Methods for treating patients with autoantibody-mediated diseases - Patents.com

Abstract

Provided herein are methods of treating an autoantibody-mediated disease in a subject, and methods of monitoring the treatment of an autoantibody-mediated disease in a subject based on the frequency of B cells in the subject.

Description

[Background technology]

[0001] It is estimated that over 2.5% of the human population is affected by autoantibody-driven autoimmune diseases in which autoreactive antibodies are directly pathogenic. Therapeutic antagonism of the neonatal Fc receptor (FcRn), a major histocompatibility complex class I-like molecule involved in immunoglobulin G (IgG) recycling and thus the long half-life of IgG, is being explored as a strategy to treat IgG-mediated autoimmune diseases such as myasthenia gravis (gMG), immune thrombocytopenia (ITP), and pemphigus (pemphigus vulgaris (PV) and pemphigus foliaceus (PF)). The remarkable clinical efficacy of FcRn antagonism appears to be directly related to the early clearance of pathogenic IgG autoantibodies from the circulation.

[0002] Although treatment with FcRn antagonists has shown remarkable clinical efficacy in the treatment of autoimmune diseases, there are currently no established biomarkers to measure therapeutic efficacy and no established prognostic methods to determine the risk of relapse in patients.

[0003] Thus, there is a need in the art for novel biomarker-based methods of monitoring therapeutic efficacy and remission following FcRn antagonist treatment in patients with autoantibody-mediated diseases. Summary of the Invention

[0004] The present disclosure shows that treatment with FcRn antagonists causes a decrease in the frequency of circulating B cells in patients who respond to the FcRn antagonists. Furthermore, patients who do not respond to treatment with FcRn antagonists do not have a decreased frequency of B cells. Thus, provided herein is a method for monitoring the therapeutic efficacy and remission of an autoantibody-mediated disease in a subject after treatment with an FcRn antagonist based on the frequency of B cells in the subject. Also provided herein is a method of using an FcRn antagonist to treat an autoantibody-mediated disease in a subject who has an increased frequency of B cells and has relapsed after a previous treatment with a first FcRn antagonist.

[0005] In one aspect, provided herein is a method for monitoring the effectiveness of a treatment of an autoantibody-mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value related to the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the treatment is not effective, and if the frequency of B cells is less than the reference value, the treatment is effective.

[0006] In one aspect, provided herein is a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, the method comprising: a) administering to the subject a therapeutically effective amount of a second FcRn antagonist; b) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and c) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, or if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0007] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, wherein a) a therapeutically effective amount of the second FcRn antagonist is administered to the subject, b) a frequency of B cells in a blood sample taken from the subject is measured in vitro, and c) the frequency of B cells is compared to a reference value associated with the autoantibody-mediated disease in the subject, and if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, and if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0008] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, the method comprising: (a) administering to the subject one or more initial doses of a therapeutically effective amount of a first FcRn antagonist; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with autoantibody-mediated disease in the subject, administering to the subject one or more further doses of a therapeutically effective amount of a second FcRn antagonist, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with active disease in the subject, discontinuing treatment with the first FcRn antagonist.

[0009] In one aspect, provided herein is an FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein: (a) one or more initial doses of a therapeutically effective amount of a first FcRn antagonist are administered to the subject; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject, one or more further doses of a therapeutically effective amount of a second FcRn antagonist are administered to the subject, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with the autoantibody-mediated disease in the subject, the first FcRn antagonist is discontinued.

[0010] In one embodiment, the therapeutically effective amount of the first FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg.

[0011] In one embodiment, the therapeutically effective amount of the first FcRn antagonist is administered subcutaneously at a dose of about 750 mg to about 3000 mg.

[0012] In one aspect, provided herein is a method for determining whether a subject who has been previously treated for an autoantibody-mediated disease using a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, then the subject requires further treatment with the second FcRn antagonist.

[0013] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the autoantibody-mediated disease recurs in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject.

[0014] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, where the autoantibody-mediated disease has recurred in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject.

[0015] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the therapeutically effective amount of the FcRn antagonist is determined based on the frequency of B cells in a blood sample taken from the subject.

[0016] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein the autoantibody-mediated disease recurs in the subject after prior therapy with a first FcRn antagonist, the method comprising administering a therapeutically effective amount of the second FcRn antagonist to the subject, the therapeutically effective amount being determined based on the frequency of B cells in a blood sample taken from the subject.

[0017] In one aspect, provided herein is a method for monitoring remission of an autoantibody-mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro a frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is at or below the reference value, the subject is in remission from the autoantibody-mediated disease.

[0018] In one embodiment, the corticosteroid dosing regimen is tapered to a lower dose or less frequent dosing. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a second FcRn antagonist if the frequency of B cells in the sample is equal to or greater than the reference value. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a second FcRn antagonist if the frequency of B cells in the sample is equal to or greater than the reference value.

[0019] In one embodiment, the reference value is about 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3.9 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 4 times, 4.1x, 4.2x, 4.3x, 4.4x, 4.5x, 4.6x, 4.7x, 4.8x, 4.9x, 5x, 5.1x, 5.2x, 5.3x, 5.4x, 5.5x, 5.6x, 5.7x, 5.8x, 5.9x, 6x, 6.1x, 6.2x, 6.3x, 6.4x, 6.5x, 6.6x, 6.7x, 6.8x, 6.9x, or 7x. In one embodiment, the normal frequency of B cells is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of lymphocytes. In one embodiment, the reference value is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of lymphocytes.

[0020] In one embodiment, the reference value is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109 ...9%, 109%, 102%, 103%, 104%, 105%, 106%, 107%, 1 %, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. In one embodiment, the reference value is greater than 60% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for the autoantibody mediated disease.

[0021] In one embodiment, the reference value is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109, 109, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 109, 109, 109, 109, 109, 109, 1 2%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% higher.

[0022] In one embodiment, the reference value is about 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.7-fold, 3.8-fold, 3.9-fold, 3.10-fold, 3.12-fold, 3.14-fold, 3.16-fold, 3.18-fold, 3.19-fold, 3.21-fold, 3.22-fold, 3.23-fold, 3.24-fold, 3.25-fold, 3.26-fold, 3.27-fold, 3.28-fold, 3.29-fold, 3.30-fold, 3.31-fold, 3.32-fold, 3.33-fold, 3.34-fold, 3.35-fold, 3.36-fold, 3.37-fold, 3.38-fold, 3.39-fold, 3.40-fold, 3.41-fold, 3.42-fold, 3.43-fold, 3.44-fold, 3.45-fold, 3.46-fold, 3.47-fold, 3.48-fold, 3.49-fold, 3.50-fold, 3.51-fold, 3.52-fold, 3.53-fold, 3.54-fold, 3.55-fold, 3. 6x, 3.7x, 3.8x, 3.9x, 4x, 4.1x, 4.2x, 4.3x, 4.4x, 4.5x, 4.6x, 4.7x, 4.8x, 4.9x, 5x, 5.1x, 5.2x, 5.3x, 5.4x, 5.5x, 5.6x, 5.7x, 5.8x, 5.9x, 6x, 6.1x, 6.2x, 6.3x, 6.4x, 6.5x, 6.6x, 6.7x, 6.8x, 6.9x, or 7x.

[0023] In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 10 mg / kg to about 30 mg / kg administered intravenously, hi one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 750 mg to about 3000 mg administered subcutaneously.

[0024] In one embodiment, the subject has also been previously treated with a corticosteroid, or an immunosuppressant.

[0025] In one embodiment, the effective amount of the second FcRn antagonist is a higher dose than the previous treatment with the first FcRn antagonist, hi one embodiment, the effective amount of the second FcRn antagonist is a lower dose than the previous treatment with the first FcRn antagonist.

[0026] In one embodiment, an effective amount of the second FcRn antagonist is administered more frequently compared to a previous treatment with the first FcRn antagonist, hi one embodiment, an effective amount of the second FcRn antagonist is administered less frequently compared to a previous treatment with the first FcRn antagonist.

[0027] In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of about 10 mg / kg to about 30 mg / kg. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of 10 mg / kg. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of 25 mg / kg.

[0028] In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0029] In one embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid, or an immunosuppressant. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.5 mg / kg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.25 mg / kg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 20 mg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 10 mg per day.

[0030] In one embodiment, the frequency of B cells is measured by flow cytometry. In one embodiment, the B cells are CD19+ B cells.

[0031] In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist. In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists.

[0032] In one embodiment, the FcRn antagonist is an anti-FcRn antibody. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody. In one embodiment, the second FcRn antagonist is an anti-FcRn antibody.

[0033] In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0034] In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0035] In one embodiment, the FcRn antagonist is efgartigimod. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is efgartigimod. In one embodiment, the FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3. In one embodiment, the first FcRn antagonist or the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is efgartigimod. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3. In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161). In one embodiment, the patient has not been previously treated with efgartigimod.

[0036] In one embodiment, the subject has a serum level of a pathogenic IgG autoantibody that is associated with recurrence of an autoantibody-mediated disease. In one embodiment, the pathogenic IgG autoantibody is an anti-Dsg-3 antibody or an anti-Dsg-1 antibody.

[0037] In one embodiment, the autoantibody mediated disease is selected from the group consisting of allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome (APS), autoimmune Addison's disease, Alzheimer's disease, antibody-mediated allograft rejection (AMR), antineutrophil cytoplasmic antibodies (ANCA), ANCA vasculitis, autoimmune diseases of the adrenal gland, autoimmune encephalitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura or idiopathic thrombocytopenic purpura). purpura) or immune-mediated thrombocytopenia), autoimmune urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman syndrome, celiac-spruce dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, COVID-19-mediated postural orthostatic tachycardia syndrome (POTS), Crohn's disease, delayed graft function after kidney transplantation, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome (GBS), Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, hemolytic disease of the fetus and newborn(HDFN), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, lupus nephritis, membranous neuropathy, membranous nephropathy, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes mellitus, multifocal motor neuropathy (MMN), myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), myasthenia gravis (MG) ), generalized myasthenia gravis (gMG), ophthalmic myasthenia gravis (OMG), myositis, neuromyelitis optica (NMO), paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigoid vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), antisynthetase syndrome (ASyS), primary gammopathy (primary agammaglobulinemia), primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis (RA), sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-man syndrome, systemic lupus erythematosus (SLE), Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), thyroid eye disease, ulcerative colitis, uveitis, warm autoimmune hemolytic anemia (wAIHA), dermatitis herpetiformis vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0038] In one embodiment, the autoantibody mediated disease is pemphigus vulgaris (PV). In one embodiment, the autoantibody mediated disease is pemphigus foliaceus (PF).

[0039] In one embodiment, the subject has one or more physical symptoms of an autoantibody-mediated disease after treatment with a first FcRn antagonist. In one embodiment, the one or more physical symptoms include, but are not limited to, eye muscle fatigue or weakness, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, fatigue, slurred speech, choking, difficulty swallowing, double or blurred vision, immobility requiring assistance, shortness of breath, respiratory failure, and blisters, including blisters on the skin and mouth. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 is a series of FACS plots showing the gating strategy used to study CD19+ IgM− IgD− DSG3+, or Col7+ cells for one representative patient. [Figure 1-2] FIG. 1 is a series of FACS plots showing the gating strategy used to study CD19+ IgM− IgD− DSG3+, or Col7+ cells for one representative patient.

[0041] [Figure 2A] Figure 2A is a bar graph showing the clinical response to efgartigimod treatment for all patients in cohorts 3 and 4. The arrows indicate when efgartigimod was administered and the dotted lines indicate the period of biweekly administration in patients who achieved EoC. [Figure 2B] FIG. 2B is a table showing the symbol shapes used throughout the figures for the selected patient. [Figure 2C] FIG. 2C is a graph showing levels of pathogenic antibodies (anti-Dsg-3) and non-pathogenic antibodies (anti-varicella zoster virus (VZV), anti-tetanus toxoid (TT), and anti-pneumococcal encapsulated polysaccharide (PCP)), as well as total IgG (tIgG) and PDAI (pemphigus lesion area index) activity scores in one representative PV patient. [Figure 2D]FIG. 2D is a graph showing the levels of pathogenic (anti-Dsg-1) and non-pathogenic (anti-VZV, anti-TT, and anti-PCP) antibodies, as well as tIgG and PDAI activity scores in one representative PF patient. The grey shaded area indicates the follow-up period without efgartigimod treatment. Abbreviations: EoT=end of treatment, DC=disease control, EoC=end of consolidation, CR=complete clinical remission, CRmin=complete clinical remission with minimal treatment, Pt=patient.

[0042] [Figure 3A] 3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL). [Figure 3B]3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL). [Figure 3C] 3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL). [Figure 3D]3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL). [Figure 3E] 3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL). [Figure 3F]3A-F are graphs showing levels of anti-Dsg IgG subtypes in patients with pemphigus at baseline, complete clinical remission (CR), end of treatment (EoT), and end of study (EoS). FIG. 3A is a graph showing anti-Dsg3 IgG1 levels in PV patients. FIG. 3B is a graph showing anti-Dsg3 IgG2 levels in PV patients. FIG. 3C is a graph showing anti-Dsg3 IgG3 levels in PV patients. FIG. 3D is a graph showing anti-Dsg3 IgG4 levels in PV patients. The dotted lines in FIG. 3A-3D indicate the threshold for positivity (2 SD above the mean value from 36 healthy donors). FIG. 3E is a graph showing anti-Dsg1 IgG1 levels in PF patients. FIG. 3F is a graph showing anti-Dsg1 IgG4 levels in PF patients. The dotted lines in FIG. 3E-3F indicate the threshold for positivity (20 RU / mL).

[0043] [Figure 4A] Figures 4A-B are graphs showing levels of circulating IgG immune complexes (IgG CIC) in patients with PV (Figure 4A) and PF (Figure 4B) after efgartigimod treatment at baseline, CR, EoT, and EoS. Dotted lines indicate clinical significance (CS). Abbreviations: CIC: circulating immune complexes. [Figure 4B] Figures 4A-B are graphs showing levels of circulating IgG immune complexes (IgG CIC) in patients with PV (Figure 4A) and PF (Figure 4B) after efgartigimod treatment at baseline, CR, EoT, and EoS. Dotted lines indicate clinical significance (CS). Abbreviations: CIC: circulating immune complexes.

[0044] [Figure 5A] FIG. 5A is a series of representative flow cytometry plots showing the frequency of Dsg-3+ switched memory B cells (MBCs) at baseline, CR, and EoT in one patient with PV. [Figure 5B]Figures 5B-5C are graphs showing the frequency of circulating Dsg-3+ switched memory B cells in three PV patients during the study in relation to Dsg-3 autoantibody serum titers (Figure 5B) and by time point (Figure 5C). [Figure 5C] Figures 5B-5C are graphs showing the frequency of circulating Dsg-3+ switched memory B cells in three PV patients during the study in relation to Dsg-3 autoantibody serum titers (Figure 5B) and by time point (Figure 5C). [Figure 5D] Figures 5D-5E are graphs showing the antibody titers of anti-Dsg-3 antibodies (Figure 5D) and the frequency of circulating Dsg-3+ switched memory B cells (Figure 5E) in five PV patients (three with sustained clinical responses as shown in Figures 5B-5C and two with relapse after CR). [Figure 5E] Figures 5D-5E are graphs showing the antibody titers of anti-Dsg-3 antibodies (Figure 5D) and the frequency of circulating Dsg-3+ switched memory B cells (Figure 5E) in five PV patients (three with sustained clinical responses as shown in Figures 5B-5C and two with relapse after CR). [Figure 5F] FIG. 5F is a series of representative ELISPOT assays measuring total IgG-ASCs (antibody-secreting cells) with 2.5×103 to 1×104 PBMCs seeded per well (top) and Dsg-1 IgG ASCs with 1×105 to 4×105 PBMCs seeded per well (bottom) detected in PBMCs from patients with PF at baseline (BL) and end of study (EoS). [Figure 5G] Figures 5G-H are graphs showing the frequency of Dsg-1-specific ASCs in peripheral blood, assessed by ELISPOT assay, in the three PF patients in the study, both in relation to Dsg-1 autoantibody serum titers (Figure 5G) and by time point (Figure 5H). Frequencies are reported as percentages of total IgG ASCs. [Figure 5H]Figures 5G-H are graphs showing the frequency of Dsg-1-specific ASCs in peripheral blood, assessed by ELISPOT assay, in the three PF patients in the study, both in relation to Dsg-1 autoantibody serum titers (Figure 5G) and by time point (Figure 5H). Frequencies are reported as percentages of total IgG ASCs.

[0045] [Figure 6A] 6A-6E are graphs showing the frequency of lymphocyte subsets in patients with pemphigus. FIG. 6A is a graph showing the frequency of leukocytes in PBMCs of patients with pemphigus in the efgartigimod study. The dotted line represents the normal range of 3.9-12.7×109 / L leukocytes. FIG. 6B is a graph showing the frequency of neutrophils, lymphocytes, and monocytes in PBMCs of patients with pemphigus in the efgartigimod study. FIG. 6C is a bar graph showing the frequency of CD4+ T cells and T cell subsets. FIG. 6D is a bar graph showing the frequency of CD19+ B cells and B cell subsets. The arrows and lines indicate how the frequencies of the parent populations were determined. FIG. 6E is a pair of graphs showing the frequency and count of CD19+ B cells at baseline, EoT, and EoS in nine patients from cohort 4 with sustained clinical response. Horizontal bars in each column represent the median. The dotted lines in the left graphs represent the normal range of 5-22% CD19+ B cells. The dotted lines in the right graphs represent the normal range of 80-616 CD19+ B cells / μl. Non-parametric one-way ANOVA with Dunn's post-hoc test was performed. *: p<0.05; **: p<0.01. Abbreviations: IQR, interquartile range. [Figure 6B]6A-6E are graphs showing the frequency of lymphocyte subsets in patients with pemphigus. FIG. 6A is a graph showing the frequency of leukocytes in PBMCs of patients with pemphigus in the efgartigimod study. The dotted line represents the normal range of 3.9-12.7×109 / L leukocytes. FIG. 6B is a graph showing the frequency of neutrophils, lymphocytes, and monocytes in PBMCs of patients with pemphigus in the efgartigimod study. FIG. 6C is a bar graph showing the frequency of CD4+ T cells and T cell subsets. FIG. 6D is a bar graph showing the frequency of CD19+ B cells and B cell subsets. The arrows and lines indicate how the frequencies of the parent populations were determined. FIG. 6E is a pair of graphs showing the frequency and count of CD19+ B cells at baseline, EoT, and EoS in nine patients from cohort 4 with sustained clinical response. Horizontal bars in each column represent the median. The dotted lines in the left graphs represent the normal range of 5-22% CD19+ B cells. The dotted lines in the right graphs represent the normal range of 80-616 CD19+ B cells / μl. Non-parametric one-way ANOVA with Dunn's post-hoc test was performed. *: p<0.05; **: p<0.01. Abbreviations: IQR, interquartile range. [Figure 6C]6A-6E are graphs showing the frequency of lymphocyte subsets in patients with pemphigus. FIG. 6A is a graph showing the frequency of leukocytes in PBMCs of patients with pemphigus in the efgartigimod study. The dotted line represents the normal range of 3.9-12.7×109 / L leukocytes. FIG. 6B is a graph showing the frequency of neutrophils, lymphocytes, and monocytes in PBMCs of patients with pemphigus in the efgartigimod study. FIG. 6C is a bar graph showing the frequency of CD4+ T cells and T cell subsets. FIG. 6D is a bar graph showing the frequency of CD19+ B cells and B cell subsets. The arrows and lines indicate how the frequencies of the parent populations were determined. FIG. 6E is a pair of graphs showing the frequency and count of CD19+ B cells at baseline, EoT, and EoS in nine patients from cohort 4 with sustained clinical response. Horizontal bars in each column represent the median. The dotted lines in the left graphs represent the normal range of 5-22% CD19+ B cells. The dotted lines in the right graphs represent the normal range of 80-616 CD19+ B cells / μl. Non-parametric one-way ANOVA with Dunn's post-hoc test was performed. *: p<0.05; **: p<0.01. Abbreviations: IQR, interquartile range. [Figure 6D]6A-6E are graphs showing the frequency of lymphocyte subsets in patients with pemphigus. FIG. 6A is a graph showing the frequency of leukocytes in PBMCs of patients with pemphigus in the efgartigimod study. The dotted line represents the normal range of 3.9-12.7×109 / L leukocytes. FIG. 6B is a graph showing the frequency of neutrophils, lymphocytes, and monocytes in PBMCs of patients with pemphigus in the efgartigimod study. FIG. 6C is a bar graph showing the frequency of CD4+ T cells and T cell subsets. FIG. 6D is a bar graph showing the frequency of CD19+ B cells and B cell subsets. The arrows and lines indicate how the frequencies of the parent populations were determined. FIG. 6E is a pair of graphs showing the frequency and count of CD19+ B cells at baseline, EoT, and EoS in nine patients from cohort 4 with sustained clinical response. Horizontal bars in each column represent the median. The dotted lines in the left graphs represent the normal range of 5-22% CD19+ B cells. The dotted lines in the right graphs represent the normal range of 80-616 CD19+ B cells / μl. Non-parametric one-way ANOVA with Dunn's post-hoc test was performed. *: p<0.05; **: p<0.01. Abbreviations: IQR, interquartile range. [Figure 6E]6A-6E are graphs showing the frequency of lymphocyte subsets in patients with pemphigus. FIG. 6A is a graph showing the frequency of leukocytes in PBMCs of patients with pemphigus in the efgartigimod study. The dotted line represents the normal range of 3.9-12.7×109 / L leukocytes. FIG. 6B is a graph showing the frequency of neutrophils, lymphocytes, and monocytes in PBMCs of patients with pemphigus in the efgartigimod study. FIG. 6C is a bar graph showing the frequency of CD4+ T cells and T cell subsets. FIG. 6D is a bar graph showing the frequency of CD19+ B cells and B cell subsets. The arrows and lines indicate how the frequencies of the parent populations were determined. FIG. 6E is a pair of graphs showing the frequency and count of CD19+ B cells at baseline, EoT, and EoS in nine patients from cohort 4 with sustained clinical response. Horizontal bars in each column represent the median. The dotted lines in the left graphs represent the normal range of 5-22% CD19+ B cells. The dotted lines in the right graphs represent the normal range of 80-616 CD19+ B cells / μl. Non-parametric one-way ANOVA with Dunn's post-hoc test was performed. *: p<0.05; **: p<0.01. Abbreviations: IQR, interquartile range.

[0046] [Figure 7] Figure 7 is a graph showing the frequency of CD19+ B cells in patients with PV and PF with sustained clinical response, patients who relapse after CR, and patients with no clinical response on study. The dotted line on the graph represents the normal range of 5-22% CD19+ B cells.

[0047] [Figure 8A] Figures 8A and 8B are graphs showing summary profiles of PV (Figure 8A) and PF (Figure 8B) patients achieving sustained clinical responses, showing prednisone dose, PDAI activity score, and frequency of total CD19+ B cells in peripheral blood, where available. Grey shaded zones indicate efgartigimod-free follow-up period. [Figure 8B]Figures 8A and 8B are graphs showing summary profiles of PV (Figure 8A) and PF (Figure 8B) patients achieving sustained clinical responses, showing prednisone dose, PDAI activity score, and frequency of total CD19+ B cells in peripheral blood, where available. Grey shaded zones indicate efgartigimod-free follow-up period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The present disclosure shows that treatment with FcRn antagonists causes a decrease in the frequency of B cells in patients who respond to the FcRn antagonists. Furthermore, patients who do not respond to treatment with FcRn antagonists do not have a decrease in the frequency of B cells. Thus, provided herein is a method for monitoring the remission of an autoantibody-mediated disease in a subject after treatment with an FcRn antagonist and monitoring the efficacy of treatment based on the frequency of B cells in the subject. Also provided herein is a method of using an FcRn antagonist to treat an autoantibody-mediated disease in a subject who has an increased frequency of B cells and has relapsed after a previous treatment with a first FcRn antagonist.

[0049] In one aspect, provided herein is a method for monitoring the effectiveness of a treatment in a subject following treatment with a first FcRn antagonist, the subject having an autoantibody-mediated disease, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value related to the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the treatment is not effective, or if the frequency of B cells is less than the reference value, the treatment is effective.

[0050] In one aspect, provided herein is a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, the method comprising: a) administering to the subject a therapeutically effective amount of a second FcRn antagonist; b) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and c) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, or if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0051] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, wherein a) a therapeutically effective amount of the second FcRn antagonist is administered to the subject, b) the frequency of B cells in a blood sample taken from the subject is measured in vitro, and c) the frequency of B cells is compared to a reference value associated with the autoantibody-mediated disease in the subject, and if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, or if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0052] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, the method comprising: (a) administering to the subject one or more initial doses of a therapeutically effective amount of a first FcRn antagonist; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with autoantibody-mediated disease in the subject, administering to the subject one or more further doses of a therapeutically effective amount of a second FcRn antagonist, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with active disease in the subject, discontinuing treatment with the first FcRn antagonist.

[0053] In one aspect, provided herein is an FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein: (a) one or more initial doses of a therapeutically effective amount of a first FcRn antagonist are administered to the subject; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject, one or more further doses of a therapeutically effective amount of a second FcRn antagonist are administered to the subject, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with the autoantibody-mediated disease in the subject, the first FcRn antagonist is discontinued.

[0054] In one aspect, provided herein is a method for determining whether a subject who has been previously treated for an autoantibody-mediated disease using a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, then the subject requires further treatment with the second FcRn antagonist.

[0055] Also provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the autoantibody-mediated disease recurs in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject.

[0056] Also provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the therapeutically effective amount of the FcRn antagonist is determined based on the frequency of B cells in a blood sample taken from the subject.

[0057] Further provided herein is a method for monitoring remission of an autoantibody-mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein the subject is in remission from the autoantibody-mediated disease if the frequency of B cells in the sample is equal to or less than the reference value.

[0058] definition As used herein, the term "FcRn" refers to neonatal Fc receptor. Exemplary FcRn molecules include human FcRn, which is encoded by the FCGRT gene described in RefSeq NM 004107. The amino acid sequence of the corresponding protein is described in RefSeq NP_004098.

[0059] As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of an immunoglobulin to FcRn (e.g., human FcRn). In one embodiment, the FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn via the Fc region and inhibits the binding of an immunoglobulin to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen-binding site that binds to a target antigen and a variant Fc region. In one embodiment, the FcRn antagonist is an Fc fragment that comprises or consists of an Fc region and lacks an antigen-binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to FcRn.

[0060] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain beginning with the hinge region and ending at the C-terminus of the antibody. Thus, a complete Fc domain includes at least a portion of the hinge (e.g., upper, middle, and / or lower hinge regions), CH2 domain, and CH3 domain.

[0061] As used herein, the term "Fc region" refers to the portion of a native immunoglobulin that is formed by the Fc domains of its two heavy chains. A native Fc region is a homodimer.

[0062] As used herein, the term "variant Fc region" refers to an Fc region having one or more alterations (multiple alterations) compared to a native Fc region. Alterations may include amino acid substitutions, additions, and / or deletions, attachment of additional moieties, and / or alterations of native glycans. The term encompasses heterodimeric Fc regions, in which each of the constituent Fc domains is different. The term also encompasses single chain Fc regions, in which the constituent Fc domains are linked together by linker moieties.

[0063] As used herein, the term "FcRn-binding fragment" refers to a portion of an Fc region sufficient to confer FcRn binding.

[0064] As used herein, the term "EU position" refers to an amino acid position in the EU numbering system for the Fc region as set forth in: Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al, in "Sequences of Proteins of Immunological Interest", US Dept. Health and Human Services, 5th edition, 1991.

[0065] As used herein, the term "baseline" refers to a measurement in a patient (e.g., B cell frequency, IgG level) before the first administration (e.g., intravenous or subcutaneous administration) of a therapy (e.g., an FcRn antagonist).

[0066] As used herein, the term "autoantibody-mediated disease" refers to any disease or disorder in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0067] As used herein, the term "B cell frequency" refers to the proportion of B cells in a patient's total peripheral blood mononuclear cell (PBMC) population.

[0068] As used herein, the terms "treat", "treating" and "treatment" refer to therapeutic or prophylactic measures as described herein. A "treatment" method utilizes administration of a polypeptide to a subject having or predisposed to a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of a disease or disorder or a recurrent disease or disorder, or to extend the subject's survival beyond that expected in the absence of such treatment.

[0069] As used herein, the term "therapeutically effective amount" in the context of administration of a therapy to a subject refers to the amount of the therapy that achieves a desired prophylactic or therapeutic effect.

[0070] As used herein, the term "remission" refers to a patient who has no new markers of autoantibody-mediated disease and has completely disappeared or healed from baseline markers of disease. In one embodiment, a pemphigus patient in clinical remission has no new lesions and all established lesions are completely healed.

[0071] As used herein, the term "relapse" or "flare-up" refers to a patient with an autoantibody-mediated disease who has a period of remission from the autoantibody-mediated disease followed by the appearance of physical symptoms and / or an increase in markers of the autoantibody-mediated disease. In one embodiment, recurrent pemphigus refers to the appearance of at least three new pemphigus lesions in a four week period that do not heal within one week or the expansion of established lesions.

[0072] As used herein, the term "subject" includes any human or non-human animal. In one embodiment, the subject is a human or non-human mammal. In one embodiment, the subject is a human.

[0073] As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as appropriate for practicing the methods disclosed herein.

[0074] FcRn antagonists FcRn antagonists useful in the methods and uses provided herein include, but are not limited to, any anti-FcRn antibody, or any variant Fc region.

[0075] Any Fc region can be modified to generate a variant Fc region for use in the methods disclosed herein. Generally, the Fc region, or an FcRn-binding fragment thereof, is derived from a human immunoglobulin. However, it is understood that the Fc region can be derived from the immunoglobulin of any other mammalian species, including, for example, camelid species, rodents (e.g., mouse, rat, rabbit, guinea pig), or non-human primate (e.g., chimpanzee, macaque) species. Furthermore, the Fc region or a portion thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3, and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region that includes portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in U.S. Patent Application Publication No. 2011 / 0243966A1, which is incorporated by reference in its entirety. A variety of Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly accessible deposits.

[0076] The Fc region may be further truncated or internally deleted to generate its smallest FcRn-binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any art-recognized binding assay, such as, for example, ELISA.

[0077] To enhance the manufacturability of the FcRn antagonists disclosed herein, the Fc region preferably does not contain any non-disulfide bonded cysteine ​​residues. Thus, in one embodiment, the Fc region does not contain any free cysteine ​​residues.

[0078] Any Fc variant or FcRn-binding fragment thereof that specifically binds to FcRn with increased affinity and decreased pH-dependence compared to a native Fc region can be used in the methods disclosed herein. In one embodiment, the variant Fc region contains amino acid alterations, substitutions, insertions, and / or deletions that confer the desired characteristics. In one embodiment, the biologic comprises or consists of a variant Fc region or FcRn-binding fragment thereof that binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region.

[0079] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, consists of two Fc domains. In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0080] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0081] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:1.

[0082] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:2.

[0083] In one embodiment, the isolated FcRn antagonist consists of a variant Fc region, the variant Fc region consisting of two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of SEQ ID NO:3.

[0084] In one embodiment, the biologic is efgartigimod (CAS Registry Number 1821402-21-4). Table 1. Amino acid sequences of variant Fc regions [Table 1]

[0085] In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0086] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nipocalimab, also known as M281. Nipocalimab is a full-length "Fc-dead" IgG1 monoclonal antibody. Nipocalimab has been administered as an intravenous infusion in Phase 2 clinical trials for the treatment of myasthenia gravis (MG), warm autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nipocalimab comprises the following light chain (SEQ ID NO: 4) and heavy chain (SEQ ID NO: 5) sequences as set forth in Table 2: Table 2. Nipocalimab heavy and light chain sequences [Table 2]

[0087] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolixizumab, also known as UCB 7665. Rozanolixizumab is a full-length humanized IgG4 monoclonal antibody. It is administered as a subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (FTP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Rozanolixizumab comprises the light chain (SEQ ID NO: 6) and heavy chain (SEQ ID NO: 7) sequences set forth in Table 3 below. Table 3. Heavy and light chain sequences of rozanolixizumab [Table 3]

[0088] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is orilanolimab, also known as SYNT001. Orilanolimab is another full-length humanized IgG4 monoclonal antibody. Orilanolimab has been administered as an intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA. Orilanolimab comprises the light chain (SEQ ID NO: 8) and heavy chain (SEQ ID NO: 9) sequences set forth in Table 4 below. Table 4. Heavy and light chain sequences of orilanolimab [Table 4]

[0089] In one embodiment, the antibody that specifically binds to FcRn and inhibits binding of the Fc region of an immunoglobulin to FcRn is batoclimab, also known as IMVT1401 / RVT1401 / HBM9161. Batoclimab is another full-length "Fc-dead" IgG1 monoclonal antibody. Batoclimab is administered as a subcutaneous injection in ongoing Phase 2 clinical trials for the treatment of MG and Graves' ophthalmopathy. Batoclimab comprises the light chain (SEQ ID NO: 10) and heavy chain (SEQ ID NO: 11) sequences set forth in Table 5 below. Table 5. Batoclimab heavy and light chain sequences [Table 5]

[0090] How to use In one aspect, provided herein is a method for monitoring the effectiveness of a treatment of an autoantibody-mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value related to the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the treatment is not effective, and if the frequency of B cells is less than the reference value, the treatment is effective.

[0091] In one aspect, provided herein is a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, the method comprising: a) administering to the subject a therapeutically effective amount of a second FcRn antagonist; b) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and c) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, or if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0092] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid dosing regimen, wherein a) a therapeutically effective amount of the second FcRn antagonist is administered to the subject, b) the frequency of B cells in a blood sample taken from the subject is measured in vitro, and c) the frequency of B cells is compared to a reference value associated with the autoantibody-mediated disease in the subject, and if the frequency of B cells in the sample is equal to or greater than the reference value, the corticosteroid dosing regimen is maintained, or if the frequency of B cells is less than the reference value, the corticosteroid dosing regimen is tapered.

[0093] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, the method comprising: (a) administering to the subject one or more initial doses of a therapeutically effective amount of a first FcRn antagonist; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with autoantibody-mediated disease in the subject, administering to the subject one or more further doses of a therapeutically effective amount of a second FcRn antagonist, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with active disease in the subject, discontinuing treatment with the first FcRn antagonist.

[0094] In one aspect, provided herein is an FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein: (a) one or more initial doses of a therapeutically effective amount of a first FcRn antagonist are administered to the subject; and (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject, one or more further doses of a therapeutically effective amount of a second FcRn antagonist are administered to the subject, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with the autoantibody-mediated disease in the subject, the first FcRn antagonist is discontinued.

[0095] In one embodiment, the therapeutically effective amount of the first FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg.

[0096] In one embodiment, the therapeutically effective amount of the first FcRn antagonist is administered subcutaneously at a dose of about 750 mg to about 3000 mg.

[0097] In one aspect, provided herein is a method for determining whether a subject who has been previously treated for an autoantibody-mediated disease using a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, then the subject requires further treatment with the second FcRn antagonist.

[0098] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the autoantibody-mediated disease recurs in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject.

[0099] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, where the autoantibody-mediated disease has recurred in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject.

[0100] In one aspect, provided herein is a method for treating an autoantibody-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist, wherein the therapeutically effective amount of the FcRn antagonist is determined based on the frequency of B cells in a blood sample taken from the subject.

[0101] In one aspect, provided herein is a second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein the autoantibody-mediated disease recurs in the subject after prior therapy with a first FcRn antagonist, the method comprising administering a therapeutically effective amount of the second FcRn antagonist to the subject, the therapeutically effective amount being determined based on the frequency of B cells in a blood sample taken from the subject.

[0102] In one aspect, provided herein is a method for monitoring the effectiveness of a treatment in a subject following treatment with a first FcRn antagonist, the subject having an autoantibody-mediated disease, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value related to the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is equal to or greater than the reference value, the treatment is not effective, or if the frequency of B cells is less than the reference value, the treatment is effective.

[0103] In one aspect, provided herein is a method for monitoring remission of an autoantibody-mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro a frequency of B cells in a blood sample taken from the subject; and b) comparing the frequency of B cells to a reference value associated with the autoantibody-mediated disease in the subject, wherein if the frequency of B cells in the sample is at or below the reference value, the subject is in remission from the autoantibody-mediated disease.

[0104] In one embodiment, the corticosteroid dosing regimen is tapered to a lower dose or less frequent dosing. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a second FcRn antagonist if the frequency of B cells in the sample is equal to or greater than the reference value. In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of a second FcRn antagonist if the frequency of B cells in the sample is equal to or greater than the reference value.

[0105] In one embodiment, the reference value is about 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4 times higher than the normal frequency of B cells. , 4.1x, 4.2x, 4.3x, 4.4x, 4.5x, 4.6x, 4.7x, 4.8x, 4.9x, 5x, 5.1x, 5.2x, 5.3x, 5.4x, 5.5x, 5.6x, 5.7x, 5.8x, 5.9x, 6x, 6.1x, 6.2x, 6.3x, 6.4x, 6.5x, 6.6x, 6.7x, 6.8x, 6.9x, or 7x higher.

[0106] In one embodiment, the normal frequency of B cells is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of lymphocytes. In one embodiment, the reference value is about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% of lymphocytes.

[0107] In one embodiment, the reference value is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109 ...9%, 109%, 102%, 103%, 104%, 105%, 106%, 107%, 1 %, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. In one embodiment, the reference value is greater than about 60% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for the autoantibody mediated disease.

[0108] In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for an autoantibody mediated disease. , 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. In one embodiment, the reference value is greater than 60% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for the autoantibody mediated disease.

[0109] In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for an autoantibody mediated disease. , 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%. In one embodiment, the reference value is greater than 65% of the maximum frequency of B cells measured in the subject prior to receiving any treatment for the autoantibody mediated disease.

[0110] In one embodiment, the reference value is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109, 109, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 109, 109, 109, 109, 109, 109, 1 2%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% higher.

[0111] In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 109%, 110%, 110%, 120%, 121%, 12 %, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% higher. In one embodiment, the reference value is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 102%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 109%, 110%, 110%, 120%, 121%, 12 %, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% higher.

[0112] In one embodiment, the reference value is about 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.8-fold, 3.9-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.8-fold, 3.9-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.7-fold, 3.8-fold, 3.9-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.7-fold, 3.8-fold, 3.9-fold, 3.1-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5 ...1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.1-fold, 3 3.6x, 3.7x, 3.8x, 3.9x, 4x, 4.1x, 4.2x, 4.3x, 4.4x, 4.5x, 4.6x, 4.7x, 4.8x, 4.9x, 5x, 5.1x, 5.2x, 5.3x, 5.4x, 5.5x, 5.6x, 5.7x, 5.8x, 5.9x, 6x, 6.1x, 6.2x, 6.3x, 6.4x, 6.5x, 6.6x, 6.7x, 6.8x, 6.9x, or 7x higher.

[0113] In one embodiment, the reference value is 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.8-fold, 3.9-fold, 3.10-fold, 3.12-fold, 3.14-fold, 3.16-fold, 3.18-fold, 3.18-fold, 3.19-fold, 3.21-fold, 3.22-fold, 3.23-fold, 3.24-fold, 3.25-fold, 3.26-fold, 3.27-fold, 3.28-fold, 3.29-fold, 3.30-fold, 3.31-fold, 3.32-fold, 3.33-fold, 3.34-fold, 3.35-fold, 3.36-fold, 3.37-fold, 3.38-fold, 3.39-fold, 3.40-fold, 3.41-fold, 3.42-fold, 3.43-fold, 3.44-fold, 3.45-fold, 3.46-fold, 3.47-fold, 3.48-fold, 3.49-fold, 3.50-fold, 3.51-fold, 3.52-fold, 3.53-fold, 3.54-fold, 3.55-fold, 3. .6x, 3.7x, 3.8x, 3.9x, 4x, 4.1x, 4.2x, 4.3x, 4.4x, 4.5x, 4.6x, 4.7x, 4.8x, 4.9x, 5x, 5.1x, 5.2x, 5.3x, 5.4x, 5.5x, 5.6x, 5.7x, 5.8x, 5.9x, 6x, 6.1x, 6.2x, 6.3x, 6.4x, 6.5x, 6.6x, 6.7x, 6.8x, 6.9x, or 7x higher.

[0114] In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 10 mg / kg to about 30 mg / kg administered intravenously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 10 mg / kg administered intravenously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 15 mg / kg administered intravenously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 20 mg / kg administered intravenously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 25 mg / kg administered intravenously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 30 mg / kg administered intravenously.

[0115] In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 10 mg / kg to about 30 mg / kg administered intravenously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 10 mg / kg administered intravenously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 15 mg / kg administered intravenously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 20 mg / kg administered intravenously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 25 mg / kg administered intravenously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 30 mg / kg administered intravenously once per week.

[0116] In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 10 mg / kg to about 30 mg / kg administered intravenously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 10 mg / kg administered intravenously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 15 mg / kg administered intravenously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 20 mg / kg administered intravenously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 25 mg / kg administered intravenously once every two weeks. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 30 mg / kg administered intravenously once every two weeks.

[0117] In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 750 mg to about 3000 mg administered subcutaneously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 750 mg administered subcutaneously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 1000 mg administered subcutaneously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 1250 mg administered subcutaneously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 1500 mg administered subcutaneously. In one embodiment, the subject has been previously treated with a first FcRn antagonist at a dose of about 1750 mg administered subcutaneously.

[0118] In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 750 mg to about 3000 mg administered subcutaneously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 750 mg administered subcutaneously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1000 mg administered subcutaneously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1250 mg administered subcutaneously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1500 mg administered subcutaneously once per week. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1750 mg administered subcutaneously once per week.

[0119] In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 750 mg to about 3000 mg administered subcutaneously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 750 mg administered subcutaneously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1000 mg administered subcutaneously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1250 mg administered subcutaneously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1500 mg administered subcutaneously once every two weeks. In one embodiment, the subject was previously treated with a first FcRn antagonist at a dose of about 1750 mg administered subcutaneously once every two weeks.

[0120] In one embodiment, the subject has also been previously treated with a corticosteroid, or an immunosuppressant, hi one embodiment, the subject has been previously treated with prednisone.

[0121] In one embodiment, the subject was previously treated with prednisone at a dose of <5 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <3 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <2 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <1 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <0.5 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <0.4 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <0.3 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <0.2 mg / kg / day. In one embodiment, the subject was previously treated with prednisone at a dose of <0.1 mg / kg / day.

[0122] In one embodiment, the effective amount of the second FcRn antagonist is a higher dose than the previous treatment with the first FcRn antagonist, hi one embodiment, the effective amount of the second FcRn antagonist is a lower dose than the previous treatment with the first FcRn antagonist.

[0123] In one embodiment, an effective amount of the second FcRn antagonist is administered more frequently compared to a previous treatment with the first FcRn antagonist, hi one embodiment, an effective amount of the second FcRn antagonist is administered less frequently compared to a previous treatment with the first FcRn antagonist.

[0124] In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of about 10 mg / kg to about 30 mg / kg. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of 10 mg / kg. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a dose of 15 mg / kg. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of 20 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of 25 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of 30 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks.

[0125] In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of about 10 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of about 15 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of about 20 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered intravenously at a dose of about 25 mg / kg once per week, once per two weeks, once per three weeks, once per four weeks, or once per six weeks. In one embodiment, the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 30 mg / kg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0126] In one embodiment, an effective amount of the second FcRn antagonist is subcutaneously administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a fixed dose of about 750 mg to about 3000 mg. In one embodiment, an effective amount of the second FcRn antagonist is subcutaneously administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a fixed dose of 1000 mg or 2000 mg. In one embodiment, an effective amount of the second FcRn antagonist is subcutaneously administered once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks at a fixed dose of about 750 mg. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1250 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1500 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of about 1750 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0127] In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1250 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of the second FcRn antagonist is administered subcutaneously at a fixed dose of 1500 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks. In one embodiment, an effective amount of a second FcRn antagonist is administered subcutaneously at a fixed dose of 1750 mg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

[0128] In one embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid, or an immunosuppressant. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.5 mg / kg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.25 mg / kg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 20 mg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 10 mg per day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 5 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 3 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 2 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 1 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.5 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.4 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.3 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.2 mg / kg / day. In one embodiment, the effective amount of corticosteroid is administered at a dose of about 0.1 mg / kg / day.

[0129] In one embodiment, the corticosteroid dosing regimen in the subject is tapered based on the amount of B cells in the subject with an autoantibody-mediated disease. In one embodiment, tapering the corticosteroid regimen is lowering the dose of the corticosteroid or reducing the frequency of administration. In one embodiment, the corticosteroid tapering dose is <2 mg prednisone / kg / day, or its equivalent. In one embodiment, the corticosteroid tapering dose is about 1.5, about 1.0, about 0.75, about 0.5, or about 0.2 mg prednisone / kg / day or its equivalent. In one embodiment, the corticosteroid tapering dose is <0.5 mg prednisone / kg / day, or its equivalent.

[0130] In one embodiment, the frequency of B cells is measured by flow cytometry. In one embodiment, the B cells are CD19+ B cells.

[0131] In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist. In one embodiment, the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists.

[0132] In one embodiment, the FcRn antagonist is an anti-FcRn antibody. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody. In one embodiment, the second FcRn antagonist is an anti-FcRn antibody.

[0133] In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0134] In one embodiment, the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0135] In one embodiment, the FcRn antagonist is efgartigimod. In one embodiment, the first FcRn antagonist or the second FcRn antagonist is efgartigimod.

[0136] In one embodiment, the FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3. In one embodiment, the first FcRn antagonist or the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3.

[0137] In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is efgartigimod. In one embodiment, the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3. In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161). In one embodiment, the patient has not been previously treated with efgartigimod.

[0138] In one embodiment, the first FcRn antagonist is selected from the group consisting of rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161), and the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the first FcRn antagonist is selected from the group consisting of rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161), and the second FcRn antagonist is efgartigimod.

[0139] In one embodiment, the subject has a serum level of a pathogenic IgG autoantibody associated with recurrence of an autoantibody-mediated disease. In one embodiment, the pathogenic IgG autoantibody is an anti-Dsg-3 antibody or an anti-Dsg-1 antibody. In one embodiment, the level of the pathogenic IgG autoantibody is measured by ELISA. In one embodiment, the serum level of the pathogenic IgG autoantibody is compared to a baseline level in the subject.

[0140] In one embodiment, the autoantibody mediated disease is selected from the group consisting of allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome (APS), autoimmune Addison's disease, Alzheimer's disease, antibody-mediated allograft rejection (AMR), antineutrophil cytoplasmic antibodies (ANCA), ANCA vasculitis, autoimmune diseases of the adrenal gland, autoimmune encephalitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura or idiopathic thrombocytopenic purpura). purpura) or immune-mediated thrombocytopenia), urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman syndrome, celiac-spruce dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, COVID-19-mediated postural orthostatic tachycardia syndrome (POTS), Crohn's disease, delayed graft function after kidney transplantation, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome (GBS), Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, hemolytic disease of the fetus and newborn(HDFN), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, lupus nephritis, membranous neuropathy, membranous nephropathy, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myelin and oligodendrocyte glycolysis Protein-Antibody-Associated Disorders (MOGAD), Myasthenia Gravis (MG), Generalized Myasthenia Severe (gMG), Ophthalmic Myasthenia Gravis (OMG), Myositis, Neuromyelitis Optica (NMO), Paraneoplastic Bullous Pemphigoid, Pemphigoid of Gestation, Pemphigus Vulgaris (PV), Pemphigus Foliaceus (PF), Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndrome, Polymyalgia Rheumatica, Polymyositis, Dermatomyositis (DMD), DM), necrotizing autoimmune myopathy (NAM), antisynthetase syndrome (ASyS), primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis (RA), sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-body syndrome, systemic lupus erythematosus (SLE), Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), thyroid eye disease, ulcerative colitis, uveitis, warm autoimmune hemolytic anemia (wAIHA), dermatitis herpetiformis type vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0141] In one embodiment, the autoantibody mediated disease is pemphigus vulgaris (PV). In one embodiment, the autoantibody mediated disease is pemphigus foliaceus (PF).

[0142] In one embodiment, the subject has one or more physical symptoms of an autoantibody-mediated disease after treatment with a first FcRn antagonist. In one embodiment, the one or more physical symptoms include, but are not limited to, eye muscle fatigue or weakness, skeletal muscle fatigue or weakness, respiratory muscle fatigue or weakness, impaired fatigue, slurred speech, choking, difficulty swallowing, double or blurred vision, immobility requiring assistance, shortness of breath, respiratory failure, and blisters, including blisters on the skin and mouth.

[0143] Working Example The following examples are offered by way of illustration and not by way of limitation.

[0144] Example 1: Analysis of clinical, serological and immunological parameters in a model IgG-mediated organ-specific autoimmune disease, pemphigus, after treatment with efgartigimod To investigate changes in systemic immune signatures during extended anti-FcRn treatment, autoreactive and protective anti-infectious antibody titers, as well as B- and T-cell phenotypes, were assessed in peripheral blood of pemphigus patients treated with efgartigimod for up to 34 weeks.

[0145] A. Method Study design and interventions Extended treatment with efgartigimod was gradually introduced in patients with mild to moderate pemphigus vulgaris (PV) or pemphigus foliaceus (PF) in an open-label, uncontrolled phase 2 study (NCT03334058). In cohort 3, seven patients (seven PV) were treated for 15 weeks, and in cohort 4, 15 patients (eight PV, seven PF) were treated for up to 34 weeks. Diagnosis of PV or PF was confirmed by positive direct immunofluorescence and positive indirect immunofluorescence and / or desmoglein (Dsg)-1 / 3 ELISA. Patients were either newly diagnosed or recurrent with mild to moderate disease severity (Pemphigus Lesion Area Index (PDAI) <45 at baseline). The treatment period was preceded by a screening period of up to 3 weeks, followed by a 10-week treatment-free follow-up period. In cohort 3, intravenous (IV) efgartigimod was administered at 10 mg / kg weekly for 4 weeks as a lead-in period, followed by IV administration every other week for 12 weeks as a maintenance period. In cohort 3, efgartigimod was initiated as monotherapy or in combination with 20 mg / day prednisone at the investigator's discretion, with prednisone tapered from the maintenance period. In cohort 4, IV efgartigimod was administered at 25 mg / kg weekly until end of consolidation (EoC, defined as the time when no new lesions had developed for at least 2 weeks and the majority, i.e., approximately 80%, of the established lesions have healed), after which patients received efgartigimod at 25 mg / kg every other week.

[0146] In cohort 4, efgartigimod was initiated in all newly diagnosed patients and in patients with relapses during treatment withdrawal, either with concomitant prednisone (20 mg / day) or at tapered doses where relapses occurred. Oral prednisone doses were allowed to be tapered at EoC. No other systemic treatments for pemphigus were allowed during the study, whereas topical corticosteroids, analgesics, and supportive care for corticosteroid therapy (e.g., vitamin D, proton pump inhibitors, specific diet) were allowed.

[0147] ethics The study followed the Guidelines for Conduct of Pharmaceutical Clinical Trials, adhered to the ethical principles of the Declaration of Helsinki, and complied with all relevant national laws. The study protocol and all other appropriate study-related information were reviewed and approved by the ethical committee or institutional review board of each center.

[0148] Immunoglobulin Assay Pharmacological analyses included serum levels of total IgG, IgG subclasses, and anti-Dsg-1 and anti-Dsg-3 autoantibodies by ELISA (Euroimmun, Germany). Serum levels of protective vaccine antibodies against tetanus toxoid (TT, indirect EIA, Virotech), vesicular zoster virus (VZV, CLIA, Diasorin), and pneumococcal capsular polysaccharide (PCP, EIA, The Binding Site Group) were measured for all patients. Customized addressable laser bead immunoassay (ALBIA) tests were performed to determine anti-Dsg-3 IgG subclasses at different time points. Briefly, 20 μg of anti-HIS antibody (clone HIS.H8) was diluted with 1.25 × 10 IgG using a Bio-PlexR amine coupling kit (Bio-Rad) according to the manufacturer's protocol. 6 1000 beads were coupled to fluorescent Bio-Plex R COOH-microspheres (Bio-Rad, USA). After coupling, the coated beads were used immediately or stored in the dark at -20°C. Before use, 100 ng of recombinant Dsg-3 expressing a 6xHis Tag was incubated with 1000 beads for 15 min at room temperature (RT) and then washed. Immediately before use, the coated beads were vortexed vigorously for 30 s. Then, 10 μL of beads (containing 1000 beads) were added to CaCl2-containing 1000 beads supplemented with 1% FCS. 2+ and Mg 2+100 μL of patient or control serum diluted 1 / 100 was added in Bio-Plex Pro Flat bottom plates (Bio-Rad) in PBS containing 0.1% Tween-20. Plates were incubated for 90 min at room temperature in the dark on a plate shaker at 850 rpm. Blanks (no serum), negative controls (healthy donor serum), and positive controls (human anti-Dsg-3 positive serum) were included in every assay. Beads were collected with a magnetic washer (Bio-Rad) and washed 3 times with 150 μL PBS 1× containing 0.1% Tween-20. Biotinylated mouse anti-human IgG subclass specific secondary antibodies (Southern Biotech, USA) were added for 45 min at room temperature under shaking conditions (1 / 125 dilution for anti-IgG1 and anti-IgG2, 1 / 200 dilution for anti-IgG3 and anti-IgG4). After washing, the beads were incubated with 50 μL of streptavidin-R-phycoerythrin at a dilution of 1 / 400 for 15 min. Finally, the beads were resuspended in 100 μL of PBS and the mean fluorescence intensity (MFI) was determined on a Bio-PlexR instrument using Bio-PlexR Manager Software 4.0 (Bio-Rad). For the determination of Dsg-3-reactive antibodies, the positive threshold was set at the mean value obtained from 36 healthy donors plus two standard deviations. Anti-Dsg-1 IgG subclasses were identified using an anti-Dsg-1 ELISA (Euroimmun, Germany) with a modified detection system. Specifically, in the ELISA, the rabbit anti-human IgG HRP detection antibody was replaced with anti-human IgG1 HRP or anti-human IgG4 HRP (Southern Biotech, USA) to detect Dsg-1 specific IgG subclasses and was used at a dilution of 1 / 10,000. A CIC-C1q EIA kit (A001, Quidel) was used to detect the levels of C1q-associated IgG aggregates (circulating immune complexes (CICs)) in the serum of selected patients at different time points according to the manufacturer's protocol.

[0149] Isolation of peripheral blood mononuclear cells (PBMCs) A total of 60-80 mL of whole blood was collected into 10 BD Vacutainer CPT tubes, immediately mixed, and centrifuged at room temperature (RT) within 2 hours of blood collection to separate PBMCs and red blood cells. After centrifugation, PBMCs were resuspended in plasma and transported within 24 hours to the analytical laboratory at Philipps University Marburg. Upon receipt of the samples, the tubes were subjected to PBMC purification and flow cytometry analysis. The remaining cells were cryopreserved for later analysis.

[0150] Phenotypic profiling by multiparameter flow cytometry and detection of Dsg3-specific B cells PBMCs were washed twice with PBS + 1% FCS and then diluted to 1 × 10 6 Cells were stained for T cells and B cell analysis including detection of Dsg3-specific B cells. The following antibodies were used for the T cell panel analysis: mouse anti-human CD4 (RPA-T4, Biolegend), mouse anti-human CD45RA (HI100, Biolegend), mouse anti-human CXCR5 (J252D4, Biolegend), mouse anti-human CD25 (M-A251, Biolegend), mouse anti-human CD127 (A019D5, Biolegend), mouse anti-human CXCR3 (G025H7, Biolegend), and mouse anti-human CCR6 (G034E3, Biolegend). The following antibodies were used for B cell panel analysis: mouse anti-human CD45 (2D1, Biolegend), mouse anti-human CD19 (HIB19, Biolegend), mouse anti-human CD27 (M-T271, Biolegend), mouse anti-human CD38 (HB-7, Biolegend), mouse anti-human CD24 (ML5, Biolegend), mouse anti-human IgM (MHM-88, Biolegend), mouse anti-human IgD (IA6-2, Biolegend), and mouse anti-human CD138 (MI15, Biolegend). AlexaFluor 647-labeled recombinant human Dsg3 (extracellular domain, aa 1-566), produced in a baculovirus expression system, was included in a separate B cell staining panel. The gating strategy is shown in Figure 1 for one representative patient.

[0151] Dsg-specific B cell detection using ELISPOT assay The frequency of circulating total IgG and Dsg-specific IgG antibody-secreting cells (ASCs) was determined by human IgG ELISPOT basic assay (Mabtech, Nacka Strand, Sweden). PBMCs from pemphigus patients from the clinical trial described above were pre-stimulated with R848 (1 μg / mL) and rhIL2 (10 ng / mL) in complete medium (RPMI-1640 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin) in 96-well plates for 72 h at 37°C. ELISPOT MAIPS-4510 (Merck Millipore, Darmstadt, Germany) plates were coated with anti-IgG human Abs overnight at 4°C. Plates were washed and blocked with complete medium before use. Pre-stimulated PBMCs were washed, resuspended in complete medium, transferred to plates, and then 1 × 10 per well were incubated at 37°C for 72 h. 5 ~4×10 5 Anti-Dsg-1 and anti-Dsg-3 IgG-secreting ASCs were detected by incubation with 2.5 × 10 PBMCs for 24 h, and 2.5 × 10 3 ~1×10 4Total IgG-ASCs were detected by incubation with 100 PBMCs. IgG-ASCs were detected by the addition of biotinylated mouse IgG anti-human IgG. The frequency of anti-Dsg-1 or anti-Dsg-3 IgG-secreting ASCs was calculated after 2 h of incubation with histidine-tagged recombinant Dsg-1 or Dsg-3 protein (1 μg / mL) in calcium-containing phosphate-buffered saline (Eurobio, Les Ulis, France). Biotinylated anti-histidine antibodies (0.5 μg / mL) (Abcam, Cambridge, UK) were then added. Spots were detected using streptavidin-conjugated peroxidase and the substrate tetramethylbenzidine. The number of spots was determined using ELISPOT Plate Readers and ImmunoSpot software (CTL Europe GmbH, Bonn, Germany). Results were expressed as the frequency of Dsg-specific IgG-ASCs in total IgG-ASCs. The sensitivity and specificity of the ELISPOT assay were estimated at 1 Dsg-3-specific ASC / 105 total ASC and 100%, respectively.

[0152] statistical analysis Data were analyzed using descriptive statistics and summaries (mean, standard error, median, range) were plotted graphically by study date / time point.

[0153] B. Results Sustained clinical response and autoantibody suppression Clinical outcomes and characteristics of patients with PV and PF from cohorts 3 and 4 who received long-term treatment with efgartigimod (15 weeks and up to 34 weeks, respectively) are shown in Table 6, and clinical outcomes are shown in Figure 2A (symbols used throughout the figures for selected patients are shown in Figure 2B). Nine patients from cohort 4 (patients 1, 3, 4, 5, 7, 8, 9, 11, and 12) achieved a CR at any time during the study, whereas six patients (patients 1, 4, 5, 7, 8, and 9) who received efgartigimod (up to day 239) and low-dose prednisone were in CR at the end of the study (end of the 10-week efgartigimod-free treatment period). Four patients achieved complete clinical remission with minimal therapy (CRmin), defined as the absence of new or established lesions while the patient was on minimal therapy, where minimal therapy was defined as administration of 10 mg / day or less of prednisone (or equivalent) for at least 2 months at any time during the study. Patient 3 showed low disease activity with a PDAI activity score of 3 after CR, and two patients (11 and 12) relapsed to a PDAI activity score >10. Three patients (patients 2, 6, and 10) improved clinically and maintained a clinically improved state until the end of the study: patients 2 and 10 reached and maintained EoC, and patient 6 reached DC and had a PDAI activity score of 1 at the end of the study. In cohort 3, 5 of 7 patients achieved a CR at any time during the study (patients 16, 19, 20, 21, and 22), and 4 of these patients were in CR at the end of treatment-free follow-up (patients 16, 20, 21, and 22). Table 6. Baseline characteristics of patients receiving long-term efgartigimod treatment in cohorts 3 and 4 [Table 6]

[0154] Figures 2C and 2D show a representative PV patient and a representative PF patient, respectively, from cohort 4, both of which responded to efgartigimod treatment. Their clinical response is demonstrated by the obvious improvement of physical symptoms, as well as their clinical and serological profiles (Figures 2C and 2D). The PV patient (patient 8) had a PDAI activity score of 10.3 at baseline, which showed a decline starting after the first treatment (Figure 2C). Furthermore, the mucosal blisters of the PV patient healed by day 15. The PF patient had a PDAI activity score of 34.5 at baseline, which also showed a decline after the first treatment. The skin lesions of the PF patient gradually decreased over time and were completely cleared by day 281 (Figure 2D). Importantly, both patients showed no disease activity during the 10-week observation period after the last efgartigimod treatment.

[0155] In a representative patient, total IgG levels, as well as TT-, PCP-, and VZV-specific antibody levels, remained suppressed by approximately 70% during the treatment period and returned to baseline levels during treatment-free follow-up (Figures 2C and 2D). In both patients, an early and long-term reduction in anti-Dsg antibody levels was observed. During 10 weeks of treatment-free follow-up, the PF patient (patient 4) did not have a recurrence of anti-Dsg1 antibodies, and the PV patient (patient 8) had a recurrence of anti-Dsg3 antibodies to levels (approximately 50%) lower than before treatment (Figures 2C and 2D). Patient 4 received 0.15 mg / kg / day prednisone during efgartigimod-free follow-up and was further tapered to 0.11 mg / kg / day at the last study visit, while patient 8's dose was 0.16 mg / kg / day during the efgartigimod-free 10-week period.

[0156] Suppression of anti-Dsg autoantibody subtypes In pemphigus, the disease is primarily due to the formation of autoantibodies against desmogleins (Dsg), a group of transmembrane desmosomal glycoproteins involved in the structural integrity of the epidermis. For pemphigus vulgaris (PV), these primarily target Dsg-3, whereas in pemphigus foliaceus (PF), these antibodies primarily target Dsg-1.

[0157] Since PV and PF are mainly associated with IgG4 and to a lesser extent with other IgG subtypes, ALBIA Dsg-3-assays were performed in 6 patients with P and modified anti-Dsg-1 Euroimmun ELISA was performed in 6 patients with PF who received long-term efgartigimod treatment in cohorts 3 and 4 and achieved a sustained clinical response. The patients used in these analyses are specified in Table 6 and anti-Dsg-1 / 3 titers are summarized in Table 7. At baseline, heterogeneous anti-Dsg-1 / 3 IgG1-4 subclasses were detected in different patients. In patients with baseline levels above the positivity threshold, a reduction of anti-Dsg-3 IgG1 autoantibodies below the positivity threshold was observed in 3 out of 3 patients (Figure 3A) and anti-Dsg-3 IgG4 in 2 out of 3 patients (Figure 3D). Anti-Dsg-3 IgG2 autoantibodies present in three patients were significantly reduced, but in only one patient were reduced below the positivity threshold at the end of the study (Figure 3B). IgG3 autoantibodies present in one patient at baseline were suppressed below the positivity threshold (Figure 3C). Six patients with PF subjected to subclass analysis showed a dominant IgG4 signature of anti-Dsg-1 autoantibodies (Figure 3F), while one patient presented with IgG1 autoantibodies (Figure 3E). Analysis of Dsg-1 IgG titers over time showed a decrease in Dsg-1 specific IgG1 and IgG4 antibodies after clinical response, which remained suppressed at the end of the study (Figures 3E and 3F). It can therefore be concluded that efgaltigimod reduces anti-Dsg titers regardless of the IgG subtype analyzed.

[0158] These results indicate that efgartigimod treatment leads to a reduction in pemphigus disease causing autoantibodies that is maintained over a long period after treatment. Furthermore, clinical benefit in patients was directly related to the reduction in titers of pathogenic autoantibodies. The reduction in anti-Dsg-1 IgG was more consistent between patients, whereas changes in anti-Dsg-3 IgG levels were more variable. Table 7. Summary of individual clinical and serological responses by patients from cohorts 3 and 4 who achieved a sustained clinical response. [Table 7]

[0159] Suppression of circulating immune complexes Although immune complexes are found in healthy individuals, their formation may be expected to be elevated in autoimmune diseases, in part driving and / or exaggerating their pathology. Since the half-life of immune complexes, mainly containing IgG, may also be influenced by the biology of FcRn, the levels of CICs were investigated in the same six PV and six PF patients. These patients were subjected to IgG CIC analysis by C1q ELISA, which detects complement-fixing IgG antibodies. IgG CIC levels are considered clinically significant if ≥ 4.0 μg equivalents / mL. Although four patients showed elevated CIC levels, a significant decrease in CICs was observed during treatment with efgaltigimod (Figures 4A and 4B), which was consistent with the observed improvement in clinical status.

[0160] Changes in Dsg-3+ and Dsg-1+ B cells Based on observing long-term suppression of anti-Dsg autoantibodies compared with total serum IgG in pemphigus patients after efgartigimod treatment, PBMCs from PV patients were analyzed to determine the fate of Dsg-3-specific B cells.PBMC collection was performed in cohort 4 patients only (n=15) and was successfully isolated in 12 patients (5 PV, 7 PF), of which 9 (3 PV, 6 PF) achieved a sustained clinical response.

[0161] The frequency of Dsg-3+ B cells in peripheral blood was identified by staining for CD45+, CD19+, and CD27+ memory B cells (MBC) and fluorescently labeled Dsg-3 antigen (Figure 5A). Additional staining with IgM and IgD was included before gating on Dsg-3+ cells to identify class-switched memory B cells (Figure 1). Dsg-3+ B cells were identified within CD27+ IgM- IgD- cells, known to harbor antigen-specific B cells (Figures 5A, B, and C). Consistent with previous reports, Dsg-3-specific B cells were scarce in peripheral blood, but were detected primarily at baseline and at higher frequencies in patients with higher anti-Dsg-3 serum IgG levels. A decrease in antigen-specific MBC was seen when patients 5, 6, and 8 reached CR, as well as at the end of treatment. Two PV patients who relapsed after CR also showed a reduction in Ag-specific B cells in CR (Figures 5D and 5E), and no increase in the frequency of Dsg-3+ B cells was further observed, potentially suggesting a sustained tissue-resident antigen-specific response in relapse.

[0162] In addition to assessing the frequency of Dsg-3+ B cells in PV patients, Dsg-1-specific ASCs were measured by ELISPOT. Although ELISPOT assays were performed on all samples, low cell viability after thawing and withdrawal of patient consent for post-hoc analysis restricted data analysis to patients 3, 4, and 7. At baseline, anti-Dsg-1 IgG ASCs were detected in all three PF patients evaluated, and at higher frequencies in patients with higher serum anti-Dsg1 levels (Figure 5F, G, and H). After treatment with efgartigimod and concomitant low-dose prednisone, anti-Dsg-1 IgG ASCs were no longer detectable at the end of the study. For two patients, disappearance of anti-Dsg-1 IgG ASCs was detected at the CR visit (days 44 and 275, respectively). One patient showed loss of anti-Dsg-1 IgG ASC at the end of treatment, and CR was achieved after 47 days during treatment-free follow-up.

[0163] T- and B-cell phenotypes during efgartigimod treatment Although classical type 2 T helper (Th2) cells, in addition to autoantibody-producing B cells, are typically considered central factors in pemphigus pathology, recent advances in clinical immunology have shown that an additional T cell subset, namely T helper-17 / T follicular helper-17 (Th17 / Tfh17) cells, efficiently promotes autoantibody production in pemphigus patients. Therefore, we then investigated whether long-term treatment affected the major T and B cell subsets in addition to the antigen-specific landscape. Importantly, treatment did not affect the overall levels of total leukocytes, total lymphocytes, monocytes, or neutrophils (Figures 6A and 6B). Longitudinal analysis of PBMCs in these patients at four different time points revealed no changes in the overall T cell subpopulations. Specifically, CD4+ T cells remained stable, and there were no significant changes in Th1, Th2, Th17, or Tfh1, Tfh2, Tfh17 subsets (Figure 6C).

[0164] The baseline frequency of total B cells as a percentage of total lymphocytes was heterogeneous, ranging from 6.2% to 30.9%, with some individuals showing high B cell frequencies that may be due to B cell activation and proliferation. Surprisingly, analysis of B cells revealed reduced median numbers of total CD19+ B cells in peripheral blood of all nine patients, but did not affect the composition of B cell subsets in the markers tested, including CD27+ memory cells (Figures 6D and 6E). After treatment, the median levels of CD19+ B cells remained within the normal range.

[0165] The highest B cell frequencies in the study were observed in patients 11 and 12 who relapsed to a PDAI activity of >10 after achieving CR. No increase from baseline in B cell frequencies was observed at the last evaluable time point. Patient 13 with PF did not show a clinical response to efgartigimod treatment and showed no change in CD19+ B cells (Figures 2A and 7).

[0166] Prednisone exposure in patients receiving long-term efgartigimod treatment The effect of efgartigimod on B cell frequency is likely not due to concomitant treatment with prednisone, since B cell levels were not affected in patients in the prednisone-only arm of the RITUX 3 study in pemphigus (rituximab clinical trial). Nevertheless, the potential impact of concomitant prednisone exposure on the observed pharmacodynamic and immunological effects described above was analyzed. As seen in the overall study population, the early clinical efficacy of efgartigimod allowed for early tapering of steroids. This effect was even more pronounced in patients who achieved a sustained clinical response after long-term treatment with efgartigimod in cohorts 3 and 4. In patients who achieved a CR at any time point in the study, the mean daily prednisone dose to CR was 0.255 mg / kg / day in cohort 4 patients (n=9) and 0.18 mg / kg / day in cohort 3 patients (n=5) (Table 8), and the decrease in B cell frequency was not associated with higher prednisone doses (Figures 8A and 8B). Table 7. Clinical status and concomitant prednisone dose levels over time in cohorts 3 and 4 [Table 8]

[0167] C. Conclusion Previous results have shown that treatment of pemphigus patients with efgartigimod results in suppression of IgG, which demonstrates the strong clinical efficacy of efgartigimod. The results discussed above show, for the first time, an immunomodulatory effect by an anti-FcRn inhibitor beyond blockade of IgG recycling in pemphigus patients. Specifically, the results show a long-term reduction in autoantibody levels during 10 weeks of efgartigimod-free follow-up, as well as a reduction in both antigen-specific B cells and changes in the B cell compartment, including a reduction in total CD19+ B cells after cessation of efgartigimod treatment. In contrast, patients who did not respond to efgartigimod treatment did not experience a reduction in the number of CD19+ B cells.

[0168] The patient's early clinical improvement allowed for early prednisone tapering, which resulted in relatively lower corticosteroid exposure throughout the study than the general pemphigus population.

[0169] The decline in CD19+ B cell frequency back to normal (approximately 10% of lymphocytes) can be used as a biomarker to indicate restored immune homeostasis and indicate the time to discontinue efgartigimod therapy. Furthermore, the effect of efgartigimod on B cell frequency in pemphigus patients provides a rationale for using B cell frequency in patients as a marker for monitoring the therapeutic efficacy of FcRn antagonists in patients with pemphigus and other autoantibody-mediated diseases. ***

[0170] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. 1. A method for monitoring the effectiveness of a treatment of an autoantibody mediated disease in a subject following treatment with a first FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from said subject; b) comparing the frequency of said B cells to a reference value associated with said autoantibody mediated disease in said subject; When the frequency of said B cells in said sample is greater than or equal to said reference value, said treatment is ineffective, and when the frequency of said B cells is less than said reference value, said treatment is effective.

2. 1. A method of treating an autoantibody mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid administration regimen, comprising: a) administering to the subject a therapeutically effective amount of a second FcRn antagonist; b) measuring in vitro the frequency of B cells in a blood sample taken from said subject; c) comparing the frequency of said B cells to a reference value associated with said autoantibody mediated disease in said subject; wherein the corticosteroid dosing regimen is maintained if the frequency of the B cells in the sample is equal to or greater than the reference value, or wherein the corticosteroid dosing regimen is tapered if the frequency of the B cells in the sample is less than the reference value.

3. 1. A method for treating an autoantibody mediated disease in a subject receiving a first FcRn antagonist and a corticosteroid administration regimen, comprising: a) administering to the subject a therapeutically effective amount of the second FcRn antagonist; b) measuring in vitro the frequency of B cells in a blood sample taken from said subject; c) comparing the frequency of said B cells to a reference value associated with said autoantibody mediated disease in said subject; if the frequency of said B cells in said sample is equal to or greater than said reference value, then said corticosteroid dosing regimen is maintained, and if the frequency of said B cells in said sample is less than said reference value, then said corticosteroid dosing regimen is tapered.

4. 1. A method for treating an autoantibody mediated disease in a subject, comprising: (a) administering to the subject one or more initial doses of a therapeutically effective amount of a first FcRn antagonist; (b) administering to the subject one or more further doses of a therapeutically effective amount of a second FcRn antagonist if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with active disease in the subject, or discontinuing treatment with the first FcRn antagonist if the frequency of B cells in the subject after step (a) is less than a reference value associated with active disease in the subject.

5. 1. An FcRn antagonist for use in a method of treating an autoantibody mediated disease in a subject, comprising: (a) administering to the subject one or more initial doses of a therapeutically effective amount of a first FcRn antagonist; (b) if the frequency of B cells in the subject after step (a) is equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject, one or more further doses of a therapeutically effective amount of a second FcRn antagonist are administered to the subject, or if the frequency of B cells in the subject after step (a) is less than a reference value associated with the autoantibody-mediated disease in the subject, the first FcRn antagonist is discontinued.

6. The method of claim 4 or claim 5, wherein the therapeutically effective amount of the first FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg.

7. The method of claim 4 or claim 5, wherein the therapeutically effective amount of the first FcRn antagonist is administered subcutaneously at a dose of about 750 mg to about 3000 mg.

8. 1. A method for determining whether a subject previously treated for an autoantibody mediated disease with a first FcRn antagonist requires further treatment with a second FcRn antagonist, the method comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from said subject; b) comparing the frequency of said B cells to a reference value associated with said autoantibody mediated disease in said subject; If the frequency of the B cells in the sample is equal to or greater than the reference value, the subject requires further treatment with the second FcRn antagonist.

9. 1. A method for treating an autoantibody-mediated disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist; The method, wherein the autoantibody-mediated disease has recurred in the subject after prior therapy with a first FcRn antagonist, and the subject has a frequency of B cells associated with the autoantibody-mediated disease in the subject that is equal to or greater than a reference value.

10. A second FcRn antagonist for use in a method of treating an autoantibody-mediated disease in a subject, wherein the autoantibody-mediated disease has recurred in the subject after previous therapy with a first FcRn antagonist, the subject has a frequency of B cells equal to or greater than a reference value associated with the autoantibody-mediated disease in the subject, and a therapeutically effective amount of the second FcRn antagonist is administered to the subject.

11. A method for treating an autoantibody-mediated disease in a subject, wherein the autoantibody-mediated disease has recurred in the subject after previous therapy with a first FcRn antagonist, and a therapeutically effective amount of a second FcRn antagonist is administered to the subject, wherein the therapeutically effective amount is determined based on a frequency of B cells in a blood sample taken from the subject.

12. A second FcRn antagonist for use in a method for treating an autoantibody-mediated disease in a subject, wherein the autoantibody-mediated disease has recurred in the subject after prior therapy with a first FcRn antagonist, and a therapeutically effective amount of the second FcRn antagonist is administered to the subject, the therapeutically effective amount being determined based on the frequency of B cells in a blood sample taken from the subject.

13. 13. The method or use of claim 11 or 12, wherein the frequency of B cells is about 1.5, 2, 3, 4, 5, 6, or 7 times the normal frequency of B cells.

14. 14. The method or use of claim 13, wherein the normal frequency of B cells is about 3%, 5%, 10%, 15%, 20%, or 30% of lymphocytes.

15. 1. A method for monitoring remission of an autoantibody mediated disease in a subject following treatment with a first FcRn antagonist, comprising: a) measuring in vitro the frequency of B cells in a blood sample taken from said subject; b) comparing the frequency of said B cells to a reference value associated with said autoantibody mediated disease in said subject; If the frequency of said B cells in said sample is less than said reference value, then the subject is in remission from said autoantibody-mediated disease.

16. 4. The method of claim 2 or claim 3, wherein the corticosteroid dosing regimen is tapered to a lower dosage or less frequent dosing.

17. The method of claim 8, further comprising administering to the subject a therapeutically effective amount of the second FcRn antagonist if the frequency of the B cells in the sample is equal to or greater than the reference value.

18. The method of any one of claims 1 or 15, further comprising administering to the subject a therapeutically effective amount of a second FcRn antagonist if the frequency of the B cells in the sample is equal to or greater than the reference value.

19. 19. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein said reference value is about 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, or 7 times the normal frequency of B cells.

20. 20. The method or use of claim 19, wherein the normal frequency of B cells is about 3%, 5%, 10%, 15%, 20%, 25%, or 30% of lymphocytes.

21. 19. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein said reference value is about 3%, 5%, 10%, 15%, 20%, 25%, or 30% of lymphocytes.

22. 19. The method or use of any one of claims 1 to 10 or 15 to 18, wherein the reference value is about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the maximum frequency of B cells measured in the subject before receiving any treatment for the autoantibody mediated disease.

23. 19. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein the reference value is more than 60% of the maximum frequency of B cells measured in the subject before receiving any treatment for the autoantibody mediated disease.

24. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein the reference value is about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the maximum frequency of B cells measured in the subject before treatment with the first FcRn antagonist for the autoantibody-mediated disease.

25. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein the reference value is at least 60% of the maximum frequency of B cells measured in the subject before treatment with the first FcRn antagonist for the autoantibody-mediated disease.

26. The method or use according to any one of claims 1 to 10 or 15 to 18, wherein the reference value is about 2-fold, 3-fold, 4-fold, 5-fold, or 6-fold the lowest frequency of B cells measured in the subject after treatment with the first FcRn antagonist for the autoantibody-mediated disease.

27. 27. The method or use of any one of claims 1 to 3 or 8 to 26, wherein the subject has previously been treated with the first FcRn antagonist administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg.

28. 27. The method or use of any one of claims 1 to 3 or 8 to 26, wherein the subject has previously been treated with the first FcRn antagonist, administered subcutaneously at a dose of about 750 mg to about 3000 mg.

29. 29. The method or use of any one of claims 1 to 28, wherein the subject has previously been treated with a corticosteroid, or an immunosuppressant.

30. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is a higher dose than a previous treatment with the first FcRn antagonist.

31. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is a lower dose than a previous treatment with the first FcRn antagonist.

32. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is administered more frequently as compared to a previous treatment with the first FcRn antagonist.

33. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is administered less frequently compared to a previous treatment with the first FcRn antagonist.

34. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is administered intravenously at a dose of about 10 mg / kg to about 30 mg / kg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

35. The method or use of claim 34, wherein the effective amount of the second FcRn antagonist is administered intravenously at a dose of 10 mg / kg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

36. The method or use of claim 34, wherein the effective amount of the second FcRn antagonist is administered intravenously at a dose of 25 mg / kg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

37. The method or use according to any one of claims 2 to 7, 9 to 14, or 16 to 18, wherein the effective amount of the second FcRn antagonist is administered subcutaneously in a fixed dose of about 750 mg to about 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

38. The method or use of claim 37, wherein the effective amount of the second FcRn antagonist is administered subcutaneously in a fixed dose of 1000 mg or 2000 mg once per week, once every two weeks, once every three weeks, once every four weeks, or once every six weeks.

39. 20. The method or use of any one of claims 1 or 4 to 18, further comprising administering to the subject an effective amount of a corticosteroid, or an immunosuppressant.

40. 40. The method or use of claim 39, wherein said effective amount of said corticosteroid is administered at a dose of about 0.5 mg / kg per day.

41. 40. The method or use of claim 39, wherein said effective amount of said corticosteroid is administered at a dosage of about 0.25 mg / kg per day.

42. 40. The method or use of claim 39, wherein said effective amount of said corticosteroid is administered in a dosage of about 20 mg per day.

43. 40. The method or use of claim 39, wherein said effective amount of said corticosteroid is administered in a dosage of about 10 mg per day.

44. 13. The method or use according to any one of the preceding claims, wherein the frequency of B cells is measured by flow cytometry.

45. 2. The method or use according to any one of the preceding claims, wherein said B cells are CD19+ B cells.

46. The method or use according to any one of claims 2 to 14 or 16 to 45, wherein the first FcRn antagonist and the second FcRn antagonist are each the same FcRn antagonist.

47. The method or use according to any one of claims 2 to 14 or 14 to 45, wherein the first FcRn antagonist and the second FcRn antagonist are each different FcRn antagonists.

48. The method or use of claim 46, wherein the FcRn antagonist is an anti-FcRn antibody.

49. The method or use of claim 47, wherein the first FcRn antagonist is an anti-FcRn antibody.

50. The method or use of claim 47, wherein the second FcRn antagonist is an anti-FcRn antibody.

51. The method or use of any one of claims 48 to 50, wherein the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

52. 47. The method or use of claim 46, wherein the FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

53. The method or use of claim 47, wherein the first FcRn antagonist or the second FcRn antagonist is an Fc region comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

54. 47. The method or use of claim 46, wherein the FcRn antagonist is efgartigimod.

55. The method or use of claim 47, wherein the first FcRn antagonist or the second FcRn antagonist is efgartigimod.

56. 47. The method or use of claim 46, wherein the FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2 or 3.

57. The method or use of claim 47, wherein the first FcRn antagonist or the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3.

58. The method or use of claim 47, wherein the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist is efgartigimod.

59. The method or use of claim 47, wherein the first FcRn antagonist is an anti-FcRn antibody and the second FcRn antagonist comprises the amino acid sequence of SEQ ID NO: 1, 2, or 3.

60. 60. The method or use of claim 58 or 59, wherein the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

61. 52. The method or use of any one of claims 1 to 51, wherein the patient has not been previously treated with efgartigimod.

62. The method of any one of the preceding claims, wherein the subject has one or more physical symptoms of an autoantibody-mediated disease after treatment with the first FcRn antagonist.

63. 10. The method of any one of the preceding claims, wherein the subject has serum levels of pathogenic IgG autoantibodies that are associated with recurrence of the autoantibody-mediated disease.

64. The method of claim 63, wherein the pathogenic IgG autoantibody is an anti-Dsg-3 antibody or an anti-Dsg-1 antibody.

65. The autoantibody-mediated disease is selected from the group consisting of allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome (APS), autoimmune Addison's disease, Alzheimer's disease, antibody-mediated allograft rejection (AMR), antineutrophil cytoplasmic antibodies (ANCA), ANCA vasculitis, autoimmune diseases of the adrenal gland, autoimmune encephalitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura or idiopathic thrombocytopenic purpura), and autoimmune vascular endothelial cell ... purpura or immune-mediated thrombocytopenia), urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman syndrome, celiac spruce dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, COVID-19-mediated postural orthostatic tachycardia syndrome (POTS), Crohn's disease, delayed graft function after kidney transplantation, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome (GBS), Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, hemolytic disease of the fetus and newborn(HDFN), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, lupus nephritis, membranous neuropathy, membranous nephropathy, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myelin oligodendrocyte glycoprotein antibody Myasthenia gravis (MOGAD), myasthenia gravis (MG), generalized myasthenia gravis (gMG), ophthalmic myasthenia gravis (OMG), myositis, neuromyelitis optica (NMO), paraneoplastic bullous pemphigoid, pemphigoid of pregnancy, pemphigus vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune 2. The method or use according to any one of the preceding claims, wherein the disease is selected from the group consisting of: myopathy (NAM), antisynthetase syndrome (ASyS), primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis (RA), sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-body syndrome, systemic lupus erythematosus (SLE), Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), thyroid eye disease, ulcerative colitis, uveitis, warm autoimmune hemolytic anemia (wAIHA), dermatitis herpetiformis type vasculitis, antineutrophil cytoplasmic antibody associated vasculitis, vitiligo, and Wegener's granulomatosis.

66. 65. The method of any one of claims 1 to 64, wherein the autoantibody mediated disease is pemphigus vulgaris (PV) or pemphigus foliaceus (PF).

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