Fcrn antibodies and use methods thereof

Abstract

To provide pharmaceutical compositions for use in novel methods for treating immune diseases.SOLUTION: Provided herein is a pharmaceutical composition for use in a method for treating or reducing the risk of developing a fetal and neonatal alloimmune and / or autoimmune disorder, where the pharmaceutical composition comprises an antibody comprising light and heavy chains of specific amino acid sequences respectively, where the method comprises administering the pharmaceutical composition to a pregnant woman, where the administration starts at from about gestational week 12 to about gestational week 16, and the fetal and neonatal alloimmune and / or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia (FNAIT).SELECTED DRAWING: None

Description

[Background technology]

[0001] Background of the Invention Therapeutic proteins, such as therapeutic antibodies, are rapidly becoming clinically applicable to patients with immune disorders. Many autoimmune and alloimmune diseases are caused by pathogenic There is a need for new methods of treating antibody-mediated immune diseases. Summary of the Invention

[0002] The present invention features novel antibodies against the human neonatal Fc receptor (FcRn). The anti-FcRn antibody can, for example, promote the removal of autoantibodies in a subject, thereby to suppress antigen presentation, to block an immune response, e.g., to inhibit an immune response in a subject to block immune complex-based activation or to treat an immune disorder (e.g., autoimmune disease) in a subject These compounds are useful for treating immune disorders.

[0003] In one aspect, the invention features an isolated antibody that binds to human FcRn. 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. wherein CDR L1 is a sequence having two or fewer amino acid substitutions relative to the sequence of TIFF2025143252000001.tif4128, and CDR L2 is A sequence with one or less amino acid substitutions relative to the sequence of RPS (SEQ ID NO:2) and CDR L3 comprises a sequence having no more than one amino acid substitution relative to the sequence of TIFF2025143252000002.tif4128, wherein CDR H1 is a sequence having no more than one amino acid substitution relative to the sequence of TIFF2025143252000003.tif4128, and CDR H2 comprising: a sequence having one or less amino acid substitutions relative to the sequence of TIFF2025143252000004.tif9158, and wherein CDR H3 is LA Contains no more than one amino acid substitution relative to the sequence of IGDSY (SEQ ID NO:11) Contains an array of

[0004] In some embodiments, the antibody is less than 200 pM, less than 150 pM, or less than 100 pM. , K less than 50 pM, or K less than 40 pM D and binds to human FcRn.

[0005] In some embodiments, the antibody is N022, N023, N024, N026, or The antibody has the light chain variable region and heavy chain variable region of N027, and the Fc region of the antibody to be compared. K of antibodies with the same Fc region D The following K D and binds to human FcRn. The present invention provides a light chain variable region comprising: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3; region, and (2) a heavy chain variable region including CDR H1, CDR H2, and CDR H3. The present invention features an isolated antibody comprising a region, wherein CDR L1 is TIFF2025143252000005.tif4128, and CDR L2 contains the sequence GDX3X4RPS (SEQ ID NO: 13). column, and CDR L3 includes TIFF2025143252000006.tif4128, and CDR H1 contains the sequence of Z1YAMG (SEQ ID NO: 15). CDR H2 is TIFF2025143252000007.tif4128, and CDR H3 is LAZ5Z6DSY (SEQ ID NO: 17) wherein X1 is a polar or hydrophobic amino acid and X2 is a hydrophobic amino acid X3 is a polar amino acid, X4 is a polar or acidic amino acid, and X5 is a polar X6 is a hydrophobic amino acid, and Z1 is a polar or acidic amino acid. Z2 is a polar or hydrophobic amino acid, and Z3 is G, S, or A. Z4 is a basic amino acid, Z5 is a hydrophobic or basic amino acid, and and Z6 is G, S, D, Q, or H, and wherein the antibody binds human FcRn, N02 6 light chain variable region and heavy chain variable region, and also has the same Fc region as the antibody to be compared. The K of the antibody D The following K D In some embodiments, X1 is T, A, S, or or I. In other embodiments, X2 is L or I. In some embodiments, In still other embodiments, X3 is S, N, or T. In still other embodiments, X4 is Q, E, or N, and X5 is C, S, I, or Y. In some embodiments, X6 is A or V, and Z1 is E, T, D, or N. In a further embodiment, Z2 is S or A. In some embodiments, Z4 is K or R. In this embodiment, Z5 is I, L, or H.

[0006] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: CDR L1 having the sequence of TIFF2025143252000008.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, and a light chain variable region comprising CDR L3 having the sequence of SEQ ID N°1 ... CDR H1 having the sequence of CDR H2 having the sequence of TIFF2025143252000010.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). and a heavy chain variable region comprising a CDR H3 having a sequence similar to that of the antibody of the present invention, , Z1 is T, D, or N, Z2 is S or A, and Z3 is G, S, or It's A.

[0007] In some embodiments, the isolated antibody comprises: CDR L1 having the sequence of TIFF2025143252000011.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, CDR L3 having the sequence of TYAMG (SEQ ID NO: 4) DR H1, CDR H2 having the sequence of TIFF2025143252000013.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). It contains a CDR H3 with a sequence.

[0008] In some embodiments, the isolated antibody comprises: CDR L1 having the sequence of TIFF2025143252000014.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, CDR L3 having the sequence of TIFF2025143252000015.tif4128, CDR L4 having the sequence of DYAMG (SEQ ID NO: 5) DR H1, CDR H2 having the sequence of TIFF2025143252000016.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). It contains a CDR H3 with a sequence.

[0009] In some embodiments, the isolated antibody comprises: CDR L1 having the sequence of TIFF2025143252000017.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, CDR L3 having the sequence of TIFF2025143252000018.tif4128, CDR L4 having the sequence of NYAMG (SEQ ID NO: 6) DR H1, CDR H2 having the sequence of TIFF2025143252000019.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). It contains a CDR H3 with a sequence.

[0010] In other embodiments, the isolated antibody comprises: CDR L1 having the sequence of TIFF2025143252000020.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, CDR L3 having the sequence of TYAMG (SEQ ID NO: 4) DR H1, CDR H2 having the sequence of TIFF2025143252000022.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). It contains a CDR H3 with a sequence.

[0011] In yet other embodiments, the isolated antibody comprises: CDR L1 having the sequence of TIFF2025143252000023.tif4128, and GDSERPS (SEQ ID NO: 2) CDR L2, CDR L3 having the sequence of TYAMG (SEQ ID NO: 4) DR H1, CDR H2 having the sequence of TIFF2025143252000025.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11). It contains a CDR H3 with a sequence.

[0012] In some embodiments, the light chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000026.tif21160.

[0013] In some embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000027.tif38160.

[0014] In other embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000028.tif38160.

[0015] In other embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000029.tif38160.

[0016] In some embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000030.tif38160.

[0017] In other embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000031.tif38160.

[0018] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000032.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000033.tif38160.

[0019] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000034.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000035.tif38160.

[0020] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000036.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000037.tif38160.

[0021] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000038.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000039.tif38160.

[0022] In yet another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein And the light chain is TIFF2025143252000040.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000041.tif38160.

[0023] In some embodiments, the heavy chain of the isolated antibody of the invention is selected from the group consisting of SEQ ID NOs:20-22 At least 95%, 97%, 99%, or 100% identity to any one of the sequences in In other embodiments, the light chain of the isolated antibody of the invention comprises a sequence having SEQ ID N have at least 95%, 97%, 99%, or 100% identity to the sequence of O:19 Contains arrays.

[0024] In some embodiments, the isolated antibody of the present invention further comprises SEQ ID NO:20-2 4, including the amino acid substitution N297A.

[0025] In other embodiments, the isolated antibody further comprises any one of SEQ ID NOs:20-24. The two sequences contain the amino acid substitutions D355E and L357M.

[0026] In other embodiments, the isolated antibody of the invention has any one or more of the following amino acid substitutions: Further comprising: A23 of any one of SEQ ID NOs: 20 to 24 V, S30R, L80V, A84T, E85D, A93V, and SEQ ID NO: Q38H, V58I, and G99D for 19 sequences.

[0027] In yet other embodiments, the isolated antibody of the invention is any of SEQ ID NOs:20-24. None of the sequences contain a C-terminal lysine at residue 446.

[0028] In some embodiments, the antibody of any of the above aspects is N022, N023, N0 24, N026, or N027, and , the K of an antibody having the same Fc region as the antibody being compared D The following K D And human Fc Binds to Rn. For example, specific K D In the assay, the K D is less than 200 pM, 1 Less than 50 pM, less than 100 pM, less than 50 pM, or less than 40 pM.

[0029] The complementarity determining regions (CDRs) and framework of any isolated antibody described herein The amino acid positions assigned to the fragment regions (FRs) are based on the EU index of Kabat (Se Quences of Proteins of Immunological Int erest,5th Ed.Public Health Service,Natio nal Institutes of Health,Bethesda,MD.(19 91)).

[0030] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000042.tif21160, and the heavy chain comprises Contains sequence TIFF2025143252000043.tif38160.

[0031] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000044.tif21160, and the heavy chain comprises Contains sequence TIFF2025143252000045.tif38160.

[0032] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000046.tif21160, and the heavy chain comprises Contains sequence TIFF2025143252000047.tif38160.

[0033] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain teeth, TIFF2025143252000048.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000049.tif38160.

[0034] In yet another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein And the light chain is TIFF2025143252000050.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000051.tif38160.

[0035] In some embodiments of any of the above aspects, the isolated antibody of the invention is monoclonal In some embodiments, the isolated antibody is an IgG1 antibody. In some embodiments, the isolated antibody comprises a λ light chain. In some embodiments, the isolated antibody comprises a kappa light chain. .

[0036] In some embodiments of any of the above aspects, the isolated antibody of the invention is a humanized antibody, Or it is a fully human antibody.

[0037] In some embodiments, the isolated antibody is 1-100, 5-150, 5-100, 5-7 K of 5, 5–50, 10–50, or 10–40 pM D and binds to human FcRn.

[0038] In some embodiments, the isolated antibodies of the present invention are derived from rodents, e.g., mice or rats. In some embodiments, the isolated antibodies of the invention bind to FcRn in rodents, e.g., Mouse or rat FcRn was measured at less than 200 pM, less than 150 pM, less than 100 pM, or 5 K<0 pM or <40 pM D Combine with.

[0039] In another aspect, the invention provides a nucleic acid molecule encoding any of the isolated antibodies described herein. It is characterized by:

[0040] In yet another aspect, the invention provides a nucleic acid sequence encoding any of the antibodies described herein. The vector containing the offspring is characterized.

[0041] In another aspect, the invention provides a host cell expressing any of the isolated antibodies described herein. The host cell comprises a nucleic acid molecule encoding any of the isolated antibodies described herein, or a vector containing a nucleic acid molecule encoding any of the isolated antibodies described herein. wherein the nucleic acid molecule or vector is expressed by a host cell.

[0042] In some embodiments, the host cell is a Chinese hamster ovary (CHO) cell. In some embodiments, the host cell is an Sp2 cell or an NS0 cell.

[0043] In another aspect, the invention features a method of preparing any of the isolated antibodies described herein. The method includes: a) a nucleic acid molecule encoding any of the isolated antibodies described herein; provides a vector containing a nucleic acid molecule encoding any of the isolated antibodies described herein. and b) infecting the nucleic acid molecule or vector in a host cell under conditions that allow for the formation of antibodies. and expressing a vector.

[0044] In some embodiments, the method comprises, for example, about 1 to 100, 1 to 50, 1 to 25, 2 to 30, The antibody was harvested from the host cells at a concentration of 50, 5-50, or 2-20 mg / ml. Includes top.

[0045] In other embodiments, the host cells used in the methods are CHO cells.

[0046] In another aspect, the invention provides any isolated antibody described herein and one or more drugs The present invention features pharmaceutical compositions comprising a physiologically acceptable carrier or excipient.

[0047] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the antibody.

[0048] In another aspect, the invention features a method of increasing IgG catabolism in a subject. In another aspect, the invention features a method of reducing autoantibodies in a subject. In an aspect, the present invention provides a method for treating or reducing the activation of an immune complex-based immune response in a subject. The method features a method for producing any of the isolated antibodies described herein, or any of the antibodies described herein. and administering to a subject a pharmaceutical composition comprising any of the isolated antibodies described.

[0049] In some embodiments, the immune response in the subject is an acute or chronic immune response. .

[0050] In some embodiments, the subject is diagnosed with pemphigus vulgaris, lupus nephritis, myasthenia gravis, giardia gravis, or gallbladder disease. Lenn-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic Purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated myocardium or an acute immune response, is activated by a medical condition selected from the group consisting of:

[0051] In some embodiments, the subject is diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), systemic Lupus, chronic forms of the disorder requiring acute treatment, reactive arthropathy, primary biliary cirrhosis , ulcerative colitis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. or a chronic immune response is selected from the group consisting of Activated by a medical condition.

[0052] In some embodiments, the subject has an autoimmune disease or the immune response is It is activated by diseases, especially autoimmune diseases such as alopecia areata, ankylosing spondylitis, and antiphospholipids. Chronic leukemia, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid Smallpox, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory Demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential Mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, Hypogonadism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA Nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, Combined connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary liver cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, monkeys Coidosis, scleroderma, Sjögren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal artery disease Selected from the group consisting of phlebitis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis will be done.

[0053] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises (1) CDR L1, CDR L2, and CDR L3 (2) a light chain variable region consisting of, or consisting essentially of, CDR H1 , CDR H1, CDR H2, and CDR H3. and a heavy chain variable region that is the light chain variable region and the heavy chain variable region, wherein CDR L1 is TGT Two or fewer amino acids relative to the sequence of GSDVGSYNLVS (SEQ ID NO: 1) comprising, consisting of, or consisting essentially of a sequence having a substitution, and 2 has one or less amino acid substitutions relative to the sequence of GDSERPS (SEQ ID NO:2) comprising, consisting of, or consisting essentially of a sequence having a CDR L3 substitution; but, A sequence comprising, consisting of, or comprising one or less amino acid substitutions relative to the sequence of TIFF2025143252000052.tif4128. CDR H1 consists essentially of the sequence TYAMG (SEQ ID NO: 4), DY AMG (SEQ ID NO: 5) or NYAMG (SEQ ID NO: 6) sequence a sequence comprising, consisting of, or consisting of a sequence having one or less amino acid substitutions relative to and CDR H2 is essentially A sequence comprising, consisting of, or comprising two or fewer amino acid substitutions relative to the sequence of TIFF2025143252000053.tif9128. and CDR H3 consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising a sequence having one or less amino acid substitutions relative to the sequence of or consisting essentially of said sequence.

[0054] In some embodiments of all aspects, the antibody binds to human IgG with a KD equal to or less than the KD of antibody N026. It binds to FcRn.

[0055] In some embodiments of all aspects, CDR L1 is TIFF2025143252000054.tif4128, and CDR L2 is selected from the group consisting of the sequence GDS ERPS (SEQ ID NO:2), and CDR L3 is TIFF2025143252000055.tif4128, wherein CDR H1 is selected from the group consisting of the sequence TYA MG (SEQ ID NO::4), and CDR H2 has the sequence TIFF2025143252000056.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence It essentially becomes

[0056] In some embodiments of all aspects, CDR L1 is TIFF2025143252000057.tif4128, and CDR L2 is selected from the group consisting of the sequence GDS ERPS (SEQ ID NO:2), and CDR L3 is TIFF2025143252000058.tif4128, wherein CDR H1 is the sequence DYA MG (SEQ ID NO::5), and CDR H2 has the sequence TIFF2025143252000059.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence It essentially becomes

[0057] In some embodiments of all aspects, CDR L1 is TIFF2025143252000060.tif4128, consisting of or consisting essentially of the sequence, and CDR L2 is ERPS (SEQ ID NO:2), and CDR L3 is TIFF2025143252000061.tif4128, wherein CDR H1 is the sequence NYA MG (SEQ ID NO::6), and CDR H2 has the sequence TIFF2025143252000062.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence It essentially becomes

[0058] In some embodiments of all aspects, CDR L1 is TIFF2025143252000063.tif4128, and CDR L2 is selected from the group consisting of the sequence GDS ERPS (SEQ ID NO:2), and CDR L3 is TIFF2025143252000064.tif4128, wherein CDR H1 is the sequence TYA MG (SEQ ID NO::4), and CDR H2 has the sequence TIFF2025143252000065.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence It essentially becomes

[0059] In some embodiments of all aspects, CDR L1 is TIFF2025143252000066.tif4128, and CDR L2 is selected from the group consisting of the sequence GDS ERPS (SEQ ID NO:2), and CDR L3 is TIFF2025143252000067.tif4128, wherein CDR H1 is the sequence TYA MG (SEQ ID NO::4), and CDR H2 has the sequence TIFF2025143252000068.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence It essentially becomes

[0060] In some embodiments of all aspects, the subject is a patient with fetal and neonatal alloimmune disorders and and / or a history of previous autoimmune disorders. For example, some In embodiments, the pregnant subject has previously administered the fetus or newborn a fetal and newborn alloimmunization. Pregnancy with an infectious and / or autoimmune disorder. In embodiments, the subject is a patient with a fetal and neonatal alloimmune and / or autoimmune disorder. There is a risk of

[0061] In some embodiments of all aspects, fetal and neonatal alloimmune disorders and / or or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal thrombocytopenia, Hemolytic disease, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal Infant myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal multiple myeloma Neonatal myositis, dermatomyositis, neonatal lupus, neonatal scleroderma, Behcet's disease, neonatal Graves' disease Neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes In some embodiments of all aspects, fetal and neonatal autoimmunity is and / or the autoimmune disorder is hemolytic disease of the fetus and newborn. In some embodiments, fetal and neonatal autoimmunity and / or autoimmune disorders include: Fetal and neonatal alloimmune thrombocytopenia. In the fetal and neonatal autoimmune and / or autoimmune disorders, congenital heart block be.

[0062] In some embodiments of all aspects, the treatment reduces the risk of miscarriage.

[0063] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises (1) CDR L1, CDR L2, and CDR L3 (2) a light chain variable region consisting of, or consisting essentially of, CDR H1 , CDR H1, CDR H2, and CDR H3. and a heavy chain variable region that is and the heavy chain variable region, wherein CDR L1 is TIFF2025143252000069.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000070.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000071.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially consisting of: X1 being a polar or hydrophobic amino acid and X2 being a hydrophobic amino acid. X3 is a polar amino acid, X4 is a polar or acidic amino acid, and X5 is a polar X6 is a hydrophobic amino acid, and Z1 is a polar or acidic amino acid. Z2 is a polar or hydrophobic amino acid, and Z3 is G, S, or A. Z4 is a basic amino acid, Z5 is a hydrophobic or basic amino acid, and Z6 is G, S, D, Q, or H, and wherein the antibody is less than 200 pM; Human F with a KD of less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 pM Binds to cRn.

[0064] In some embodiments of all aspects, CDR L1 is TIFF2025143252000072.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000073.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000074.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0065] In some embodiments of all aspects, CDR L1 is A sequence comprising, consisting of, or comprising two or fewer amino acid substitutions relative to the sequence of TIFF2025143252000075.tif4128. and CDR L2 consists essentially of the sequence of GDSERPS (SEQ ID NO:2). comprising, consisting of, or having no more than one amino acid substitution relative to the sequence The CDR L3 consists essentially of a column A sequence comprising, consisting of, or comprising one or less amino acid substitutions relative to the sequence of TIFF2025143252000076.tif4128. and CDR H1 consists essentially of the sequence A sequence comprising, consisting of, or comprising one or less amino acid substitutions relative to the sequence of TIFF2025143252000077.tif4128. and CDR H2 consists essentially of the sequence A sequence comprising, consisting of, or comprising two or fewer amino acid substitutions relative to the sequence of TIFF2025143252000078.tif9140. and CDR H3 consists essentially of the sequence LAIGDSY (SEQ ID NO: 11), comprising a sequence having one or less amino acid substitutions relative to the sequence of or consisting essentially of said sequence.

[0066] In some embodiments of all aspects, the subject is a patient with fetal and neonatal alloimmune disorders and and / or a history of previous autoimmune disorders. For example, some In embodiments, the pregnant subject has previously been diagnosed with fetal and neonatal alloimmune disorders and / or Having had a baby or fetus with an autoimmune disorder. In some embodiments, the subject is a patient with fetal and neonatal alloimmune disorders and / or autoimmune disorders. There is a risk of having an autoimmune disorder.

[0067] In some embodiments of all aspects, fetal and neonatal alloimmune disorders and / or or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal thrombocytopenia, Hemolytic disease, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal Infant myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal multiple myeloma Neonatal myositis, dermatomyositis, neonatal lupus, neonatal scleroderma, Behcet's disease, neonatal Graves' disease Neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes In some embodiments of all aspects, fetal and neonatal autoimmunity is and / or the autoimmune disorder is hemolytic disease of the fetus and newborn. In some embodiments, fetal and neonatal autoimmunity and / or autoimmune disorders include: Fetal and neonatal alloimmune thrombocytopenia. In the fetal and neonatal autoimmune and / or autoimmune disorders, congenital heart block In some embodiments of all aspects, the treatment reduces the risk of miscarriage.

[0068] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: where the antibody has the sequence CDR L1 with TIFF2025143252000079.tif4128, CDR with sequence GDSERPS (SEQ ID NO:2) L2, and array TIFF2025143252000080.tif4128 and CDR H1, CDR H2, and CDR H3. a heavy chain variable region consisting essentially of, or comprising, CDR H1 having the sequence Z1YAMG (SEQ ID NO: 15) , CDR H2 is the sequence TIFF2025143252000081.tif4128, consisting of or consisting essentially of the sequence, and CDR H3 is LAIGDSY (SEQ ID NO: 11), comprising, consisting of, or consisting of the sequence and wherein Z1 is T, D, or N and Z2 is S or A. and Z3 is G, S, or A. The antibody may consist of the light chain variable region and the heavy chain variable region, or may consist essentially of the light chain variable region and the heavy chain variable region.

[0069] In some embodiments of all aspects, the light chain is TIFF2025143252000082.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0070] In some embodiments of all aspects, the heavy chain is TIFF2025143252000083.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0071] In some embodiments of all aspects, the heavy chain is TIFF2025143252000084.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0072] In some embodiments of all aspects, the heavy chain is TIFF2025143252000085.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0073] In some embodiments of all aspects, the heavy chain is TIFF2025143252000086.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0074] In some embodiments of all aspects, the heavy chain is TIFF2025143252000087.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0075] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000088.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of TIFF2025143252000089.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0076] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000090.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of TIFF2025143252000091.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0077] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000092.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of TIFF2025143252000093.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0078] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000094.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of TIFF2025143252000095.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0079] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000096.tif21160, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of TIFF2025143252000097.tif38160, comprising, consisting of, or having at least 90% identity to the sequence of It essentially consists of:

[0080] In some embodiments of all aspects, the heavy chain is selected from the group consisting of SEQ ID NOs:20-24 have at least 95%, 97%, 99%, or 100% identity with any one of the sequences Some of the embodiments of the present invention may comprise, consist of, or consist essentially of a sequence In some embodiments, the light chain has at least 95% identical sequence to SEQ ID NO:19. comprising, consisting of, or having 7%, 99%, or 100% identity to a sequence Consists essentially of an array.

[0081] In some embodiments of all aspects, the antibody further comprises SEQ ID NO:20 24 sequences, and In some embodiments of all aspects, the antibody further comprises a nucleotide sequence selected from the group consisting of: Q Amino acid substitution D355 in any one of the sequences of ID NO: 20 to 24 E and L357M. All In some embodiments of the aspect, the antibody further comprises any one of the following amino acid substitutions: comprising, consisting of, or consisting essentially of one or more of: SEQ ID NO: A23V, S30R, L80V, A84T, E for any one of the sequences 20 to 24 85D, A93V, and Q38H, V58I relative to the sequence of SEQ ID NO: 19 , and G99D.

[0082] In some embodiments of all aspects, the antibody has the structure of SEQ ID NOs:20-24. None of the sequences contain a C-terminal lysine at residue 446.

[0083] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000098.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence It comprises, consists of, or consists essentially of the sequence TIFF2025143252000099.tif38160.

[0084] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000100.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence It comprises, consists of, or consists essentially of the sequence TIFF2025143252000101.tif38160.

[0085] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000102.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence It comprises, consists of, or consists essentially of the sequence TIFF2025143252000103.tif38160.

[0086] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000104.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence It comprises, consists of, or consists essentially of the sequence TIFF2025143252000105.tif38160.

[0087] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, and a method for treating fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to the fetus or neonate a therapeutically effective amount of a compound selected from the group consisting of: wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. where the light chain is TIFF2025143252000106.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence It comprises, consists of, or consists essentially of the sequence TIFF2025143252000107.tif38160.

[0088] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering to the fetus an anemia-reducing agent a therapeutically effective amount of the compound. The antibody comprises (1) CDR L1, CDR L2, and CDR L3; (2) a light chain consisting of, or consisting essentially of, CDR H1, CDR H2, and a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H3 and CDR H4; and, wherein CDR L1 But the array TIFF2025143252000108.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000109.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000110.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0089] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering to the fetus an anemia-reducing agent a therapeutically effective amount of the compound. and an antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain has a sequence having at least 90% identity with the sequence of SEQ ID NO: 19. the heavy chain comprises, consists of, or consists essentially of SEQ ID NO: 1; D NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID and at least one sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO: 24. comprising, consisting of, or consisting essentially of a sequence having at least 90% identity with the sequence do.

[0090] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering to the fetus an anemia-reducing agent a therapeutically effective amount of the compound. and an antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or has the sequence of SEQ ID NO: 19. and the heavy chain consists essentially of SEQ ID NO: 20, SEQ ID NO: 2 1, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO 24. becomes.

[0091] In some embodiments of all aspects, the method comprises administering to a pregnant subject, a fetus of the pregnant subject, , and / or combinations thereof.

[0092] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating an autoimmune disorder, wherein the antibody comprises: (1) a CDR L1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28 CDR L2, and CDR L3. and (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3. and a heavy chain variable region consisting of or consisting essentially of the light chain variable region. and the heavy chain variable region, or essentially consisting of the light chain variable region and the heavy chain variable region. wherein CDR L1 is TIFF2025143252000111.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000112.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000113.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially consisting of: where X1 is T, A, S, or I; X2 is L or I, X3 is S, N, or T, and X4 is Q, E, or N. X5 is C, S, I, or Y, X6 is A or V, and Z1 is E, T, D or N, Z2 is S or A, Z3 is G, S, or A, and Z4 is K or R, Z5 is I, L, or H, and Z6 is G, S, D, Q, or It's H.

[0093] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating an autoimmune disorder, wherein the antibody comprises a light chain and a heavy chain. wherein the light chain consists of, or consists essentially of, SEQ ID NO: 19 sequences, comprising, consisting of, or having at least 90% identity to the sequence of and the heavy chain consists essentially of the sequence SEQ ID NO: 20, SEQ ID NO: :21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID No. 24. The nucleic acid sequence may comprise, consist of, or consist essentially of the sequence.

[0094] In another aspect, the present invention provides a method for administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering the antibody to a pregnant subject, The present invention features a method for treating an autoimmune disorder, wherein the antibody comprises a light chain and a heavy chain. wherein the light chain consists of, or consists essentially of, SEQ ID NO: 19, and the heavy chain comprises, consists of, or consists essentially of the sequence S EQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SE A sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO: 24 The sequence may comprise, consist of, or consist essentially of the sequence:

[0095] In some embodiments of all aspects, the autoimmune disease is alopecia areata, ankylosing spondylitis, Antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, hydration Bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, localized systemic Scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus , essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroid disease adenitis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis , IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease Lewy disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis , polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis inflammation, sarcoidosis, scleroderma, Sjögren's syndrome, stiff man syndrome, Takayasu's arteritis , temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis is selected from.

[0096] In some embodiments of all aspects, treatment reduces the risk of miscarriage / fetal loss. do.

[0097] In another aspect, the present invention provides a method for administering an FcRn antibody to a pregnant subject. or administering an FcRn antibody to a pregnant subject. the risk of autoimmune or alloimmune disorders or autoimmune disorders that essentially result from The present invention features a method for reducing the risk of developing an immune disorder or alloimmune disorder, wherein the antibody (1) comprises or consists of CDR L1, CDR L2, and CDR L3; or a light chain variable region consisting essentially of them; and (2) CDR H1, CDR H2, and a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H3 and CDR H4; and and a heavy chain variable region, wherein CDR L1 is TIFF2025143252000114.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000115.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000116.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0098] In another aspect, the present invention provides a method for administering an FcRn antibody to a pregnant subject. or administering an FcRn antibody to a pregnant subject. the risk of autoimmune or alloimmune disorders or autoimmune disorders that essentially result from The present invention features a method for reducing the risk of developing an immune disorder or alloimmune disorder, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, The strand comprises a sequence having at least 90% identity to the sequence of SEQ ID NO: 19. , consisting of, or consisting essentially of, the sequence, and the heavy chain is :20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO: 23, and SEQ ID NO: 24, and at least 90 % identity to a sequence comprising, consisting of, or consisting essentially of a sequence having that sequence.

[0099] In another aspect, the present invention provides a method for administering an FcRn antibody to a pregnant subject. or administering an FcRn antibody to a pregnant subject. the risk of autoimmune or alloimmune disorders or autoimmune disorders that essentially result from The present invention features a method for reducing the risk of developing an immune disorder or alloimmune disorder, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, The strand comprises, consists of, or essentially consists of the sequence of SEQ ID NO:19. The heavy chain is selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: Q ID NO:22, SEQ ID NO:23, and SEQ ID NO:24 The present invention may comprise, consist of, or consist essentially of a sequence selected from the group consisting of:

[0100] In some embodiments of all aspects, the autoimmune disease is alopecia areata, ankylosing spondylitis, Antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, hydration Bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, localized systemic Scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus , essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroid disease adenitis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis , IgA nephropathy, insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease Lewy disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis , polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis inflammation, sarcoidosis, scleroderma, Sjögren's syndrome, stiff man syndrome, Takayasu's arteritis , temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis is selected from.

[0101] In some embodiments of all aspects, treatment reduces the risk of miscarriage / fetal loss. do.

[0102] In another aspect, the invention features a method of increasing antibody catabolism in a subject, the method comprising: from administering an antibody to a pregnant subject, including administering an antibody to a pregnant subject. or consisting essentially of administering an antibody to a pregnant subject, wherein the administered The antibody comprises (1) a CDR L1, a CDR L2, and a CDR L3, (2) a light chain variable region comprising, or consisting essentially of, CDR H1, CDR H2, and CDR H3. a light chain variable region, and the heavy chain variable region, wherein CDR L1 is TIFF2025143252000117.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000118.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000119.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0103] In another aspect, the invention features a method of increasing antibody catabolism in a subject, the method comprising: from administering an antibody to a pregnant subject, including administering an antibody to a pregnant subject. or consisting essentially of administering an antibody to a pregnant subject, wherein the administered An antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, The light chain has a sequence having at least 90% identity with the sequence of SEQ ID NO: 19. and the heavy chain comprises, consists of, or consists essentially of the sequence set forth in SEQ ID NO: NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID N and at least one sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO: 24. It comprises, consists of, or consists essentially of a sequence with 90% identity.

[0104] In another aspect, the invention features a method of increasing antibody catabolism in a subject, the method comprising: from administering an antibody to a pregnant subject, including administering an antibody to a pregnant subject. or consisting essentially of administering an antibody to a pregnant subject, wherein the administered An antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, The light chain comprises, consists of, or consists of the sequence of SEQ ID NO: 19. and the heavy chain is SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:2 4. do.

[0105] In some embodiments of all aspects, increasing antibody catabolism includes increasing the catabolism of pathogenic antibodies. In some implementations of all aspects, the pathogenic antibodies include increasing the catabolism of maternal antibodies. Pathogenic to the parent, the fetus, or both the mother and the fetus. In some embodiments of all aspects, the pathogenic antibody is an IgG antibody. , in a fetus within a pregnant subject, fetal and neonatal alloimmune disorders and / or autoimmune disorders Causes immune disorders.

[0106] In some embodiments of all aspects, fetal and neonatal alloimmune disorders and / or or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia and fetal and neonatal thrombocytopenia. Hematologic disorders, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonates Myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal multiple myeloma Myositis, dermatomyositis, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease , neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes. are selected.

[0107] In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising administering to a subject a therapeutically effective amount of steroids to the subject during pregnancy. administering the antibody to a pregnant subject, including administering the antibody to a pregnant subject; or administering to a pregnant subject an antibody, wherein the antibody comprises: (1) C Comprising, consisting of, or consisting of DR L1, CDR L2, and CDR L3 (2) a light chain variable region consisting essentially of CDR H1, CDR H2, and CDR a heavy chain variable region comprising, consisting of, or consisting essentially of H3; The light chain variable region and the heavy chain variable region are combined, or the light chain variable region and the heavy chain variable region are combined. wherein CDR L1 is TIFF2025143252000120.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000121.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000122.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially consisting of: where X1 is T, A, S, or I; X2 is L or I, X3 is S, N, or T, and X4 is Q, E, or N. X5 is C, S, I, or Y, X6 is A or V, and Z1 is E, T, D or N, Z2 is S or A, Z3 is G, S, or A, and Z4 is K or R, Z5 is I, L, or H, and Z6 is G, S, D, Q, or It's H.

[0108] In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising administering to a subject a therapeutically effective amount of steroids to the subject during pregnancy. administering the antibody to a pregnant subject, including administering the antibody to a pregnant subject; The method consists essentially of administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain. comprising, consisting of, or consisting essentially of, wherein the light chain is comprising a sequence having at least 90% identity with the sequence of NO:19, or the heavy chain consists essentially of said sequence, and D NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ having at least 90% identity with a sequence selected from the group consisting of ID NO: 24 Comprising, consisting of, or consisting essentially of the sequence.

[0109] In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising administering to a subject a therapeutically effective amount of steroids to the subject during pregnancy. administering the antibody to a pregnant subject, including administering the antibody to a pregnant subject; or consisting essentially of administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain. and a light chain of SEQ ID NO: 1, wherein the light chain is comprising, consisting of, or consisting essentially of the sequence of ID NO: 19; and the heavy chain is SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO: From the group consisting of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24 It comprises, consists of, or consists essentially of a selected sequence.

[0110] In another aspect, the present invention provides a method for reducing immune complex-based activation of an immune response in a subject. The method includes administering an antibody to a pregnant subject. or consisting essentially of administering an antibody to a pregnant subject. wherein the antibody comprises (1) CDR L1, CDR L2, and CDR L3. (2) a light chain variable region consisting of, or consisting essentially of, CDR H1 , CDR H1, CDR H2, and CDR H3. and a heavy chain variable region that is and the heavy chain variable region, wherein CDR L1 is TIFF2025143252000123.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000124.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000125.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0111] In another aspect, the present invention provides a method for reducing immune complex-based activation of an immune response in a subject. The method includes administering an antibody to a pregnant subject. administering the antibody to a pregnant subject; Here, an antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. wherein the light chain has at least 90% identity with the sequence of SEQ ID NO: 19. and the heavy chain comprises, consists of, or consists essentially of the sequence SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ and a sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO: 24. comprising, consisting of, or essentially consisting of a sequence having at least 90% identity becomes.

[0112] In another aspect, the present invention provides a method for reducing immune complex-based activation of an immune response in a subject. The method includes administering an antibody to a pregnant subject. administering the antibody to a pregnant subject; Here, an antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. wherein the light chain comprises, consists of, or has the sequence of SEQ ID NO:19. and the heavy chain consists essentially of the sequence SEQ ID NO: 20, SEQ ID NO: :21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID The present invention relates to a method for producing a medicament for the treatment of a pulmonary arthritis, comprising or consisting of a sequence selected from the group consisting of NO:24. Become qualitative.

[0113] In some embodiments of all aspects, the immune response is an acute or chronic immune response in the subject. It is an immune response.

[0114] In some embodiments of all aspects, the acute immune response is in the setting of a condition such as pemphigus vulgaris, lupus nephritis, or inflammation, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, severe antiphospholipid antibodies syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathies, neuromyelitis optica, autoimmune rheumatoid arthritis Hearing, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated myocardium The immune system is activated by a medical condition selected from the group consisting of: In some embodiments, the acute immune response is activated by a medical condition in a pregnant subject. For example, in some embodiments, the acute immune response is associated with a medical condition in a pregnant subject. Thus, it is activated in the fetus or neonate. An acute immune response is activated by a medical condition in a pregnant subject. In some embodiments, the acute immune response is directed against the fetus or the host, depending on the medical condition of the pregnant subject. In some embodiments of all aspects, the acute immune response is activated in the neonate. In some embodiments of all aspects, the antibody is activated by thrombocytopenic purpura. An acute immune response is activated by pemphigus vulgaris. In this condition, the acute immune response is activated by fulminant antiphospholipid syndrome. In some embodiments of the aspect, the acute immune response is activated by neuromyelitis optica. In some embodiments of all aspects, the acute immune response is mediated by antibody-mediated rejection. In some embodiments of all aspects, the acute immune response is activated by myasthenia gravis. It is activated by

[0115] Additionally, pregnant subjects were given M281 (e.g., 15 mg / kg or 30 mg / kg a dose, e.g., a weekly dose), and the subject has hypoalbuminemia (e.g., If serum albumin levels below 30g / l, 25g / l, or 20g / l are observed, including, consisting of, or consisting essentially of, terminating the fetus and newborn Also described herein are methods for treating alloimmune and / or autoimmune disorders in newborns. In addition, pregnant subjects should be given M281 (e.g., 15 mg / kg or 30 mg / kg a dose, e.g., a weekly dose), and the subject has hypoalbuminemia (e.g., serum albumin levels below 30g / l, 25g / l, and 20g / l), Treatment of fetal and neonatal alloimmune disorders and / or autoimmune disorders, including administering buprenorphine comprising, consisting of, or consisting essentially of treating a disorder Also described is a method for administering M281 (e.g., 15 mg / kg) to a pregnant subject. and administering a dose of 100 mg / kg or 30 mg / kg, e.g., a weekly dose, and the subject has a low albuminemia (e.g., serum albumin levels less than 30 g / L, 25 g / L, or 20 g / L) If indicated, use a hypertonic solution (e.g., mannitol, or other solution known in the art). ) for the treatment of fetal and neonatal alloimmune and / or autoimmune disorders, including administering comprising, consisting of, or consisting essentially of treating Also described are methods for administering M281 (e.g., 15 mg / kg or less) to pregnant subjects. or 30 mg / kg, e.g., weekly doses), and Test the subject's serum albumin levels at least once before or after M281 administration. Treating fetal and neonatal alloimmune and / or autoimmune disorders, including Also described are methods comprising, consisting of, or consisting essentially of said treating. In some instances of this method, administration of M281 may be continued or may not be continued. It's not necessary.

[0116] In some embodiments of all aspects, the chronic immune response is a chronic inflammatory demyelinating polyneuropathy. CIDP, systemic lupus erythematosus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis and antineutrophil cytoplasmic antibody-associated vasculitis. In some embodiments of all aspects, the chronic immune response is a chronic inflammatory demyelination. It is activated by genital polyneuropathy.

[0117] In some embodiments of all aspects, the subject has an autoimmune disease. In some embodiments, the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipidosis syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, heparin-induced Thrombocytopenia, sensitization transplantation, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiac Myopathy, Celiac sprue dermatitis, Chronic fatigue and immune dysfunction syndrome, Chronic inflammatory demyelinating polymyalgia Neuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic sclerosis (CRE) ST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed crohn's disease Myoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, thyroid function hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, Insulin-dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue tissue diseases, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, Polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis , psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis sis, scleroderma, Sjögren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, colitis The disease is selected from the group consisting of ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments of all aspects, the autoimmune disease is warm autoimmune hemolytic anemia. In some embodiments of all aspects, the autoimmune disease is anti-factor antibody. In some embodiments of all aspects, the autoimmune disease heparin-induced thrombocytopenia. In some embodiments of all aspects, the autoimmune disease is transplantation.

[0118] In another aspect, the present invention provides a method for reducing antibody transfer across the placenta in a pregnant subject. The method includes administering an antibody to a pregnant subject. a method for administering an antibody to a pregnant subject, comprising administering to the subject an antibody to a pregnant subject, The antibody comprises (1) CDR L1, CDR L2, and CDR L3; (2) a light chain variable region consisting of, or consisting essentially of, CDR H1, CDR H2, CDR H3, CDR H4, CDR H5, CDR H6, CDR H7, CDR H8, CDR H9, CDR H10, CDR H11, CDR H12, CDR H13, CDR H14, CDR H15, CDR H16, CDR H17, CDR H18, CDR H19, CDR H20, a heavy chain comprising, consisting of, or consisting essentially of CDR H2, and CDR H3 a light chain variable region, consisting of the light chain variable region and the heavy chain variable region, or and the heavy chain variable region, wherein CDR L1 is TIFF2025143252000126.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000127.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 has the sequence TIFF2025143252000128.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0119] In another aspect, the present invention provides a method for reducing antibody transfer across the placenta in a pregnant subject. The method includes administering an antibody to a pregnant subject. the method consists essentially of administering an antibody to a pregnant subject, wherein the antibody The body comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein: The light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID NO:19. and the heavy chain comprises, consists of, or consists essentially of the sequence of SEQ ID N O:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO 23, and SEQ ID NO: 24, and at least 9 0% identity to a sequence comprising, consisting of, or consisting essentially of a sequence having 0% identity to a sequence.

[0120] In another aspect, the present invention provides a method for reducing antibody transfer across the placenta in a pregnant subject. The method includes administering an antibody to a pregnant subject. the method consists essentially of administering an antibody to a pregnant subject, wherein the antibody The body comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein: The light chain comprises, consists of, or is derived from the sequence of SEQ ID NO:19. The heavy chain is selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: EQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24 comprising, consisting of, or consisting essentially of a sequence selected from the group consisting of: .

[0121] In another aspect, the present invention provides a method for antibody-mediated enhancement of viral disease in a fetus or newborn. The present invention features a method for treating a pulmonary edema during pregnancy, the method comprising administering an antibody to a pregnant subject. or administering the antibody to a pregnant subject. wherein the antibody comprises: (1) CDR L1, CDR L2, and CDR L3 (2) a light chain variable region comprising, consisting of, or consisting essentially of: comprising, consisting of, or consisting of CDR H1, CDR H2, and CDR H3 a heavy chain variable region consisting essentially of said light chain variable region and said heavy chain variable region, or consisting essentially of said light chain variable region and said heavy chain variable region, wherein CDR L1 is array TIFF2025143252000129.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO: 13) Essentially, the CDR L3 has the sequence TIFF2025143252000130.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO: 15), comprising, consisting of, or essentially consisting of the sequence and CDR H2 is TIFF2025143252000131.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially wherein X1 is T, A, S, or I, and X2 is L or I; X3 is S, N, or T, X4 is Q, E, or N, and X5 is C, S, I, or or Y, X6 is A or V, Z1 is E, T, D, or N, and Z2 is Z3 is G, S, or A; Z4 is K or R; and Z5 is I. , L, or H, and Z6 is G, S, D, Q, or H.

[0122] In another aspect, the present invention provides a method for antibody-mediated enhancement of viral disease in a fetus or newborn. The present invention features a method for treating a pulmonary edema during pregnancy, the method comprising administering an antibody to a pregnant subject. or administering the antibody to a pregnant subject. and wherein the antibody comprises, consists of, or is composed of a light chain and a heavy chain. wherein the light chain has at least 90% identity with the sequence of SEQ ID NO: 19. comprising, consisting of, or consisting essentially of a sequence having identity, and The strands are SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:2 2, SEQ ID NO: 23, and SEQ ID NO: 24 comprising, consisting of, or comprising a sequence having at least 90% identity to a sequence It essentially consists of columns.

[0123] In another aspect, the present invention provides a method for antibody-mediated enhancement of viral disease in a fetus or newborn. The present invention features a method for treating a pulmonary edema during pregnancy, the method comprising administering an antibody to a pregnant subject. or administering the antibody to a pregnant subject. and wherein the antibody comprises, consists of, or is composed of a light chain and a heavy chain. wherein the light chain comprises or consists of the sequence of SEQ ID NO: 19. and the heavy chain comprises or consists essentially of the sequence SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, and S comprising, consisting of a sequence selected from the group consisting of EQ ID NO:24, or It consists essentially of said sequence.

[0124] In some embodiments of all aspects, the viral disease is an alphavirus infection, Viral infections, Zika virus infection, Chikungunya virus infection, Ross River virus infection Severe Acute Respiratory Syndrome Coronavirus Infection, Middle East Respiratory Syndrome, Avian Influenza influenza virus infection, human respiratory syncytial virus infection, Bolavirus infection, yellow fever virus infection, dengue virus infection, human immunodeficiency virus infection virus infection, respiratory syncytial virus infection, hantavirus infection, getah virus infection disease, Sindbis virus infection, Bunyamwera virus infection, West Nile virus infection Japanese encephalitis virus B infection, rabbitpox virus infection, elevated lactate dehydrogenase and viral infection infectious diseases, reovirus infection, rabies virus infection, foot-and-mouth disease virus infection, porcine reproductive organs Respiratory syndrome virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection disease, caprine arthritis virus infection, African swine fever virus infection, lentivirus infection , BK papovavirus infection, Murray Valley encephalitis virus infection, enterovirus infection , cytomegalovirus infection, pneumovirus infection, morbillivirus infection and The measles virus infection is caused by a virus selected from the group consisting of:

[0125] In some embodiments of all aspects, the pregnant subject is have or are at risk of having a medical condition that activates the response. In some embodiments of the aspect, the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis, Antibody-mediated rejection, Guillain-Barré syndrome, fulminant antiphospholipid syndrome, immunological Complex-mediated vasculitis, glomerulitis, channelopathies, neuromyelitis optica, autoimmune deafness, idiopathic hematologic malignancies Thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy (dial ated cardiomyopathy), serum sickness, chronic inflammatory demyelinating polyneuritis, Systemic lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, antineutrophil cytoplasmic antibody ANCA-associated vasculitis, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease , hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, ceria Chronic sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Jerg-Strauss syndrome, cicatricial pemphigoid, limited systemic sclerosis (CREST syndrome) , cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulin Hypothyroidism, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammation enteropathy, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin dependence Diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis Sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, rheumatoid arthritis Myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, leprosy No phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma , Sjogren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, These are uveitis, vitiligo, and Wegener's granulomatosis.

[0126] In some embodiments of all aspects, the pregnant subject receives fetal and neonatal alloimmunization. Previously had a fetus or newborn with an infectious and / or autoimmune disorder For example, in some embodiments, a pregnant subject has a history of fetal and neonatal Previous pregnancy with a fetus or newborn with fetal alloimmune and / or autoimmune disorders I have been pregnant before.

[0127] In some embodiments of all aspects, in a biological sample obtained from a pregnant subject In some embodiments of all aspects, antibodies associated with immune disorders are detected. The sample is a blood sample or a urine sample. In some embodiments of all aspects, the biological sample is the blood sample.

[0128] In some embodiments of all aspects, the administered antibody is a monoclonal antibody. In some embodiments of all aspects, the antibody administered is an IgG1. In some embodiments of the aspect, the administered antibody comprises, consists of, or comprises a λ light chain. consists essentially of it.

[0129] In another aspect, the present invention provides methods for treating fetal and neonatal alloimmune and / or autoimmune disorders. to treat harms or to prevent alloimmune and / or autoimmune disorders in the fetus and newborn The method comprises: a light chain having the amino acid sequence of SEQ ID NO: 24 and a heavy chain having the amino acid sequence of SEQ ID NO: 25; administering to a pregnant woman a composition comprising an antibody (M281) comprising: is terminated after 34 weeks of gestational age.

[0130] In another aspect, the present invention provides methods for treating fetal and neonatal alloimmune and / or autoimmune disorders. to treat harms or to prevent alloimmune and / or autoimmune disorders in the fetus and newborn The present invention relates to a method for reducing the risk of developing a cancer, comprising administering to a patient a cancer-related gene having the amino acid sequence of SEQ ID NO: 19. an antibody comprising a light chain having the amino acid sequence of SEQ ID NO:24 and a heavy chain having the amino acid sequence of SEQ ID NO:25 (M281) to a pregnant woman, wherein the administration of M281 It ends at least one week before birth.

[0131] In various embodiments of both methods, the method includes: Prenatal (e.g., 40–100 hours or 1–15 days before birth) IVIG in pregnant women M281 administration should be discontinued after 35 weeks of gestation; administration should be discontinued after 36, 37, or 3 Terminate M281 administration before 8 weeks; 200 mg / kg to 100 mg / kg based on maternal weight IVIG at 0 mg / kg; M281 at 30 mg / kg based on maternal weight Administer M281 at 15 mg / kg based on the weight of the pregnant woman; the dose is The dose is based on the weight of the woman at the time of the first dose and on the weight gain of the woman. Not adjusted upward; dose is per dose and is based on maternal weight at time of first dose and adjusted upward based on maternal weight gain; the composition is administered at least every other week the composition is administered every other week; The composition is administered at least weekly; the composition is administered weekly; administration is during the first trimester of pregnancy administration begins in the second trimester; administration begins in the third trimester The route of administration is intravenous; the pregnant woman has an obstetric history of severe fetal anemia; the pregnant woman has elevated antibodies Have RhD, anti-Rhc, or anti-Kell immunoglobulin alloantibody titers; pregnant women should have elevated anti-Rhc or anti-Kell immunoglobulin isoantibody titers; pregnant women have elevated anti-Lu a, Lub, Bg, Kna, Yta, EcKCw, Fya, cE, ce, D, Ce ,cE,K,Kpa,Kpb,Fya,M,N,S,Lea,Leb,Fy,Jka.D For one or more antibodies selected from the group consisting of iego, P, and Mia / Mur have elevated immunoglobulin alloantibody titers; pregnant women have severe fetal anemia or obstetric history of stillbirth at ≤24 weeks and elevated anti-D or anti-Kell IgG alloantibody titers and pregnant with an antigen-positive fetus; first dose at 12-16 weeks of gestation; first dose at 12-16 weeks of gestation; Administration begins at 14 weeks of gestation; and administration begins in the first trimester of pregnancy.

[0132] definition The term "antibody" is used herein in the broadest sense and includes monoclonal antibodies, polyclonal antibodies, and Reclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and FcRn antigen binding activity The term "antibody fragment" encompasses various antibody structures, including but not limited to antibody fragments, as long as they exhibit the same properties.

[0133] "Antibody fragments" refer to fragments of intact antibodies, preferably fragments that retain the antigen-binding or antigen-binding properties of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv. These include fragments, diabodies, linear antibodies, single chain antibody molecules, and multispecific antibodies.

[0134] As used herein, the term "isolated antibody" refers to an antibody in the context of its production host cell environment. refers to an antibody that has been separated and / or recovered from the elements and contaminants of its manufacturing host cell environment. Contaminants are substances that interfere with the research, diagnostic, or therapeutic use of antibodies. may contain enzymes, hormones, and other proteinaceous or non-proteinaceous solutes In some embodiments, the antibody is (1) purified by, for example, the Lowry method; and in some embodiments, greater than 95% by weight of the antibody, as determined by OD). (2) For example, in a spinning cup sequenator N-terminal or internal amino acids can be identified by using a ning cup sequenator. (3) enough to obtain at least 15 residues of the sequence, or SDS-PAGE under reducing or non-reducing conditions using erythrocyte blue or silver staining An isolated antibody contains the antibody in situ within recombinant cells. Ordinarily, however, isolated antibody will be prepared by at least one purification step. Pharmaceutical preparations of isolated antibodies typically follow recommendations from FDA "Guidance for Industry" documents. Host cell proteins as determined by an ELISA-based HCP assay performed as per instructions 250 ppm (e.g., 200 ppm, 150 ppm, 100 ppm or less) of human carbohydrates (HCP) is less than 100 years.

[0135] As used herein, the term "monoclonal antibody" refers to a substantially homogeneous antibody. Refers to antibodies obtained from a population of organisms, i.e., individual antibodies within a population may be present in small amounts They have identical primary sequences except for naturally occurring mutations. It is specific for a single antigenic site (i.e., an epitope on human FcRn). Polyclonal antibodies typically contain different antibodies directed against different epitopes. In contrast to monoclonal antibody preparations, each monoclonal antibody is directed against a single epitope on the antigen. Modifiers "monoclonal" are derived from a substantially homogeneous population of antibodies. These characteristics of the antibody should not be construed as requiring production of the antibody by any particular method. .

[0136] As used herein, the terms "variable region" and "variable domain" refer to complementary CDRs (e.g., CDR L1, CDR L2, CDR L3, CDR H1) , CDR H2, and CDR H3), and the amino acid sequences of the framework regions (FR) According to the method used in the present invention, the CDRs refer to the portions of the light and heavy chains of an antibody that contain the CDRs. and the amino acid positions assigned to FR are defined according to Kabat (Seq. nces of Proteins of Immunological Intere st, 5th Ed.Public Health Service, National Institutes of Health, Bethesda, MD. (1991) ). Using this numbering system, the actual linear amino acid sequence is a shortening of DR (further defined herein) or FR (further defined herein) or CDRs (as further defined herein) or FRs (as further defined herein) of the variable region. fewer or additional amino acids corresponding to insertions into the For example, the heavy chain variable region may contain a single insertion after residue 52 of CDR H2. after the residue identified by Kabat (i.e., residue 52a according to Kabat) and residue 82 of the heavy chain FR. Contains inserted residues (i.e., residues 82a, 82b, 82c, etc. according to Kabat) The Kabat numbering of residues indicates the area of ​​agreement in the region of homology of the antibody sequences. Align the antibody sequence with the "standard" Kabat numbering sequence at the homologous region by This can be determined for a given antibody by performing

[0137] As used herein, "complementarity determining region" and "CDR" refer to regions that are frequently found in a sequence. antibody variable domains, which are variable and / or form structurally defined loops CDRs are also known as hypervariable regions. Each variable region has three CDRs. The light chain variable region has CDR L1, CDR L2, and The heavy chain variable region includes CDR H1, CDR H2, and CDR L3. Each CDR is a complementarity determining region (CDR) as defined by Kabat. The light chain variable region may contain amino acid residues from approximately residues 24-3 4 (CDR L1), 50-56 (CDR L2), and 89-97 (CDR L3) and in the heavy chain variable region, approximately residues 31-35 (CDR H1), 50-65 (CDR H2), DR H2), and 95–102 (CDR H3).

[0138] As used herein, the term "FcRn" refers to IgG antibodies, e.g., IgG1 Refers to a neonatal Fc receptor that binds to the Fc region of an antibody. An exemplary FcRn is UniPro Human FcRn has ID number P55899. Human FcRn is involved in the lysis of IgG. By constitutively binding and transporting endogenous IgG back to the cell surface, , which is thought to be responsible for maintaining the half-life of IgG.

[0139] As used herein, the terms "affinity" and "binding affinity" refer to two different Binding affinity refers to the strength of the binding interaction between an antibody and its target. (e.g., isolated anti-FcRn antibodies of the present invention and human FcRn), a single binding site of the molecule and its Unless otherwise indicated, the strength of the combined non-covalent interactions between the binding partner and the resulting Binding affinity refers to the intrinsic binding affinity that reflects a 1:1 interaction between the members of a binding pair. The binding affinity between molecules is generally expressed as the dissociation constant (K D ) or affinity constant (K A ) Two molecules with low binding affinity to each other generally bind slowly and dissociate easily. There is a tendency for large K D Two molecules with high affinity for each other are generally easily They simply bind and tend to remain bound for longer, with a small K D Human FcRn K of antibodies to D One method for determining is described in Example 2 ("SPR method"). Using this method, K of N022, N023, N024, N026, and N027 D were 31, 31.4, 35.5, 36.5, and 19.3 pM, respectively.

[0140] As used herein, "inhibiting IgG binding to FcRn" refers to inhibiting IgG binding to human FcRn. Anti-F antibody of the present invention for blocking or inhibiting the binding of IgG (e.g., IgG1) to cRn. In some embodiments, the anti-FcRn antibodies of the present invention are capable of, e.g., , binds to FcRn at the site on human FcRn where IgG binds. The anti-FcRn antibodies of the present invention inhibit the binding of IgG (e.g., a subject's autoantibody) to FcRn. In some embodiments, the molecule (e.g., an anti-FcRn antibody of the present invention) can inhibit the ) substantially or completely inhibits binding to IgG. In some embodiments, The binding is 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 1 It can be reduced to 00%.

[0141] As used herein, "inhibiting binding of pathogenic antibodies to FcRn" means Blocking or inhibiting the binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to human FcRn In some embodiments, the anti-FcRn antibody binds to FcRn, for example, at the site on human FcRn where pathogenic antibodies bind Therefore, anti-FcRn antibodies are pathogenic antibodies against FcRn (e.g., pathogenic IgG In some embodiments, the molecule (e.g., anti-Fc antibody) can inhibit binding. Rn antibodies) substantially or completely inhibit binding to pathogenic antibodies. In this study, the binding of pathogenic antibodies to FcRn was 10%, 20%, 30%, 50%, 70%, and 8%. It may be reduced by 0%, 90%, 95%, or even 100%.

[0142] As used herein, the term "hydrophobic amino acid" refers to an amino acid that has relatively low water solubility. Hydrophobic amino acids include leucine, isoleucine, alanine, and phenylalanine. These include, but are not limited to, thiamin ... Particularly preferred hydrophobic amino acids in the present invention are alanine, leucine, isoleucine, and valine. is.

[0143] As used herein, the term "polar amino acids" refers to amino acids having different electronegativities. Polar amino acids refer to amino acids that have chemical polarity in their side chains, induced by the atoms present in the side chains. The polarity of amino acids is determined by the electronegativity between atoms in the amino acid side chain and the asymmetry of the side chain structure. The polar amino acids are serine, threonine, cysteine, methionine, and thiamine. These include, but are not limited to, thiamin, tryptophan, asparagine, and glutamine. Particularly preferred polar amino acids of the present invention are serine, threonine, asparagine , glutamine, cysteine, and tyrosine.

[0144] As used herein, the term "acidic amino acid" refers to an amino acid whose side chain has a length of 3.5 to 4. In some embodiments, the amino acid refers to an amino acid containing a carboxylic acid group having a pKa of 5. The acidic amino acids are aspartic acid and glutamic acid.

[0145] As used herein, the term "basic amino acid" refers to an amino acid whose side chain is 9.5 to 1 In some embodiments, the amino acid is an amino acid containing an amino group with a pKa of 3. The basic amino acids are histidine, lysine, and arginine.

[0146] As used herein, the term "percent (%) identity" refers to the percentage of a sequence that is aligned. and, if necessary, gaps to achieve the maximum percent identity. (i.e., for optimal alignment, either the candidate sequence or the reference sequence) Gaps can be introduced in either or both sequences to allow for comparison of non-homologous sequences. The reference antibody, e.g., a wild-type anti-FcRn antibody, is used after the ELISA (the column can be ignored). The amino acid (or nucleic acid) residues of the reference sequence are identical, for example, to the anti-FcRn antibodies of the present invention. Percent means the percentage of amino acid (or nucleic acid) residues in a candidate sequence. Alignment for identity determination can be performed using BLAST, ALIGN, or Megali. Publicly available computer software, such as gn(DNASTAR) software This can be achieved in a variety of ways within the art using algorithms. Contains any algorithm needed to achieve maximal alignment across the entire length of the string. , appropriate parameters for measuring alignment can be determined. In this embodiment, the sequence of interest is a sequence of interest to, with, or against a given reference sequence. percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to a given reference sequence to a particular percent amino acid with or relative to a given reference sequence (or nucleic acid) sequence identity to or containing a given candidate sequence. ) is calculated as follows: 100 x (fraction A / B) where A is the amino acid sequence scored as identical in the alignment of the candidate sequence with the reference sequence. is the number of amino acid (or nucleic acid) residues, and 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 sequence is not equal to the length of the reference sequence, The percent amino acid (or nucleic acid) sequence identity of a candidate sequence to a reference sequence is determined by the percent amino acid (or nucleic acid) sequence identity of the candidate sequence to the reference sequence. It is not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence.

[0147] In certain embodiments, the reference sequence aligned for comparison to the candidate sequence is the full length of the candidate sequence. Candidate sequences that show 50% to 100% identity across the entire sequence, or consecutive amino acids of the candidate sequence Selected portions of the acid (or nucleic acid) residues may be shown. Candidate sequences aligned for comparison purposes The length of the reference sequence is at least 30%, e.g., at least 40%, e.g., at least 10% of the length of the reference sequence. At least 50%, 60%, 70%, 80%, 90%, or 100% of the candidate sequences. a position is occupied by the same amino acid (or nucleic acid) residue as the corresponding position in the reference sequence If a position is altered by substitution, deletion, or insertion, the molecules are identical at that position. The substitutions, deletions, or insertions may be of a certain number of amino acids (e.g., 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) When describing a substitution, deletion, or insertion of n or fewer amino acids, this may include, for example: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, … or means a substitution, deletion, or insertion containing n amino acids. is a percentage of the total sequence (e.g., 1%, 5%, 10%, 15%, 20%, or more) The number of substitutions, deletions, or insertions may be greater than or equal to the number of amino acids in the total sequence. Changes of 5%, 10%, 15%, 20% or more.

[0148] As used herein, "fetal and neonatal alloimmune disorders and / or autoimmune disorders" refers to disorders of the fetus and newborn. The term "immune disorder" refers to maternal antibodies against fetal and / or neonatal antigens (e.g., in the fetus and / or newborn caused by the transplacental transfer of immunizing maternal antibodies For example, antibodies (e.g., pathogenic antibodies) in a pregnant subject may be transmitted to the fetus. The fetus may react to antigens inherited from its father (e.g., antigens inherited by the fetus from its father). Examples of alloimmune and / or autoimmune disorders are provided herein.

[0149] As used herein, the term "pathogenic antibody" refers to an antibody that is present in a subject (e.g., a pregnant subject). elephant), one or more immune disorders in the fetus, and / or newborn in a pregnant subject, or In some embodiments, pathogenic antibodies refer to antibodies that cause a disorder. autoantibodies produced in a subject (e.g., a pregnant subject) against one or more of the proteins In some embodiments, the autoimmune disease or disorder in a subject is caused by: Pathogenic antibodies in pregnant subjects may cross the placenta to the fetus, potentially resulting in the transfer of antigens from the fetus (e.g. , antigens inherited by the fetus from its father) and thus Alloimmune and / or autoimmune disorders occur in the offspring.

[0150] As used herein, the term "antibody-mediated enhancement of viral disease" refers to an antibody can facilitate viral entry into host cells, thus increasing intracellular infectivity or In some embodiments, antibodies to the virus surface The antibody / virus complex binds to the surface protein and is released through the interaction between the antibody and the receptor. The antibody / virus complex can then bind to the FcRn receptor on the cell surface. It may be internalized.

[0151] As used herein, the term "host cells" refers to cells that are capable of transforming cells from their corresponding nucleic acid. A biogenesis complex that contains the necessary cellular components, such as organelles, required for the expression of a protein. Nucleic acids may be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, etc.). introduced into host cells by various methods (e.g., transfection, electroporation, calcium phosphate precipitation, direct microinjection, etc.) The host cell may be a prokaryotic cell, such as a bacterial cell, or a or eukaryotic cells, such as mammalian cells (e.g., CHO cells). As described, the host cell can be transformed with one or more polypeptides encoding the anti-FcRn antibodies of the present invention. It is used to express peptides.

[0152] As used herein, the term "vector" refers to a nucleic acid molecule that can transport another nucleic acid molecule to which it has been linked. A vector refers to a nucleic acid molecule capable of delivering a specific gene. One type of vector is a "plasmid." , which is a circular double-stranded DNA into which additional DNA segments can be ligated Another type of vector is a phage vector. Another type of vector is a viral vector in which an additional DNA segment is inserted into the viral genome Certain vectors are capable of self-replicating in a host cell into which they are introduced. can be used (e.g., bacterial vectors and episomes with a bacterial origin of replication). mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) When introduced into a host cell, it can integrate into the genome of the host cell, thereby Moreover, certain vectors replicate along with the genome to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors." Generally, recombinant DNA vectors are called recombinant vectors. Expression vectors useful in A technology are often in the form of plasmids.

[0153] As used herein, the term "subject" refers to a mammal, e.g., preferably a human. Mammals include, but are not limited to, humans and monkeys (e.g., cynomolgus monkeys). animals, such as mice, dogs, cats, horses, and cattle.

[0154] As used herein, the term "gestational age" refers to how long a baby has been pregnant. Gestational age can be stated in weeks. How to determine gestational age known in the art (e.g., Committee on Obstetric Practice American Institute of Ultrasoun d in Medicine Society for Maternal-Fetal Medicine, Committee Opinion.Number 700.2 May 017; (The entire contents of which are incorporated herein by reference.) In some instances, gestational age is determined by: by ultrasound, by week since the first day of the last menstrual period (LMP), or a combination This can be determined by combining

[0155] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition containing an active ingredient, as well as A pharmaceutical product containing one or more excipients and diluents to make the product suitable for the method of administration The pharmaceutical composition of the present invention refers to a pharmaceutical preparation that is pharmaceutically compatible with an anti-FcRn antibody. The pharmaceutical composition is in aqueous form for intravenous or subcutaneous administration. Alternatively, it may be in tablet or capsule form for oral administration.

[0156] As used herein, the term "pharmaceutically acceptable carrier" refers to a compound that is present in a pharmaceutical composition. A pharmaceutically acceptable carrier refers to an excipient or diluent that is compatible with the other ingredients of the formulation. In the present invention, the pharmaceutical An acceptable carrier must provide adequate pharmaceutical stability for the Fc construct. The dosage varies depending on the mode of administration. For example, for intravenous administration, an aqueous carrier is generally used. For oral administration, a solid carrier is preferred.

[0157] As used herein, the term "therapeutically effective amount" refers to the amount of a desired therapeutic effect in a subject or patient. in eliciting a desirable biological effect or in treating a patient with a condition or disorder described herein. "Therapeutically effective amount" refers to an amount, e.g., a pharmaceutical dose, effective in treating a patient. In a single dose or any dosage or route, alone or in combination with other therapeutic agents It is also understood herein that the amount of a compound that provides a desired therapeutic effect can be interpreted as the amount of a compound that provides a desired therapeutic effect. should be.

[0158] As used herein, the term "less than" refers to an amount that is less than or equal to This can be an integer quantity. For example, up to two permutations can be 0, 1, or 2 permutations. It can refer to a conversion.

[0159] As used herein, the terms "treatment" or "treating" refer to a specific disease or reduce, decrease, or decrease the risk of a particular disease or condition; refers to reducing the side effects of a particular disease or condition. The benefits of taking the medicine, reducing the risk, or reducing the side effects are not as bad as those of not taking the medicine. Subjects who have been tested, e.g., controls, baseline or known control levels, or have received measurements This is in comparison with subjects who did not have the condition. [Brief explanation of the drawings]

[0160] [Figure 1] FIG. 1 includes two graphs and a table showing the competitive binding of IgG to human or cynomolgus monkey FcRn at pH 6.0 by antibodies N022-N024, N026, and N027. [Figure 2] FIG. 2 contains graphs showing the effect of antibodies N023, N024, N026, and N027 on IgG catabolism in mice. [Figure 3] FIG. 3 contains graphs showing the dose-dependent effect of antibody N027 on IgG levels and target occupancy in mice. [Figure 4] 4A-4C include graphs showing selective induction of IgG catabolism and target occupancy in cynomolgus monkeys following administration of different doses of antibody N027. [Figure 5] FIG. 5 contains graphs showing the biodistribution of N027 in mice. [Figure 6] FIG. 6 includes an experimental timeline and a graph showing the efficacy of N027 in a mouse collagen antibody-induced arthritis model. [Figure 7] FIG. 7 includes an experimental timeline and two graphs showing the efficacy of N027 in a murine chronic idiopathic thrombocytopenic purpura (ITP) model. [Figure 8] 8A-8C show graphs depicting the dose-dependent FcRn occupancy achieved with N027 on aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively. [Figure 9] 9A-9C show graphs demonstrating that 100% FcRn occupancy by N027 increased intracellular IgG accumulation in aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively. [Figure 10]FIG. 10 shows a graph depicting the amount of time it takes for N027 to achieve 100% FcRn occupancy. [Figure 11] 11A and 11B show graphs demonstrating that N027 treatment does not alter FcRn turnover rates in human endothelial cells and villous trophoblast cells, respectively. [Figure 12] 12A and 12B show images of FcRn localized within endosomes in human endothelial cells and villous trophoblast cells. [Figure 13A] FIG. 13A shows a graph depicting the effect of N027 treatment on the kinetics of IgG transport in human endothelial cells. [Figure 13B] FIG. 13B shows a graph depicting the effect of N027 treatment on the kinetics of IgG transport in human placental trophoblasts. [Figure 13C] FIG. 13C shows images demonstrating that N027 increases intracellular IgG and co-localization of IgG with lysosomes (lysosomal markers: Lamp-1 and dextran). [Figure 13D] FIG. 13D shows images demonstrating that N027 increases intracellular IgG and co-localization of IgG with lysosomes (lysosomal markers: Lamp-1 and dextran). [Figure 14] Figure 14 is a graph showing transplacental transfer of antipyrine over 4 hours of perfusion (n = 14). Data are presented as mean ± standard deviation (SD) of antipyrine concentrations in the fetal (squares) and maternal (circles) circulation after administration of 100 μg / ml antipyrine at t = 0. [Figure 15] Figure 15 is a graph showing the transplacental transfer of N027 over a 4-hour perfusion. Data are presented as mean ± SD of N027 concentrations in the fetal and maternal circulation after maternal administration of the indicated concentrations of N027 at t=0. [Figure 16] FIG. 16 is a graph showing maternal IgG concentrations after treatment with N027 during gestation. [Figure 17] FIG. 17 is a graph showing fetal IgG levels after maternal treatment with N027 during gestation. [Figure 18] FIG. 18 is a graph showing the mean (SD) FcRn receptor occupancy on circulating monocytes following a single dose of 0.3, 3, 10, 30, and 60 mg / kg of N027. [Figure 19] FIG. 19 is a graph showing the mean (SD) serum IgG levels following single doses of 0.3, 3, 10, 30, and 60 mg / kg of N027. [Figure 20] Figures 20A and 20B are graphs showing the mean (SD) FcRn receptor occupancy among monocytes in the 30 and 15 mg / kg MAD cohorts by number of doses given. [Figure 21] Figures 21A and 21B are graphs showing mean (SD) serum IgG in the 30 and 15 mg / kg MAD cohorts by number of doses given. [Figure 22] 22 is a graph showing transplacental transfer of antipyrine (Humira® in maternal reservoirs, n=8). Data represent antipyrine concentrations in the fetal (filled squares) and maternal (filled circles) circulation as mean±SD after maternal administration of 100 μg / ml antipyrine at t=0. [Figure 23] 23 is a graph showing transplacental transfer of Humira® over 6 hours of perfusion (n=8). Data represent Humira® concentrations in fetal and maternal circulation as mean±SD after maternal administration of 270 μg / ml of Humira® at t=0. [Figure 24] 24 is a graph showing transplacental transfer of antipyrine (HUMIRA® in maternal reservoir + N027; n=9). Data represent antipyrine concentrations in the fetal (filled squares) and maternal (filled circles) circulation as mean±SD after maternal administration of 100 μg / ml antipyrine at t=0. [Figure 25]Figure 25 is a graph showing the placental transfer of Humira® in the presence of various concentrations of N027. Data represent Humira® concentrations in the fetal and maternal circulation as mean ± SD following maternal administration of 270 μg / ml of Humira® + N027 at t=0. [Figure 26] 26 is a graph showing transplacental transfer of antipyrine (Humira® in maternal reservoir + IVIg; n=5). Data represent antipyrine concentrations in fetal (filled squares) and maternal (filled circles) circulation as mean ± SD after maternal administration of 100 μg / ml antipyrine at t=0. [Figure 27] Figure 27 is a graph showing transplacental transfer of Humira® in the presence of IVIg. Data represent Humira® concentrations in fetal (filled squares) and maternal (filled circles) circulation as mean ± SD following maternal administration of 270 μg / ml Humira® + N027 at t=0. [Figure 28] 28 is a graph showing transplacental transfer of antipyrine (Humira® + IVIg + N027 in maternal reservoirs; n=4). Data represent antipyrine concentrations in the fetal (filled squares) and maternal (filled circles) circulation as mean±SD after maternal administration of 100 μg / ml antipyrine at t=0. [Figure 29] Figure 29 is a graph showing transplacental transfer of Humira® in the presence of IVIg+N027. Data represent Humira® concentrations in fetal (filled squares) and maternal (filled circles) circulation as mean±SD following maternal administration of 270 μg / ml Humira®+IVIg+N027 at t=0. [Figure 30] FIG. 30 is a graph showing the effect on serum albumin in subjects treated with three doses of N027 at 15 mg / kg or 30 mg / kg. [Figure 31] FIG. 31 is a graph showing the effect on serum albumin in cynomolgus monkeys treated with N027 in a 26-week repeat dose toxicity study. [Figure 32] FIG. 32 is a table showing the effect on serum albumin in pregnant cynomolgus monkeys treated with N027 during gestation at the EFD and ePPND stages. DETAILED DESCRIPTION OF THE INVENTION

[0161] Detailed Description of the Invention The present invention features isolated antibodies that bind to the human neonatal Fc receptor (FcRn) with high affinity. The present invention relates to anti-FcRn antibodies, methods and compositions for preparing anti-FcRn antibodies, as well as blocking FcRn activity, reducing activation of immune complex-based immune responses, and The present disclosure features anti-FcRn antibodies, anti-FcRn antibodies, and methods for treating immune disorders. Methods and compositions for modulating FcRn antibodies and immunocomplexes that block FcRn activity The present invention relates to a method for reducing activation of immune responses based on fusion proteins and for treating immune disorders. Additionally, anti-FcRn antibodies can be used to detect pathogenic antibodies that cross the placenta in pregnant subjects. Reduces body transport and enhances catabolism of pathogenic antibodies in pregnant subjects, resulting in fetal or neonatal It can treat antibody-mediated enhancement of viral diseases in infants.

[0162] I. Anti-FcRn antibody In general, the invention features an isolated antibody that binds to human FcRn with high affinity. The anti-FcRn antibody binds to human FcRn and inhibits the expression of IgG (e.g., IgG autoantibodies). In some embodiments, the antibody is an antibody capable of inhibiting binding to FcRn. In some embodiments, the antibody is a monoclonal antibody. In other embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a chimeric antibody, an affinity matured antibody, a humanized antibody, and a human antibody. In certain embodiments, the antibody is an antibody fragment, e.g., a Fab fragment. , Fab', Fab'-SH, F(ab')2, or scFv.

[0163] In some embodiments, the antibody is a chimeric antibody. For example, the antibody is a xenogeneic non-human, or humanized sequences (e.g., framework and / or constant domain sequences). In one embodiment, the non-human donor is a donor that has been transplanted with the antigen-binding sequence. In another embodiment, the antigen-binding sequence is synthetic, e.g., mutagenesis (e.g., by phage display screening, etc.). In some embodiments, chimeric antibodies have non-human (e.g., murine) variable regions and human constant regions. In one example, the murine light chain variable region is fused to a human kappa light chain. The mouse heavy chain variable region is fused to a human IgG1 constant region.

[0164] In one aspect, the invention features an isolated antibody capable of binding to human FcRn. The isolated 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. wherein CDR L1 is TIFF2025143252000132.tif4128, and CDR L2 is S (SEQ ID NO: 2), CDR L3 is TIFF2025143252000133.tif4128, and CDR H1 comprises: TIFF2025143252000134.tif4128, and CDR H2 comprises: TIFF2025143252000135.tif9149, and wherein CDR H3 is LAIG A sequence having at least 85% identity with the sequence of DSY (SEQ ID NO: 11) was In some embodiments, the antibody is present at a concentration of less than 200 pM, less than 150 pM, less than 100 pM K less than, less than 50 pM, or less than 40 pM D and binds to human FcRn. In embodiments, the antibody is N022, N023, N024, N026, or N027 and a light chain variable region and a heavy chain variable region of the same Fc region as the antibody to be compared. K of antibodies with D The following K D and binds to human FcRn.

[0165] In some embodiments, the isolated antibody of the invention comprises: The sequence of CDR L1, GDX3X4RPS (SEQ ID NO: 13), containing the sequence of TIFF2025143252000136.tif4128 Includes CDR L2, CDR L3 containing the sequence of TIFF2025143252000137.tif4128, C containing the sequence of Z1YAMG (SEQ ID NO: 15) DR H1, CDR H2 containing the sequence of TIFF2025143252000138.tif4128, and LAZ5Z6DSY (SEQ ID NO: 17) and a CDR H3 comprising the sequence, wherein X1 is a polar or hydrophobic amino acid (e.g., X2 is a hydrophobic amino acid (e.g., preferably T, A, S, or I), and X2 is a X3 is a polar amino acid (e.g., preferably S, N, or T). ), X4 is a polar or acidic amino acid (e.g., preferably Q, E, or N), X5 is a polar or hydrophobic amino acid (e.g., preferably C, S, I, or Y); X6 is a hydrophobic amino acid (e.g., preferably A or V), and Z1 is a polar or acidic Z2 is a polar or sparse amino acid (e.g., preferably E, T, D, or N); Z3 is G, S, or A. Z4 is a basic amino acid (e.g., preferably K or R), and Z5 is a hydrophobic or or a basic amino acid (e.g., preferably I, L, or H), and Z6 is G, S, D, Q, or H, and wherein the antibody is less than 200 pM, less than 150 pM K less than 100 pM, less than 50 pM, or less than 40 pM D and binds to human FcRn do.

[0166] In other embodiments, the isolated antibody of the invention comprises: CDR L1 containing the sequence of TIFF2025143252000139.tif4128, C containing the sequence of GDSERPS (SEQ ID NO: 2) DR L2, CDR L3 containing the sequence of TIFF2025143252000140.tif4128, C containing the sequence of Z1YAMG (SEQ ID NO: 15) DR H1, CDR H2 containing the sequence of TIFF2025143252000141.tif4128, and the sequence of LAIGDSY (SEQ ID NO: 11) wherein Z1 is E, D, or N and Z2 is S or A. and Z3 is G, S, or A.

[0167] Table 1 shows the light chain complementarity determining regions and heavy chain complementarity determining regions of some exemplary anti-FcRn antibodies of the present invention. The amino acid sequences of the complementarity determining regions (CDRs) are shown.

[0168] (Table 1) TIFF2025143252000142.tif64158

[0169] Table 2 shows the SEQ ID NOS: 1-14 of the light and heavy chains of these exemplary anti-FcRn antibodies of the present invention. Indicates O:.

[0170] (Table 2) TIFF2025143252000143.tif52128

[0171] In some embodiments, the light chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000144.tif21160.

[0172] In some embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000145.tif38160.

[0173] In some embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000146.tif38160.

[0174] In some embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000147.tif38160.

[0175] In other embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000148.tif38160.

[0176] In yet other embodiments, the heavy chain of the isolated antibody of the invention comprises: Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000149.tif38160.

[0177] The invention features an isolated antibody including a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000150.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000151.tif38160.

[0178] The invention features an isolated antibody including a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000152.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000153.tif38160.

[0179] The invention features an isolated antibody including a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000154.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000155.tif38160.

[0180] The invention features an isolated antibody including a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000156.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000157.tif38160.

[0181] The invention features an isolated antibody including a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000158.tif21160, and the heavy chain comprises a sequence having at least 90% identity to the sequence of Contains a sequence having at least 90% identity with the sequence of TIFF2025143252000159.tif38160.

[0182] Additionally, in any of the anti-FcRn antibodies described herein, the heavy chain of the antibody is at least 95% of any one of SEQ ID NOs: 20 to 24 %, 97%, 99%, or 100% identity to the sequences described herein. In any of the anti-FcRn antibodies, the light chain has the sequence of SEQ ID NO: 19. Contains a sequence having at least 95%, 97%, 99%, or 100% identity to .

[0183] The antibodies of the present invention may contain amino acids outside the CDRs (i.e., in the framework regions (FRs)). , may further contain amino acid substitutions, additions, and / or deletions. The antibodies of the invention may further comprise any one or more of the following amino acid substitutions: A23V, S30R, L for any one of SEQ ID NOs: 20 to 24 80V, A84T, E85D, A93V, and the sequence of SEQ ID NO: 19 Q38H, V58I, and G99D.

[0184] The antibody contains amino acids outside the CDRs (i.e., in the framework regions (FR)). It may further contain amino acid substitutions, additions, and / or deletions. Or deletions of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more) The amino acid substitutions, additions, and / or deletions may be or deletions are 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 The following single amino acid substitutions, additions, and / or deletions may be made: In embodiments, the antibody may further comprise any one or more of the following amino acid substitutions: A23V, S30R, or the like for any one of SEQ ID NOs: 20 to 24 L80V, A84T, E85D, A93V, and the sequence of SEQ ID NO: 19 Q38H, V58I, and G99D.

[0185] In some embodiments, the antibodies of the invention have, for example, reduced effector function, e.g. , complement-dependent cytolysis (CDC), antibody-dependent cell-mediated cytolysis (ADCC), and / or or decreased antibody-dependent cell-mediated phagocytosis (ADCP) and / or decreased B-cell killing Amino acid substitutions, additions, and modifications in the constant region (e.g., Fc region) of antibodies that result in reduced The constant regions may contain deletions and / or deletions. Although the constant regions are not directly involved in binding the antibody to its target, , and exhibit various effector functions, such as antibody participation in antibody-dependent cellular cytotoxicity. In some embodiments, the antibodies of the invention bind to human complement factors on natural killer (NK) cells. Reduced binding to C1q and / or human Fc receptors (i.e., absence of binding) In another embodiment, the antibody of the present invention is characterized by binding to human FcγRI, F Binding to FcγRIIA, and / or FcγRIIIA (i.e., absence of binding) These are characterized by a decrease in CDC, ADCC, ADCP, and / or B cell killing. In order to alter or reduce antibody-dependent effector functions, the antibodies of the present invention may be used in combination with Ig G class, with one or more amino acid substitutions E233, L234, G23 6, D265, D270, N297, E318, K320, K322, A327, A33 0, P331, and / or P329 (numbered according to the EU Index in Kabat) (Sequences of Proteins of Immunological Interest, 5th Ed.Public Health Service, Na tional Institutes of Health, Bethesda, MD. (1991)). In some embodiments, the antibody may contain the mutation L234A / The anti-FcRn antibody of the present invention contains L235A or D265A / N297A. Q For any one of the sequences of ID NO: 20 to 24, the amino acid hdfn substitution N2 97A, so that the antibodies of the invention are preferably converted to a non-glycosylated form. The resulting effector-less antibody is preferably capable of binding to complement or Fc receptors. (i.e., complement C1q binding) is very low, indicating a low likelihood of CDC.

[0186] In other embodiments, the antibodies of the invention have specific amino acid changes that improve the stability of the antibody. The antibody may include an antibody that

[0187] Additionally, in other embodiments, amino acids D355 and D365 may be used to minimize potential immunogenicity. and L357 (for any one of SEQ ID NOs: 20 to 24) By substituting glutamic acid and methionine, respectively, some antibodies of the invention, e.g. For example, N024, N026, and N027 are allotropes from G1m17.1 to G1m17. May undergo type change.

[0188] In other embodiments, antibodies of the invention, such as N022-N024, N026, and N0 27 has a sequence corresponding to residue 446 of any one of SEQ ID NOs: 20 to 24. Does not contain a C-terminal lysine.

[0189] The invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000160.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000161.tif38160.

[0190] The invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000162.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000163.tif38160.

[0191] The invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000164.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000165.tif38160.

[0192] The invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000166.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000167.tif38160.

[0193] The invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain comprises: TIFF2025143252000168.tif21160, and the heavy chain comprises Contains the sequence TIFF2025143252000169.tif38160.

[0194] In any of the anti-FcRn antibodies described herein, in some embodiments: The antibody may be present at less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 pM. K below pM D It binds to mouse or rat FcRn at 1000kJ / s.

[0195] In any of the anti-FcRn antibodies described herein, in some embodiments: Antibodies are available in 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, and binds to human FcRn with an affinity of 10-40 pM.

[0196] The anti-FcRn antibodies of the present invention are immunoglobulin antibody isotypes IgG, IgE, and IgM. The anti-FcRn antibody may be an immunoglobulin antibody isoform. Preferably, the anti-FcRn antibody is of the type IgG. The anti-FcRn antibody may also be any immunoglobulin antibody. The antibody may be an isotype subclass. For example, an anti-FcRn antibody may be an IgG subclass. Anti-FcRn antibodies may be of the IgG1, IgG2, IgG3, or IgG4 subtype. The antibody is preferably of the subclass IgG1. In particular, the anti-FcRn antibody of the present invention is Some embodiments contain a heavy chain allotype of gG G1m17 or G1m17.1. In some embodiments, the light chain of the anti-FcRn antibody is a κ light chain, a λ light chain, or a κ-λ chimeric light chain. In a preferred embodiment, the anti-FcRn antibody of the present invention contains a full-length λ light chain. do.

[0197] In some embodiments, the antibodies of the invention are monoclonal. The antibody may be polyclonal, chimeric, humanized, or fully human. In other embodiments, the antibodies of the invention may be affinity matured. It may also be a body fragment.

[0198] Without being bound by theory, the anti-FcRn antibodies of the present invention bind to human FcRn via Ig It is believed that the antibody of the present invention competes with and inhibits the binding of G. Group mapping identifies antibodies located at and / or adjacent to the Fc-FcRn interaction interface. This indicates that the antibodies of the present invention bind to epitopes on FcRn that are in close proximity to the target site. These results suggest that the inhibition of FcRn blocks IgG binding to FcRn. The loop-mapped binding site is distant from the albumin-binding site of FcRn. Therefore, serum albumin binding should not be inhibited and serum albumin levels should be reduced. Indeed, experimental evidence suggests that mouse albumin levels may be related to anti-FcRn antibody administration. albumin recycling is a key factor in determining whether antibody binding to FcRn is important. This indicates that the compound is not inhibited by the combination.

[0199] II. FcRn Inhibition FcRn functions as an IgG- and serum albumin-binding, intracellular vesicle transport protein. FcRn is a type I transmembrane protein that binds to endothelial cells, luminal epithelial cells, and hepatocytes. It is expressed in podocytes, granulocytes, monocytes, macrophages, dendritic cells, and NK cells. FcRn is not expressed on B or T cells. It constitutively binds endogenous IgG. and transports it back to the cell surface, maintaining the half-life of IgG. Binding of both c and serum albumin occurs in early endosomes at pH 6.0, followed by The FcRn in the vesicles is sorted by the FcRn-binding IgG or albumin. FcRn transports IgG or albumin back to the cell surface where it rapidly releases IgG at pH 7.4. This transport cycle is completed by recycling IgG and albumin into the circulation. and by preventing trafficking to the lysosome for degradation. FcRn also captures endogenous IgG Fc in epithelial cells, maintaining the half-life of IgG. and transport them bidirectionally to the opposing apical or basal membranes. G is transported into the lumen of organs such as the gastrointestinal tract, or the IgG or IgG-antigen complexes are transported between the This allows transport from the lumen of the stromal layer to the vascular system or lymphatic tissue.

[0200] To investigate the contribution of FcRn to IgG homeostasis, we analyzed the light and heavy chain regions of FcRn. Mice were engineered so that these proteins were not expressed by "knocked out" of the target protein. (Junghans et al., Proc Natl Acad Sci USA 93:5512, 1996). In these mice, the serum half-life and IgG The concentration was dramatically reduced, suggesting an FcRn-dependent mechanism of IgG homeostasis. Studies in rodent models, such as those described above, have demonstrated that blockade of FcRn inhibits the production of antibodies, including those of pathogenic autoantibodies. This can increase the catabolism of IgG, which can lead to disease (e.g., autoimmune diseases). FcRn also mediates antigen degradation and the MHC loading compartment ( Antibodies are released through the transport of immune complexes to MHC loading compartments. May contribute to the original presentation.

[0201] The present invention provides isolated anti-FcRn antibodies that bind to human FcRn with high affinity. The anti-FcRn antibody may be used in combination with other anti-FcRn antibodies against FcRn (e.g., IgG, IgG1, It competes with and effectively inhibits the binding of other anti-Fc antibodies, thereby enhancing their catabolism. The anti-FcR of the present invention reduces the half-life of Rn antibodies (e.g., IgG, IgG autoantibodies). nAntibodies are compounds that inhibit immune responses in a subject, such as those caused by autoantibodies in autoimmune diseases. The compounds may be used in methods of treating or reducing immune complex-based activation of the immune system.

[0202] Transplacental transfer of maternal IgG antibodies to the fetus occurs while the humoral response in the newborn is inefficient. This is an important FcRn-dependent mechanism that provides protection to the neonate. FcRn in the syncytiotrophoblast of the fetus is involved in the transfer of maternal IgG antibodies to the fetus. Pathogenic maternal antibodies (e.g., pathogenic maternal IgG antibodies) also bind to FcRn. and cross the placenta via HIV-1 and HIV-2, resulting in alloimmune and / or autoimmune disorders in the fetus and newborn. In some embodiments, the pathogenic antibodies in a pregnant subject may cause an infectious disorder. , in a fetus within a pregnant subject, fetal and neonatal alloimmune disorders and / or autoimmune disorders The anti-FcRn antibodies described herein (e.g., N022 to N0 24, N026, and N027, preferably N027 and / or N024) are F Competing with and inhibiting the binding of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) to cRn This can impair the immune system, thereby increasing the catabolism and decreasing the half-life of these pathogenic antibodies. Cut.

[0203] The present disclosure provides isolated anti-FcRn antibodies that bind to human FcRn. , compete with the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn. It binds to and inhibits FcRn, thereby enhancing catabolism and inhibiting other anti-FcRn antibodies (e.g., IgG, Anti-FcRn antibodies decrease the half-life of IgG autoantibodies. and the treatment of immune complex-based activation of an immune response in a subject, such as an immune response caused by The reduction of the immune response can be used in a manner that is beneficial to subjects not receiving treatment (e.g., Anti-FcR may be described as reducing the immune response compared to, for example, a control subject. Antibodies also play a role in pathogenic antibody transfer across the placenta in pregnant subjects (e.g., pathogenic maternal Ig Methods for reducing G antibody transfer and enhancing catabolism of pathogenic antibodies in pregnant subjects - Patents.com and administering to a pregnant subject an isolated antibody that binds to human FcRn. and used in a method for treating antibody-mediated enhancement of viral disease in a fetus or newborn. Reducing pathogenic antibody transfer across the placenta in pregnant subjects may be beneficial in preventing or alleviating the effects of treatment. and reducing pathogenic antibody transfer compared to untreated subjects (e.g., control subjects). can be described as follows.

[0204] IV. Vectors, Host Cells, and Antibody Production The anti-FcRn antibodies of the present invention can be produced from host cells. necessary for expressing the polypeptides and constructs described herein from the corresponding nucleic acid Nucleic acids refer to vehicles that contain essential cellular components, such as organelles. Conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate dehydrogenase) can be used. in nucleic acid vectors that can be introduced into host cells by various methods (e.g., precipitation, direct microinjection, infection, etc.) The choice of nucleic acid vector will depend in part on the host cell to be used. Preferred host cells are prokaryotic (e.g., bacterial) or eukaryotic (e.g., mammalian) It is either of the following origins.

[0205] Nucleic acid vector construction and host cells Nucleic acid sequences encoding the amino acid sequences of the anti-FcRn antibodies of the present invention can be prepared using nucleic acid sequences known in the art. These methods include oligonucleotide-mediated These include, but are not limited to, site-directed mutagenesis and PCR mutagenesis. Without limitation, nucleic acid molecules encoding the anti-FcRn antibodies of the present invention can be prepared using standard techniques, e.g. Alternatively, a nucleic acid encoding a wild-type anti-FcRn antibody can be prepared using gene synthesis. The molecules may be modified using standard techniques known in the art, for example, QuikChange™ mutagenesis. Nucleic acid molecules may be mutated to contain specific amino acid substitutions using techniques. It can be synthesized using a nucleotide synthesizer or PCR technology.

[0206] Nucleic acid sequences encoding the anti-FcRn antibodies of the present invention can be expressed in prokaryotic or eukaryotic host cells. The nucleic acid molecule can be inserted into a vector that is capable of replicating and expressing the molecule. Many vectors are suitable for this purpose. Vectors are available in the art and can be used for the purposes of the present invention. It may contain various components that can be tailored and optimized for compatibility with cells. Vector components include, but are not limited to, an origin of replication, a selectable marker gene, a promoter, a ribosome binding site, a signal sequence, a nucleic acid sequence encoding a protein of interest, and It may include a transcription termination sequence.

[0207] In some embodiments, mammalian cells are used as host cells in the present invention. Examples of cell types include, but are not limited to, human embryonic kidney (HEK) (e.g., HEK293 , HEK 293F), Chinese hamster ovary (CHO), HeLa, COS, P C3, Vero, MC3T3, NS0, Sp2 / 0, VERY, BHK, MDCK, W1 38, BT483, Hs578T, HTB2, BT20, T47D, NS0 (any immunity) Mouse myeloma cell lines CRL7030 and H (which do not endogenously produce immunoglobulin chains) In another embodiment, E. coli cells are used as host cells in the present invention. Examples of E. coli species include, but are not limited to, E. coli 294 (ATCC )31,446), E. coli λ 1776 (ATCC®31,537, E. coli BL21(DE3) (ATCC® BAA-1025), and E. coli R V308 (ATCC® 31,608). Different host cells produce proteins It has characteristics and specific mechanisms for post-translational processing and modification of the product. The host system or system is chosen to ensure the correct modification and processing of the expressed anti-FcRn antibody. The above-mentioned expression vectors can be selected by, for example, transformation, transfection, electroporation, phosphate catalysis, etc. Calcium precipitation and direct microinjection using conventional techniques in the art. When a vector is introduced into a host cell for protein production, the host The cells are then transfected with the desired sequence for induction of the promoter or for selection of transformants. The cells are cultured in conventional nutrient media modified to be suitable for amplifying the gene encoding the sequence. Methods for the expression of therapeutic proteins are known in the art and include, for example, Paulina Balbas, Argelia Lawrence (eds.) Reco mbinant Gene Expression: Reviews and Pro tocols(Methods in Molecular Biology), Hum ana Press; 2nd ed. 2004 (July 20, 2004) and Vla dimir Voynov and Justin A. Caravella (eds. )Therapeutic Proteins: Methods and Proto cols(Methods in Molecular Biology)Humana Press; 2nd ed. 2012 (June 28, 2012) sea ​​bream.

[0208] Protein production, recovery, and purification Host cells used to produce the anti-FcRn antibodies of the present invention are known in the art. and may be grown in a medium suitable for the culture of the selected host cells. Examples of suitable media include Minimum Essential Medium (MEM), Dulbecco's Modified Eagle's Medium (DME), MEM), Expi293™ Expression Medium, DM supplemented with fetal bovine serum (FBS) Examples of media suitable for bacterial host cells include, for example, RPMI-1640, EM, and RPMI-1640. For example, Luria Broth (LB) plus necessary supplements such as ampicillin. The cells are heated at a temperature of, for example, about 20°C to about 39°C, for example, 25°C to about 37°C, preferably 37°C. Incubate at an appropriate temperature and CO2 level, for example, 5-10% (preferably 8%). The pH of the medium is generally about 6.8 to 7.4, e.g., 7.0, depending mainly on the host organism. When an inducible promoter is used in the expression vector of the present invention, the activity of the promoter is Protein expression is induced under conditions suitable for activation.

[0209] Protein recovery is typically achieved by methods such as osmotic shock, sonication, or lysis. This involves disrupting the host cells by means of centrifugation. Once the cells are disrupted, the cell debris is removed by centrifugation. Alternatively, the protein may be removed by filtration. The protein may be further purified. cRn antibodies can be purified by any method known in the art for protein purification, e.g., protein A affinity chromatography. other chromatography (e.g., ion exchange, affinity, and size exclusion columns) chromatography, centrifugation, absorption differential solubility, or any other method for protein purification. It may be purified by any other standard technique (Process Scale Purification ation of Antibodies, Uwe Gottschalk(ed.)J (See also Wiley & Sons, Inc., 2009). In an illustrative example, an anti-FcRn antibody is conjugated to a marker sequence, such as a peptide, and purified. An example of a marker amino acid sequence is a hexa-histidine peptide (H is tag), which is attached to nickel-functionalized agarose affinity column with micromolar affinity. Other peptide tags useful for purification include, but are not limited to, hemagglutinin (HbA), ... It contains the "HA" tag, which is derived from the influenza hemagglutinin protein The epitope corresponds to the epitope.

[0210] Alternatively, the anti-FcRn antibody of the present invention can be synthesized by using a nucleic acid molecule encoding the anti-FcRn antibody of the present invention. vectors containing the vector (e.g., retroviral vectors, adenoviral vectors, pop a vaccinia virus vector (e.g., a vaccinia virus vector such as modified vaccinia Ankara (MVA)) virus vectors), adeno-associated virus vectors, and alphavirus vectors By administering, for example, in a therapeutic setting, Once inside the subject's cells (e.g., transformation, by transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), and then The present invention promotes the expression of anti-FcRn antibodies secreted from cells in the presence of inflammatory cytokines. If the result is negative, no further action is required. If protein collection is desired, The protein is collected from the subject and purified from the blood by methods known in the art. Quality.

[0211] V. Pharmaceutical Compositions and Preparations The invention features pharmaceutical compositions comprising one or more anti-FcRn antibodies described herein. In some embodiments, the pharmaceutical compositions of the present invention contain as a therapeutic protein the containing one or more of the antibodies, e.g., N022 to N024, N026, and N027. In other embodiments, pharmaceutical compositions of the invention comprising one or more antibodies of the invention, e.g., N022-N024, N026, and N027 are not intended to be used with other drugs (e.g., therapeutic biologics and and / or small molecules) or compositions in therapy. In addition to a quantity of antibody, pharmaceutical compositions may contain one or more It may contain the above pharmaceutically acceptable carriers or excipients.

[0212] Acceptable carriers and excipients in pharmaceutical compositions are compatible with the recipe at the dosages and concentrations used. Acceptable carriers and excipients include buffers, antioxidants, preservatives, The pharmaceutical compositions of the present invention may include injectable It can be administered parenterally in the form of a suitable formulation for injection (i.e., intravenous injection). The pharmaceutical composition for this purpose may use a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include sterile water, saline, and the like. , and cell culture medium (e.g., Dulbecco's Modified Eagle Medium (DMEM), α-modified IGF-1). These include, but are not limited to, Eagle's medium (α-MEM), F-12 medium. Methods are known in the art. See, e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation,Proc. essing and Delivery Systems (2nd ed.) Tayl See Or & Francis Group, CRC Press (2006) .

[0213] The pharmaceutical composition may be formulated into a unit dose as needed. , for example, one or more anti-FcRn antibodies of the present invention (e.g., N022 to N024, N026 and N027, preferably N027 and / or N024) in the amounts within the specified ranges. An appropriate dose is provided (e.g., a dose in the range of 0.01 to 500 mg / kg of body weight). .

[0214] VI. Route, Dosage, and Administration One or more anti-FcRn antibodies (e.g., N022 to N024, N026, and N027, preferably N027 and / or N024) of the present invention. The pharmaceutical composition may be administered intravenously, parenterally, subcutaneously, intramuscularly, intraarterially, or spinally. The drug may be formulated for intravenous or intraperitoneal administration, with intravenous administration being particularly preferred. The compositions may be formulated for oral, nasal, spray, aerosol, rectal, or vaginal administration. Injectable formulations may be administered in or via various effective Suitable pharmaceutical carriers are known in the art.

[0215] The dosage of the pharmaceutical composition of the present invention will depend on the route of administration, the disease to be treated, and, for example, the age of the subject. It depends on factors including physical characteristics such as age, weight, and relative health. The anti-FcRn antibodies of the present invention (e.g., N022 to N024, N026, and N027) 027, preferably N027 or N024) without inducing significant toxicity. The pharmaceutical composition of the present invention may be in an amount of 0.01 to 100 mg / kg or more, which effectively prevents, delays or treats the disease. ~500mg / kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg / kg) In a more specific embodiment, the dose of the anti-FcRn antibody of the present invention is in the range of about 1 to about 10 0 mg / kg, and in a more specific embodiment, about 1 to about 50 mg / kg of the anti-FcR of the present invention. The dosage may include the dosage of the antibody. The dosage may vary depending on the extent of the disease and various parameters of the subject, such as The dosage can be adjusted by the physician according to conventional factors. In addition, the dosage may vary depending on factors such as gestational age, time of birth, and other factors. The procedure is tailored by a physician according to factors such as the patient's preparation, the woman's weight gain, and / or the length of the pregnancy. It is possible.

[0216] In some cases, the compositions and pharmaceutical compositions described herein are administered throughout pregnancy. In some cases, the compositions and medicaments described herein are administered to pregnant women. The composition may be administered during approximately weeks 5 to 25 of gestation (e.g., weeks 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, In some instances, the compositions and pharmaceutical compositions are administered to pregnant women at 25 weeks of age or earlier. is after approximately gestational age 34 (34 weeks) (e.g., 34, 35, 36 weeks, or In some instances, IVIG is administered in a composition and pharmaceutical composition. In some instances, the composition and the pharmaceutical composition are administered to the pregnant woman after the administration of the composition has ended. After the end of administration, IVIG should be administered for approximately 3 to 15 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, In some cases, the composition and The time of IVIG administration after the end of the pharmaceutical composition administration was adjusted according to factors such as the woman's weight gain. In some instances, the compositions and pharmaceutical compositions described herein are administered to infants aged 1 year or older. 2 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 2 3, 24, 25, 26, 27, 28, 29, or 30). In some cases, they are born at a gestational age of 14-26 (e.g., 14-25, 15-25, or In some cases, it is administered during pregnancy between gestational ages 12 and 36 (e.g., 15-26). For example, 12~36, 12~35, 12~34, 13~36, 13~35, 13~34, 14~36, 14~35, 14~34, 15~36, 15~35, 15~34, 16~3 6, 16-35, or 16 and 34) during pregnancy.

[0217] Pharmaceutical compositions are administered in a manner compatible with the dosage formulation, and in such amount as is therapeutically effective to alleviate symptoms or The pharmaceutical compositions may be administered in a variety of dosage forms, for example, intravenous dosage forms, subcutaneous dosage forms, or the like. pharmaceutical forms, and administered in oral dosage forms (e.g., ingestible solutions, drug-release capsules) Typically, therapeutic proteins are administered at 1-100 mg / kg, e.g., 1-50 mg / kg. Anti-FcRn antibodies (e.g., N022 to N024, N026, and N027, The pharmaceutical composition of the present invention containing N027 or N024 is administered daily, for example, weekly, monthly, semi-annually, yearly, more than once (e.g., 1-10 times or more), or as medically necessary The dosage may be administered to a subject in need thereof in a single or multiple doses. Once the medical condition improves, the timing between doses may be adjusted. The amount of blood flow decreases and can increase as the patient's health declines.

[0218] VII. Treatment Methods and Indications Blockade of human FcRn by the anti-FcRn antibodies of the present invention is driven by IgG autoantibodies. Serum albumin, a small circulating metabolite, or global IgG catabolism and multiple autoantibodies without disrupting lipoproteins. The ability of FcRn blocking to induce clearance of autoantibody-driven autoimmune disease pathology The present invention provides a method for broadening the public interest and availability of autoantibody removal strategies to patients with rheumatoid arthritis. Without being bound by theory, the primary mechanism of action of the anti-FcRn antibodies of the present invention is the inhibition of circulating pathogens. Increased catabolism of autoantibodies and autoantibody and immune complex deposition in affected tissues The goal may be to reduce the

[0219] one or more anti-FcRn antibodies (e.g., N022 to N024, N026, and N027) Pharmaceutical compositions and methods of the present invention containing N027 and / or N024 The method involves catabolizing and clearing pathogenic antibodies (e.g., IgG and IgG autoantibodies) in a subject. to reduce an immune response, e.g., to promote immune complex removal in a subject. to block activation of the immune response and to treat an immunological condition or immune disease in a subject In particular, the pharmaceutical compositions and methods of the present invention are useful for immunoconjugate-based rapid immunotherapy. These compounds are useful for reducing or treating activation of acute or chronic immune responses. , pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection reaction, fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathy, Neuromyelitis optica, autoimmune deafness, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic Anemia (AIHA), immune neutropenia, dilated cardiomyopathy cytomegalomyopathy, and serum sickness. Chronic immune responses can lead to chronic inflammatory demyelinating polyneuropathy (CIDP), a systemic loop s, chronic forms of the disorder requiring acute treatment, reactive arthropathy, primary biliary cirrhosis, ulcers and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. It can be activated by a medical condition.

[0220] In some embodiments, the pharmaceutical compositions and methods of the present invention are directed to a compound active in an autoimmune disease. The present invention is useful for reducing or treating an inactivated immune response. disease, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune system Dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial Pemphigus, limited systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis inflammation, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, grepa Hayes' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome group, 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, nodular polyarteritis Phlebitis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Globulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatism Fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's syndrome The compound may be selected from the group consisting of: granulomatous diseases.

[0221] In particular, the pharmaceutical compositions and methods of the present invention are useful for treating systemic lupus erythematosus, antiphospholipid syndrome, , pemphigus vulgaris / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis To reduce or treat the immune response activated by asthenia gravis or neuromyelitis optica It is useful.

[0222] In some embodiments, the pharmaceutical compositions and methods reduce the risk of anemia in the fetus. It is useful for preventing or reducing the risk of developing the disease. In some embodiments, the pharmaceutical compositions and methods are intended to reduce or avoid the need for IUT (intrauterine transfusion). In some embodiments, the pharmaceutical compositions and methods are useful for prenatal PP+IVI. Reduce or avoid the need for postnatal transfusions, IVIg, and / or phototherapy It is useful for

[0223] In some embodiments, the pharmaceutical compositions and methods are directed to a method for treating a disease activated by an autoimmune disease. The present invention is useful for reducing or treating an immune response caused by an autoimmune disease, such as alopecia areata, ankylosing steroid hormone (ASH), or steroid hormone (SHR). spondylitis, antiphospholipid syndrome (e.g., antiphospholipid antibody syndrome), Addison's disease, hemolytic anemia Hematologic (e.g., warm autoimmune hemolytic anemia), autoimmune hepatitis, hepatitis, Behçet's disease, bullous vesicles Pemphigoid, Cardiomyopathy, Celiac Sprue Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome, Chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, localized generalized Scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, Essential mixed cryoglobulinemia, epidermolysis bullosa, fibromyalgia, fibromyositis, Graves' 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 , membranous nephropathy, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, nodular multifocal Arteritis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary non-cancer Magloglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff neck Syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's syndrome In some embodiments, the pharmaceutical compositions and methods may be selected from the group consisting of granulomatous diseases. The method is useful for reducing or treating an immune response in a fetus or newborn. In embodiments, the pharmaceutical compositions and methods are directed to treatments for autoimmune diseases activated by maternal autoimmune disease in pregnant women. The present invention is useful for reducing or treating immune responses in fetuses or newborns.

[0224] In particular, the pharmaceutical compositions and methods are directed to the treatment of systemic lupus erythematosus, antiphospholipid syndrome, and idiopathic steroids. Pemphigus / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis, or are useful for reducing or treating the immune response activated by neuromyelitis optica. In some embodiments, the pharmaceutical compositions and methods enhance the immune response of a fetus or newborn. In some embodiments, the pharmaceutical compositions and methods are useful for reducing or treating is a pregnant mother with systemic lupus erythematosus, antiphospholipid syndrome, pemphigus vulgaris / varicella bullosa pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis, or optic nerve It is useful for reducing or treating the immune response activated by myelitis.

[0225] The pharmaceutical compositions and methods are directed to preventing pathogenic antibody transfer across the placenta in pregnant subjects (e.g., Methods for reducing maternal IgG antibody transfer, catabolism of pathogenic antibodies in pregnant subjects and a method for enhancing the immune response of pregnant subjects by administering an isolated antibody that binds to human FcRn to a pregnant subject. and treating antibody-mediated enhancement of viral disease in the fetus or newborn. The isolated anti-FcRn antibodies described herein (e.g., N022 to N0 24, N026, and N027, preferably N027 and / or N024) Diseases and disorders that may benefit from FcRn inhibition include fetal and / or neonatal The infant is exposed to maternal pathogenic antibodies (e.g., maternal pathogenic IgG) that cross the placenta from the pregnant subject. Diseases and disorders in the fetus and / or newborn caused by the transfer of antibodies include.

[0226] In some embodiments, an isolated anti-FcRn antibody described herein (e.g., N02 2 to N024, N026, and N027, preferably N027 and / or N024 Diseases and disorders that may benefit from FcRn inhibition by Fetal and neonatal alloimmune disorders are alloimmune and / or autoimmune disorders. fetal and / or neonatal disorders caused by pathogenic antibodies in pregnant subjects Pathogenic antibodies in pregnant subjects may be due to antigens present in the fetus (e.g., antigens inherited by the fetus from its father). antigens) and the fetus or newborn may develop alloimmune disorders and / or can cause autoimmune disorders.

[0227] Fetal and neonatal alloimmune disorders that can be treated by the methods described herein and Examples of autoimmune disorders include, but are not limited to, fetal and neonatal alloimmune platelet Hemolytic disease of the fetus and newborn (FNAIT), hemolytic disease of the fetus and newborn (HDFN), alloimmune panemia Thrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune disease Immune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, Neonatal autoimmune thyroid disease and neonatal type 1 diabetes.

[0228] In some embodiments, an isolated anti-FcRn antibody described herein (e.g., N02 2 to N024, N026, and N027, preferably N027 and / or N024 Diseases and disorders that may benefit from FcRn inhibition by where antibodies facilitate viral entry into host cells, e.g., antibodies for viral diseases. In some embodiments, the infectivity of the virus increases or increases within the cell, such as by mediated enhancement. The antibody binds to the viral surface protein, and the antibody / virus complex binds to the receptor. The antibody / virus complex can then bind to FcRn on the cell surface through interactions between the two. The body may internalize the virus into cells. For example, the virus forms complexes with maternal IgG antibodies. By doing so, they may gain entry into fetal cells and / or tissues. IgG antibodies bind to viral surface proteins, and IgG / virus complexes are transported to the syncytial trophoblasts of the placenta. It can bind to FcRn on foetal cells, which then transfers the complex into the fetus.

[0229] In some embodiments, the methods described herein include antibody-mediated inhibition of viral disease. In some embodiments, pathogenic antibodies (e.g., Viral diseases enhanced by IgG antibodies include, but are not limited to, alpha virus infections disease, flavivirus infection, Zika virus infection, chikungunya virus infection, Rossli virus infection Barr virus infection, severe acute respiratory syndrome coronavirus infection, Middle East respiratory syndrome, Avian influenza infection, influenza virus infection, human respiratory syncytial virus infection infectious diseases, Ebola virus infection, yellow fever virus infection, dengue virus infection, human immune system Respiratory syncytial virus infection, Hantavirus infection, Getawi Rus infection, Sindbis virus infection, Bunyamwera virus infection, West Nile virus infection Rabbitpox virus infection, Japanese encephalitis virus B infection, rabbitpox virus infection, elevated lactate dehydrogenase virus infection, reovirus infection, rabies virus infection, foot-and-mouth disease virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection rus infection, caprine arthritis virus infection, African swine fever virus infection, lentivirus infection, BK papovavirus infection, Murray Valley encephalitis virus infection, enterovirus infections, cytomegalovirus infections, pneumovirus infections, morbillivirus infections This includes viral diseases caused by infectious diseases and measles virus infections.

[0230] Blockade of human FcRn by anti-FcRn antibodies prevents the production of pathogenic antibodies (e.g., pathogenic IgG antibodies). ) may be of therapeutic benefit in diseases driven by Catabolism of various pathogenic antibodies and multiple autoantibodies, small circulating metabolites, or lipoproteins The ability of FcRn blockade to induce protein clearance may contribute to the pathogenesis of pathogenic antibody-driven autoimmune diseases. To provide a method for expanding the public interest and availability of pathogenic antibody removal strategies for patients with Without being bound by theory, the primary mechanism of action of anti-FcRn antibodies is the inhibition of circulating pathogenic antibodies. Increased catabolism of β-lactamases and reduced pathogenic antibody and immune complex deposition in affected tissues It may be possible to make it so.

[0231] The anti-FcRn antibodies described herein (e.g., N022 to N024, N026, and and N027, preferably N027 and / or N024) to stimulate the immune response of pregnant subjects administered to pregnant subjects with or at risk of having a medical condition that activates In some embodiments, the pregnant subject may be In some embodiments, the patient may have had a medical condition that activates the Pregnant subjects are those with fetal and neonatal alloimmune and / or autoimmune disorders. In some embodiments, the patient has a history of having previously had a fetus or newborn. In the present study, pathogenic antibodies associated with immune disorders were detected in biological samples obtained from pregnant subjects (e.g., an anti-FcRn antibody described herein when detected in a blood sample or a urine sample In some embodiments, a biological sample from a pregnant subject may be administered Pathogenic antibodies detected in pregnant subjects are likely to be due to exposure to fetal antigens (e.g., the fetus is exposed to the fetus's It is known to bind to antigens inherited from the father.

[0232] In some embodiments, the anti-FcRn antibodies described herein (e.g., N022- N024, N026, and N027, preferably N027 and / or N024) , in subjects planning pregnancy, and in pregnant subjects, and medical conditions that activate the immune response in subjects with or at risk of having, and / or in previously pregnant subjects It may also be administered to a subject who has had a medical condition that activates an immune response. In some embodiments, the subject is planning a pregnancy and is receiving fetal and neonatal alloimmunization. Previously had a fetus or newborn with an infectious and / or autoimmune disorder In some embodiments, the anti-FcRn antibodies described herein are used in pregnancy. Subjects planning pregnancy and whose biological samples contain pathogenic antibodies associated with immune disorders may be administered to

[0233] In some embodiments, the anti-FcRn antibodies described herein are used to treat acute myocardial infarction in a subject. or to reduce or treat immune complex-based activation of a chronic immune response in a subject (e.g., The acute immune response may be induced in a medical condition (e.g., common flu virus). Smallpox, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, fulminant Type 2 antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathy, optic nerve and spinal cord disease inflammation, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia Dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy, systemic lupus erythematosus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis ulcerative colitis, or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis) do.

[0234] In some embodiments, the anti-FcRn antibodies described herein are used to treat autoimmune diseases. to reduce or treat an immune response activated by the The autoimmune disease may be, for example, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, or the like. group, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia (wAIHA), anti-factor antibodies, Heparin-induced thrombocytopenia (HICT), sensitized transplant, autoimmune hepatitis, hepatitis, Behcet's disease gallbladder disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue and immune dysfunction syndrome syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, Localized systemic sclerosis (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid Lupus, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' 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, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, multiple sclerosis chondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia Hemoglobinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff man syndrome, hypertension in ulcerative colitis, temporal arteritis, uveitis, vitiligo, or Wegener's granulomatosis It's possible. [Example]

[0235] Example 1 - Antibody production IgG heavy and light chain nucleic acid molecules were transfected into vectors using the osteonectin secretion signal. HEK 293F cells were cultured at 37°C, 8% CO, and 10% CO for 1 hour. Cells were grown in Expi293 medium at 0°C for 1 hour and 1 mg of total DNA per liter. Using 3x10 6 The cells were transfected at a density of 2000 / ml according to the manufacturer's instructions. Add enhancer on days 1 and 3, and wait until cell viability drops below 50%-60%. The cells were cultured for 5 or 6 days. Then, the cells were spun out by centrifugation. The spent medium was sterile filtered and stored at 4°C until antibody purification. The antibody was purified using a two-column procedure. Prepared by POROS Protein A chromatography followed by POROS HS chromatography. -50 cation exchange chromatography. The former is used to separate most of the host cell proteins from the expressed antibody. The latter separated heavy chain dimers, light chain dimers, and half antibodies, and Fractions from the HS-50 cation exchange column were purified by SDS-P Pooling was performed based on AGE gel analysis to maximize the purity of the full-length antibody. 7.2 onto a Sephadex G50 buffer exchange column equilibrated in PBS The peak fractions were pooled and diluted to 10 mg / ml using a 30 kDa spin concentrator. The final protein sample was concentrated to ultrapure water and frozen at -30°C in 2 mg and 5 mg aliquots. The material was checked for purity by SDS-PAGE.

[0236] Example 2 - Binding Affinity Through affinity maturation, we have achieved K values ​​in the submicromolar range. D to human FcRn Over 100 anti-FcRn antibodies with binding affinities of 100 or more were identified. Five antibodies (N022 ~N024, N026, and N027) were selected for further characterization. Using Sensitivity Resonance (SPR), the on- and off-rates were measured for each of these five antibodies. Rate (respectively k a , and k d ) was determined. Briefly, Bio-Rad The GLC sensor chip was inserted into the ProteOn XPR 36 and the air was initialized. After incubation, the running buffer was replaced with freshly prepared buffer, HBSP+ (0.01%), as appropriate. M HEPES, 0.15 M NaCl, 0.05% P20, pH 7.4) or Sodium phosphate buffer (0.02 M sodium phosphate, 0.15 M NaCl, 0.05% P20, pH 6.0), and this was used for the remainder of the assay. The chips were buffered with 0.5% SDS, 50 mM NaCl, and 100 mM MgCl. NaOH and 10 mM HCl were each added at 30 μl / min for 60 seconds (s). The mice were pretreated with 100% mouse guinea pigs (from GE Healthcare, BR100839). Anti-human Fc mAb diluted to 10 μg / ml in 10 mM acetate buffer, pH 5.0 Approximately 5,700 response units (RU) were obtained using standard amine coupling chemistry. The anti-hFcRn mAb to be tested was immobilized horizontally on a C sensor chip. Vertically on the surface, with targets fixed at approximately 200 response units (RU) per spot. rhFcRn was diluted in a five-point, three-fold dilution series starting at 1.25 μg / ml. One lane was left as buffer only for double referencing. Analytes were dissociated for 3600 seconds. The solution was flowed horizontally across the sensor surface at 100 μl / min for 240 seconds. MmgCl2 was injected at 100 μl / min for 30 seconds in both the horizontal and vertical directions. Regeneration was achieved by: These procedures were repeated for all ligands.

[0237] Data analysis was performed using ProteOn Manager software. The steps are adjusted in the Y and X directions using an automated process tool, and then spot Inter-channel referencing eliminates nonspecific interactions, and blank lane double referencing ensures accurate analysis of the assayed data. Lift was removed. Data were grouped using the Langmuir 1:1 kinetic model. The k obtained from the ProteOn Manager in one run was matched with the Rmax. a , k d and K. D The values ​​are averaged and, if N is 3 or greater, the percent CV is The calculations were performed using Microsoft Excel.

[0238] Table 3 shows five anti-FcRn antibodies of the present invention: N022, N022, N024, N026, and N027, all of which bind to human FcRn with high affinity at pH 7.4. The equilibrium dissociation constant, K D Human F at pH 7.4 Binding to cRn ranges from 19.4 pM (N027) to 36.5 pM (N026) Table 3 also shows the rapid on-rates and slow off-rates of the five anti-FcRn antibodies. At pH 7.4, the on-rate for binding to human FcRn was 0.93-1. 42 x 10 6 The off-rate was in the range of 2.31 to 4.44X10 6 It was within the range of 1 / s.

[0239] (Table 3) TIFF2025143252000170.tif72128

[0240] Example 3 - IgG competition The Ig of the anti-FcRn antibody of the present invention for binding to human or cynomolgus monkey FcRn The ability to compete with G was determined by cell surface, glycophosphatidylinositol (GPI)-linked Fc Rn was evaluated on human embryonic kidney (HEK) 293 cells ectopically expressing Rn. The FcRn alpha amino acid sequence of ferret monkeys shows 97.5% sequence identity. Nine of these amino acid residues differ between human and cynomolgus monkey FcRn alpha. The level of cell-bound IgG was 66 nM The IgG binding to cell surface FcRn was determined using a fluorescent probe-labeled nonspecific IgG. The binding was performed at pH 6.0, which allows the Fc portion of IgG to interact with FcRn. As shown in Figure 1, the anti-FcRn antibodies (N022 to N024, N026, and As the concentration of Ig (N027) increased, the amount of cell-bound IgG decreased significantly. Binding of G was concentration- and saturation-dependent by each of the five exemplary anti-FcRn antibodies of the present invention. The anti-FcRn antibodies N022 to N024, N026, and N027 inhibited the activity of the FcRn receptor in a manner similar to that of the FcRn receptor. It effectively competes with IgG binding to FcRn at pH 6.0 and inhibits IgG binding to FcRn. The EC50 values ​​of the antibodies ranged from 2 to 6 nM.

[0241] Example 4 - Effect of anti-FcRn antibodies on IgG catabolism in mice To determine the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, mouse It lacks mouse FcRn but has a tissue distribution similar to that of endogenous mouse and human FcRn. Human FcRn transgenic mouse strain FcRn- / -hFc expressing FcRn Rn(32)Tg mice were used. They were injected with 500 mg / kg of human IgG on day 0. FcRn- / - hFcRn(32) Tg mice were administered 10 mg / mL of erythropoietin on days 1 and 4. As shown in Figure 2, the anti-FcRn antibody-treated mice were administered a single dose of 1000 mg / kg of anti-FcRn antibody. IgG catabolism was observed, as seen in the lower levels of IgG measured over time in was increased by administration of anti-FcRn antibody. D =35.5pM), N02 6(K D = 36.5 pM), and N027 (K D =19.4 pM) activity is 10 mg / kg were considered similar.

[0242] Example 5 - Functional properties of anti-FcRn antibodies in vitro and in vivo In vitro The cell binding affinity of the antibodies of the present invention was determined by measuring the binding affinity of the antibodies to cell surface glycophosphatidylinositol (G Human embryonic kidney (HKE) cells ectopically expressing human or cynomolgus monkey FcRn (PI)-binding FcRn is transported to the luminal side of the endosomal membrane or to the plasma membrane. When activated, it has IgG and albumin binding domains that are directed to the cell surface. It is a type I transmembrane protein that binds to the cell surface, membrane-associated FcRn on HEK293 cells. The binding of the anti-FcRn antibody at pH 7.4 was observed only in the Fab domain of the antibody, but not in the Fc domain. In a physiologically relevant environment and pH, where FcRn interacts with FcRn, rather than The FcRn extracellular domain is densely packed with GPI-linked FcRn molecules through a C-terminal engineered GPI linkage. The anti-FcRn antibody of the present invention was labeled with a fluorescent probe and displayed on the cell surface. The antibodies were allowed to bind on ice for 30 minutes. The cells were then washed at 4°C and the bound antibodies were removed by fluorophores. Detection was performed using a fluorophore-labeled secondary antibody, e.g., goat anti-human IgG F(ab)2. The binding to human FcRn is concentration-dependent, and the antibodies of the present invention exhibit EC50 values ​​in the range of 4 to 7 nM. did.

[0243] The cell binding affinity of the antibodies of the present invention was also measured against endogenously expressed human FcRn. Monocytes express the highest levels of FcRn and are the major regulator of FcRn expression in mouse and human blood. The highest percentage of positives was observed using the monocytic cell line THP-1 at pH 7.4. The binding of anti-FcRn antibodies to FcRn was evaluated. Endogenous FcRn was expressed in THP-1 cells. Since the cells are primarily located in intracellular endosomal vesicles within the endothelial cells, the cells are first permeabilized with mild detergent and then The cells were fixed and non-fixed before being incubated with anti-FcRn antibody in the presence of serum for 30 min at 4 °C. This assay blocks specific Fc receptor binding to endogenous human FcRn. The binding of anti-FcRn antibodies to THP-1 cells was significantly enhanced by the ELISA. Binding is concentration dependent. All antibodies of the present invention, e.g., N022 to N024, N026, and N027 showed better binding affinity than IgG1. Antibody N027 had a binding affinity of 3.0 n The highest binding affinity was observed with an EC50 value of M.

[0244] The Ig of the anti-FcRn antibody of the present invention for binding to human or cynomolgus monkey FcRn The ability of FcRn to compete with G was assessed in human embryonic kidney cells ectopically expressing cell surface, GPI-linked FcRn. The level of cell-bound IgG was assessed using fluorescent probe-labeled nonspecific IgG. The binding of IgG to cell surface FcRn was determined at pH 6.0. This allowed the Fc portion of IgG to interact with FcRn. See Example 3 and Figure 1. As shown in Fig. 1 and Fig. 2, the amount of cell-bound IgG increased with increasing concentration of anti-FcRn antibody. IgG binding was significantly reduced with five exemplary anti-FcRn antibodies of the present invention, e.g., N N022-N024, N026, and N027, respectively, in a concentration- and saturation-dependent manner. and effectively competes with the binding of IgG to FcRn at pH 6.0 by anti-FcRn antibodies. The antibodies showed the ability to inhibit the binding of IgG to FcRn. The EC50 values ​​of the antibodies ranged from 2 to 6. The concentrations were in the nM range.

[0245] Epitope mapping of the antibodies of the present invention by hydrogen-deuterium exchange is carried out to determine whether the antibody binds to Fc-FcR Binds to epitopes on human FcRn that are located at and / or adjacent to the FcRn interaction interface This indicates that the antibodies of the present invention inhibit Ig binding to FcRn by directional inhibition. Furthermore, the epitope-mapped binding site was It is located away from the albumin-binding site of FcRn. SA) to confirm that the antibodies of the present invention do not inhibit serum albumin binding to FcRn. The soluble His-tagged extracellular domain of human FcRn was bound to the plate surface. The mixture was combined and pre-incubated with increasing concentrations of anti-FcRn antibody at pH 6.0. HRP-conjugated human serum albumin was lysed into soluble His-tagged F Neither antibody inhibited albumin binding to FcRn. Furthermore, in vivo experimental evidence also shows that mouse albumin levels correlate with anti-FcRn antibody administration. albumin recycling is a key factor in determining whether antibody binding to FcRn is important. It was shown that the activity of ATP is not inhibited by the combination of ATP and ATP.

[0246] In vivo To test the in vivo effect of the anti-FcRn antibodies of the present invention on IgG catabolism, Although it lacks mouse FcRn, it expresses human FcRn with tissue distribution similar to that of endogenous mouse and human FcRn. Human FcRn transgenic mouse strain FcRn- / -hF cRn(32) Tg mice were used. FcRn − / − mice were injected with human IgG on day 0. hFcRn(32)Tg mice were treated with 10 mg / kg anti-FcRn on days 1 and 4. As shown in Example 3 and Figure 2, the anti-FcRn antibody-treated mice IgG catabolism is seen in the lower levels of IgG measured over time in It was increased by administration of anti-FcRn antibody. D =35.5pM), N026( K D = 36.5 pM), and N027 (K D =19.4pM) activity is 10mg / kJ were considered similar in g.

[0247] Example 6 - Effect of anti-FcRn antibodies on IgG levels and target occupancy in mice 500 mg / kg IVIg (tracer) Tg32 human FcRn (hFCGRT ) after administration to transgenic and mouse FcRn (mFCGRT) knockout mice Circulating human IgG was measured daily by ELI. Incubation of cells with immunophenotyping cell surface markers detected by SA. After fixation and permeabilization, cells were isolated by fluorescence-activated cell sorting (FACS). Target occupancy was measured daily in monocytes from lysed whole blood. Unoccupied FcRn was detected by Dy The results were measured by staining with 650-labeled N027 (n = 4 males / group). As shown, IgG levels and the percentage of unoccupied FcRn increased in a dose-dependent manner. The effects of N027 on the serotonin-dependent ATP production were significantly reduced by administration of N027.

[0248] Example 7 - Selective induction of IgG catabolism and target occupancy in cynomolgus monkeys N027 was administered intravenously to cynomolgus monkeys at time 0. Circulating endogenous IgG and arginine were measured. Immunophenotyping of cells using cell surface markers was performed. After fixation and permeabilization followed by incubation, target occupancy is determined by FACS. Unoccupied FcRn was measured in monocytes from whole blood. 7 (n=3 males / group). As shown in Figure 4, IgG The level and percentage of unoccupied FcRn increased in a dose-dependent manner following administration of N027. was decreased by 100mg / kg / day, whereas plasma albumin levels were unchanged.

[0249] Example 8 - Biodistribution of N027 in mice Fluorophore (VT680) labeled N027 or isotype human IgG1 pair The control antibody was used in Tg32 human FcRn transgenic and mouse FcRn knockout mice. The antibody was administered intravenously to mice at 30 mg / kg. Quantitative ex vivo optical imaging was used to measure the expression of leukocytes in individual organs. Figure 1 shows the biodistribution of N027 in various organs.

[0250] Example 9 - Efficacy of N027 in murine collagen antibody-induced arthritis Collagen antibody-induced arthritis was observed in Tg32 human FcRn transgenic mice, In cRn knockout mice, ArthritoMab™ cocktail on day 1 The mice were induced by intraperitoneal (ip) injection of IL-1 (MD Biosciences) and then treated with 100 mg / kg of 10 ... Inflammatory disease activity was induced by intraperitoneal (ip) administration of 100 μg LPS. 7 was administered therapeutically intravenously at 5 mg / kg (arrow) on day 6 after disease induction and randomization. 1 g / kg IVIG (positive control group) or the vehicle PBS (negative control group) , and administered on day 6 after randomization (n=5 / group). As shown in Figure 6, N027 When administered therapeutically, collagen antibodies were detected in human transgenic FcRn mice. Effectively inhibits body-induced arthritis.

[0251] Example 10 - Efficacy of N027 in Murine Chronic Idiopathic Thrombocytopenic Purpura (ITP) Thrombocytopenia was treated with subcutaneous (sc) mini-infusion of antiplatelet antibodies (anti-CD41, MWReg30). Continuous infusion of osmotic pumps allowed the Tg32 human FcRn (hFCGRT) transgene to be transfected with oocytes. Nick, induced in mouse FcRn (mFCGRT) knockout mice. Platelet levels were 300 × 10 by 72 hours (day 3) after pump implantation. 9 / L or less At 72 hours (day 3) and 120 hours (day 5) after pump implantation, N027 was administered intravenously (A, n=4 / group, B, n=7 / group). 1 shows the effect of N027 on platelet levels in mice with the disease.

[0252] Example 11 - Concentration-dependent FcRn occupancy achieved by N027 in target cell types was Receptor occupancy by N027 was observed in primary human aortic endothelial cells (HAECs), human umbilical vein endothelial cells (HUVECs), and human umbilical vein endothelial cells (HUVECs). in different cell types, such as human uveocyte (HUVEC) cells and placental trophoblasts (HVT). Cells were grown in complete EBM-2 medium (Lonza, Waterville) or Thorax. Cells were grown to confluency in lophoblast medium (ScienCell). The monolayers were then inoculated with 1 ml of medium containing different concentrations of unlabeled N027 for 1 h at 37 °C. After washing, the cells were incubated with VivoTag645-labeled N027 (10 μg / ml ) before incubating the cells with cold HyQTase for 30 min at 4°C in the dark. After incubation, the cells were resuspended in FACS buffer. Before the experiment, cells were washed with permeabilization buffer. Measured by flow cytometry. Values ​​are geometric mean fluorescence intensity (gMFI) ± SD (n=2). Figures 8A, 8B, and 8C show the results of HAEC, HUVEC, and IFN-γ-α-β-glucanase-1 (IFN-γ-α)-induced leukocyte proliferation in HAEC, HUVEC, and IFN-γ ... The results are summarized in Table 4. Human EC (HAEC, HUVEC) and placental HVT were treated with N027 at similar concentrations. Showing dependence receptor occupancy.

[0253] (Table 4) TIFF2025143252000171.tif30143

[0254] Example 12 - The concentration of N027 that achieved 100% receptor occupancy increased intracellular IgG accumulation Add The relationship between the level of receptor occupancy and changes in IgG intracellular trafficking induced by N027 was examined in different cell types. Human endothelial cells (HAEC and HUVEC) were cultured in endothelial cell culture medium (EBM). -2, Lonza), while human placental trophoblasts (HVTs) were cultured in trophoblast medium. The cell monolayer was then cultured in blast medium (ScienCell). Pulsed for 4-5 hours at 37°C in 1 mL medium containing: 1. Various concentrations of N027 + VivoTag645-IgG (50 μg / mL) 2. Various concentrations of isotype control IgG + VivoTag645-IgG (50 μg / mL) The cell monolayer was then washed with cold medium, followed by cell detachment by HyQtase treatment. Cell-associated VivoTag645-N027 was measured by flow cytometry. Values ​​represent geometric mean fluorescence intensity (gMFI) ± SD (n = 2). 9B and 9C show the results of HAEC, HUVEC and HUVEC cultures in response to various doses of N027. The intracellular IgG levels of each VT are shown. N027 corresponds to >100% FcRn occupancy. The dose resulted in significantly higher IgG accumulation compared to the isotype control. The effective N027 concentration required to saturate IgG accumulation levels was determined for these target cell types. The concentrations were similar across types, ranging from 4.99 to 2.43 μg / mL, as summarized in Table 5. Demonstrate that.

[0255] (Table 5) TIFF2025143252000172.tif30155

[0256] Example 13 - Measurement of time to 100% FcRn occupancy Determine the time taken by N027 to saturate FcRn and block IgG transport. To determine the phenotype, a confluent vascular endothelial cell (HUVEC) monolayer was cultured in EBM-2 medium. , in the presence or absence of a saturating concentration of N027 (16.6 μg / ml) for the indicated times. The cells were incubated at 37°C for 1 h (Figure 10). At the end of the incubation, the cells were washed. The cells were washed, harvested with cold HyQtase, and then fixed and permeabilized. These cells were incubated in permeabilization buffer + 10% human serum and VivoTag645-labeled NO The cells were then incubated in 27 (10 μg / mL) for 30 minutes at 4°C in the dark. Wash with permeabilization buffer, resuspend in FACS buffer, and incubate with cell-associated VivoTag645- N027 was measured by FACS. Values ​​represent the mean gMFI ± SD (n = 2). Figure 10 The results shown in Figure 1 demonstrate 100% FcRn uptake by N027 in approximately 30 minutes in this endothelial cell type. -Indicates that possession has been achieved.

[0257] Example 14 - Human vascular endothelial cells and placental trophoblasts are modified by N027 show similar FcRn turnover rates FcRn in human vascular endothelial cells (HUVEC) and placental trophoblasts (HVT) Turnover rates were compared in the presence and absence of N027. Cells were cultured at 75 cm 2 Hula The cells were cultured for 3 days in a medium containing 25% D2O (deuterium oxide, Aldrich) at 37°C. After 2 days, the medium was replaced with N027 (100 μg / mL), or control IgG (100 μg / mL), The medium was then replaced with normal medium containing either a medium change or a mock treatment. The cells were harvested from the flask (Figures 11A and 11B). The cell monolayer was washed and the cells were harvested. The individual pellets were dissolved and digested separately. Quantitative and targeted proteomics were performed. Extract the relative intensity of each isotopomer and calculate the fraction for each isotopomer by dividing each intensity by the sum. The fractional abundance values ​​were used to calculate the amount of D2O-labeled Fc remaining in the system. The percentage of FcRn turnover was calculated. Figures 11A and 11B show that the FcRn turnover rate is Similarities between human vascular endothelial cells (HUVECs) and placental trophoblasts (HVTs) Furthermore, treatment with N027 did not alter the FcRn turnover rate. It was.

[0258] Example 15 - Localization of FcRn in target cells The localization of N027 was observed in human vascular endothelial cells (HUVECs) and placental trophoblasts ( Cells were grown on glass coverslips in EBM-2 / TM medium. Live cells were grown in DyLight594-N027 (2 μg / mL) at 37°C for 1 hour. The cells were then washed and transferred to appropriate filters. Live images were taken on a fluorescence microscope in confocal mode using a 60X dry objective. Representative single-cell images show the endocytic activity of FcRn in both cell types. A similar localization pattern of N027 bound to the cis pool is shown (Figures 12A and 12B). The circle in the center of the cell indicates the location of the nucleus.

[0259] Example 16 - Effect of N027 treatment on the kinetics of IgG transport: intracellular IgG accumulation and Colocalization with lysosomes The effect of N027 treatment on the kinetics of intracellular IgG accumulation was investigated in human vascular endothelial cells (HUVE). C) and target cell types that express FcRn, such as placental trophoblasts (HVTs). Cells were grown in EBM-2 medium (Lonza, Waterville) or The cells were grown to confluency in TM1 medium (ScienCell). Confluent cell monolayers were incubated with N027 (2 μg / ml) + VivoTag645-IgG (50 μg / mL) or isotype control IgG (2 μg / mL) + VivoTag 645-IgG (50 μg / ml) at 37°C for 20 min. The cell monolayer was then washed and then pulsed with N027 (2 μg / mL), The mice were incubated at 37°C for 0 min in chase medium containing either 0 μg / ml or an isotype control (2 μg / ml). After each chase period, cells were washed, isolated, and then lysed in Hydrated Water. Cell-associated VivoTag645-N027 was collected by Qtase treatment. Values ​​are geometric mean fluorescence intensity (gMFI) ± SD (n=2) Cells treated with N027 showed higher levels of intracellular IgG. Furthermore, the effect of N027 on the kinetics of intracellular IgG accumulation was shown in Figure 13A and 13B was similar between the two cell types tested.

[0260] Furthermore, in primary human umbilical vein endothelial cells (HUVECs), N027 stimulated intracellular IgG, We then determined whether the co-localization of IgG and lysosomes with the cells was increased. Grown on coverslips and treated with 10 μg / ml Alexa Fluor 594 dextran. Incubate at 37°C for 2 hours in a medium containing tetracycline (10,000 MW, anionic, fixable). After incubation, the cells were washed and incubated with N027 (2 μg / ml) + DyLight 488-IgG (50 μg / ml) containing medium or isotype Contains control IgG (2 μg / ml) + DyLight 488-IgG (50 μg / ml) The cells were pulsed for 20 hours at 37°C in medium with or without any IgG treatment. Plates were washed with cold medium and then chased at 37°C for 0 or 30 minutes. The tracking conditions used were: N027 + DyLight 488-IgG pulse set to N02 7 (2 μg / mL); isotype + DyLight 488-IV The IG pulse set was followed in the presence of isotype control IgG (2 μg / mL). A set without any IgG treatment was chased in medium alone. Cells were washed and Incubate in the dark for 30 min at 4 °C in Cytoperm / Cytoperm solution and perm Wash with perm wash buffer followed by perm wash buffer + In 10% normal mouse serum + 5 μg / ml mouse anti-human Lamp1 antibody, incubated at 4°C in the dark. The cells were then washed with palm wash buffer and PBS, and then The cells were mounted on glass slides. Using the confocal mode of an Olympus fluorescence microscope, Cell imaging was performed with a 60X dry objective at 10X optical magnification. As can be seen, N027 treatment significantly increased the expression of lysosomal compartments compared to isotype control IgG-treated cells. It has been shown to increase the accumulation of IgG in the sera.

[0261] Example 17 - Suppression of endogenous maternal and fetal IgG in cynomolgus monkeys by N027 and lack of N027 transfer to the fetal circulation Pregnant female cynomolgus monkeys were given IVF injections from gestational day 45 (GD45) to gestational day 100 (GD100). The animals were given weekly until cesarean section at gestational age 140 days (mid-term) or gestational age 140 days (late-term). A cohort of animals available for follow-up was also included in the study (date of birth [BD1]). The study design is shown in Table 8. vinegar.

[0262] (Table 8) Research design TIFF2025143252000173.tif42160 a Twenty-four pregnant females were initially enrolled in the study (8 per group). Four pregnancies per group were maintained at 1 gestational age. The remaining pregnancies, four per group, were assigned to cesarean section cohorts at 40 ± 2 days gestation. were assigned to the second cohort.

[0263] in maternal and neonatal blood samples using a standard, validated total IgG ELISA. The IgG concentration of each sample was measured (Table 9). Briefly, a polystyrene plate (96 wells) was ) was coated with a commercially available anti-human IgG antigen. The coated plate was washed to remove the bound Remove any remaining sample, then block with blocking buffer, and wash to remove any remaining blocking buffer. Serum samples were diluted and added to the anti-human IgG coated wells and incubated at room temperature for 60±10 min. The wells were then washed and incubated for 5 minutes with horseradish peroxidase ( Add a secondary (detection) antibody conjugated with HRP (Human Red Chromatin Receptor Peptide) and incubate at room temperature for 60 ± 5 minutes. Tetramethylbenzidine (TMB) substrate was then added to each well, and the plates were incubated. Incubate at room temperature for 20 ± 5 min on a rate shaker, followed by addition of 2N H2SO4. The enzyme reaction was stopped. SpectraMax® 190 Microplate Reader The absorbance of each well was read at 450 nm using an anti-human IgG capture antibody and total I HRP-conjugated anti-human I recognizes IgG and cross-reacts with cynomolgus monkey IgG Any commercially available or proprietary pairing with a IgG detection antibody can be used to detect total cynomolgus Ig in an ELISA. IgG detection antibodies can be used to measure intact Ig G, which can be a polyclonal serum antibody, a monoclonal antibody, or a Fab(2) fragment .

[0264] (Table 9) Method TIFF2025143252000174.tif87150

[0265] All pregnant adult females assigned to the study were administered femoral vein (IV) injections according to Table 10. Blood was collected by venipuncture from the cephalic / saphenous vein (recommended) or the peritoneal / peritoneal vein. For all fetuses obtained by cesarean section on or after 140 ± 2 days of gestation, the umbilical cord was removed according to Table 10. Blood was collected from the cord. Samples (1 mL) were allowed to clot for at least 60 minutes, centrifuged, and the resulting Separate the collected serum and transfer it to an appropriately labeled (e.g., IgG) polypropylene tube. The cells were immediately frozen in a freezer set to maintain -80°C.

[0266] Table 10. Sample collection times for evaluation TIFF2025143252000175.tif224156 a Time points were collected only from animals in the 100 day gestational age Cesarean section cohort. b Collection ranges listed based on potential dosing dates between gestational days 44 and 46. All time points are It was based on Yobi.

[0267] Suppression of endogenous maternal IgG Administration of N027 resulted in a dose-dependent increase in serum IgG levels in adult females beginning 72 hours after administration. A significant decrease in the serotonin level was observed in both 100 and 300 mg / kg dosed animals. Gestational days 51-53: The maximum decrease in serum IgG concentrations was observed at pre-dose (Figure 16). Serum IgG levels in Group 2 (100 mg / kg) increased to pre-dose levels in a dose-dependent manner. 65-67 days of gestation: Starting from the time before administration, This continued until the next dose on days 135-137 of gestation, after which a similar magnitude of reduction occurred. Animals in Group 3 (300 mg / kg) remained refractory for the entire treatment period. nadir IgG levels were maintained at all pre-dose time points throughout the study (see Table 10). No change in IgG from baseline was observed in vehicle-treated animals. None (Group 1).

[0268] Dose-dependent increases in serum IgG concentrations were observed on gestational days 44-46, 93-95, and 100. These increases were present 2 hours after administration at gestational ages 135-137 and 2 hours after administration at gestational ages 135-137. This is likely a result of the detection of N027 by the assay and is not thought to be related to the pharmacology of N027. Fetal serum I was significantly higher than control values ​​at 100 and 140 days of gestation. There was a dose-dependent decrease in gG levels, also present in the newborn pups at day of birth (Figure 17).

[0269] Lack of transfer of N027 from maternal to fetal circulation The transfer of N027 from maternal circulation to fetal circulation is due to the N027FcRn expression in fetal circulating monocytes. N027 receptor occupancy was assessed by measuring the level of N027 saturation. The activity of fluorescently labeled NO against free / unbound FcRn in the presence and absence of a combined concentration of A flow cytometry (FACS) assay was used to measure the binding of 27 The saturation samples were evaluated on monocytes, granulocytes, B lymphocytes, and T lymphocytes. At the time points after administration, the free or unbound FcRn receptors present on each leukocyte subset were Any FcR that remained free / unbound at each post-dose time point is shown. Saturation was achieved at a concentration of unlabeled N027 determined to completely saturate the n receptors. The samples were spiked. N027 receptor occupancy was measured at 100 days and 140 days of gestation. In whole blood of pups or in newborns on the day of birth, in the context of the unsaturated sample analysis described above , was not detected.

[0270] Example 18 - Evaluation of transplacental transfer of N027 Human placentas obtained from uncomplicated full-term pregnancies were subjected to ex vivo dual perfusion single placental mini-transplantation. The placental transfer of N027 was assessed using the placental rupture method. Two chorionic vessels (one artery and one vein) supply a single intact surrounding placental cotyledon The placental cotyledons were cannulated with 3F and 5F umbilical catheters, respectively. The lamina propria was trimmed and placed in a perfusion chamber with the maternal surface facing upward. Perfusion was performed by two catheters penetrating the basal plate. The flow rates of the perfusion medium were 3.0 and 12 mL / min, respectively. Fetal perfusate equilibrated with a gas mixture made of 5% O2 and 5% CO2 The cells were equilibrated with a mixture of 95% N2 and 5% CO2. All experiments were performed at a temperature of 37°C. It was carried out at

[0271] Each placental lobule was perfused for an initial control period of 1 hour, during which the tissue was perfused through the open-close perfusion system. Stable in new environments using open-open configuration During the control period, perfusion was terminated if any of the following occurred: Volume loss in the fetal circulation of more than 3 mL / hour or inadequate perfusion between the two circulations A pO2 difference of less than 60 mmHg between the fetal venous and arterial Closed-closed configuration of the flow system ( The latter was followed by a 4-hour experimental period using a 2-hour incubation period (i.e., medium recirculation). The incubation was initiated by replacing the medium in the reservoir and adding 3 mg / ml BSA.

[0272] Transfer of N027 across the lobules of human placenta was assessed at three different concentrations: 0.3 mg / ml, 3 Fourteen individual placentas were tested at 0.3 mg / ml and 30 mg / ml. N027 was added to the maternal perfusion solution at 1, 3, and 30 mg / ml, and the mice were perfused for 4 hours. Samples from the maternal artery and fetal vein were collected in 0.5 mL aliquots at 0°C for the duration of the experiment. , 15, 30, 60, 90, 120, 150, 180, 210, and 240 min. Antipyrine was used as a positive control to confirm the integrity of the circulation (Figure 14). ~15) Highly sensitive mesoscale discovery (MSD) immunoassay with a lower limit of quantification of 5 ng / ml. Assay (Meso Scale Discovery (MSD) immunoassay ay) was used to determine the concentrations of N027 in maternal and fetal samples. The method involves a sandwich format using anti-idiotypic antibody pairs, where the MSD protein Plates are coated with anti-idiotypic Abs and then incubated with the sample. , and revealed with a second biotinylated anti-idiotypic Ab, followed by MSD-tagged This was followed by detection with streptavidin and the addition of read buffer. The concentration is 26 after liquid-liquid extraction. The results were determined using an HPLC assay with UV detection at 0 nm. The mean fetal transfer rate of the antipyrine was 41±2.8%. The mean fetal transfer rate of 027 was 0.0027±0.0021%, indicating a very low level of transfer. The results showed that N02 could be used to treat pregnant patients without causing fetal exposure. This suggests that 7 can be used.

[0273] Example 19 - Pharmacokinetic and Pharmacodynamic Data of N027 Phase 1, single-center, randomized, double-blind, placebo-controlled SAD / MA in NHVs A D study was conducted to evaluate the safety, tolerability, PK, and PD of N027. Five cohorts received a single IV infusion of placebo (n=2 / cohort) or 0.3 (n=3), 3(n=3), 10(n=6), 30(n=6), or 60(n=6)m Received escalating doses of N027 at 100 mg / kg and evaluated safety, PK, and PD for 8 weeks. The results were followed up (Figures 18 and 19).

[0274] In the MAD portion of the study, subjects received up to four weekly IV infusions of N027 or placebo. The subjects in the first cohort were followed for safety, PK, and PD for 10 weeks after administration. , received 30 mg / kg N027 or placebo. Results showed that intact FcRn RO The results showed that the serotonin-dependent agonist effect was achieved and maintained at 30 mg / kg (Figure 20A). Patients were enrolled to receive 15 mg / kg N027 (or placebo) and complete RO was 15%. It was determined that the effect was not maintained at 1 mg / kg (Figure 20B).

[0275] Mean serum N027 concentrations for subjects in the 30 mg / kg and 15 mg / kg cohorts The data (Cmax and trough on Day 1) are summarized graphically in Figure 18. / kg of N027, the 2-hour (Cmax) value after the first dose was 500-700 μg / m Trough values ​​on days 7, 14, and 21 were within the expected range of L (based on SAD data) of 4. The range was 0-140 μg / mL. Repeated administration resulted in a range of 100-200 μg / mL. Group variability was reduced as a steady state of The Cmax value 2 hours after the first administration was 200-400 μg / mL. Considerable variability was observed in the concentrations of acetaminophen, with the majority of this data falling below 10 μg / mL. and provide a possible explanation for the failure to maintain a complete RO of 15 mg / kg. It was served.

[0276] At both dose levels, serum IgG was suppressed to a similar extent during the treatment period (Figure 21A and 21B).

[0277] Both the 15 mg / kg and 30 mg / kg doses were safe in this phase 1 study. The study was effective and well tolerated.

[0278] Example 20 - Effect of M281 (N027) and M281 (N027) on transplacental transfer of IgG1 monoclonal antibodies and the impact of IVIg In this example, a typical IgG1 monoclonal antibody was used, which is known to cross the placenta. The average maternal-fetal transfer of the known Humira® was studied, and The potential of M281 (i.e., M281) to inhibit this transplacental transfer of RA® The effect of M281 on IgG translocation was increased due to its target-mediated nature. This is close to the threshold for M281 removal and complete loss of FcRn receptor occupancy. The time frame for the administration of M281 from 10 μg / ml to The highest dose initially evaluated in a study of healthy volunteers was 60 mg / kg Treatment ranged up to 3000 μg / ml, a concentration that was 2-3 times the Cmax of M281. The dose was evaluated at selected concentrations relative to the range of serum concentrations expected for that dose. This blockade of IgG transfer also inhibits the cation transporter, a known competitive inhibitor of FcRn for IgG transfer. The efficacy of IVIg was evaluated using a gender control IVIg (polyclonal IgG mixture).

[0279] Placental perfusion Placentas from normal, healthy, full-term pregnancies (38-40 weeks) were obtained according to approved clinical trial protocols. Maternal infections, systemic diseases, and medications during pregnancy were collected immediately after cesarean abdominal delivery. Placentas with any evidence of gestational age or alcohol abuse were excluded from the study.

[0280] The technique of dual perfusion of human placental lobules (DPPL) was established as described in The protocol was followed (Nanovskaya T, Deshmukh S, Bro oks M, Ahmed MS. Transplacental transfer a nd metabolism of buprenorphine.J Pharmac ol Exp Ther.2002;300(1):26-33). Briefly, each The placenta was examined for rupture, revealing two chorionic vessels (one artery) supplying a single intact peripheral placental cotyledon. The venous and venous systems were cannulated with 3F and 5F umbilical catheters, respectively. The placental cotyledons were trimmed and placed in a perfusion chamber with the maternal surface facing up. The intervillous space was perfused by two catheters penetrating the basal plate. A pulsed drain is connected to a peristaltic pump, which continuously removes fluid from the chamber and transfers it to The fetus and mother were either returned to the maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusate medium in the systemic circulation were 3.0 and 12 mL / min, respectively. The fluid was equilibrated with a gas mixture made up of approximately 95% O2 and 5% CO2, and the fetus The perfusate was equilibrated with a mixture of 95% N2 and 5% CO2. All experiments were performed at 37°C. was carried out at temperature.

[0281] Each placental lobule was perfused for an initial control period of 1 hour, during which the tissue was perfused through the open-close perfusion system. Stable in new environments using open-open configuration During the control period, perfusion was discontinued if any of the following quality criteria were not met: Terminated: i) volume loss in the fetal circulation >3 mL / hour, or ii) volume loss in both circulations An O2 pressure difference of less than 60 mmHg between the fetal venous and arterial veins indicates insufficient perfusion overlap between them. .

[0282] At the end of the control period, 10 ml of maternal effluent and 10 ml of fetal venous effluent were collected to determine baseline levels of endogenous IgG. At the end of the control period, perfusion The system is in a closed-closed configuration (culture The medium was replaced in both the maternal and fetal reservoirs, and then both 3 mg / ml BSA was added to the reservoir. Then, the test substance (Humira®) , or Humira® + M281, or Humira® + IVIg, or or Humira® + IVIg + M281) was added to the maternal reservoir and aliquots ( The experimental period began after withdrawing 1 mL of the test substance and storing it as T=0. Co-transfusion with 0 μg / ml of the positive control, antipyrine (AP). Aliquots of 0 mL were collected from the maternal artery and fetal vein at 0, 30, and 60 mL for the duration of the experiment. , 120, 180, 240, 270, 300, 330, and 360 minutes. At termination, the perfused area was dissected from adjacent placental tissue, weighed, and the perfused lobule was analyzed. Pieces were placed in 4% PFA for IHC analysis.

[0283] Humira® concentrations in all maternal and fetal sample aliquots were determined by Sandoz. The lower limit of quantitation (LLOQ) was determined to be approximately 1 ng / ml using a switch ELISA. Transfer of HUMIRA® from the maternal to the fetal reservoir is This was determined by the fetal transfer rate (FTR), calculated as in TIFF2025143252000176.tif9140.

[0284] M281 concentrations were determined in aliquots of all maternal and fetal samples. Transfer from the maternal to the fetal reservoir is This was determined by the fetal transfer rate (FTR), calculated as in TIFF2025143252000177.tif8132.

[0285] Table 11. Composition of maternal and fetal compartments TIFF2025143252000178.tif60148

[0286] Antipyrine analysis Antipyrine (AP) is a small molecule (188 Da), pH 7.4 (pKa 1.4), and non-isopropyl It can be activated and, as a result, freely migrates across the placenta via passive diffusion. Its low octanol / water partition coefficient of 0.33 and its affinity to plasma proteins and serum amino acids in the aqueous maternal and fetal circulation with minimal retention in tissues due to its minimal binding to albumin It is important to consider the internal structure of the placenta to account for variations within the placenta across different experiments. It has been used extensively in perfusion models as a positive permeability control.

[0287] Antipyrine concentrations were measured according to previous reports (Morck TJ, Sorda G., Be chi N., Rasmussen BS, Nielsen JB, Ietta. F., Rytting E., Mathiesen L., Paulesu L., Kn. udsen LEPlacental transport and in vit ro effects of Bisphenol A.Reproductive T A modified HPLC method was used, as described in Oxicol. 2010;30: 131-137. The transfer of antipyrine from maternal to fetal reservoirs was measured in the samples used. The fetal transfer rate (FTR) was calculated as follows:

[0288] A high degree of perfusion overlap is considered. Antipyrine FTR of 35-45% is considered. This was used to validate and compare the experiments. Furthermore, maternal-fetal responses to AP transitions were also examined. The (FTM) ratio was calculated at each time point to confirm the balance between maternal and fetal sides. The TM ratio is expected to be greater than 0.75, approximately 60-120 minutes. Ideally, placental integrity should be confirmed by a CT scan.

[0289] Briefly, proteins were added to each 200 μl sample with 10 μl / ml of internal standard fraction. The sample was precipitated with 200 μl of ice-cold acetonitrile containing phenacetin. The mixture was centrifuged at 500 rpm for 25 min and the supernatant was analyzed by HPLC. Chipirin and phenacetin were analyzed using an Agilent 1200 HP equipped with a UV detector. The analysis was carried out using an LC system. The stationary phase used was a reversed-phase C18-based column (W aters Atlantis T3, Atlantis T3 Column, 100 The column was also pre-coated with 1000 Å, 3 μm, 3 mm × 150 mm granules prior to the start of each sample set. Modified guard cartridge (Waters T3, 3 μm, 2.1 mm x 150 mm) The column and sample temperatures were maintained at 25°C and 4°C, respectively. The samples were diluted in a range of 25–95% methanol-water at a flow rate of 0.3 mL / min for 14 min. A linear gradient was run, the injection volume was 10 μL, and detection was performed using absorbance at 260 nm. was carried out.

[0290] Humira® Transition The transplacental transfer of Humira® was studied at a fixed concentration of 270 μg / ml. Maintain placental integrity over the study period, with an antipyrine FTM ratio of >0.75, and Quality criteria for successful perfusion include volume loss from the fetal reservoir of 3 ml / hour or less. All eight matched experiments are reported in Table 12. For these experiments, perfusion Oxygen transport levels and consumption were also monitored as markers of replication and tissue viability, respectively. It was turned.

[0291] Table 12. Transplacental transfer of Humira® TIFF2025143252000180.tif74128 1 Ratio of fetal perfusate concentration to maternal perfusate concentration x 100% 2 Antipyrine transfer range: 35-45%

[0292] The transplacental transfer of antipyrine during the course of these experiments is shown in Figure 22 and is In this study, fetal to maternal (FTM) concentration ratios were measured at each time point, as well as at the terminal All experiments reached equilibrium (FTM ratio, 0.9–1.0) within 60–180 min. It was observed that the mean ± SD fetal mortality at the end of eight experiments was achieved. The fetal to maternal FTM ratio was calculated to be 1.03 ± 0.11, indicating adequate fetal maternal ... The maternal-to-fetal transfer levels of antipyrine were >35%, indicating a high degree of perfusion overlap relative to the reported experiments.

[0293] Transplacental transfer of Humira® in eight experiments is shown in Figure 23. Table 1 As shown in Figure 2, the mean ± SD fetal transfer rate was approximately 0.23 ± 0.21%. was calculated, while the approximate mean ± SD fetal concentration at the end of the experiment was 0.49 ± 0.49 μg / The range was in the mL range.

[0294] Humira® Transfer in the Presence of M281 The Humira® concentration was kept constant at 270 μg / ml, and the M2 Studying the transplacental transfer of Humira® in the presence of M281 at varying M281 concentrations All experiments maintained placental integrity over the experimental period, with antipyretic activity greater than 0.75. Fetal to maternal (FTM) ratio of phosphorus and volume loss from the fetal reservoir of 3 ml The quality criteria for successful perfusion, such as a time to complete perfusion of 1000 mg / hour or less, were met. A summary of the studies and results is shown in Table 1. As previously mentioned, oxygen transport was used as a marker of tissue viability for these experiments. Levels were also monitored (note: experiment PP 75 was performed in the absence of antipyrine). However, other parameters such as fetal volume and oxygen transfer were measured and were associated with good perfusion quality. conformed to the standards).

[0295] Table 13. Transplacental transfer of Humira® in the presence of M281 TIFF2025143252000181.tif75145 1 Ratio of fetal perfusate concentration to maternal perfusate concentration x 100%

[0296] The transplacental transfer of antipyrine during the course of these experiments is shown in Figure 24 and is In this study, fetal to maternal (FTM) transfer ratios were measured at each time point, as well as at the terminal end. Calculated at the end of the experiment. Average of the end points of eight experiments with antipyrine. ±SD FTM ratio was 1.1 ± 0.11 (equilibrium achieved in maternal and fetal circulation). was calculated, indicating adequate placental integrity over the experimental period. The level of transfer to the fetus was observed to be >35%, a high degree of perfusion stress compared to reported experiments. It showed complex.

[0297] Transplacental transfer of Humira® in the presence of M281 in nine experiments is shown in Figure 2 5. The effect of Humira® on the fetus in the presence of 300 μg / ml of M281 The fetal transition rate (mean ± SD) was calculated to be 0.06 ± 0.01% (n = 5), while Experiments with Humira® in the presence of 10 μg / mL M281 (n=3) showed an average The fetal transfer rate was 0.07±0.01% (mean±SD). The fetal transfer rate of Humira® in the presence of M281 was 0.06 (n=1). The fetal transfer rates of Humira® for all nine experiments reported in Table 13 were , collectively, were calculated to average approximately 0.07±0.01%, while the mean terminal fetal concentration was 0.12±0.02μg / mL.

[0298] The collective mean fetal transfer rate of M281 from nine experiments was 0.003 ± 0.007%. As shown in Table 13, in experiments PP77-79, the fetal side M281 levels were below the detection limit, whereas 300 μg / ml of M281 (n= 5) The mean fetal transfer rate in the experiments with The observed minimal transplacental transfer rate of M281 is consistent with previous experiments (data not shown).

[0299] Humira® Transfer in the Presence of IVIg Transuterine Humira® (maternal concentration maintained constant at 270 μg / ml) Interstitial migration was studied in five experiments in the presence of IVIg (6.7 mg / ml). All experiments maintained placental integrity over the experimental period and maintained antipyrimidin levels above 0.75. Successful perfusion, including fetal FTM rate and volume loss from the fetal reservoir of 3 ml / hour or less These experiments met the quality criteria for oxygen transfer levels, as previously described. Cells were also monitored as a marker of tissue viability. A summary of the study and results is provided in

[0300] Table 14. Transplacental transfer of Humira® in the presence of IVIg TIFF2025143252000182.tif54128 1 Ratio of fetal perfusate concentration to maternal perfusate concentration x 100%

[0301] The transplacental transfer of antipyrine during the course of these experiments is shown in Figure 26 and is In this experiment, FTM was calculated at the terminal end point. PP38 finished at 5.5 hours, Therefore, FTR was calculated after 5.5 hours compared to 6 hours for other experiments. Note that the mean ± SD fetal to maternal ( FTM) concentration ratio was 1.04 ± 0.04 (equilibrium was achieved in the maternal and fetal circulation). was calculated, indicating adequate placental integrity over the experimental period. The level of transfer to the fetus was observed to be ≥35%, a high degree of perfusion stress relative to reported studies. It showed complex.

[0302] Transplacental transfer of Humira® in the presence of IVIg in five experiments is shown in Figure 2 7. The fetal transfer rate of Humira® in the presence of IVIg was, on average, was calculated to be approximately 0.07±0.03% (n=5), while the average Mean terminal fetal concentrations ranged from 0.12±0.06 μg / ml.

[0303] Humira® Transfer in the Presence of IVIg+M281 Transplacental transfer of Humira® in the presence of IVIg+M281 was evaluated in maternal and fetal rats. In Xaver, the concentration of Humira® was 270 μg / ml and IVIg was 6.7 mg / Four experiments were performed with M281 maintained at 300 μg / mL and M281 maintained at 300 μg / mL. All experiments maintained placental integrity over the experimental period and maintained antipyrimidin levels above 0.75. fetal-to-maternal (FTM) ratio and fetal reservoir volume loss of 3 ml / All quality criteria for successful perfusion were met, including a time of 0.05 hours or less. A summary of the experiment is shown in Table 15. For these experiments, as previously mentioned, oxygen transport levels were also used as a marker of tissue viability. It was monitored as a

[0304] Table 15. Transplacental transfer of Humira® in the presence of IVIg+M281 TIFF2025143252000183.tif48135 1 Ratio of fetal perfusate concentration to maternal perfusate concentration x 100%

[0305] The transplacental transfer of antipyrine in these experiments is shown in Figure 28. FTM was calculated at all individual time points as well as at the terminal endpoint. The mean ± SD FTM for antipyrine across four experiments was 1.04 ± 0.03 (equilibrium achieved in maternal and fetal circulation) over the duration of the experiment. Adequate placental integrity was demonstrated. Antipyrine maternal-to-fetal transfer levels were >35%. was observed, indicating a high degree of perfusion overlap relative to the reported experiments.

[0306] Transuterine efficacy of Humira® in the presence of IVIg and M281 in four experiments The fetal transition is shown in Figure 29. As shown in Table 15, the fetal transition rate was 0.2% on average. The mean terminal fetal concentration was calculated to be 0.04±0.05% (n=4), while the mean terminal fetal concentration was 0.07± The range of M281 translocation was not measured in this series of experiments. It was.

[0307] statistical analysis All experimental data were subjected to statistical analysis. To account for correlation, random values ​​for both the slope and intercept for each donor ID were used. A linear mixed-effects (LME) model was used to analyze data from all experiments with the term Fetal concentrations were divided by maternal concentrations at the corresponding time points and then log-transformed. The sensitivity of the results to variability was also assessed and determined to be robust. P values ​​were calculated for multiple comparisons. was adjusted.

[0308] Table 16. Transplacental transfer of Humira® in the presence / absence of M281 / IVIg Overview TIFF2025143252000184.tif92154 Undetected: Undetected Not applicable: Not applicable * Calculated using a linear mixed-effects model with random slopes and intercepts

[0309] Example 21 - Effect of M281 (N027) on albumin levels Administration of M281 (N027) was associated with a decrease in serum albumin levels in subjects For example, a maximum decrease of approximately 20-25% below baseline was observed at 60 mg / kg when given as a single dose, and when the 15 and 30 mg / kg doses were given multiple times weekly. Hypoalbuminemia was asymptomatic. Proteinuria, edema, and was not associated with any other adverse events.

[0310] The analysis results of the effect of M281 on albumin are shown in Figures 30-32. All subjects receiving a single dose of M281 had blood glucose levels below the normal range (normal range = 34-50 g / L). A decrease in serum albumin to less than 1 week after reaching the nadir The mean nadir was 23 ± 9% below baseline at approximately day 14. (range 8.6-33%). Recovery to baseline occurred within 3-4 weeks of nadir. and began when FcRn receptor occupancy was lost. Weekly treatment with 15 or 30 mg / kg Albumin levels in the subjects studied reached a mean nadir of 21-25% below baseline. Recovery to baseline occurred within 3–4 weeks of the nadir. The lower the albumin level, the greater the degree of hypoalbuminemia. Subjects treated with the lower dose of M281 had a similar immediate albumin reduction of about 10%. The albumin reduction was greater than that observed with placebo. Small adverse events were observed following single doses of M281 of 30 mg / kg or higher.

[0311] Other embodiments While the present invention has been described in connection with specific embodiments thereof, it is understood that further modifications may be made thereto. It is to be understood that the present application is generally in accordance with the principles of the present invention and that the present invention relates to This invention includes departures from the present disclosure that are well known or customary within the relevant art. is intended to cover any variations, uses, or adaptations of the above. This can be applied to various features.

[0312] All publications, patents, and patent applications are incorporated by reference. to the same extent as if each were specifically indicated to be incorporated in its entirety by No. 6,239,999, filed Dec. 1, 2003, which is incorporated herein by reference in its entirety.

[0313] Other embodiments are within the scope of the following claims.

Claims

1. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, , comprising administering to a pregnant subject an antibody, the antibody comprising: (1) CDR L1, CDR L2, CDR L3, CDR L4, CDR L5, CDR L6, CDR L7, CDR L8, CDR L9, CDR L10, CDR L11, CDR L12, CDR L13, CDR L14, CDR L15, CDR L16, CDR L17, CDR L18, CDR L19, CDR L (2) a light chain variable region comprising CDR H1, CDR L2, and CDR L3; and a heavy chain variable region comprising CDRs H1, H2, and H3; said CDR L1 being a sequence having no more than two amino acid substitutions relative to the sequence of The CDR L2 has one amino acid sequence identical to that of GDSERPS (SEQ ID NO: 2). including sequences with the following amino acid substitutions: said CDR L3 being a sequence having no more than one amino acid substitution relative to the sequence of the CDR H1 is a sequence having no more than one amino acid substitution relative to the sequence of the CDR H2 is and The CDR H3 is identical to the sequence of LAIGDSY (SEQ ID NO: 11). The method includes a sequence having no more than two amino acid substitutions.

2. The antibody is a K Ｄ The following K Ｄ The method of claim 1, which binds to human FcRn at How to post.

3. said CDR L1 having the sequence Including, the CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), said CDR L3 having the sequence Including, the CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4); the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

4. said CDR L1 having the sequence Including, the CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), said CDR L3 having the sequence Including, the CDR H1 comprises the sequence DYAMG (SEQ ID NO: 5); the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

5. said CDR L1 having the sequence Including, the CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), said CDR L3 having the sequence Including, the CDR H1 comprises the sequence NYAMG (SEQ ID NO: 6); the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

6. said CDR L1 having the sequence Including, the CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), said CDR L3 having the sequence Including, the CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4); the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

7. said CDR L1 having the sequence Including, the CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), said CDR L3 having the sequence Including, the CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4); the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

8. The subject has previously suffered from a fetal or neonatal alloimmune disorder and / or an autoimmune disorder. The method according to any one of claims 1 to 7, wherein the method has a history of being used in a medical device.

9. The subject is at risk of having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. The method according to any one of claims 1 to 8, which is hazardous.

10. The fetal and neonatal alloimmune and / or autoimmune disorders are Infantile alloimmune thrombocytopenia, hemolytic disease of the fetus and newborn, alloimmune panthrombocytopenia Hypothyroidism, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune Hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, Neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes. The method according to any one of claims 1 to 5.

11. The fetal and neonatal autoimmunity and / or autoimmune disorders are The method of claim 10, wherein the disease is a hemolytic disease.

12. The fetal and neonatal autoimmunity and / or autoimmune disorders are The method of claim 10, which is alloimmune thrombocytopenia.

13. The fetal and neonatal autoimmune and / or autoimmune disorder is congenital heart block. The method of claim 10.

14. 14. The method of any one of claims 1 to 13, wherein the treatment reduces the risk of miscarriage.

15. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, , comprising administering to a pregnant subject an antibody, the antibody comprising: (1) CDR L1, CDR L2, CDR L3, CDR L4, CDR L5, CDR L6, CDR L7, CDR L8, CDR L9, CDR L10, CDR L11, CDR L12, CDR L13, CDR L14, CDR L15, CDR L16, CDR L17, CDR L18, CDR L19, CDR L (2) a light chain variable region comprising CDR H1, CDR L2, and CDR L3; and a heavy chain variable region comprising CDRs H1, H2, and H3; said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17) 、 X １ is a polar or hydrophobic amino acid, X ２ is a hydrophobic amino acid, X ３ is a polar amino acid, X ４ is a polar or acidic amino acid, X ５ is a polar or hydrophobic amino acid, X ６ is a hydrophobic amino acid, Z １ is a polar or acidic amino acid, Z ２ is a polar or hydrophobic amino acid, Z ３ is G, S, or A; Z ４ is a basic amino acid, Z ５ is a hydrophobic or basic amino acid, and Z ６ is G, S, D, Q, or H, and the antibody is less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or is less than 40 pM Ｄ Binding to human FcRn by

16. said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H; 16. The method of claim 15.

17. said CDR L1 being a sequence having no more than two amino acid substitutions relative to the sequence of The CDR L2 has one amino acid sequence identical to that of GDSERPS (SEQ ID NO: 2). including sequences with the following amino acid substitutions: said CDR L3 being a sequence having no more than one amino acid substitution relative to the sequence of the CDR H1 is a sequence having no more than one amino acid substitution relative to the sequence of the CDR H2 is and The CDR H3 is identical to the sequence of LAIGDSY (SEQ ID NO: 11). including sequences with no more than two amino acid substitutions, 17. The method of claim 15 or 16.

18. The subject has previously suffered from a fetal or neonatal alloimmune disorder and / or an autoimmune disorder. The method according to any one of claims 15 to 17, wherein the method has a history of having been performed by a person skilled in the art.

19. The subject is at risk of having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. The method according to any one of claims 15 to 18, which is hazardous.

20. The fetal and neonatal alloimmune and / or autoimmune disorders are Infantile alloimmune thrombocytopenia, hemolytic disease of the fetus and newborn, alloimmune panthrombocytopenia Hypothyroidism, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune Hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, Neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune 20. The method according to claim 15, wherein the thyroid disease is selected from the group consisting of thyroid disease and neonatal type I diabetes.

10. The method according to any one of claims 1 to 9.

21. The fetal and neonatal autoimmunity and / or autoimmune disorders are 21. The method of claim 20, wherein the disease is a hemolytic disease.

22. The fetal and neonatal autoimmunity and / or autoimmune disorders are 21. The method of claim 20, wherein the condition is alloimmune thrombocytopenia.

23. The fetal and neonatal autoimmune and / or autoimmune disorder is congenital heart block. The method of claim 20.

24. 24. The method of any one of claims 15 to 23, wherein the treatment reduces the risk of miscarriage.

25. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a sequence CDR L1 having the sequence GDSERPS (SEQ ID NO: 2) L2, and a CDR having the sequence SSYAGSGIYV (SEQ ID NO: 3) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; a heavy chain variable region comprising said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence and the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); and Z １ is T, D, or N; Z ２ is S or A, and Z ３ is G, S or A

26. the light chain Any one of claims 1 to 25, comprising a sequence having at least 90% identity with the sequence The method described below.

27. the heavy chain Any one of claims 1 to 26, comprising a sequence having at least 90% identity with the sequence The method described below.

28. the heavy chain Any one of claims 1 to 26, comprising a sequence having at least 90% identity with the sequence The method described below.

29. the heavy chain Any one of claims 1 to 26, comprising a sequence having at least 90% identity with the sequence The method described below.

30. the heavy chain Any one of claims 1 to 26, comprising a sequence having at least 90% identity with the sequence The method described below.

31. the heavy chain Any one of claims 1 to 26, comprising a sequence having at least 90% identity with the sequence The method described below.

32. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain and the heavy chain The method comprises the step of preparing a sequence having at least 90% identity to the sequence of

33. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain and the heavy chain The method comprises the step of preparing a sequence having at least 90% identity to the sequence of

34. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain and the heavy chain The method comprises the step of preparing a sequence having at least 90% identity to the sequence of

35. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain and the heavy chain The method comprises the step of preparing a sequence having at least 90% identity to the sequence of

36. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain and the heavy chain The method comprises the step of preparing a sequence having at least 90% identity to the sequence of

37. the heavy chain has at least 95% homology to any one of SEQ ID NOs: 20-24; 97%, 99%, or 100% identity to the sequence of any one of claims 27 to 36.

10. The method according to any one of claims 1 to 9.

38. the light chain has at least 95%, 97%, 99%, or 100% identity with the sequence of SEQ ID NO: 19; or a sequence having 100% identity.

39. The antibody has an amino acid sequence corresponding to any one of SEQ ID NOs: 20 to 24.

39. The isolated antibody of any one of claims 1-38, further comprising the substitution N297A.

40. The antibody has an amino acid sequence corresponding to any one of SEQ ID NOs: 20 to 24.

39. The method of claim 1 further comprising the substitutions D355E and L357M. Isolated antibodies.

41. The antibody comprises any one of the following amino acid substitutions: SEQ ID NOs: 20-24 A23V, S30R, L80V, A84T, E85D, A93V, and Q38H, V58I, and G99D relative to the sequence of SEQ ID NO: 19 41. The isolated antibody of any one of claims 1 to 40, further comprising any one or more of:

42. The antibody has a sequence similar to that of any one of SEQ ID NOs: 20 to 24, and a sequence similar to that of residue 4.

42. The isolated antibody of any one of claims 1 to 41, wherein the antibody does not contain a C-terminal lysine at position 46.

43. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain contains an array of the heavy chain The method includes an array of

44. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain contains an array of the heavy chain The method includes an array of

45. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain contains an array of the heavy chain The method includes an array of

46. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain contains an array of the heavy chain The method includes an array of

47. 1. A method for treating fetal and neonatal alloimmune and / or autoimmune disorders, administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain; the light chain contains an array of the heavy chain The method includes an array of

48. 1. A method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering a fetal anemia treatment to a fetus during pregnancy. administering to a subject an antibody, wherein the antibody comprises (1) CDR L1, CDR L2, and and CDR L3; and (2) a light chain variable region comprising CDR H1, CDR H2, and CDR L3. a heavy chain variable region comprising CDR H1 and CDR H2; said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

49. 1. A method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering a fetal anemia treatment to a fetus during pregnancy. administering to a subject an antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises a SE Q ID NO: 19, and comprising a sequence having at least 90% identity with the sequence of said The heavy chain is selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24 The method includes obtaining a sequence having at least 90% identity to the sequence being analyzed.

50. 1. A method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering a fetal anemia treatment to a fetus during pregnancy. administering to a subject an antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain is and the heavy chain comprises the sequence of SEQ ID NO: 20, SEQ SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and S A method comprising the step of:

51. treating said pregnant subject, said pregnant subject's fetus, and / or a combination thereof. The method of any one of claims 48 to 50, wherein the method comprises treating a patient with rhesus mastitis.

52. 1. A method of treating an autoimmune disorder, comprising administering an antibody to a pregnant subject, 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. fruit, said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

53. 1. A method of treating an autoimmune disorder, comprising administering an antibody to a pregnant subject, The antibody comprises a light chain and a heavy chain, wherein the light chain has a sequence at least as large as that of SEQ ID NO:

19. and the heavy chain comprises a sequence having 90% identity with SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and and SEQ ID NO:

24. The method includes a sequence having the following properties:

54. 1. A method of treating an autoimmune disorder, comprising administering an antibody to a pregnant subject, the antibody comprises a light chain and a heavy chain, the light chain comprising the sequence of SEQ ID NO: 19; and the heavy chain is selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: No. 22, SEQ ID No. 23, and SEQ ID No.

24. The method includes selecting a sequence.

55. The autoimmune disorder may be alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, lytic leukemia, or rheumatoid arthritis. Hemophilic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac Sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, char Strauss-Holstein syndrome, cicatricial pemphigoid, limited systemic sclerosis (CREST syndrome), cold Cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease Disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes Diarrhea, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis Anemia, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatoid arthritis Pain, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's disease phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Egren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, bud 52 to 54. A skin condition selected from the group consisting of uveitis, vitiligo, and Wegener's granulomatosis.

10. The method according to any one of the preceding claims.

56. 56. Any one of claims 52 to 55, wherein the treatment reduces the risk of miscarriage / fetal loss. The method described in paragraph .

57. Risk of or autoimmune or alloimmune disorders A method for reducing the risk of developing HIV-1, comprising administering an FcRn antibody to a pregnant subject. wherein the antibody comprises: (1) a light chain comprising CDR L1, CDR L2, and CDR L3; (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3; and a region, said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

58. Risk of or autoimmune or alloimmune disorders A method for reducing the risk of developing HIV-1, comprising administering an FcRn antibody to a pregnant subject. the antibody comprises a light chain and a heavy chain, the light chain having the sequence of SEQ ID NO: 19 and the heavy chain comprises a sequence having at least 90% identity with SEQ ID N O: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO 23, and SEQ ID NO: 24 and at least 9 sequences selected from the group consisting of 0% identity to the sequence.

59. Risk of or autoimmune or alloimmune disorders A method for reducing the risk of developing HIV-1, comprising administering an FcRn antibody to a pregnant subject. wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises the sequence of SEQ ID NO:

19. and the heavy chain comprises SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24 The method of claim 1, wherein the sequence comprises a sequence selected from the group consisting of:

60. The autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, lytic Hemophilic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac Sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, char Strauss-Holstein syndrome, cicatricial pemphigoid, limited systemic sclerosis (CREST syndrome), cold Cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease Disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin-dependent diabetes Diarrhea, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis Anemia, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatoid arthritis Pain, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's disease phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Egren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, bud 59. A skin condition selected from the group consisting of uveitis, vitiligo, and Wegener's granulomatosis.

10. The method according to any one of the preceding claims.

61. 61. Any one of claims 57 to 60, wherein the treatment reduces the risk of miscarriage / fetal loss. The method described in paragraph .

62. A method of increasing the catabolism of an antibody in a subject, comprising administering the antibody to a pregnant subject. and wherein the antibody administered comprises (1) CDR L1, CDR L2, and CDR H (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; a heavy chain variable region comprising said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

63. A method of increasing the catabolism of an antibody in a subject, comprising administering the antibody to a pregnant subject. and wherein the antibody administered comprises a light chain and a heavy chain, and the light chain comprises SEQ ID and wherein the heavy chain comprises a sequence having at least 90% identity with the sequence of SEQ ID NO:

19. EQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SE A sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO: 24 The method comprises the step of preparing a sequence having at least 90% identity to

64. A method of increasing the catabolism of an antibody in a subject, comprising administering the antibody to a pregnant subject. and wherein the antibody administered comprises a light chain and a heavy chain, and the light chain is and the heavy chain comprises the sequence of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID A method comprising the step of:

65. 7. The method of claim 6, wherein increasing the catabolism of antibodies comprises increasing the catabolism of pathogenic antibodies.

65. The method of any one of 2 to 64.

66. The pathogenic antibody is pathogenic to the mother, the fetus, or both the mother and the fetus.

66. The method of claim 65.

67. 67. The method of claim 65 or 66, wherein the pathogenic antibody is an IgG antibody.

68. said antibodies inhibiting fetal and neonatal alloimmune disorders and The method according to any one of claims 62 to 67, wherein the method causes a pulmonary and / or autoimmune disorder. 。

69. The fetal and neonatal alloimmune and / or autoimmune disorders are Infantile alloimmune thrombocytopenia, hemolytic disease of the fetus and newborn, alloimmune panthrombocytopenia Hypothyroidism, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune Hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, Neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune 69. The method of claim 68, wherein the patient is selected from the group consisting of thyroid disease and neonatal type I diabetes. method.

70. A method for reducing autoantibodies in a subject, comprising administering antibodies to a pregnant subject. wherein the antibody comprises: (1) a light chain comprising CDR L1, CDR L2, and CDR L3; (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3; Including variable regions, said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

71. A method for reducing autoantibodies in a subject, comprising administering antibodies to a pregnant subject. the antibody comprises a light chain and a heavy chain, the light chain having the sequence of SEQ ID NO: 19 and the heavy chain comprises a sequence having at least 90% identity with SEQ ID N O: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO 23, and SEQ ID NO: 24 and at least 9 sequences selected from the group consisting of 0% identity to the sequence.

72. A method for reducing autoantibodies in a subject, comprising administering antibodies to a pregnant subject. wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises the sequence of SEQ ID NO:

19. and the heavy chain comprises SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24 The method of claim 1, wherein the sequence comprises a sequence selected from the group consisting of:

73. 1. A method of reducing immune complex-based activation of an immune response in a subject during pregnancy. the antibody comprising: (1) a CDR L1, a CDR L2, and CDR L3; and (2) a light chain variable region comprising CDR H1, CDR H2, and a heavy chain variable region comprising CDR H3; said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

74. 1. A method of reducing immune complex-based activation of an immune response in a subject during pregnancy. administering to a subject an antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises a sequence having at least 90% identity with the sequence of EQ ID NO: 19, The heavy chain is SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO:

24. The method includes selecting a sequence having at least 90% identity to the selected sequence.

75. 1. A method of reducing immune complex-based activation of an immune response in a subject during pregnancy. administering to a subject an antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain is The heavy chain comprises the sequence of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ A method comprising the step of:

76. 7. The immune response of claim 73, wherein the immune response is an acute or chronic immune response in the subject.

6. The method according to any one of claims 5 to 5.

77. The acute immune response is pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, syndrome, antibody-mediated rejection, fulminant antiphospholipid antibody syndrome, immune complex-mediated vasculitis, thread Glomerulitis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune Selected from the group consisting of immune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, and serum sickness 77. The method of claim 76, wherein the method is activated by a medical condition that is being treated.

78. 78. The method of claim 77, wherein the acute immune response is activated by idiopathic thrombocytopenic purpura. The method described.

79. 78. The method of claim 77, wherein the acute immune response is activated by pemphigus vulgaris.

80. 78. Claim 77, wherein the acute immune response is activated by fulminant antiphospholipid syndrome. The method described below.

81. 78. The method of claim 77, wherein the acute immune response is activated by neuromyelitis optica.

82. 78. The method of claim 77, wherein the acute immune response is activated by antibody-mediated rejection. method.

83. 78. The method of claim 77, wherein the acute immune response is activated by myasthenia gravis.

84. The chronic immune response may be associated with chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus erythematosus, allergic reactions, or other conditions. Reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody-associated vascular 77. The method of claim 76, wherein the method is activated by a medical condition selected from the group consisting of inflammation. 。

85. 84. The method of claim 83, wherein the chronic immune response is activated by chronic inflammatory demyelinating polyneuropathy. The method described below.

86. 77. The method of claim 76, wherein the subject has an autoimmune disease.

87. The autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, lytic Blood anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, heparin-induced thrombocytopenia, sensitization Transplant, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac disease Pru dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (CREST syndrome), cold coagulation Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, Fibromyalgia, fibromyositis, Graves' 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, Meniere's disease, mixed connective tissue disease, multiple sclerosis , pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, Polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon , Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sharp's syndrome Glenn syndrome, stiff man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveal ulcer 87. The method of claim 86, wherein the inflammatory bowel disease is selected from the group consisting of vitiligo, vitiligo, and Wegener's granulomatosis. Law.

88. 88. The method of claim 87, wherein the autoimmune disease is warm autoimmune hemolytic anemia.

89. 88. The method of claim 87, wherein the autoimmune disease is anti-factor antibody.

90. 88. The method of claim 87, wherein the autoimmune disease is heparin-induced thrombocytopenia.

91. 88. The method of claim 87, wherein the autoimmune disease is sensitized transplantation.

92. A method for reducing antibody transfer across the placenta in a pregnant subject, comprising administering to the pregnant subject an antibody administering to a subject the antibody, wherein the antibody comprises (1) CDR L1, CDR L2, and CDR (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; a heavy chain variable region comprising H3, said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

93. A method for reducing antibody transfer across the placenta in a pregnant subject, comprising administering to the pregnant subject an antibody administering to a subject the antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain is selected from the group consisting of SEQ ID NO: and the heavy chain comprises a sequence having at least 90% identity to the sequence of SEQ ID NO:

19. SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, S A sequence selected from the group consisting of SEQ ID NO: 23, and SEQ ID NO:

24. The method includes determining a sequence having at least 90% identity to the sequence.

94. A method for reducing antibody transfer across the placenta in a pregnant subject, comprising administering to the pregnant subject an antibody administering to a subject the antibody, wherein the antibody comprises a light chain and a heavy chain, and the light chain is and the heavy chain comprises the sequence of SEQ ID NO: 20, SEQ ID NO: 21, No. 21, SEQ ID No. 22, SEQ ID No. 23, and SEQ ID No. The method of claim 1, wherein the sequence comprises a sequence selected from the group consisting of:

95. 1. A method of treating antibody-mediated enhancement of viral disease in a fetus or newborn, comprising: administering to a pregnant subject an antibody, wherein the antibody comprises: (1) CDR L1, CDR L2, CDR L3, CDR L4, CDR L5, CDR L6, CDR L7, CDR L8, CDR L9, CDR L10, CDR L11, CDR L12, CDR L13, CDR L14, CDR L15, CDR L16, CDR L17, CDR L18, CDR L19, CDR L19 (2) a light chain variable region comprising CDR H1, CDR L2, and CDR L3; and a heavy chain variable region comprising CDRs H1, H2, and H3; said CDR L1 having the sequence Including, said CDR L2 having the sequence GDX ３ X ４ RPS (SEQ ID NO: 13), said CDR L3 having the sequence Including, said CDR H1 having the sequence Z １ YAMG (SEQ ID NO: 15), the CDR H2 has the sequence Including, the CDR H3 has the sequence LAZ ５ Z ６ DSY (SEQ ID NO: 17), X １ is T, A, S, or I; X ２ is L or I, X ３ is S, N, or T; X ４ is Q, E, or N; X ５ is C, S, I, or Y; X ６ is A or V, Z １ is E, T, D, or N; Z ２ is S or A, Z ３ is G, S, or A; Z ４ is K or R, Z ５ is I, L, or H, and Z ６ is G, S, D, Q, or H.

96. 1. A method of treating antibody-mediated enhancement of viral disease in a fetus or newborn, comprising: administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises a sequence having at least 90% identity with the sequence of SEQ ID NO: 19, and the heavy chain is selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: The group consisting of SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24 A method comprising: selecting a sequence having at least 90% identity to a sequence selected from

97. 1. A method of treating antibody-mediated enhancement of viral disease in a fetus or newborn, comprising: administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, and the light chain comprises the sequence of SEQ ID NO: 19, and the heavy chain comprises the sequence of SEQ ID NO: 20 , SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO:

24.

98. The viral disease is an alphavirus infection, a flavivirus infection, a Zika virus infection, or Chikungunya virus infection, Ross River virus infection, Severe acute respiratory syndrome Coronavirus infection, Middle East respiratory syndrome, avian influenza infection, influenza virus Rus infection, human respiratory syncytial virus infection, Ebola virus infection, yellow fever virus Infectious diseases, dengue virus infection, human immunodeficiency virus infection, respiratory syncytial virus Infections, Hantavirus infections, Getah virus infections, Sindbis virus infections, Buny virus infections Yamwera virus infection, West Nile virus infection, Japanese encephalitis virus B infection, domestic rabbits Pox virus infection, lactate dehydrogenase elevated virus infection, reovirus infection, rabies virus virus infection, foot-and-mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection, simian Blood fever virus infection, equine infectious anemia virus infection, caprine arthritis virus infection, af Rica swine fever virus infection, lentivirus infection, BK papovavirus infection, Malay Valley encephalitis virus infection, enterovirus infection, cytomegalovirus infection, neutropenia Selected from the group consisting of rabies virus infection, morbillivirus infection, and measles virus infection The method according to any one of claims 95 to 97, which is caused by a virus selected from Law.

99. the pregnant subject has a medical condition that activates an immune response in the pregnant subject.

99. The method of claim 1, wherein the patient has or is at risk of having Law.

100. The medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome group, antibody-mediated rejection, fulminant antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerular corpitis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune Hemolytic anemia, immune neutropenia, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy inflammation, systemic lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, antineutrophilic cells Antibody-associated vasculitis (ANCA), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, and aji Son's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, Celiac sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy inflammation, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic sclerosis (CREST syndrome) syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulin Globulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism , inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin Diabetes mellitus, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease , multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, rheumatoid arthritis Polymyalgia nervosa, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis , Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, Scleroderma, Sjögren's syndrome, stiff man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis 100. The method of claim 99, wherein the disease is enteritis, uveitis, vitiligo, and Wegener's granulomatosis.

101. The pregnant subject is a patient with an alloimmune and / or autoimmune disorder of the fetus and newborn. Claims 1 to 100, having a history of having previously had a fetus or newborn 10. The method according to any one of the preceding claims.

102. and detecting antibodies associated with an immune disease in a biological sample obtained from the pregnant subject. The method according to any one of claims 1 to 101,

103. 103. The method of claim 102, wherein the biological sample is a blood sample or a urine sample.

104. 104. The method of claim 103, wherein the biological sample is a blood sample.

105. 105. Any one of claims 1 to 104, wherein the antibody administered is a monoclonal antibody. The method described below.

106. The method according to any one of claims 1 to 105, wherein the antibody administered is IgG1. Law.

107. 107. The method of any one of claims 1 to 106, wherein the antibody administered comprises a lambda light chain. 。

108. 107. The method of claim 1, wherein the antibody administered is an aglycosylated antibody. The method described.

109. Claims 1 to 9 and 12 to 47, wherein the fetus or newborn is at risk of developing anemia 10. The method according to any one of the preceding claims.

110. The antibodies administered are those of SEQ ID NO: 19 and SEQ ID NO: 24 (NO 27). The method of any one of claims 1 to 109, comprising:

111. for treating alloimmune and / or autoimmune disorders in fetuses and neonates; or A method for reducing the risk of developing the disease, comprising: an antibody comprising a light chain having the sequence of SEQ ID NO: 24 and a heavy chain having the amino acid sequence of SEQ ID NO: 25 A method comprising administering a composition comprising (N027) to a pregnant woman.

112. 112. The method of claim 111, wherein the antibody is administered at 30 mg / kg based on the weight of the pregnant woman. The method described.

113. 112. The method of claim 111, wherein the antibody is administered at 15 mg / kg based on the weight of the pregnant woman. The method described.

114. the dose is per administration and is based on the weight of the pregnant woman at the time of the first administration; and is not adjusted upward based on maternal weight gain. How to post.

115. the dose is per administration and is based on the weight of the pregnant woman at the time of the first administration; and is adjusted upward based on the maternal weight gain. How to do it.

116. 116. The method of any one of claims 111 to 115, wherein the composition is administered at least every other week. How to post.

117. 117. The method of claim 116, wherein the composition is administered every other week.

118. 116. The method of any one of claims 111 to 115, wherein the composition is administered at least weekly. How to do it.

119. 119. The method of claim 118, wherein the composition is administered weekly.

120. The method according to any one of claims 111 to 119, wherein administration begins in the first trimester of pregnancy. Law.

121. The method according to any one of claims 111 to 119, wherein administration begins in the second trimester of pregnancy. Law.

122. The method according to any one of claims 111 to 119, wherein administration begins in the third trimester of pregnancy. Law.

123. 123. The method of any one of claims 111 to 122, wherein the route of administration is intravenous.

124. 124. A method according to any one of claims 111 to 123, wherein the pregnant woman has an obstetric history of severe fetal anemia. The method described.

125. the pregnant woman has elevated anti-RhD, anti-Rhc, or anti-Kell immunoglobulin alloantibodies 125. The method of any one of claims 111 to 124, wherein the antibody has a potent antibody.

126. The pregnant woman has elevated anti-Rhc or anti-Kell immunoglobulin alloantibody titers. The method of claim 125.

127. The pregnant woman is ａ , Lu ｂ , Bg, Kn ａ , Yt ａ , E. c. K.C. ｗ , Fy ａ , cE、ce、D、Ce、cE、K、Kp ａ 、Kp ｂ 、Fy ａ 、M、N、S、Le ａ 、Le ｂ , Fy, Jk ａ Diego, P., and Mi ａ / Mur 111 to 113, having elevated immunoglobulin alloantibody titers for one or more antibodies.

125. The method of any one of claims 125 to 125.

128. The pregnant woman had an obstetric history of severe fetal anemia or stillbirth before 24 weeks of gestation, and elevated have anti-D or anti-Kell IgG alloantibody titers and are pregnant with an antigen-positive fetus 128. The method according to any one of claims 111 to 127.

129. Claims 111 to 119 and 123 to 128, wherein the first administration is at 12 to 16 weeks of pregnancy 10. The method according to any one of the preceding claims.

130. 130. The method of claim 129, wherein the first administration is at 14 weeks of pregnancy.

131. for treating alloimmune and / or autoimmune disorders in fetuses and neonates; or A method for reducing the risk of developing the disease, comprising: an antibody comprising a light chain having the sequence of SEQ ID NO: 24 and a heavy chain having the amino acid sequence of SEQ ID NO: 25 (M281) to a pregnant woman, wherein the administration of M281 is at a gestational age of 34 weeks. Exit after, method.

132. 131. IVIG is administered to the pregnant woman after completion of M281 administration and before birth. The method described below.

133. 132. The method of claim 131, wherein IVIG is administered to the pregnant woman 40 to 100 hours before birth. How to do it.

134. 132. The method of claim 131, wherein administration of M281 is terminated after 35 weeks of gestation.

135. 132. The method of claim 131, wherein administration of M281 is terminated before 36, 37, or 38 weeks of gestation. How to post.

136. IVIG is administered at 200 mg / kg to 1000 mg / kg based on the weight of the pregnant woman. The method of claim 131,

137. 132. The method of claim 131, wherein the antibody is administered at 30 mg / kg based on the weight of the pregnant woman. The method described.

138. 132. The method of claim 131, wherein the antibody is administered at 15 mg / kg based on the weight of the pregnant woman. The method described.

139. the dose is per administration and is based on the weight of the pregnant woman at the time of the first administration; and is not adjusted upward based on maternal weight gain. How to post.

140. the dose is per administration and is based on the weight of the pregnant woman at the time of the first administration; and is adjusted upward based on the maternal weight gain. How to do it.

141. 141. The method of any one of claims 131 to 140, wherein the composition is administered at least every other week. How to post.

142. 142. The method of claim 141, wherein the composition is administered every other week.

143. 142. The method of claim 141, wherein the composition is administered at least weekly.

144. 119. The method of claim 118, wherein the composition is administered weekly.

145. The method according to any one of claims 131 to 144, wherein administration is initiated in the first trimester of pregnancy. Law.

146. The method according to any one of claims 131 to 144, wherein administration begins in the second trimester of pregnancy. Law.

147. The method according to any one of claims 131 to 144, wherein administration begins in the third trimester of pregnancy. Law.

148. 148. The method of any one of claims 131 to 147, wherein the route of administration is intravenous.

149. 149. Any one of claims 131 to 148, wherein the pregnant woman has an obstetric history of severe fetal anemia. The method described below.

150. the pregnant woman has elevated anti-RhD, anti-Rhc, or anti-Kell immunoglobulin alloantibodies 149. The method of any one of claims 131 to 148, wherein the antibody has a potent antibody.

151. The pregnant woman has elevated anti-Rhc or anti-Kell immunoglobulin alloantibody titers. The method of claim 150.

152. The pregnant woman is ａ , Lu ｂ , Bg, Kn ａ , Yt ａ , E. c. K.C. ｗ , Fy ａ , cE、ce、D、Ce、cE、K、Kp ａ 、Kp ｂ 、Fy ａ 、M、N、S、Le ａ 、Le ｂ , Fy, Jk ａ Diego, P., and Mi ａ / Mur 131 to 133, having elevated immunoglobulin alloantibody titers for one or more antibodies.

148. The method of any one of claims 148 to 148.

153. The pregnant woman had an obstetric history of severe fetal anemia or stillbirth before 24 weeks of gestation, and elevated have anti-D or anti-Kell IgG alloantibody titers and are pregnant with an antigen-positive fetus 149. The method of any one of claims 131 to 148.

154. Claims 131 to 144 and 149 to 153, wherein the first administration is at 12 to 16 weeks of pregnancy.

10. The method according to any one of the preceding claims.

155. 155. The method of claim 154, wherein the first administration is at 14 weeks of pregnancy.

156. The method according to any one of claims 131 to 144, wherein administration is initiated in the first trimester of pregnancy. Law.

157. for treating alloimmune and / or autoimmune disorders in fetuses and neonates; or A method for reducing the risk of developing the disease, comprising: an antibody comprising a light chain having the sequence of SEQ ID NO: 24 and a heavy chain having the amino acid sequence of SEQ ID NO: 25 (M281) to a pregnant woman, wherein the administration of M281 comprises at least A method that ends one week before birth.

158. The method according to claim 132, wherein administration of IVIg is initiated 1 to 15 days after the end of administration of M281. How to post.

Images