undergo visits every 4 weeks (± 7 days) after the final study dose. Figure 2B: INGS neutralization - Changes in the neutralization rate of 21-gene type I INGS from the start of the MUSE trial to the end of follow-up (week 60). From week 52 to week 60, INGS performance increased more rapidly in the aniluzumab 300 mg group compared to the 1000 mg group. [Figure 3]: Efficacy in the MUSE trial

[0010] Figure 3A: Measures of disease activity at the efficacy endpoint (week 52) and end of follow-up (week 60) of the MUSE trial. From week 52 to the end of follow-up (week 60), the mean global SLEDAI-2K score increased in patients coming off anilumabumab 300 mg and 1000 mg, but not in the placebo group. A similar trend was observed in the mean global BILAG-2004 score in patients coming off anilumabumab 300 mg compared to placebo. The mean CLASI score increased slightly from week 52 to week 60 in the anilumabumab 300 mg, 1000 mg, and placebo groups. Disease activity, as measured by the MDGA score, increased between weeks 52 and 60 in both the anilumabumab 300 mg and 1000 mg groups; there was no change in the placebo group. In the aniluzumab 300 mg, aniluzumab 1000 mg, and placebo groups, the active joint count increased slightly from week 52 to week 60. Figure 3B: Number of relapses from the efficacy endpoint of the MUSE trial (week 52) to the end of follow-up (week 60). Compared to placebo, more patients who discontinued aniluzumab 300 or 1000 mg treatment experienced ≥ 1 BILAG relapse from week 52 to week 60 [Figure 4]: Efficacy in the mucocutaneous organ domain.

[0011] Percentage changes in the BILAG-2004 score of A / B and C / D / E in the mucocutaneous domain from the efficacy endpoint of the MUSE trial (week 52) to the end of follow-up (week 60). The mucocutaneous domain (left) is the most common organ system associated with deterioration in patients who discontinued aniluzumab, with the percentage of patients with BILAG C / D / E scores changing towards BILAG A / B scores. Deterioration in the mucocutaneous domain was most common in patients who discontinued aniluzumab, with the percentage of patients with BILAG-2004 C / D / E scores changing towards A / B scores [Figure 5]: Baseline patient demographics, disease characteristics, and lupus medications.

[0012] In the aniluzumab and placebo groups, most patients had ≥ 1 BILAG A organ domain score or no A items and ≥ 2 B items. [Figure 6]: Baseline organ domain score

[0013] Baseline (Fig. 6A) organ involvement of BILAG-2004 and (Fig. 6B) SLEDAI-2K and (Fig. 6C) organ domain scores of BILAG-2004. Pb = placebo; ANI = aniluzumab. The most commonly affected organ domains at baseline were mucocutaneous, musculoskeletal, and immunological domains. Due to the exclusion of patients with severe active lupus nephritis or severe active CNS manifestations, central nervous system (CNS) / neuromnographic and renal involvement at baseline was relatively uncommon for both BILAG-2004 and SLEDAI-2K. Baseline organ domain involvement assessed by BILAG-2004 and SLEDAI-2K was similar between treatment groups. [Fig. 7]: BILAG-2004 responders at week 52 in TULIP-1 and TULIP-2.

[0014] At week 52, patients receiving more aniluzumab treatment showed improvement in the BILAG-2004 mucocutaneous and musculoskeletal domain scores compared to placebo. Improvements were also observed in most less frequently affected domains. [Figure 8]: Patients with a baseline OCS dose ≥10 mg / day in TULIP-1 and TULIP-2 relapsed at week 52 due to maintained OCS dosage reduction.

[0015] BILAG, British Isles Lupus Assessment Group; OCS, Oral Corticosteroid; SLEDAI, SLE Disease Activity Index. Maintenance of OCS dose reduction was defined as achieving an OCS dose ≤ 7.5 mg / day by week 40 and maintaining it through week 52. OCS was described as "Prisson or equivalent". OCS administered as needed was not considered when calculating daily doses. Relapse was defined as a score of ≥ 1 new BILAG-2004 A or ≥ 2 new BILAG-2004 B domain compared to the initial visit. Randomization in TULIP-1 and TULIP-2 was stratified by OCS dose (< 10 vs. ≥ 10 mg / day), SLEDAI-2K score (< 10 vs. ≥ 10), and type I interferon gene marker (high vs. low). [Figure 9]: Efficacy of aniluzumab in the rash.

[0016] Figure 9A: Patients with SLEDAI-2K defined remission. In summary, more patients receiving aniluzumab achieved SLEDAI-2K defined complete rash remission compared to placebo. Figure 9B: Patients with BIILAG defined rash improvement. For rash, the more sensitive measure of improvement ≥ 1 grade was required by BIILAG, which showed aniluzumab superior to placebo (difference 15.5%, nominal P < 0.001); results were comparable in the high subset of the INGS test. Figure 9C: Patients with ≥ 50% improvement in mCLASI score from baseline to week 52 (mCLASI > 0 at baseline). In patients with a baseline mCLASI activity score > 0, ≥ 50% improvement from baseline to week 52, as defined by mCLASI, was achieved more frequently with aniluzumab compared to placebo. Data from the TULIP-1 and TULIP-2 trials. Regression was defined as: SLEDAI-2K rash component = 0 (patients with SLEDAI-2K rash component = 2 at baseline); SLEDAI-2K arthritis component = 0 (patients with SLEDAI-2K arthritis component = 4 at baseline); Improvement was defined as: a BILAG rash mucocutaneous baseline score of A changing to B, C, or D, or a baseline score of B changing to C or D. mCLASI was defined as the CLASI activity component describing cutaneous erythema, scaling / hypertrophy, and scalp inflammation. BILAG, British Isles Lupus Assessment Group; IFUGS, interferon gene markers; mCLASI, modified cutaneous lupus disease area and severity index; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000. [Figure 10]: Baseline organ domain involvement assessed using BILAG-2004 and SLEDAI-2K

[0017] Baseline organ domain involvement assessed using BILAG-2004 (Figure 10A) and SLEDAI-2K (Figure 10B) was similar between treatment groups. BILAG-2004, British Isles Lupus Assessment Group-2004; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000. BILAG-2004 scores ranged from Grade A (severe / active disease) to Grade E (no current or past disease). BILAG-2004 organ domain involvement was defined as a score of A or B. SLEDAI-2K organ domain involvement was defined as any SLEDAI-2K organ system score. a. Exclusion of fever. [Figure 11]: BILAG organ domain scores

[0018] BILAG organ domain scores were balanced across treatment groups. BILAG-2004 scores ranged from Grade A (severe / active disease) to Grade E (no current or past disease). BILAG-2004 organ domain involvement was defined as a score of A or B. SLEDAI-2K organ domain involvement was defined as any SLEDAI-2K organ system score. [Figure 12]: Heatmap of individual patient BILAG-2004 mucocutaneous organ domain scores over time.

[0019] Patients with BILAG-2004 mucocutaneous organ domain involvement at baseline were sorted by baseline score (A or B) and week 52 score. Each row represents an individual patient, and each column represents the BILAG-2004 organ domain score every 4 weeks from week 0 (baseline) to week 52. Colors indicate the patient's BILAG-2004 score, from dark gray (A, severe / active disease) to light gray (D, no current disease). [Figure 13]: BILAG-2004 responders at week 52, by score change.

[0020] A 1-point change refers to the change from baseline A score to week 52 B score or from baseline B score to week 52 C score; a 2-point change refers to the change from A to C or B to D; a 3-point change refers to the change from A to D. Improvement in the BILAG-2004 organ domain score was defined as a decrease from A or B score to B, C, or D score in patients with a baseline A or B score. BILAG responders were patients who showed improvement from baseline at week 52. **P < 0.01; ***P < 0.001 (based on the Cochran-Mantel-Haenszel method for comparing BILAG-2004 responder rates between aniluzumab and placebo). [Figure 14]: BILAG-2004 organ domain responders over time

[0021] Improvements in aniluzumab in the mucocutaneous-skin BILAG-2004 domain were observed at weeks 4 and 32. BILAG-2004, British Isles Lupus Assessment Group-2004. BILAG-2004 organ domain responders were defined as a decrease in baseline A or B score at week 52. Point-based estimates. Estimates were calculated using a stratified Cochran-Mantel-Haenszel method, where stratification factors are listed in the Methods section. *P < 0.05; **P < 0.01; ***P < 0.001 (based on the Cochran-Mantel-Haenszel method for comparing aniluzumab with placebo). [Figure 15]: SLEDAI-2K mucocutaneous-skin organ domain responders over time.

[0022] SLEDAI-2K organ domain responders were defined as those with a reduction in the baseline SLEDAI-2K mucocutaneous organ domain score. Estimates were calculated using a stratified Cochran-Mantel-Haenszel method, with stratification factors listed in the Methods section. *P < 0.05; **P < 0.01; ***P < 0.001 (based on the Cochran-Mantel-Haenszel method for comparing aniluzumab with placebo). [Figure 16]. Response rate to complete remission as defined by SLEDAI-2K.

[0023] (Figure 16A), rash improvement as defined by BILAG-2004 (Figure 16A) and ≥50% improvement in mCLASI from baseline in patients with mCLASI > 0 at 52 weeks (C). BILAG-2004, British Isles Lupus Assessment Group-2004; INGS, interferon gene marker; mCLASI, modified cutaneous lupus disease area and severity index; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000. Data from the TULIP-1 and TULIP-2 trials. In patients with a SLEDAI-2K rash component score of 2 at baseline, regression was defined as a SLEDAI-2K rash component score of 0; improvement was defined as a change in BILAG rash, mucocutaneous baseline score A to B, C, or D, or a change in baseline score B to C or D. mCLASI was defined as the active component of CLASI describing cutaneous erythema, scaling / hypertrophy, and scalp inflammation. [Figure 17]: Response rate of rash resolution as defined by SLEDAI-2K

[0024] SLEDAI-2K defined rash regression response rate from baseline to week 52, for all (Fig. 17A), high (Fig. 17A), and low (Fig. 17A) IFNGS patients. IFNGS, interferon gene marker; SLEDAI-2K, systemic lupus erythematosus disease activity index 2000. Data pooled from the TULIP-1 and TULIP-2 trials. Regression was defined as a SLEDAI-2K rash component score of 0 in patients with a SLEDAI-2K rash component score of 2 at baseline. [Fig. 18]: Response rate to rash improvement as defined by BILAG-2004.

[0025] Response rate of rash improvement as defined by BILAG-2004 in all patients (Fig. 18A), those with high INGS (Fig. 18A), and those with low INGS (Fig. 18A) from baseline to week 52. BILAG-2004, British Isles Lupus Assessment Group-2004; INGS, interferon gene marker. Data pooled from the TULIP-1 and TULIP-2 trials. Improvement was defined as a change in BILAG rash, a change in mucocutaneous skin baseline score A to B, C, or D, or a change in baseline score B to C or D. [Fig. 19]: Response rate of ≥50% mCLASI improvement from baseline to week 52.

[0026] Response rate of ≥50% mCLASI improvement from baseline to week 52 in all patients with baseline mCLASI > 0 (Figure 19A), high INGS (Figure 19B), and low INGS (Figure 19C) [Figure 20]: Percentage of patients with ≥50% reduction in CLASI-A over time relative to baseline and in the number of swollen and tender joints over time relative to baseline.

[0027] CLASI response was defined as a ≥50% decrease in CLASI-A from baseline in patients with a baseline CLASI-A ≥ 10. Point-based estimates. Estimates were calculated using a stratified Cochran-Mantel-Haenszel method, with stratification factors listed in the Methods section. *P < 0.05; **P < 0.01; ***P < 0.001 (based on the Cochran-Mantel-Haenszel method for comparing aniluzumab with placebo). [Figure 21]: Mean aniluzumab serum concentration-time curve

[0028] Figure 21A: Study MI-CP180 in SSc - mean anilumarub serum concentration-time curve after a single IV dose. Data represent + / - SD. Mean data below LLOQ were not plotted. IV, intravenous; LLOQ, lower limit of quantitation; MEDI 546, anilumarub; n, number of patients in the subgroup; SSc, systemic sclerosis. Figure 21B: Study 06 in healthy volunteers - mean anilumarub serum concentration-time curve after a single SC and IV dose. Samples with a deviation of >10% from the nominal collection time were excluded from the mean. IV, intravenous; N, number of subjects; SC, subcutaneous. [Figure 22]: Study 1013 (MUSE), study design and efficacy results (20)

[0029] Figure 22A: Phase II study design of SC aniluzumab in SLE patients. Study 08 (NCT02962960) evaluated the effects of two aniluzumab doses every other week. Figure 22B: Mean serum concentration of aniluzumab over time. Figure 22C: Neutralization of aniluzumab with type I IFN gene markers [Figure 23]: Calculated median AUC ratio (SC / IV)

[0030] Figure 23A: Median AUC ratio (SC / IV) calculated for different SC doses between weeks 0 and 52. The median AUC ratio (SC / IV) was calculated based on the estimated bioavailability in Study 06 between weeks 0 and 52, where the subcutaneous dose was 75 mg (+ sign), 90 mg (hollow square), 105 mg (circle), 120 mg (triangle), or 135 mg (solid square). The subcutaneous dose was administered every 7 days (QW); the IV dose was administered every 4 weeks (Q4W) at a dose of 300 mg. Based on AUC, both 90 mg and 105 mg SC QW showed similar results to 300 mg IV. Figure 23B: Calculated median AUC ratio (SC / IV) for 90 mg and 105 mg SC QW. The median AUC ratio (SC / IV) was calculated based on an estimated bioavailability that was approximately 7% lower than that calculated from Study 06 during weeks 0–52, where the subcutaneous dose was 90 mg SC QW or 105 mg SC. [Figure 24]: Anilumab concentrations over time at different doses.

[0031] Figure 24A: A graph (straight line) showing the calculated trough concentrations of plasma anilumab in patients receiving the following: (i) 105 mg anilumab subcutaneously every 7 days; (ii) 300 mg anilumab intravenously every 4 weeks (lower dashed line); (ii) 1000 mg anilumab intravenously every 4 weeks (upper dashed line). The shaded area represents the region between the 5th and 95th percentiles of the 300 mg IV Q4W dose. Figure 24B: Anilumab trough concentrations in subjects with high INGS-related SLE. The calculated trough concentrations of plasma anilumab in patients with high INGS after administration were as follows: (i) 300 mg IV Q4W; (ii) 90 mg SC QW; (iii) 105 mg SC QW; (iv) 135 mg SC QW; (v) 1000 mg IV Q4W. SC = Subcutaneous. Based on trough values, both 90 mg and 105 mg SC QW are expected to have higher PD suppression than 300 mg IV. [Figure 25]: Exposure observed in TULIP 1 & TULIP 2 in patients with high INGS was positively correlated with BICLA.

[0032] Figure 25A: TULIP I, for placebo, 150 mg and 300 mg aniluzumab. Figure 25B: TULIP II, for placebo and 300 mg. [Figure 26]: BICLA dose response

[0033] Figure 26A: Dose-response curves showing the predicted mean (grey line) and 95% confidence interval (CI) (dashed area) for the probability of meeting the BICLA response criteria relative to the aniluzumab C mean within 52 weeks (in patients with high INGS). Patients were grouped by dose (150 mg, n = 62; 300 mg, n = 242; and 1000 mg). Figure 26B: Predicted PK and efficacy for different SC doses. Probability of meeting BICLA (in patients with high INGS) with weekly subcutaneous injection doses starting from 105 mg up to 150 mg. The assumptions used to generate the data did not include dose delay / interruption. [Figure 27]: C-valence after thigh injection compared to abdominal injection.

[0034] Figure 27A: 150 mg SC Q2W. Figure 27B: 300 mg SC Q2W [Figure 28]: Exposure prediction based on 81%-87% biological availability and preliminary PK model.

[0035] Based on preliminary PK modeling and bioavailability assumptions, the median ratio of aniluzumab C predicted for 90-150 mg SC QW to 300 mg Q4W. [Figure 29]: Median aniluzumab C over 52 weeks for different SC and IV doses in high-dose INGS patients.

[0036] Figure 29A: 105 mg SC QW. Figure 29B: 120 mg SC QW. Figure 29C: Overlap with 1000 mg IV Q4W. [Figure 30]: Median C-mean ratio of SC QW to 300 mg IV Q4W.

[0037] Figure 30A: Assuming an 81% bioavailability. Figure 30B: Assuming a 70% bioavailability. [Figure 31]: Relationship between average aniluzumab concentration and shingles incidence.

[0038] The incidence (%) of herpes zoster in patients in Study 1013 who received placebo, 300 mg IV aniluzumab, or 1000 mg IV aniluzumab. [Figure 32]. Delivery device

[0039] Aniluzumab was administered via an injection device [1] [9] such as a pre-filled syringe (PFS) (Fig. 32A) or an auto-injector (AI) (Fig. 32B). [Fig. 33]. Auto-injector

[0040] Exploded view (Fig. 33A), assembled view (Fig. 33B), and automated injector filled with drug substance (Fig. 33C) for administering aniluzumab or a functional variant thereof. [Fig. 34]. Pre-filled injector with accessories.

[0041] Prefilled syringe with accessories (APFS) for aniluzumab or a functional variant thereof. The primary tube is shown in assembled form (Fig. 34A) and exploded view (Fig. 34B). The APFS with its additional components is shown in assembled form (Fig. 34C) and exploded view (Fig. 34D). [Fig. 35]. Packaging for delivery device [Biomaterial Storage]

[0216] None [Sequence List]

[0217] <![CDATA[ <110> AstraZeneca AB, a Swedish company <![CDATA[ <120> Treatment of cutaneous lupus erythematosus <![CDATA[ <130> IFNAR-775-WO-PCT <![CDATA[ <150> US63 / 178750]]> <![CDATA[ <151> 2021-04-23 <![CDATA[ <160> 24]]> <![CDATA[ <170> BiSSAP 1.3.6 <![CDATA[ <210> 1]]> <![CDATA[ <211> 117]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Aniluzumab VH]]> <![CDATA[ <400> 1]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Ser Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg His Asp Ile Glu Gly Phe Asp Tyr Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[ <210> 2]]> <![CDATA[ <211> 108]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213>Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Aniluzumab VL]]> <![CDATA[ <400> 2]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Phe Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Ala 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <![CDATA[ <210> 3]]> <![CDATA[ <211> 5]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> HCDR1]]> <![CDATA[ <400> 3]]> Asn Tyr Trp Ile Ala 1 5 <![CDATA[ <210> 4]]> <![CDATA[ <211> 17]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> HCDR2]]> <![CDATA[ <400> 4]]> Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe Gln 1 5 10 15 Gly <![CDATA[ <210> 5]]><![CDATA[ <211> 8]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> HCDR3]]> <![CDATA[ <400> 5]]> His Asp Ile Glu Gly Phe Asp Tyr 1 5 <![CDATA[ <210> 6]]> <![CDATA[ <211> 12]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> LCDR1]]> <![CDATA[ <400> 6]]> Arg Ala Ser Gln Ser Val Ser Ser Ser Phe Phe Ala 1 5 10 <![CDATA[ <210> 7]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> LCDR2 <![CDATA[ <400> 7]]> Gly Ala Ser Ser Arg Ala Thr 1 5 <![CDATA[ <210> 8]]> <![CDATA[ <211> 9]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> LCDR3]]> <![CDATA[ <400> 8]]> Gln Gln Tyr Asp Ser Ser Ala Ile Thr 1 5 <![CDATA[ <210> 9]]> <![CDATA[ <211> 107]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> Light chain constant region <![CDATA[ <400> 9]]> Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val ValCys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 10]]> <![CDATA[<211> 330]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Heavy Chain Constant Region]]> <![CDATA[<400> 10]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Arg Val Glu Pro Lys SerCys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val MetHis Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <![CDATA[<210> 11]]> <![CDATA[<211> 440]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Heavy Chain]]> <![CDATA[<400> 11]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Ser Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg His Asp Ile Glu Gly Phe Asp Tyr Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 ValLys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser 435 440 <![CDATA[<210> 12]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> Light Chain]]> <![CDATA[<400> 12]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Phe Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Ala 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 13]]> <![CDATA[<211> 80]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> H15D10 (VH)]]> <![CDATA[<400> 13]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Val Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Ser Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly His Val Thr Ile Ser Ala Asp LysSer Ile Ser Thr Ala Tyr 65 70 75 80 <![CDATA[<210> 14]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> L8C3 (VL)]]> <![CDATA[<400> 14]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asn Val Gly Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Arg Ala Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Met Glu His Ala Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 15]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> L16C]]>11 (VL) <![CDATA[<400> 15]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ile Gly Tyr 20 25 30 TyrLeu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Ser Val Ser Thr Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Arg Phe Pro 85 90 95 Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 16]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> H19B7 (VH)]]> <![CDATA[<400> 16]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Met Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Ser Met 35 40 45 Gly Ile Ile Tyr Pro Ser Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 9 '5 Ala Arg His Asp Val Glu Gly Tyr Asp Tyr Trp Gly GlnGly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 17]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> QX006N (VH)]]> <![CDATA[<400> 17]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Asn Val Tyr Gly Gly Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Asp Val Ala Val Tyr Met Ala Ile Asp Leu Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 18]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> QX006N (VL)]]> <![CDATA[<400> **************18]]> Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val It should be noted that there seems to be an issue with the "**************" part in the original text which might be a formatting error. I've translated it as best as possible while maintaining the integrity of the original. If this is incorrect, please check and provide the correct text.Thr Ile Thr Cys Gln Ala Ser Gln Ser Ile Ser Asn Gln 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Lys Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gly Ile Tyr Gly Asp Gly Ala 85 90 95 Asp Asp Gly Ile Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110 <![CDATA[<210> 19]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> QX006N (HCDR1)]]> <![CDATA[<400> 19]]> Ser Tyr Tyr Met Thr 1 5 <![CDATA[<210> 20]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> QX006N (HCDR2)]]> <![CDATA[<400> 20]]> Val Ile Asn Val Tyr Gly Gly Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 1 5 10 15 <![CDATA[<210> 21]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220> ]]> <![CDATA[<223> QX006N (HCDR3)]]> <![CDATA[<400>21]]> Glu Asp Val Ala Val Tyr Met Ala Ile Asp Leu 1 5 10 <![CDATA[ <210> 22]]> <![CDATA[ <211> 11]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> QX006N (LCDR1) <![CDATA[ <400> 22]]> Gln Ala Ser Gln Ser Ile Ser Asn Gln Leu Ser 1 5 10 <![CDATA[ <210> 23]]> <![CDATA[ <211> 7]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> QX006N (LCDR2) <![CDATA[ <400> 23]]> Asp Ala Ser Ser Leu Ala Ser 1 5 <![CDATA[ <210> 24]]> <![CDATA[ <211> 13]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial sequence <![CDATA[ <220> ]]> <![CDATA[ <223> QX006N (LCDR3) <![CDATA[ <400> 24]]> Leu Gly Ile Tyr Gly Asp Gly Ala Asp Asp Gly Ile Ala 1 5 10

Claims

1. Use of a type I IFN receptor (IFNAR1) inhibitor in the preparation of a medicament for the treatment of cutaneous lupus erythematosus (CLE) in an individual in need, wherein the medicament is for the treatment of the individual's rash, and wherein the IFNAR1 inhibitor is a human monoclonal antibody specific to IFNAR1, the antibody comprising: (a) a heavy chain variable region complementarity-determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 3; (b) a heavy chain variable region complementarity-determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 4; (c) a heavy chain variable region complementarity-determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 5; (d) a light chain variable region complementarity-determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 6; (e) a light chain variable region complementarity-determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; and (f) a light chain variable region complementarity-determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 7; 8-chain light chain variable region complementary determinant region 3 (LCDR3).

2. As claimed in claim 1, wherein the antibody comprises: (a) a human heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1; (b) a human light chain variable region comprising the amino acid sequence of SEQ ID NO: 2; (c) a human light chain constant region comprising the amino acid sequence of SEQ ID NO: 9; and (d) a human heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

10.

3. As claimed in claim 1, wherein the antibody contains an amino acid substitution of L234F in the Fc region, numbered by the EU index shown in Kabat, and wherein the antibody exhibits reduced affinity for at least one Fc ligand compared to an unmodified antibody.

4. As claimed in claim 1, wherein the antibody comprises: (a) a human heavy chain comprising the amino acid sequence of SEQ ID NO: 11; and (b) a human light chain comprising the amino acid sequence of SEQ ID NO:

12.

5. As requested in claim 1, wherein the IFNAR1 inhibitor is anifrolumab.

6. As claimed in claim 5, wherein the treatment comprises administering an intravenous dose of aniluromab to the individual.

7. As claimed in item 6, wherein the intravenous dose is about 300 mg, about 900 mg, or about 1000 mg.

8. As requested in item 6 or 7, wherein the intravenous dose is administered every four weeks (Q4W).

9. As claimed in claim 5, wherein the treatment comprises administering a subcutaneous dose of aniluromab.

10. As claimed in claim 9, wherein the subcutaneous dose is > 105 mg and < 150 mg of aniluzumab.

11. As requested in claim 10, wherein the subcutaneous dose is ≤ 135 mg of aniluzumab.

12. As claimed in claim 11, wherein the subcutaneous dose is approximately 120 mg.

13. The use as described in any one of claims 9 to 12, wherein the subcutaneous dose is administered in a single administration step.

14. The use as described in any of claims 9 to 12, wherein the subcutaneous dose is administered at intervals of 6 to 8 days.

15. The use as described in any of claims 9 to 12, wherein the subcutaneous dose is administered once weekly.

Images