FCRN antibody and its method of use

Abstract

To provide a method of treating a fetal and neonatal alloimmune and / or autoimmune disorder.SOLUTION: There is provided a method of treating a fetal and neonatal alloimmune and / or autoimmune disorder comprising administering an FcRn antibody to a pregnant subject. These anti-FcRn antibodies are useful, e.g., to promote clearance of autoantibodies in a subject, to suppress antigen presentation in a subject, to block an immune response, e.g., block an immune complex-based activation of the immune response in a subject, and to treat immunological diseases (e.g., autoimmune diseases) in a subject. These anti-FcRn antibodies are also useful, e.g., to decrease pathogenic antibody transport across the placenta of a pregnant subject, to increase pathogenic antibody catabolism in a pregnant subject, and to treat an antibody-mediated infection enhancement of viral disease in a fetus or a neonate.SELECTED DRAWING: None

Description

[Background Art]

[0001] Therapeutic proteins, for example, therapeutic antibodies, have rapidly become clinically important drug classes for patients with immune disorders. Many autoimmune and alloimmune diseases are caused by pathogenic antibodies( pathogenic antibody). For example, numerous fetal and neonatal immune disorders result from the transfer of maternal-derived antibodies from a pregnant subject, particularly a pregnant subject with an immune disorder, to the fetus via the human neonatal Fc receptor (FcRn) in the placenta. There is a need for novel methods for treating immune disorders. [Summary of Invention]

[0002] In a first aspect, the present application features a method for treating alloimmune disorders and / or autoimmune disorders in a fetus and a neonate, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises (1) a light chain variable region comprising CDR L1, CDR L2 and CDR L3 and (2) a heavy chain variable region comprising CDR H1, CDR H2 and CDR H3 ( include), the antibody includes the light chain variable region and the heavy chain variable region, the antibody includes the light chain variable region and the heavy chain variable region, the antibody comprises the light chain variable region and the heavy chain variable region, the antibody consists of the light chain variable region and the heavy chain variable region, or consists substantially of the light chain variable region and the heavy chain variable region, the antibody consists of the light chain variable region and the heavy chain variable region, or consists substantially of the light chain variable region and the heavy chain variable region, wherein CDR L1 comprises, consists of, or consists substantially of the sequence TIFF0007914147000001.tif4128, comprises the sequence, comprises the sequence, consists of the sequence, or consists substantially of the sequence, consists of the sequence, or consists substantially of the sequence, and CDR L2 has the sequence GDX​​ comprises 3X4RPS (SEQ ID NO: 13), comprises said sequence, comprises said sequence, said sequence consists of, or consists essentially of, consists of said sequence, or consists essentially of said sequence , wherein CDR L3 has the sequence comprises TIFF0007914147000002.tif4128, comprises said sequence, comprises said sequence, consists of said sequence, or consists essentially of said sequence, consists of said sequence, or consists essentially of said sequence, wherein CDR H1 has the sequence Z1Y comprises AMG (SEQ ID NO: 15), comprises said sequence, comprises said sequence, consists of said sequence , or consists essentially of said sequence, consists of said sequence, or consists essentially of said sequence , wherein CDR H2 has the sequence comprises TIFF0007914147000003.tif4128, comprises said sequence, comprises said sequence, consists of said sequence, or consists essentially of said sequence, consists of said sequence, or consists essentially of said sequence, wherein CDR H3 has the sequence LAZ comprises 5Z6DSY (SEQ ID NO: 17), comprises said sequence, comprises said sequence, said sequence consists of, or consists essentially of, consists of said sequence, or consists essentially of said sequence , wherein X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid, X 3 is a polar amino acid, X4 is a polar or acidic amino acid, X5 is a polar or hydrophobic amino acid, X6 is a hydrophobic amino acid, Z1 is a polar or acidic amino acid , Z2 is a polar or hydrophobic amino acid, Z3 is G, S or A, Z4 is a basic amino acid, Z5 is a hydrophobic or basic amino acid, Z6 is G, S, D, Q or H , Z7 is S or T.

[0003] In some embodiments, the antibodies are (1) CDR L1, CDR L2 and CDR (2) Light chain variable region including L3, and CDR H1, CDR H2 and CDR H3 A light chain variable region including a heavy chain variable region and a light chain variable region including a heavy chain variable region and It consists of a heavy chain variable region, or substantially consists of the light chain variable region and the heavy chain variable region, C DR L1 is the sequence CD R L2 includes the sequence GDX3ERPS or GDSX4RPS, the sequence It consists of, or substantially consists of, the sequence, and CDR L3 is sequence CD R H1 is sequence TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 4) :5) or containing the sequence of NYAMG (SEQ ID NO:6), containing the sequence, the sequence CDR H2 consists of, or substantially consists of, the sequence, A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000006.tif22156 CDR H3 includes the sequence LAZ5GDSY or LAIZ6DSY, the sequence, It consists of an array, or substantially consists of such an array.

[0004] In some embodiments, the antibodies are (1) CDR L1, CDR L2 and CDR (2) Light chain variable region including L3, and CDR H1, CDR H2 and CDR H3 A light chain variable region including a heavy chain variable region and a light chain variable region including a heavy chain variable region and A light chain variable region and a heavy chain variable region, or substantially the light chain variable region, including a heavy chain variable region. A variable chain region and a variable heavy chain region, a variable light chain region and a variable heavy chain region, Alternatively, it consists substantially of the light chain variable region and the heavy chain variable region, and CDR L1 is arranged Including TIFF0007914147000007.tif4128, including the sequence, including the sequence, consisting of the sequence, or substantially consisting of the sequence, The sequence consists of, or substantially consists of, the sequence, and CDR L2 is sequence GDS Including ERPS (SEQ ID NO:2), including the sequence, including the sequence, from the sequence or substantially consisting of the sequence, or consisting of the sequence, or substantially consisting of the sequence Yes, CDR L3 is, array TIFF0007914147000008.tif4128, including the sequence, including the sequence, consisting of the sequence, or substantially consisting of the sequence The sequence consists of, or substantially consists of, the sequence, and CDR H1 is sequence TYA MG (SEQ ID NO:4) includes the sequence, includes the sequence, consists of the sequence or substantially consisting of the sequence, or substantially consisting of the sequence CDR H2 is, CD R H3 contains the sequence LAIGDSY (SEQ ID NO: 11), the sequence, the It consists of an array, or substantially consists of such an array.

[0005] In some embodiments, the subject is a previously treated fetus and neonatal alloimmune disorder and / or The subject has a history of having an autoimmune disorder. In some embodiments, the subject This carries a risk of alloimmune disorders and / or autoimmune disorders in the fetus and newborn. In this embodiment, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal are treated as fetal. and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolytic disorders, alloimmune pancyme Pan-thrombocytopenia, congenital heart block, fetal Joint contractures, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid antibodies Syndrome, polymyositis of the newborn, dermatomyositis, lupus of the newborn, scleroderma of the newborn, Behçet's disease, Neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes It is selected from a group consisting of diseases.

[0006] In some embodiments, the autoimmune disorder of the fetus and neonatal and / or autoimmune disorder is , hemolytic disease of the fetus and neonatal. In some embodiments, the fetus and neonatal Autoimmune disorders and / or autoimmune disorders are alloimmune thrombocytopenia in fetuses and neonates. In some embodiments, the autoimmune disorder of the fetus and neonatal and / or autoimmune disorder It is a congenital heart block.

[0007] In some embodiments, the treatment reduces the risk of miscarriage.

[0008] In another embodiment, this application includes administering antibodies to a pregnant subject, and the fetus and This invention is characterized by a method for treating fetal anemia associated with hemolytic disease in newborns, and the anti The body comprises (1) a light chain variable region including CDR L1, CDR L2 and CDR L3, and (2 ) A heavy chain variable region including CDR H1, CDR H2 and CDR H3, and the light chain variable A variable region and a heavy chain variable region, consisting of a light chain variable region and a heavy chain variable region, or Qualitatively, it consists of the light chain variable region and the heavy chain variable region, and CDR L1 is sequence CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence X5 Including SYX6GSGIYV (SEQ ID NO: 14), including the sequence, from the sequence It consists of, or substantially consists of, the sequence, and CDR H1 is sequence Z1YAMG(SE Q ID NO:15) includes, includes, consists of, or substantially comes from the sequence CDR H2 is a sequence TIFF0007914147000011.tif4128, including, comprising, or substantially comprising the sequence, CDR H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence A combination comprising, consisting of, or substantially consisting of the sequence, wherein X1 is polar or hydrophobic. X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is a polar or hydrophobic amino acid, X6 is a hydrophobic amino acid. It is an amino acid, where Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or salt. These are basic amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0009] In some embodiments, this method involves the pregnant subject, the fetus of the pregnant subject, and / Alternatively, treat a combination of these conditions.

[0010] In another embodiment, this application includes administering antibodies to a pregnant subject, It is characterized by a method for treating infectious disorders. In some embodiments, this autoimmune disorder is Alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune disease Hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, Chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Chrg-Strom Uss syndrome, pemphigoid scarring, limited systemic sclerosis (CREST syndrome), cold agglutinin disease Crohn's disease, dermatomyositis, lupus discoid, essential mixed cryoglobulinemia, fibromuscular Pain syndrome, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune disease Lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, young Arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, malignant Anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyalgia Inflammation, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Writer - Syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome Stiffman syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo Alternatively, the group consisting of Wegener's granulomatosis is selected.

[0011] In some embodiments, the antibodies are (1) CDR L1, CDR L2 and CDR (2) Light chain variable region including L3, and CDR H1, CDR H2 and CDR H3 A light chain variable region including a heavy chain variable region and a light chain variable region including a heavy chain variable region and It consists of a heavy chain variable region, or substantially consists of the light chain variable region and the heavy chain variable region, C DR L1 is the sequence CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0012] In some embodiments, the treatment reduces the risk of miscarriage / fetal loss.

[0013] In another embodiment, this application includes administering FcRn antibodies to a pregnant subject. , reduce the risk of autoimmune disorders or alloimmune disorders, or autoimmune disorders or It features methods that reduce the risk of developing alloimmune disorders.

[0014] In some embodiments, this autoimmune disorder manifests as alopecia areata, ankylosing spondylitis, and antiphosphate Lipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, water Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, localized Systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid leukemia Cryoglobulinemia (essential mixed type), fibromyalgia, fibromyositis, Graves' disease, Hashimoto's disease Thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic lung Fibrosis, IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, lupus, Nieille's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polymolar tumor Osteitis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's artery A group consisting of inflammation, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, or Wegener's granulomatosis. Selected from.

[0015] In some embodiments, the treatment reduces the risk of miscarriage / fetal loss.

[0016] In another embodiment, this application relates to a method for increasing the catabolic effect of an antibody in a subject. This is a characteristic, and the method includes administering an antibody to a pregnant subject, and the antibody is (1) Light chain variable region including CDR L1, CDR L2 and CDR L3, and (2) CD The light chain variable region includes a heavy chain variable region containing R H1, CDR H2 and CDR H3. A light chain variable region and a heavy chain variable region, including the heavy chain variable region, or substantially comprising the light chain variable region and the heavy chain variable region. The CDR L1 consists of a light chain variable region and a heavy chain variable region, and the arrangement CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0017] In some embodiments, increasing the catabolic activity of antibodies is the catabolic activity of pathogenic antibodies. This includes increasing the catabolic activity of pathogenic antibodies, including increasing the catabolic activity of pathogenic antibodies. This involves increasing the effect, or substantially increasing the catabolic effect of pathogenic antibodies. Yes.

[0018] In some embodiments, pathogenic antibodies are effective against the mother, the fetus, or both the mother and the fetus. It becomes a pathogen.

[0019] In some embodiments, the antibody is an IgG antibody.

[0020] In another embodiment, this application features a method for reducing autoantibodies in a subject. The method comprises administering an antibody to a pregnant subject, wherein the antibody is (1)CD (2) CDR H1, A light chain variable region and a heavy chain variable region including CDR H2 and CDR H3. A variable light chain region and a variable heavy chain region, including a variable region, or substantially the same variable light chain region It consists of a region and a heavy chain variable region, and CDR L1 is sequence CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0021] In another embodiment, this application relates to the activity of immune complexes in an immune response in a subject. The method is characterized by a method to reduce the effects of the disease, and this method involves administering antibodies to a pregnant subject. The antibody includes (1) a light chain comprising CDR L1, CDR L2 and CDR L3. (2) A variable region and a heavy chain variable region including CDR H1, CDR H2 and CDR H3 Including the light chain variable region and the heavy chain variable region, the light chain variable region and the heavy chain variable region CDR L1 consists of, or substantially consists of, the light chain variable region and the heavy chain variable region, array CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0022] In some embodiments, the immune response is an acute or chronic immune response in the subject. That is the case.

[0023] In some embodiments, the acute immune response is used in cases of pemphigus vulgaris, lupus nephritis, and myasthenia gravis. Mycosis, Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immunotherapy Complex-mediated vasculitis, glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic hematology Thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy and serum It is activated by a medical condition selected from a group of diseases.

[0024] In some embodiments, the chronic immune response is chronic inflammatory demyelinating polyneuropathy ( CIDP, systemic lupus, reactive joint disorder, primary A group consisting of biliary cirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody-associated vasculitis is selected. It is activated by the medical condition. In some embodiments, the chronic immune response is chronic It is activated by inflammatory demyelinating polyneuropathy.

[0025] In some embodiments, the subject has an autoimmune disease. This autoimmune disease includes alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome, and Addison's disease. , hemolytic anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, heparin-induced thrombocytopenia, sensitized transplant, autoimmune hepatitis, hepatitis, - Chet's disease, bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue, immune function Disorder syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring Pemphigoid, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, skin Dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative disorder Syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus Anesthetic, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polycystic nodule Arteritis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary acanthosis Maglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis Zi's ​​fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman Syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's meat The group is selected from those with blastomatosis.

[0026] In another aspect, this application reduces the transfer of antibodies across the placenta of a pregnant subject. The method is characterized by the administration of antibodies to a pregnant subject, The antibody comprises (1) a light chain variable region including CDR L1, CDR L2, and CDR L3, (2) The light chain variable region including CDR H1, CDR H2 and CDR H3 A chain variable region and a heavy chain variable region, comprising a light chain variable region and a heavy chain variable region, It substantially consists of the light chain variable region and the heavy chain variable region, and CDR L1 is the arrangement CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0027] In another embodiment, this application increases the catabolic effect of antibodies in pregnant subjects. The method is characterized by the administration of antibodies to a pregnant subject, The antibody comprises (1) a light chain variable region including CDR L1, CDR L2 and CDR L3, and ( 2) The light chain includes a heavy chain variable region including CDR H1, CDR H2 and CDR H3. A variable region and a heavy chain variable region, comprising a light chain variable region and a heavy chain variable region, or It substantially consists of the light chain variable region and the heavy chain variable region, and CDR L1 is arranged CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0028] In some embodiments, the antibody is used in the fetus of a pregnant subject, affecting both the fetus and the newborn. It causes alloimmune disorders and / or autoimmune disorders.

[0029] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal are Alloimmune thrombocytopenia in fetuses and neonates, hemolytic diseases in fetuses and neonates, alloimmune Panthrombocytopenia, congenital heart block, fetal joint contractures, neonatal myasthenia gravis, neonatal Autoimmune hemolytic anemia, neonatal antiphospholipid antibody syndrome, neonatal polymyositis, dermatomyositis, neonatal Lupus in infants, scleroderma of the newborn, Behçet's disease, Graves' disease of the newborn, Kawasaki disease of the newborn The group is selected from those with autoimmune thyroid disease and neonatal type 1 diabetes.

[0030] In some embodiments, the antibody is an IgG antibody.

[0031] In another embodiment, this application relates to antibody-mediated transmission of viral diseases in fetuses or neonates. The method is characterized by a treatment for sexually transmitted infection enhancement, which involves administering antibodies to pregnant subjects. The antibody includes (1) CDR L1, CDR L2, and CDR L3. (1) Light chain variable region and (2) Heavy chain variable including CDR H1, CDR H2 and CDR H3 The light chain variable region and the heavy chain variable region include the region and the heavy chain variable A region consisting of, or substantially consisting of, the light chain variable region and the heavy chain variable region, CDR L 1 is an array CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0032] In some embodiments, viral diseases include alphavirus infections and flavivirus infections. Ross River virus infection, Zika virus infection, Chikungunya virus infection, Ross River virus infection Infectious diseases, severe acute respiratory syndrome (Coronavirus infection), Middle East respiratory syndrome, avian influenza Infectious diseases, influenza virus infection, human respiratory syncytial virus infection, Ebola virus infection Infectious diseases, yellow fever virus infection, dengue virus infection, human immunodeficiency virus infection, RSV infection, hantavirus infection, getavirus infection, sindovis virus Infectious diseases, Bunyamwella virus infection, West Nile virus infection, Japanese encephalitis virus B Infectious diseases, rabbitpox virus infection, lactate dehydrogenase-elevated virus infection, reovirus infection Rabies virus infection, Foot-and-mouth disease virus infection, Porcine genitourinary respiratory syndrome virus infection Infections, monkey hemorrhagic fever virus infection, equine infectious anemia virus infection, goat arthritis virus Infectious diseases, African swine fever virus infection, lentivirus infection, BK papovavirus infection Infections, Murray Valley Encephalitis virus infection, enterovirus infection, cytomegalovirus Infectious diseases, including Pneumovirus infection, Morbillivirus infection, and measles virus infection. It is caused by a virus selected from a group of viruses.

[0033] In some embodiments, pregnant subjects activate an immune response within the pregnant subjects. Having a medical condition that causes or being at risk of developing such a medical condition.

[0034] In some embodiments, the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis. Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immunosuppression Pseudo-vasculitis, glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic hemoptysis Platelet-clonic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, serum sickness, Chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive joint disorder, primary biliary Cirrhosis of the liver, ulcerative colitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, alopecia areata, ankylostosis Spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, - Chet's disease, bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue, immune function Disorder syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring Pemphigoid, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, skin Dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative disorder Syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus Anesthetic, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polycystic nodule Arteritis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary acanthosis Maglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis Zi's ​​fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman Syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's meat It is blastomatosis.

[0035] In some embodiments, the pregnant subject is subjected to alloimmune disorders of the fetus and neonatal and / or She has a history of having previously given birth to a fetus or newborn with an autoimmune disorder. .

[0036] In some embodiments, biological samples obtained from pregnant subjects contain immunologically related substances. Antibodies are detected.

[0037] In some embodiments, the biological sample is a blood sample or a urine sample.

[0038] In some embodiments, the isolated antibodies are (1) CDR L1, CDR L2 and (2) CDR H1, CDR H2 and CDR A light chain variable region including a heavy chain variable region containing H3, and a light chain variable region including the heavy chain variable region, It consists of a variable region and the heavy chain variable region, or substantially the light chain variable region and the heavy chain variable region. CDR L1 is, The sequence has two or fewer amino acid substitutions compared to the sequence of TIFF0007914147000033.tif4128, and CDR L2 is GDSER The sequence has one or fewer amino acid substitutions compared to the sequence of PS (SEQ ID NO:2). CDR L3 is, The sequence has one or fewer amino acid substitutions compared to the sequence of TIFF0007914147000034.tif4128, and CDR H1 is TYAMG (SEQ ID NO:4), DYAMG (SEQ ID NO:5) or NYAMG (SE The sequence has one or fewer amino acid substitutions compared to the sequence of Q ID NO:6), and CDR H2 is The sequence has two or fewer amino acid substitutions compared to the sequence of TIFF0007914147000035.tif22164, and CDR H3 is LAIGD The sequence has one or fewer amino acid substitutions compared to the sequence of SY (SEQ ID NO:11). do.

[0039] In some embodiments, the isolated antibodies are (1) CDR L1, CDR L2 and (2) CDR H1, CDR H2 and CDR A light chain variable region including a heavy chain variable region containing H3, and a light chain variable region including the heavy chain variable region, It consists of a variable region and the heavy chain variable region, or substantially the light chain variable region and the heavy chain variable region. CDR L1 is an array CD R L2 includes the sequence GDX3ERPS or GDSX4RPS, the sequence It consists of, or substantially consists of, the sequence, and CDR L3 is sequence CD R H1 is TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5 ) or containing the sequence of NYAMG (SEQ ID NO:6), containing the sequence, from the sequence CDR H2 is, or substantially consists of the said sequence, A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000038.tif22156 CDR H3 includes the sequence LAZ5GDSY or LAIZ6DSY, and includes the sequence It consists of, or substantially consists of, the sequence.

[0040] In some embodiments, the antibody is sequence CDR L1 of TIFF0007914147000039.tif4128, CDR L2 of sequence GDSERPS (SEQ ID NO:2), sequence CDR L3 of TIFF0007914147000040.tif4128, CDR H1 of sequence TYAMG (SEQ ID NO:4), sequence CDR H2 of TIFF0007914147000041.tif4131, and CDR H3 of sequence LAIGDSY (SEQ ID NO:11) A, including the above six CDRs, including the six CDRs, consisting of the six CDRs, It essentially consists of the six CD-Rs.

[0041] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000042.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000043.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H1 of the antibody contains the sequence DYAMG (SEQ ID NO: 5), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000044.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0042] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000045.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000046.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence NYAMG (SEQ ID NO: 6), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000047.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0043] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000048.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000049.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence TYAMG (SEQ ID NO: 4), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000050.tif4134, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0044] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000051.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000052.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence TYAMG (SEQ ID NO: 4), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000053.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0045] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000054.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDX3X4RPS (SEQ ID NO: 13). a, including, consisting of, or substantially consisting of the sequence, isolated The CDR L3 of the antibody is sequence Including TIFF0007914147000055.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence Z1YAMG (SEQ ID NO: 15). An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR H2 is, Including TIFF0007914147000056.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAZ5Z6DSY (SEQ ID NO: 17). X1 is a combination of the sequence, the sequence, or a combination of the sequence, where X1 is X2 is T, A, S, or I, X3 is S, N, or T, and X4 is Q , is E or N, X5 is C, S, I or Y, X6 is A or V, Z1 is E, It is T, D or N, Z2 is S or A, Z3 is G, S or A, Z4 is K or R is Z5 is I, L or H, Z6 is G, S, D, Q or H, Z7 is S or It is T.

[0046] In some embodiments, the CDR L1 of the isolated antibody is sequence Including TIFF0007914147000057.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000058.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H1 of the antibody contains the sequence Z1YAMG (SEQ ID NO: 15). An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR H2 is, Including TIFF0007914147000059.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). A sequence containing, consisting of, or substantially consisting of, where Z1 is T, D or N, Z2 is S or A, Z3 is G, S or A, and Z7 is S or T. ru.

[0047] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000060.tif22165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0048] In some embodiments, the heavy chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000061.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0049] In some embodiments, the heavy chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000062.tif41165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0050] In some embodiments, the heavy chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000063.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0051] In some embodiments, the heavy chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000064.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0052] In some embodiments, the heavy chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000065.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0053] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000066.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, It has a sequence that is at least 90% identical to the sequence TIFF0007914147000067.tif41165.

[0054] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000068.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000069.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0055] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000070.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000071.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0056] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000072.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000073.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0057] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000074.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000075.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0058] In some embodiments, the heavy chain variable region of the isolated antibody is SEQ ID NO:2 One of the sequences from 0 to 24 and at least 95%, 97%, 99%, or 100% A sequence having the same identity as, containing, consisting of, or substantially from Yes.

[0059] In some embodiments, the light chain variable region of the isolated antibody is SEQ ID NO:1 A sequence having at least 95%, 97%, 99%, or 100% identity with the sequence shown in 9. Includes, contains, consists of, or substantially consists of.

[0060] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000076.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000077.tif41165.

[0061] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000078.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000079.tif40165.

[0062] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000080.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000081.tif40165.

[0063] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000082.tif22165, isolated The heavy chain variable region of the antibody is It has the sequence TIFF0007914147000083.tif40165.

[0064] In some embodiments, the light chain variable region of the isolated antibody is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000084.tif22165, is isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000085.tif40165.

[0065] In some embodiments, the antibody is K1 to 100 nM. D And it binds with human FcRn To combine.

[0066] In some embodiments, the isolated antibody is K of antibody N026. D Less than or the K D K is equal to D It then binds to human FcRn.

[0067] In some embodiments, the isolated antibody is a monoclonal antibody.

[0068] In some embodiments, the isolated antibody is IgG1 or a variant thereof.

[0069] In some embodiments, the isolated antibody contains a λ light chain, a λ light chain, a λ light chain It consists of, or substantially consists of, a λ light chain.

[0070] In some embodiments, the isolated antibody is a sialic acid-added antibody.

[0071] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. It is characterized by an isolated antibody that binds to human FcRn, including a chain variable region. (a) CDR L1 is sequence SDVGSYNL(SEQ ID NO: 47 ) or VG_Y NL (SEQ ID NO:34) includes, contains, consists of, or substantially comprises the sequence. The sequence consists of the above, where "_" can be any amino acid. (b) CDR L2 contains the sequence GDSE (SEQ ID NO: 35), and the sequence (c) CDR L3 is, A sequence containing the sequence YAGSGIY (SEQ ID NO: 36), a sequence comprising the sequence , or substantially consisting of the sequence, (d) CDR H1 is sequence TYA(SEQ ID NO:37) includes, contains, consists of, or substantially consists of the sequence (e) CDR H2 is sequence SIGASGSQTR(SEQ ID NO: 38) or SI_AS_SQ_R (SEQ ID NO:39), including the sequence, A sequence consisting of, or substantially consisting of, such that "_" represents any amino acid. It is possible to do so, and (f) CDR H3 has sequence LAI (SEQ ID NO: 40) It includes, contains, consists of, or substantially consists of the sequence.

[0072] In some embodiments, the antibody is used in human FcRn a) SEQ ID NO:2 5 and b) Recognize the amino acid sequence of SEQ ID NO:26.

[0073] In some embodiments, the antibodies are K80, A81, L8 of SEQ ID NO:30 2, G83, G84, K85, G86, P87, Y88, L112, N113, E115 G129, D130, W131, P132, E133, L135, A136 and Q13 At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 are selected from the group consisting of 9. Fc containing amino acids 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20 Binds to an epitope on Rn.

[0074] In some embodiments, the antibodies are K80, A81, L8 of SEQ ID NO:30 2, G83, G84, K85, G86, P87, Y88, L112, N113, G129 It consists of D130, W131, P132, E133, L135, A136 and Q139. At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 are selected from the group. E on FcRn containing amino acids 13, 14, 15, 16, 17, 18, 19, or 20 It binds to a pitope.

[0075] In some embodiments, the epitope on FcRn is W of SEQ ID NO:30 A substance comprising 131 and / or Y88, comprising the amino acid, consisting of the amino acid, or substantially It consists of the amino acid.

[0076] In some embodiments, the epitope on FcRn is D of SEQ ID NO:30 Including 130W131, W131P132, P87Y88 and / or Y88T89, the A compound comprising, or substantially comprising, an amino acid, including a amino acid.

[0077] In some embodiments, the epitope on FcRn is G of SEQ ID NO:30 129D130W131, W131P132E133, D130W131P132, P8 The amino acid comprising 7Y88T89, G86P87Y88 and / or Y88T89L90. It contains, consists of, or substantially consists of the amino acid.

[0078] In some embodiments, the epitope on FcRn is G of SEQ ID NO:30 129D130W131P132, D130W131P132E133, W131P13 2E133A134, G128G129D130W131, K85G86P87Y88, G86P87Y88T89, P87Y88T89L90 and / or Y88T89L90Q 91, containing the amino acid, consisting of the amino acid, or substantially consisting of the amino acid .

[0079] In some embodiments, the epitope on FcRn is G of SEQ ID NO:30 129D130W131P132E133, D130W131P132E133A134 , W131P132E133A134L315, G128G129D130W131P1 32, W127G128G129D130W131, G84K85G86P87Y88, K85G86P87Y88T89, G86P87Y88T89L90, P87Y88T8 The amino acid comprising 9L90Q91 and / or Y88T89L90T91Q92, It consists of the amino acid, or is substantially composed of the amino acid.

[0080] In some embodiments, the epitope on FcRn is T of SEQ ID NO:30 126W127G128G129D130W131, W127G128G129D130 W131P132, G128G129D130W131P132E133, G129D1 30W131P132E133A134, D130W131P132E133A134L 135, W131P132E133A134L135A136, G83G84K85G8 6P87Y88, G84K85G86P87Y88T89, K85G86P87Y88T 89L90, G86P87Y88T89L90Q91, P87Y88T89L90T91 The amino acid comprising Q92 and / or Y88T89L90Q91G92L93, It consists of amino acids, or is substantially composed of such amino acids.

[0081] In some embodiments, the epitope on FcRn is approximately 3 amino acids from W131. Or one or more amino acids within 10 angstroms, or approximately 5 amino acids from Y88. One or more amino acids or no acids within 8 angstroms, or the first set is either SEQ ID NO:30 W131 or contains the amino acid, and The second set is either SEQ ID NO:30 Y88 or contains the amino acid. is, contains any two sets of amino acids, contains said amino acids, consists of said amino acids, or It consists substantially of the amino acid.

[0082] In some embodiments, the epitopes on FcRn are K80, A81, L82, G 83, G84, K85, G86, P87, Y88, L112, N113, E115, G1 Includes 29, D130, W131, P132, E133, L135, A136 and Q139 or containing the amino acid, consisting of the amino acid, or substantially consisting of the amino acid.

[0083] In some embodiments, the isolated antibodies are I1, Q2 of SEQ ID NO:31. , containing at least one amino acid selected from the group consisting of P32 and V85, β(2 )- Binds to epitopes on microglobulins.

[0084] In some embodiments, the isolated antibody is amino at positions 66-68 in Kabat. The acid sequence KSG is included, the sequence is included, the sequence is composed of, or substantially composed of the sequence.

[0085] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. (a) CDR L1 is characterized by an isolated antibody containing a chain variable region, SDVGSYNL is included, the sequence is included, consists of the sequence, or is substantially derived from the sequence. However, (b) CDR L2 includes GDSE, includes the sequence, consists of the sequence, and Or it consists substantially of the sequence, except that GDSERPS (SEQ ID NO:2) is not included. First, (c) CDR L3 comprises YAGSGIY, contains said sequence, or consists of said sequence, or substantially consists of said sequence, with the proviso that TIFF0007914147000087.tif4128 is not included; (d) CDR H1 comprises TYA, contains said sequence, consists of said sequence, or substantially consists of said sequence, with the proviso that TYAMG (SEQ ID NO: 4) is not included, (e) CDR H2 comprises SIGASGSQTR, contains said sequence, or consists of said sequence, or substantially consists of said sequence, with the proviso that TIFF0007914147000088.tif4128 is not included; or (f) CDR H3 comprises LAI, contains said sequence, or consists of said sequence , or substantially consists of said sequence, with the proviso that LAIGDSY (SEQ ID NO: 11 ) is not included.

[0086] In another aspect, the present application features an isolated antibody comprising (1) a light chain variable region containing CDR L1, CDR L2 and CDR L 3, and (2) a heavy chain variable region containing CDR H1, CDR H2 and CDR H3, wherein (a) CDR L1 is a sequence that comprises TIFF0007914147000089.tif4128, contains said sequence, consists of said sequence, or substantially consists of said sequence, wherein 6 or fewer single amino acids are deleted or substituted, with the proviso that no amino acid within the subsequence SDVGSYN L is deleted or substituted, (b) CDR L2 is a sequence that comprises GDSER PS (SEQ ID NO: 2), contains said sequence, consists of said sequence, or substantially consists of said sequence, wherein 3 or fewer single amino acids are deleted or substituted, with the proviso that no amino acid within the subsequence GDSE is deleted or substituted, (c) CDR with the proviso that no amino acid within the subsequence GDSE is deleted or substituted, (c) CDR L3 is Including TIFF0007914147000090.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, here And, three or fewer single amino acids are deleted or substituted, however, the subsequence YAGSGIY No amino acids within this range are deleted or substituted, and (d) CDR H1 is sequence TYAM G (SEQ ID NO:4), DYAMG (SEQ ID NO:5), and NYAMG (S The sequence includes a sequence selected from the group consisting of EQ ID NO:6), the sequence includes, and the sequence This consists of, or substantially consists of, the sequence in which three or fewer single amino acids are deleted or The amino acids are substituted, however, amino acids within the subsequence YA range are not substituted, (e )CDR H2 is, A sequence selected from the group consisting of TIFF0007914147000091.tif22159, including, consisting of, or substantially the It consists of a sequence in which three or fewer single amino acids are deleted or substituted, ( f) CDR H3 contains LAIGDSY (SEQ ID NO: 11), and the sequence contains , consisting of or substantially consisting of the said sequence, where 4 or fewer single meshes No acids are deleted or substituted, however amino acids within the range of subsequence LAI are deleted or substituted. Not replaced.

[0087] In some embodiments, CDR L1 is 5 or less (e.g., 4, 3, 2, or 1) This includes the substitution or deletion of a single amino acid. In some embodiments, CDR L2 is 2 or less. This includes the substitution or deletion of a single amino acid as shown below (for example, 1). In some embodiments, C DR L3 includes substitutions or deletions of two or fewer (e.g., one) single amino acids. Morphologically, CDR H1 is a single amino acid substitution or deletion of 2 or fewer (e.g., 1) amino acids. This includes. In some embodiments, CDR H2 is a single mesh of 2 or fewer (e.g., 1) This includes substitution or deletion of anoacids. In some embodiments, CDR H3 is 3 or less (for example) This includes a single amino acid substitution or deletion in 2 or 1).

[0088] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. (a) CDR L1 is characterized by an isolated antibody containing a chain variable region, Including TIFF0007914147000092.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, Here, in SEQ ID NO:1, a single amino acid of 9 or less is deleted or substituted. However, amino acids within the range of subsequences VG and YNL of SEQ ID NO:1 The acid is neither deleted nor substituted, and (b) CDR L2 is GDSERPS(SEQ ID NO:2) including, including, consisting of, or substantially consisting of Therefore, there are three or fewer single amino acids that are deleted or substituted, however sub No amino acids are deleted or substituted within the GDSE range of the sequence, and (c) CDR L3 is, TIFF0007914147000093.tif4128 is included, the sequence is included, consists of the sequence, or is substantially composed of the sequence. Here, three or fewer single amino acids are deleted or substituted, except for the subsequence YAG. No amino acids within the SGIY range are deleted or substituted, and (d) CDR H1 is TY AMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5) and NYAMG comprises a sequence selected from the group consisting of (SEQ ID NO: 6), includes said sequence, consists of said sequence or consists substantially of said sequence, wherein up to 3 single amino acids are deleted or substituted, but no amino acid within the subsequence YA is substituted , (e) CDR H2 is comprises a sequence selected from the group consisting of TIFF0007914147000094.tif22164, includes said sequence, consists of said sequence or substantially consists of said sequence, wherein up to 7 single amino acids are deleted or substituted , provided that no amino acid within the subsequence SI, AS, SQ or R is deleted or substituted , or (f) CDR H3 comprises LAIGDSY (SEQ ID NO: 11) , includes said sequence, consists of said sequence or substantially consists of said sequence, wherein up to 4 single amino acids are deleted or substituted, provided that no amino acid within the subsequence LAI is deleted or substituted.

[0089] In some embodiments, CDR L1 comprises up to 8 (e.g., 7, 6, 5, 4, 3, 2 or 1) single amino acid substitutions or deletions. In some embodiments, CDR L2 comprises up to 2 (e.g., 1) single amino acid substitutions or deletions. In some embodiments,[[]] CDR L3 comprises up to 2 (e.g., 1) single amino acid substitutions or deletions . In some embodiments, CDR H1 comprises up to 2 (e.g., 1) single amino acid substitutions or deletions. In some embodiments, CDR H2 comprises up to 6 (e.g., 5 This includes substitutions or deletions of a single amino acid in 4, 3, 2, or 1). In some embodiments, CDR H3 includes substitutions or deletions of three or fewer (e.g., two or one) single amino acids.

[0090] In some embodiments, the antibody is used in human FcRn a) SEQ ID NO:2 5 and b) Recognize the amino acid sequence of SEQ ID NO:26.

[0091] In some embodiments, the antibody is W131 and / or Y of SEQ ID NO:30 It recognizes the amino acid sequence on FcRn, including 88. In some embodiments, the antibody , including DW, WP, PY and / or YT of SEQ ID NO:30, on FcRn It recognizes the no-acid sequence. In some embodiments, the antibody is G of SEQ ID NO:30 Amino acids on FcRn, including DW, WPE, DWP, PYT, GPY, and / or YTL. Recognizes the sequence. In some embodiments, the antibody is used for GDW of SEQ ID NO:30. P, DWPE, WPEA, GGDW, KGPY, GPYT, PYTL and / or YTLQ It recognizes the amino acid sequence on FcRn, including S. In some embodiments, the antibody recognizes S EQ ID NO:30 GDWPE, DWPEA, WPEAL, GGDWP, WGGDW Fc It recognizes the amino acid sequence on Rn. In some embodiments, the antibody is SEQ ID N O:30 TWGGDW, WGGDWP, GGDWPE, GDWPEA, DWPEAL, WPEALA, GGKGPY, GKGPYT, KGPYTL, GPYTLQ, PYTLT Recognizes amino acid sequences on FcRn including Q and / or YTLQGL. Some implementations In this state, the antibody is within approximately 3 amino acids or 10 angstroms from W131. One or more amino acids, or approximately 5 amino acids or 8 angstroms from Y88. One or more of the amino acids, or the first set being W13 of SEQ ID NO:30 It is either 1 or contains the amino acid, and the second set is SEQ ID NO: 30 Y88 or those containing the amino acid (for example, Y88 and surrounding Y88 It recognizes an amino acid sequence on FcRn that contains any two pairs of amino acids (amino acids).

[0092] In another embodiment, this application features isolated antibodies that bind to human FcRn. The antibody is, (a) A first amino acid sequence containing at least one amino acid from the sequence TIFF0007914147000095.tif4128, (b) The sequence TIFF0007914147000096.tif4128 binds to an epitope containing a second amino acid sequence that includes at least one amino acid from the sequence. This antibody inhibits the binding of IgG to human FcRn.

[0093] In another embodiment, this application features isolated antibodies that bind to human FcRn. The antibody is, The antibody binds to an epitope containing at least one amino acid of the sequence TIFF0007914147000097.tif4128, and the antibody is SEQ ID Binds to at least one of amino acid residues 9, 12, or 13 of NO:25, and the antibody The body inhibits the binding of IgG to human FcRn.

[0094] In another embodiment, this application features isolated antibodies that bind to human FcRn. This antibody is used in FcRn The antibody binds to an epitope containing at least one amino acid of the sequence TIFF0007914147000098.tif4128, and the antibody is sequence It did not bind to the peptide consisting of TIFF0007914147000099.tif4128, nor to the sequence of EEFMNFDL (SEQ ID NO:28). Furthermore, the antibody inhibits the binding of IgG to human FcRn.

[0095] In some embodiments, the epitope is WGGDWPEAL(S) in FcRn. The sequence of EQ ID NO:29) contains at least one amino acid, containing an amino acid, consisting of at least one such amino acid, or substantially consisting of at least one such amino acid It consists of amino acids.

[0096] In some embodiments, the epitope is SEQ ID NO:25 in FcRn. The at least amino acid residue 9, the at least amino acid residue 9, the at Consists of 9 amino acid residues, or substantially consists of at least 9 amino acid residues. In terms of application form, the epitope is at least SEQ ID NO:25 in FcRn It also contains amino acid residue 12, it contains at least amino acid residue 12, it contains at least amino Consists of 12 acid residues, or substantially consists of at least 12 amino acid residues. Partial implementation Morphologically, the epitope is at least SEQ ID NO:25 in FcRn The amino acid residue 13 is included, the amino acid residue 13 is included, the amino acid Consists of 13 residues, or substantially consists of at least 13 amino acid residues. Partial implementation In this state, the epitope is in FcRn. The sequence TIFF0007914147000100.tif4128 contains at least one amino acid, the sequence containing at least one amino acid, A product consisting of at least one amino acid, or substantially consisting of at least one amino acid. In some embodiments, the epitope is in FcRn. The sequence TIFF0007914147000101.tif4128 contains at least two amino acids, the sequence containing at least two amino acids, A product consisting of at least two amino acids, or substantially consisting of at least two amino acids. ru.

[0097] In some embodiments, the antibody is present in FcRn. It binds to an epitope containing at least one amino acid from the sequence TIFF0007914147000102.tif4128, and the antibody The body inhibits the binding of IgG to human FcRn. In some embodiments, the epitome P is in FcRn The sequence TIFF0007914147000103.tif4128 contains at least two amino acids, the sequence containing at least two amino acids, A product consisting of at least two amino acids, or substantially consisting of at least two amino acids. ru.

[0098] In some embodiments, the epitope is in FcRn The sequence TIFF0007914147000104.tif4128 further comprises at least one amino acid, said at least one amino acid Furthermore, further comprising, further consisting of at least one amino acid, or even more substantially less Each consists of a single amino acid.

[0099] In some embodiments, the antibody is present in FcRn. It binds to at least two amino acids in the sequence TIFF0007914147000105.tif4128.

[0100] In some embodiments, the antibody is used to target SEQ ID NO:25 in FcRn. It binds to at least one of the no-acid residues 9, 12, or 13.

[0101] In some embodiments, the antibody is less likely to have SEQ ID NO:25 in FcRn It also binds to amino acid residue 9. In some embodiments, the antibody is in FcRn It binds to at least amino acid residue 12 of SEQ ID NO:25. In this case, the antibody is at least one amino acid residue of SEQ ID NO:25 in FcRn. Combine with 13.

[0102] In some embodiments, the antibody is 1 pM to 100 nM K D It binds to human FcRn. do.

[0103] In some embodiments, the antibody is antibody N026 K D The following K D And human FcRn and Combine.

[0104] In some embodiments, the antibody is a monoclonal antibody.

[0105] In some embodiments, the antibody is IgG1.

[0106] In some embodiments, the antibody is composed of a λ light chain, a λ light chain, a λ light chain, Or it consists substantially of λ light chains.

[0107] In some embodiments, the antibody is a sialic acid-modified antibody.

[0108] In some embodiments, antibodies are used to alloimmune and / or autoimmune disorders of fetuses and neonates. It is used for the treatment of disease-related illnesses.

[0109] In some embodiments, antibodies are used to alloimmune and / or autoimmune disorders of fetuses and neonates. It is intended to reduce the risk of developing infectious diseases.

[0110] In some embodiments, antibodies increase the risk of developing autoimmune disorders or alloimmune disorders. It is for mitigation purposes.

[0111] In some embodiments, antibodies are used to alloimmune and / or autoimmune disorders of fetuses and neonates. It is used for the treatment of disease-related illnesses.

[0112] In another embodiment, this application relates to the isolation of an antibody in any of the above embodiments. The invention is characterized by nucleic acid molecules. In another embodiment, the invention relates to a vein containing these nucleic acid molecules. It is characterized by a host cell that can express isolated antibodies. The host cell contains nucleic acid molecules or vectors, and Including, consisting of nucleic acid molecules or vectors, or substantially from nucleic acid molecules or vectors This nucleic acid molecule or vector is expressed within the host cell. The host cell, These could be Chinese hamster ovary (CHO) cells.

[0113] In another embodiment, this application relates to an isolated antibody from any of the embodiments described above, and 1 A pharmaceutical composition characterized by comprising one or more pharmaceutically acceptable carriers or excipients. Antibodies can be formulated in therapeutically effective doses.

[0114] In another embodiment, this application relates to the preparation of an isolated antibody in any of the embodiments described above. The method is characterized by the following: a) Provide a host cell containing the nucleic acid molecule described in claim 178 or the vector described in claim 179. To provide, b) Express nucleic acid molecules or vectors in host cells under conditions that enable antibody formation. This includes the act of doing so.

[0115] In some embodiments, the method is approximately 1-100, 1-50, 1-25, 2-50 The procedure may further include a step of recovering antibodies at a concentration of 5-50 or 2-20 mg / ml. stomach.

[0116] In some embodiments, the host cell is a CHO cell.

[0117] In another embodiment, this application relates to alloimmune disorders and / or autoimmune disorders of fetuses and neonates. A method for treating a disorder, characterized by a method that includes administering antibodies to a pregnant subject. The antibody is one of the embodiments described above.

[0118] In some embodiments, the subjects are those who previously had alloimmune disorders and / or autoimmune disorders in fetuses and neonates. He has a history of having an autoimmune disorder.

[0119] In some embodiments, the subjects are fetuses and neonates with alloimmune disorders and / or autoimmune disorders. There is a risk of developing a disability.

[0120] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal are Alloimmune thrombocytopenia in fetuses and neonates, hemolytic diseases in fetuses and neonates, alloimmune Panthrombocytopenia, congenital heart block, fetal joint contractures, neonatal myasthenia gravis, neonatal Autoimmune hemolytic anemia, neonatal antiphospholipid antibody syndrome, neonatal polymyositis, dermatomyositis, neonatal Lupus in infants, scleroderma of the newborn, Behçet's disease, Graves' disease of the newborn, Kawasaki disease of the newborn The group is selected from those with autoimmune thyroid disease and neonatal type 1 diabetes.

[0121] In some embodiments, the treatment reduces the risk of miscarriage.

[0122] In another embodiment, this application relates to fetal anemia associated with hemolytic disorders of the fetus and neonatal A method of treatment, which involves administering one of the antibodies described above to a pregnant subject. The method is characterized by including this.

[0123] In some embodiments, this method involves the pregnant subject, the fetus of the pregnant subject, and / Alternatively, treat a combination of these conditions.

[0124] In another embodiment, this application relates to a method for treating an autoimmune disorder, which is for pregnant women. The method is characterized by administering an antibody to an elephant in any of the above embodiments.

[0125] In some embodiments, this autoimmune disorder manifests as alopecia areata, ankylosing spondylitis, and antiphosphate Lipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, water Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, localized Systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid leukemia Cryoglobulinemia (essential mixed type), fibromyalgia, fibromyositis, Graves' disease, Hashimoto's disease Thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic lung Fibrosis, IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, lupus, Nieille's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polymolar tumor Osteitis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's artery A group consisting of inflammation, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, or Wegener's granulomatosis. Selected from.

[0126] In some embodiments, the treatment reduces the risk of miscarriage / fetal loss.

[0127] In another embodiment, this application reduces the risk of autoimmune disorders or alloimmune disorders. A method to cause or reduce the risk of developing autoimmune disorders or alloimmune disorders. This method is characterized by administering one of the antibodies described above to a pregnant subject. Let's assume that.

[0128] In some embodiments, this autoimmune disorder manifests as alopecia areata, ankylosing spondylitis, and antiphosphate Lipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, water Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, localized Systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid leukemia Cryoglobulinemia (essential mixed type), fibromyalgia, fibromyositis, Graves' disease, Hashimoto's disease Thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic lung Fibrosis, IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, lupus, Nieille's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polymolar tumor Osteitis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's artery A group consisting of inflammation, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, or Wegener's granulomatosis. Selected from.

[0129] In some embodiments, the treatment reduces the risk of miscarriage / fetal loss.

[0130] In another embodiment, this application relates to a method for increasing the catabolic effect of an antibody in a subject. The method is characterized by the use of any isolated antibody or pharmaceutical compound as described above. This includes administering the substance to the subject.

[0131] In some embodiments, increasing the catabolic activity of antibodies is the catabolic activity of pathogenic antibodies. This includes increasing the catabolic activity of pathogenic antibodies, including increasing the catabolic activity of pathogenic antibodies. This involves increasing the effect, or substantially increasing the catabolic effect of pathogenic antibodies. Yes.

[0132] In some embodiments, pathogenic antibodies are effective against the mother, the fetus, or both the mother and the fetus. It becomes a pathogen.

[0133] In some embodiments, the antibody is an IgG antibody.

[0134] In another embodiment, this application is characterized by a method for reducing autoantibodies in a subject. The method involves using any of the above embodiments to isolate an antibody or pharmaceutical composition. This includes administering the substance to the subject.

[0135] In another embodiment, this application relates to the activity of immune complexes in an immune response in a subject. The method is characterized by a method that reduces the amount of chemicals produced, and the method is one of the embodiments described above. This includes administering the released antibody or pharmaceutical composition to the subject.

[0136] In some embodiments, the immune response is an acute or chronic immune response in the subject. That is the case.

[0137] In some embodiments, the acute immune response is used in cases of pemphigus vulgaris, lupus nephritis, and myasthenia gravis. Mycosis, Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immunotherapy Complex-mediated vasculitis, glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic hematology Thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy and serum It is activated by a medical condition selected from a group of diseases.

[0138] In some embodiments, the autoimmune disorder of the fetus and neonatal and / or autoimmune disorder is It is a hemolytic disease affecting the fetus and newborn.

[0139] In some embodiments, the autoimmune disorder of the fetus and neonatal and / or autoimmune disorder is This is alloimmune thrombocytopenia in fetuses and neonates.

[0140] In some embodiments, the autoimmune disorder of the fetus and neonatal and / or autoimmune disorder is It is a congenital heart block.

[0141] In some embodiments, the chronic immune response is chronic inflammatory demyelinating polyneuropathy ( CIDP), systemic lupus, reactive joint disorders, primary biliary cirrhosis, ulcerative colitis and Depending on the medical condition selected from the group consisting of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis It becomes activated.

[0142] In some embodiments, the subjects have an autoimmune disease.

[0143] In some embodiments, autoimmune diseases include alopecia areata, ankylosing spondylitis, and antiphospholipids. Antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammation Demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, localized pemphigoid CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid loop S, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis Adenitis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrillation IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease Ruhl's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis Polymyalgia, polymyositis, primary agammaglobulinemia, Original biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's arteritis, From the group consisting of temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis Selected.

[0144] In another aspect, this application reduces the transfer of antibodies across the placenta of a pregnant subject. The method is characterized by the use of an isolated antibody in any of the above embodiments. This may include administering a pharmaceutical composition to a pregnant subject.

[0145] In some embodiments, reducing antibody transfer reduces the transfer of pathogenic antibodies. Reducing the transfer of pathogenic antibodies, including reducing the transfer of pathogenic antibodies This consists of, or substantially reduces, the transfer of pathogenic antibodies.

[0146] In another embodiment, this application increases the catabolic effect of antibodies in pregnant subjects. The method is characterized by an isolated antibody or This includes administering a pharmaceutical composition to a pregnant subject.

[0147] In some embodiments, increasing the catabolic activity of antibodies is the catabolic activity of pathogenic antibodies. This includes increasing the catabolic activity of pathogenic antibodies, including increasing the catabolic activity of pathogenic antibodies. This involves increasing the effect, or substantially increasing the catabolic effect of pathogenic antibodies. Yes.

[0148] In another embodiment, this application relates to antibody-mediated transmission of viral diseases in fetuses or neonates. The method is characterized by a method for treating enhancement of sexually transmitted infections, and the method is any of the above embodiments. This includes administering the isolated antibody or pharmaceutical composition to a pregnant subject.

[0149] In some embodiments, pathogenic antibodies are used in the fetus of a pregnant subject, affecting both the fetus and the newborn. It causes alloimmune disorders and / or autoimmune disorders in children.

[0150] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal are Alloimmune thrombocytopenia in fetuses and neonates, hemolytic diseases in fetuses and neonates, alloimmune Panthrombocytopenia, congenital heart block, fetal joint contractures, neonatal myasthenia gravis, neonatal Autoimmune hemolytic anemia, neonatal antiphospholipid antibody syndrome, neonatal polymyositis, dermatomyositis, neonatal Lupus in infants, scleroderma of the newborn, Behçet's disease, Graves' disease of the newborn, Kawasaki disease of the newborn The group is selected from those with autoimmune thyroid disease and neonatal type 1 diabetes.

[0151] In some embodiments, the antibody is an IgG antibody.

[0152] In some embodiments, viral diseases include alphavirus infections and flavivirus infections. Ross River virus infection, Zika virus infection, Chikungunya virus infection, Ross River virus infection Infectious diseases, severe acute respiratory syndrome (Coronavirus infection), Middle East respiratory syndrome, avian influenza Infectious diseases, influenza virus infection, human respiratory syncytial virus infection, Ebola virus infection Infectious diseases, yellow fever virus infection, dengue virus infection, human immunodeficiency virus infection, RSV infection, hantavirus infection, getavirus infection, sindovis virus Infectious diseases, Bunyamwella virus infection, West Nile virus infection, Japanese encephalitis virus B Infectious diseases, rabbitpox virus infection, lactate dehydrogenase-elevated virus infection, reovirus infection Rabies virus infection, Foot-and-mouth disease virus infection, Porcine genitourinary respiratory syndrome virus infection Infections, monkey hemorrhagic fever virus infection, equine infectious anemia virus infection, goat arthritis virus Infectious diseases, African swine fever virus infection, lentivirus infection, BK papovavirus infection Infections, Murray Valley Encephalitis virus infection, enterovirus infection, cytomegalovirus Infectious diseases, including Pneumovirus infection, Morbillivirus infection, and measles virus infection. It is caused by a virus selected from a group of viruses.

[0153] In some embodiments, pregnant subjects activate an immune response within the pregnant subjects. Having a medical condition that causes or being at risk of developing such a medical condition.

[0154] In some embodiments, the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis. Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immunosuppression Pseudo-vasculitis, glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic hemoptysis Platelet-clonic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, serum sickness, Chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive joint disorder, primary biliary Cirrhosis of the liver, ulcerative colitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, alopecia areata, ankylostosis Spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, - Chet's disease, bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue, immune function Disorder syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring Pemphigoid, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, skin Dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Basedow's disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus lupus erythematosus, lupus erythematosus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa arteritis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia macroglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulo matosis.

[0155] In some embodiments, the pregnant subject has a history of having previously given birth to a fetus or neonate that had fetal and neonatal alloimmune disorders and / or autoimmune disorders.

[0156] In some embodiments, antibodies associated with an immune disease are detected in a biological sample obtained from the pregnant subject.

[0157] In some embodiments, the biological sample is a blood sample or a urine sample.

[0158] In some embodiments, the antibody binds to human FcRn with a K D of 1 pM to 100 nM .

[0159] In some embodiments, the isolated antibody binds to human FcRn with a K D that is less than or equal to the K D of antibody N026 D .

[0160] ​In some embodiments, the isolated antibody is a monoclonal antibody.

[0161] In some embodiments, the isolated antibody is IgG1 or a variant thereof.

[0162] In some embodiments, the isolated antibody contains a λ light chain, a λ light chain, a λ light chain It consists of, or substantially consists of, a λ light chain.

[0163] In some embodiments, the isolated antibody is a sialic acid-added antibody.

[0164] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. A chain variable region, including for the treatment of alloimmune disorders and / or autoimmune disorders in fetuses and neonates. It is characterized by isolated antibodies, and CDR L1 is sequence CD R L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13), and the sequence , consisting of or substantially consisting of the sequence, CDR L3 is sequence CD R H1 contains the sequence Z1YAMG (SEQ ID NO: 15), the sequence containing, the Consists of a sequence, or substantially consists of such sequence, and CDR H2 is sequence CD R H3 contains the sequence LAZ5Z6DSY (SEQ ID NO: 17), and the sequence , consisting of or substantially consisting of the sequence, where X1 is polar or hydrophobic X2 is a hydrophobic amino acid, X3 is a polar amino acid, and X4 is a polar amino acid. X5 is an acidic amino acid, X6 is a polar or hydrophobic amino acid, and X6 is a hydrophobic amino acid. It is an acid, Z1 is a polar or acidic amino acid, and Z2 is a polar or hydrophobic amino acid. Z3 is G, S, or A, Z4 is a basic amino acid, and Z5 is hydrophobic or basic These are amino acids, where Z6 is G, S, D, Q, or H, and Z7 is S or T.

[0165] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, isolated antibodies include (1) CDR L1, CDR L2, and CDR L3. (1) Light chain variable region and (2) Heavy chain variable including CDR H1, CDR H2 and CDR H3 The light chain variable region and the heavy chain variable region include the region and the heavy chain variable A region consisting of, or substantially consisting of, the light chain variable region and the heavy chain variable region, C DR L1 is, A sequence containing, or derived from, a sequence having two or fewer amino acid substitutions compared to the sequence TIFF0007914147000109.tif4128 It consists of, or substantially consists of, the sequence, and CDR L2 is GDSERPS(SEQ The sequence includes a sequence having one or fewer amino acid substitutions compared to the sequence of ID NO:2). The sequence consists of, or substantially consists of, the sequence, and CDR L3 is A sequence containing one or fewer amino acid substitutions compared to the sequence TIFF0007914147000110.tif4128, a sequence containing, a sequence derived from It consists of, or substantially comprises, the sequence, and CDR H1 is TYAMG(SEQ I D NO:4), DYAMG (SEQ ID NO:5) or NYAMG (SEQ ID N The sequence includes a sequence having one or fewer amino acid substitutions compared to the sequence O:6), the sequence includes the Consists of columns, or substantially of such sequence, and CDR H2 is, A sequence containing, from, a sequence having 2 or fewer amino acid substitutions compared to the sequence TIFF0007914147000111.tif22158 It consists of, or substantially consists of, the sequence, and CDR H3 is LAIGDSY(SEQ The sequence includes a sequence having one or fewer amino acid substitutions compared to the sequence of ID NO:11. It includes, consists of, or substantially consists of the sequence.

[0166] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000112.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), and The CDR L3 of the detached antibody is sequence Including TIFF0007914147000113.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H1 of the antibody contains the sequence TYAMG (SEQ ID NO: 4), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000114.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0167] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000115.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000116.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence DYAMG (SEQ ID NO: 5), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000117.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0168] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000118.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000119.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence NYAMG (SEQ ID NO: 6), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000120.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of, an array.

[0169] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000121.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000122.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence TYAMG (SEQ ID NO: 4), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000123.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0170] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000124.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000125.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence TYAMG (SEQ ID NO: 4), A C of an isolated antibody comprising, or substantially comprising, the sequence, including, the sequence. DR H2 is a sequence Including TIFF0007914147000126.tif4131, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). It includes, consists of, or substantially consists of the sequence.

[0171] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000127.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR L2 of the antibody contains the sequence GDX3X4RPS (SEQ ID NO: 13). a, including, consisting of, or substantially consisting of the sequence, isolated The CDR L3 of the antibody is sequence Including TIFF0007914147000128.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, and isolated The CDR H1 of the antibody contains the sequence Z1YAMG (SEQ ID NO: 15). An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR H2 is, Including TIFF0007914147000129.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAZ5Z6DSY (SEQ ID NO: 17). The sequence includes, consists of, or substantially consists of the sequence, and X1 is T , is A, S or I, X2 is L or I, X3 is S, N or T, X4 is Q, It is E or N, X5 is C, S, I or Y, X6 is A or V, Z1 is E or T , is D or N, Z2 is S or A, Z3 is G, S or A, Z4 is K or R Z5 is I, L or H, Z6 is G, S, D, Q or H, and Z7 is S or It is T.

[0172] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the isolated antibody CDR L1 is sequence Including TIFF0007914147000130.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR L2 of the antibody contains the sequence GDSERPS (SEQ ID NO:2), An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR L3 is, Including TIFF0007914147000131.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H1 of the antibody contains the sequence Z1YAMG (SEQ ID NO: 15). An isolated antibody containing, consisting of, or substantially consisting of a sequence The CDR H2 is, Including TIFF0007914147000132.tif4128, including the sequence, consisting of the sequence, or substantially consisting of the sequence, isolated The CDR H3 of the antibody contains the sequence LAIGDSY (SEQ ID NO: 11). A sequence containing, consisting of, or substantially consisting of, where Z1 is T, D or N, Z2 is S or A, Z3 is G, S or A, and Z7 is S or T. ru.

[0173] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000133.tif22165, and a sequence containing the sequence from the sequence It consists of, or substantially comprises, the said arrangement.

[0174] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the heavy chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000134.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially comprises, the said arrangement.

[0175] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the heavy chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000135.tif41165, and a sequence containing the sequence from the sequence It consists of, or substantially comprises, the said arrangement.

[0176] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the heavy chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000136.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially comprises, the said arrangement.

[0177] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the heavy chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000137.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0178] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the heavy chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000138.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0179] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000139.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000140.tif41165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0180] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000141.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000142.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0181] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000143.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000144.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0182] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000145.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000146.tif40165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0183] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000147.tif22165, and a sequence containing the sequence from the sequence The heavy chain variable region of an isolated antibody, which consists of or substantially comprises the sequence, A sequence containing a sequence having at least 90% identity with the sequence TIFF0007914147000148.tif41165, and a sequence containing the sequence from the sequence It consists of, or substantially consists of, the said arrangement.

[0184] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the heavy chain variable region of isolated antibodies is selected from among SEQ ID NO: 20-24. A sequence having at least 95%, 97%, 99%, or 100% identity with one of the sequences. Including a column, including the sequence, consisting of the sequence, or substantially consisting of the sequence.

[0185] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic use, the light chain variable region of the isolated antibody is less than the sequence shown in SEQ ID NO:19. A sequence containing at least 95%, 97%, 99%, or 100% identity. , consisting of the sequence, or substantially consisting of the sequence.

[0186] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence that includes, contains, consists of, or substantially consists of the sequence TIFF0007914147000149.tif22165 The heavy chain variable region of the isolated antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000150.tif40165.

[0187] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000151.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000152.tif40165.

[0188] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000153.tif22165, is isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000154.tif41165.

[0189] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000155.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000156.tif41165.

[0190] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal For therapeutic purposes, the light chain variable region of isolated antibodies is A sequence containing, comprising, or substantially comprising the sequence TIFF0007914147000157.tif22165, isolated The heavy chain variable region of the antibody is A sequence that includes, contains, consists of, or substantially consists of, the sequence TIFF0007914147000158.tif41166.

[0191] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. It is characterized by isolated antibodies containing a chain variable region, and CDR L1 is sequence V A sequence containing GX1YNX2, a sequence consisting of the sequence, or a sequence substantially consisting of the sequence Therefore, CDR L2 includes the sequence GDX3X4, includes the sequence, and consists of the sequence. Or substantially consisting of the sequence, and CDR L3 includes the sequence YX6GSGIY , including the sequence, consisting of the sequence, or substantially consisting of the sequence, CDR H 1 includes the sequence Z1YA, includes the sequence, consists of the sequence, or is substantially composed of the sequence. The CDR H2 includes the sequence Z8IZ2Z3SZ4Z5QZ6R, and the sequence A sequence comprising, or substantially comprising, CDR H3 is distributed A sequence containing column LAZ7, a sequence consisting of, or substantially consisting of Yes, X1 is any amino acid, X2 is L or I, and X3 is S, N or T. X4 is Q, E, or N, X6 is A or V, and Z1 is E, T, D, or N. Z2 is any amino acid, Z3 is S or A, Z4 is any amino acid, Z 5 is G, S, or A, Z6 is any amino acid, Z7 is I, L, or H, Z 8 is either S or T.

[0192] In another embodiment, this application includes (1) CDR L1, CDR L2 and CDR L (2) A light chain variable region including 3, and heavy chain including CDR H1, CDR H2 and CDR H3. It is characterized by isolated antibodies containing a chain variable region, and CDR L1 is sequence V A sequence containing GX1YNX2, a sequence consisting of the sequence, or a sequence substantially consisting of the sequence Therefore, CDR L2 includes the sequence GDX3X4, includes the sequence, and consists of the sequence. Or substantially consisting of the sequence, and CDR L3 includes the sequence YX6GSGIY , including the sequence, consisting of the sequence, or substantially consisting of the sequence, CDR H 1 includes the sequence Z1YA, includes the sequence, consists of the sequence, or is substantially composed of the sequence. The CDR H2 includes the sequence Z8IZ2Z3SZ4Z5QZ6R, and the sequence A sequence comprising, or substantially comprising, CDR H3 is distributed A sequence containing column LAZ7, a sequence consisting of, or substantially consisting of Yes, X1 is any amino acid, X2 is a hydrophobic amino acid, and X3 is a polar amino acid. X4 is a polar or acidic amino acid, X6 is a hydrophobic amino acid, and Z1 is polar It is a polar or acidic amino acid, Z2 is any amino acid, and Z3 is a polar or hydrophobic amino acid. It is an amino acid, Z4 is any amino acid, Z5 is G, S or A, and Z5 is hydrophobic. or a basic amino acid, Z6 is any amino acid, and Z7 is hydrophobic or basic It is an amino acid, and Z8 is either S or T.

[0193] In some embodiments, antibodies are used to alloimmune and / or autoimmune disorders of fetuses and neonates. It is for the treatment of infectious diseases. In some embodiments, the antibodies of the two embodiments described above are used in the method described above. It is used in conjunction with one of the following.

[0194] In some embodiments, the isolated antibody is an anti-FcRn antibody. In some cases, The antibody inhibits the binding of IgG to FcRn. In some embodiments, isolated The antibody does not bind to E115 of FcRn (SEQ ID NO: 30). (Some embodiments) In this study, the isolated antibody contained FcRn E115 (SEQ ID NO: 30). It binds to an epitope that does not exist.

[0195] This invention also provides a method for reducing the transfer of pathogenic antibodies across the placenta of a pregnant subject. A method to increase the catabolic activity of pathogenic antibodies in a subject, and a method for pregnant subjects to receive human neonatal type Fc By administering isolated antibodies that bind to the compound (FcRn), the fetus or newborn can be treated. A key feature is the treatment of antibody-mediated enhancement of viral infections in some cases. In this state, pathogenic antibodies in the pregnant subject are present in the fetus of the pregnant subject, and It causes alloimmune disorders and / or autoimmune disorders in newborns.

[0196] In some embodiments, the isolated antibodies are (1) CDR L1, CDR L2 and (2) CDR H1, CDR H2 and CDR It contains a heavy chain variable region including H3, and CDR L1 is The sequence has two or fewer amino acid substitutions compared to the sequence of TIFF0007914147000159.tif4128, and CDR L2 is GDSER The sequence has one or fewer amino acid substitutions compared to the sequence of PS (SEQ ID NO:2). CDR L3 is, The sequence has one or fewer amino acid substitutions compared to the sequence of TIFF0007914147000160.tif4128, and CDR H1 is TYAMG (SEQ ID NO:4), DYAMG (SEQ ID NO:5) or NYAMG (SE The sequence has one or fewer amino acid substitutions compared to the sequence of Q ID NO:6), and CDR H2 is The sequence has two or fewer amino acid substitutions compared to the sequence TIFF0007914147000161.tif10131, and CDR H3 is LAIGD The sequence has one or fewer amino acid substitutions compared to the sequence of SY (SEQ ID NO:11). do.

[0197] In some embodiments, the antibody concentration is less than 200, 150, 100, 50, or 40 pM. K D It then binds to human FcRn.

[0198] In some embodiments, the antibody is N022, N023, N024, N026 or N It has a light chain variable region and a heavy chain variable region of 027, and the same Fc region as the antibody being compared. K of antibodies that further possess the region D Less than or the K D K is equal to D It then binds to human FcRn.

[0199] In other embodiments, the isolated antibodies are (1) CDR L1, CDR L2 and (2) CDR H1, CDR H2 and CDR H It contains a heavy chain variable region including 3, and CDR L1 is The sequence TIFF0007914147000162.tif4128 is present, and CDR L2 is the sequence GDX3X4RPS (SEQ ID NO:13) CDR L3 has, The sequence TIFF0007914147000163.tif4128 is present, and CDR H1 has the sequence Z1YAMG (SEQ ID NO:15) CDR H2 is, The sequence TIFF0007914147000164.tif4128 is present, and CDR H3 has the sequence LAZ5Z6DSY (SEQ ID NO:17) It has, where X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid, and X3 is It is a polar amino acid, X4 is a polar or acidic amino acid, and X5 is a polar or hydrophobic amino acid. It is an amino acid, X6 is a hydrophobic amino acid, Z1 is a polar or acidic amino acid, Z 2 is a polar or hydrophobic amino acid, Z3 is G, S, or A, and Z4 is a basic amino acid. It is an acid, Z5 is a hydrophobic or basic amino acid, and Z6 is G, S, D, Q, or H. The antibody has a light chain variable region and a heavy chain variable region of N026, and is being compared. K of antibodies that also have the same Fc region as the antibody D Less than or the K D K is equal to D Human Fc It is coupled with Rn. In some embodiments, X1 is T, A, S, or I. Other embodiments In the form, X2 is L or I. In some embodiments, X3 is S, N or It is T. In yet another embodiment, X4 is Q, E or N, and X5 is C, S, It is I or Y. In some embodiments, X6 is A or V, and Z1 is E, T, or D. or N. In further embodiments, Z2 is S or A. In some embodiments In this embodiment, Z4 is K or R. In another embodiment, Z5 is I, L or H. be.

[0200] In yet another embodiment, the isolated antibody is CDR L1 having the sequence TIFF0007914147000165.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, A light chain variable region including CDR L3 having the sequence TIFF0007914147000166.tif4128, and Z1YAMG(SEQ ID NO CDR H1 having the sequence :15), CDR H2 having the sequence TIFF0007914147000167.tif4128 and LAIGDSY (SEQ ID NO:11) It contains a heavy chain variable region including CDR H3, and Z1 is T, D or N. Yes, Z2 is S or A, and Z3 is G, S or A.

[0201] In some embodiments, the isolated antibody is CDR L1 having the sequence TIFF0007914147000168.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000169.tif4128 and C having the sequence TYAMG (SEQ ID NO:4) DR H1 and, CDR H2 having the sequence TIFF0007914147000170.tif4128 and LAIGDSY (SEQ ID NO:11) It contains CDR H3.

[0202] In some embodiments, the isolated antibody is CDR L1 having the sequence TIFF0007914147000171.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000172.tif4128 and C having the sequence DYAMG (SEQ ID NO:5) DR H1 and, CDR H2 having the sequence TIFF0007914147000173.tif4128 and LAIGDSY (SEQ ID NO:11) It contains CDR H3.

[0203] In some embodiments, the isolated antibody is CDR L1 having the sequence TIFF0007914147000174.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000175.tif4128 and C having the sequence NYAMG (SEQ ID NO:6) DR H1 and, CDR H2 having the sequence TIFF0007914147000176.tif4128 and LAIGDSY (SEQ ID NO:11) It contains CDR H3.

[0204] In your embodiment, the isolated antibody is CDR L1 having the sequence TIFF0007914147000177.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000178.tif4128 and C having the sequence TYAMG (SEQ ID NO:4) DR H1 and, CDR H2 having the sequence TIFF0007914147000179.tif4128 and LAIGDSY (SEQ ID NO:11) It contains CDR H3.

[0205] In other embodiments, the isolated antibody is CDR L1 having the sequence TIFF0007914147000180.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000181.tif4128 and C having the sequence TYAMG (SEQ ID NO:4) DR H1 and, CDR H2 having the sequence TIFF0007914147000182.tif4128 and LAIGDSY (SEQ ID NO:11) It contains CDR H3.

[0206] In some embodiments, the light chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000183.tif22165.

[0207] In some embodiments, the heavy chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000184.tif41165.

[0208] In other embodiments, the heavy chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000185.tif40165.

[0209] In other embodiments, the heavy chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000186.tif40165.

[0210] In some embodiments, the heavy chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000187.tif40165.

[0211] In other embodiments, the heavy chain variable region of the isolated antibody of this application is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000188.tif41165.

[0212] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence has at least 90% identity with the sequence TIFF0007914147000189.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000190.tif40165.

[0213] In other embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The light chain variable region is The sequence has at least 90% identity with the sequence TIFF0007914147000191.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000192.tif40165.

[0214] In other embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The light chain variable region is The sequence has at least 90% identity with the sequence TIFF0007914147000193.tif23165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000194.tif40165.

[0215] In other embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The light chain variable region is The sequence has at least 90% identity with the sequence TIFF0007914147000195.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000196.tif41165.

[0216] In other embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The light chain variable region is The sequence has at least 90% identity with the sequence TIFF0007914147000197.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000198.tif41165.

[0217] In some embodiments, the heavy chain variable region of the isolated antibody of this application is SEQ I D NO: One of the sequences from 20-24 and at least 95%, 97%, or 99% or having an array with 100% identity. In other embodiments, the isolation of this application The light chain variable region of the antibody was found to be at least 95% of the sequence with SEQ ID NO:19. It has sequences with 97%, 99%, or 100% identity.

[0218] In some embodiments, the isolated antibodies of this application are SEQ ID NO:20~ Compared to any one of the 24 sequences, it further contains the amino acid substitution N297A.

[0219] In other embodiments, isolated antibodies are selected from among SEQ ID NO: 20-24. Compared to any one of the sequences, it further contains amino acid substitutions D355E and L357M.

[0220] In other embodiments, the isolated antibodies of this application are SEQ ID NO:20~2 Compared to any one of the 4 sequences, the following amino acid substitutions: A23V, S30R, L8 Compared to the sequences of 0V, A84T, E85D, A93V, and SEQ ID NO:19 The following amino acid substitutions: Q38H, V58I, and G99D, one or more of these. It also includes numbers.

[0221] In another embodiment, the isolated antibody of this application is SEQ ID NO:20 Compared to any one of the 24 sequences, the sequence containing C-terminal lysine at residue 446 do not have.

[0222] In some embodiments, any of the antibodies in the above embodiments are N022, N023 , having light chain variable region and heavy chain variable region of N024, N026 or N027, and comparative The K of the antibody that has the same Fc region as the antibody being tested. D Less than or the K D K is equal to D It binds to human FcRn. For example, a specific K D In the assay, the K of the antibody D is, 2 It is less than 00, 150, 100, 50, or 40 pM.

[0223] The complementarity-determining region (CDR) and frame of any isolated antibody described herein. The amino acid positions assigned to the FR region are determined by the Kabat EU index (S sequences of Proteins of Immunological In terest,5th Ed.Public Health Service,Nati onal Institutes of Health,Bethesda,MD.(1 It was defined in accordance with 991)).

[0224] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence is TIFF0007914147000199.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000200.tif40165.

[0225] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence is TIFF0007914147000201.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000202.tif41165.

[0226] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence is TIFF0007914147000203.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000204.tif40165.

[0227] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence is TIFF0007914147000205.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000206.tif40165.

[0228] In some embodiments, the isolated antibody contains a light chain variable region and a heavy chain variable region. The variable light chain region is, The sequence is TIFF0007914147000207.tif23165, and the heavy chain variable region is It has the sequence TIFF0007914147000208.tif41165.

[0229] In some of the embodiments described above, the isolated antibody of this application is It is a monoclonal antibody. In some embodiments, the isolated antibody is IgG1 In some embodiments, the isolated antibody contains a λ light chain. In this embodiment, the isolated antibody contains a kappa light chain. In some embodiments, the isolated The glycosylation sites on the Fc region of the antibody are sialic acid-added (for example, disialization). (disialylated).

[0230] In some of the embodiments described above, the isolated antibody of this application is These are humanized antibodies or fully human antibodies.

[0231] In some embodiments, isolated antibodies are 1-100, 5-150, 5-100 , 5-75, 5-50, 10-50 or 10-40 pM K D It binds to human FcRn. .

[0232] In some embodiments, the isolated antibodies of this application are used in rodents, such as mice. Alternatively, it binds to rat FcRn. In some embodiments, the isolated antibody of this application The body has a K content of less than 200, 150, 100, 50, or 40 pM. D So, rodents, for example, ma It binds to FcRn in mice or rats.

[0233] This invention features novel antibodies against the human neonatal type Fc receptor (FcRn). Anti-FcRn antibodies, for example, promote the clearance of autoantibodies in the target, Suppression of antigen presentation, for example, inhibiting the activation of immune complexes in the immune response to a target. It is useful for inhibiting the immune response or for treating immune diseases (e.g., autoimmune diseases) in the target. These anti-FcRn antibodies also prevent the transfer of pathogenic antibodies across the placenta of pregnant subjects. Methods to reduce, methods to increase the catabolic activity of pathogenic antibodies in pregnant subjects, pregnant By administering isolated antibodies that bind to FcRn to the target, the fetus or neonatal can be stimulated. It is also useful in treating antibody-mediated enhancement of viral infections. In the embodiment, pathogenic antibodies in a pregnant subject are present in the fetus of the pregnant subject. It causes alloimmune disorders and / or autoimmune disorders in the fetus and newborn.

[0234] In one embodiment, this application is characterized by an isolated antibody that binds to FcRn. Yes, and the antibody is (a) (b) At least one amino acid from the sequence TIFF0007914147000209.tif4128 The antibody binds to at least one amino acid in the sequence TIFF0007914147000210.tif4128, and the antibody is human IgG. It inhibits binding to FcRn.

[0235] In another embodiment, this application features isolated antibodies that bind to human FcRn. The antibody is, The antibody binds to at least one amino acid in the sequence TIFF0007914147000211.tif4128, and the antibody has SEQ ID NO:25 The antibody binds to at least one of the amino acid residues 5, 12, or 13 of Ig Inhibits the binding of G to human FcRn.

[0236] In another embodiment, this application features isolated antibodies that bind to human FcRn. The antibody is, The antibody binds to at least one amino acid in the sequence TIFF0007914147000212.tif4128, and the antibody is sequence The peptide consisting of TIFF0007914147000213.tif4128 also contains one of the sequences of EEFMNFDL (SEQ ID NO:28). Alternatively, it does not bind to multiple amino acids, and the antibody inhibits the binding of IgG to human FcRn. do.

[0237] In some embodiments, the antibody is WGGDWPEAL (SEQ ID NO:29) It binds to at least one amino acid in the sequence.

[0238] In some embodiments, the antibody has at least one amino acid residue of SEQ ID NO:25. It binds to group 5. In some embodiments, the antibody is less than SEQ ID NO:25 Both bind to amino acid residue 12. In some embodiments, the antibody is SEQ ID N It binds to at least 13 amino acid residues of O:25.

[0239] In some embodiments, the antibody is It binds to at least one amino acid in the sequence TIFF0007914147000214.tif4128. In some embodiments, the antibody teeth, At least two amino acids from the sequence TIFF0007914147000215.tif4128.

[0240] In another embodiment, this application features isolated antibodies that bind to human FcRn. The antibody is, The antibody binds to at least one amino acid in the sequence TIFF0007914147000216.tif4128, and the antibody then binds to the human FcRn of IgG. It inhibits the binding of the antibody. In some embodiments, the antibody is It binds to at least two amino acids in the sequence TIFF0007914147000217.tif4128.

[0241] In some embodiments, the antibody is Further binding occurs to at least one amino acid in the sequence TIFF0007914147000218.tif4128. In some embodiments, Antibodies are, It further binds to at least two amino acids in the sequence TIFF0007914147000219.tif4128.

[0242] In some embodiments, the antibody is derived from amino acid residues 5 and 12 of SEQ ID NO:25. Or it binds to at least one of 13. In some embodiments, the antibody is SE It binds to at least amino acid residue 5 of Q ID NO:25. In some embodiments, The antibody binds to at least amino acid residue 12 of SEQ ID NO:25. In the application form, the antibody binds to at least amino acid residue 13 of SEQ ID NO:25. To combine.

[0243] In some embodiments, the antibody described herein is the K of antibody N026. D Less than or The K D K is equal to D It then binds to human FcRn.

[0244] In some embodiments, the antibody is a monoclonal antibody. In this embodiment, the antibody is IgG1. In some embodiments, the antibody contains a λ light chain. In some embodiments, the isolated antibody contains kappa light chains. In this case, the antibody is an antibody that has undergone sialic acid addition (e.g., disialylation). Some implementations In this context, the antibody is either a humanized antibody or a fully human antibody.

[0245] In another embodiment, this application relates to the isolated anti-FcRn antibody described herein. It is characterized by nucleic acid molecules that do.

[0246] In another embodiment, this application relates to the isolated anti-FcRn antibody described herein. It is characterized by a vector containing nucleic acid molecules.

[0247] In another embodiment, this application expresses the isolated anti-FcRn antibody described herein. It is characterized by host cells that coat isolated anti-FcRn antibodies. The nucleic acid molecule or vector containing the nucleic acid molecule is , expressed within host cells. In some embodiments, the host cells are Chinese ham These are star ovarian (CHO) cells.

[0248] In another embodiment, this application relates to the isolated anti-FcRn antibody described herein and 1 A pharmaceutical composition characterized by comprising one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the antibody is present in a therapeutically effective amount.

[0249] In another embodiment, this application relates to the preparation of isolated anti-FcRn antibodies as described herein. The method is characterized by a) encoding an isolated anti-FcRn antibody a) To provide a host cell containing a nucleic acid molecule or a vector containing the nucleic acid molecule, and b) the antibody This includes expressing nucleic acid molecules or vectors in host cells under conditions that enable their formation. nothing.

[0250] In some embodiments, the method is approximately 1-100, 1-50, 1-25, 2-50 The method further comprises a step of recovering antibodies at a concentration of 5-50 or 2-20 mg / ml.

[0251] In some embodiments, the host cells used in this method are CHO cells.

[0252] In another embodiment, this application relates to the different types of pathogenic antibodies (e.g., IgG antibodies) in a subject. The invention is characterized by a method for increasing the chemical effect. In another embodiment, this application relates to the subject It is characterized by a method for reducing autoantibodies. In another embodiment, this application is characterized by the subject This method is characterized by reducing the activation of immune complexes in the immune response. To administer the isolated antibody or the pharmaceutical composition described herein. Includes.

[0253] In some embodiments, the immune response is an acute or chronic immune response in the subject. That is the case.

[0254] In some embodiments, the acute immune response is used in cases of pemphigus vulgaris, lupus nephritis, and myasthenia gravis. Mycosis, Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immunotherapy Complex-mediated vasculitis, glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic hematology Thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia It is activated by a medical condition selected from the group consisting of dilated cardiomyopathy and serum sickness.

[0255] In some embodiments, the chronic immune response is chronic inflammatory demyelinating polyneuropathy ( CIDP), systemic lupus, reactive joint disorders, primary biliary cirrhosis, ulcerative colitis and Depending on the medical condition selected from the group consisting of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis It becomes activated.

[0256] In some embodiments, the subject has an autoimmune disease. Autoimmune diseases include alopecia areata. Ankylosing spondylitis, antiphospholipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, Hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac pruritus, chronic fatigue Immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome Group, scarring pemphigoid, limited systemic scleroderma (CREST syndrome), cold agglutinin disease, crow Lupus, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Physiomyelitis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune phosphorus Pablo-proliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis Lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, Polyarteritis nodalis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary Sexual agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome Rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, Sty Uvemann syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo or ureitis It could be Gener's granulomatosis.

[0257] In another embodiment, this application reduces the transfer of pathogenic antibodies across the placenta of a pregnant subject. The invention is characterized by a method for causing [something] in a pregnant subject. In another embodiment, this application is characterized by a method for causing [something] in a pregnant subject The present invention is characterized by a method for increasing the catabolic activity of antibodies. In another embodiment, this application is characterized by: This method is characterized by its treatment of antibody-mediated enhancement of viral infections in fetuses or neonates. This method involves using the isolated antibody or pharmaceutical composition described herein to induce pregnancy. This includes administering the drug to pregnant subjects.

[0258] In some embodiments, pathogenic antibodies are used in the fetus of a pregnant subject, affecting both the fetus and the newborn. It causes alloimmune disorders and / or autoimmune disorders in children.

[0259] In some embodiments, alloimmune disorders and / or autoimmune disorders of the fetus and neonatal are Alloimmune thrombocytopenia purpura (FNAIT) in fetuses and neonates, hemolytic diseases in fetuses and neonates (HDFN), alloimmune panthrombocytopenia, congenital heart block, fetal joint contractures, Neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal The diagnosis is selected from a group consisting of polymyositis of the infant, dermatomyositis, neonatal lupus, and neonatal scleroderma. Chet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease and neonatal Type I diabetes.

[0260] In some embodiments, the pathogenic antibody is an IgG antibody.

[0261] In some embodiments, viral diseases include alphavirus infections and flavivirus infections. Ross River virus infection, Zika virus infection, Chikungunya virus infection, Ross River virus infection Infectious diseases, severe acute respiratory syndrome (Coronavirus infection), Middle East respiratory syndrome, avian influenza Infectious diseases, influenza virus infection, human respiratory syncytial virus infection, Ebola virus infection Infectious diseases, yellow fever virus infection, dengue virus infection, human immunodeficiency virus infection, RSV infection, hantavirus infection, getavirus infection, sindovis virus Infectious diseases, Bunyamwella virus infection, West Nile virus infection, Japanese encephalitis virus B Infectious diseases, rabbitpox virus infection, lactate dehydrogenase-elevated virus infection, reovirus infection Rabies virus infection, Foot-and-mouth disease virus infection, Porcine genitourinary respiratory syndrome virus infection Infections, monkey hemorrhagic fever virus infection, equine infectious anemia virus infection, goat arthritis virus Infectious diseases, African swine fever virus infection, lentivirus infection, BK papovavirus infection Infections, Murray Valley Encephalitis virus infection, enterovirus infection, cytomegalovirus Infectious diseases, including Pneumovirus infection, Morbillivirus infection, and measles virus infection. It is caused by a virus selected from a group of viruses.

[0262] In some embodiments, pregnant subjects activate an immune response within the pregnant subjects. Having or being at risk of having such a medical condition. Some embodiments In this context, medical conditions include pemphigus vulgaris, lupus nephritis, myasthenia gravis, and Guillain-Barré syndrome. – syndrome, antibody-mediated rejection, fulminant antiphospholipid antibody syndrome, immune complex-mediated vasculitis Glomerulitis, channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, Autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating Multiple neuropathy, systemic lupus, reactive joint disorder, primary biliary cirrhosis, ulcerative colitis Enteritis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, alopecia areata, ankylosing spondylitis, antiphosphate Lipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, water Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, localized Systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid leukemia Cryoglobulinemia (essential mixed type), fibromyalgia, fibromyositis, Graves' disease, Hashimoto's disease Thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic lung Fibrosis, IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, lupus, Nieille's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polymolar tumor Osteitis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu's artery These include inflammation, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis.

[0263] In some embodiments, the pregnant subject is subjected to alloimmune disorders of the fetus and neonatal and / or She has a history of having previously given birth to a fetus or newborn with an autoimmune disorder. .

[0264] In some embodiments, biological samples obtained from pregnant subjects (e.g., blood samples or urine samples) are used. In the sample, pathogenic antibodies related to immune diseases are detected.

[0265] In some embodiments, the isolated anti-FcRn antibody of this application is used in rodents, for example. For example, it binds to mouse or rat FcRn. In some embodiments, the single application of this invention The released anti-FcRn antibody has a K content of less than 200, 150, 100, 50, or 40 pM. D in, It binds to FcRn in rodents, such as mice or rats.

[0266] definition In this specification, the term "antibody" is used in a broad sense, including monoclonal antibodies and polyclonal antibodies. Single antibody, multispecific antibody (for example) If it contains a bispecific antibody and an antibody fragment, but exhibits FcRn antigen-binding activity However, this is not limited to these, and encompasses a variety of antibody structures.

[0267] The "antibody fragment" contains a portion of the intact antibody, preferably the antigen of the intact antibody. Includes a binding region or variable region. Examples of antibody fragments include Fab, Fab', and F(ab'). 2 and Fv fragments, bispecific antibody, linear antibody, single Examples include chain antibody molecules and multispecific antibodies.

[0268] As used herein, the term "isolated antibody" means the antibody produced in the host cell environment. This refers to antibodies isolated and / or recovered from one of the components. Antibodies for research purposes, Substances that would interfere with diagnostic or therapeutic applications may interfere with the host cell environment for antibody production. These are the interfering components. The interfering components include enzymes, hormones, and other proteinaceous solutions. It may contain protein or non-proteinaceous solutes. In some embodiments, a certain antibody is ( 1) Purified to more than 95% by weight of antibody, as determined by, for example, the Lowry method. In some embodiments, the antibody is purified to more than 99% by weight, and (2) for example, Using a spinning cup sequencer And there is enough to obtain at least 15 residues from the N-terminus or internal amino acid sequence. (3) Reducing conditions using, for example, Coomassie blue staining or silver staining. Alternatively, the antibodies are homogeneously purified by SDS-PAGE under non-reducing conditions. The isolated antibodies are recombinant It contains antibodies in situ within the cell. However, typically, isolated antibodies are used. The body will be prepared by at least one purification step. The isolated antibody Pharmaceuticals typically comply with the FDA's "Guidance for Industry" ELISA performed as recommended in the "r Industry" document for HCP As determined by the company, less than 250 ppm (e.g., 200 ppm, 150 ppm) It contains host cell-derived proteins (HCPs) at a concentration of less than 100 ppm (pm).

[0269] As used herein, the term "monoclonal antibody" refers to a collection of substantially homogeneous antibodies. This refers to antibodies obtained from the group, that is, antibodies that may occur spontaneously, even if only in small quantities. Except for mutations, each antibody in the population has the same primary sequence. Monoclonal antibody It is highly specific, and targets a single antigen site. This refers to a specific epitope on the human FcRn. In contrast to polyclonal antibody drugs, which typically contain a variety of antibodies, monoclonal antibodies Each antibody is specific to a single epitope on an antigen. "Monoclonal" and The modifier indicates a characteristic of antibodies that they are obtained from a substantially homogeneous population. Therefore, it should be interpreted as requiring the production of antibodies by any specific method. It's not.

[0270] As used herein, the terms "variable region" and "variable domain" refer to complementary determination regions. area (e.g. CDR L1, CDR L2, CDR L3, CDR H1, CDR H2 and The CDR (CDR H3) and the amino acid sequence of the framework region (FR) are included. This refers to the light chain and heavy chain portions of an antibody. According to the method used in this disclosure, these are divided into CDR and FR. The amino acid positions that can be assigned are determined by Kabat (Sequences of Protein). s of Immunological Interest,5th Ed.Publi c Health Service,National Institutes of This is stipulated in accordance with Health, Bethesda, MD. (1991)). Using the baring system, actual linear amino acids The sequence is a variable region CDR (as further defined herein) or FR (as defined herein) Further shortening (as further defined), or equivalent to insertion into the CDR or FR, It may contain amino acids that are not present or additional amino acids. For example, the heavy chain variable region is C A single inserted residue after residue 52 of DR H2 (i.e., according to Kabat, residue 52a) and the residue inserted after residue 82 of the heavy chain FR (i.e., according to Kabat) It can include residues 82a, 82b, 82c, etc. Kabat numbering of residues The rings are numbered with the "standard" Kabat for each given antibody. The sequence is determined by aligning it with the homologous region of the antibody sequence. obtain.

[0271] As used herein, the terms "complementarity determination region" and "CDR" are superimposed within the sequence. Antibody variable domains that are denatured and / or form structurally defined loops This refers to a region. CDR is also known as the excess variable region. Light chain variable region and heavy chain variable region. Each region has three CDRs. The light chain variable region has CDR L1, CDR L2 and It contains CDR L3. The heavy chain variable regions are CDR H1, CDR H2, and CDR H3. It contains. Each CDR is a complementarity determination region as defined by Kabat or It may contain the following amino acid residues (i.e., within the light chain variable region, approximately residues 24-34 (C) DR L1), 50-56 (CDR L2) and 89-97 (CDR L3), and heavy chain Within the variable region, residues 31-35 (CDR H1), 50-65 (CDR H2) and 95-102 (CDR H3).

[0272] As used herein, the term "FcRn" refers to, for example, an IgG1 antibody, which is an IgG antibody. This refers to neonatal Fc receptors that bind to the Fc region of the body. An example of an FcRn is Uni There is a human FcRn with Prot ID No. P55899. Human FcRns are internal It binds to resident IgG, transports it constitutively, and returns it to the cell surface for IgG recycling. This is thought to be involved in maintaining the half-life of IgG.

[0273] As used herein, the terms "affinity" and "binding affinity" refer to the binding phase between two molecules. This refers to the strength of the interaction. Generally, binding affinity is the strength of the interaction between the isolated antibody and its target (e.g., mono The binding site and its binding phase of a molecule, such as a detached anti-FcRn antibody and human FcRn. This refers to the total strength of non-covalent interactions between the hands. Unless otherwise specified, bond Affinity is an inherent characteristic that reflects the 1:1 interaction between the components of a bonded pair. This refers to the binding affinity between two molecules. The binding affinity between two molecules is usually expressed by the dissociation constant (K). D ) or affinity constant (K A ) is described by. Two molecules that have low binding affinity to each other are generally, The combination is slow, and it dissociates easily, resulting in a large K D They tend to exhibit this characteristic. They have a high binding affinity for each other. Generally, two molecules bond quickly and maintain that bond for a long time, with a small K D tendencies to show There is a K antibody against human FcRn. D One method for determining this is shown in Example 2 ("SPR (Surface Plasmon Resonance method) This is explained in ). Using this method, N022, N023, N024, N026 and N027's K D These are 31, 31.4, 35.5, 36.5, and 19.3 pM, respectively. .

[0274] As used herein, the phrase "inhibits the binding of IgG to FcRn" means IgG The ability of anti-FcRn antibodies to block or inhibit the binding of (e.g., IgG1) to human FcRn. It refers to force. In some embodiments, the anti-FcRn antibody is, for example, on human FcRn. At the site where IgG binds, it binds to FcRn. Therefore, anti-FcRn antibodies This can inhibit the binding of IgG (for example, an autoantibody possessed by the target) to FcRn. In some embodiments, the molecule (e.g., an anti-FcRn antibody) substantially binds to IgG. It inhibits or completely inhibits IgG binding by 10%, 20%. The reduction is 30%, 50%, 70%, 80%, 90%, 95%, or 100%.

[0275] As used herein, the phrase "inhibits the binding of pathogenic antibodies to FcRn" means pathogenic Anti-FcRn blocks or inhibits the binding of antibodies (e.g., pathogenic IgG antibodies) to human FcRn. This refers to the ability of the Rn antibody. In some embodiments, the anti-FcRn antibody is, for example, human F It binds to FcRn at the site where pathogenic antibodies bind on cRn. Therefore, it is an anti- FcRn antibodies inhibit the binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to FcRn. This is possible. In some embodiments, the molecule (e.g., anti-FcRn antibody) is a pathogenic antibody. It substantially or completely inhibits binding to the pathogenic antibody. In some embodiments, the FcR of the pathogenic antibody The binding to n is 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, and It is reduced by 100%.

[0276] As used herein, the term "hydrophobic amino acid" means having relatively low water solubility. This refers to amino acids that are hydrophobic. Hydrophobic amino acids include glycine, leucine, isoleucine, and alanine. These are phenylalanine, methionine, tryptophan, valine, and proline. The particularly preferred hydrophobic amino acids are alanine, leucine, isoleucine, and valine. .

[0277] As used herein, the term "polar amino acid" refers to an amino acid having different electronegativity. This refers to amino acids that possess chemical polarity within their side chains, induced by atoms. The polarity of a sexual amino acid depends on the electronegativity between atoms in the amino acid side chain and the structural asymmetry of the side chain. Dependent. Polar amino acids are serine, threonine, cysteine, histidine, and methionine. These are tyrosine, tryptophan, asparagine, and glutamine. Particularly preferred in this disclosure The polar amino acids are serine, threonine, asparagine, glutamine, cysteine, and cysteine. It is rosin.

[0278] As used herein, the term "acidic amino acid" refers to amino acids with a pKa of 3.5 to 4.5 This refers to amino acids whose side chains contain a carboxylic acid group. Acidic amino acids are found in asparagus. These are nic acid and glutamic acid.

[0279] As used herein, the term "basic amino acid" refers to an amino acid with a pKa of 9.5 to 13 This refers to amino acids whose side chains contain an amino group. Basic amino acids include histidine, These are lysine and arginine.

[0280] As used herein, the term "percent (%) identity" means, for example, anti-FcRn anti Amino acid (or nucleic acid) residues of a candidate sequence, which are arranged in sequence, if necessary If a gap is introduced to achieve the greatest percentage identity (i.e., optimal To achieve proper alignment, introduce gaps in either the candidate sequence or the reference sequence, or both. (This is possible, and non-uniform arrangements can be ignored for comparison purposes.) It matches the amino acid (or nucleic acid) residues of the reference sequence of wild-type anti-FcRn antibodies, etc. This refers to the percentage of amino acid (or nucleic acid) residues in the above candidate sequence. Alignment for sex determination can be done in various ways within the scope of technology in this field, for example For example, BLAST, ALIGN, or Megal(DNASTAR) software. This can be achieved using publicly available computer software. The person will need to perform the necessary steps to achieve the maximum alignment across the entire length of the sequences being compared. It is possible to determine appropriate parameters for alignment measurement, including the algorithm for determining the correct parameters. It is possible. In some embodiments, with respect to a given reference array, in or to the reference array. In contrast, the percentage amino acid (or nucleic acid) sequence identity of a given candidate sequence (or given A specific percentage of amino acids in or relative to the reference sequence ( A given candidate sequence (which may be described as having or containing sequence identity, or nucleic acid) is as follows: It will be calculated as follows: 100×(Fraction A / B) In the formula, A is an amino acid that has been scored as identical within the alignment of the candidate sequence and the reference sequence. B is the number of amino acid (or nucleic acid) residues in the reference sequence, where B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In some embodiments where the length of the candidate array is not equal to the length of the reference array, the reference array is used in relation to The percentage amino acid (or nucleic acid) sequence identity of the candidate sequence is determined by the reference sequence of the candidate sequence. The percentage amino acid (or nucleic acid) sequence identity of the column should not be equal.

[0281] In certain embodiments, the entire length of the candidate sequence or the continuous amino acids of the candidate sequence (or The candidate sequence shows 50% to 100% identity across selected portions of nucleic acid residues. This can sometimes be demonstrated by a reference sequence that has been aligned for comparison with the candidate sequence. The length of the aligned candidate sequences for comparison purposes is at least 30% of the length of the reference sequence. For example, at least 40%, for example, at least 50%, 60%, 70%, 80%, 90% Or 100%. A position in the candidate sequence is the same amino acid as the corresponding position in the reference sequence. If occupied by (or nucleic acid) residues, the molecules will coincide at their respective positions. It is present. Its position may change due to substitution, deletion, or insertion. Substitution, deletion, or insertion is, A certain number of amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, May contain 13, 14, 15 or more amino acids. Substitutions, deletions, or insertions of n or fewer amino acids. When written as such, this means that substitution, deletion, or insertion occurs, for example, 1, 2, 3, 4, 5, 6, 7 , 9, 10, 11, 12, 13, 14, 15, ... or n amino acids This means that a number, substitution, deletion, or insertion is a percentage of the entire sequence (for example, 1 It may include (%), 5%, 10%, 15%, 20%, or more, and substitutions, omissions The number of missing or inserted amino acids represents 5%, 10%, 15%, 20%, or more of the total amino acids in the sequence. The above is what changes. When used in this specification, "alloimmune disorders and / The term "or autoimmune disorder" refers to maternal antibodies against fetal and / or neonatal antigens (e.g., For example, transplacental transfer of pathogenic maternal antibodies can cause in the fetus and / or newborn. This refers to an immune disorder. For example, antibodies in a pregnant woman (e.g., pathogenic antibodies) can affect the fetus. The ability to react to an antigen (for example, an antigen that a fetus inherits from its father) Examples of alloimmune disorders and / or autoimmune disorders in fetuses and neonates are provided herein. It is.

[0282] As used herein, "pathogenic antibody" and The word refers to the subject (for example, a pregnant subject), the fetus of the pregnant subject, and / or the newborn. This refers to antibodies that cause one or more immune diseases or immune disorders. In this state, pathogenic antibodies target one or more of the target's own proteins. (For example, a pregnant subject) is produced in the subject and thereby causes autoimmune disease or autoimmune disease It is an autoantibody that causes autoimmune disorders. In some embodiments, it is administered to pregnant subjects. Pathogenic antibodies in this case are transferred to the fetus via the placenta, and antigens from the fetus (for example, when the fetus...) It can react to antigens inherited from the father, thereby, for example, the fetus and It causes alloimmune disorders and / or autoimmune disorders in newborns.

[0283] As used herein, the term "antibody-mediated enhancement of viral diseases" means that antibodies This can facilitate the entry of the virus into host cells, thereby increasing or enhancing its infectivity within the cells. This refers to a viral disease that can lead to [something]. In some embodiments, a certain antibody It can bind to proteins on the surface of the virus, and the antibody / virus complex can bind to the cell surface. The antibody can bind to FcRn receptors on the surface via interactions between the antibody and the receptor. Subsequently, this antibody / virus complex may become endogenous within the cell.

[0284] Here, the term "host cell" refers to the cell that expresses proteins from their corresponding nucleic acids. It refers to a carrier that contains necessary cellular components, such as organelles. Nucleic acids are Typically, conventional techniques known in this field (e.g., transformation, transfection) It is introduced into host cells by means of electroporation, calcium phosphate precipitation, direct microinjection, etc. It is possible to include it in nucleic acid vectors. The host cell is a prokaryotic cell, such as a bacterial cell. It can be a cell, or a eukaryotic cell, such as a mammalian cell (e.g., a CHO cell). As described herein, using host cells, one or more of the antibodies encoding anti-FcRn antibodies are used. It expresses multiple types of polypeptides.

[0285] As used herein, the term "vector" refers to another nucleic acid that is already bound to it. This refers to nucleic acid molecules capable of transporting offspring. One type of vector is called a "plasmin vector." This is a ring in which further DNA segments can be ligated inside. It refers to a double-stranded DNA loop. Another type of vector is a phage vector. This type of vector is a viral vector, which further transmits DNA segments to the virus. This is a viral vector that can be ligated into the genome. It can self-replicate within the host cell into which the vector is introduced (for example, Bacterial vectors containing bacterial replication origins and mammalian episomal vectors. Other vectors. - (For example, mammalian non-episomal vectors) are introduced into host cells and then... It can be incorporated into the genome of the cell, thereby replicating together with the host genome. Furthermore, certain vectors control the expression of the gene to which the vector is manipulably linked. It can be directed. In this specification, such vectors are referred to as "recombinant expression vectors" (or single These are commonly referred to as "recombinant vectors." They are expression vectors that are typically useful in recombinant DNA technology. These are often in plasmid form.

[0286] As used herein, the term "subject" means, for example, a mammal, preferably a human. It refers to objects. Mammals include humans, monkeys (e.g., crab-eating macaques), mice, dogs, and cats. This includes, but is not limited to, livestock such as horses and cattle.

[0287] As used herein, the term "pharmaceutical composition" refers not only to the active ingredient but also to the active ingredient. It contains one or more excipients and diluents that can be adapted to a suitable administration method. This refers to a medicinal preparation or pharmaceutical preparation. The pharmaceutical composition is compatible with anti-FcRn antibodies and is a pharmaceutical product. It contains ingredients that are acceptable. The pharmaceutical composition is in aqueous form or for intravenous or subcutaneous administration. It may be in tablet or capsule form for oral administration.

[0288] Here, the term "pharmacoagulable carrier" refers to an excipient or diluent in a pharmaceutical composition. This refers to a pharmacopoeia-acceptable carrier that is compatible with the other components of the formulation and is suitable for recipients. It must not be harmful to them. A pharmacoagulable carrier is Fc con The struct needs to be given sufficient pharmacodynamic stability. The properties of the carrier are related to the dosage form. It varies depending on the method. For example, in intravenous administration, an aqueous solution carrier is generally used, while in oral administration... Therefore, a solid carrier is preferable.

[0289] Here, the term "therapeutic dose" refers to, for example, the amount of drug administered, in relation to the target or patient. to induce the desired biological effect, or in patients having the conditions or disorders described herein. This refers to the amount that is effective for treatment. In this specification, "effective therapeutic dose" refers to a single dose or an optional dose. Ingestion in the prescribed dosage or route, either alone or in combination with other therapeutic drugs. However, it should also be understood that this can be interpreted as the amount that produces the desired therapeutic effect.

[0290] As used herein, the phrase "no more than" means "no more than" This refers to a small quantity. This can be an integer quantity. For example, a permutation of 2 or less is 0. It can mean a substitution of 1 or 2.

[0291] As used herein, the terms "treatment" or "to treat" also apply to specific diseases. Or to alleviate a condition, reduce a specific disease or condition, a specific disease or condition This refers to reducing the risk of a condition, or reducing the side effects of a specific disease or condition. Compared to subjects who did not receive treatment, for example, control, baseline, or publicly known To reduce or decrease the risk compared to the control level or measured value. This means reducing the amount of the substance or its side effects. [Brief explanation of the drawing]

[0292] [Figure 1] Figure 1 shows two graphs and a table illustrating the competitive binding of IgG antibodies N022-N024, N026, and N027 to human FcRn or cynomolgus monkey FcRn at pH 6.0. [Figure 2-1] Figure 2 shows graphs illustrating the effects of antibodies N023, N024, N026, and N027 on IgG catabolism in transgenic mice. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 3] Figure 3 shows a graph illustrating the dose-dependent effect of antibody N027 on IgG concentration and target occupancy in transgenic mice. [Figure 4A] Figures 4A-4C show graphs illustrating the selective induction of IgG catabolism and target occupancy in cynomolgus monkeys after administration of various doses of antibody N027. [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 5] Figure 5 shows a graph illustrating the in vivo distribution of N027 in transgenic mice. [Figure 6] Figure 6 shows the experimental timeline and a graph illustrating the efficacy of N027 in a mouse collagen antibody-induced arthritis model using transgenic mice. [Figure 7] Figure 7 shows the experimental timeline and two graphs illustrating the efficacy of N027 in a mouse model of chronic idiopathic thrombocytopenic purpura (ITP) in transgenic mice. [Figure 8A] Figures 8A to 8C show graphs illustrating the dose-dependent FcRn occupancy achieved with N027 in aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively. [Figure 8B] Same as above. [Figure 8C] Same as above. [Figure 9A] Figures 9A-9C show graphs illustrating that 100% FcRn occupancy by N027 leads to increased intracellular IgG accumulation in aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively. [Figure 9B] Same as above. [Figure 9C] Same as above. [Figure 10] Figure 10 shows a graph illustrating the time required to achieve 100% FcRn occupancy with N027. [Figure 11A] Figures 11A and 11B show graphs demonstrating that treatment with N027 does not alter the FcRn metabolic rate in human endothelial cells and villous trophoblast cells, respectively. [Figure 11B] Same as above. [Figure 12] Figures 12A and 12B show images of FcRn localized in endosomes of human endothelial cells and villous trophoblast cells. [Figure 13A] Figures 13A and 13B show graphs illustrating the effects of N027 treatment and the dynamics of IgG transport in human endothelial cells and human placental trophoblasts, respectively. [Figure 13B] Same as above. [Figure 13C] Figures 13C and 13D show images demonstrating that N027 increases intracellular IgG and the co-localization of IgG in lysosomes (lysosomal markers: Lamp-1 and Dextran). [Figure 13D] Same as above. [Figure 14] Figure 14 shows an image comparing the Fab binding site of N027 on FcRn with the Fc binding site and albumin binding site. The Fab binding site and the Fc binding site overlap with each other, but they are separate from the albumin binding site. [Figure 15] Figure 15 shows images of the epitope on the Fab surface of N027 (left) and the paratope on the FcRn surface (right). [Figure 16] Figure 16 shows the epitope and paratope of Fab:FcRn of N027 as mapped to the sequence. [Figure 17] Figure 17 is a graph showing the transplacental transfer of antipyrine by perfusion over 4 hours (n=14). The data shows the antipyrine concentrations in the fetal circulation (square) and maternal circulation (circle) as mean ± standard deviation (SD) after maternal administration of 100 μg / ml of antipyrine at t=0. [Figure 18]Figure 18 is a graph showing the transplacental transfer of N027 by perfusion over 4 hours. The data represents the N027 concentration in the fetal and maternal circulation as mean ± SD after maternal administration of N027 at the indicated concentration at t=0. [Figure 19] Figure 19 is a graph showing maternal IgG levels after treatment with N027 during pregnancy. [Figure 20] Figure 20 is a graph showing fetal IgG levels after the mother was treated with N027 during pregnancy. [Modes for carrying out the invention]

[0293] Detailed explanation This disclosure relates to an isolated receptor that binds to the human neonatal type Fc receptor (FcRn) with high affinity. This disclosure is characterized by an antibody. This disclosure relates to an anti-FcRn antibody, a method for preparing an anti-FcRn antibody, and The composition, as well as the ability to inhibit FcRn activity and the activation of the immune response based on immune complexes. It features methods to alleviate and treat immune diseases. It also uses anti-FcRn antibodies, It reduces the transfer of pathogenic antibodies across the placenta in pregnant subjects, thereby reducing pathogenic antibodies in pregnant subjects. It increases the body's catabolic activity, leading to increased antibody-mediated infection of viral diseases in fetuses or newborns. It is possible to treat severe cases.

[0294] I. Anti-FcRn antibody This disclosure generally features isolated antibodies that bind to human FcRn. n antibodies bind to human FcRn, and IgG (e.g., IgG autoantibodies or pathogenic antibodies) This refers to an antibody capable of inhibiting binding to FcRn. In some embodiments, the antibody In other embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is IgG1. The antibody contains a λ light chain. In some embodiments, the antibody is sialic acid-added to the antibody. It is a body. In some embodiments, the antibody is a chimeric antibody, affinity mature antibody (affi A group consisting of human matured antibodies, humanized antibodies, and human antibodies. They are selected. In one embodiment, the antibody is, for example, Fab, Fab', Fab'- This is an antibody fragment that is SH, F(ab′)2, or scFv.

[0295] In some embodiments, the antibody is a chimeric antibody. For example, a certain antibody is a chimeric antibody of a different species Non-human sequences, human sequences, or humanized sequences (e.g., frameworks and / or constant domains) It contains an antigen-binding sequence from a non-human donor that has been transplanted into the sequence. In one embodiment, In this embodiment, the non-human donor is a mouse. In another embodiment, the antigen-binding sequence is synthetically For example, obtained by mutation introduction (e.g., phage display screening method). In further embodiments, the chimeric antibody is a non-human (e.g., mouse) variable region It has a human constant region. In one embodiment, the mouse light chain variable region is a human κ light chain and They fuse. In another embodiment, the mouse heavy chain variable region fuses with the human IgG1 constant region. do.

[0296] In some embodiments, when describing the CDR sequence of an antibody, the antibody is a set It is defined as containing six CDR sequences. If it contains a set of CDR sequences This means that these CDR sequences consist of, contain, or substantially contain the CDR sequences This describes antibodies arranged in a series.

[0297] In one embodiment, this disclosure includes (1) CDR L1, CDR L2 and CDR L3 (2) A light chain variable region including CDR H1, CDR H2 and CDR H3 Isolated antibodies that bind to the human neonatal type Fc receptor (FcRn), including a variable region, are particularly important. This is a characteristic feature, and CDR L1 is sequence SDVGSYNL(SEQ ID NO: 47 ) or VG_YNL (SEQ ID NO:34), where "_" represents any amino acid. It is possible to do so, and CDR L2 uses the sequence GDSE (SEQ ID NO:35) Including, CDR L3 contains sequence YAGSGIY (SEQ ID NO: 36), CDR H1 contains sequence TYA (SEQ ID NO: 37), and CDR H2 contains sequence SIG ASGSQTR (SEQ ID NO:38) or SI_AS_SQ_R (SEQ ID N O:39) is included, where "_" can be any amino acid, CDR H 3 includes sequence LAI (SEQ ID NO: 40), and optionally, (a) CDR L1 teeth Compared to the sequence TIFF0007914147000220.tif4128, it has a deletion or two or more amino acid substitutions, and (b) CDR L2 may have deletions compared to the GDSERPS (SEQ ID NO:2) sequence. (c)CDR L3 has one or more amino acid substitutions, and Compared to the sequence TIFF0007914147000221.tif4128, it has a deletion or one or more amino acid substitutions, and (d) CDR H1 is TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5) and Compared to each of the sequences of NYAMG (SEQ ID NO:6), there may be deletions. (e)CDR H2 has one or more amino acid substitutions, and Compared to each of the sequences of TIFF0007914147000222.tif16161, it has a deletion or two or more amino acid substitutions, or (f) CDR H3 is missing from the sequence of LAIGDSY (SEQ ID NO: 11). It has a loss or has one or more amino acid substitutions. In some embodiments, isolation The antibody contains the amino acid sequence KSG at positions 66-68 in Kabat.

[0298] In another embodiment, this disclosure features isolated antibodies that bind to human FcRn. The antibody is derived from the amino acids K103, A104, L105, and G1 of wild-type FcRn. 06, G107, K108, G109, P110, Y111, L135, N136, E1 38, G152, D153, W154, P155, E156, L158, A159, Q1 K80, A81, L82, G83, which correspond to SEQ ID NO:30, respectively to 62. G84, K85, G86, P87, Y88, L112, N113, E115, G129, The group consists of D130, W131, P132, E133, L135, A136, and Q139. At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 selected from Epi on FcRn containing amino acids 3, 14, 15, 16, 17, 18, 19, or 20 It binds to a tope. In some embodiments, this epitope on FcRn is wild-type It does not contain amino acid E115, which corresponds to amino acid E138 in FcRn.

[0299] In another embodiment, this disclosure is a group consisting of I21, Q22, P52 and V105. An epithelium on β(2)-microglobulin containing at least one amino acid selected from It is characterized by isolated antibodies that bind to the globule.

[0300] In another embodiment, this disclosure features isolated antibodies that bind to FcRn. Therefore, the antibody is (a) (b) The antibody binds to at least one amino acid in the sequence TIFF0007914147000224.tif4128, and this antibody then converts to human FcRn of IgG. It inhibits the binding.

[0301] This disclosure also features isolated antibodies that bind to human FcRn, Antibodies are, The antibody binds to at least one amino acid in the sequence TIFF0007914147000225.tif4128, and the antibody has SEQ ID NO:25 The antibody binds to at least one of the amino acid residues 5, 12, or 13 of Ig Inhibits the binding of G to human FcRn.

[0302] This disclosure also features isolated antibodies that bind to human FcRn, Antibodies are, The antibody binds to at least one amino acid in the sequence TIFF0007914147000226.tif4128, and the antibody is sequence It did not bind to the peptide consisting of TIFF0007914147000227.tif4128, nor to the sequence of EEFMNFDL (SEQ ID NO:28). Furthermore, this antibody inhibits the binding of IgG to human FcRn.

[0303] In some embodiments, the anti-FcRn antibody described herein is WGGDWPEA It binds to at least one amino acid in the sequence of L (SEQ ID NO:29). In one embodiment, the anti-FcRn antibody is at least amine of SEQ ID NO:25. It binds to no-acid residue 5. In some embodiments, the anti-FcRn antibody is SEQ ID N It binds to at least one amino acid residue 12 of O:25. In some embodiments, it is anti-Fc The Rn antibody binds to at least amino acid residue 13 of SEQ ID NO:25.

[0304] In some embodiments, the anti-FcRn antibody is It binds to at least one amino acid in the sequence TIFF0007914147000228.tif4128. The anti-FcRn antibody also It may bind to at least two amino acids in the sequence TIFF0007914147000229.tif4128.

[0305] In another aspect, this disclosure also features isolated antibodies that bind to human FcRn. This means that the antibody is, The antibody binds to at least one amino acid in the sequence TIFF0007914147000230.tif4128, and this antibody then converts to human FcRn of IgG. It inhibits the binding.

[0306] In some embodiments of this model, the anti-FcRn antibody is It binds to at least two amino acids in the sequence TIFF0007914147000231.tif4128. In some embodiments, it binds to anti-F cRn antibodies are Further binding occurs to at least one amino acid in the sequence TIFF0007914147000232.tif4128. In some embodiments, Anti-FcRn antibodies are, It further binds to at least two amino acids in the sequence TIFF0007914147000233.tif4128. In some embodiments, The anti-FcRn antibody is one of the amino acid residues 5, 12, or 13 of SEQ ID NO:25 It binds to at least one. In some embodiments, the anti-FcRn antibody is SEQ I D binds to at least 5 amino acid residues of NO:25. In some embodiments, anti The FcRn antibody binds to at least amino acid residue 12 of SEQ ID NO:25. In one embodiment, the anti-FcRn antibody is at least amine of SEQ ID NO:25. It binds to the 13th acid residue.

[0307] In another embodiment, this disclosure relates to an isolated FcRn capable of binding to human FcRn It is characterized by antibodies. These isolated antibodies are (1) CDR L1, CDR L2 and C (2) Light chain variable region including DR L3, and CDR H1, CDR H2 and CDR H3 It contains a heavy chain variable region including, and CDR L1 is The sequence has at least 92% identity with the sequence of TIFF0007914147000234.tif4128, and CDR L2 is GDSERPS The sequence has at least 85% identity with the sequence of (SEQ ID NO:2), CD R L3 is The sequence has at least 90% identity with the sequence of TIFF0007914147000235.tif4128, and CDR H1 is TYAMG(S EQ ID NO:4), DYAMG(SEQ ID NO:5) or NYAMG(SEQ The sequence has at least 80% identity with the sequence of ID NO:6), and CDR H2 teeth The sequence has at least 92% identity with the sequence of TIFF0007914147000236.tif22164, and CDR H3 is LAIGDSY It has a sequence that is at least 85% identical to the sequence of (SEQ ID NO:11). In some embodiments, the antibody concentration is less than 200, 150, 100, 50, or 40 pM. K D It binds to human FcRn. In some embodiments, the antibody is N022, N02 3, N024, N026 or N027 has a light chain variable region and a heavy chain variable region, and ratio The K of an antibody that also has the same Fc region as the antibody being compared. D Less than or the K D Equivalent to ( For example, K (which is less than that). D It then binds to human FcRn.

[0308] In some embodiments, the isolated antibody is A CDR containing the sequence TIFF0007914147000237.tif4128, consisting of, substantially consisting of, or having said sequence L1 and the sequence GDX3X4RPS (SEQ ID NO: 13) are included in the sequence. , a CDR L2 consisting substantially of or having the sequence, A CDR containing the sequence TIFF0007914147000238.tif4128, consisting of, substantially consisting of, or having said sequence The sequence consisting of L3 and the sequence Z1YAMG (SEQ ID NO: 15) is essentially A CDR H1 consisting of or having the sequence, CDRs containing the sequence TIFF0007914147000239.tif4128, consisting of, substantially consisting of, or having said sequence The sequence consists of H2 and LAZ5Z6DSY (SEQ ID NO: 17). , comprising a CDR H3 substantially consisting of or having said sequence, X 1 is a polar or hydrophobic amino acid (for example, preferably T, A, S, or I), and X2 is It is a hydrophobic amino acid (for example, preferably L or I), and X3 is a polar amino acid (for example, Preferably S, N, or T), and X4 is a polar or acidic amino acid (for example, preferably Q, E, or N) and X5 is a polar or hydrophobic amino acid (for example, preferably C, S, I or Y), X6 is a hydrophobic amino acid (for example, preferably A or V), and Z1 is a polar or acidic amino acid (for example, preferably E, T, D, or N), and Z2 is polar or a hydrophobic amino acid (for example, preferably S or A), where Z3 is G, S or A. Z4 is a basic amino acid (for example, preferably K or R), and Z5 is hydrophobic or salt The base amino acid (for example, preferably I, L, or H), and Z6 is G, S, D, Q, or H is present, Z7 is S or T, and the antibody is 200, 150, 100, 50 or 40 K less than pM D Then, it binds to human FcRn.

[0309] In your embodiment, the isolated antibody is CDR L1 having the sequence TIFF0007914147000240.tif4128 and GDSERPS (SEQ ID NO:2) having the sequence CDR L2 and, CDR L3 having the sequence TIFF0007914147000241.tif4128 and having the sequence Z1YAMG (SEQ ID NO:15) CDR H1 and, CDR H2 having the sequence TIFF0007914147000242.tif4128 and LAIGDSY (SEQ ID NO:11) It has a CDR H3, where Z1 is T, D or N, and Z2 is S or A. Yes, Z3 is G, S, or A, and Z7 is S or T.

[0310] Table 1 shows the complementarity-determining regions (CDRs) of the light and heavy chains of some exemplary anti-FcRn antibodies. This shows the amino acid sequence.

[0311] (Table 1) TIFF0007914147000243.tif68168

[0312] Table 2 shows the sequence numbers for the variable regions of the light and heavy chains of these exemplary anti-FcRn antibodies. Yes, they are.

[0313] (Table 2) TIFF0007914147000244.tif56128

[0314] In some embodiments, the light chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000245.tif22165.

[0315] In some embodiments, the heavy chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000246.tif40165.

[0316] In some embodiments, the heavy chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000247.tif40165.

[0317] In some embodiments, the heavy chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000248.tif40165.

[0318] In other embodiments, the heavy chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000249.tif40165.

[0319] In another embodiment, the heavy chain variable region of the isolated antibody is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000250.tif40165.

[0320] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Yes, the light chain variable region is, The sequence has at least 90% identity with the sequence TIFF0007914147000251.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000252.tif40165.

[0321] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Yes, the light chain variable region is, The sequence has at least 90% identity with the sequence TIFF0007914147000253.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000254.tif40165.

[0322] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Yes, the light chain variable region is, The sequence has at least 90% identity with the sequence TIFF0007914147000255.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000256.tif40165.

[0323] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Yes, the light chain variable region is The sequence has at least 90% identity with the sequence TIFF0007914147000257.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000258.tif40165.

[0324] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Yes, the light chain variable region is, The sequence has at least 90% identity with the sequence TIFF0007914147000259.tif22165, and the heavy chain variable region is It has a sequence that is at least 90% identical to the sequence TIFF0007914147000260.tif40165.

[0325] Furthermore, in any of the anti-FcRn antibodies described herein, the heavy chain variable region of the antibody is , one of the sequences with SEQ ID NO:20~24 and at least 95%, 97 The sequence has %, 99%, or 100% identity. Anti-FcRn anti- In any part of the body, the light chain variable region is at least 9 sequences of SEQ ID NO:19. The sequences have 5%, 97%, 99%, or 100% identity.

[0326] Antibodies have amino acids located outside the CDR (i.e., within the framework region (FR)). It may further contain substitutions, additions, and / or deletions of amino acids. The deletion is one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8 or so) It is possible to make substitutions, additions, and / or deletions of the above. Amino acid substitutions and additions. , and / or absences are 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. Substitution, addition, and / or deletion of the following single amino acids are possible. Some implementations In this state, the antibody compares the sequence of any one of the sequences with SEQ ID NO:20~24. The amino acid substitutions A23V, S30R, L80V, A84T, E85D, A93V, and Compared to the sequence of SEQ ID NO:19, the following amino acid substitutions were made: Q38H, V58I and G It may further include one or more of 99D.

[0327] In some embodiments, the antibody is used for complement-dependent cell damage (complement-dependent cell damage). t-dependent cytolysis) (CDC), antibody-dependent cell-mediated cell Disorder (ADCC) and / or antibody-dependent cell-mediated phagocytosis (ADCP) This is a decrease in and / or a decrease in B cell death, for example, a decrease in effector function. Such as amino acid substitutions and additions in the constant region of an antibody (e.g., the Fc region) / May include deletions. The constant region is not directly involved in the binding of the antibody to its target. However, the antibody exhibits various effector functions, such as its involvement in antibody-dependent cytotoxicity. In this embodiment, the antibody is used on human complement factor C1q on natural killer (NK) cells. Characterized by reduced binding to the human Fc receptor (i.e., no binding) and / or absence of binding. In other embodiments, the antibody is human FcγRI, FcγRIIA and / or F Characterized by reduced binding to cγRIIIA (i.e., no binding). Antibody-dependent effector functions such as CDC, ADCC, ADCP, and / or B cell death. To alter or reduce the antibody, it may be of the IgG class, and one or This involves multiple amino acid substitutions: E233, L234, G236, D265, D270, N297 , E318, K320, K322, A327, A330, P331 and / or P329 ( Kabat EU Index (Sequence of Proteins of Immunological Interest,5th Ed.Public Hea National Institutes of Health It may contain (numbered according to h, Bethesda, MD. (1991)). In this embodiment, the antibody is used to treat mutations L234A / L235A or D265A / N297A. It contains. Preferably, the anti-FcRn antibody is one of the SEQ ID NO: 20~24. Compared to any one of the sequences, this antibody contains the amino acid substitution N297A, therefore, it is glycosylated. It changes to an aglycosylated form. Effectorless antibodies do not bind to complement or Fc receptors. (That is, complement C1q binding) is very low, indicating a low probability of CDC. That is the case.

[0328] In other embodiments, the antibody undergoes specific amino acid changes to improve antibody stability. It may contain antibodies.

[0329] Furthermore, in other embodiments, in order to minimize potential immunogenicity, for example, Some antibodies, N024, N026, and N027, have amino acids D355 and L357. By substituting glutamic acid and methionine respectively (SEQ ID NO:20 (Compared to any one of the ~24 sequences) Allo from G1m17.1 to G1m17 It can be affected by type changes.

[0330] In other embodiments, for example, the antibodies are N022-N024, N026 and N027. The body compares, for example, residues, with any one of the sequences among SEQ ID NO:20~24. It does not contain C-terminal lysine, which is located at position 446.

[0331] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Therefore, the light chain variable region is The sequence is TIFF0007914147000261.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000262.tif41165.

[0332] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Therefore, the light chain variable region is The sequence is TIFF0007914147000263.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000264.tif40165.

[0333] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Therefore, the light chain variable region is The sequence is TIFF0007914147000265.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000266.tif40166.

[0334] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Therefore, the light chain variable region is The sequence is TIFF0007914147000267.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000268.tif40165.

[0335] This disclosure features isolated antibodies containing light chain variable regions and heavy chain variable regions. Therefore, the light chain variable region is The sequence is TIFF0007914147000269.tif22165, and the heavy chain variable region is It has the sequence TIFF0007914147000270.tif40165.

[0336] In another embodiment, the antibody is a sialic acid-added antibody.

[0337] In some embodiments, any of the anti-FcRn antibodies described herein may be used. And the antibody is K less than 200, 150, 100, 50 or 40 pM. D in mice or rats It binds with FcRn.

[0338] In some embodiments, any of the anti-FcRn antibodies described herein may be used. And the antibodies are 1-100, 5-150, 5-100, 5-75, 5-50, 10-50 or It binds to human FcRn with an affinity of 10-40 pM.

[0339] Anti-FcRn antibodies are immunoglobulin antibody isotypes IgG, IgE, IgM, and IgA. Alternatively, it may be an IgD antibody. Preferably, the anti-FcRn antibody is an immunoglobulin. The antibody isotype shall be IgG. Anti-FcRn antibodies may also be any immunoglobulin. It can also be a subclass of the anti-FcRn antibody isotype. For example, an anti-FcRn antibody is , it may be a subclass of IgG, IgG1, IgG2, IgG3, or IgG4. Yes, it is possible. Preferably, the anti-FcRn antibody is of subclass IgG1. In particular, anti-F The cRn antibody contains the heavy chain of the IgG G1m17 or G1m17.1 allotype. In some embodiments, the light chain of the anti-FcRn antibody is a κ light chain, a λ light chain, or a κ-λ chemimetric chain. It may be a λ light chain. In a preferred embodiment, the anti-FcRn antibody contains a full-length λ light chain. To possess.

[0340] In some embodiments, antibodies (e.g., N022-N024, N026 and N02) 7, preferably N027 and / or N024, is monoclonal. The antibody is They may be polyclonal antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. In one embodiment, the antibody may be affinity-mature. In another embodiment, The antibody may be an antibody fragment.

[0341] Without being constrained by theory, anti-FcRn antibodies compete with IgG for binding to human FcRn. This is thought to inhibit the binding. Epitope mapping by hydrogen-deuterium exchange of antibodies According to the research, this antibody is located at and / or adjacent to the interaction interface between Fc-FcRn. This indicates that it binds to an epitope on FcRn, and this suggests that the The body's IgG levels are inhibited by direction (direction inhibition). This suggests that it blocks binding to FcRn. Furthermore, epitope mapping was performed. The binding site is located away from the albumin-binding site of FcRn.

[0342] In some embodiments, serum albumin binding is not inhibited. In some cases, anti-F Serum albumin levels do not decrease after administration of cRn antibodies.

[0343] II. Sialic acid-modified anti-FcRn antibodies In some embodiments, the glycosylation sites of the Fc region of the anti-FcRn antibody are molar in number At least 25%, 50%, 75%, or more of the antibody is sialic acid-added. Sialyltransferase (ST6 Gal-I) is an enzyme that sequentially adds sialic acid to substrates. Sialic acid can be added by ). More specifically, under certain conditions, ST6 sialic acid transferase Among the polysaccharides on the Fc region of the anti-FcRn antibody, sialic acid addition on the α1,3 arms, Next, a second sialic acid addition occurs on the α1,6 arm, followed by sialic acid addition from the α1,3 arm. It catalyzes the removal of acid.

[0344] Isolated anti-FcRn antibodies are used in host cells for production (e.g., mammalian cells, e.g., ST6). Mammals that have been co-introduced with sialic acid transferase or that overexpress ST6 sialic acid transferase. Sialic acid can be added during production within cells. In other embodiments, isolated The anti-FcRn antibody, after purification from host cells for production, is converted, for example, enzymatically or chemically. Sialic acid can be added in vitro. The method for producing the anti-FcRn antibody is described in the PCT publication, International Publication No. 2014 / 179. It is described in issue 601.

[0345] III. FcRn Inhibition Human neonatal Fc receptor (FcRn) is a cell-mediated receptor that binds to IgG and serum albumin. FcRn is a type I transmembrane protein that functions as an endothelial IgG transport protein. Cells, luminal epithelial cells, hepatocytes, podocytes, granulocytes, monocytes, macrophages, dendritic cells and It is expressed in NK cells but not in B cells or T cells. FcRn is endogenous IgG By binding to and constitutively transporting IgG back to the cell surface, it preserves the half-life of IgG. The binding of FcRn to both Fc and serum albumin is observed at pH 6.0 in the initial endoscopy. This process occurs within the cell, and then FcRn is sorted into vesicles, which then bind to FcRn. IgG and / or albumin are transported, and at pH 7.4, FcRn is transported to IgG and / or albumin. Lubumin is immediately released and returned to the cell surface. This transport cycle allows both By recycling the substance into the circulation and preventing its transport to lysosomes for degradation, This preserves the half-lives of IgG and albumin. FcRn is also endogenous within epithelial cells. It captures the Fc of sex IgG and transports them bidirectionally to the opposing apical or basolateral membranes. This function allows IgG to be transported into the lumen of organs such as the digestive tract, or into the lumen of the interstitial cell layer. This makes it possible to transport IgG or IgG antigen complexes from vascular structures or lymphoid tissue. Yes.

[0346] To investigate the contribution of FcRn IgG to homeostasis, the light chain and heavy chain of FcRn were examined. By "knocking out" the chain portion, these proteins are prevented from being expressed. Modified mice (Junghans et al., Proc Natl Academia) Sci USA 93:5512,1996). In these mice, serum IgG The half-life and concentration decreased dramatically, which is due to the FcRn-dependent nature of IgG homeostasis. This suggests a mechanism. In the rodent models described above, Therefore, suppression of FcRn function increases IgG catabolism, including that of pathogenic autoantibodies. This makes it possible to inhibit the onset of diseases (e.g., autoimmune diseases). This suggests that FcRn also has an antigen degradation compartment and an MHC load compartment. It may also contribute to antigen presentation via the transport of immune complexes to the treatment.

[0347] The transfer of maternal IgG antibodies to the fetus through the placenta is an important FcRn-dependent process that protects newborns. The mechanism is that, on the other hand, the humoral response of newborns is inefficient. During the fetal period, the placenta's syncytial FcRn in the thium trophoblast layer is involved in the transfer of maternal IgG antibodies to the fetus. Pathogenicity The maternal antibody (for example, the pathogenic maternal IgG antibody) also binds to FcRn. It crosses the placenta and causes alloimmune disorders and / or autoimmune disorders in the fetus and newborn. This can occur. In some embodiments, pathogenic antibodies in a pregnant subject may be present in a pregnant partner. In elephant fetuses, it causes alloimmune disorders and / or autoimmune disorders in the fetus and neonatal population. The anti-FcRn antibodies described herein (e.g., N022-N024, N026 and N02) 7. Preferably N027 and / or N024) are maternal pathogenic antibodies against FcRn (e.g., It can compete with and inhibit the binding of maternal pathogenic IgG antibodies, thereby inhibiting the different types of these pathogenic antibodies. It increases the chemical effect and decreases its half-life.

[0348] This disclosure provides an isolated anti-FcRn antibody that binds to human FcRn. Rn antibodies bind to FcRn by other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). It can compete with and inhibit other anti-FcRn antibodies (e.g., IgG, IgG auto-antibody), thereby inhibiting other anti-FcRn antibodies (e.g., IgG, IgG auto-antibody). It increases the catabolic activity of antibodies and also decreases their half-life. Anti-FcRn antibodies are auto In immune diseases, immune responses are those caused by autoantibodies, etc. The answer is that it can be used in methods to treat or mitigate immune complex-based activation. Reducing the immune response is more effective than in untreated subjects (e.g., control subjects) It may be described as a condition that reduces the immune response. Anti-FcRn antibodies are also found in the placenta of pregnant subjects. Methods to reduce the transfer of pathogenic antibodies beyond a certain point (e.g., the transfer of pathogenic maternal IgG antibodies), A method to increase the catabolic activity of pathogenic antibodies in pregnant subjects, and human FcR in pregnant subjects. By administering isolated antibodies that bind to n, the virus in the fetus or neonatal region can be controlled. It can also be used in methods to treat antibody-mediated enhancement of sexually transmitted infections. Reducing the transfer of pathogenic antibodies across the board is important for untreated subjects (e.g., con It may be described as reducing the transfer of pathogenic antibodies compared to the target group.

[0349] IV. Production of vectors, host cells, and antibodies Anti-FcRn antibodies can be produced from host cells. Host cells are defined herein. The polypeptides and constructs described herein are necessary for expressing them from their corresponding nucleic acids. This refers to a carrier containing essential cellular components, such as organelles. The nucleic acid is , prior art known in this field (e.g., transformation, transfection, electrolysis) It is introduced into host cells by means of pores, calcium phosphate precipitation, direct micro-injection, infection, etc. It is possible to include it within a nucleic acid vector. The nucleic acid vector is used in the host cell. Partially dependent on selection. Generally, preferred host cells are prokaryotes (e.g., bacterial) or It is of eukaryotic origin (for example, mammalian origin).

[0350] Nucleic acid vector composition and host cell The nucleic acid sequence encoding the amino acid sequence of the anti-FcRn antibody is known in the art. It may be prepared by various methods. These methods involve oligonucleotides. This includes, but is not limited to, site-specific (or site-directed) mutation introduction and PCR mutation introduction. Nucleic acid molecules encoding anti-FcRn antibodies can be obtained using standard techniques, such as gene synthesis. Alternatively, a nucleic acid molecule encoding a wild-type anti-FcRn antibody can be used, for example, Qui kChange(trademark) mutation introduction is a standard technique in this field that uses specific amino acids. They may be mutated to include nucleotide substitutions. Nucleic acid molecules are nucleotide synthesizers. Alternatively, it can be synthesized using PCR technology.

[0351] The nucleic acid sequence encoding the anti-FcRn antibody is found in the nucleus of a prokaryotic or eukaryotic host cell. It can be inserted into a vector that allows for the replication and expression of acid molecules. Vectors are available and can be used in this technical field. Each vector is special It contains various components that can be adjusted and optimized for compatibility with specific host cells. This can be done. For example, the vector components can include a replication origin, a selection marker gene, and a promoter. , ribosome binding site, signal sequence, nucleic acid sequence encoding the protein of interest, and This may include, but is not limited to, image termination sequences.

[0352] In some embodiments, mammalian cells are used as host cells. Examples of types include human embryonic kidney cells (HEK) (e.g., HEK293, HEK293) F) Chinese hamster ovary cells (CHO), HeLa, COS, PC3, Ver o, MC3T3, NS0, Sp2 / 0, VERY, BHK, MDCK, W138, BT4 83, Hs578T, HTB2, BT20, T47D, NS0 (intrinsically derived immunoglobulin chain) (A mouse myeloma cell line that produces nothing) CRL7O3O and HsS78Bst Examples of cells include, but are not limited to, those of Escherichia coli (E. coli). E. coli cells are used as host cells. An example of an E. coli species is... Enterobacteriaceae (E.coli) 294 (ATCC (registered trademark) 31,446), Escherichia coli (E.coli) li) λ1776 (ATCC (registered trademark) 31,537, E. coli BL2 1(DE3)(ATCC(registered trademark)BAA-1025) and Escherichia coli (E. coli)® Examples include, but are not limited to, V308 (ATCC(registered trademark) 31,608). Various host cells have characteristics related to the post-translational processing and modification of protein products and It has a specific mechanism. Select an appropriate cell line or host system and express anti-FcRn anti This ensures precise modification and processing of the body. The expression vector described above. - Conventional technologies in this field, such as transformation, transfection, and electrical It is introduced into suitable host cells using perforation, calcium phosphate precipitation, and direct microinjection. To obtain, once the vector is introduced into a host cell for protein production, the host cell is... Generators used to induce promoters, select transformants, or encode desired sequences. Cultivate in a conventional nutrient medium modified to be suitable for gene amplification. For therapeutic use. Since methods for expressing proteins are publicly known in this field, for example, Paulina Balbas, Argelia Lorence (eds.) Recombinant Gene Expression:Reviews and Protocols ( Methods in Molecular Biology), Humana Pre ss;2nd ed.2004(July 20,2004)and Vladimir Voynov and Justin A. Caravella (eds.) Ther. apeutic Proteins:Methods and Protocols(M methods in Molecular Biology)Humana Press See 2nd ed. 2012 (June 28, 2012).

[0353] Protein production, recovery, and purification The host cells used for the production of anti-FcRn antibodies are known and selected hosts in this art. It can be grown in a culture medium suitable for cell culture. Suitable for mammalian host cells. Examples of culture media include Minimum Essential Medium (MEM) and Dulbecco's Modified Eagle Medium (Du lbecco's Modified Eagle's Medium) (DMEM), Expi293 (trademark) Expression Medium, Fetal Bovine Serum (FBS) Examples include DMEM containing and RPMI-1640. Suitable culture media for bacterial host cells. For example, L medium (L) supplemented with necessary adjuvants such as the selective reagent ampicillin. Uria broth (LB) is one example. Host cells thrive in temperatures ranging from approximately 20°C to 39°C. The appropriate temperature is, for example, 25°C to about 37°C, preferably 37°C, and the CO2 concentration is 5-10%. The culture is performed in a solution such as (preferably 8%). The pH of the culture medium is generally about 6.8 to 7.4, for example 7. It is 0 and is mainly dependent on the host organism. When an inducible promoter is used in the expression vector. Protein expression is induced under conditions favorable to promoter activation.

[0354] Protein recovery is generally performed by osmotic shock, sonication, or lysis, etc., in the host cells. This typically involves destroying the cells. Once the cells are destroyed, the cell fragments are removed by centrifugation or filtration. It can be removed. The protein may be further purified. Anti-FcRn antibody is protein Any method known in the field of quality purification, e.g., protein A affinity, other chromatography Graphs (e.g., ion exchange, affinity, and size exclusion column chromatography) (i), centrifugation, solubility difference, or other standard techniques relating to protein purification , can be purified. (Process Scale Purification of An tibodies,Uwe Gottschalk(ed.)John Wiley&S (See ons, Inc., 2009). In some cases, anti-FcRn antibodies, It is possible to bind to the labeled sequence of peptides, etc., to facilitate purification. An example of a column is hexahistidine peptide (His-tagged), which is micromolar. Nickel-functionalized bonding due to its affinity level It binds to a galose affinity column. Other peptide tags useful for purification are limited to... It is not the same as influenza, but it contains the hemagglutinin "HA" tag, which is the influenza hemagglutinin. This corresponds to an epitope derived from a chromosome protein.

[0355] Alternatively, anti-FcRn antibodies can be produced by target cells (e.g., human cells). It is possible, and for example in the context of therapy, a nucleotide molecule containing an anti-FcRn antibody can be used. Vectors (e.g., retroviral vectors, adenovirus vectors, poxviruses) Vector (poxviral vector) (for example, modified Vaxinia Ankara (Mo Vaccinia virus bacilli such as dified Vaccinia Ankara (MVA) Vaccina Viral Vector (VATIN), Adeno-associated virus vector It can be produced by administering (and alpha virus vectors). Yes. The vector, once it enters the target cell (e.g., transformation, transfection), (By electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), and then cells This promotes the expression of anti-FcRn antibodies secreted from the body. Treatment of the disease or disorder is performed at If the desired result is achieved, no further action is required. In this case, blood is collected from the subject and proteins are extracted from the blood using methods known in this art. The quality may be refined.

[0356] V. Pharmaceutical Compositions and Formulations This disclosure includes one or more anti-FcRn antibodies described herein (e.g., N022) ~N024, N026 and N027, preferably N027 and / or N024) The pharmaceutical composition is characterized by containing a therapeutic protein. In some embodiments, the pharmaceutical composition contains a therapeutic protein It contains one or more types of antibodies as components. In other embodiments, one or more types A pharmaceutical composition containing antibodies is used in treatment with other reagents (e.g., therapeutic biologics and It may be used in combination with (or small molecules) or compositions. The pharmaceutical composition contains a therapeutically effective amount of antimicrobial In addition to the body, one or more can be prepared by methods known to those skilled in the art. It may contain a variety of pharmaceutically acceptable carriers or excipients.

[0357] Acceptable carriers and excipients in pharmaceutical compositions are determined by the dosage and concentration used in the recipe. It is non-toxic to the user. Acceptable carriers and excipients include buffers, antioxidants, and preservatives. It may also contain polymers, amino acids, and carbohydrates. The pharmaceutical composition is available in the form of an injectable formulation. It can be administered orally. Pharmaceutical compositions for injection (i.e., intravenous injection) use as a carrier. It can be prepared using a sterile solution or any pharmaceutically acceptable liquid. The carrier consists of sterile water, physiological saline, and cell culture medium (e.g., Dulbecco's modified Eagle medium). (DMEM), α-modified Eagle medium (α-MEM), F-12 medium) are included, The preparation methods are known in the art, for example, Banga(e d.) Therapeutic Peptides and Proteins:For mulation,Processing and Delivery Systems (2nd ed.)Taylor&Francis Group,CRC Press( See (2006).

[0358] Pharmaceutical compositions can be formed in the required unit dose form. The amount of the active ingredient, for example, one or more types of anti-FcRn antibodies (e.g., N022~N024, The amounts of N026 and N027, preferably N027 and / or N024, are specified. The amount should be such that a suitable dose is given within the range (for example, 0.01 per kg of body weight). (A single dose within the range of 500 mg).

[0359] VI. Route, Dosage, and Administration As a therapeutic protein, one or more anti-FcRn antibodies described herein (e.g., , N022~N024, N026 and N027, preferably N027 and / or N Pharmaceutical compositions containing 024) are for intravenous, parenteral, subcutaneous, and intramuscular administration. It can be prepared for administration, intra-arterial administration, intrathecal administration, or intraperitoneal administration. Intravenous administration is preferred. The pharmaceutical composition is also available for oral, nasal, spray, and aerosol applications. It may be prepared or administered for oral, rectal, or vaginal administration. Regarding injectable formulations, various Effective drug carriers are publicly known in this technology field.

[0360] The dosage of a pharmaceutical composition depends on the route of administration, the disease to be treated, and, for example, the age of the target individual. It depends on factors including physical characteristics, which are the overall health condition. Typically, the amount contained in a single dose The anti-FcRn antibodies described herein (e.g., N022-N024, N026 and The amounts of N027 and / or N024 (preferably N027 and / or N024) induce significant toxicity. It can be formulated to effectively prevent, delay, or treat the disease without requiring any additional steps. The substance contains anti-FcRn antibody at concentrations of 0.01 to 500 mg / kg (for example, 0.01, 0.1, 0.01). 2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 3 5, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 4 It may be included in doses ranging from 50 or 500 mg / kg, and in more detailed embodiments, The amount is approximately 1 to 100 mg / kg, and in more detailed embodiments, it is approximately 1 to 50 The dose is mg / kg. The conventional dosage is determined based on the severity of the disease and various parameters of the subject. It may be applied by a physician depending on the factors.

[0361] The pharmaceutical composition is administered in a therapeutically effective amount using a method compatible with the dosage form. , bringing about improvement or treatment of symptoms. Pharmaceutical compositions, for example, intravenous dosage forms, subcutaneous dosage forms. , and various agents in oral dosage forms (e.g., ingestible solutions, drug-releasing capsules). It is administered in the form of 1-100 mg / kg, for example, 1-5 The medication is administered at a dose of 0 mg / kg. For example, daily, weekly, monthly, every six months, annually, or once a year. Multiple times (for example, 1 to 10 times or more), or as medically necessary, this item The anti-FcRn antibodies described in the book (for example, N022-N024, N026 and N027) A pharmaceutical composition containing, preferably N027 and / or N024, is administered to the target of the patient. It can be administered to [the patient]. The medication can be either a single-dose regimen or a multi-dose regimen. It can be provided as follows. The timing between each dose may be reduced as the medical condition improves, This can be increased if the patient's health condition deteriorates.

[0362] VII. Treatment Methods and Indications Suppression of human FcRn with anti-FcRn antibodies is affected by IgG autoantibodies. It may be therapeutically effective in diseases. Serum albumin, small blood metabolites, or lipoproteins Without disrupting the overall catabolism of pathogenic antibodies (e.g., IgG antibodies) and multiple types of autoantibodies Due to its ability to suppress FcRn, which induces removal, it is effective in patients with autoimmune diseases caused by autoantibodies. A method is provided to improve the usefulness and ease of implementation of autoantibody removal strategies for [the disease]. This disclosure does not necessarily link to theory, but the dominant mechanism of action of anti-FcRn antibodies is, To increase the catabolism of pathogenic autoantibodies in circulation and the relationship between autoantibodies and immunity within affected tissues. This may reduce the deposition of the complex.

[0363] One or more anti-FcRn antibodies described herein (e.g., N022-N024, N A pharmaceutical compound containing 026 and N027, preferably N027 and / or N024) The product and method involve catabolism and, for example, the target IgG and pathogenic antibodies which are IgG autoantibodies. Promoting clearance and, for example, the immune response in a target, based on immune complexes. This involves inhibiting activation, reducing the immune response, and preventing immune symptoms or immunity in the target. It is useful for treating diseases. More specifically, the pharmaceutical composition and method are for acute or chronic diseases. It is useful in reducing or treating immune complex-based activation of the immune response. Sexual immune responses include pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, and anti- Somatic rejection, fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, Channel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura (ITP), auto Autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated cardiomyopathy, and serum sickness It can be activated by a medical condition selected from the group. Chronic immune responses include chronic inflammatory demyelination. CIDP (Compromised Polyneuropathy of the Genitals), systemic lupus, chronic forms indicated for acute treatment Disorders, reactive joint disorders, primary biliary cirrhosis, ulcerative colitis, and anti-neutrophil cytoplasmic antibodies (A It may be activated by medical conditions selected from the group consisting of NCA-associated vasculitis.

[0364] In some embodiments, pharmaceutical compositions and methods reduce the risk of fetal anemia. Alternatively, it is useful in reducing the risk of fetal anemia. In some embodiments, The pharmaceutical composition and method is IUT (intrauterine transfusion). Useful in reducing or preventing the need for nsfusion. Some implementations In this context, the pharmaceutical composition and method involve PP and IVIg before birth, and blood transfusion and IVI after birth. Useful in reducing or preventing the need for g and / or phototherapy. Some implementations In this context, the pharmaceutical composition and method reduce the immune response activated by autoimmune diseases. It is useful for treating or eliminating autoimmune diseases such as alopecia areata, ankylosing spondylitis, and anti-inflammatory drugs. Lipid antibody syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, Bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring pemphigoid, limited Localized systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid dermatomyositis Lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, pons This thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic Pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, multiple Chondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, arthritis Matiasis, sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman syndrome, Takayasu It consists of pulsitis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis. They can be selected from the group.

[0365] In detail, the pharmaceutical composition and method are for systemic lupus erythematosus, antiphospholipid syndrome, Pemphigus vulgaris / bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis Useful for reducing or treating the immune response activated by mycosis or neuromyelitis optica. be.

[0366] The pharmaceutical composition and method are for the transfer of pathogenic antibodies across the placenta of a pregnant subject (e.g., pathogenicity Methods to reduce the transfer of maternal IgG antibodies, and the catabolism of pathogenic antibodies in pregnant subjects. A method to increase this involves administering isolated antibodies that bind to human FcRn to pregnant subjects. This is for treating antibody-mediated enhancement of viral infections in fetuses or newborns. Useful in law. Isolated anti-FcRn antibodies described herein (e.g., N022) ~N024, N026 and N027, preferably N027 and / or N024) Diseases and disorders for which FcRn inhibition may be effective include those involving pregnant subjects and / or the fetus. The transfer of maternal pathogenic antibodies (e.g., pathogenic maternal IgG antibodies) across the placenta to the newborn This may include diseases and disorders in the fetus and / or neonatal in which the disease is caused.

[0367] In some embodiments, isolated anti-FcRn antibodies described herein (e.g., N) These are 022~N024, N026 and N027, preferably N027 and / or N02 4) Diseases and disorders for which FcRn inhibition may be effective include alloimmune disorders of the fetus and neonatal period. It is a harmful and / or autoimmune disorder. Alloimmune disorders of the fetus and neonat are present in pregnant subjects. This is a disorder in the fetus and / or neonatal period caused by pathogenic antibodies. Pathogenic antibodies in the pregnant subject are related to fetal antigens (for example, those inherited by the fetus from the father). It may attack a certain antigen, causing fetuses or newborns to develop fetal and neonatal alloimmune disorders. / or it can cause autoimmune disorders.

[0368] Alloimmune disorders of fetuses and neonates that can be treated by the methods described herein. And / or examples of autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia (FN). AIT), hemolytic disease of the fetus and neonat (HDFN), alloimmune panthrombocytopenia, Congenital heart block, fetal joint contractures, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia Neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, neonatal dysplasia Dermatitis is one example, but it is not limited to these. Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease in infants, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes.

[0369] In some embodiments, isolated anti-FcRn antibodies described herein (e.g., N) These are 022~N024, N026 and N027, preferably N027 and / or N02 4) Diseases and disorders for which FcRn inhibition may be effective are viral diseases, and The body facilitates the entry of viruses into host cells, for example, antibody-mediated infection of viral diseases. Enhancement is a viral disease that leads to an increase or exacerbation of infectivity within cells. In this state, antibodies can bind to proteins on the surface of the virus, and the antibody / virus The complex binds to FcRn on the cell surface via interactions between the antibody and the receptor. This can then occur. Subsequently, the antibody / virus complex can become endogenous within the cell. For example If the virus forms a complex with maternal IgG antibodies, it can infect fetal cells and / or It can invade tissues. Maternal IgG antibodies bind to the viral surface protein. The IgG / virus complex then binds to FcRn in the placental syncytium trophoblast layer. The complex is then transported to the fetus.

[0370] In some embodiments, the methods described herein are used to treat antibody media for viral diseases. It can treat enhanced mediated infection. In some embodiments, pathogenic antibodies (e.g., Viral diseases that are enhanced by pathogenic IgG antibodies include alphavirus infections and f Rabivirus infection, Zika virus infection, Chikungunya virus infection, Rothriva Illegal infections, severe acute respiratory syndrome, coronavirus infection, Middle East respiratory syndrome, avian influenza Influenza infection, influenza virus infection, human respiratory syncytial virus infection, Evoluvirus infection Virus infections, yellow fever virus infections, dengue virus infections, human immunodeficiency virus Infectious diseases, RSV infection, hantavirus infection, getavirus infection, Sindhias Viral infections, Bunyamwella virus infection, West Nile virus infection, Japanese encephalitis Virus B infection, rabbitpox virus infection, lactate dehydrogenase-elevated virus infection, Leowy Rabies virus infection, foot-and-mouth disease virus infection, porcine reproductive tract respiratory syndrome Illuscultation, monkey hemorrhagic fever virus infection, equine infectious anemia virus infection, goat arthritis Viral infections, African swine fever virus infection, lentivirus infection, BK papobau Virus infections, Murray Valley encephalitis virus infection, enterovirus infections, cytomegalovirus Viral infections, Pneumovirus infection, Morbillivirus infection, and measles virus infection This includes, but is not limited to, viral diseases caused by infection.

[0371] Suppressing human FcRn with anti-FcRn antibodies is equivalent to suppressing pathogenic antibodies (e.g., pathogenic Ig). It may be therapeutically effective in diseases affected by G antibodies. Serum albumin, Without disrupting small blood metabolites or lipoproteins, it promotes the catabolic action of the entire pathogenic antibody and multiple types of diseases. By inducing the removal of proto-antibodies and suppressing FcRn, the pathology of autoimmune diseases caused by pathogenic antibodies is suppressed. A method to improve the usefulness and ease of implementation of pathogenic antibody removal strategies for patients with [condition]. This is provided. Although not linked to theory, the dominant mechanism of action of anti-FcRn antibodies is, By increasing the catabolism of pathogenic antibodies in circulation and by the interaction of pathogenic antibodies and immunity within diseased tissues This may reduce the deposition of the complex.

[0372] Anti-FcRn antibodies described herein (e.g., N022-N024, N026 and N02 7, preferably N027 and / or N024), in which the immune response occurs in pregnant subjects. In pregnant subjects who are at risk of having or are at risk of having a medical condition that could activate the virus. It can be administered. In some embodiments, the pregnant subject has been pregnant in the past. The subject may have a medical condition in which the immune response is activated. Some embodiments In this case, the pregnant subject will have alloimmune disorders and / or autoimmune disorders in the fetus and newborn. Having previously given birth to a fetus or newborn. (Some embodiments) In this case, in biological samples (e.g., blood samples or urine samples) obtained from pregnant subjects, immuno If disease-related pathogenic antibodies are detected, the anti-FcR described herein should be administered to pregnant subjects. The n antibody can be administered. In some embodiments, in a biological sample of a pregnant subject... The pathogenic antibodies detected are antigens from the fetus of the pregnant subject (for example, the fetus is the father of the fetus) It is known to bind to antigens (which are inherited from humans).

[0373] In some embodiments, the anti-FcRn antibodies described herein (e.g., N022~N) are used. N024, N026 and N027, preferably N027 and / or N024) are pregnant. Medical treatments that activate the immune response in individuals who are planning to become pregnant and who are pregnant. In subjects with or at risk of having a medical condition, and / or in pregnant subjects It can be administered to subjects who have previously had a medical condition that activated the immune response. In some embodiments, the subject is planning to become pregnant and has a fetus and If you have previously given birth to a fetus or newborn that had neonatal alloimmune disorders and / or autoimmune disorders It has a history of having done so. In some embodiments, the anti-FcR described herein n antibody is used in subjects planning to become pregnant, and in biological samples of said subjects related to immune diseases. It can be administered to subjects that contain related pathogenic antibodies.

[0374] In some embodiments, the anti-FcRn antibody described herein is used in a target (e.g., pregnancy). Administered to the subject (in which the drug was administered), the drug was used to stimulate the acute or chronic immune response in the subject, based on immune complexes. The activation can be reduced or treated. The acute immune response is a medical condition (e.g., , pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection Reactions, fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, channel diseases, Neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immunodeficiency Epidemic neutropenia, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy, systemic Lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, or antineutrophil cells It can be activated by anechoic antibodies (ANCA-associated vasculitis).

[0375] In some embodiments, the anti-FcRn antibody described herein is used in a target (e.g., pregnancy). To reduce or treat the immune response activated by autoimmune diseases in the target population. This autoimmune disease can include, for example, alopecia areata, ankylosing spondylitis, and antiphospholipid anemia. systemic syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia (wAIHA), antifactor Antibodies, heparin-induced thrombocytopenia (HICT), sensitized transplantation, autoimmune hepatitis, hepatitis, - Chet's disease, bullous pemphigoid, cardiomyopathy, celiac plue dermatitis, chronic fatigue, immune function Disorder syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scarring Pemphigoid, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, skin Dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative disorder Syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus Anesthetic, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polycystic nodule Arteritis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary acanthosis Maglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis Zi's ​​fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, Stiffman Syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's meat It could be blastomatosis. [Examples]

[0376] Example 1 - Antibody Production IgG heavy chain and light chain nucleic acid molecules are converted using the osteonectin secretion signal. The cells were cloned into pCDNA 3.3. HEK293F cells were mixed with 8% CO2. The cells were then grown in Expi293 medium at 37°C. The cells were given 1 mg of total per liter. Along with DNA, density 3x10 6 Transfected with / ml. On day 2 and day 3, The enhancer was added according to the manufacturer's instructions. Cell viability dropped to 50%-60% or less. The cells were previously cultured until day 5 or 6. Then the cells were centrifuged and the used culture medium was used. The sample was aseptically filtered and stored at 4°C until antibody purification. The antibodies were purified using the following two column procedures. Purified: POROS Protein A chromatography, followed by POROS HS-5 0. Cation exchange chromatography. The former allows for the large-scale extraction of host cell proteins from expressed antibodies. While the portion was separated, the latter yielded heavy chain dimers, light chain dimers and semi-antibodies, as well as more High molecular weight seeds were extracted. The fraction from the HS-50 cation exchange column was completely removed. To maximize the purity of the full-length antibody, it was stored based on SDS-PAGE gel analysis. The collected fraction was equilibrated in PBS at pH 7.2 using Sephadex. The column was run on a dex)G50 buffer exchange column. The peak fraction was collected and stored at 30k Concentrate to over 10 mg / ml using a Da spin concentrator, then 2m The g aliquots and 5 mg aliquots were frozen at -30°C. The final protein sample was... The purity was confirmed by SDS-PAGE.

[0377] Example 2 - Binding Affinity After affinity maturation, K in the sub-micromolar range D More than 100 anti-FcRn antibodies with binding affinity to human FcRn were identified. Five antibodies (N022-N024, N026 and N02) are used to determine the characteristics. 7) was selected. Using surface plasmon resonance (SPR), each of these five antibodies was analyzed. Regarding this, the binding rate and dissociation rate (each, k a and k d ) was decided. In short, Insert the Bio-Rad GLC sensor chip into the ProteOn XPR 36, A was initialized. After initialization, the running buffer will be HBSP+(0. (0.1M HEPES, 0.15M NaCl, 0.05% P2O, pH 7.4) or Sodium phosphate buffer (0.02M sodium phosphate, 0.15M NaCl, 0.0 We switched to a newly prepared buffer solution that was either 5% P20 or pH 6.0, but This was also used in subsequent assays and as all diluents. The above tip is 0.5% For each of SDS, 50 mM NaOH, and 10 mM HCl, 30 μl / mil Preconditioning was performed by injecting n for 60 seconds at a time, once per session. GE Healthcare Mouse anti-human Fc mAb (BR100839) in 10 mM acetate buffer at pH 5.0 Dilute to 10 μg / ml to obtain approximately 5,700 response units. (RU) is placed horizontally on the GLC sensor chip in a standard amine coupling chemistry configuration. It was more fixed. The anti-hFcRn mAb under test was oriented perpendicularly to the surface, and interacting sponges The goal was to immobilize approximately 200 reaction units (RU) per set by capturing rhFcRn. Then, starting with a concentration of 1.25 μg / ml, it was diluted in a 5-step 3-fold dilution series, and lane 1 was... For blue reference, only the buffer solution was used. The analyte was set to a dissociation time of 3,600 seconds. For example, flow at a rate of 100 μl / min horizontally across the sensor surface for 240 seconds. The following was done: 3M MgCl was dissolved at 100 μl / min for 30 seconds in both horizontal and vertical orientations. By injecting step 2, regeneration was achieved. These steps This was repeated for all ligands.

[0378] Data analysis was performed using ProteOn Manager software. Adjust the steps in the Y and X directions using the Auto Process tool, then Furthermore, nonspecific interactions are excluded by interspot channel referencing, Assay drift was eliminated by double referencing the blank lane. The data is grouped into Rmax using Langmuir's 1:1 dynamic model. A fitting was performed. The results obtained from ProteOn Manager were obtained in a single run. k a , k d and K D The values ​​are averaged, and if N is 3 or greater, their percentage changes I calculated the dynamic coefficient CV using Microsoft Excel.

[0379] Table 3 lists five anti-FcRn antibodies, N022, N023, N024, N026 and All of the N027 samples demonstrate high affinity binding to human FcRn at pH 7.4. Regarding binding to human FcRn at pH 7.4 and 298K, the equilibrium solution of the anti-FcRn antibody separation constant K D The range was from 19.4 pM (N027) to 36.5 pM (N026). Table 3 also shows the fast binding and slow dissociation rates of the five anti-FcRn antibodies. At H7.4 and 298K, the binding rate to human FcRn was 0.93 ~1.42 × 10 6 The range was 1 / Ms. The dissociation rate was 2.31~4.44 × 10⁻⁶. 6 It was within the range of 1 / s.

[0380] (Table 3) TIFF0007914147000271.tif49128

[0381] Example 3 - Competition with IgG Anti-FcRn antibodies that compete with IgG for binding to human or cynomolgus monkey FcRn Regarding its capabilities, it binds glycophosphatidylinositol (GPI)-bound FcRn on the cell surface. The evaluation was performed on human embryonic kidney (HEK) 293 cells, which express human FcRn ectopically. The alpha amino acid sequence and the alpha amino acid sequence of cynomolgus monkey FcRn show a 97.5% correspondence. This shows column identity. Between human FcRn alpha and cynomolgus monkey FcRn alpha, 355 Nine of the amino acid residues differ, but all are within the epitope-mapped binding region. It is not present. The concentration of IgG bound to cells was measured using a non-specific fluorescent probe labeled at 66 nM. The determination was made using different IgG molecules. IgG binding to cell surface FcRn was determined at pH 6.0. This allows the Fc portion of IgG to interact with FcRn. (See Figure 1) As shown, the amount of IgG bound to cells is the amount of anti-FcRn antibody (N022~N024, N0 As the concentration of 26 or N027 increased, it decreased significantly. IgG binding was 5 Each of the exemplary anti-FcRn antibodies inhibited the process in a concentration-dependent and saturation-dependent manner. Therefore, at pH 6.0, it effectively competes with IgG and inhibits the binding of IgG to FcRn, thus inhibiting anti-F The capabilities of cRn antibodies N022-N024, N026, and N027 will be demonstrated. The EC5 of the antibodies will be analyzed. The zero value was in the range of 2 to 6 nM.

[0382] Example 4 - Effect of anti-FcRn antibody on IgG catabolism in mice To measure the effect of anti-FcRn antibodies on IgG catabolism in vivo. Therefore, a human FcRn transgenic mouse strain is used, in which mouse FcRn is lacking. However, it expresses human FcRn with a tissue distribution similar to that of endogenous FcRn in mice and humans. Homozygous B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr / DcrJ Mice were used. On day 0, they were injected with a tracer containing human IVIG at a dose of 500 mg / kg. FcRn- / -hFcRn(32)Tg mice were given 10 mg / kg on day 1 and day 4. A single dose of anti-FcRn antibody was administered. As shown in Figure 2, the catabolic effect of IgG was anti-Fc This can be seen from the fact that low concentrations of IgG were measured over time in mice treated with Rn antibodies. As shown, it increased with the administration of anti-FcRn antibodies. N024(K D =35.5pM), N 026(K D =36.5pM) and N027(KD The activity (=19.4 pM) is present in 10 mg A similar observation was made at / kg.

[0383] Example 5 - In vitro characterization of anti-FcRn antibody The cell binding affinity of antibodies is determined by glycophosphatidylinositol (GPI) on the cell surface. Human embryonic kidney (HEK) 2 ectopically expresses conjugated human or cynomolgus monkey FcRn. Measurements were taken on 93 cells. FcRn was transported to the luminal side of the endosomal membrane or to the plasma membrane. In this case, the I has an IgG-binding domain and an albumin-binding domain oriented toward the cell surface. It is a type transmembrane protein. Membrane binding on the cell surface of HEK293 cells at pH 7.4. Anti-FcRn antibodies bind to FcRn only through the Fab domain of the antibody, not the Fc domain. It mimics binding in a physiologically appropriate environment and pH, where it interacts with FcRn. The extracellular FcRn domain, via its C-terminus incorporating GPI binding, is densely cellular. Observed on the surface. Anti-FcRn antibody was labeled with a fluorescent probe. The antibody was left on ice for 30 minutes. The antibodies were then bound together. After washing the cells at 4°C, the bound antibodies were converted to fluorescently labeled secondary antibodies. For example, detection was performed using a goat anti-human IgG F(ab)2 antibody. Binding to human FcRn. The response was concentration-dependent, with antibodies exhibiting EC50 values ​​in the range of 4–7 nM.

[0384] The cell binding affinity of the antibody was also measured on endogenously expressed human FcRn. Monocytes, It expresses the highest concentration of FcRn and has the highest FcRn expression in mouse and human blood. It shows a high percentage positivity. Monocyte cell line THP-1 Using this method, the binding of anti-FcRn antibodies to endogenous human FcRn at pH 7.4 was evaluated. Since pathogenic FcRn is mainly found in intracellular endosomal vesicles, first THP-1 cells After fixation, the sample was permeableated with a mild surfactant and then fixed in the presence of bovine serum. Incubate with FcRn antibody at 4°C for 30 minutes to inhibit nonspecific Fc receptor binding. The assay was stopped. This assay allowed for the identification of antibodies that bind better to endogenous human FcRn. We were able to differentiate them. The binding of anti-FcRn antibodies to THP-1 cells is concentration-dependent. All antibodies, such as N022-N024, N026, and N027, performed better than IgG1. It showed excellent binding affinity. Antibody N027 showed the highest binding affinity with an EC50 value of 3.0 nM. It was presented.

[0385] In epitope mapping by hydrogen-deuterium exchange of antibodies, antibodies are found to be on two human FcRn It has been shown that it binds to a certain epitope that includes at least a portion of one amino acid sequence. One amino acid sequence is located at and / or adjacent to the Fc-FcRn interaction interface. ru, It contains at least one amino acid from the sequence TIFF0007914147000272.tif4128, which means the antibody is oriented Inhibition by direction of IgG to FcRn This suggests that it inhibits binding. The first amino acid sequence is W131 of FcRn. (Includes SEQ ID NO:30). The second amino acid sequence is: It contains at least one amino acid from the sequence TIFF0007914147000273.tif4128. The second amino acid sequence is FcRn Y Includes 88 (SEQ ID NO:30). The epitope of the anti-FcRn antibody is a) FcRn a) One of the amino acid sequences containing W131 of (b) and the amino acid sequence containing Y88 of (b) FcRn This includes one or both. In some embodiments, the epitope is at least a) FcR b) The amino acid sequence includes n W131 and b) the amino acid sequence includes FcRn Y88. In some embodiments, the epitope is an amino acid sequence containing W131 of FcRn. or b) containing any of the amino acid sequences including Y88 of FcRn. Epitope mapping The binding site is distant from the albumin-binding site of FcRn. Therefore, serum albumin Min binding should not be inhibited, and serum albumin concentration should not decrease. Using the ELISA assay, antibodies bind to FcRn in serum albumin. It was confirmed that it does not inhibit synthesis. Human FcRn cells with soluble His tag attached. The outer domain was bound to the plate surface, and the concentration of anti-FcRn antibody was increased at pH 6.0. Pre-incubation was performed while the samples were being incubated with horseradish peroxidase (HRP) labeled human serum. Albumin was conjugated to soluble His-tagged FcRn. All antibodies were conjugated to FcRn It did not inhibit albumin binding to [the target substance]. Furthermore, in vivo experimental evidence supports... Furthermore, it was found that the albumin concentration in cynomolgus monkeys remained constant after administration of anti-FcRn antibodies. It has also been shown that albumin recycling is hindered by antibodies bound to FcRn. This indicates that it could not be done (Figure 4C).

[0386] Example 6 - Effect of anti-FcRn antibody on IgG concentration and target occupancy rate in mice 500 mg / kg of human IVIg (tracer) is used in homozygous B6.Cg-Fcgrt t m1Dcr24 hours after administration to Tg(FCGRT)32Dcr / DcrJ mice, N O27 was administered intravenously (iv). Circulating human IgG was detected daily by ELISA. Cells are incubated while immunophenotyping is performed to identify the label on the cell surface, and then fixed and... After permeabilization, fluorescence-activated cells are separated. Among monocytes from RBC-lysed whole blood obtained by (FACS) cell sorting, Target occupancy was measured daily. Unoccupied FcRn were labeled with Dy650 N027. The measurement was performed by staining with (n=4 males per group). As shown in Figure 3, IgG The concentration and percentage of unoccupied FcRn were determined by administering N027 using a dose-dependent method. It decreased as a result of [the following factors].

[0387] Example 7 - Selective induction of IgG catabolism and target occupancy in cynomolgus monkeys To investigate the effects of N027 on the induction of IgG catabolism and target receptor occupancy, On day 0, N027 was administered intravenously (iv) to cynomolgus monkeys. Circulating endogenous IgG and Albumin was detected by ELISA. Cells possessing cell surface markers for immunophenotyping. The RBCs were incubated, then fixed and permeabilized, and finally dissolved by FACS. Target occupancy was measured in monocytes from whole blood. Unoccupied FcRn was Dy650 Measurements were taken by staining with labeled N027 (n=3 males per group). Figure 4A As shown in ~4C, the IgG concentration and the percentage of unoccupied FcRn are dose-dependent. While the N027 dose decreased with the administration of this method, plasma albumin concentration remained unchanged. It has been until now.

[0388] Example 8 - In vivo distribution of N027 in mice To compare the in vivo distribution of N027 and human IgG in non-target-mediated distributions, full Isopropyl alcohol (VivoTag 680) labeled with N027 or human IgG1 Type control antibody administered at 30 mg / kg to homozygous B6.Cg-Fcgrt tm1 Dcr The drug was administered intravenously (iv) to Tg(FCGRT)32Dcr / DcrJ mice. The concentration of labeled antibodies was measured in individual organs using quantitative ex vivo fluorescence imaging. It was determined. As shown in Figure 5, the in vivo distribution of N027 in various organs of mice is as follows: It is similar to that of the sotype control antibody.

[0389] Example 9 - Efficacy of N027 in mouse collagen antibody-induced arthritis Homozygous B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr / Dcr J mice were given the ArthritoMab(trademark) cocktail on day 1 (MD Biosciences). The company administered the drug intraperitoneally (IP) to induce collagen antibody-induced arthritis, and on the fourth day... Inflammatory disease activity was induced by intraperitoneal (IP) administration of 100 μg of LPS. On day 6 after induction and randomization, N027 was administered therapeutically intravenously (iv) at a dose of 5 mg / kg. Administered (arrow). After randomization, on day 6, IVIG was administered at 1 g / kg (positive control). The group administered either the trol group or the carrier PBS (negative control) (per group) n=5). As shown in Figure 6, when N027 is administered therapeutically, it is a human transgenic agent. It strongly inhibited collagen antibody-induced arthritis in Nick FcRn mice.

[0390] Example 10 - Efficacy of N027 in mouse chronic idiopathic thrombocytopenic purpura (ITP) Homozygous B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr / Dcr In J mice, antiplatelet antibodies (anti-CD41 antibodies) were transmitted via a mini osmotic pump. Thrombocytopenia was induced by continuous subcutaneous infusion of MWReg30. Pump implantation 7 Within 2 hours (day 3), the circulating platelet concentration was 300 x 10⁶. 9 It decreased to below / L. N027 was administered intravenously therapeutically 72 hours (day 3) and 120 hours (day 5) after implantation. Intravenous (IV) administration was performed (n=4 per group in A, n=7 per group in B). Figure 7 shows N When 027 is administered therapeutically, it affects platelet concentration in mice with thrombocytopenia. This indicates that it is possible to effectively restore it.

[0391] Example 11 - Concentration-dependent FcR achieved by N027 in the target cell type noccupancy The receptor occupancy rate by N027 was measured in primary human aortic endothelial cells (HAECs) and human umbilical veins. Various cell types such as endothelial cells (HUVECs) and placental trophoblasts (HVTs) We compared the two. Cells were placed in complete EBM-2 medium (Lonza, Waterville) and The cells were grown in a trophoblast culture medium (ScienCell) until confluence. Cellular monolayers were placed in 1 ml of medium containing various concentrations of unlabeled N027 and incubated at 37°C for 1 hour. The cells were incubated. After washing, the cells were harvested with cooled HyQTase, fixed, and permeabilized. After processing, it was stored in the dark along with VivoTag645-labeled N027 (10 μg / ml). The cells were incubated at 4°C for 30 minutes. Following incubation, the cells were permeabilized. After washing with a buffer solution, the cells were resuspended in FACS buffer. ag645-N027 was measured by flow cytometry. The value was the geometric mean of the fluorescent lamp. It is expressed as light intensity (gMFI) ± SD (n=2). Figures 8A, 8B, and 8C show H This shows the FcRn occupancy rate at multiple N027 concentrations for AEC, HUVEC, and HVT. The results summarized in Table 4 show that not only human EC (HAEC, HUVEC) but also placental HV This indicates that T exhibits a similar concentration-dependent receptor occupancy rate due to N027.

[0392] (Table 4) TIFF0007914147000274.tif36148

[0393] Example 12 - Intracellular IgG resulting from N027 concentration achieving 100% receptor occupancy. Increase in accumulation Relationship between receptor occupancy levels and changes in intracellular IgG transport, as reported by N027. This was compared across various cell types. Human endothelial cells (HAEC and HUVEC) were used as internal cells. While skin cells were cultured in EBM-2 (Lonza Corporation), human placental trophoblasts ( HVT cells were cultured in trophoblast culture medium (ScienCell). Subsequently, the cell monolayer was cultured. The following were pulsed at 37°C for 4-5 hours in 1 mL of culture medium containing one of the following: 1. Various concentrations of N027+VivoTag645-IgG (50 μg / mL), or , 2. Isotype control IgG + VivoTag645-IgG at various concentrations 50 μg / mL).

[0394] The cell monolayer was then washed in a cooling medium, followed by cell separation using HyQtase treatment. VivoTag645-N027 bound to cells was measured by flow cytometry. The values ​​are expressed as geometric mean fluorescence intensity (gMFI) ± SD (n=2). Figure 9A. 9B and 9C contain various doses of N0 for HAEC, HUVEC, and HVT, respectively. This shows the intracellular IgG concentration corresponding to 27. It corresponds to an FcRn occupancy rate of >100%. The N027 dose resulted in significantly higher IgG accumulation compared to the isotype control. This result shows that the effective N027 concentration required to achieve a saturated concentration of IgG accumulation is Among these target cell types, those that are similar, as summarized in Table 5, are 4.99-2. This demonstrates that the concentration ranges from 43 μg / mL.

[0395] (Table 5) TIFF0007914147000275.tif32160

[0396] Example 13 - Measurement of time required to reach 100% FcRn occupancy We determined the time it takes for N027 to saturate FcRn and block IgG transport. Therefore, at 37°C for the specified time (Figure 10), a saturated concentration of N0 in EBM-2 medium was maintained. Vascular endothelial cells (HUVECs) with or without 27 (16.6 μg / ml) The monolayer was incubated to confluence. Once incubation was complete, the cells The sample was washed, recovered with cooled HyQtase, and then fixed and permeabilized. These cells were mixed with 10% human serum and VivoTag645-labeled N027 (10 μg / m³). The mixture was incubated in a permeabilization buffer containing L) in the dark at 4°C for 30 minutes. The cells are washed with a permeabilization buffer, resuspended in FACS buffer, and then bound to the cells. VivoTag645-N027 was measured using FACS. The values ​​are the mean gMFI ± SD( This is represented as n=2). The results shown in Figure 10 indicate that in this endothelial cell type, N027 This indicates that 100% FcRn occupancy was achieved in approximately 30 minutes.

[0397] Human vascular endothelial cells exhibiting a similar FcRn metabolic rate that does not change according to Example 14-N027. cysts and placental trophoblasts Rapid FcRn metabolism of human vascular endothelial cells (HUVECs) and placental trophoblasts (HVTs) The degree was compared in the presence and absence of N027. The cells were 75 cm². 2 In a flask, 25% The cells were cultured for 3 days in a medium containing D2O (heavy water, Aldrich). After 3 days, the culture medium was... This can be N027 (100 μg / mL) or control IgG (100 μg / mL) or mo The medium was replaced with normal medium containing the treatment. The cells were then placed in the medium for the time specified after the change. Figures 11A and 11B) show the cells recovered from the flask. The cell monolayer was washed, and the cells were collected. The material was pelletized, and each pellet was dissolved and digested separately. Shotgun proteomics We performed isotopic relative strength testing using Qual Browser. By extracting the intensity and dividing the fraction's relative abundance by the sum of each intensity, the isotopoma is obtained. -Calculated for each. Using the fractional abundance ratio, the D2O-labeled F remaining in the system was calculated. The percentage of cRn was calculated. Figures 11A and 11B show human vascular endothelial cells (HUVECs) and It was shown that FcRn metabolic rates were similar between placental trophoblasts (HVT). Furthermore, treatment with N027 did not alter the FcRn metabolic rate.

[0398] Example 15 - Localization of FcRn in target cells Localization of N027 was observed in human vascular endothelial cells (HUVECs) and placental trophoblasts (HV The comparison was made in T). Cells were grown in EBM-2 / TM medium on glass coverslips. The living cells were placed in a medium containing DyLight594-N027 (2 μg / mL) for 37 minutes. The cells were incubated at °C for 1 hour. Then the cells were washed and filtered using an appropriate filter. Live images were captured using a fluorescence microscope in confocal mode with a 0× dry objective lens. Representative images. The single-cell images show the endocytosis pool of FcRn in both cell types (endoc This shows a similar localization pattern for N027 bound to the ytic pool (Figure 12). A and 12B). The circle in the center of the cell indicates the location of the nucleus.

[0399] Example 16 - Effect of N027 treatment on the dynamics of IgG transport: accumulation of intracellular IgG and co-localization in sosomes The effect of N027 treatment on the dynamics of intracellular IgG accumulation in human vascular endothelial cells (HUV) Comparison between target cell types expressing FcRn, such as EC and placental trophoblasts (HVT). The cells were compared in EBM-2 medium (Lonza, Waterville) or TM1 medium (S (cienCell Corporation) The cells were propagated until confluent. After that, the confluent cells were grown into fine particles. The monolayer of the cell was treated with N027 (2 μg / ml) + VivoTag645-IgG (50 μg / m³). L) or Isotype control IgG (2 μg / mL) + VivoTag645-I In 1 ml of culture medium containing either γ (50 μg / ml), the cells were incubated at 37°C for 20 hours. The cell monolayer was then washed, followed by N027 (2 μg / mL) or isotyl. In a follow-up medium containing one of the control (2 μg / ml), at 37°C for 0 minutes, Cells were followed for 30 minutes and 90 minutes. After each follow-up period, the cells were washed, separated, and treated with HyQt. It was recovered by ASE treatment. VivoTag645-N027 bound to cells was collected using a flow filter. Measurements were taken by cytometry. The values ​​are geometric mean fluorescence intensity (gMFI) ± SD (n=2). This is represented as follows. Cells treated with N027 showed high concentrations of intracellular IgG. The effect of N027 on the dynamics of IgG accumulation is shown in Figures 13A and 13B, as in the test. The results were similar between the two cell types.

[0400] We also found that N027 is intracellular within primary human umbilical vein endothelial cells (HUVECs). We determined whether or not it increased the co-localization of IgG in lysosomes. Grow on a glass cover glass and add 10 μg / ml of Alexa Fluor 594 Culture medium containing Dextran (10,000 MW, anionic, fixable) The cells were incubated in soil at 37°C for 2 hours. Then, the incubated cells were washed. , Contains N027 (2μg / ml) + DyLight 488-IgG (50μg / ml) In the culture medium, or with isotype control IgG (2 μg / ml) + DyLight Medium containing 488-IgG (50 μg / ml), or medium without any IgG treatment. The plates were pulsed at 37°C for 20 hours. The plates were washed with cooled culture medium and then heated at 37°C. Tracking was performed for 0 or 30 minutes. The following tracking conditions were used: N027+DyLight Tracking 488-IgG pulse sets in the presence of N027 (2 μg / mL), isotype +DyLight 488-IVIG pulse set with isotype control IgG ( Tracking was performed in the presence of 2 μg / mL, and a set without any IgG treatment was tracked in culture medium only. Traces. Wash the cells and leave them in BD Cytofix / Cytoperm solution in the dark at 4°C for 3 minutes. Incubate for 0 minutes, wash with perm wash buffer, then perm was h buffer + 10% normal mouse serum + 5 μg / ml mouse anti-human Lamp1 antibody, in the dark. The cells were incubated overnight at 4°C. Afterward, the cells were washed with perm wash buffer and PBS. It was cleaned and then placed on a coverslip. Using an Olympus fluorescence microscope, 60× dry Cell imaging was performed using a dry objective lens at 2x optical magnification in confocal mode. As shown in Figures 13C and 13D, the N027 treatment is performed on the isotype control IgG. Compared to cells treated with [method], it increased the amount of IgG accumulated in the lysosomal compartment. This demonstrated that.

[0401] Example 17-N027 FcRn(FcRn / p51 and β2- in a complex containing Fab Determination and analysis of the structure of a heterodimer composed of microglobulin / p14. The N027 Fab:FcRn complex was purified and then mixed with 30 mM HEPES (pH 7.5). ), in a buffer consisting of 200 mM NaCl and 3% glycerol, approximately 9 mg / ml It was concentrated. This complex was then set up for crystallization experiments using the sitting drop vapor diffusion method. It was added. A 0.3 μl protein solution consisting of 0.3 μl reservoir solution was added. The rop was mixed above the reservoir of 80 μl of reservoir solution. The plate was sealed. The sample was then equilibrated at 4°C.

[0402] Plate-like crystals were grown under various conditions over a period ranging from 4 days to 7 weeks. Finally, the composite was The crystals that give the structure are formed from a mother liquor consisting of 10% PEG1000 and 10% PEG8000. It was grown inside. The crystal is composed of 25% PEG1000, 10% PEG8000, and 100 Immerse in mM NaCl solution for approximately 2 minutes to protect from freezing, then apply the cryoloop (Cr Place it on a YOLOOP and immerse it in liquid nitrogen to freeze it (plunge-freezing). Ta.

[0403] X-ray diffraction data was obtained from the Stanford Synchrotron Radiation Facility. Synchrotron Radiation Lightsource)(SSRL) At beamline BL9-2, using the Dectris Pilatus 6M detector, The image was collected at a wavelength of 0.97946 Å. The diffraction image was captured using HKL-2000 with a resolution of 2.7 Processed in Å, then CCP4 (Collaborative Computation l Various programs of the software suite of Project, Number 4) The data was processed using [method / tool ​​name]. Details of the data collection and processing are summarized in Table 6.

[0404] The 2.7 Å structure of the N027 Fab:FcRn complex is from the Protein Data Bank. (Protein Data Bank) (PDB) ID number 4k71, complete FcRn (complete FcRn) (These are the major subunits on p51 and p14 respectively) (Heterodimer of the pit and small subunit) and human Fa from PDB ID number 5v7u Using a search model consisting of the individual heavy and light chains of b, the program Phaser This was elucidated using molecular substitution. Within the asymmetric unit with approximately 65% ​​solvent capacity, there is one complete A complex exists. Next, in the program Coot, manual construction and real-space precision are performed. Densification is performed, and then the X-ray data is restricted and refined using the program Refmac5. (restricted refinement) and the program Molprobity and This involves a series of tasks, including validation using various tools within Coot. Then the structure is completed and refined. The final few structural refinements in Refmac 5. The work involved refining the TLS structure using each chain defined as an individual TLS group. Details of the structural analysis and refinement are summarized in Table 7.

[0405] (Table 6) TIFF0007914147000276.tif99128 * The values ​​in parentheses are for the highest resolution shell. That is the case.

[0406] (Table 7) TIFF0007914147000277.tif91128

[0407] Structural analysis of FcRn epitopes The epitopes of FcRn, as determined by their crystal structure, are primarily FcRn / p51 subunits. It is composed of amino acids on a knitted surface, but is it the β2-microglobulin / p14 subunit? These four amino acids are also involved. Overall, the interaction between Fab and FcRn in N027 The interaction is approximately 1020 Å. 2 The distance between the light chain and FcRn is 470 Å. 2 , heavy chain and Fc 414 Å between Rn 2 , 136 Å between the light chain and β2-microglobulin 2 It fluctuates as follows: N All three CDR loops on both strands of Fab 027 are contained within the paratope, CDR H2 Both CDR L1 and CDR L1 contribute approximately half of the interacting amino acids, eight each. H1, CDR H3, and CDR L2 each give three amino acids, and CDR L 3 gives five amino acids. Light chain flame between CDR L2 and CDR L3. The three amino acids (KSG) located at positions 66-68 in Kabat within the molecule are also involved in the binding. The epitope / paratope interface is completely defined by electron density, and is clear. It is indeed perfectly modeled. The Fab-binding epitope on FcRn is a canonical Fc binding epitope. The binding site is very closely overlapping, and binding by the FcRn antibody is expected to inhibit Fc binding. Furthermore, the albumin-binding site remains available. Cosamine is located on Gln102 of FcRn, which is well determined by electron density. Figures 14-16 show an overview of the epitopes determined by the crystal structure. It is also mapped onto the sequence. The residues W131 and Y88 on FCGRT are hydrogen CDR L3(YAGSGIY) and C on the anti-FcRn N027 antibody molecule via binding This appears to be the most significant residue that binds to DR H2(R58).

[0408] Suppression of maternal and fetal endogenous IgG in cynomolgus monkeys by Example 18-N027 and lack of N027 transport to fetal circulation For pregnant female crab-eating macaques, from day 45 of gestation (GD45) to GD100 (GD100) The medication was administered weekly until a cesarean section was performed in the second trimester (mid-pregnancy) or at GD140 (third trimester). Cohorts of animals capable of giving birth (birth date [BD1]) were also included in the study. The experimental design is shown in Table 8.

[0409] (Table 8) Experimental Design TIFF0007914147000278.tif39166a Initially, 24 pregnant females were enrolled in the trial (8 per group). Four pregnant females per group were selected for the G group. Assigned to a cesarean section cohort at D140±2, the remaining 4 pregnancies per group were assigned to a cohort at GD100±2. I assigned it to Hort.

[0410] Using a standard, proven total IgG ELISA, maternal and neonatal blood samples were analyzed. IgG concentration was measured (Table 9). Briefly, commercially available polystyrene plates (96 wells) were used. Coated with anti-human IgG antigen. The coated plates were washed and bound. Remove the samples that did not contain the substance, then block them with a blocking agent, and then remove the remaining blocks. The samples were washed to remove the coating agent. The serum samples were diluted and coated with anti-human IgG antibodies. The solution was added to the prepared wells and incubated at room temperature for 60 ± 5 minutes. After washing each well, Then, a second (detection) antibody bound to horseradish peroxidase (HRP) is added. Then, incubate at room temperature for 60±5 minutes. Next, add tetramethylbenzidine ( Add the TMB substrate and incubate on a plate shaker at room temperature for 20±5 minutes. Then, 2N H2SO4 was added to stop the enzymatic reaction. SpectraMax ( Using a 190 microplate reader (registered trademark), the absorbance of each well at 450 nm was measured. The degree was read. Anti-human IgG capture antibody and total IgG recognized and cynomolgus monkey IgG Any commercially available antibody that shows cross-reactivity with HRP-bound anti-human IgG detection antibodies Alternatively, using a proprietary pair, it is possible to measure total IgG in cynomolgus monkeys in ELISA. IgG detection antibodies include, for example, intact IgG, polyclonal serum antibodies, and mono It can be expressed as a clonal antibody or a Fab(2) fragment.

[0411] (Table 9) Method TIFF0007914147000279.tif111160

[0412] For all pregnant, mature female animals assigned to the experiment, the femoral vein (preferred) was used according to Table 10. Blood was collected by venous puncture from the cephalic vein or saphenous vein. GD100±2 For all fetuses obtained by cesarean section at GD140±2, the umbilical cord was examined according to Table 10. Blood was collected. The sample (1 mL) was allowed to coagulate for at least 60 minutes, then centrifuged to obtain... The extracted serum is separated and placed in polypropylene tubes with appropriate labels (e.g., IgG). It was then transferred and immediately frozen in a freezer set to maintain a temperature of -80°C.

[0413] (Table 10) Time of sample collection for evaluation TIFF0007914147000280.tif238166 a At these points in time, samples were taken only from animals in the GD100 cesarean section cohort. b The range of sample collection dates listed is based on possible medication dates for GD44-46. All time points are based on the administration date. The medication date was used as the basis.

[0414] Suppression of maternal endogenous IgG N027 administration begins 72 hours after administration, and serum IgG concentration in mature female animals is measured. This results in a dose-independent decrease, with the most significant decrease in serum IgG concentration occurring at GD51-53: Before administration, animals that had been administered 100 mg / kg and animals that had been administered 300 mg / kg This was observed in both animals (Figure 19). Serum IgG levels in group 2 (100 mg / kg) were used There is a dose-dependent tendency towards pre-medication concentrations, which is GD65-67: starting at the pre-medication point. This continues until the next dose is administered at GD93-95 and GD135-137, and thereafter, A reduction in the scale of the disease was observed within 72 hours of drug administration. (Animal group 3: 300 mg / kg) Throughout the entire course of medication, the IgG level was the lowest at all pre-medication time points (mentioned in Table 10). The value remained unchanged. In animals treated with the carrier (Group 1), IgG did not change from baseline. It was.

[0415] A dose-dependent increase in serum IgG concentration occurred at GD44-46, GD93-95, and GD13 This was observed 2 hours after dose administration at a dose of 5–137. These increases are likely due to an increase in total IgG levels. This was the result of N027 detection by Sei, and is related to the pharmacology of N027. This was inconceivable. Compared to the control values ​​at GD100 and GD140, the fetus A dose-dependent decrease in serum IgG concentration was observed, and also at BD1 in neonates. (Figure 20).

[0416] Lack of N027 transfer from maternal to fetal circulation The transition of N027 from maternal circulation to fetal circulation is related to the FcRn occupancy of N027 in fetal circulating monocytes. The presence of N027 was evaluated by measuring its concentration. In the state where it is not present, the fluorescent label N027 for free / unbound FcRn To measure binding, a flow cytometry (FACS) assay was used to measure monocytes and granules. The occupancy rate of N027 receptors was evaluated on granulocytes, B lymphocytes, and T lymphocytes. In this study, the presence of each white blood cell subset at both the pre-medication and post-medication time points was observed. The percentage of free or unbound FcRn receptors was shown. Saturated samples were shown after each dose. It completely saturates all FcRn receptors that were free / unbound at that point in time. Unlabeled N027 was added at the determined concentration. The N027 receptor occupancy rate is as described above. In the context of unsaturated sample analysis as described above, fetuses at GD100 and GD140 days, It was not detected in whole blood in newborns on day 1 of BD.

[0417] Evaluation of transplacental transfer in Example 19-N027 Human placentas obtained from complication-free full-term pregnancies were subjected to ex vivo biparietal studies of a single placental lobe. The transplacental transfer of N027 was evaluated using the dual perfusion method. In short, examine each placenta for tears and supply the surrounding area of ​​one intact placental lobe. Two villous vessels (one artery and one vein) are inserted using 3F and 5F umbilical cord catheters, respectively. The cannula was inserted using the following method. The placental lobe was cut off and placed in the perfusion chamber with the maternal side facing upwards. The fetus was placed. Two catheters penetrating the base of the fetus were used to perfuse the intervillous space on the maternal side. The flow rates of the perfusion fluid in the infant circulation and maternal circulation were 3.0 mL / min and 12 mL, respectively. The rate was set to / min. Maternal perfusion was performed with a gas mixture consisting of 95% O2 and 5% CO2. The fetal perfusion was equilibrated with a mixture of 95% N2 and 5% CO2. The experiment was 37 o The procedure was performed at temperature C.

[0418] During the initial control period of 1 hour, each placental lobe was perfused to open up the tissue. Stable in the new environment through a perfusion system (open-open configuration). The following conditions were met during the control period: If any of the following occurs, the perfusion should be terminated. Ru: A decrease in circulating volume exceeding 3 mL / h in fetal circulation, or pO2 between fetal veins and arteries. 2. When the difference is less than 60 mmHg (these are cases of perfusion overload between the two circulations) (This indicates that the top is inappropriate). Subsequently, closed configuration (closed-closed The perfusion system of configuration d (i.e., the perfusion fluid is recirculated), A control period of 4 hours was followed by the experiment. The latter involved maternal reservoir and fetal reservoir. The system was reset by replacing the perfusion fluid in the reservoir and adding 3 mg / ml of BSA.

[0419] The transfer of N027 across human placental lobes was tested at the following three different concentrations: 0 .3mg / ml, 3mg / ml and 30mg / ml. 0.3mg / ml, 3mg / ml and Perfusing 14 separate placentas for 4 hours while adding N027 at 30 mg / ml to maternal perfusion. The samples were collected at concentrations of 0, 15, 30, 60, 90, 120, 150, and 180 during the experiment. At 210 and 240 minutes, a fixed volume of 0.5 mL was collected from the maternal artery and fetal vein. Antipyrine was used as a sex control to confirm circulatory integrity (Figures 17-18). The concentration of N027 in maternal and fetal samples was measured using a highly sensitive assay with a limit of quantification of 5 ng / ml. The determination was made using a mesoscale discovery (MSD) immunoassay. This involves a sandwich method using anti-idiotype antibody pairs, and MSD plate The material is coated with an anti-idiotype antibody and then incubated with the sample. The MSD plate is then treated with MSD-labeled streptavidin and read buffer (read Biotinylated second anti-idiotype antibody detected by adding buffer This was revealed by detecting the concentration of antipyrine using UV detection at 260 nm after liquid-liquid extraction. Detection was performed using an HPLC assay. Antipyrine transfer to the fetus was detected in 14 experiments. The average percentage was 41 ± 2.8%. The average percentage of N027 that transitioned to the fetus across 14 experiments. The percentage was 0.0027±0.0021%, indicating a very low concentration for transfer. This result suggests a way to treat pregnant patients without causing fetal exposure. This suggests that N027 can be used.

[0420] Other Embodiments While specific embodiments of this disclosure have been described, further modifications are possible. This application generally adheres to the principles of disclosure and the scope of the technical field to which this disclosure relates. It is within the scope of what is publicly known or commonly practiced within the given context, and can be applied to the essential characteristics mentioned above. Any variation, use, or adaptation of this disclosure, including deviations from this disclosure, is prohibited. It will be understood that this is intended to be comprehensive.

[0421] All published gazettes, patents, and patent applications are treated as if they were individual published gazettes, patents, or patent applications. Each is shown specifically and individually, as if the whole were incorporated by reference. The entirety of that work shall be incorporated into this specification by reference to the same extent.

[0422] Other embodiments are within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising an anti-FcRn antibody for use in a method of treating a disease or disorder selected from the group consisting of warm autoimmune hemolytic anemia, rheumatoid arthritis, bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, Sjögren's syndrome, and myasthenia gravis, The method includes administering the anti-FcRn antibody to a pregnant subject, The aforementioned anti-FcRn antibody is The light chain of the antibody It includes an array that is, The heavy chain of the antibody is Includes an array which The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the disease or disorder is warm autoimmune hemolytic anemia.

3. The pharmaceutical composition according to claim 1, wherein the disease or disorder is rheumatoid arthritis.

4. The pharmaceutical composition according to claim 1, wherein the disease or disorder is bullous pemphigoid.

5. The pharmaceutical composition according to claim 1, wherein the disease or disorder is chronic inflammatory demyelinating polyneuropathy.

6. The pharmaceutical composition according to claim 1, wherein the disease or disorder is Sjögren's syndrome.

7. The pharmaceutical composition according to claim 1, wherein the disease or disorder is myasthenia gravis.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the antibody is a monoclonal antibody.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is IgG1 or a variant thereof.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the antibody comprises a λ light chain.

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