BR122024003611A2 - PHARMACEUTICAL COMPOSITIONS, ANTI-BDCA2 ANTIBODY, USE THEREOF, AND SYRINGE OR PUMP - Google Patents

Abstract

The present invention relates to formulations and dosage regimens of Anti-Blood Dendritic Cell Antigen 2 (BDCA2) antibodies. These formulations and dosage regimens find use in the treatment of BDCA2-associated disorders such as systemic lupus erythematosus, cutaneous lupus erythematosus and discoid lupus erythematosus and cytokine release syndrome.

Description

Cross-Reference to Related Requests

[0001] This application claims priority from US Provisional Application 62/328,959, filed April 28, 2016, the contents of which are incorporated herein by reference in their entirety.

Field of Invention

[0002] The present application generally relates to pharmaceutical compositions and dosage regimens for the clinical use of anti-dendritic cell blood antigen 2 antibodies.

Background

[0003] Blood dendritic cell antigen 2 (BDCA2) is a C-type lectin expressed on human plasmacytoid dendritic cells (pDCs) (Dzionek et al., J. Immunol., 165:6037-6046 (2000)), a specialized population of bone marrow-derived cells that secrete type I interferons (IFNs) in response to toll-like ligands (TLRs). BDCA2 consists of a single extracellular carbohydrate recognition domain (CRD), which belongs to the group of C-type lectins, at its C-terminus, a transmembrane region, and a short cytoplasmic tail at its N-terminus that does not harbor a signaling motif. BDCA2 transmits intracellular signals through an associated transmembrane adaptor, FcεRIγ, and induces a B cell receptor (BCR)-like signaling cascade.

Summary

[0004] The present invention relates, in part, to compositions and dosage regimens of anti-BDCA2 antibodies or BDCA2-binding fragments thereof and their use in the treatment of BDCA2-associated disorders such as systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and discoid lupus erythematosus (DLE).

[0005] In one aspect, the disclosure features a pharmaceutical composition comprising an anti-BDCA2 antibody or a BDCA2-binding fragment thereof, sucrose, and arginine hydrochloride (Arg.HCl).

[0006] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), the VH and the VL comprising the CDRs of BIIB059. In some cases, the six CDRs of BIIB059 comprise or consist of the amino acid sequences set forth in SEQ ID NO: 1 or 17; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5; and SEQ ID NO: 6.

[0007] In some embodiments, the composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 50 mg/ml to 225 mg/ml. In other embodiments, the composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml. In certain embodiments, the composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml.

[0008] In some embodiments, the composition comprises sucrose at a concentration of 0.05% to 10%. In other embodiments, the composition comprises sucrose at a concentration of 1% to 5%. In certain embodiments, the composition comprises sucrose at a concentration of 3%.

[0009] In some embodiments, the composition comprises Arg.HCl at a concentration of 50 mM to 250 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75 mM to 125 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 100 mM.

[00010] In some embodiments, the composition further comprises Polysorbate-80 (PS80). In some embodiments, the composition comprises PS80 at a concentration of 0.01% to 0.1%. In other embodiments, the composition comprises PS80 at a concentration of 0.03% to 0.08%. In certain embodiments, the composition comprises PS80 at a concentration of 0.05%.

[00011] In some embodiments, the composition further comprises histidine. In some embodiments, the composition comprises histidine at a concentration of 5 mM to 50 mM. In other embodiments, the composition comprises histidine at a concentration of 15 mM to 25 mM. In certain embodiments, the composition comprises histidine at a concentration of 20 mM.

[00012] In some embodiments, the composition has a pH of 5.3 to 5.7. In other embodiments, the composition has a pH of 5.5.

[00013] In some embodiments, the composition further comprises methionine. In some embodiments, the composition comprises methionine at a concentration of 1 mM to 20 mM. In other embodiments, the composition comprises methionine at a concentration of 5 mM to 15 mM. In certain embodiments, the composition comprises methionine at a concentration of 10 mM.

[00014] In some embodiments, the composition further comprises glutamic acid. In some embodiments, the composition comprises glutamic acid at a concentration of 50 mM to 100 mM. In other embodiments, the composition comprises glutamic acid at a concentration of 50 mM to 80 mM. In certain embodiments, the composition comprises glutamic acid at a concentration of 70 mM.

[00015] In some embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment at a concentration of 125 mg/ml to 175 mg/ml; sucrose at a concentration of 1% to 5%; histidine at a concentration of 15 mM to 25 mM; Arg.HCl at a concentration of 75 mM to 125 mM; and PS80 at a concentration of 0.03% to 0.08%. The composition has a pH of 5.3 to 5.7. In certain embodiments, the composition also comprises methionine at a concentration of 5 mM to 15 mM. In certain embodiments, the composition also comprises glutamic acid at a concentration of 60 mM to 80 mM.

[00016] In some embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml; sucrose at a concentration of 3%; histidine at a concentration of 20 mM; Arg.HCl at a concentration of 100 mM; and PS80 at a concentration of 0.05%. The composition has a pH of 5.5. In certain embodiments, the composition also comprises methionine at a concentration of 10 mM. In certain embodiments, the composition also comprises glutamic acid at a concentration of 70 mM.

[00017] In some embodiments, the VH comprises or consists of a sequence at least 80% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7 and the VL comprises or consists of the sequence of SEQ ID NO: 8.

[00018] In some embodiments, the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In certain cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 10. In other cases, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 10. In still other cases, the heavy chain comprises or consists of the sequence of SEQ ID NO: 9 and the light chain comprises or consists of the sequence of SEQ ID NO: 10.

[00019] In another aspect, the disclosure features a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method involves administering to the human a pharmaceutical composition described herein.

[00020] In some embodiments, the pharmaceutical composition is administered subcutaneously to the human.

[00021] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 50 mg every four weeks.

[00022] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 150 mg every four weeks.

[00023] In other embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 450 mg every four weeks.

[00024] In another aspect, the disclosure provides a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method comprises subcutaneously administering to the human an anti-BDCA2 antibody or a BDCA2-binding fragment thereof at a dose of 50 mg every four weeks. The anti-BDCA2 antibody or BDCA2-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and a light chain variable domain (VL). The VH and VL, respectively, comprise:

[00025] VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6.

[00026] In some embodiments, the human is administered a loading dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain cases, the loading dose is 50 mg.

[00027] In another aspect, the disclosure provides a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method comprises subcutaneously administering to the human an anti-BDCA2 antibody or a BDCA2-binding fragment thereof at a dose of 150 mg every four weeks. The anti-BDCA2 antibody or BDCA2-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and a light chain variable domain (VL). The VH and VL, respectively, comprise:

[00028] VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6.

[00029] In some embodiments, the human is administered a loading dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain cases, the loading dose is 150 mg.

[00030] In another aspect, the disclosure provides a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method comprises subcutaneously administering to the human an anti-BDCA2 antibody or a BDCA2-binding fragment thereof at a dose of 450 mg every four weeks. The anti-BDCA2 antibody or BDCA2-binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and a light chain (VL) variable domain. The VH and VL regions, respectively, comprise: VH complementarity determining regions (CDRs), wherein the H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6.

[00031] In some embodiments, the human is administered a loading dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain cases, the loading dose is 450 mg.

[00032] These embodiments apply to all of the methods described above. In some embodiments, the human is administered at least 4 doses of the anti-BDCA2 antibody or antigen-binding fragment thereof. In some embodiments, the human is administered at least 7 doses of the anti-BDCA2 antibody or antigen-binding fragment thereof. In certain embodiments, the human is administered at least 10 doses of the anti-BDCA2 antibody or antigen-binding fragment thereof. In some embodiments, the VH comprises or consists of a sequence at least 80% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7 and the VL comprises or consists of the sequence of SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In certain cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 10. In other cases, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 10. In still other cases, the heavy chain comprises or consists of the sequence of SEQ ID NO: 9 and the light chain comprises or consists of the sequence of SEQ ID NO: 10. In certain embodiments, the condition is systemic lupus erythematosus. In other embodiments, the condition is cutaneous lupus erythematosus (with or without SLE). In some embodiments, the condition is discoid lupus erythematosus (with or without SLE). In certain embodiments, the condition is cytokine release syndrome.

[00033] In another aspect the disclosure features a syringe, injector (e.g., autoinjector, subcutaneous large volume injector) or pump comprising a sterile preparation of the pharmaceutical composition described herein adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a fixed dose of 50 mg, 150 mg or 450 mg.

[00034] In another aspect, the disclosure provides a syringe, injector or pump comprising a sterile preparation of an anti-BDCA2 antibody or a BDCA2 binding fragment thereof. The syringe or pump is adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a fixed dose of 50 mg, 150 mg or 450 mg. The anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and a light chain (VL) variable domain. The VH and VL regions, respectively, comprise: VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6.

[00035] In some embodiments, the VH comprises or consists of a sequence at least 80% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 80% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL comprises or consists of a sequence at least 90% identical to SEQ ID NO: 8. In some embodiments, the VH comprises or consists of the sequence of SEQ ID NO: 7 and the VL comprises or consists of the sequence of SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain. In certain cases, the heavy chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 80% identical to SEQ ID NO: 10. In other cases, the heavy chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain comprises or consists of a sequence at least 90% identical to SEQ ID NO: 10. In still other cases, the heavy chain comprises or consists of the sequence of SEQ ID NO: 9 and the light chain comprises or consists of the sequence of SEQ ID NO: 10.

[00036] In another aspect, the disclosure provides a pharmaceutical composition comprising an anti-BDCA2 antibody or a BDCA2 binding fragment, sucrose, and arginine hydrochloride (Arg.HCl), wherein the pharmaceutical composition has a pH of 5.0 to 6.5. In certain embodiments of this aspect, sucrose is not part of the pharmaceutical composition.

[00037] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), the VH and the VL comprising the CDRs of BIIB059. In some cases, the six CDRs of BIIB059 comprise or consist of the amino acid sequences set forth in SEQ ID NO: 1 or 17; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5; and SEQ ID NO: 6.

[00038] In some embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 50 mg/ml to 225 mg/ml. In some embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml. In other embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml. In certain embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 200 mg/ml. In certain embodiments, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 225 mg/ml.

[00039] In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of 1% to 10%. In other embodiments, the pharmaceutical composition comprises sucrose at a concentration of 1% to 5%. In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 1%. In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 3%.

[00040] In some embodiments, the composition comprises Arg.HCl at a concentration of 50 mM to 250 mM. In some embodiments, the composition comprises Arg.HCl at a concentration of 50 mM to 200 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75 mM to 150 mM. In other embodiments, the composition comprises Arg.HCl at a concentration of 75 mM to 125 mM. In some embodiments, the composition comprises Arg.HCl at a concentration of 100 mM to 250 mM. In some embodiments, the composition comprises Arg.HCl at a concentration of 100 mM to 200 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 100 mM. In certain embodiments, the composition comprises Arg.HCl at a concentration of 250 mM.

[00041] In some embodiments, the pharmaceutical composition comprises polysorbate-80. In certain cases, the composition comprises PS80 at a concentration of 0.02% to 0.08%. In other cases, the composition comprises PS80 at a concentration of 0.03% to 0.08%. In still other cases, the composition comprises PS80 at a concentration of 0.05%.

[00042] In some embodiments, the pharmaceutical composition further comprises histidine. In certain cases, the composition comprises histidine at a concentration of 10 mM to 30 mM. In other cases, the composition comprises histidine at a concentration of 15 mM to 25 mM. In still other cases, the composition comprises histidine at a concentration of 20 mM.

[00043] In some embodiments, the pharmaceutical composition has a pH of 5.3 to 6.5. In certain cases, the composition has a pH of 5.3 to 6.0. In certain cases, the composition has a pH of 5.5. In certain cases, the composition has a pH of 6.0.

[00044] In some embodiments, the pharmaceutical composition comprises a thiol-containing antioxidant. In certain cases, the thiol-containing antioxidant is GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, or the combination of cysteine and cystine. In one example, the thiol-containing antioxidant is GSH. In one example, the thiol-containing antioxidant is GSSG. In yet another case, the thiol-containing antioxidant is the combination of GSH and GSSG. In one example, the thiol-containing antioxidant is cysteine. In yet another case, the thiol-containing antioxidant is the combination of cysteine and cystine. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.02 mM to 2 mM. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.2 mM. In other cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.4 mM. In some cases, the thiol-containing antioxidant is found in the pharmaceutical composition at a concentration of 1.0 mM. In certain cases, GSH and GSSG are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively. In other cases, cysteine and cystine are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively.

[00045] In another aspect, the disclosure provides a pharmaceutical composition comprising a blood dendritic cell antigen 2 (BDCA2) antibody or BDCA2 binding fragment thereof and histidine at a concentration of 10 mM to 30 mM, Arg.HCl at a concentration of 50 mM to 250 mM, and PS80 at a concentration of 0.02% to 0.08%, wherein the composition has a pH of 5.0 to 6.5.

[00046] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6.

[00047] In certain embodiments, the pharmaceutical composition has an anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 50 mg/ml to 225 mg/ml.

[00048] In certain embodiments, the pharmaceutical composition comprises sucrose at a concentration of 1% to 10%.

[00049] In certain embodiments, the pharmaceutical composition comprises a thiol-containing antioxidant. In certain cases, the thiol-containing antioxidant is GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, or the combination of cysteine and cystine. In one example, the thiol-containing antioxidant is GSH. In one example, the thiol-containing antioxidant is GSSG. In yet another case, the thiol-containing antioxidant is the combination of GSH and GSSG. In one example, the thiol-containing antioxidant is cysteine. In yet another case, the thiol-containing antioxidant is the combination of cysteine and cystine. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.02 mM to 2 mM. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.2 mM. In other cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.4 mM. In some cases, the thiol-containing antioxidant is found in the pharmaceutical composition at a concentration of 1.0 mM. In certain cases, GSH and GSSG are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively. In other cases, cysteine and cystine are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively.

[00050] In one embodiment, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml, sucrose at a concentration of 3%, histidine at a concentration of 20 mM, Arg.HCl at a concentration of 100 mM, PS80 at a concentration of 0.05%, and GSH or cysteine at a concentration of 0.4 mM. The composition has a pH of 5.5. In certain instances, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6. In certain cases, sucrose is not part of this composition.

[00051] In another embodiment, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml, sucrose at a concentration of 3%, histidine at a concentration of 20 mM, Arg.HCl at a concentration of 100 mM, PS80 at a concentration of 0.05%, and GSSG or cysteine at a concentration of 0.2 mM. The composition has a pH of 5.5. In certain cases, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6. In certain cases, sucrose is not part of this composition.

[00052] In yet another embodiment, the pharmaceutical composition comprises the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 150 mg/ml, sucrose at a concentration of 3%, histidine at a concentration of 20 mM, Arg.HCl at a concentration of 100 mM, PS80 at a concentration of 0.05%, and GSH (or cysteine) at a concentration of 0.4 mM and GSSG (or cysteine) at a concentration of 0.2 mM. The composition has a pH of 5.5. In certain cases, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6. In certain cases, sucrose is not part of this composition.

[00053] In another aspect, the disclosure features a pharmaceutical composition comprising an anti-BDCA2 antibody or BDCA2-binding fragment thereof at a concentration of 200 mg/ml, sucrose at a concentration of 3%; histidine at a concentration of 20 mM, Arg.HCl at a concentration of 250 mM, and PS80 at a concentration of 0.05%. The composition has a pH of 6.0. This pharmaceutical composition is especially suitable for subcutaneous administration to a subject in need thereof. In certain instances, the anti-BDCA2 antibody or BDCA2-binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6. In certain cases, sucrose is not part of this composition.

[00054] In yet another aspect, the disclosure features a pharmaceutical composition comprising an anti-BDCA2 antibody or BDCA2 binding fragment thereof at a concentration of 225 mg/ml, sucrose at a concentration of 1%; histidine at a concentration of 20 mM, Arg.HCl at a concentration of 250 mM, and PS80 at a concentration of 0.05%. The composition has a pH of 6.0. This pharmaceutical composition is especially suitable for subcutaneous administration to a subject in need thereof. In certain instances, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6. In certain cases, sucrose is not part of this composition.

[00055] In certain embodiments of the above two aspects, the pharmaceutical composition comprises a thiol-containing antioxidant. In certain cases, the thiol-containing antioxidant is GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, or the combination of cysteine and cystine. In one example, the thiol-containing antioxidant is GSH. In one example, the thiol-containing antioxidant is GSSG. In yet another case, the thiol-containing antioxidant is the combination of GSH and GSSG. In one example, the thiol-containing antioxidant is cysteine. In yet another case, the thiol-containing antioxidant is the combination of cysteine and cystine. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.02 mM to 2 mM. In some cases, the thiol-containing antioxidant is in the pharmaceutical composition at a concentration of 0.2 mM. In other cases, the thiol-containing antioxidant is found in the pharmaceutical composition at a concentration of 0.4 mM. In some cases, the thiol-containing antioxidant is found in the pharmaceutical composition at a concentration of 1.0 mM. In certain cases, GSH and GSSG are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively. In other cases, cysteine and cystine are found in the pharmaceutical composition at concentrations of 0.4 mM and 0.2 mM, respectively.

[00056] These embodiments apply to all of the above aspects. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises a VH and a VL, wherein the VH consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:7; and the VL consists of a sequence at least 80% identical, at least 90% identical, or at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:8. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:9; and the light chain consists of a sequence at least 80% identical, at least 90% identical, or at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:10.

[00057] In another aspect, the disclosure features a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method comprises administering to the human a pharmaceutical composition comprising an anti-BDCA2 antibody or BDCA2 binding fragment described herein.

[00058] In certain embodiments, the pharmaceutical composition is administered subcutaneously to the human. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 25 mg every four weeks. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 50 mg every four weeks. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 150 mg every four weeks. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the pharmaceutical composition is administered to the human at a dose of 450 mg every four weeks. In certain cases, the anti-BDCA2 antibody or BDCA2-binding fragment thereof of the pharmaceutical composition is administered to the human being at a dose corresponding to the human being's weight, as indicated below:

[00059] In certain cases, the anti-BDCA2 antibody or BDCA2-binding fragment thereof of the pharmaceutical composition is administered to the human at a dose corresponding to the human's weight, as indicated below:

[00060] In another aspect, the disclosure provides a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method involves subcutaneously administering to the human an anti-BDCA2 antibody or a BDCA2 binding fragment thereof in a dose corresponding to the weight of the human as recited below:

[00061] In certain cases, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises a VH and a VL, wherein the VH consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 7; and the VL consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:8. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:9; and the VL consists of a sequence at least 80% identical, at least 90% identical, or at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:10. In certain embodiments, the human is 20 years of age or younger. In certain embodiments, the human is 18 years of age or younger. In certain modalities, the human being is 16 years of age or younger. In certain modalities, the human being is 14 years of age or younger. In certain modalities, the human being is 12 years of age or younger. In certain modalities, the human being is 10 years of age or younger. In certain modalities, the human being is 8 years of age or younger. In certain modalities, the human being is 6 years of age or younger. In certain modalities, the human being is 4 years of age or younger. In certain modalities, the human being is 2 years of age or younger.

[00062] In yet another aspect, the disclosure features a method of treating a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human in need thereof. The method involves subcutaneously administering to the human an anti-BDCA2 antibody or a BDCA2 binding fragment thereof in a dose corresponding to the weight of the human as recited below:

[00063] In certain cases, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises a VH and a VL, wherein the VH consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 7; and the VL consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:8. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:9; and the VL consists of a sequence at least 80% identical, at least 90% identical, or at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:10. In certain embodiments, the human is 20 years old, or the human is 12 years old or younger. In certain embodiments, the human is 10 years old or younger. In some cases, the human being is 8 years old or younger. In some cases, the human being is 6 years old or younger. In some cases, the human being is 4 years old or younger. In some cases, the human being is less than 4 years old. In some cases, the human being is 18 years old or younger. In some cases, the human being is 16 years old or younger. In some cases, the human being is 2 years old or younger.

[00064] In another aspect, the disclosure features a syringe or pump comprising a sterile preparation of a pharmaceutical composition described herein adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a fixed dose of 18 mg, 22 mg, 25 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, or 450 mg.

[00065] In another aspect, the disclosure features a syringe or pump comprising a sterile preparation of a pharmaceutical composition described herein adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a fixed dose of 18 mg, 22 mg, 25 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, or 450 mg, wherein the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising VH complementarity determining regions (CDRs), wherein VH-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; VH-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:2; and VH-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:3; and VL CDRs, wherein VL-CDR1 consists of the amino acid sequence set forth in SEQ ID NO:4; VL-CDR2 consists of the amino acid sequence set forth in SEQ ID NO:5; and VL-CDR3 consists of the amino acid sequence set forth in SEQ ID NO:6. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises a VH and a VL, wherein the VH consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:7; and the VL consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:8. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein the heavy chain consists of a sequence at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:9; and the VL consists of a sequence at least 80% identical, at least 90% identical, or at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO:10.

[00066] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, this application, including definitions, will serve as the basis for control. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[00067] Other features and advantages of the invention will be apparent from the following detailed description and claims.

Brief Description of the Drawings

[00068] FIGURE 1 is a graph depicting the viscosity of the antibody formulation.

[00069] FIGURE 2A is a graph showing the aggregation of anti-BDCA2 antibodies formulated at a concentration of 150 mg/ml in a formulation containing 20 mM buffer as shown, 140 mM Arg.HCl, and 0.05% PS80 after 0-4 weeks of incubation at 40°C. Buffers are identified by the symbols shown in the figure.

[00070] FIGURE 2B is a graph showing the aggregation of anti-BDCA2 antibodies formulated at a concentration of 150 mg/ml in a formulation containing 20 mM buffer as shown, 140 mM Arg.HCl, and 0.05% PS80 after 0-3 months of incubation at 5°C. Buffers are identified using the same symbols shown in Figure 2A.

[00071] FIGURE 2C is a graph showing the aggregation of anti-BDCA2 antibodies formulated at a concentration of 200 mg/ml in a formulation containing 20 mM buffer as shown, 140 mM Arg.HCl, and 0.05% PS80 after 0-3 months of incubation at 5°C. Buffers are identified using the same symbols shown in Figure 2A.

[00072] FIGURE 2D is a graph showing the aggregation of anti-BDCA2 antibodies formulated at a concentration of 225 mg/ml in a formulation containing 20 mM buffer as shown, 140 mM Arg.HCl, and 0.05% PS80 after 0-3 weeks of incubation at 5°C. Buffers are identified by the symbols shown in Figure 2A.

[00073] FIGURE 3 is a bar graph representing the viscosity of anti-BDCA2 antibodies at different pH (5.5, 6 or 6.5), different concentration (150 mg/ml, 225 mg/ml or 250 mg/ml) and in different buffers (citrate or bistidine).

[00074] FIGURE 4 is a graph depicting the aggregation of BDCA2 at 225 ng/ml in the formulations shown.

[00075] FIGURE 5A is a bar graph showing the formation of subvisible particles (particles > 2 μm) at time zero (first bar), after 2 weeks at 25°C (second bar), or 2 weeks at 5°C (third bar). Particle concentration is plotted on a logarithmic scale. The formulations contained the excipient(s) shown, as well as 20 mM citrate pH 6.0, 0.05% PS80.

[00076] FIGURE 5B is a bar graph showing the formation of subvisible particles (particles >10 μm) at time zero (first bar), after 2 weeks at 25°C (second bar), or 2 weeks at 5°C (third bar). Particle concentration is plotted on a logarithmic scale. The formulations contained the excipient(s) shown, as well as 20 mM citrate, pH 6.0, and 0.05% PS80.

[00077] FIGURE 6 is a bar graph depicting aggregation at time zero (first bar), after 2 weeks at 25°C (second bar), or 2 weeks at 5°C (third bar). The formulations contained the excipients shown, as well as 20 mM citrate, pH 6.0, and 0.05% PS80.

[00078] FIGURE 7 is a graph comparing the aggregation of 150 mg/mL anti-BDCA2 antibody formulated in Formulation 2 (20 mM His, 100 mM Arg.HCl, 3% sucrose, 0.05% PS80, pH 5.5) vs. Formulation 1 (20 mM citrate, 140 mM Arg.HCl, 0.05% PS80, pH 6.0). The left panel shows aggregation at 5°C from 0 to 3 months; the right panel shows aggregation at 25°C from 0 to 3 months. Formulation 1 is indicated as "Cit 150" and Formulation 2 as "His 150" in the graphs.

[00079] FIGURE 8 is a graph representing the viscosity of the anti-BDCA2 antibody in Formulation 2.

[00080] FIGURE 9 is a graph showing the percentage of high molecular weight species that form over time at 5°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00081] FIGURE 10 is a graph showing the percentage of high molecular weight species that form over time at 25°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00082] FIGURE 11 is a graph showing the percentage of high molecular weight species that form over time at 30°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00083] FIGURE 12 is a graph showing the percentage of high molecular weight species that form over time at 40°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00084] FIGURE 13 is a graph showing the percentage of basic isoforms that form over time at 25°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00085] FIGURE 14 is a graph showing the percentage of basic isoforms that form over time at 30°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00086] FIGURE 15 is a graph showing the percentage of basic isoforms that form over time at 40°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00087] FIGURE 16 is a graph showing the percentage of basic isoforms that form over time at 5°C in the ten formulations tested. The caption text corresponds to: protein concentration (mg/mL)/Arginine.HCl (mM)/Sucrose (%)/pH.

[00088] FIGURE 17 provides graphs representing the percentage of HMW species of an anti-BDCA2 antibody formulation comprising sucrose (150 mg/ml antibody; 20 mM histidine; 100 mM Arg.HCl; 3% sucrose; 0.05% PS80, pH 5.5) with or without GSH (0.4 mM) at 25°C and 40°C.

[00089] FIGURE 18 provides an overlay of the graph in Figure 17 with a graph representing the percentage of HMW species of an anti-BDCA2 antibody formulation without sucrose (150 mg/ml antibody; 20 mM histidine; 100 mM Arg.HCl; 0.05% PS80, pH 5.5) with or without GSH (0.4 mM) at 25°C and 40°C. This shows that the presence of sucrose has no effect on the action of GSH.

[00090] FIGURE 19 provides graphs showing the percentage of HMW species of a BENEPALI® (an Enbrel® reference etanercept biosimilar) formulation (50 mg/mL SB4; 10 mM sodium phosphate; 140 mM NaCl; 1% sucrose, pH 6.2) with or without GSH (0.4 mM) at 25°C and 40°C.

[00091] FIGURE 20 provides graphs representing the percentage of HMW species of an anti-αvβ5 integrin antibody (STX200) formulation (50 mg/ml antibody; 20 mM histidine; 5% sorbitol; 0.05% PS80, pH 6.5) with or without GSH (0.4 mM) at 25°C and 40°C.

DETAILED DESCRIPTION

[00092] This application provides pharmaceutical compositions and dosage regimens of anti-BDCA2 antibodies or BDCA2-binding fragments thereof and their use in the treatment of BDCA2-associated disorders, such as SLE, CLE, and DLE). BDCA2

[00093] BDCA2 is a C-type II lectin that is specifically expressed on plasmacytoid dendritic cells (pDCs). BDCA2 consists of a single extracellular carbohydrate recognition domain (CRD) at its C-terminus, a transmembrane region, and a short cytoplasmic tail at its N-terminus that does not harbor a signaling motif. BDCA2 transmits intracellular signals through an associated transmembrane adaptor, FcεRIγ. Antibody-mediated binding of BDCA2 leads to the recruitment of spleen tyrosine kinase (SYK) to the phosphorylated immunoreceptor tyrosine-based activation motif (rrAM) of FcεRIγ. Syk activation leads to the activation of B-cell ligand (Blnk), Bruton's tyrosine kinase (BTK), and phospholipase Cy2 (PLCy2), leading to Ca2+ mobilization.

[00094] The amino acid sequence of the human BDCA2 protein (Genbank® Accession No. NP_569708.1) is shown below (the transmembrane domain is in italics; the ectodomain is underlined).

[00095] The amino acid sequence of human FcεRIy (Genbank® Accession No. NP_004097.1) is shown below.

Anti-BDCA2 Antibodies

[00096] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof used in the compositions and methods described herein comprises the three heavy chain variable domain complementarity determining regions (CDRs) of an antibody referred to as "BIIB059". In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the three light chain variable domain CDRs of BIIB059. In still other embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the three heavy chain variable domain CDRs and the three light chain variable domain CDRs of BIIB059. The CDRs can be based on any CDR definition in the art, e.g., the Kabat, Chothia, Chothia of Abysis, Chothia/Improved AbM definitions, or based on the Contact definition. The CDR sequences of BIIB059 according to these exemplary CDR definitions are set out in Table 1 below.

[00097] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VH CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1 or 17, a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 2; and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VL CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5; and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 6.

[00098] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the CDRs comprising or consisting of the amino acid sequences set forth in SEQ ID NOs: 1 to 6. In other embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the CDRs comprising or consisting of the amino acid sequences set forth in SEQ ID NOs: 11 to 16. In still other embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the CDRs comprising or consisting of the amino acid sequences set forth in SEQ ID NO: 17 to 22. In yet another embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the CDRs comprising or consisting of the amino acid sequences set forth in SEQ ID NOs: 23 to 28. In one embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the CDRs comprising or consisting of the amino acid sequences set forth in SEQ ID NOs: 24 to 26. anti-BDCA2 or BDCA2 binding fragment thereof comprises a VH CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1 or 17, a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 2; and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 3; and a VL CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5; and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 6

[00099] 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 that specifically bind to BDCA2 on the surface of plasmacytoid dendritic cells. The wild-type IgG1 sequence contains a single N-linked glycosylation site and binds to Fc receptors with affinities typical of this class of molecules. This Fc-competent IgG1 monoclonal antibody exhibits high affinity for BDCA2 and binds equally well to native human and cynomolgus BDCA2. BIIB059 is a potent inhibitor of all TLR9-induced type I interferons (IFNs) as well as other cytokines and chemokines by pDCs. BIIB059 is equally potent in inhibiting TLR9-induced type I interferon by pDCs from healthy human donors and SLE patients. BIIB059 specifically inhibits TLR9-induced type I IFN by pDCs and does not affect IFN production by other cell types triggered with different TLR ligands. BIIB059 also causes rapid internalization of BDCA2 from the cell surface. Upon stimulation, BDCA2 colocalizes with TLR9 in the endosomal/lysosomal compartment, which appears to be required for its inhibition of TLR9 signaling. BIIB059 was also found to cause shedding of CD62L from the surface of human pDCs. In vitro antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) studies suggest that BIIB059 may have cell-depleting activity in cell lines overexpressing BDCA2.

[000100] The variable heavy chain (VH) of BIIB059 comprises or consists of the following amino acid sequence:

[000101] The variable heavy (VL) chain of BIIB059 comprises or consists of the following amino acid sequence:

[000102] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VH having the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises 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 differs by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15 or 10, residues, from SEQ ID NO: 7. In certain ... In these cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2 but do not significantly bind to BDCA2 from species phylogenetically lower than primates; and/or (ii) inhibit TLR7/TLR9-induced type I interferon and other cytokine or chemokine production by human pDCs; and/or (iii) mediate the internalization of BDCA2 from the surface of pDCs; and/or (iv) upregulate CD32a and/or CD62L from the surface of pDCs; and/or (v) deplete pDCs in vitro by ADCC or CDC.

[000103] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VL having the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises 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 by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15 or 10, residues, from SEQ ID NO: 8. In certain ... In these cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2 but do not significantly bind to BDCA2 from species phylogenetically lower than primates; and/or (ii) inhibit TLR7/TLR9-induced type I interferon and other cytokine or chemokine production by human pDCs; and/or (iii) mediate the internalization of BDCA2 from the surface of pDCs; and/or (iv) upregulate CD32a and/or CD62L from the surface of pDCs; and/or (v) deplete pDCs in vitro by ADCC or CDC.

[000104] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VH having the amino acid sequence set forth in SEQ ID NO: 7 and a VL having the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises (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 by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15 or 10 residues, from SEQ ID NO: 7 and/or SEQ ID NO: 8. In certain cases, these antibodies (i) bind to human or cynomolgus monkey BDCA2, but do not significantly bind to BDCA2 from species phylogenetically lower than primates; and/or (ii) inhibit TLR7/TLR9-induced type I interferon and other cytokine or chemokine production by human pDCs; and/or (iii) mediate the internalization of BDCA2 from the surface of pDCs; and/or (iv) upregulate CD32a and/or CD62L from the surface of pDCs; and/or (v) deplete pDCs in vitro by ADCC or CDC.

[000105] An antibody consisting of the mature heavy chain (SEQ ID NO: 9) and the mature light chain (SEQ ID NO: 10) listed below is termed "BIIB059" as used herein.

[000106] In the VH, VL, HC and LC sequences above, CDRs 1, 2 and 3 based on the Kabat definition are underlined and bolded. The italicized and bolded sequence in VH and HC is the additional N-terminal sequence found in CDR1 based on the improved Chothia/AbM definition.

[000107] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a HC having the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises a HC 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 SEQ ID NO: 9, or differs by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15, or 10, residues, from SEQ ID NO: 9.

[000108] In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a LC having the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises a LC 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 SEQ ID NO: 10, or differs by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15, or 10, residues, from SEQ ID NO: 10.

[000109] In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a HC having the amino acid sequence set forth in SEQ ID NO: 9 and a LC having the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises (i) a HC 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 SEQ ID NO: 9, and (ii) a LC 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 SEQ ID NO: 10, or differs in at least 1 to 5 amino acid residues, but in less than 40, 30, 20, 15 or 10 residues, from SEQ ID NO: 9 and/or SEQ ID NO:10.

[000110] In certain embodiments, the anti-BDCA2 antibody is an IgG antibody. In specific embodiments, the anti-BDCA2 antibody has a heavy chain constant region chosen 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 other embodiments, the antibody has a light chain constant region chosen from, for example, a human kappa or human lambda light chain. In a certain embodiment, the anti-BDCA2 antibody is an IgG1/kappa antibody. In certain embodiments, the anti-BDCA2 antibody includes a human Fc region that binds to FcyRIIa (CD32a) with an EC50 of 7 to 15 μg/mL. In certain embodiments, the antibody includes a human Fc region that binds to FcyRIIa (CD32a) with an EC50 of 10 μg/mL. In certain embodiments, the antibody includes a human Fc region that binds to FcyRIIa (CD32a) with an EC50 of 11 μg/mL. In certain embodiments, the antibody includes a human Fc region that binds to FcyRIIa (CD32a) with an EC50 of 12 μg/mL. In some cases, the heavy chain constant region is human or a modified form of a human constant region. In certain cases, the human constant region can include at least 1 and up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 substitutions. In a particular embodiment, the modified human Fc region is a modified IgG1 Fc region. In some cases, the constant region of an anti-BDCA2 antibody can be modified by mutating one or more amino acid residues to confer a desired functional property (e.g., altered effector function or reduced glycosylation, half-life). For example, the N-linked glycosylation site can be replaced to prevent or reduce N-linked glycosylation of the Fc region (e.g., human IgG1 Fc region).

[000111] In some embodiments, the anti-BDCA2 antibody is a full-length (entire) or substantially full-length antibody. The protein can include at least one, and preferably two full-length heavy chains, and at least one, and preferably two full-length light chains. In some embodiments, the anti-BDCA2 antibody is a BDCA2-binding fragment. In some cases, the BDCA2-binding fragment is a Fab, a Fab’, a F(ab’)2, a Facb, a Fv, a single chain Fv (scFv), a sc(Fv)2, or a diabody.

[000112] Antibodies such as BIIB059, or BDCA2-binding fragments thereof, can be made, for example, by preparing and expressing synthetic genes encoding the recited amino acid sequences or by mutating human germline genes to provide a gene encoding the recited amino acid sequences. In addition, this antibody and other anti-BDCA2 antibodies can be produced, for example, using one or more of the following methods.

Antibody Production Methods

[000113] Anti-BDCA2 antibodies or BDCA2-binding fragments can be produced in bacterial or eukaryotic cells. Some antibodies, e.g., Fab’s, can be produced in bacterial cells, e.g., E. coli cells. Antibodies can also be produced in eukaryotic cells, such as transformed cell lines (e.g., CHO, 293E, COS). In addition, antibodies (e.g., scFv’s) can be expressed in a yeast cell, such as Pichia (see, e.g., Powers et al., J Immunol Methods. 251:123-35 (2001)), Hanseula, or Saccharomyces. To produce the antibody of interest, a polynucleotide encoding the antibody is constructed, introduced into an expression vector, and then expressed in suitable host cells. Polynucleotides encoding an anti-BDCA2 antibody comprising the VH and/or VL, HC and/or LC of the BDCA2 antibodies described herein would be readily appreciated by one of ordinary skill in the art. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select transformants, culture the host cells, and recover the antibody.

[000114] If anti-BDCA2 antibodies or BDCA2-binding fragments are expressed in bacterial cells (e.g., E. coli), the expression vector must have characteristics that allow amplification of the vector in the bacterial cells. Additionally, when using E. coli such as JM109, DH5α, HB101 or XL1-Blue as the host, the vector should have a promoter, e.g., a lacZ promoter (Ward et al., 341:544-546 (1989), araB promoter (Better et al., Science, 240:1041-1043 (1988)), or T7 promoter that can allow efficient expression in E. coli. Examples of such vectors include, e.g., M13 series vectors, pUC series vectors, pBR322, pBluescript, pCR-Script, pGEX-5X-1 (Pharmacia), QIAexpress system (QIAGEN), pEGFP and pET (when using this expression vector, the host is preferably BL21 expressing T7 RNA polymerase). The expression vector may contain a signal sequence for antibody secretion. For production in the periplasm from E. coli, the pelB signal sequence (Lei et al., J. Bacteriol., 169:4379 (1987)) can be used as the signal sequence for antibody secretion. For bacterial expression, electroporation methods or methods can be used to introduce the expression vector into the bacterial cell.

[000115] If the antibody is to be expressed in animal cells, such as CHO, COS, and NIH3T3 cells, the expression vector includes a promoter necessary for expression in these cells, for example, an SV40 promoter (Mulligan et al, Nature, 277:108 (1979)), MMLV-LTR promoter, EF1α promoter (Mizushima et al, Nucleic Acids Res., 18:5322 (1990)), or CMV promoter. In addition to the nucleic acid sequence encoding the immunoglobulin or domain thereof, recombinant expression vectors may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Patent Nos. 4,399,216 , 4,634,665 , and 5,179,017 ). For example, the selectable marker gene typically confers resistance to drugs such as G418, hygromycin, or methotrexate in a host cell into which the vector has been introduced. Examples of vectors with selectable markers include pMAM, pDR2, pBK-RSV, pBK-CMV, pOPRSV, and pOP13.

[000116] In a preferred embodiment, the antibodies are produced in mammalian cells. Examples of mammalian host cells for expression of an antibody include Chinese Hamster Ovary cells (CHO cells) (including CHO dhfr- cells, described in Urlaub and Chasin (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp, (1982), Mol. Biol. 159:601-621), human embryonic kidney 293 cells (e.g., 293, 293E, 293T), COS cells, NIH3T3 cells, lymphocytic cell lines, e.g., NS0 myeloma cells and SP2 cells, and a cell from a transgenic animal, e.g., a transgenic mammal. For example, the cell is a mammary epithelial cell.

[000117] In an exemplary system for antibody expression, a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain of an anti-BDCA2 antibody (e.g., BIIB059) is introduced into dhfr- CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the antibody heavy and light chain genes are each operably linked to enhancer/promoter regulatory elements (e.g., derived from SV40, CMV, adenovirus, and the like, such as a CMV enhancer/AdMLP promoter regulatory element or an SV40 enhancer/AdMLP promoter regulatory element) to drive high levels of transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. Selected transformant host cells are cultured to allow expression of light and heavy chains and antibody is recovered from the culture medium.

[000118] Antibodies can also be produced by a transgenic animal. For example, U.S. Patent 5,849,992 describes a method for expressing an antibody in the mammary gland of a transgenic mammal. A transgene is constructed including a milk-specific promoter and nucleic acid encoding the antibody of interest and a signal sequence for secretion. Milk produced by females of these transgenic mammals includes, secreted therein, the antibody of interest. The antibody can be purified from the milk, or for some applications, used directly. Animals comprising one or more of the nucleic acids described herein are also provided.

[000119] The antibodies of the present disclosure can be isolated from inside or outside (such as medium) the host cell and purified as substantially pure and homogeneous antibodies. Methods for isolation and purification commonly used for antibody purification can be used for the isolation and purification of antibodies, and are not limited to any particular method. Antibodies can be isolated and purified by appropriately selecting and combining, for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization. Chromatography includes, for example, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reversed-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual. Ed Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press, 1996). Chromatography can be performed using liquid chromatography, such as HPLC and FPLC. Columns used for affinity chromatography include protein A column and protein G column. Examples of columns that use the protein A column include Hyper D, POROS, and Sepharose FF (GE Healthcare Biosciences). This disclosure also includes antibodies that are highly purified using these purification methods.

Anti-BDCA2 Antibody Compositions

[000120] This disclosure also provides compositions (e.g., pharmaceutical compositions) comprising the anti-BDCA2 antibodies or BDCA2 binding fragments described herein. For example, the anti-BDCA2 antibody compositions comprise an anti-BDCA2 antibody or BDCA2 binding fragment comprising an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), wherein the VH comprises the H-CDRs and the VL comprises the L-CDRs of BIIB059. In certain instances, the H-CDRs comprise or consist of the amino acid sequences set forth in SEQ ID NO: 1 or 17, SEQ ID NO: 2, and SEQ ID NO: 3; and the L-CDRs comprise or consist of the amino acid sequences set forth in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In some embodiments, the anti-BDCA2 antibody compositions comprise an anti-BDCA2 antibody or a BDCA2 binding fragment thereof comprising (i) a VH 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 set forth in SEQ ID NO: 7; and (ii) a VL 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 set forth in SEQ ID NO: 8. In certain embodiments, the anti-BDCA2 antibody compositions comprise an anti-BDCA2 antibody comprising (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 set forth in SEQ ID NO: 9; and (ii) 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 set forth in SEQ ID NO: 10.

[000121] In certain embodiments, these compositions are a high concentration anti-BDCA2 antibody composition. By "high concentration anti-BDCA2 antibody composition" is meant a composition comprising anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration greater than 50 mg/mL and less than 300 mg/mL. In certain cases, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 50 mg/mL to 240 mg/mL. In certain cases, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 50 mg/mL to 225 mg/mL. In other instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 75 mg/mL to 225 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments at a concentration of 100 mg/mL to 225 mg/mL. In still other instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments at a concentration of 125 mg/mL to 225 mg/mL. In other instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 125 mg/mL to 175 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 240 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 225 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 200 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 175 mg/mL. In certain instances, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 150 mg/mL. In still other cases, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 125 mg/mL. In some cases, the anti-BDCA2 antibody composition comprises anti-BDCA2 antibodies or BDCA2 binding fragments thereof at a concentration of 100 mg/mL.

[000122] A composition (e.g., a pharmaceutical composition) comprising an anti-BDCA2 antibody or BDCA2-binding fragment thereof described herein can be in any of a variety of forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions, or suspensions. The preferred form may depend on the intended mode of administration and therapeutic application. In certain embodiments, a pharmaceutical composition described herein is in the form of a sterile injectable or infusible solution.

[000123] Sterile injectable solutions can be prepared by incorporating an antibody described herein in the required amount with one or a combination of ingredients, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating an antibody described herein into a sterile vehicle containing a basic dispersion medium and the other required ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, exemplary methods of preparation are vacuum drying and freeze drying, which produce a powder of an antibody described herein plus any additional desired ingredient from a previously sterile filtered solution thereof. Proper fluidity of a solution can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.

[000124] Anti-BDCA2 antibody compositions (e.g., pharmaceutical compositions) may additionally comprise one or more excipients.

[000125] In one embodiment, the excipient decreases/reduces the aggregation and/or viscosity of the antibody in the composition compared to the aggregation and/or viscosity of the antibody in the pharmaceutical composition without such excipient. In certain embodiments, such excipient is arginine. In one case, the excipient is arginine hydrochloride. Arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 50 mM to 250 mM, 50 mM to 200 mM, 50 mM to 150 mM, 50 mM to 125 mM, 50 mM to 100 mM, 75 mM to 250 mM, 75 mM to 200 mM, 75 mM to 150 mM, or 75 mM to 100 mM. In certain embodiments, arginine (e.g., Arg.HCl) is present in the composition at a concentration of 50 mM to 250 mM. In other embodiments, arginine (e.g., Arg.HCl) is present in the composition at a concentration of 50 mM to 200 mM. In certain cases, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 100 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, or 150 mM. In a specific case, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 100 mM. In another specific case, arginine (e.g., arginine hydrochloride) can be included in the composition at a concentration of 250 mM.

[000126] Arginine-containing solutions sometimes develop visible particles after incubation at room temperature or higher temperatures (e.g., 40°C). Surprisingly, it has been found that the addition of sucrose can reduce or prevent the formation of visible particles. Furthermore, it has also been unexpectedly found that sucrose decreases subvisible particle counts. In some embodiments, the anti-BDCA2 antibody composition comprises sucrose at a concentration of 0.05% to 15%, 0.05% to 10%, 0.05% to 5%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 8%, 2% to 6%, or 2% to 4%. In certain embodiments, the anti-BDCA2 antibody composition comprises sucrose at a concentration of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In a particular embodiment, the anti-BDCA2 antibody composition comprises sucrose at a concentration of 3%. In another particular embodiment, the anti-BDCA2 antibody composition comprises sucrose at a concentration of 1%.

[000127] The manufacture of antibody products is a complex process that may involve several steps, such as, for example, drug substance and bulk formulation, filtration, transportation, pooling, filling, lyophilization, inspections, packaging, and storage. During these steps, antibodies may be subjected to many different forms of stress, for example, agitation, temperature, light exposure, and oxidation. These types of stresses can lead to denaturation and aggregation of the antibody, which compromises product quality and may even lead to the loss of a production batch. Agitation is one of the common physical stresses to which antibody therapeutics are subjected during the manufacturing process. Agitation occurs, for example, during mixing, ultrafiltration/diafiltration, pumping, transportation, and filling. To protect the antibody composition against agitation-induced stress, the composition may include a polysorbate. In certain embodiments, the composition comprises polysorbate-80 at a concentration of 0.01% to 0.5%, 0.01% to 0.1%, 0.01% to 0.09%, 0.01% to 0.08%, 0.01% to 0.07%, 0.01% to 0.06%, 0.01% to 0.05%, 0.01% to 0.04%, or 0.01% to 0.03%. In certain embodiments, the composition comprises polysorbate-80 at a concentration of 0.02% to 0.08%. In some embodiments, the composition comprises polysorbate-80 at a concentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, or 0.1%. In a particular embodiment, the composition comprises polysorbate-80 at a concentration of 0.05%.

[000128] Any antibody composition benefits from a buffer that provides good buffering capacity. In certain embodiments, the antibody composition comprises histidine as a buffering agent. In certain embodiments, the composition comprises histidine at a concentration of 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 25 mM, 10 mM to 50 mM, 10 mM to 40 mM, 10 mM to 30 mM, 10 mM to 25 mM, 15 mM to 50 mM, 15 mM to 40 mM, 15 mM to 30 mM, or 15 mM to 25 mM. In certain embodiments, the composition comprises histidine at a concentration of 10 mM to 30 mM. In some embodiments, the composition comprises histidine at a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 30 mM. In a particular embodiment, the composition comprises histidine at a concentration of 20 mM.

[000129] The pH of the antibody composition can be from 5.0 to 6.5. In certain cases, the pH of the antibody composition can be from 5.0 to 6.0. In certain cases, the pH of the antibody composition is 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5. In a particular embodiment, the pH of the antibody composition is 5.5. In another particular embodiment, the pH of the antibody composition is 6.0. In yet another particular embodiment, the pH of the antibody composition is 6.5.

[000130] In certain embodiments, the composition comprises a thiol-containing antioxidant (e.g., reduced glutathione (GSH), oxidized glutathione (GSSG), GSH+GSSG, cysteine, cysteine+cystine) at a concentration of 0.02 mM to 2 mM (e.g. 0.02, 0.03, 0.05, 0.06, 0.08, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mM). Such thiol-containing antioxidants may cleave unfavorable or erroneous disulfide bonds and promote the formation of favorable or properly bonded disulfide bonds. This would result in stabilization of the native confirmation of the antibody or fragment thereof and slow the rates of aggregation. The antioxidant properties of these molecules may slow oxidative processes that lead to aggregation. In some cases, the composition comprises GSH at a concentration of 0.4 mM. In some cases, the composition comprises GSSG at a concentration of 0.2 mM. In some cases, the composition comprises GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In some cases, the composition comprises cysteine at a concentration of 0.4 mM. In some cases, the composition comprises cystine at a concentration of 0.2 mM. In some cases, the composition comprises cysteine at a concentration of 0.4 mM and cystine at a concentration of 0.2 mM. In certain embodiments, the composition comprises methionine at a concentration of 5 mM to 15 mM (e.g., 10 mM). In certain embodiments, the composition comprises glutamic acid at a concentration of 50 mM to 80 mM (e.g., 70 mM).

[000131] In certain embodiments, the composition (e.g., a pharmaceutical composition) comprises an anti-BDCA2 antibody or a BDCA2 binding fragment thereof at a concentration of 50 mg/ml to 225 mg/ml, sucrose at a concentration of 0.05% to 10%, arginine (e.g., arginine hydrochloride) at a concentration of 50 mM to 250 mM, polysorbate-80 at a concentration of 0.01% to 0.1%, and histidine at a concentration of 10 mM to 30 mM. The composition has a pH of 5.0 to 6.0. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of BIIB059 (e.g., SEQ ID NOs: 1 or 17, 2, 3, 4, 5, and 6). In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively. In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively. In one embodiment, the composition has a pH of 5.5 and comprises BIIB059 or a BIIB059-binding fragment thereof at a concentration of 150 mg/ml, sucrose at a concentration of 3%, arginine hydrochloride at a concentration of 100 mM, polysorbate-80 at a concentration of 0.05%, and histidine at a concentration of 20 mM. This embodiment can be made by dissolving, for example, in 1,833.50 mg of sterile water (e.g., reverse osmosis deionized (RODI) water), 285 mg of BIIB059, 6.69 mg of histidine hydrochloride monohydrate, 0.94 mg of histidine free base, 40.03 mg of arginine hydrochloride, 57.0 mg of sucrose, and 0.95 mg of polysorbate-80. In certain embodiments, the composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH+GSSG, cysteine, cystine, cysteine+cystine) at a concentration of 0.02 mM to 2 mM.

[000132] In certain embodiments, the composition (e.g., a pharmaceutical composition) comprises an anti-BDCA2 antibody or a BDCA2 binding fragment thereof, arginine (e.g., arginine hydrochloride) at a concentration of 50 mM to 250 mM, polysorbate-80 at a concentration of 0.02% to 0.08%, and histidine at a concentration of 10 mM to 30 mM. The composition has a pH of 5.0 to 6.5. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof is present in the composition at a concentration of 50 mg/ml to 225 mg/ml. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of BIIB059 (e.g., SEQ ID NOs: 1 or 17, 2, 3, 4, 5, and 6). In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively. In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively. In certain embodiments, the composition comprises sucrose at a concentration of 1% to 10%. In certain embodiments, the composition comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH+GSSG, cysteine, cystine, or cysteine+cystine) at a concentration of 0.02 mM to 2 mM. In one embodiment, the composition has a pH of 5.5 and comprises BIIB059 or a BIIB059-binding fragment at a concentration of 150 mg/ml, sucrose at a concentration of 3%, arginine hydrochloride at a concentration of 100 mM, polysorbate-80 at a concentration of 0.05%, and histidine at a concentration of 20 mM. In another embodiment, the above-listed composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH+GSSG, cysteine, cystine, or cysteine+cystine) at a concentration of 0.02 mM to 2 mM. In a specific embodiment, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM.

[000133] For subcutaneous administration, the composition (e.g., a pharmaceutical composition) can comprise a higher concentration of the anti-BDCA2 antibody or BDCA2-binding fragment thereof. In one embodiment, such a composition comprises an anti-BDCA2 antibody or a BDCA2-binding fragment at a concentration of 200 mg/ml; arginine (e.g., arginine hydrochloride) at a concentration of 250 mM; sucrose at a concentration of 3%; polysorbate-80 at a concentration of 0.05%; and histidine at a concentration of 20 mM. In some cases, the pH of this composition is 6.0. In some cases, the composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH+GSSG, cysteine, cystine, or cysteine+cystine) at a concentration of 0.02 mM to 2 mM. In a specific case, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM. In another specific case, the thiol-containing antioxidant is GSSG at a concentration of 0.2 mM. In another specific case, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In another embodiment, such a high concentration composition comprises an anti-BDCA2 antibody or a BDCA2-binding fragment thereof at a concentration of 225 mg/ml; arginine (e.g., arginine hydrochloride) at a concentration of 250 mM; sucrose at a concentration of 1%; polysorbate 80 at a concentration of 0.05%; and histidine at a concentration of 20 mM. In some cases, the pH of this composition is 6.0. In some cases, the composition further comprises a thiol-containing antioxidant (e.g., GSH, GSSG, GSH+GSSG, cysteine, cystine, or cysteine+cystine) at a concentration of 0.02 mM to 2 mM. In one specific case, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM. In another specific case, the thiol-containing antioxidant is GSSG at a concentration of 0.2 mM. In yet another specific case, the thiol-containing antioxidant is GSH at a concentration of 0.4 mM and GSSG at a concentration of 0.2 mM. In another specific case, the thiol-containing antioxidant is cysteine at a concentration of 0.4 mM. In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising the CDRs of BIIB059 (e.g., SEQ ID NO: 1 or 17, 2, 3, 4, 5, and 6). In certain embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a VH and a VL comprising SEQ ID NOs: 7 and 8, respectively. In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof of the composition comprises a heavy chain and a light chain comprising SEQ ID NOs: 9 and 10, respectively.

Dosage

[000134] The anti-BDCA2 antibody (e.g., BIIB059) or BDCA2-binding fragment thereof described above may be administered to a subject, e.g., a human, at different doses. The anti-BDCA2 antibody (e.g., BIIB059) or BDCA2-binding fragment thereof may be administered as a fixed dose (i.e., independent of the subject's weight), or at a mg/kg dose (i.e., a dose that varies based on the subject's weight). Unit dosage form or "fixed dose" herein refers to physically discrete units suitable as unitary dosages for the subjects to be treated; each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier and, optionally, in association with the other agent. Single or multiple dosages may be given. Treatment may continue for days, weeks, months, or even years.

[000135] In one embodiment, for treating an indication described herein in an adult human, the dosage of the anti-BDCA2 antibody (e.g., BIIB059) or BDCA2 binding fragment thereof is a fixed dose of 25 mg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 50 mg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 150 mg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 450 mg.

[000136] In one embodiment, to treat an indication described herein in a pediatric human, the dosage of the anti-BDCA2 antibody (e.g., BIIB059) or BDCA2 binding fragment thereof is a fixed dose of 18 mg, wherein the child has a weight of 10 to 18 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 22 mg, wherein the child has a weight of 18.1 kg to 25 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 28 mg, wherein the child has a weight of 25.1 kg to 48 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 50 mg, where the child weighs more than 48 kg. These doses are equivalent to an adult dose of 50 mg.

[000137] In one embodiment, to treat an indication described herein in a pediatric human, the dosage of the anti-BDCA2 antibody (e.g., BIIB059) or BDCA2 binding fragment thereof is a fixed dose of 40 mg, wherein the child has a weight of 10 to 18 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 56 mg, wherein the child has a weight of 18.1 kg to 25 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 80 mg, wherein the child has a weight of 25.1 kg to 48 kg. In another embodiment, the dosage of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is a fixed dose of 150 mg, where the child weighs more than 48 kg. These doses are equivalent to an adult dose of 150 mg.

[000138] The fixed doses described above may be administered daily, weekly, 2 weeks, 4 weeks, 6 weeks, 8 weeks, monthly, biweekly, weekly, or daily, as appropriate, over a period of time to encompass at least 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, 12 doses, 14 doses, 16 doses, 18 doses, 20 doses, 22 doses, 24 doses, or more.

[000139] In certain embodiments, a fixed dose of 25 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 2 weeks or every 4 weeks for a period of time determined to be beneficial to the subject by the healthcare provider. In some cases, a fixed dose of 25 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 4 weeks. In certain embodiments, the subject is also administered a loading dose of 25 mg, 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to the subject. In one embodiment, the loading dose is 25 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In another embodiment, the loading dose is 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 doses of the 25 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered 4, 5, 6, 7, 8, 9, or 10 doses of the 25 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some cases, the subject is administered 2 to 24, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 doses of the 25 mg fixed dose of the anti-BDCA2 antibody or BDCA2-binding fragment thereof.

[000140] In certain embodiments, a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 2 weeks or every 4 weeks for a period of time determined to be beneficial to the subject by the healthcare provider. In some cases, a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 4 weeks. In certain embodiments, the subject is also administered a loading dose of 25 mg, 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to the subject. In one embodiment, the loading dose is 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 doses of the 50 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered 4, 5, 6, 7, 8, 9, or 10 doses of the 50 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some cases, the subject is administered 2 to 24, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 doses of the 50 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof.

[000141] In certain embodiments, a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 2 weeks or every 4 weeks for a period of time determined to be beneficial to the subject by the healthcare provider. In some cases, a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 4 weeks. In certain embodiments, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to the subject. In one embodiment, the loading dose is 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 doses of the 150 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered 4, 5, 6, 7, 8, 9, or 10 doses of the 150 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some cases, the subject is administered 2 to 24, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 doses of the 150 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof.

[000142] In certain embodiments, a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 2 weeks or every 4 weeks for a period of time determined to be beneficial to the subject by the healthcare provider. In some cases, a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human subject every 4 weeks. In certain embodiments, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to the subject. In one embodiment, the loading dose is 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 doses of the 450 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some embodiments, the subject is administered 4, 5, 6, 7, 8, 9, or 10 doses of the 450 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In some cases, the subject is administered 2 to 24, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 doses of the 450 mg fixed dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof.

[000143] A pharmaceutical composition may include a "therapeutically effective amount" of an agent described herein. Such effective amounts may be determined based on the effect of the administered agent, or the combinatorial effect of agents if more than one agent is used. A therapeutically effective amount of an agent may also vary depending on factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to induce a desired response in the subject. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects. In one embodiment, the therapeutically effective amount of the anti-BDCA2 antibody or BDCA2-binding fragment thereof is 25 mg. In another embodiment, the therapeutically effective amount of the anti-BDCA2 antibody or BDCA2-binding fragment thereof is 50 mg. In another embodiment, the therapeutically effective amount of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is 150 mg. In yet another embodiment, the therapeutically effective amount of the anti-BDCA2 antibody or BDCA2 binding fragment thereof is 450 mg. In one embodiment, the therapeutically effective amount of the anti-BDCA2 antibody or BDCA2 binding fragment thereof for a pediatric human subject (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger) is 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, or 150 mg.

[000144] In some cases, the anti-BDCA2 antibody or BDCA2 binding compositions described above are administered to the subject at a dose of 25 mg. In other cases, the anti-BDCA2 antibody or BDCA2 binding compositions described above are administered to the subject at a dose of 50 mg. In still other cases, the anti-BDCA2 antibody or BDCA2 binding compositions described above are administered to the subject at a dose of 150 mg. In certain cases, the anti-BDCA2 antibody or BDCA2 binding compositions described above are administered to the subject at a dose of 450 mg.

[000145] For human pediatric subjects (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger), to achieve the equivalent of a 50 mg adult dose of the anti-BDCA2 antibody or BDCA2-binding fragment thereof, the dose is determined based on the child's weight as follows:

[000146] For human pediatric subjects, to achieve the equivalent of a 150 mg adult dose of the anti-BDCA2 antibody or BDCA2 binding fragment compositions thereof described above, the dose is determined based on the child's weight as follows:

[000147] The route and/or mode of administration of the anti-BDCA2 antibody or BDCA2 binding fragment can be tailored to the individual subject. For many applications, the route of administration is one of the following: subcutaneous (SC) injection, intravenous (IV) injection or infusion, intraperitoneal (IP) administration, or intramuscular injection. In one embodiment, the route of administration is subcutaneous. In another embodiment, the route of administration is intravenous.

[000148] Pharmaceutical compositions comprising the anti-BDCA2 antibody or BDCA2-binding fragment thereof alone or in combination with non-BDCA2 antibody agent(s) may be administered with a medical device. The device may be designed with features such as portability, room temperature storage, and ease of use, so that it can be used in emergency situations, for example, by an inexperienced subject or by emergency personnel in the field, removed to medical facilities and other medical equipment. The device may include, for example, one or more housings for storing pharmaceutical preparations that include the anti-BDCA2 antibody or BDCA2-binding fragment thereof, and may be configured to administer one or more unit doses of the blocking agent.

[000149] For example, the pharmaceutical composition may be administered with a needleless hypodermic injection device, such as the devices disclosed in US 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules include: US 4,487,603, which discloses an implantable micro-infusion pump for delivering medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for delivering medication through the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable-flow implantable infusion device for continuous drug administration; US 4,439,196, which discloses an osmotic drug delivery system with multiple chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other devices, implants, delivery systems, and modules are also known.

[000150] In one embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human with a syringe. In another embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human with a pump for subcutaneous administration. In some embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human with an autoinjector. In other embodiments, the anti-BDCA2 antibody or BDCA2 binding fragment thereof is administered to a human with a subcutaneous large volume injector.

[000151] This disclosure provides a pump or syringe comprising a sterile preparation of an anti-BDCA2 antibody (e.g., BIIB059) or a BDCA2-binding fragment thereof. The syringe or pump may be adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2-binding fragment thereof. In some cases, the syringe or pump delivers a fixed dose(s) (e.g., 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, 450 mg) of the anti-BDCA2 antibody or BDCA2-binding fragment thereof.

[000152] The disclosure also provides a pump, syringe, or injector (e.g., autoinjector, large volume subcutaneous injector) comprising a sterile preparation of the pharmaceutical compositions described above. The syringe or pump may be adapted for subcutaneous administration of the pharmaceutical compositions comprising the anti-BDCA2 antibody or BDCA2-binding fragment thereof. In some cases, the syringe or pump administers a fixed dose(s) (e.g., 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, 450 mg) of the anti-BDCA2 antibody or BDCA2-binding fragment thereof.

Treatment Methods

[000153] An anti-BDCA2 antibody or BDCA2 binding fragment thereof described herein can be used to treat or prevent a variety of immunological disorders, such as inflammatory and autoimmune disorders. Anti-BDCA2 antibodies or BDCA2 binding fragment thereof can disable or deplete pDCs and/or inhibit inflammatory cytokines and chemokines produced by pDCs and/or upregulate CD32a and/or inhibit immune complex stimulation of pDCs and/or upregulate or cause shedding of CD62L. The anti-BDCA2 antibodies or BDCA2 binding fragment thereof of this disclosure can be combined with an antimalarial agent (e.g., HCQ) for enhanced therapeutic effects in the treatment of inflammatory and autoimmune disorders. 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 family of multiple cytokines, including 13 subtypes of IFN-α, IFN-β, -ε, -K, -W, -δ and -T. (Theofilopoulos, Annu. Rev. Immunol., 23:307-36 (2005)). Type III interferons consist of three IFN-α molecules called IFN-α1, IFN-α2 and IFNα3 (also referred to as IL29, IL28A and IL28B, respectively). By depleting and/or dampening pDC function, the anti-BDCA2 antibodies described here provide a more robust treatment approach than treatments that attempt to reduce specific IFN subtypes with neutralizing antibodies. Furthermore, the pDC-focused treatment approach of anti-BDCA2 antibodies is more selective and potentially safer than global blockade of the IFN response. For example, the anti-BDCA2 antibodies described here effectively eliminate pDC-derived type I IFNs while maintaining other sources of IFN that may be required in the event of viral infections.

[000154] This disclosure provides methods of treating BDCA2-associated disorders using the antibodies and compositions described herein. Non-limiting examples of BDCA2-associated disorders include SLE, CLE, DLE, lupus nephritis, systemic sclerosis (scleroderma), morphea, psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), dermatomyositis, polymyositis, type I diabetes, and cytokine release syndrome. In some embodiments, the anti-BDCA2 antibodies and compositions described herein can be used to treat a lupus disorder (e.g., SLE, CLE, and DLE).

[000155] In one embodiment, the disclosure features a method of treating SLE (e.g., moderate or severe lupus) in a human in need thereof. The method involves administering to a human in need thereof a therapeutically effective amount of an anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain cases, the subject is administered the pharmaceutical compositions described herein to provide a dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. In certain cases, where the subject is a pediatric subject (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger), the subject is administered the pharmaceutical compositions described herein to provide a dose of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, or 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. The dose is chosen based on the child's weight as detailed above. In some cases, the subject is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 doses, at least 11 doses, at least 12 doses, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, of 12 doses. In certain cases, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof approximately 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In one embodiment, the subject with SLE is administered a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In another embodiment, the subject with SLE is administered a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In yet another embodiment, the subject with SLE is administered a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment.

[000156] The disclosure also features a method of treating cutaneous lupus erythematosus (with or without SLE) in a human in need thereof. The method involves administering to a human in need thereof a therapeutically effective amount of an anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain instances, the subject is administered the pharmaceutical compositions described herein to provide a dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. In certain cases, where the subject is a pediatric subject (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger), the subject is administered the pharmaceutical compositions described herein to provide a dose of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, or 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. The dose is chosen based on the child's weight as detailed above. In some cases, the subject is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 doses, at least 11 doses, at least 12 doses, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses. In certain cases, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof approximately 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In one embodiment, the subject with CLE (with or without SLE) is administered a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In another embodiment, the subject with CLE (with or without SLE) is administered a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In yet another embodiment, the subject with CLE (with or without SLE) is administered a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment.

[000157] The disclosure also provides a method of treating discoid lupus erythematosus (with or without SLE) in a human in need thereof. The method involves administering to a human in need thereof a therapeutically effective amount of an anti-BDCA2 antibody or BDCA2 binding fragment thereof. In certain cases, the subject is administered the pharmaceutical compositions described herein to provide a dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. In certain cases, where the subject is a pediatric subject (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger), the subject is administered the pharmaceutical compositions described herein to provide a dose of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, or 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment. The dose is chosen based on the child's weight as detailed above. In some cases, the subject is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 doses, at least 11 doses, at least 12 doses, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses. In certain cases, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof approximately 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In one embodiment, the subject with discoid lupus erythematosus (with or without SLE) is administered a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment at 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In another embodiment, the subject with discoid lupus erythematosus (with or without SLE) is administered a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment at 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In yet another embodiment, the subject with discoid lupus erythematosus (with or without SLE) is administered a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment at 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment.

[000158] In one embodiment, the disclosure features a method of treating cytokine release syndrome and/or cytokine storms in a human in need thereof. Cytokine release syndrome (CRS) is a common immediate complication that occurs with the use of T cell engagement therapies (e.g., chimeric antigen receptor modified T cell (CART) therapy). Severe cases of this disorder are known as cytokine storms. CRS is a symptom complex associated with the use of many monoclonal antibodies. Commonly referred to as an infusion reaction, CRS results from the release of cytokines from antibody target cells as well as immune effector cells recruited to the area. The antibodies bind to the T cell receptor, activating the T cells before they are destroyed. The cytokines released by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infection. When cytokines are released into the circulation, the subject may develop systemic symptoms such as fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, sore throat, and dyspnea. In most cases, the symptoms are mild to moderate in severity and can be treated relatively easily. However, some patients may experience severe, life-threatening reactions resulting from massive cytokine release. Severe reactions occur most commonly during the first infusion in patients with hematologic malignancies who have not received prior chemotherapy. Severe reactions are marked by their rapid onset and the severity of associated symptoms. Massive cytokine release is an oncologic emergency and can lead to life-threatening complications. The method of treatment for CRS involves administering to a human in need thereof an anti-BDCA2 antibody or a BDCA2-binding fragment thereof. In certain instances, the subject is administered the pharmaceutical compositions described herein to provide a 50 mg, 150 mg, or 450 mg dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In certain instances, where the subject is a pediatric subject (e.g., a subject 21 years of age or younger, a subject 18 years of age or younger, or a subject 16 years of age or younger), the subject is administered the pharmaceutical compositions described herein to provide a 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, or 150 mg dose of the anti-BDCA2 antibody or BDCA2 binding fragment. The dose is chosen based on the child's weight, as detailed above. In some cases, the subject is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 doses, at least 11 doses, at least 12 doses, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses. In certain cases, the subject is also administered a loading dose of 50 mg, 150 mg, or 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment thereof approximately 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof. In one embodiment, the subject with CRS is administered a fixed dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 50 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In another embodiment, the subject with CRS is administered a fixed dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 150 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In yet another embodiment, the subject with CRS is administered a fixed dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment and a loading dose of 450 mg of the anti-BDCA2 antibody or BDCA2 binding fragment 2 weeks after administration of the first dose of the anti-BDCA2 antibody or BDCA2 binding fragment. In certain cases, the human patient is scheduled for, or is undergoing CART therapy (e.g., CART-19 therapy). In certain cases, the human subject has been, is scheduled for, or is undergoing therapy with an anti-T-cell antibody (e.g., ATG, OKT3, TGN1412) or bispecific antibody (e.g., blinatumomab). In certain cases, the subject has, is scheduled for, or is undergoing therapy with an anti-CD20 antibody (e.g., rituximab). In certain cases, the human being treated for CRS is also administered a corticosteroid (e.g., hydrocortisone) and/or an antihistamine (e.g., chlorphenamine) simultaneously, separately, or sequentially during treatment with the anti-BDCA2 antibody or BDCA2-binding fragment thereof. In some cases, the subject is also administered an agent that inhibits IL-6 simultaneously, separately, or sequentially during treatment with the anti-BDCA2 antibody or BDCA2-binding fragment thereof. The agent that inhibits IL-6 may be an anti-IL-6 antibody or an IL6-binding fragment thereof, an IL6 receptor (IL6R) antagonist (e.g., tocilizumab, or a soluble IL6R).

[000159] In one embodiment in all of the above-described methods of treatment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises the three heavy chain variable domain CDRs and the three light chain variable domain CDRs of BIIB059. In another embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment comprises the amino acid sequences set forth in SEQ ID NO: 1-6. In another embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment comprises the amino acid sequences set forth in SEQ ID NO: 12-16. In yet another embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment comprises the amino acid sequences set forth in SEQ ID NO: 18-22. In a further embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment comprises the amino acid sequences set forth in SEQ ID NO: 24-28. In one embodiment, the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises a VH CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 1 or 17, a VH CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 2; and a VH CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 3; and a VL CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 4, a VL CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 5; and a VL CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 6.

[000160] In some embodiments, in all of the above-described treatment methods, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises (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 by at least 1 to 5 amino acid residues, but by less than 40, 30, 20, 15, or 10, residues, from SEQ ID NO: 7 and/or SEQ ID NO: 8. In certain cases, these anti-BDCA2 antibodies or BDCA2 binding fragments (i) bind to human or cynomolgus monkey BDCA2, but do not significantly bind to BDCA2 from phylogenetic species below primates; and/or (ii) inhibit TLR7/TLR9-induced type I interferon and other cytokine or chemokine production by human pDCs; and/or (iii) mediate the internalization of BDCA2 from the surface of pDCs; and/or (iv) upregulate CD32a and/or CD62L on the surface of pDCs; and/or (v) deplete pDCs in vitro by ADCC or CDC.

[000161] In certain embodiments, in all of the treatment methods described above, the anti-BDCA2 antibody or antigen-binding fragment thereof selectively binds to the ectodomain of human BDCA2 and comprises (i) a HC 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 SEQ ID NO: 9, and/or (ii) a LC 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 SEQ ID NO: 9. ID NO: 10, or differs in at least 1 to 5 amino acid residues, but in less than 40, 30, 20, 15 or 10, residues, from SEQ ID NO: 9 and/or SEQ ID NO:10.

[000162] The following are examples of the practice of the invention. They should not be construed as limiting the scope of the invention in any way.

Examples Example 1: Viscosity Evaluation of Anti-BDCA2 Antibody Formulations

[000163] In order to develop a high concentration anti-BDCA2 antibody formulation, the highest concentration of antibody that could be used was determined. The antibody formulation used in these studies comprised BIIB059, 10 mM citrate buffer, 140 mM Arg.HCl, and 0.05% PS80. The formulation had a pH of 6.0. The highest concentration in these studies would be limited by viscosity and the limit imposed by the large volume subcutaneous pump: 50 cP. Viscosity was measured in the low concentration formulation (Figure 1). The threshold viscosity was found to be crossed between 225 and 250 mg/mL, and 225 mg/mL was chosen as the highest concentration for anti-BDCA2 antibody formulations.

Example 2; Testing of Different Excipients and Conditions for Antibody Formulation

[000164] Initially, very high aggregation rates at 40°C, as well as significant visible particles and subvisible particulate charges, were observed in the antibody formulation of Example 1. Several causal factors were identified:

[000165] 1. Behavior at 40°C is not apparently predictive of that at 5°C.

[000166] 2. Process-related stresses, e.g. during UF/DF, can cause aggregates to form. Processing in the presence of excipients prevents this from occurring.

[000167] 3. Different batches of drug substances used had different initial levels of HMW which may influence subsequent aggregation

[000168] 4. The protein appeared at least moderately sensitive to light.

[000169] 5. There may be a link with oxidation occurring.

[000170] The material was therefore prepared in the presence of at least minimal excipients, before spiking with any other excipients. The formulations tested for stability are shown in Table 2. Table 2: Initial formulation studies

Study 1

[000171] In Study 1, although high aggregation was observed at 40°C, excellent stability was observed at 5°C, with no significant increases in high molecular weight (HMW) species over 3 months at concentrations up to 225 mg/mL. Further analysis of the data showed that lower pH resulted in less aggregation, and histidine outperformed citrate (Figure 2).

[000172] Visible particles could be observed after incubation at 40°C at the higher pH, while the microflow subvisible particle count (MFI) remained acceptable. A similar trend was observed after 3 months at 5°C, although fewer particles could be seen. Viscosity in these formulations increased with concentration. A weak dependence on buffer and pH could also be observed, although this effect was small (Figure 3).

[000173] Experiments were also performed to determine whether the Tween levels used, 0.05% PS80, were still adequate at high anti-BDCA2 antibody concentration. Appearance, MFI and size exclusion chromatography (SEC) showed that at levels of 0.02% PS80 and above, no additional protection against agitation was obtained. Maintaining the target concentration at 0.05% PS80 was therefore determined to be adequate.

Study 2

[000174] This second study analyzed different excipients and some combinations of excipients (see Table 2).

[000175] At 40°C, high aggregation was again observed, although some excipients, notably Arg.HCl, provided a clear advantage in a concentration-dependent manner (Figure 4).

[000176] When considering the viscosity of these formulations, Arg.HCl was again seen as an advantage as it reduces viscosity in a concentration-dependent manner. Solutions containing Arg had a propensity to form visible particles after incubation at 40°C. Surprisingly, sucrose prevented the formation of visible particles (Table 3). Sucrose also reduced subvisible particle counts (Figure 5). Table 3: Viscosity (at time zero) and visible particles after incubation at 40°C for 1 month. The formulations were 20 mM citrate, pH 6.0, 0.05% PS80, with the additional excipients as shown.

[000177] Based on these results, a developmental stability study using the combination of sucrose and Arg.HCl was initiated to verify that the combination would result in reduced aggregation, good viscosity, and no particle formation. No visible particles could be observed after incubation at 40°C. Interestingly, the combination of sucrose and Arg.HCl also significantly reduced the subvisible particle count (Figure 5). Although the number of particles in 70 mM Arg.HCl was quite low, the addition of sucrose surprisingly reduced the particle count even further (Figure 5). The presence of sucrose did not significantly affect aggregate formation (Figure 6). Additional data up to 6 weeks at 5°C continued this trend and showed acceptable stability in the Arg.HCl/sucrose combination formulations. At 200 mg/mL, the viscosity of 70 mM Arg.HCl with 3.5% sucrose was 22.5 cP; with 7% sucrose the viscosity was 23.5 cP.

[000178] Combining the results of Study 1 and Study 2, several observations led to the proposal of a new "better" high concentration formulation (Table 4). This "better" formulation is referred to as Formulation 2 in Examples 3 and 4. Table 4: Details of a proposed "better" formulation combining data from Study 1 and Study 2

[000179] Since there was a history of aggregation, subvisible particles, and visible particles in anti-BDCA2 formulations, it was decided that the anti-BDCA2 antibody be formulated at 150 mg/mL.

Example 3: Comparison of Aggregation in Anti-BDCA2 Antibody Formulations

[000180] A 50 mg/mL anti-BDCA2 antibody (BIIB059) formulation formulated in 10 mM Citrate, 150 mM Arg.HCl, 0.05% PS80, pH 6.0 was concentrated by ultrafiltration/diafiltration. Two different concentrated formulations were created: Formulation 1: 150 mg/mL 0.059, 20 mM citrate, 140 mM Arg.HCl, 0.05% PS80, pH 6.0; and Formulation 2: 150 mg/mL 0.059, 20 mM histidine, 100 mM Arg.HCl, 3% sucrose, 0.05% PS80, pH 5.5. With this format, it was possible to explore high concentration in two different formulations.

[000181] Interestingly, although the Formulation 2 material was concentrated and reprocessed from the Citrate/Arg buffer, Formulation 2 (with the His/Sucrose/Arg excipients) showed lower levels of initial aggregate (Figure 7). The aggregation rate of this material was also lower (Table 5). Table 5: Aggregation rates (% increase in HMW per month) comparing Formulations 1 and 2

[000182] Based on the observed initial % HMW (Figure 7), the aggregation rate at 5°C (Table 5) and the increase in HMW after 1 month at 25°C (Figure 7), it was possible to predict the shelf life of each product: i.e. the time required to reach 5% HMW, the typical specification threshold for early stage products. The predicted shelf life for Formulation 1 was 9.5 months, whilst for Formulation 2 it was 26 months (this is likely to be an underestimate as the 5°C aggregation rate was based on the first three months of data where aggregation was most rapid and the 1 month ambient temperature was probably well beyond what the product could realistically be subjected to). In summary, the data show that Formulation 2 provides significantly increased stability against aggregation compared to Formulation 1.

Example 4: Viscosity of Anti-BDCA2 Antibody Formulation 2

[000183] The viscosity of Formulation 2 was then measured. As can be seen in Figure 8, the viscosity profile was amenable to incorporating this formulation into a device. The 10 cP threshold for an autoinjector was not crossed until ~155 mg/mL, suggesting that material as high as ~140 mg/mL could enter this device. The 50 cP threshold was not crossed at concentrations as high as 200 mg/mL, suggesting the possibility of escalating to this concentration should a large volume subcutaneous injector be required.

Example 5: Reasons for Dosing Regimen

[000184] Dosing regimens were selected based on safety, pharmacokinetics (PK), PK-BDCA2 internalization ratio, and extrapolated inhibitory potency (concentration resulting in 90% inhibition of response [IC90]) of pDN IFNa production.

[000185] Single IV doses of BIIB059 up to and including 20 mg/kg in healthy subjects demonstrated acceptable tolerability. Targeted BDCA2 engagement, as measured by BDCA2 internalization and reappearance, was observed in a dose-dependent manner over the dose range of 0.3 mg/kg to 20 mg/kg. EC90 values for BDCA2 internalization were derived from population-based PK and PD models with the median value of 1.5 μg/mL. The IC90 for IFNa inhibition was estimated from in vitro to in vivo extrapolation of BDCA2 internalization and IFNa inhibition.

[000186] Fixed doses of BIIB059 of 50 mg, 150 mg, and 450 mg subcutaneously (SC) every 4 weeks (Q4W) with an additional dose (“loading dose”) two weeks after administration of the first dose (Week 2) are supported by the following:

[000187] (1) The low dose of 50 mg SC Q4W was chosen to maintain BDCA2 internalization throughout most of the dosing interval.

[000188] (2) The mean dose of 150 mg SC Q4W was selected to achieve minimum observed concentration (Cmin) levels similar to the calculated IC90 for IFNa.

[000189] (3) The higher dose of 450 mg SC Q4W was selected to achieve Cmin levels similar to 3-fold of the calculated IC90 for IFNa inhibition. Furthermore, this dose regimen with an additional 450 mg dose at week 2 and a bioavailability (F) of 0.45 is expected to result in a cumulative exposure over 3 months comparable to that achieved with the single 20 mg/kg IV dose for a 65 kg person, the highest dose tested in healthy volunteers.

[000190] To ensure sufficient drug exposure and concentration levels above fixed target values within 1 month after SC administration, a SC loading dose at Week 2 (Day 15 - i.e. 15 days after administration of the first dose) will be included.

[000191] Pharmacokinetic data using weight-adjusted dosing showed that body weight is not an influential covariate for BIIB059 exposure. Furthermore, population PK simulations showed that both weight-adjusted dosing and fixed dosing result in comparable exposure to BIIB059. Fixed dose regimens are therefore reasonable.

[000192] A high dose of 450 mg SC Q4W (for 12 weeks) and a loading dose at Week 2 is based on PK simulations using data with SC and IV Q2W regimens, and the expectation that the 450 mg dose level will have adequate target coverage (BDCA2) to suppress pDC function, including type I IFN production, over 12 weeks.

Example 6: High Concentration Anti-BDCA2 Formulation Study

[000193] An anti-BDCA2 antibody drug product was formulated at a concentration of 150 mg/mL in 20 mM histidine, 100 mM Arg.HCl 100, 3% sucrose, 0.05% polysorbate-80 at pH 5.5. To enable subcutaneous administration of anti-BDCA2 antibodies at high doses, a formulation study was conducted to examine the stability of liquid formulations of anti-BDCA2 antibodies at concentrations above 150 mg/mL. Concentrations of 200, 225, and 240 mg/mL were examined in this study. Arginine and sucrose levels were also varied to understand the role of these excipients in the stability of high concentration formulations. Additionally, the pH of the formulations was increased to 6.0 or 6.5 to reduce the formation of basic species. A total of ten formulations were tested (see Table 6 for formulation compositions). Table 6: Formulations Tested

[000194] All formulations were incubated under four conditions: (i) 5°C, (ii) 25°C/60%RH, (iii) 30°C/70%RH and (iv) 40°C/75%RH. At predetermined time points, samples were withdrawn for analysis, which included size exclusion chromatography (SEC) for quantification of aggregates and imaging capillary isoelectric focusing (icIEF) for quantification of basic isoforms.

[000195] At 5°C, Formulations 1 and 5, labeled as 200/250/3/6 and 225/250/1/6, respectively, had the lowest aggregation at all time points tested (0, 4, and 12 weeks) (Figure 9). At 25°C (Figure 10), 30°C (Figure 11), and 40°C (Figure 12), Formulation 1 consistently exhibited the lowest aggregate formation compared to other formulations. Thus, Formulation 1 was identified as the best performing formulation in this study. Linear modeling of the aggregation data from this study indicated that protein concentration, arginine concentration, and formulation pH significantly impacted aggregation.

[000196] Basic species formation was highly pH dependent: increased levels were observed in formulations at pH 6.0 compared to formulations at pH 6.5. This trend was particularly evident at 25°C (Figure 13), 30°C (Figure 14), and 40°C (Figure 15). Formulations at pH 6.0 also tended to exhibit an increase in basic isoforms over time at 25°C (Figure 13), 30°C (Figure 14), and 40°C (Figure 15). At 5°C, there was no consistent increase in basic isoforms in either formulation (Figure 16), contrary to previous findings in the exemplary BDCA2 formulation (i.e., where the anti-BDCA2 drug is formulated at a concentration of 150 mg/mL in 20 mM histidine, 100 mM Arg.HCl 100, 3% sucrose, 0.05% polysorbate-80 at pH 5.5).

Example 7: Evaluation of the Impact of Thiol-Containing Oxidizing Agent(s) on anti-BDCA2 Antibody Formulations Materials and methods: Proteins and Reagents

[000197] Anti-BDCA2 antibody (BIIB059), SB4 (BENEPALI®) and anti-αvβ5 antibody (STX 200) were formulated according to the table below:

[000198] Reduced and oxidized forms of L-Glutathione (GSH and GSSG) were obtained from Sigma Aldrich (St. Louis, MO).

Size Exclusion HPLC

[000199] Size exclusion HPLC (SEC) experiments were performed on a Waters Acquity UPLC instrument equipped with an Acquity UPLC BEH200 SEC analytical column coupled to a guard column. UV detection was performed at 280 nm. A 20 μg sample amount was injected onto the column by a constant flow of 0.35 mL/min of mobile phase. Each sample was run for 10 min.

Stability Studies

[000200] SB4 and STX 200 were concentrated to 150 mg/mL on 10K centrifugal filters. Stock solutions of 20 mM GSH and 10 mM GSSG, prepared in corresponding formulation buffers, were mixed into protein solutions to achieve final concentrations of 0.4 mM and 0.2 mM, respectively. The prepared solutions were plated onto WebSeal plates with glass inserts, sealed, and incubated at 25°C/60%RH and 40°C/75%RH for 3 months. %HMW analysis was performed by SEC at predetermined time points.

Results and discussion:

[000201] Glutathione, a tripeptide (Y-Glu-Cys-Gly), regulates disulfide bond formation. The reduced form (GSH) cleaves unformed disulfide bonds at the point and the oxidized form (GSSG) facilitates their formation. Thus, aggregated proteins incubated with the redox couple (i.e., GSH + GSSG) would refold to the correct native conformation and affect aggregation kinetics.

[000202] The anti-BDCA2 antibody in the presence of glutathione shows an initial reversible aggregation followed by an aggregation rate that is slower for the formulation without glutathione at 25°C (Figure 17, left panel). Higher temperatures (40°C) increase the diversity of aggregation mechanisms, with conformational stability also at play (Figure 17, right panel). Thus, glutathione alone was not able to achieve a similar reduction at 25°C.

[000203] Sucrose is a widely used excipient for protein stabilization. It is preferentially excluded from the protein surface, thus favoring its native conformation. The absence of sucrose in the anti-BDCA2 antibody formulation did not affect the aggregation profile (Figure 18), further emphasizing the role of the disulfide bond struggling to control aggregation in BDCA2.

[000204] The addition of glutathione negatively affects STX200, where an increase in aggregation was observed (Figure 20). STX 200 is an aglycosylated molecule, demonstrating low conformational stability at higher temperatures. Thus, the unfolding of the molecule exposes the thiol group, making it more susceptible to crosslinking with the thiol in glutathione and promoting greater aggregation. Glutathione also had no effect on the aggregation kinetics of SB4, a fusion protein at 25°C, but facilitated faster aggregation at 40°C (Figure 19).

Other Modalities

[000205] It should be understood that, although the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the claims.

Claims (17)

1. Pharmaceutical composition, characterized by the fact that it comprises an anti-blood dendritic cell antigen 2 (BDCA2) antibody or its BDCA2-binding fragment, sucrose and arginine hydrochloride (Arg.HCl), in which the anti-BDCA2 antibody or BDCA2-binding fragment thereof comprises an immunoglobulin heavy chain variable domain (VH) and an immunoglobulin light chain variable domain (VL), VH and VL, respectively, comprising: (a) VH complementarity determining regions (CDRs), in which H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and (b) VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6, and wherein the composition has a pH of 5.0 to 6.0 or 5.0 to 6.5. 2. Pharmaceutical composition, according to claim 1, characterized by the fact that it comprises: (i) the anti-BDCA2 antibody or a BDCA2 binding fragment thereof at a concentration of: (a) 50 mg/ml to 225 mg/ml; (b) 125 mg/ml to 175 mg/ml; or (c) 150 mg/ml; and/or (ii) sucrose at a concentration of: (a) 0.05% to 10%; (b) 1% to 5%; or (c) 3%; and/or (iii) Arg.HCl at a concentration of: (a) 50 mM to 250 mM; (b) 75 mM to 125 mM; or (c) 100 mM. 3. Pharmaceutical composition according to claim 1 or 2, characterized by the fact that it comprises: (i) Polysorbate-80 (PS80), optionally at a concentration of 0.01% to 0.1%, 0.03% to 0.08% or 0.05%; and/or (ii) histidine, optionally at a concentration of 5 mM to 50 mM, 15 mM to 25 mM or 20 mM. 4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it has a pH of 5.3 to 6.0, 5.3 to 5.7, 5.5 or 6.0. 5. Pharmaceutical composition, characterized by the fact that it comprises an anti-blood dendritic cell antigen 2 (BDCA2) antibody or BDCA2-binding fragment thereof, optionally at a concentration of 50 mg/ml to 225 mg/ml, and: histidine at a concentration of 10 mM to 30 mM; Arg.HCl at a concentration of 50 mM to 250 mM; and PS80 at a concentration of 0.02% to 0.08%, wherein the composition has a pH of 5.0 to 6.5, and wherein the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising: (a) VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1 or 17; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and (b) VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence (c) (d) shown in SEQ ID NO: 6. 6. Pharmaceutical composition according to claim 1, characterized by the fact that it comprises: (i) the anti-BDCA2 antibody or the BDCA2-binding fragment thereof at a concentration of 200 mg/ml; sucrose at a concentration of 3%; histidine at a concentration of 20 mM; Arg.HCl at a concentration of 250 mM; PS80 at a concentration of 0.05%; and in which the composition has a pH of 6.0; or (ii) the anti-BDCA2 antibody or the BDCA2-binding fragment thereof at a concentration of 225 mg/ml; sucrose at a concentration of 1%; histidine at a concentration of 20 mM; Arg.HCl at a concentration of 250 mM; PS80 at a concentration of 0.05%; and in which the composition has a pH of 6.0; or (iii) the anti-BDCA2 antibody or the BDCA2 binding fragment thereof at a concentration of 125 mg/ml to 175 mg/ml; sucrose at a concentration of 1% to 5%; histidine at a concentration of 15 mM to 25 mM; Arg.HCl at a concentration of 75 mM to 125 mM; and PS80 at a concentration of 0.03% to 0.08%, wherein the composition has a pH of 5.3 to 5.7; or (iv) the anti-BDCA2 antibody or the BDCA2 binding fragment thereof at a concentration of 150 mg/ml; sucrose at a concentration of 3%; histidine at a concentration of 20 mM; Arg.HCl at a concentration of 100 mM; and PS80 at a concentration of 0.05%, wherein the composition has a pH of 5.5. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it comprises a thiol-containing antioxidant, optionally, wherein the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. 8. Pharmaceutical composition according to claim 7, characterized by the fact that the thiol-containing antioxidant is at a concentration of 0.02 mM to 2 mM, 0.2 mM, 0.4 mM or 1 mM, optionally wherein the GSH is at a concentration of 0.4 mM and the GSSG is at a concentration of 0.2 mM. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it is for use in the treatment of a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma and cytokine release syndrome in a human subject, optionally wherein the pharmaceutical composition is to be administered subcutaneously to the human subject. 10. Pharmaceutical composition according to claim 9, characterized in that the anti-BDCA2 antibody or BDCA2-binding fragment thereof of the pharmaceutical composition is to be administered to the human subject at a dose of: (i) 50 mg every four weeks; (ii) 150 mg every four weeks; or (iii) 450 mg every four weeks. 11. Pharmaceutical composition, according to claim 9, characterized by the fact that the anti-BDCA2 antibody or BDCA2-binding fragment thereof of the pharmaceutical composition is to be administered to the human subject in the dose corresponding to the weight of the human subject, as follows: 12. An anti-BDCA2 antibody or BDCA2 binding fragment thereof for use in the treatment of a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma, and cytokine release syndrome in a human subject, wherein the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising: (a) VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and (b) VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6, which is to be administered subcutaneously to the human subject at a dose of: (i) 50 mg every four weeks, optionally wherein the human subject should receive a loading dose of the anti-BDCA2 antibody or BDCA2-binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2-binding fragment thereof, optionally wherein the loading dose is 50 mg; or (ii) 150 mg every four weeks, optionally wherein the human subject is to receive a loading dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof, optionally wherein the loading dose is 150 mg; or (iii) 450 mg every four weeks, optionally wherein the human subject is to receive a loading dose of the anti-BDCA2 antibody or BDCA2 binding fragment thereof two weeks after the first administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof, optionally wherein the loading dose is 450 mg; or (iv) corresponding to the weight of the human subject, as follows: 13. The anti-BDCA2 antibody or BDCA2-binding fragment of claim 12, wherein the human subject must receive at least 4, 7 or 10 doses of the anti-BDCA2 antibody or antigen-binding fragment thereof. 14. Syringe or pump, characterized by the fact that it comprises (i) a sterile preparation of the pharmaceutical composition, as defined in any one of claims 1 to 11, adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2-binding fragment thereof, in a fixed dose of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg or 450 mg; or (ii) a sterile preparation of an anti-BDCA2 antibody or BDCA2 binding fragment thereof, wherein the syringe or pump is adapted for subcutaneous administration of the anti-BDCA2 antibody or BDCA2 binding fragment thereof at a fixed dose of 18 mg, 22 mg, 28 mg, 40 mg, 50 mg, 56 mg, 80 mg, 150 mg, or 450 mg, and wherein the anti-BDCA2 antibody or BDCA2 binding fragment thereof comprises an immunoglobulin heavy chain (VH) variable domain and an immunoglobulin light chain (VL) variable domain, VH and VL, respectively, comprising: (a) VH complementarity determining regions (CDRs), wherein H-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 1; H-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 2; and H-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 3; and (b) VL CDRs, wherein L-CDR1 consists of the amino acid sequence set forth in SEQ ID NO: 4; L-CDR2 consists of the amino acid sequence set forth in SEQ ID NO: 5; and L-CDR3 consists of the amino acid sequence set forth in SEQ ID NO: 6. 15. Pharmaceutical composition according to any one of claims 1 to 11, anti-BDCA2 antibody or BDCA2 binding fragment according to claim 12 or 13, or syringe or pump according to claim 14, characterized by the fact that: (i) the VH consists of a sequence at least 80% identical to SEQ ID NO: 7 and the VL consists of a sequence at least 80% identical to SEQ ID NO: 8; (ii) the VH consists of a sequence at least 90% identical to SEQ ID NO: 7 and the VL consists of a sequence at least 90% identical to SEQ ID NO: 8; or (iii) the VH consists of the amino acid sequence set forth in SEQ ID NO: 7 and the VL consists of the amino acid sequence set forth in SEQ ID NO: 8; and/or wherein the anti-BDCA2 antibody comprises an immunoglobulin heavy chain and an immunoglobulin light chain, wherein: (iv) the heavy chain consists of a sequence at least 80% identical to SEQ ID NO: 9 and the light chain consists of a sequence at least 80% identical to SEQ ID NO: 10; (v) the heavy chain consists of a sequence at least 90% identical to SEQ ID NO: 9 and the light chain consists of a sequence at least 90% identical to SEQ ID NO: 10; or (vi) the heavy chain consists of the amino acid sequence set forth in SEQ ID NO: 9 and the light chain consists of the amino acid sequence set forth in SEQ ID NO: 10. 16. Use of an anti-BDCA2 antibody or BDCA2 binding fragment thereof, characterized by the fact that it is for the manufacture of a composition or a medicament for the treatment of a condition selected from the group consisting of systemic lupus erythematosus, cutaneous lupus erythematosus, discoid lupus erythematosus, Sjogren's syndrome, dermatopolymyositis, scleroderma and cytokine release syndrome in a human subject. 17. Invention, characterized in any form of its embodiments or in any applicable category of claim, for example, of product or process or use or any other type of claim encompassed by the subject matter initially described, revealed or illustrated in the patent application.