Treatment methods for cutaneous lupus erythematosus and systemic lupus erythematosus

Abstract

To provide treatment methods for cutaneous lupus erythematosus and systemic lupus erythematosus. [Solution] The present invention provides a dosage regimen for an anti-blood dendritic cell antigen 2 antibody for use in the treatment of cutaneous lupus erythematosus and systemic lupus erythematosus. The present invention relates, in part, to a dosage regimen for an anti-BDCA2 antibody for use in the treatment of CLE and SLE. In a first aspect, the present invention features a method for treating CLE or SLE in a human subject requiring treatment. The method comprises subcutaneously administering an anti-BDCA2 antibody to the human subject at a dose of 225 mg every four weeks.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 121,194, filed on December 3, 2020. The content of the provisional application is hereby incorporated by reference in its entirety into this specification.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety into this specification. The ASCII copy created on November 12, 2021, is named 13751 - 0337WO1_SL.txt and has a size of 17,573 bytes.

[0003] This application relates to the clinical use of anti - blood dendritic cell antigen 2 antibodies in the treatment of cutaneous erythematosus and systemic erythematosus.

Background Art

[0004] Blood dendritic cell antigen 2 (BDCA2) is a C - type lectin expressed on human plasmacytoid dendritic cells (pDC) (Dzionek et al., J. Immunol., 165:6037 - 6046 (2000)), and is a special population of bone - marrow - derived cells that secrete type I interferon (IFN) in response to Toll - like receptor (TLR) ligands. BDCA2 consists of a single extracellular carbohydrate - recognition domain (CRD) belonging to the type II C - type lectin family at its C - terminus, a transmembrane region, and a short cytoplasmic tail that does not have a signaling motif at its N - terminus. BDCA2 transmits intracellular signals via the associated transmembrane adapter FcεRIγ and induces a B - cell receptor (BCR) - like signaling cascade.

[0005] Cutaneous erythematosus (CLE) is an autoimmune disease that affects the skin and can appear either with or without systemic symptoms.

[0006] Systemic lupus erythematosus (SLE) is a chronic, complex autoimmune disease affecting multiple organ systems, with unpredictable disease severity and alternating periods of illness or relapse and remission. Given the lack of specific treatments for CLE and SLE, and the significant impact these diseases have on quality of life, there remains a great unmet need for the development of new, targeted, and effective therapies. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Dzionek et al., J. Immunol., 165:6037-6046(2000) [Overview of the Initiative]

[0008] This disclosure relates, in part, to a regimen for administering anti-BDCA2 antibodies for use in the treatment of CLE and SLE.

[0009] In a first aspect, the present disclosure features a method for treating a human subject in need of treatment for CLE or SLE. The method comprises subcutaneously administering an anti-BDCA2 antibody to the human subject at a dose of 225 mg every four weeks. The anti-BDCA2 antibody comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 comprises the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 comprises the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 comprises the amino acid sequence described in SEQ ID NO: 3. VH-CDR1, VH-CDR2, and VH-CDR3, comprising the amino acid sequences described, and VL-CDR1, VL-CDR2, and VL-CDR3, which are CDRs of VL, wherein VL-CDR1 comprises the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 comprises the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 comprises the amino acid sequence described in SEQ ID NO: 6. In some cases, the human subject is administered a loading dose of the anti-BDCA2 antibody two weeks after the first administration of the anti-BDCA2 antibody. In some cases, the loading dose is 225 mg. In some cases, the loading dose is 450 mg. The patient population may be adult or pediatric CLE or adult or pediatric SLE.

[0010] This disclosure also features a method of treatment in human subjects requiring treatment for lupus nephritis, neuropsychiatric lupus (NPSLE), Sjögren's syndrome, systemic sclerosis (scleroderma), Morphea, psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), dermatomyositis, polymyositis, type 1 diabetes mellitus, or cytokine release syndrome. The patient population for any of these indications may be adults or children. The method comprises subcutaneous administration of an anti-BDCA2 antibody to the human subject at a dose of 225 mg every four weeks. The anti-BDCA2 antibody comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise the following: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 consists of the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 consists of the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 consists of the amino acid sequence described in SEQ ID NO: 3. VH-CDR1, VH-CDR2, and VH-CDR3, which consist of the amino acid sequences described, and VL-CDR1, VL-CDR2, and VL-CDR3, which are CDRs of VL, wherein VL-CDR1 consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 consists of the amino acid sequence described in SEQ ID NO: 6. In some cases, the human subject is administered a loading dose of the anti-BDCA2 antibody two weeks after the first administration of the anti-BDCA2 antibody. In some cases, the loading dose is 225 mg. In some cases, the loading dose is 450 mg.

[0011] In certain cases, the human subject receives a second loading dose of the anti-BDCA2 antibody at 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 weeks (e.g., 18 weeks) after the initial administration of the anti-BDCA2 antibody. In some cases, the second loading dose is 225 mg. In other cases, the second loading dose is 450 mg.

[0012] In some cases, the anti-BDCA2 antibody is administered in doses of 225 mg every 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days (e.g., every 4 weeks) for at least 16 weeks. In some cases, the anti-BDCA2 antibody is administered in doses of 225 mg once a month for at least 16 weeks. In some cases, the anti-BDCA2 antibody is administered in doses of 225 mg every 4 weeks for at least 52 weeks. In some cases, the anti-BDCA2 antibody is administered indefinitely in doses of 225 mg every 4 weeks. In some cases, the anti-BDCA2 antibody is administered in doses of 225 mg every 4 weeks until the healthcare professional determines that it is no longer needed. In some cases, the anti-BDCA2 antibody is administered in doses of 225 mg every 4 weeks for the lifetime of the patient (i.e., chronic use).

[0013] In certain cases, the human subject receives at least four doses of the anti-BDCA2 antibody (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 doses, etc.). In some cases, the human subject receives at least twelve doses of the anti-BDCA2 antibody. In other cases, the human subject receives at least thirteen doses of the anti-BDCA2 antibody. In certain cases, the human subject receives at least fourteen doses of the anti-BDCA2 antibody. In some cases, the human subject receives at least 15 doses of the anti-BDCA2 antibody. In other cases, the human subject receives at least 16 doses of the anti-BDCA2 antibody. In other cases, the anti-BDCA2 antibody is administered to the human subject until the healthcare professional determines that it is no longer necessary. In other cases, the anti-BDCA2 antibody is administered to the human subject at least 16 doses. In other cases, the anti-BDCA2 antibody is administered to the human subject for the lifetime of the patient (i.e., chronic use).

[0014] In some cases, the CLE disease is mildly active. In some cases, the CLE disease is moderately active. In other cases, the CLE disease is severely active. In some cases, the type of CLE is acute CLE (ACLE). In some cases, the type of CLE is subacute CLE (SCLE). In some cases, the type of CLE is chronic CLE (CCLE). In certain cases, the CLE is discoid lupus erythematosus (DLE). In some cases, the CLE is active CLE. In some cases, the CLE is active CLE and the human subject is intolerant and / or unresponsive to antimalarial and topical steroid therapy. In certain cases, the active CLE is CLE with systemic symptoms of lupus and the human subject is intolerant and / or unresponsive to antimalarial and topical steroid therapy. In some cases, the active CLE is CLE without systemic lupus symptoms, and the human subject is intolerant to or unresponsive to antimalarial and / or topical steroid therapy. In certain cases, the human subject achieves a clinically meaningful reduction, e.g., a 4-point reduction, from baseline in the Disease Area and Severity Index A (CLASI-A) score for cutaneous lupus erythematosus, approximately 16 to 24 weeks after the first dose of the anti-BDCA2 antibody. In some cases, the human subject achieves a clinically meaningful reduction in disease activity from baseline in the CLE-specific Investigator Overall Assessment (IGA) (CLA-IGA-R), e.g., a score of 0, 1, 2, or 3, approximately 16 to 24 weeks after the first dose of the anti-BDCA2 antibody.

[0015] In certain cases, the SLE is active SLE. In some cases, the human subject has active autoantibody-positive SLE. In certain cases, the human subject has active autoantibody-positive SLE and is receiving non-biological standard treatment for SLE. In some cases, the SLE is moderate. In certain cases, the SLE is severe. In some cases, the SLE is active SLE with active joint and / or skin symptoms. In some cases, the human subject has SLEDAI-2K ≥ 6 at the start of treatment, excluding alopecia, lupus-related headache, and organic brain disease. In certain cases, the human subject has clinical SLEDAI-2K ≥ 4 at the start of treatment, excluding alopecia, lupus-related headache, and organic brain disease, anti-dsDNA, low complement C3 and / or C4 levels, or fever. In certain cases, the human subject has BILAG-2004 grade A in one or more organ systems, or BILAG-2004 grade B in two or more organ systems at the start of treatment. In certain cases, the human subject achieves an SRI-4 response approximately 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, or 52 weeks after the start of treatment with the anti-BDCA2 antibody. In certain cases, the human subject, who has swelling and tenderness in at least four joints at the start of treatment, achieves a Joint-50 response rate approximately 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, or 52 weeks after the start of treatment with the anti-BDCA2 antibody.

[0016] In some cases, the anti-BDCA2 antibody is formulated as a sterile liquid pharmaceutical composition comprising 150 mg / ml of the anti-BDCA2 antibody, 3% of sucrose, 20 mM of L-histidine, 100 mM of L-arginine HCl, 0.4 mM of glutathione (GSH or a combination of GSH and GSSG), and 0.05% of polysorbate 80 (PS80), the pharmaceutical composition having a pH of 5.7.

[0017] In some cases, the VH contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8. In certain specific examples, the VH contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8. In other examples, the VH contains or consists of the amino acid sequence described in SEQ ID NO: 7, and the VL contains or consists of the amino acid sequence described in SEQ ID NO: 8.

[0018] In some cases, the anti-BDCA2 antibody used in the method described herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 comprises or consists of the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 comprises or consists of the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 comprises or consists of the amino acid sequence described in SEQ ID NO: 3. R3, and VL-CDR1, VL-CDR2, and VL-CDR3 are CDRs of VL, where VL-CDR1 contains or consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains or consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 contains or consists of the amino acid sequence described in SEQ ID NO: 6, where VH contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and VL contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8.

[0019] In some cases, the anti-BDCA2 antibody used in the method described herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 comprises or consists of the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 comprises or consists of the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 comprises or consists of the amino acid sequence described in SEQ ID NO: 3. R3, and VL-CDR1, VL-CDR2, and VL-CDR3 are CDRs of VL, where VL-CDR1 contains or consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains or consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 contains or consists of the amino acid sequence described in SEQ ID NO: 6, where VH contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and VL contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8.

[0020] In some cases, the anti-BDCA2 antibody used in the method described herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 comprises or consists of the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 comprises or consists of the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 comprises or consists of the amino acid sequence described in SEQ ID NO: 3. R3, and VL-CDR1, VL-CDR2, and VL-CDR3 are CDRs of VL, where VL-CDR1 contains or consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains or consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 contains or consists of the amino acid sequence described in SEQ ID NO: 6, where VH contains or consists of a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7, and VL contains or consists of a sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 8.

[0021] In some cases, the anti-BDCA2 antibody used in the method described herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity-determining regions (CDRs) of VH, where VH-CDR1 comprises or consists of the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 comprises or consists of the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 comprises or consists of the amino acid sequence described in SEQ ID NO: 3. R3, and VL-CDR1, VL-CDR2, and VL-CDR3 are CDRs of VL, where VL-CDR1 contains or consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains or consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 contains or consists of the amino acid sequence described in SEQ ID NO: 6, where VH contains or consists of a sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 7, and VL contains or consists of a sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 8.

[0022] In some cases, the anti-BDCA2 antibody used in the methods described herein comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL each comprise: VH complementarity determining regions (CDRs) VH-CDR1, VH-CDR2, and VH-CDR3, wherein VH-CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 1, VH-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 2, VH-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 3, VH-CDR1, VH-CDR2, and VH-CDR3, and VL CDRs VL-CDR1, VL-CDR2, and VL-CDR3, wherein VL-CDR1 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 4, VL-CDR2 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 5, VL-CDR3 comprises or consists of the amino acid sequence set forth in SEQ ID NO: 6, VL-CDR1, VL-CDR2, and VL-CDR3, where the VH comprises or consists of a sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 7, and the VL comprises or consists of a sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0023] In some cases, the anti-BDCA2 antibody used in the methods described herein is the antibody described in U.S. Patent No. 9,902,775, which is incorporated herein by reference.

[0024] In certain instances, the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In some cases, the heavy chain comprises, or consists of, a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:9, and the light chain comprises, or consists of, a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:10. In other cases, the heavy chain comprises, or consists of, a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9, and the light chain comprises, or consists of, a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:10. In some cases, the heavy chain comprises, or consists of, the amino acid sequence set forth in SEQ ID NO:9, and the light chain comprises, or consists of, the amino acid sequence set forth in SEQ ID NO:10.

[0025] In some cases, the method further comprises administering to the human subject at least one of an anti-malarial drug, a corticosteroid, an immunosuppressive agent, or an anti-B lymphocyte stimulator (BLyS) monoclonal antibody. In certain instances, the method further comprises administering to the human subject at least one of mycophenolic acid, azathioprine, methotrexate, a calcineurin inhibitor, or cyclophosphamide.

[0026] In another embodiment, the present disclosure features a pre-filled syringe containing a sterile preparation of an anti-BDCA2 antibody. The pre-filled syringe is suitable for subcutaneous administration of the anti-BDCA2 antibody at a fixed dose of 225 mg. The anti-BDCA2 antibody comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH and VL are complementarity-determining regions (CDRs) of the VH, VH-CDR1, VH-CDR2, and VH-CDR3, respectively, where VH-CDR1 contains or comprises the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 contains or comprises the amino acid sequence described in SEQ ID NO: 2, and VH-CDR3 contains or comprises the amino acid sequence described in SEQ ID NO: 3. VH-CDR1, VH-CDR2, and VH-CDR3, which consist of the same, and VL-CDR1, VL-CDR2, and VL-CDR3, which are CDRs of VL, wherein VL-CDR1 contains or consists of the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains or consists of the amino acid sequence described in SEQ ID NO: 5, and VL-CDR3 contains or consists of the amino acid sequence described in SEQ ID NO: 6.

[0027] The pre-filled syringes described herein may be fitted with device components such as finger flanges and safety needle shields to facilitate administration. These may also be fitted to auto-injectors to facilitate self-administration by patients and / or by caregivers.

[0028] In some cases, the VH contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8. In certain specific examples, the VH contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8. In other examples, the VH contains or consists of the amino acid sequence described in SEQ ID NO: 7, and the VL contains or consists of the amino acid sequence described in SEQ ID NO: 8.

[0029] In other cases, the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In some cases, the heavy chain contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 9, and the light chain contains or consists of a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 10. In other cases, the heavy chain contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 9, and the light chain contains or consists of a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 10. In some cases, the heavy chain contains or consists of the amino acid sequence described in SEQ ID NO: 9, and the light chain contains or consists of the amino acid sequence described in SEQ ID NO: 10.

[0030] In some cases, the anti-BDCA2 antibody is formulated as a sterile liquid pharmaceutical composition comprising 150 mg / ml of the anti-BDCA2 antibody, 3% of sucrose, 20 mM of L-histidine, 100 mM of L-arginine HCl, 0.4 mM of glutathione (GSH or a combination of GSH and GSSG), and 0.05% of polysorbate 80 (PS80), the pharmaceutical composition having a pH of 5.7.

[0031] In some cases, the syringe is a clear glass syringe of the United States Pharmacopeia or European Pharmacopeia Type 1, sealed with a rubber stopper.

[0032] In some cases, the syringe is a Type I glass 2.25 mL pre-filled syringe equipped with a butyl rubber plunger (ethylene tetrafluoroethylene coated).

[0033] To avoid any doubt, expressions such as “in some embodiments,” “in a particular embodiment,” “in a particular example,” “in some cases,” “in further embodiments,” “in one embodiment,” and “in further embodiments” are used, and each embodiment described herein is meant to be read with the combination of features of each of those embodiments in mind, and this disclosure emphasizes that combinations of features of these embodiments should be treated in the same way as those detailed in one embodiment. The same applies to any combination of embodiments and features shown in the appended claims and examples, which are also intended to be combined with features of the corresponding embodiments disclosed herein, and for the sake of consistency and brevity only, such embodiments are characterized by dependencies, but in practice, each combination of embodiments and features that may be interpreted by (multiple) dependencies should be considered literally disclosed and not as a choice from different options. In this regard, it will be understood by those skilled in the art that the embodiments and features disclosed in the examples are intended to be generalized to equivalents having the same function as illustrated therein.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which the present invention pertains. Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, but exemplary methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated collectively by reference. In case of any conflict, this application shall prevail, including definitions. The materials, methods, and examples are illustrative and not intended to be limiting.

[0035] Other features and advantages of the present invention will become apparent from the following detailed description and claims. [Brief explanation of the drawing]

[0036] [Figure 1] This chart shows the time course of pharmacokinetics of BIIB059 throughout the Phase 2 trial. The median concentrations (dots) observed for each BIIB059 dose—50 mg (bottom curve), 150 mg (middle curve), and 450 mg (top curve)—are shown for the corresponding 90% predicted interval (shaded area) (n=500) in participants with CLE in the Phase 2 trial. The thick lines represent the predicted median. The target engagement level for BDCA2 (0.64 μg / mL), the IC90 level for IFN-α (9.7 μg / mL), and the 3x IC90 level are also shown. [Figure 2] Forest plot of CLASI-A scores: Percentage change from baseline at week 16, showing the Mixed Model for Repeated Measures subgroup analysis. [Figure 3] A and B provide exposure-response analyses from the Phase 2 trial. A shows observations for a simulation of the exposure-response model using the trough concentration of CLASI-A at week 16 in the Phase 2 trial. The observed change from baseline and associated standard deviation in CLASI-A were determined according to four bins of observed trough concentrations of BIIB059 (plus readings at placebo, i.e., concentration 0), and plotted against the median exposure within each bin. The solid line is the median of the simulated exposure-response trend (1,000 replicates). The shaded area shows the associated 90% CI. B is a box plot showing the range of observed trough concentrations (median, interquartiles, and 5 / 95 percentile). EC90 is the target engagement of BDAC2 at 0.64 μg / mL. IFN90 is the inhibitory level at 9.7 μg / mL. [Figure 4]This graph shows the percentage of participants with a BIIB059 level of CLASI-A EC90 (10.1 μg / mL) or higher at week 16. The simulation is based on 1,000 Phase 3 trials, assuming a BIIB059 dose of 50 mg to 450 mg in Q4W, a loading dose at week 2 (the same as the initial dose), and an assumed ADA incidence of 19%. The dashed line represents 80% of the participants. [Figure 5] The graphs show the time course of pharmacokinetics of BIIB059 at doses of 150 mg and 225 mg. Simulated time course of BIIB059 PK after Q4W administration of 150 mg (left) and 225 mg (right) to CLE patients (n=1,000). The time points of PK observed at the 150 mg dose in the Phase 2 trial are indicated by filled circles (ADA positive) and circles (ADA negative). The 80% prediction interval is shown in the shaded area, along with the median shown by the solid black line. The blue dashed line shows the estimated EC90 (10.1 μg / mL) for CLASI-A, and the IC90 (9.7 μg / mL) of IFNα is shown in black. For 225 mg (right), an ADA incidence of 19% was assumed. [Figure 6A] This is a schematic diagram of the Phase 3 CLE trial design. [Figure 6B] Another schematic diagram of the CLE exam design. [Figure 7] This graph shows the time course of pharmacokinetics of BIIB059 over administration in SLE participants. The median concentrations (dots) observed for each BIIB059 dose—50 mg (bottom trace), 150 mg (middle trace), and 450 mg (top trace)—are shown for the corresponding 90% predictive interval (n=500) in SLE participants. The thick lines represent the predicted median for 50 mg, 150 mg, and 450 mg, respectively. The target engagement level of BDCA2 (0.64 μg / mL) is shown by a dashed line at the bottom. The other dashed line represents the INF-α IC90 level (9.7 μg / mL), and the thick black line from above represents the 3x IC90 level. The top thick line represents the mean BIIB059 concentration from the highest IV dose of 20 mg / kg, which was considered safe and well-tolerated in Phase 1. [Figure 8]This is a visual predictive check plot for the BIIB059 Cavg of the exposure-response SRI-4 model in participants with SLE. SRI-4 response = a decrease of 4 or more in the systemic lupus response index. [Figure 9] This describes the percentages of simulated Phase 3 trials that achieved mean differences in SRI-4 response compared to placebo of 0.17, 0.2, 0.23, and 0.25, based on the SRI-4 exposure-response model at week 52. SRI-4 response = a reduction of 4 or more in the Systemic Lupus Erythematosus Response Index. [Figure 10] This shows the predicted time course of pharmacokinetics in SLE participants after Q4W SC at 225 mg and 450 mg in Phase 3. The simulated time course of BIIB059 after Q4W SC administration at 225 mg and 450 mg in SLE patients (n=500). The 80% prediction interval, along with the black median, is shown in the lower (225 mg) and upper (450 mg) shaded areas. The upper black dashed line represents the estimated EC90 (10.1 μg / mL) for CLASI-A, and the lower dashed line represents the IC90 (9.7 μg / mL) for IFNα. The upper solid line represents the mean BIIB059 concentration from the highest IV dose of 20 mg / kg, which was considered safe and well-tolerated in Phase 1. An ADA incidence of 19% was assumed. [Figure 11A] This is a schematic diagram of the Phase 3 SLE trial design. [Figure 11B] Another schematic diagram of the SLE trial design. [Modes for carrying out the invention]

[0037] This application provides a dosing regimen for an anti-BDCA2 antibody for use in the treatment of CLE or SLE.

[0038] BDCA2 BDCA2 is a type II C lectin specifically expressed in plasmacytoid dendritic cells (pDCs). BDCA2 consists of a single extracellular carbohydrate recognition domain (CRD) at its C-terminus, a transmembrane domain, and a short cytoplasmic tail at its N-terminus that lacks a signaling motif. BDCA2 transmits intracellular signals via its associated transmembrane adapter, FcεRIγ. Antibody-mediated ligation of BDCA2 recruits spleen tyrosine kinase (SYK) to the phosphorylated immunoreceptor-activating tyrosine motif (ITAM) of FcεRIγ. Activation of Syk leads to the activation of the B-cell linker (Blnk), Bruton's tyrosine kinase (BTK), and phospholipase Cγ2 (PLCγ2), and Ca2 + This will trigger mobilization.

[0039] The amino acid sequence of the human BDCA2 protein (Genbank® accession number NP_569708.1) is shown below (the transmembrane domain is italicized, and the extradomain is underlined). [ka]

[0040] The amino acid sequence of human FcεRIγ (Genbank® accession number NP_004097.1) is shown below. 1 MIPAVVLLLL LLVEQAAALG EPQLCYILDA ILFLYGIVLT LLYCRLKIQV 51 RKAAITSYEK SDGVYTGLST RNQETYETLK HEKPPQ*(Sequence ID 30)

[0041] Anti-BDCA2 antibody In some embodiments, the anti-BDCA2 antibody or its BDCA2-conjugated fragment used in the compositions and methods described herein includes a complementarity-determining region (CDR) of three heavy-chain variable domains of the antibody, referred to as "BIIB059". In some embodiments, the anti-BDCA2 antibody or its BDCA2-conjugated fragment includes a CDR of three light-chain variable domains of BIIB059. In yet other embodiments, the anti-BDCA2 antibody or its BDCA2-conjugated fragment includes a CDR of three heavy-chain variable domains and a CDR of three light-chain variable domains of BIIB059. The CDR may be based on any definition of CDR in the art, e.g., the definitions of Kabat, Chothia, Abysis Chothia, Modified Chothia / AbM, or the definition of contact. The CDR sequences of BIIB059 according to these exemplary CDR definitions are shown in Table A below. [Table A]

[0042] In some embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises VH CDR1 containing or consisting of the amino acid sequence described in SEQ ID NO: 1 or 17, VH CDR2 containing or consisting of the amino acid sequence described in SEQ ID NO: 2, and VH CDR3 containing or consisting of the amino acid sequence described in SEQ ID NO: 3. In some embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises VL CDR1 containing or consisting of the amino acid sequence described in SEQ ID NO: 4, VL CDR2 containing or consisting of the amino acid sequence described in SEQ ID NO: 5, and VL CDR3 containing or consisting of the amino acid sequence described in SEQ ID NO: 6.

[0043] In one particular embodiment, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises the amino acid sequences described in SEQ ID NOs: 1-6, or a CDR comprising them. In another embodiment, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises the amino acid sequences described in SEQ ID NOs: 11-16, or a CDR comprising them. In yet another embodiment, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises the amino acid sequences described in SEQ ID NOs: 17-22, or a CDR comprising them. In yet another embodiment, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises the amino acid sequences described in SEQ ID NOs: 23-28, or a CDR comprising them. In one embodiment, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises a VH CDR1 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 1 or 17, a VH CDR2 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 2, and a VH CDR3 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 3, as well as a VL CDR1 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 4, a VL CDR2 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 5, and a VL CDR3 comprising or consisting thereof the amino acid sequence described in SEQ ID NO: 6.

[0044] BIIB059 is an exemplary anti-BDCA2 antibody that can be used in the compositions and methods described herein. BIIB059 is a humanized antibody having two glycosylated human IgG1 heavy chains and two human kappa light chains, which specifically binds to BDCA2 on the surface of plasmacytoid dendritic cells. The wild-type IgG1 sequence contains a single N-linked glycosylation site and binds to the Fc receptor with affinity typical of molecules in this class. BIIB059 is described in U.S. Patent No. 9,902,775.

[0045] The variable heavy chain (VH) of BIIB059 contains or consists of the following amino acid sequence: [ka]

[0046] The variable light chain (VL) of BIIB059 contains or consists of the following amino acid sequence: [ka]

[0047] In certain embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment contains a VH having the amino acid sequence described in SEQ ID NO: 7. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment selectively binds to the external domain of human BDCA2 and contains a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VH domain of BIIB059 (SEQ ID NO: 7), or that is at least 1 to 5 amino acid residues different from SEQ ID NO: 7, but less than 40, 30, 20, 15, or 10 residues. In certain cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2 but not significantly bind to BDCA2 of subprimate species, and / or (ii) inhibit the production of TLR7 / TLR9-induced type I interferon and other cytokines or chemokines by human pDCs, and / or (iii) mediate the internalization of BDCA2 from the surface of pDCs, and / or (iv) downregulate CD32a and / or CD62L from the surface of pDCs, and / or (v) deplete pDCs in vitro by ADCC or CDC.

[0048] In certain embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment includes a VL having the amino acid sequence described in SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment selectively binds to the external domain of human BDCA2 and includes a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VL domain of BIIB059 (SEQ ID NO: 8), or that is at least 1 to 5 amino acid residues different from SEQ ID NO: 8, but less than 40, 30, 20, 15, or 10 residues. In certain cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2 but not significantly bind to BDCA2 of subprimate species, and / or (ii) inhibit the production of TLR7 / TLR9-induced type I interferon and other cytokines or chemokines by human pDCs, and / or (iii) mediate the internalization of BDCA2 from the surface of pDCs, and / or (iv) downregulate CD32a and / or CD62L from the surface of pDCs, and / or (v) deplete pDCs in vitro by ADCC or CDC.

[0049] In some embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises VH having the amino acid sequence described in SEQ ID NO: 7 and VL having the amino acid sequence described in SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment selectively binds to the external domain of human BDCA2 and includes (i) a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VH domain of BIIB059 (SEQ ID NO: 7), and (ii) a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VL domain of BIIB059 (SEQ ID NO: 8), or differs from SEQ ID NO: 7 and / or SEQ ID NO: 8 by at least 1 to 5 amino acid residues, but less than 40, 30, 20, 15, or 10 residues. In certain cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2 but not significantly bind to BDCA2 of subprimate species, and / or (ii) inhibit the production of TLR7 / TLR9-induced type I interferon and other cytokines or chemokines by human pDCs, and / or (iii) mediate the internalization of BDCA2 from the surface of pDCs, and / or (iv) downregulate CD32a and / or CD62L from the surface of pDCs, and / or (v) deplete pDCs in vitro by ADCC or CDC.

[0050] The antibody consisting of the mature heavy chain (SEQ ID NO: 9) and mature light chain (SEQ ID NO: 10) listed below will be referred to as "BIIB059" in this specification. [ka]

[0051] In the above VH, VL, HC, and LC sequences, CDR1, 2, and 3, based on Kabat's definition, are underlined and in bold. The italicized and bold sequences in VH and HC are further N-terminal sequences found in CDR1, based on the modified Chothia / AbM definition.

[0052] In certain embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment contains an HC having the amino acid sequence described in SEQ ID NO: 9. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment contains an HC that selectively binds to the external domain of human BDCA2 and is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 9, or contains an HC that differs from SEQ ID NO: 9 by at least 1 to 5 amino acid residues but less than 40, 30, 20, 15, or 10 residues.

[0053] In certain embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises an LC having the amino acid sequence described in SEQ ID NO: 10. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment comprises an LC that selectively binds to the external domain of human BDCA2 and is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 10, or comprises an LC that differs from SEQ ID NO: 10 by at least 1 to 5 amino acid residues but less than 40, 30, 20, 15, or 10 residues.

[0054] In some embodiments, the anti-BDCA2 antibody or its BDCA2-binding fragment comprises an HC having the amino acid sequence described in SEQ ID NO: 9 and an LC having the amino acid sequence described in SEQ ID NO: 10. In some embodiments, the anti-BDCA2 antibody or its antigen-binding fragment selectively binds to the external domain of human BDCA2 and includes (i) HC which is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 9, and (ii) LC which is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 10, or differs from SEQ ID NO: 9 and / or SEQ ID NO: 10 by at least 1 to 5 amino acid residues but less than 40, 30, 20, 15, or 10 residues.

[0055] In certain embodiments, the anti-BDCA2 antibody is an IgG antibody. In certain embodiments, the anti-BDCA2 antibody has a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE. In one embodiment, the anti-BDCA2 antibody is of the IgG1 isotype. In another embodiment, the anti-BDCA2 antibody is of the IgG2 isotype. In yet another embodiment, the anti-BDCA2 antibody is of the IgG3 isotype. In further embodiments, the antibody has a light chain constant region selected from, for example, human kappa or human lambda light chains. In some embodiments, the anti-BDCA2 antibody is an IgG1 / kappa antibody. In certain embodiments, the anti-BDCA2 antibody has an EC of 7-15 μg / mL 50 It contains a human Fc region that binds to FcγRIIa(CD32a). In certain embodiments, the antibody is 10 μg / mL EC 50 It contains a human Fc region that binds to FcγRIIa(CD32a). In certain embodiments, the antibody is 11 μg / mL EC 50It contains a human Fc region that binds to FcγRIIa(CD32a). In certain embodiments, the antibody is 12 μg / mL EC 50 The antibody contains a human Fc region that binds to FcγRIIa(CD32a). In some cases, the heavy chain constant region is human or a modified version of the human constant region. In certain examples, the human constant region may contain at least one and up to two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, three, three, nine, or twenty substitutions. In certain embodiments, the modified human Fc region is the Fc region of modified human IgG1. In some cases, the constant region of the anti-BDCA2 antibody may be modified by mutations of one or more amino acid residues to confer a desired functional property (e.g., effector function or alteration of half-life, reduction of glycosylation). For example, the N-linked glycosylation site may be substituted to prevent or reduce N-linked glycosylation of the Fc region (e.g., the Fc region of human IgG1).

[0056] In some embodiments, the anti-BDCA2 antibody is a full-length (complete) antibody or substantially full-length. The protein may comprise at least one, preferably two, complete heavy chains and at least one, preferably two, complete light chains. In some embodiments, the anti-BDCA2 antibody is a BDCA2 binding fragment. In some cases, the BDCA2 binding fragment is Fab, Fab', F(ab')2, Fabc, Fv, single-chain Fv(scFv), sc(Fv)2, or a diabody.

[0057] Antibodies, such as BIIB059, or its BDCA2-binding fragments, can be produced, for example, by preparing and expressing synthetic genes encoding the listed amino acid sequences, or by mutating human germline genes to obtain genes encoding the listed amino acid sequences. Furthermore, this antibody and other anti-BDCA2 antibodies can be produced, for example, using one or more of the following methods.

[0058] Anti-BDCA2 antibody composition This disclosure also provides compositions (e.g., pharmaceutical compositions) comprising the anti-BDCA2 antibody described herein. For example, the anti-BDCA2 antibody composition comprises an anti-BDCA2 antibody comprising an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH comprises the VH-CDR of BIIB059 and the VL comprises the VL-CDR. In certain examples, the VH-CDR comprises or consists of the amino acid sequences described in SEQ ID NO: 1 or 17, SEQ ID NO: 2, and SEQ ID NO: 3, and the VL-CDR comprises or consists of the amino acid sequences described in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In some embodiments, the anti-BDCA2 antibody composition comprises (i) an anti-BDCA2 antibody comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence described in SEQ ID NO: 7, and (ii) an anti-BDCA2 antibody comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence described in SEQ ID NO: 8. In certain embodiments, the anti-BDCA2 antibody composition comprises (i) a heavy chain comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence described in SEQ ID NO: 9, and (ii) an anti-BDCA2 antibody comprising a light chain comprising or consisting of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence described in SEQ ID NO: 10. The pharmaceutical composition may further comprise any pharmaceutically acceptable carrier and / or excipient.

[0059] In some cases, the pharmaceutical composition comprises 150 mg / ml of the anti-BDCA2 antibody, 3% of sucrose, 20 mM of L-histidine, 100 mM of L-arginine HCl, 0.4 mM of glutathione (GSH or a combination of GSH and GSSG), and 0.05% of polysorbate 80 (PS80). In some cases, the pharmaceutical composition has a pH of 5.5 to 6.0. In one example, the pharmaceutical composition has a pH of 5.7.

[0060] In some cases, the pharmaceutical composition comprises the anti-BDCA2 antibody at a concentration of 100-200 mg / ml, sucrose at a concentration of 1-4%, L-histidine at a concentration of 10-30 mM, L-arginine HCl at a concentration of 75-150 mM, glutathione (GSH or a combination of GSH and GSSG) at a concentration of 0.2-0.6 mM, and polysorbate 80 (PS80) at a concentration of 0.02-0.08%. In some cases, the pharmaceutical composition has a pH of 5.5-6.0. In one example, the pharmaceutical composition has a pH of 5.7.

[0061] In some cases, the pharmaceutical composition is a pharmaceutical composition described in US20190284281, which is incorporated herein by reference.

[0062] In some cases, the compositions described herein may be formulated with or administered together with at least one of the following: an antimalarial drug, a corticosteroid, an immunosuppressant, or an anti-B lymphocyte-stimulating factor (BLyS) monoclonal antibody. In certain specific cases, the compositions disclosed herein may be formulated with or administered together with at least one of the following: mycophenolic acid, azathioprine, methotrexate, a calcineurin inhibitor, or cyclophosphamide. In one example, the compositions described herein are administered together with an antimalarial drug. In another example, the compositions described herein are administered together with a corticosteroid.

[0063] The antibody or the pharmaceutical composition may be supplied in a pre-filled syringe or pump. The pharmaceutical composition comprises a sterile preparation of the anti-BDCA2 antibody described herein. The pre-filled syringe or pump may be suitable for subcutaneous administration of the anti-BDCA2 antibody at a fixed dose of 225 mg.

[0064] The compositions of this disclosure may be packaged as a kit containing information on how the antibody may be used to treat CLE or SLE. The kit may contain at least one of the following: an antimalarial drug, a corticosteroid, an immunosuppressant, or an anti-B lymphocyte-stimulating factor (BLyS) monoclonal antibody. In certain examples, the kit may contain at least one of the following: mycophenolic acid, azathioprine, methotrexate, a calcineurin inhibitor, or cyclophosphamide. In one example, the kit contains an antimalarial drug. In another example, the kit contains a corticosteroid.

[0065] Treatment method The anti-BDCA2 antibodies described herein, or pharmaceutical compositions comprising the anti-BDCA2 antibodies described herein, may be used to treat or prevent various immunological diseases, such as inflammatory and autoimmune diseases (e.g., CLE, SLE, lupus nephritis, neuropsychiatric lupus (NPSLE), Sjögren's syndrome, systemic sclerosis (scleroderma), Morphea, psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), dermatomyositis, polymyositis, type 1 diabetes, or cytokine release syndrome). In vitro data suggest that anti-BDCA2 antibodies may inactivate and / or inhibit inflammatory cytokines and chemokines produced by pDCs, downregulate CD32a, inhibit immune complex stimulation of pDCs, and / or cause downregulation or shedding of CD62L. The anti-BDCA2 antibodies or their BDCA2-binding fragments may be combined with antimalarial drugs (e.g., HCQ) to enhance their potential therapeutic effects in the treatment of inflammatory and autoimmune diseases. Anti-BDCA2 antibodies can be used to reduce the levels of cytokines and chemokines, such as type I interferons, type III interferons, IL-6, TNF-α, MIP1-α and MIP1-β, CCL5, and IP-10. Type I IFNs constitute a multi-member family of cytokines, including 13 IFN-α subtypes, IFN-β, -ε, -κ, -ω, -δ, and -τ (Theofilopoulos, Annu. Rev. Immunol., 23:307-36 (2005)). Type III interferons consist of three IFN-λ molecules called IFN-λ1, IFN-λ2, and IFN-λ3 (also known as IL29, IL28A, and IL28B, respectively). The anti-BDCA2 antibodies described herein offer a more potent therapeutic approach than treatments that attempt to reduce specific IFN subtypes with neutralizing antibodies by depleting and / or attenuating pDC function. Furthermore, the pDC-specific therapeutic approach using the anti-BDCA2 antibody is more selective and potentially safer than the overall blockade of the IFN response. For example, the anti-BDCA2 antibody described herein effectively eliminates type I IFN from pDCs while maintaining other IFN sources that may be necessary in the case of viral infection.

[0066] For example, an anti-BDCA2 antibody as described herein, or a pharmaceutical composition comprising an anti-BDCA2 antibody as described herein, is used for the treatment of CLE in a human subject requiring treatment. In some cases, the CLE disease is mildly active. In some cases, the CLE disease is moderately active. In other cases, the CLE disease is severely active. In some cases, the CLE disease is acute CLE (ACLE). In some cases, the CLE disease is subacute CLE (SCLE). In some cases, the CLE disease is chronic CLE (CCLE). In certain specific cases, the CLE disease is discoid lupus erythematosus (DLE). In some cases, the CLE disease is active CLE. In some cases, the CLE disease is active CLE and the human subject is intolerant and / or unresponsive to antimalarial and topical steroid therapy. In certain cases, the active CLE disease is CLE with systemic lupus symptoms, and the human subject is intolerant to or unresponsive to antimalarial and / or topical steroid therapy. In other cases, the active CLE disease is CLE without systemic lupus symptoms, and the human subject is intolerant to or unresponsive to antimalarial and / or topical steroid therapy. In certain cases, the human subject achieves a clinically meaningful reduction in disease area and severity index A (CLASI-A) score from baseline, e.g., a 4-point reduction, approximately 16 to 24 weeks after the first administration of the anti-BDCA2 antibody. Albrecht et al., “The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus” J Invest Dermatol. 2005;125(5):889-94, Bonilla-Martinez et al., “The cutaneous lupus erythematosus disease area and severity index: a responsive instrument to measure activity and damage in patients with cutaneous lupus erythematosus” Arch Dermatol. 2008;144(2):173-80, Klein et al., “Using the CLASI to assess disease severity and responsiveness to therapy in cutaneous lupus erythematosus” Arthritis Rheumatism. 2009;60:903, Klein et al., “Development of the CLASI as a tool to measure disease severity and responsiveness to therapy in cutaneous lupus erythematosus” Arch Dermatol. 2011;147(2):203-8, and Chakka et al., “Evaluating change in disease activity needed to reflect meaningful improvement in quality of life for clinical trials in cutaneous lupus erythematosus” J Am Acad Dermatol. 2021 Jun;84(6):1562-1567. Please refer to these sources.In some cases, the human subjects achieve a clinically meaningful reduction in disease activity from baseline, e.g., a score of 0, 1, 2, or 3, in CLE-specific IGA approximately 16 to 24 weeks after the first administration of the anti-BDCA2 antibody.

[0067] In another example, the anti-BDCA2 antibody described herein, or a pharmaceutical composition comprising the anti-BDCA2 antibody described herein, is used for the treatment of a human subject requiring treatment for SLE. In certain examples, the SLE is active SLE. In some cases, the human subject has active autoantibody-positive SLE. In certain cases, the human subject has active autoantibody-positive SLE and is receiving standard treatment for SLE. In some cases, the SLE is moderate SLE. In some cases, the SLE is severe SLE. In some cases, the SLE is active SLE with active joint and / or skin symptoms. In some cases, the human subject has SLEDAI-2K ≥ 6 at the start of treatment, excluding alopecia, lupus-related headache, and organic brain disease. In certain cases, the human subject has clinical SLEDAI-2K ≥ 4 at the start of treatment, excluding alopecia, lupus-related headache and organic brain disease, anti-dsDNA, low complement C3 and / or C4 levels, or fever. In certain cases, the human subject has BILAG-2004 grade A in one or more organ systems, or BILAG-2004 grade B in two or more organ systems at the start of treatment. In certain cases, the human subject achieves an SRI-4 response approximately 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, or 52 weeks after the start of treatment with the anti-BDCA2 antibody. In certain cases, human subjects with swelling and tenderness in at least four joints at the start of treatment achieve a Joint-50 response rate approximately 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, or 52 weeks after initiation of treatment with the anti-BDCA2 antibody. In certain cases, human subjects with a CLASI-A score ≥ 10 at baseline achieve a CLASI-50 response approximately 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, or 52 weeks after initiation of treatment with the anti-BDCA2 antibody.

[0068] In some cases, the anti-BDCA2 antibody is administered to the human subject by subcutaneous injection at a dose of 225 mg every four weeks. In some cases, the subject receives at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, four, six, six, seven, eight, nine, ten, eleven, twelve, thirteen, four, fifteen, six, six, seven, eight, nine, nine, twenty In some cases, the subject is administered a loading dose of the anti-BDCA2 antibody approximately two, three, four, or five weeks after the initial dose of the anti-BDCA2 antibody. In some cases, the loading dose is 225 mg. In some cases, the subject is administered a second loading dose of the anti-BDCA2 antibody at 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, 25, or 26 weeks (e.g., 18 weeks) after the initial dose of the anti-BDCA2 antibody. In some cases, the second loading dose is 225 mg.

[0069] In some cases, the treatment method for the human subject involves administering a pharmaceutical composition of an anti-BDCA2 antibody. The pharmaceutical composition comprises the anti-BDCA2 antibody at a concentration of 150 mg / ml, 3% sucrose, 20 mM L-histidine, 100 mM L-arginine HCl, 0.4 mM glutathione (GSH or a combination of GSH and GSSG), and 0.05% polysorbate 80 (PS80). In some cases, the pharmaceutical composition has a pH of 5.5 to 6.0. In one example, the pharmaceutical composition has a pH of 5.7. The pharmaceutical composition is administered subcutaneously to the human subject every four weeks to provide a dose of 225 mg of the anti-BDCA2 antibody.

[0070] In some embodiments, in all of the above therapeutic methods, the anti-BDCA2 antibody selectively binds to the external domain of human BDCA2 and includes (i) a VH domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VH domain of BIIB059 (SEQ ID NO: 7), and / or (ii) a VL domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of the VL domain of BIIB059 (SEQ ID NO: 8), or differs from SEQ ID NO: 7 and / or SEQ ID NO: 8 by at least 1 to 5 amino acid residues, but less than 40, 30, 20, 15, or 10 residues. In certain cases, these anti-BDCA2 antibodies (i) bind to human or cynomolgus monkey BDCA2 but do not significantly bind to BDCA2 of subprimate species, and / or (ii) inhibit TLR7 / TLR9-induced production of type I interferon and other cytokines or chemokines by human pDCs, and / or (iii) mediate the internalization of BDCA2 from the surface of pDCs, and / or (iv) downregulate CD32a and / or CD62L from the surface of pDCs, and / or (v) deplete pDCs in vitro by ADCC or CDC.

[0071] In a particular embodiment, in all of the above therapeutic methods, the anti-BDCA2 antibody selectively binds to the external domain of human BDCA2 and includes (i) an HC which is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 9, and / or (ii) an LC which is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identical to the amino acid sequence of SEQ ID NO: 10, or differs from SEQ ID NO: 9 and / or SEQ ID NO: 10 by at least 1 to 5 amino acid residues but less than 40, 30, 20, 15, or 10 residues.

[0072] The following are embodiments of the present invention. They are not intended to limit the scope of the present invention in any way. [Examples]

[0073] Example 1: Pharmacokinetic study over time using BIIB059 In the Phase 2 trial of CLE, fixed doses of BIIB059 at 50, 150, and 450 mg were administered subcutaneously (SC) every four weeks (Q4W). A loading dose was administered in week 2 (patients receiving 50 mg SC Q4W also received a loading dose of 50 mg; patients receiving 150 mg SC Q4W also received a loading dose of 150 mg; and patients receiving 450 mg SC Q4W also received a loading dose of 450 mg). As shown in Figure 1, these three BIIB059 doses showed different exposures with minimal overlap. The observed PK was consistent with the predictions of the PK / PD model, indicating that the doses tested in this trial were within the expected effective range of BIIB059. All doses were considered safe and well-tolerated.

[0074] The primary endpoint at week 16, defined as the percentage change from baseline in the CLASI-A score, was met (Table 1), demonstrating a dose-response. [Table 1]

[0075] Statistical significance was achieved at doses of 150 mg and 450 mg. The efficacy of BIIB059 was demonstrated across subgroups, particularly at the 150 mg and 450 mg doses, although more inconsistent clinical results were observed at the 50 mg dose (Figure 2). Overall, the Phase 2 data indicate that doses of 150 mg or higher of BIIB059 are required to achieve clinically meaningful improvement in skin disease activity of CLE across multiple thresholds and subgroups.

[0076] The relationship between serum exposure to BIIB059 and its efficacy (assessed by CLASI-A) in CLE participants was characterized using data from a Phase 2 trial. The effect of BIIB059 on the percentage change from baseline in CLASI-A at week 16 was described using the Emax function. The predicted trough concentration of the model was used as input data for the exposure-response analysis. The point estimate of the BIIB059 concentration associated with 90% of the maximum effect on CLASI-A (EC90) (10.1 ug / mL) was comparable to the IC90 of IFN-α (9.7 ug / mL). Figure 3 shows the observed (±SD) and predicted (90% CI) change from baseline in CLASI-A at week 16 as a function of BIIB059 trough concentration in CLE participants (primary endpoint). The proportion of participants achieving a CLASI-50 response increased with increasing BIIB059 exposure, and the maximum effect was estimated to be achieved at exposure levels equivalent to 150 mg of SC Q4W (approximately IFN-α IC90).

[0077] Notably, the reduced efficacy at a 50 mg dose suggests that maximizing the therapeutic effect of BIIB059 in CLE participants requires modulation of downstream IFN-α levels, rather than internalization of BDAC2.

[0078] Example 2: Dose selection for Phase 3 trial of CLE An exposure-response model was used to simulate the Q4W SC regimen for BIIB059. Based on the exposure levels of participants achieving a CLASI-A EC of 90 or higher, a 225 mg dose of Q4W SC was selected for the Phase 3 trial.

[0079] Figure 4 is a model simulation showing the percentage of participants with BIIB059 levels exceeding 10.1 ug / mL (or CLASI-A EC90). Figure 5 is a model simulation showing the time course of PK after administration of 150 mg and 225 mg of BIIB059. This model simulation suggests that a higher percentage of participants will have EC90 above 225 mg compared to 150 mg at week 16. At 50 mg, less than 5% of subjects had trough levels of BIIB059 above EC90, resulting in reduced efficacy at week 16 (Figure 3). Based on the exposure-response analysis of the Phase 2 trial, the Q4W SC at 225 mg is expected to maximize the potential efficacy of BIIB059 in participants with CLE. The exposure levels at trough concentrations of this proposed Phase 3 dose are expected to maintain CLASI-A EC90 above 225 mg in at least 80% of participants.

[0080] The effects of immunogenicity were also evaluated for BIIB059 exposure in relation to Phase 3 dose selection. Among CLE participants in the Phase 2 trial, 5 (19.2%), 4 (16.0%), and 5 (10.4%) of participants in the 50, 150, and 450 mg BIIB059 dose groups were evaluated as positive for anti-BIIB059 antibodies. All participants in the placebo group were negative for anti-BIIB059 antibodies. As shown in Figure 5, participants who were ADA-positive at the 150 mg dose in Phase 2 (filled dots in Figure 5) consistently had exposure levels above EC90 throughout the dosing phase. In Phase 3, assuming an ADA incidence of 19%, BIIB059 exposure is expected to remain above effective levels in at least 80% of participants receiving 225 mg (shaded area in the right panel of Figure 5). This indicates that the effects of immunogenicity on exposure are not expected to lead to clinically significant differences in efficacy or safety.

[0081] In short, BIIB059 225 mg Q4W SC is an appropriate dose for CLE based on safety, PK, PD (BDCA2 internalization), efficacy, and ability to inhibit IFN-α production by estimated pDCs (concentration [IC90] that results in 90% inhibition of the response).

[0082] Example 3: Phase 3 CLE test design This trial was a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (Figure 6A). Approximately 384 participants were enrolled from 160 sites worldwide and randomly assigned in each trial, in a 2:1 ratio, to receive either BIIB059 225 mg Q4W SC or the corresponding placebo for a 24-week double-blind, placebo-controlled (DBPC) administration period. Participants who completed the DBPC period then proceeded to a 28-week blinded extension (BE) administration period, during which all participants received BIIB059 225 mg SC Q4W, maintaining blinding to their initial dosing assignment.

[0083] Study participants have active CLE with or without systemic symptoms and are refractory and / or intolerant to antimalarial drugs. The diagnosis of CLE has been histologically confirmed in the past or at screening. Disease activity is defined by CLASI-A. All participants must have active skin symptoms as defined: at least one SCLE lesion with a total CLASI-A score ≥ 10 and a CLA-IGA-R score ≥ 3, as determined at screening and confirmed at randomization, and / or at least one active SCLE lesion with a minimum CLASI-A erythema score ≥ 2 and a CLASI-A scaling score ≥ 1, a CLA-IGA-R erythema score ≥ 3 and a score of ≥ 1 for any of the four morphological features (scalding, edema, follicular involvement, or secondary changes) in CLA-IGA-R association. Participants with active ACLE in addition to active SCLE and / or CCLE lesions, regardless of whether they have SLE, are permitted to participate in this trial. Furthermore, at the time of screening, participants must have documentation of a current failure to respond to antimalarial drug treatment used for 12 weeks or more, or documentation of having previously discontinued antimalarial drugs due to poor tolerability and / or side effects and / or lack of therapeutic effect after 12 weeks of use. Other standard lupus treatments, such as but not limited to oral corticosteroids, mycophenolate, or azathioprine, are permitted within the specifications set forth in the protocol and should have been initiated at least 12 weeks prior to randomization. Dosage received at the time of randomization should remain constant throughout the trial period.

[0084] The objective of this Phase 3 trial is to confirm the efficacy and safety of BIIB059 in participants with active CLE who are intolerant to or unresponsive to antimalarial drug treatment, regardless of the presence or absence of systemic symptoms.

[0085] This trial will incorporate primary and important secondary endpoints defined for each region. One set of endpoints will be defined for the United States, and another set of endpoints will be defined for other regions of the world (ROW).

[0086] The primary objective was to demonstrate the efficacy of BIIB059 in reducing disease activity in CLE, assessed in the US by the response rate of a CLA-IGA-R score of 0 or 1, defined as clear or almost clear skin disease activity, in BIIB059-treated and placebo-treated participants at week 16. In ROW, this was assessed by the CLASI-70 responder rate in BIIB059-treated and placebo-treated participants at week 24. CLASI-70 was defined as a reduction of at least 70% in the CLASI-A score from baseline (Table 2). [Table 2-1] [Table 2-2]

[0087] The key secondary objectives (Table 2) are to evaluate the efficacy of BIIB059 225 mg Q4W SC compared to placebo in participants at week 16 in the US and week 24 in ROW, by reduction of skin disease activity as measured by a CLA-IGA-R score of 0–1, four morphological features of erythematous or symmetry in CLA-IGA-R, and the CLASI-70 response rate at week 16 in the US.

[0088] Table 2 shows important secondary endpoints that support the secondary objectives.

[0089] Eligible participants who complete the 52-week administration period with the investigational drug will be offered participation in the Long-Term Extension Study (LTE). Participants who discontinue the study or the investigational drug prematurely, and participants who complete the blinded extension period but choose not to participate in the LTE, will complete a 24-week safety follow-up.

[0090] This LTE trial is a multicenter, open-label intervention study that will enroll approximately 400-500 participants from the parent Phase 3 trial. The LTE trial is planned to further evaluate the safety and efficacy profile of BIIB059 with at least two additional years of follow-up. The eligible population includes all participants who have completed two 52-week Phase 3 trials and have agreed to continue. The primary objective of this LTE trial is to evaluate the long-term safety (frequency of all exposures and adverse events [AEs]) of BIIB059. The proposed dose of BIIB059 225 mg Q4W SC in this LTE trial is the same as that planned for use in the Phase 3 trial of BIIB059.

[0091] Another schematic diagram of the CLE test design is shown in Figure 6B.

[0092] Example 4: Dose selection in a Phase 3 trial for SLE In the Phase 2 trial for SLE, fixed doses of BIIB059 at 50, 150, and 450 mg were administered subcutaneously (SC) every four weeks (Q4W). As shown in Figure 7, these 50, 150, and 450 mg doses in SLE showed different exposures with minimal overlap. The observed pharmacokinetics (PK) were consistent with the predictions of the PK / PD model, indicating that the doses tested in Phase 2 in SLE were within the therapeutic range for BIIB059. All doses were considered safe and well-tolerated.

[0093] To characterize the relationship between BIIB059 exposure and efficacy as measured through the SLE Responder Index-4 (SRI-4), exposure-response (ER) analysis was performed. Subsequently, clinical trial simulations were performed using the ER model to assist in the selection of the Phase 3 dose plan in participants with active SLE.

[0094] This SRI-4 model was developed using data from a trial that included placebo (43%) and primarily active treatment patients (48%) who received BIIB059 450 mg. The remaining 9% of this data was evenly distributed between lower doses of 50 mg and 150 mg. The ER model for the probability of SRI4 was a logistic regression model that included a piecewise linear function of power over time and BIIB059 Cavg (fixed at 55 μg / mL based on sensitivity analysis). Figure 8 shows the predicted proportion (95% CI) of patients receiving SRI4 relative to BIIB059 Cavg, with the simulated dataset (dotted line) and observational data (solid line) superimposed.

[0095] Clinical trial simulations were performed using the final ER model of the SRI4 response, and the Phase 3 dose selection for SLE participants was reported. Higher doses of BIIB059 had a greater probability of success in achieving a significant therapeutic difference in the SRI4 response compared to placebo (Figure 9).

[0096] This Phase 3 trial proposes BIIB059 doses of 225 mg (low dose) and 450 mg (high dose) as the standardized test for Q4W, with an additional dose in week 2. In previous clinical trials, exposure associated with doses ranging from 50 mg to 450 mg Q4W (additional dose in week 2) was considered well-tolerated among participants with SLE and / or CLE. The exposure level at trough concentration of the 225 mg dose was related to the IC of IFN-α associated with the efficacy of BIIB059 in Phase 2. 90 This is expected to consistently exceed (Figure 10), explaining the immunogenicity rate of up to 19% observed in Phase 2, which is not expected to affect efficacy.

[0097] Example 5: Phase 3 SLE Test Design This Phase 3 trial is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of BIIB059 in participants with active SLE (Figure 11A). Approximately 540 participants (180 participants / treatment group / study) were enrolled worldwide and randomly assigned in a 1:1:1 ratio to receive either BIIB059 450 mg or BIIB059 225 mg Q4W SC or a corresponding placebo for a 52-week DBPC treatment period, followed by a 24-week SFU period (no treatment). Participants who complete this Phase 3 trial will be eligible to participate in a separate Long-Term Extension (LTE) trial.

[0098] All participants must have a diagnosis of SLE and moderate to severe disease activity. All participants must be treated with stable nonbiological standard care (SoC) for lupus, have initiated treatment at least 12 weeks prior to trial enrollment, and have received a constant dose for at least 4 weeks prior to randomization. For participants receiving a dose greater than 10 mg / day at baseline, a forced tapering of corticosteroids should be initiated 4 weeks after the initial dose to achieve the target corticosteroid dose of 7.5 mg / day. One corticosteroid rescue dose is permitted between weeks 5 and 12.

[0099] These study populations include participants with active SLE who are being treated with lupus seroconjugates (SoCs). 1. At the time of informed consent, participants must be 16 years of age or older in the area permitted by the regulations of each facility. 2. Participants must have been diagnosed with SLE at least 24 weeks prior to screening by a physician who meets the diagnostic requirements and must meet the 2019 EULAR / ACR SLE classification criteria. 3. Participants must have a modified SLEDAI-2K score of 6 or higher (excluding alopecia, lupus-related headache, and organic brain syndromes) at the time of screening (central assessment) and randomization, according to the following criteria: a. If four of the required SLEDAI-2K entry points are related to arthritis, then, based on the 28-joint count assessment, at least four joints that are both swollen and tender (at least four occurring in the PIP, MCP, or wrist joints) must also be included. If two of the required SLEDAI-2K entry points are due to a rash, then that rash must be attributable to a skin manifestation of ACLE, SCLE, and / or CCLE (e.g., DLE). 4. Participants must have a modified clinical SLEDAI-2K score of 4 or higher at screening (central assessment) and randomization (excluding anti-dsDNA, low complement C3 and / or C4 levels, alopecia, fever, lupus-related headache, and organic brain syndrome). 5. Participants have BILAG-2004 grade A in one or more organ systems or BILAG-2004 grade B in two or more organ systems at the time of screening (central determination) and randomization. Participants must have been treated with one of the following specific lupus SOC treatments for at least 12 weeks prior to screening, and must have been receiving a fixed dose for at least 4 weeks prior to randomization. a. Combination therapy of antimalarial drugs with corticosteroids and / or immunosuppressants b. Monotherapy with antimalarial drugs c. Treatment with oral corticosteroids (OCS) and / or immunosuppressants. 6. Participants must have one of the following at the time of screening by a central laboratory: a. ANA ≥ 1:80 by immunofluorescence assay b. Anti-dsDNA antibodies exceeding normal levels c. Anti-Smith antibodies exceeding normal levels

[0100] Table 3 shows the primary objectives and endpoints of this study, as well as important secondary objectives and endpoints. [Table 3-1] [Table 3-2]

[0101] Another schematic diagram of the SLE trial design is shown in Figure 11B.

[0102] Other embodiments The present invention has been described in detail, but the foregoing is intended to illustrate, and not limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. In certain embodiments, for example, the following are provided: (Item 1) A method for treating cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) in a human subject requiring treatment, comprising subcutaneous administration of an anti-BDCA2 antibody at a dose of 225 mg every four weeks to the human subject, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), and the VH and VL each comprise the following: (a) VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity determination regions (CDRs) of VH, VH-CDR1 consists of the amino acid sequence described in Sequence ID No. 1. VH-CDR2 consists of the amino acid sequence described in Sequence ID No. 2. VH-CDR3 consists of the amino acid sequence described in SEQ ID NO: 3, and VH-CDR1, VH-CDR2, and VH-CDR3, as well as (b) VL-CDR1, VL-CDR2, and VL-CDR3, which are VL CD-Rs. VL-CDR1 consists of the amino acid sequence described in Sequence ID No. 4. VL-CDR2 consists of the amino acid sequence described in Sequence ID No. 5. VL-CDR3 is the same as VL-CDR1, VL-CDR2, and VL-CDR3, having the amino acid sequence described in Sequence ID No. 6. (Item 2) The method according to item 1, wherein the human subject is administered a loading dose of the anti-BDCA2 antibody two weeks after the initial administration of the anti-BDCA2 antibody. (Item 3) A method for treating cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) in a human subject requiring treatment, comprising subcutaneously administering an anti-BDCA2 antibody to the human subject at a dose of 225 mg every four weeks, wherein the human subject receives a loading dose of 225 mg of the anti-BDCA2 antibody two weeks after the first dose of the anti-BDCA2 antibody, the anti-BDCA2 antibody comprising an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), the VH and VL each comprising the following: (a) VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity determination regions (CDRs) of VH, VH-CDR1 consists of the amino acid sequence described in Sequence ID No. 1. VH-CDR2 consists of the amino acid sequence described in Sequence ID No. 2. VH-CDR3 consists of the amino acid sequence described in SEQ ID NO: 3, and VH-CDR1, VH-CDR2, and VH-CDR3, as well as (b) VL-CDR1, VL-CDR2, and VL-CDR3, which are VL CD-Rs. VL-CDR1 consists of the amino acid sequence described in Sequence ID No. 4. VL-CDR2 consists of the amino acid sequence described in Sequence ID No. 5. VL-CDR3 is the same as VL-CDR1, VL-CDR2, and VL-CDR3, having the amino acid sequence described in Sequence ID No. 6. (Item 4) The method according to any one of items 1 to 3, wherein the human subject is administered a second loading dose of the anti-BDCA2 antibody. (Item 5) The method according to item 4, wherein the second loading dose is 225 mg. (Item 6) The method according to any one of items 1 to 3, wherein the anti-BDCA2 antibody is administered at a dose of 225 mg every 4 weeks for at least 16 weeks. (Item 7) The method according to any one of items 1 to 6, wherein the anti-BDCA2 antibody is administered at a dose of 225 mg every four weeks for at least 52 weeks. (Item 8) The method according to any one of items 1 to 5, wherein the human subject is administered the anti-BDCA2 antibody at least four times. (Item 9) The method according to any one of items 1 to 5, wherein the human subject is administered at least 12 doses of the anti-BDCA2 antibody. (Item 10) The method according to any one of items 1 to 5, wherein the human subject is administered at least 14 doses of the anti-BDCA2 antibody. (Item 11) The method according to any one of items 1 to 5, wherein the human subject is administered at least 16 doses of the anti-BDCA2 antibody. (Item 12) The method described in any one of items 1 to 11, wherein the CLE disease is moderate CLE. (Item 13) The method described in any one of items 1 to 11, wherein the CLE disease is severe CLE. (Item 14) The method described in any one of items 1 to 11, wherein the type of CLE is acute CLE (ACLE). (Item 15) The method described in any one of items 1 to 11, wherein the type of CLE is subacute CLE (SCLE). (Item 16) The method described in any one of items 1 to 11, wherein the type of CLE is chronic CLE (CCLE). (Item 17) The method according to item 16, wherein the CCLE is discoid lupus erythematosus (DLE). (Item 18) The method according to any one of items 1 to 11, wherein the CLE disease is active CLE. (Item 19) The method according to item 18, wherein the active CLE is accompanied by systemic symptoms of lupus, and the human subject is intolerant to or unresponsive to antimalarial therapy. (Item 20) The method according to item 18, wherein the active CLE is not accompanied by systemic symptoms of lupus, and the human subject is intolerant to or unresponsive to antimalarial therapy. (Item 21) The method according to any one of items 1 to 20, wherein the human subject achieves a clinically meaningful reduction in disease area and severity index A (CLASI-A) score of cutaneous lupus erythematosus from baseline approximately 16 to 24 weeks after the first administration of the anti-BDCA2 antibody. (Item 22) The method according to any one of items 1 to 20, wherein the human subject achieves a clinically meaningful reduction from baseline in CLA-IGA-R specific to CLE approximately 16 to 24 weeks after the first administration of the anti-BDCA2 antibody. (Item 23) The method according to any one of items 1 to 11, wherein the SLE disease is active SLE. (Item 24) The method according to any one of items 1 to 11, wherein the human subject has active autoantibody-positive SLE. (Item 25) The method according to any one of items 1 to 11, wherein the human subject has active autoantibody-positive SLE and the human subject is receiving standard treatment for SLE. (Item 26) The method according to any one of items 1 to 11, wherein the SLE disease is moderate SLE. (Item 27) The method described in any one of items 1 to 11, wherein the SLE disease is severe SLE. (Item 28) The method according to any one of items 1 to 11, wherein the human subject has modified SLEDAI-2K ≥ 6 at the start of treatment, excluding alopecia, fever, lupus-related headache, and organic brain syndrome. (Item 29) The method according to any one of items 1 to 11, wherein the human subject has clinical SLEDAI-2K ≥ 4 at the start of treatment, excluding alopecia, lupus-related headache and organic brain disease, anti-dsDNA, low complement C3 and / or C4 levels, or fever. (Item 30) The method according to any one of items 1 to 11, wherein the human subject has BILAG-2004 grade A in one or more organ systems, or BILAG-2004 grade B in two or more organ systems at the start of treatment. (Item 31) The method according to any one of items 1 to 11, wherein the human subject is treated with an antimalarial drug, an oral corticosteroid, and / or an immunosuppressant before initiating treatment with the anti-BDCA2 antibody. (Item 32) The aforementioned anti-BDCA2 antibody The anti-BDCA2 antibody at a concentration of 150 mg / ml, 3% concentration sucrose, L-histidine at a concentration of 20 mM, L-arginine HCl at a concentration of 100 mM, Glutathione at a concentration of 0.4 mM, and 0.05% concentration of polysorbate 80 (PS80) The method according to any one of items 1 to 31, wherein the pharmaceutical composition is formulated as a sterile liquid pharmaceutical composition comprising, the pharmaceutical composition having a pH of 5.7. (Item 33) A method described in any one of items 1 to 32, (i) The VH contains a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8, (ii) The method wherein VH comprises a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and VL comprises a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8, or (iii) VH comprises the amino acid sequence described in SEQ ID NO: 7, and VL comprises the amino acid sequence described in SEQ ID NO: 8. (Item 34) The anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, according to the method described in any one of items 1 to 33. (i) The heavy chain contains at least 80% of the same amino acid sequence as SEQ ID NO: 9, and the light chain contains at least 80% of the same amino acid sequence as SEQ ID NO: 10, (ii) The heavy chain contains at least 90% the same amino acid sequence as SEQ ID NO: 9, and the light chain contains at least 90% the same amino acid sequence as SEQ ID NO: 10, or (iii) The method wherein the heavy chain comprises the amino acid sequence described in SEQ ID NO: 9, and the light chain comprises the amino acid sequence described in SEQ ID NO: 10. (Item 35) A pre-filled syringe containing a sterile preparation of an anti-BDCA2 antibody, the pre-filled syringe being suitable for subcutaneous administration of the anti-BDCA2 antibody at a fixed dose of 225 mg, wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), and the VH and VL each contain the following: The aforementioned pre-filled syringe: (a) VH-CDR1, VH-CDR2, and VH-CDR3, which are complementarity determination regions (CDRs) of VH, VH-CDR1 contains the amino acid sequence described in SEQ ID NO: 1, VH-CDR2 contains the amino acid sequence described in SEQ ID NO: 2, VH-CDR3 contains the amino acid sequence described in SEQ ID NO: 3, and VH-CDR1, VH-CDR2, and VH-CDR3, as well as (b) VL-CDR1, VL-CDR2, and VL-CDR3, which are VL CD-Rs. VL-CDR1 contains the amino acid sequence described in SEQ ID NO: 4, VL-CDR2 contains the amino acid sequence described in Sequence ID No. 5, VL-CDR3 comprises the amino acid sequence described in SEQ ID NO: 6, as described above for VL-CDR1, VL-CDR2, and VL-CDR3. (Item 36) A pre-filled syringe as described in item 35, (i) The VH contains a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and the VL contains a sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8, (ii) The pre-filled syringe wherein VH contains a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7, and VL contains a sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8, or (iii) the pre-filled syringe wherein VH contains the amino acid sequence described in SEQ ID NO: 7, and VL contains the amino acid sequence described in SEQ ID NO: 8. (Item 37) The anti-BDCA2 antibody is a pre-filled syringe according to item 35 or 36, comprising an immunoglobulin heavy chain and an immunoglobulin light chain. (i) The heavy chain contains at least 80% of the same amino acid sequence as SEQ ID NO: 9, and the light chain contains at least 80% of the same amino acid sequence as SEQ ID NO: 10, (ii) The heavy chain contains at least 90% the same amino acid sequence as SEQ ID NO: 9, and the light chain contains at least 90% the same amino acid sequence as SEQ ID NO: 10, or (iii) The pre-filled syringe wherein the heavy chain comprises the amino acid sequence described in SEQ ID NO: 9, and the light chain comprises the amino acid sequence described in SEQ ID NO: 10. (Item 38) The aforementioned anti-BDCA2 antibody The anti-BDCA2 antibody at a concentration of 150 mg / ml, 3% concentration sucrose, L-histidine at a concentration of 20 mM, L-arginine HCl at a concentration of 100 mM, Glutathione at a concentration of 0.4 mM, and 0.05% concentration of polysorbate 80 (PS80) A pre-filled syringe according to any one of items 35 to 37, formulated as a sterile liquid pharmaceutical composition containing, wherein the pharmaceutical composition has a pH of 5.7. (Item 39) A pre-filled syringe as described in any one of items 35-38, a clear glass vial of type 1 of the United States Pharmacopeia or the European Pharmacopeia, sealed with a rubber stopper.

Claims

[Claim 1] The invention described in the specification.

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