FcRn antibodies and methods of using the same

Abstract

To provide a method of treating a fetal and neonatal alloimmune and / or autoimmune disorder.SOLUTION: A method comprises administering an antibody to a pregnant subject, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3.SELECTED DRAWING: None

Description

Background Art

[0001] Background of the Invention Therapeutic proteins, such as therapeutic antibodies, have rapidly become a clinically important class of drugs for patients with immune diseases. A number of autoimmune and alloimmune diseases are mediated by pathogenic antibodies. There is a need for new methods of treating immune diseases.

Summary of the Invention

[0002] The present invention features novel antibodies against the human neonatal Fc receptor (FcRn). These anti-FcRn antibodies are useful, for example, for promoting the removal of autoantibodies in a subject, for suppressing antigen presentation in a subject, for blocking an immune response, for example, for blocking activation based on immune complexes of an immune response in a subject, or for treating an immune disease (e.g., an autoimmune disease) in a subject.

[0003] In one aspect, the present invention features an isolated antibody that binds to human FcRn. The isolated antibody has (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 comprises a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000001.tif4128, CDR L2 comprises a sequence having no more than one amino acid substitution relative to the sequence of GDSE Contains a sequence having one or fewer amino acid substitutions relative to the sequence of TIFF0007690538000003.tif4128, wherein CDR H2 is Contains a sequence having one or fewer amino acid substitutions relative to the sequence of TIFF0007690538000004.tif9158, and CDR H3 is LA Contains a sequence having one or fewer amino acid substitutions relative to the sequence of IGDSY (SEQ ID NO:11) and

[0004] In some embodiments, the antibody has a K of less than 200 pM, less than 150 pM, less than 100 pM D and binds to human FcRn.

[0005] In some embodiments, the antibody has a light chain variable region and a heavy chain variable region of N022, N023, N024, N026, or N027, and a K of the antibody compared to the Fc region of the antibody having the same Fc region D less than or equal to the following K D and binds to human FcRn. In another aspect the invention features an isolated antibody comprising (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 comprises the sequence of TIFF0007690538000005.tif4128, CDR L2 comprises GDX X 3 X 4 the sequence of RPS (SEQ ID NO:13) CDR L3 comprises the sequence of TIFF0007690538000006.tif4128, CDR H1 comprises Z 1 the sequence of YAMG (SEQ ID NO:15) CDR H2 comprises TIFF0007690538000007.tif contains an array of 4128, and CDR H3 is LAZ 5 Z 6 DSY (SEQ ID NO:17) contains the array of, where X 1 is a polar or hydrophobic amino acid, X 2 is a hydrophobic amino acid and X 3 is a polar amino acid, X 4 is a polar or acidic amino acid, X 5 is polar or a hydrophobic amino acid, X 6 is a hydrophobic amino acid, Z 1 is polar or acidic amino acid, Z 2 is a polar or hydrophobic amino acid, Z 3 is G, S, or A and Z 4 is a basic amino acid, Z 5 is a hydrophobic or basic amino acid, and also Z 6 is G, S, D, Q, or H, and where the antibody has a light chain variable region and a heavy chain variable region of N02 6 and has the same Fc region as the antibody to be compared and the K D of the antibody that binds with a K D below. In some embodiments, X 1 is T, A, S, or I. In other embodiments, X 2 is L or I. In some embodiments X 3 is S, N, or T. In still other embodiments, X 4 is Q, E, or N, and X 5 is C, S, I, or Y. In some embodiments, X 6 is A or V, and Z 1 is E, T, D, or N. In further embodiments, Z 2 is S or A. In some embodiments, Z 4 is K or R. In still other embodiments, Z 5 is I, L, or H.

[0006] In another aspect, the invention has a CDR L1 having the sequence of TIFF0007690538000008.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), and a CDR L3 having the sequence of TIFF0007690538000009.tif4128, and a light chain variable region comprising a CDR H1 having the sequence of YAMG (SEQ ID NO:15), 1 a CDR H2 having the sequence of TIFF0007690538000010.tif4128, and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11), and a heavy chain variable region, wherein Z is T, D, or N, Z is S or A, and Z is G, S, or 1 A. 2 In some embodiments, the isolated antibody 3 has a CDR L1 having the sequence of TIFF0007690538000011.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), a CDR L3 having the sequence of TIFF0007690538000012.tif4128, a CDR H1 having the sequence of TYAMG (SEQ ID NO:4),

[0007] a CDR H2 having the sequence of TIFF0007690538000013.tif4128, and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). In some embodiments, the isolated antibody has a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), a CDR L3 having the sequence of TIFF0007690538000012.tif4128, a CDR H1 having the sequence of TYAMG (SEQ ID NO:4), a CDR H1 having the sequence of TYAMG (SEQ ID NO:4), a CDR H2 having the sequence of TIFF0007690538000013.tif4128, and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). It contains a CDR H3 having columns.

[0008] In some embodiments, the isolated antibody has a CDR L1 having the sequence of TIFF0007690538000014.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2) and has a CDR L3 having the sequence of TIFF0007690538000015.tif4128, a CDR H1 having the sequence of DYAMG (SEQ ID NO:5) and has a CDR H2 having the sequence of TIFF0007690538000016.tif4128, and contains a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). It contains a CDR H3 having columns.

[0009] In some embodiments, the isolated antibody has a CDR L1 having the sequence of TIFF0007690538000017.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2) and has a CDR L3 having the sequence of TIFF0007690538000018.tif4128, a CDR H1 having the sequence of NYAMG (SEQ ID NO:6) and has a CDR H2 having the sequence of TIFF0007690538000019.tif4128, and contains a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). It contains a CDR H3 having columns.

[0010] In other embodiments, the isolated antibody has a CDR L1 having the sequence of TIFF0007690538000020.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2) and has a CDR L3 having the sequence of TIFF0007690538000021.tif4128, a CDR H1 having the sequence of TYAMG (SEQ ID NO:4) DR H1, a CDR H2 having the sequence of TIFF0007690538000022.tif4128, and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). It contains.

[0011] In yet other embodiments, the isolated antibody has a CDR L1 having the sequence of TIFF0007690538000023.tif4128, a CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), a CDR L3 having the sequence of TIFF0007690538000024.tif4128, and a CDR H1 having the sequence of TYAMG (SEQ ID NO:4), a CDR H2 having the sequence of TIFF0007690538000025.tif4128, and a CDR H3 having the sequence of LAIGDSY (SEQ ID NO:11). It contains. In some embodiments, the light chain of the isolated antibody of the present invention contains a sequence having at least 90% identity with the sequence of TIFF0007690538000026.tif21160.

[0012] In some embodiments, the heavy chain of the isolated antibody of the present invention contains a sequence having at least 90% identity with the sequence of TIFF0007690538000027.tif38160.

[0013] In other embodiments, the heavy chain of the isolated antibody of the present invention contains a sequence having at least 90% identity with the sequence of TIFF0007690538000028.tif38160.

[0014] In yet other embodiments, the heavy chain of the isolated antibody of the present invention contains a sequence having at least 90% identity with the sequence of TIFF0007690538000028.tif38160.

[0015] In yet other embodiments, the heavy chain of the isolated antibody of the present invention It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000029.tif38160.

[0016] In some embodiments, the heavy chain of the isolated antibody of the present invention It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000030.tif38160.

[0017] In other embodiments, the heavy chain of the isolated antibody of the present invention It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000031.tif38160.

[0018] In another aspect, the present invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000032.tif21160, and the heavy chain It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000033.tif38160.

[0019] In another aspect, the present invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000034.tif21160, and the heavy chain It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000035.tif38160.

[0020] In another aspect, the present invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000036.tif21160, and the heavy chain It includes a sequence having at least 90% identity with the sequence of TIFF0007690538000037.tif38160.

[0021] In another aspect, the present invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is includes a sequence having at least 90% identity with the sequence of TIFF0007690538000038.tif21160, and the heavy chain includes a sequence having at least 90% identity with the sequence of TIFF0007690538000039.tif38160.

[0022] In yet another aspect, the present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain includes a sequence having at least 90% identity with the sequence of TIFF0007690538000040.tif21160, and the heavy chain includes a sequence having at least 90% identity with the sequence of TIFF0007690538000041.tif38160.

[0023] In some embodiments, the heavy chain of the isolated antibody of the present invention has at least 95%, 97%, 99%, or 100% identity with any one of the sequences of SEQ ID NO:20 - 24. In other embodiments, the light chain of the isolated antibody of the present invention has at least 95%, 97%, 99%, or 100% identity with the sequence of SEQ ID NO:19. with the sequence of SEQ ID NO:19. and includes the sequence.

[0024] In some embodiments, the isolated antibody of the present invention further includes the amino acid substitution N297A with respect to any one of the sequences of SEQ ID NO:20 - 24. In some embodiments, the isolated antibody of the present invention further includes the amino acid substitution N297A with respect to any one of the sequences of SEQ ID NO:20 - 24.

[0025] In other embodiments, the isolated antibody further includes any one of SEQ ID NO:20 - 24 For one array, it includes amino acid substitutions D355E and L357M.

[0026] In other embodiments, the isolated antibody of the present invention further includes any one or more of the following amino acid substitutions : A23V for any one of the sequences of SEQ ID NOs: 20 - 24 , S30R, L80V, A84T, E85D, A93V, and Q38H, V58I, and G99D for the sequence of SEQ ID NO: 19.

[0027] In still other embodiments, the isolated antibody of the present invention does not contain a C - terminal lysine at residue 446 for any one of the sequences of SEQ ID NOs: 20 - 24.

[0028] In some embodiments, the antibody of any of the above aspects has the light - chain variable region and heavy - chain variable region of N022, N023, N024, N026, or N027, and also , has the same Fc region as the Fc region of the antibody being compared, and the K of the antibody binds to human FcRn with a K D as follows. The K D of the antibody binds to human FcRn with a K of, for example, less than 200 pM, 1 D less than 50 pM, less than 100 pM, less than 50 pM, or less than 40 pM in a specific K D assay.

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

[0030] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is contains the sequence of TIFF0007690538000042.tif21160, and the heavy chain contains the sequence of TIFF0007690538000043.tif38160.

[0031] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is contains the sequence of TIFF0007690538000044.tif21160, and the heavy chain contains the sequence of TIFF0007690538000045.tif38160.

[0032] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is contains the sequence of TIFF0007690538000046.tif21160, and the heavy chain contains the sequence of TIFF0007690538000047.tif38160.

[0033] In another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is contains the sequence of TIFF0007690538000048.tif21160, and the heavy chain contains the sequence of TIFF0007690538000049.tif38160.

[0034] In yet another aspect, the invention features an isolated antibody containing a light chain and a heavy chain, wherein the light chain is TIFF0007690538000050.tif contains an array of 21160, and the heavy chain is TIFF0007690538000051.tif contains an array of 38160.

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

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

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

[0038] In some embodiments, the isolated antibody of the present invention binds to rodent, e.g., mouse or rat FcRn. In some embodiments, the isolated antibody of the present invention binds to rodent, e.g., mouse or rat FcRn with a K of less than 200 pM, less than 150 pM, less than 100 pM, 5 D 0 pM, or less than 40 pM.

[0039] In another aspect, the present invention features a nucleic acid molecule encoding any of the isolated antibodies described herein .

[0040] In yet another aspect, the present invention features a vector containing a nucleic acid molecule encoding any of the antibodies described herein .

[0041] In another aspect, the invention features a host cell that expresses any of the isolated antibodies described herein. The host cell contains 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 the host cell.

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

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

[0044] In some embodiments, the method includes a step of recovering the antibody from the host cell at a concentration of, for example, about 1-100, 1-50, 1-25, 2- 50, 5-50, or 2-20 mg / ml.

[0045] In other embodiments, the host cell used in the method is a CHO cell.

[0046] In another aspect, the invention features a pharmaceutical composition comprising any of the isolated antibodies described herein and one or more pharmaceutically acceptable carriers or excipients.

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

[0048] In another aspect, the invention features a method of enhancing the catabolism of IgG in a subject. In another aspect, the invention features a method of reducing autoantibodies in a subject. In yet another aspect, the invention features a method of treating or reducing the activation of an immune response based on immune complexes in a subject. The method comprises administering to the subject any of the isolated antibodies described herein, or a pharmaceutical composition comprising any of

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

[0050] In some embodiments, the subject has a medical condition selected from the group consisting of pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, catastrophic antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune deafness, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated cardiomyopathy, and serum sickness, or an acute immune response is

[0051] activated by a medical condition selected from the group consisting of them. In some embodiments, the subject has a medical condition selected from the group consisting of chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus, chronic forms of disorders requiring acute treatment, reactive arthritis, primary biliary cirrhosis, It is activated by the medical condition.

[0052] In some embodiments, the subject has an autoimmune disease or the immune response is activated by an autoimmune disease. In particular, the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, myocarditis, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis.

[0053] In another aspect, the invention features a method of treating alloimmune and / or autoimmune disorders in a fetal and neonatal subject that comprises, consists of, or essentially consists of administering an antibody to a pregnant subject. and here, the antibody comprises (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1 , CDR H2, and CDR H3, and consists of or consists essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of a sequence having two or fewer amino acid substitutions relative to the sequence of TGT GSDVGSYNLVS (SEQ ID NO:1), CDR L2 comprises, consists of, or consists essentially of a sequence having one or fewer amino acid substitutions relative to the sequence of GDSERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of a sequence having one or fewer amino acid substitutions relative to the sequence of TIFF0007690538000052.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having one or fewer amino acid substitutions relative to the sequence of TYAMG (SEQ ID NO:4), DY AMG (SEQ ID NO:5) or NYAMG (SEQ ID NO:6), CDR H2 comprises, consists of, or consists essentially of a sequence having two or fewer amino acid substitutions relative to the sequence of TIFF0007690538000053.tif9128, and CDR H3 comprises, consists of, or consists essentially of a sequence having one or fewer amino acid substitutions relative to the sequence of LAIGDSY (SEQ ID NO :11).

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

[0055] In some embodiments of all aspects, CDR L1 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000054.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDS ERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000055.tif4128, CDR H1 comprises, consists of, or consists essentially of the sequence TYA MG (SEQ ID NO::4), CDR H2 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000056.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO:11). including TIFF0007690538000056.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO:11), comprises, consists of, or consists essentially of the sequence from it.

[0056] In some embodiments of all aspects, CDR L1 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000057.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDS ERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000058.tif4128, CDR H1 comprises, consists of, or consists essentially of the sequence DYA MG (SEQ ID NO::5), CDR H2 comprises, consists of, or consists essentially of the sequence from it, and CDR H3 comprises, consists of, or consists essentially of the sequence including TIFF0007690538000058.tif4128, CDR H1 comprises, consists of, or consists essentially of the sequence DYA MG (SEQ ID NO::5), comprises, consists of, or consists essentially of the sequence from it.​​​ Comprising TIFF0007690538000059.tif4128, consisting of or consisting essentially of said sequence, and CDR H3 is a sequence Comprising LAIGDSY (SEQ ID NO:11), consisting of or consisting essentially of said sequence.

[0057] In some embodiments of all aspects, CDR L1 is a sequence Comprising TIFF0007690538000060.tif4128, consisting of or consisting essentially of said sequence, CDR L2 is the sequence GDS Comprising ERPS (SEQ ID NO:2), consisting of or consisting essentially of said sequence, CDR L3 is a sequence Comprising TIFF0007690538000061.tif4128, consisting of or consisting essentially of said sequence, CDR H1 is the sequence NYA Comprising MG (SEQ ID NO::6), consisting of or consisting essentially of said sequence, CDR H2 is a sequence Comprising TIFF0007690538000062.tif4128, consisting of or consisting essentially of said sequence, and CDR H3 is a sequence Comprising LAIGDSY (SEQ ID NO:11), consisting of or consisting essentially of said sequence.

[0058] In some embodiments of all aspects, CDR L1 is a sequence Comprising TIFF0007690538000063.tif4128, consisting of or consisting essentially of said sequence, CDR L2 is the sequence GDS Comprising ERPS (SEQ ID NO:2), consisting of or consisting essentially of said sequence, CDR L3 is a sequence TIFF0007690538000064.tif4128, comprising, consisting of or consisting essentially of the sequence, and CDR H1 is the sequence TYA MG (SEQ ID NO::4), and CDR H2 has the sequence TIFF0007690538000065.tif4128, and CDR H3 is LAIGDSY (SEQ ID NO: 11), It essentially becomes

[0059] In some embodiments of all aspects, CDR L1 has the sequence TIFF0007690538000066.tif4128, comprising, consisting of or consisting essentially of the sequence, and CDR L2 is ERPS (SEQ ID NO:2), and CDR L3 is the sequence TIFF0007690538000067.tif4128, comprising, consisting of or consisting essentially of the sequence, wherein CDR H1 is the sequence TYA MG (SEQ ID NO::4), and CDR H2 has the sequence TIFF0007690538000068.tif4128, and CDR H3 is LAIGDSY (SEQ ID NO: 11), 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 an embodiment, the subject during pregnancy has previously had a pregnancy in which the fetus or neonate has a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a risk of having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder.

[0061] In some embodiments of all aspects, the fetal and neonatal alloimmune disorder and / or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolytic disease, alloimmune pancytopenia, 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 mellitus. In some embodiments of all aspects, the fetal and neonatal autoimmune and / or autoimmune disorder is fetal and neonatal hemolytic disease. In some embodiments of all aspects, the fetal and neonatal autoimmune and / or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia. In some embodiments of all aspects, the fetal and neonatal autoimmune and / or autoimmune disorder is congenital heart block.

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

[0063] In another aspect, the invention comprises administering an antibody to a subject during pregnancy, consists of administering an antibody to a subject during pregnancy, or consists essentially of administering an antibody to a subject during pregnancy A method for treating alloimmune and / or autoimmune disorders in fetuses and neonates, characterized in that the antibody comprises (1) a light chain variable region comprising, consisting of, or essentially consisting of CDR L1, CDR L2, and CDR L3, and (2) CDR H1 , CDR H2, and CDR H3, comprising, consisting of, or essentially consisting of the same, and the light chain variable region and the heavy chain variable region consisting of or essentially consisting of the light chain variable region and the heavy chain variable region, wherein CDR L1 comprises the sequence TIFF0007690538000069.tif4128, consisting of or essentially consisting of the sequence, CDR L2 is the sequence GDX 3X4RPS (SEQ ID NO:13), consisting of or essentially consisting of the sequence, CDR L3 comprises the sequence TIFF0007690538000070.tif4128, consisting of or essentially consisting of the sequence, CDR H1 is the sequence Z1Y AMG (SEQ ID NO:15), consisting of or essentially consisting of the sequence, CDR H2 comprises the sequence TIFF0007690538000071.tif4128, consisting of or essentially consisting of the sequence, CDR H3 is the sequence LAZ 5Z6DSY (SEQ ID NO:17), consisting of or essentially consisting of the sequence, wherein X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid X3 is a polar amino acid, X4 is a polar or acidic amino acid, X5 is a polar or hydrophobic amino acid, X6 is a hydrophobic amino acid, Z1 is a polar or acidic amino acid, Z2 is a polar or hydrophobic amino acid, Z3 is G, S, or A and wherein X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid X3 is a polar amino acid, X4 is a polar or acidic amino acid, X5 is a polar or hydrophobic amino acid, X6 is a hydrophobic amino acid, Z1 is a polar or acidic amino acid, Z2 is a polar or hydrophobic amino acid, Z3 is G, S, or A amino acid, and wherein X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid X3 is a polar amino acid, X4 is a polar or acidic amino acid, X5 is a polar wherein Z4 is a basic amino acid, Z5 is a hydrophobic or basic amino acid, and wherein Z6 is G, S, D, Q, or H, and wherein the antibody binds to human F cRn with a KD of less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 pM.

[0064] In some embodiments of all aspects, CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000072.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX 3X4RPS (SEQ ID NO:13), CDR L3 comprises, consists of, or consists essentially of the sequence TIFF0007690538000073.tif4128, CDR H1 comprises, consists of, or consists essentially of the sequence Z1Y TIFF0007690538000073.tif4128, CDR H1 comprises, consists of, or consists essentially of the sequence AMG (SEQ ID NO:15), CDR H2 comprises, consists of, or consists essentially of the sequence AMG (SEQ ID NO:15), CDR H2 comprises, consists of, or consists essentially of the sequence TIFF0007690538000074.tif4128, CDR H3 comprises, consists of, or consists essentially of the sequence LAZ TIFF0007690538000074.tif4128, CDR H3 comprises, consists of, or consists essentially of the sequence 5Z6DSY (SEQ ID NO:17), where X1 is T, A, S, or I, X2 is L or I, 5Z6DSY (SEQ ID NO:17), where X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N, X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I , L, or H, and Z6 is G, S, D, Q, or H.

[0065] In some embodiments of all aspects, CDR L1 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000075.tif4128, CDR L2 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of GDSERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000076.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). TIFF0007690538000075.tif4128 relative to the sequence of TIFF0007690538000075.tif4128, CDR L2 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of GDSERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000076.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of GDSERPS (SEQ ID NO:2), CDR L3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000076.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000076.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000076.tif4128, CDR H1 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000077.tif4128, CDR H2 comprises, consists of, or consists essentially of a sequence having no more than two amino acid substitutions relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of TIFF0007690538000078.tif9140, and CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of LAIGDSY (SEQ ID NO:11), CDR H3 comprises, consists of, or consists essentially of a sequence having no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO:11). relative to the sequence of LAIGDSY (SEQ ID NO:11).

[0066] In some embodiments of all aspects, the subject has a history of having had a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. For example, in some embodiments, the subject during pregnancy has previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. For example, in some embodiments, the subject during pregnancy has previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. For example, in some embodiments, the subject during pregnancy has previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. For example, in some embodiments, the subject during pregnancy has previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. For example, in some embodiments, the subject during pregnancy has previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune disorder and / or an autoimmune disorder. In some embodiments of all aspects, the subject has a fetal and neonatal alloimmune disorder and / or an autoimmune There is a risk of having immune disorders.

[0067] In some embodiments of all aspects, fetal and neonatal alloimmune disorders and / or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolytic disease, alloimmune pancytopenia, 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, selected from the group consisting of. In some embodiments of all aspects, fetal and neonatal autoimmunity and / or autoimmune disorders are fetal and neonatal hemolytic disease. In some embodiments of all aspects, fetal and neonatal autoimmunity and / or autoimmune disorders are fetal and neonatal alloimmune thrombocytopenia. In some embodiments of all aspects, fetal and neonatal autoimmunity and / or autoimmune disorders are congenital heart block. In some embodiments of all aspects, the treatment reduces the risk of miscarriage.

[0068] In another aspect, the present invention features a method for treating fetal and neonatal alloimmune disorders and / or autoimmune disorders in a pregnant subject, comprising administering an antibody to the pregnant subject, consisting of administering an antibody to the pregnant subject, or essentially consisting of administering an antibody to the pregnant subject, wherein the antibody has a CDR L1 having the sequence TIFF0007690538000079.tif4128, a CDR L2 having the sequence GDSERPS (SEQ ID NO:2), and a sequence A light chain variable region comprising, consisting of, or consisting essentially of a CDR L3 having TIFF0007690538000080.tif4128 and a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein CDR H1 comprises, consists of, or consists essentially of the sequence Z1YAMG (SEQ ID NO:15), CDR H2 comprises, consists of, or consists essentially of the sequence TIFF0007690538000081.tif4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO:11), and wherein Z1 is T, D, or N, Z2 is S or A , Z3 is G, S, or A, the heavy chain variable region, and the light chain variable region and the heavy chain variable region consisting of, or consisting essentially of. In some embodiments of all aspects, the light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to the sequence of TIFF0007690538000082.tif21160 . In some embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to the sequence of TIFF0007690538000083.tif38160 .

[0069] In some embodiments of all aspects, the heavy chain

[0070] In some embodiments of all aspects, the heavy chain

[0071] In some embodiments of all aspects, the heavy chain ​​​​Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000084.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of.

[0072] In some embodiments of all aspects, the heavy chain is Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000085.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of.

[0073] In some embodiments of all aspects, the heavy chain is Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000086.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of.

[0074] In some embodiments of all aspects, the heavy chain is Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000087.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of.

[0075] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy Wherein the antibody 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 with the sequence of TIFF0007690538000088.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain is Wherein the light chain comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000088.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain is Consisting essentially of said sequence, and wherein the light chain Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000088.tif21160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of said sequence, and the heavy chain is Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000089.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of the foregoing

[0076] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, wherein the antibody 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 with the sequence of TIFF0007690538000090.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000091.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of the foregoing Wherein the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000090.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain Consisting essentially of the foregoing Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000091.tif38160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of the foregoing

[0077] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, wherein the antibody 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 with the sequence of TIFF0007690538000092.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000092.tif21160, consisting of said sequence, or consisting essentially of said sequence Consisting essentially of the foregoing Wherein the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000092.tif21160, consisting of said sequence, or consisting essentially of said sequence, and the heavy chain Consisting essentially of the foregoing Comprising a sequence having at least 90% identity with the sequence of TIFF0007690538000093.tif38160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of

[0078] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000094.tif21160, consisting of such sequence, or consisting essentially of such sequence, and the heavy chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000095.tif38160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of Where the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000094.tif21160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of, and the heavy chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000095.tif38160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of

[0079] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000096.tif21160, consisting of such sequence, or consisting essentially of such sequence, and the heavy chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000096.tif21160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of Where the light chain Comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000096.tif21160, consisting of such sequence, or consisting essentially of such sequence Consisting essentially of, and the heavy chain A sequence that has at least 90% identity with the sequence of TIFF0007690538000097.tif38160, consists of such a sequence, or is essentially composed of such a sequence. Consists essentially of.

[0080] In some embodiments of all aspects, the heavy chain has at least 95%, 97%, 99%, or 100% identity with any one of the sequences of SEQ ID NOs: 20 - 24, consists of such a sequence, or is essentially composed of such a sequence. In some embodiments of all aspects, the light chain has at least 95%, 9 7%, 99%, or 100% identity with the sequence of SEQ ID NO: 19, consists of such a sequence, or is essentially composed of such a sequence. Consists essentially of such a sequence. In some embodiments of all aspects, the antibody further contains the amino acid substitution N297A with respect to any one of the sequences of SEQ ID NOs: 20 - 24, consists of it, or is essentially composed of it. In some embodiments of all aspects, the antibody further contains the amino acid substitutions D355 E and L357M with respect to any one of the sequences of SEQ ID NOs: 20 - 24, consists of them, or is essentially composed of them. In some embodiments of all aspects, the antibody further contains any one or more of the following amino acid substitutions, consists of them, or is essentially composed of them: A23V, S30R, L80V, A84T, E

[0081] 85D, A93V with respect to any one of the sequences of SEQ ID NOs: 20 - 24, and Q38H, V58I With respect to any one of the sequences of SEQ ID NOs: 20 - 24, and G99D with respect to the sequence of SEQ ID NO: 19. In some embodiments of all aspects, the antibody further contains any one or more of the following amino acid substitutions, consists of them, or is essentially composed of them: A23V, S30R, L80V, A84T, E 85D, A93V with respect to any one of the sequences of SEQ ID NOs: 20 - 24, and Q38H, V58I And G99D with respect to the sequence of SEQ ID NO: 19, consists of them, or is essentially composed of them. In some embodiments of all aspects, the antibody further contains any one or more of the following amino acid substitutions, consists of them, or is essentially composed of them: For any one of the sequences of SEQ ID NOs: 20 - 24, A23V, S30R, L80V, A84T, E 85D, A93V, and for the sequence of SEQ ID NO: 19, Q38H, V58I , and G99D.

[0082] In some embodiments of all aspects, the antibody does not contain a C-terminal lysine at residue 446 with respect to any one of the sequences of SEQ ID NOs: 20 to 24.

[0083] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising, consisting essentially of, or consisting of administering an antibody to a pregnant subject, where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000098.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000099.tif38160.

[0084] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising, consisting essentially of, or consisting of administering an antibody to a pregnant subject, where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000100.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000101.tif38160.

[0085] In another aspect, the present invention features a method of treating alloimmune and / or autoimmune disorders in a fetus and a neonate, comprising administering an antibody to a pregnant subject. ​​​​​​​​​​​​​Comprising administering an antibody, or consisting essentially of administering an antibody to a subject during pregnancy, a method for treating alloimmune and / or autoimmune disorders in fetuses and neonates characterized in that, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000102.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000103.tif38160.

[0086] In another aspect, the present invention comprises administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, a method for treating alloimmune and / or autoimmune disorders in fetuses and neonates characterized in that, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000104.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000105.tif38160.

[0087] In another aspect, the present invention comprises administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, a method for treating alloimmune and / or autoimmune disorders in fetuses and neonates characterized in that, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000102.tif21160, and the heavy chain comprises, consists of, or consists essentially of the sequence of TIFF0007690538000103.tif38160. comprises, consists of, or consists essentially of the sequence of TIFF0007690538000104.tif21160, and the heavy chain​​​​​ TIFF0007690538000106.tif, comprising the sequence 21160, consisting of the sequence, or consisting essentially of the sequence, and the heavy chain is TIFF0007690538000107.tif, comprising the sequence 38160, consisting of the sequence, or consisting essentially of the sequence.

[0088] In another aspect, the invention features a method for treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of (1) a light chain comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000108.tif 4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX 3X4RPS (SEQ ID NO:13), CDR L3 comprises, consists of, or consists essentially of the sequence TIFF0007690538000109.tif 4128, CDR H1 comprises, consists of, or consists essentially of the sequence Z1Y AMG (SEQ ID NO:15), CDR H2 comprises, consists of, or consists essentially of the sequence TIFF0007690538000110.tif 4128, and CDR H3 comprises, consists of, or consists essentially of the sequence LAZ 3X4RPS(SEQ ID NO:13), consisting of the sequence, or consisting essentially of the sequence, and CDR L3 is, consists of, or consists essentially of the sequence TIFF0007690538000109.tif 4128, CDR H1 is, consists of, or consists essentially of the sequence Z1Y AMG(SEQ ID NO:15), consisting of the sequence, or consisting essentially of the sequence and CDR H2 is, consists of, or consists essentially of the sequence TIFF0007690538000110.tif 4128, CDR H3 is, consists of, or consists essentially of the sequence LAZ Comprising 5Z6DSY (SEQ ID NO:17), consisting of said sequence, or consisting essentially of said sequence, wherein X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N, X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I L, or H, and Z6 is G, S, D, Q, or H.

[0089] In another aspect, the invention features a method of treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of 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 a sequence having at least 90% identity to a sequence 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.

[0090] In another aspect, the invention features a method of treating fetal anemia associated with hemolytic disease of the fetus and newborn, comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, ​ wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, and the wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:2 1, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO :24.

[0091] In some embodiments of all aspects, the method treats a subject during pregnancy, a fetus of a subject during pregnancy, and / or a combination thereof.

[0092] In another aspect, the invention features a method of treating an autoimmune disorder that comprises, consists of, or consists essentially of administering an antibody to a subject during pregnancy, wherein the antibody comprises, consists of, or consists essentially of: (1) a light chain variable region that comprises, consists of, or consists essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region that comprises, consists of, or consists essentially of CDR H1, CDR H2, and CDR H3, wherein CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000111.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX 3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence and the light chain variable region and the heavy chain variable region consist of or consist essentially of the light chain variable region and the heavy chain variable region, where TIFF0007690538000111.tif4128, and CDR L3 comprises, consists of, or consists essentially of a sequence Comprising TIFF0007690538000112.tif4128, consisting of or consisting essentially of said sequence, wherein CDR H1 is the sequence Z1Y Comprising AMG (SEQ ID NO:15), consisting of or consisting essentially of said sequence wherein CDR H2 is the sequence Comprising TIFF0007690538000113.tif4128, consisting of or consisting essentially of said sequence, wherein CDR H3 is the sequence LAZ Comprising 5Z6DSY (SEQ ID NO:17), consisting of or consisting essentially of said sequence wherein X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N wherein X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I, L, or H, and Z6 is G, S, D, Q, or H.

[0093] In another aspect, the invention features a method of treating an autoimmune disorder in a pregnant subject, comprising, consisting of, or consisting essentially of administering an antibody to the pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of 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 a sequence having at least 90% identity to a sequence 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. 19, consisting of or consisting essentially of said sequence and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence 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. mu, consisting of or consisting essentially of said sequence.

[0094] In another aspect, the invention comprises administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, a method of treating an autoimmune disorder, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO: 19, and the heavy chain consists of a sequence 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, consisting of or consisting essentially of said 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, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, juvenile arthritis, lichen planus, lupus, Meniere's disease, , polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatic joint inflammation, sarcoidosis, scleroderma, Sjogren'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 consisting essentially of The present invention features a method for reducing the risk of developing an immune disorder or an alloimmune disorder, comprising administering to said patient an antibody that is capable of inhibiting said immune disorder or an alloimmune disorder. (1) comprises and 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 and CDR H3. and and a heavy chain variable region, wherein CDR L1 is TIFF0007690538000114.tif4128, comprising, 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 TIFF0007690538000115.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO:15), and CDR H2 is TIFF0007690538000116.tif4128, consisting of or consisting essentially of the sequence, wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially where 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 consisting essentially of The present invention features a method for reducing the risk of developing an immune disorder or an alloimmune disorder, comprising administering to said patient an antibody that is capable of inhibiting said immune disorder or an alloimmune disorder. 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: a sequence selected from the group consisting of SEQ ID NO:23 and SEQ ID NO:24 and having at least 90 % identity, consisting of, or consisting essentially of, such a sequence.

[0099] In another aspect, the invention features a method of reducing the risk of an autoimmune or alloimmune disorder or the risk of developing an autoimmune or alloimmune disorder, including administering an FcRn antibody to a pregnant subject, where the antibody consists of, consists essentially of, or includes a light chain and a heavy chain, where the light chain consists of, consists essentially of, or includes the sequence of SEQ ID NO:19, and the heavy chain consists of, consists essentially of, or includes a sequence 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.

[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, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, 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, 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, Sjogren's syndrome, stiff man syndrome, Takayasu arteritis , temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis. Selected from the group consisting of.

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

[0102] In another aspect, the present invention features a method of enhancing the catabolism of an antibody in a subject, the method comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or essentially consisting of administering an antibody to a pregnant subject, wherein the administered antibody comprises, consists of, or essentially consists of (1) a light chain variable region comprising, consisting of, or essentially consisting of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or essentially consisting of CDR H1, CDR H2, and CDR H3, the light chain variable region and the heavy chain variable region consisting of or essentially consisting of the light chain variable region and the heavy chain variable region, wherein CDR L1 comprises, consists of, or essentially consists of the sequence TIFF0007690538000117.tif4128, CDR L2 comprises, consists of, or essentially consists of the sequence GDX 3X4RPS (SEQ ID NO:13), consisting of, or essentially consisting of the sequence, and CDR L2 consists of the sequence GDX 3X4RPS (SEQ ID NO:13) and consists of or essentially consists of the sequence. becomes essentially, and CDR L3 consists of, consists essentially of, or consists of an array containing TIFF0007690538000118.tif4128, and CDR H1 consists of, consists essentially of, or consists of an array containing the sequence Z1Y AMG (SEQ ID NO:15), and CDR H2 consists of, consists essentially of, or consists of an array containing becomes essentially, and CDR H3 consists of, consists essentially of, or consists of an array containing the sequence TIFF0007690538000119.tif4128, and CDR H3 consists of, consists essentially of, or consists of an array containing the sequence LAZ 5Z6DSY (SEQ ID NO:17), and here, X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N, X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I L, or H, and Z6 is G, S, D, Q, or H.

[0103] In another aspect, the present invention features a method for enhancing the catabolism of an antibody in a subject, the method comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, or consisting essentially of administering an antibody to a pregnant subject, where the administered antibody contains, consists of, or consists essentially of a light chain and a heavy chain, where the light chain contains, consists of, or consists essentially of a sequence having at least 90% identity with the sequence of SEQ ID NO:19, and the heavy chain has SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID N O:23, or SEQ ID NO:24, and consists of, consists essentially of, or consists of an array containing the sequence NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID N a sequence selected from the group consisting of SEQ ID NO:23 and SEQ ID NO:24 and having at least 90% identity, consisting of, or consisting essentially of, such sequence.

[0104] In another aspect, the invention features a method of enhancing catabolism of an antibody in a subject, the method including, consisting of, or consisting essentially of, administering an antibody to a pregnant subject, where the administered antibody includes, consists of, or consists essentially of a light chain and a heavy chain, where the light chain includes, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain includes, consists of, or consists essentially of a sequence 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:2 4. In some embodiments of all aspects, enhancing catabolism of the antibody includes enhancing catabolism of a pathogenic antibody. In some embodiments of all aspects, the pathogenic antibody is pathogenic to the

[0105] mother, the fetus, or both the mother and the fetus. In some embodiments of all aspects, the pathogenic antibody is an IgG antibody. In some embodiments of all aspects, the antibody causes alloimmune and / or autoimmune disorders in the fetus and neonate in the fetus within a pregnant subject. In some embodiments of all aspects, the alloimmune and / or autoimmune disorders in the fetus and neonate

[0106] In some embodiments of all aspects, the alloimmune and / or ​or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia (FIT) and fetal and neonatal lytic thrombocytopenia (CTH). Hematologic dyscrasias, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonates Myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal multiple myasthenia Myositis, dermatomyositis, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease , neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes. is 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 a medicament for the treatment of a pregnancy disorder. 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 including CDR L1, CDR L2, and CDR L3 (2) a light chain variable region consisting essentially of CDR H1, CDR H2, and CDR and 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 TIFF0007690538000120.tif4128, comprising, 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 TIFF0007690538000121.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y Comprising AMG (SEQ ID NO:15), consisting of said sequence, or consisting essentially therefrom, wherein CDR H2 consists of the sequence TIFF0007690538000122.tif4128, consisting of said sequence, or consisting essentially thereof, wherein CDR H3 is the sequence LAZ comprising 5Z6DSY (SEQ ID NO:17), consisting of said sequence, or consisting essentially thereof, wherein X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N wherein X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I, L, or H, and Z6 is G, S, D, Q, or H.

[0108] In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising, consisting essentially of, or consisting of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of 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 a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO:20, SEQ I D NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24. In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising, consisting essentially of, or consisting of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of 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 a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO:20, SEQ I NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence 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. D NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24. In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising, consisting essentially of, or consisting of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of 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 a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ

[0109] In another aspect, the present invention features a method of reducing autoantibodies in a subject, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:21, SEQ ID N O:22, SEQ ID NO:23, and SEQ ID NO:24.

[0110] In another aspect, the present invention features a method of reducing activation based on immune complexes of an immune response in a subject, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, wherein the antibody comprises (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1 , CDR H2, and CDR H3, and wherein CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000123.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX 3X4RPS (SEQ ID NO:13), and wherein the antibody comprises, consists of, or consists essentially of the light chain variable region and the heavy chain variable region, or consists essentially of the light chain variable region and the heavy chain variable region, Essentially, the CDR L3 has the sequence TIFF0007690538000124.tif4128, consisting of or consisting essentially of the sequence, and wherein CDR H1 is the sequence Z1Y AMG (SEQ ID NO:15), and CDR H2 is TIFF0007690538000125.tif4128, consisting of or consisting essentially of the sequence, wherein CDR H3 is 5Z6DSY (SEQ ID NO: 17), essentially where 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 present invention relates to a method of administering an antibody to a pregnant subject, the method comprising administering an antibody to the pregnant subject. administering the antibody to a pregnant subject; Here, the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain. wherein the light chain has 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 represented by SEQ ID NO: ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ An array selected from the group consisting of SEQ ID NO: 23 and SEQ ID NO: 24 and having at least 90% identity, consisting of the array, or consisting essentially of the array. In another aspect, the present invention features a method for reducing activation based on immune complexes of the immune response in a subject, the method comprising administering an antibody to a pregnant subject, consisting of administering an antibody to a pregnant subject, consisting essentially of administering an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain,

[0112] wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO: 19, and the heavy chain comprises, consists of, or consists essentially of a sequence 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. In some embodiments of all aspects, the immune response is an acute or chronic immune response in the subject. In some embodiments of all aspects, the acute immune response is activated by a medical condition selected from the group consisting of pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, severe antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, and serum sickness. For example,

[0113]

[0114] In some embodiments, the acute immune response is activated by the medical condition of a subject during pregnancy. For example, in some embodiments, the acute immune response is activated within the fetus or neonate by the medical condition of a subject during pregnancy. In some embodiments of all aspects, the acute immune response is activated by the medical condition of a subject during pregnancy. In some embodiments of all aspects, the acute immune response is activated within the fetus or neonate by the medical condition of a subject during pregnancy. In some embodiments of all aspects, the acute immune response is activated within the fetus or neonate by the medical condition of a subject during pregnancy. In some embodiments of all aspects, the acute immune response is idiopathic thrombocytopenic purpura. In some embodiments of all aspects, the acute immune response is activated by pemphigus vulgaris. In some embodiments of all aspects, the acute immune response is activated by catastrophic antiphospholipid syndrome. In some embodiments of all aspects, the acute immune response is activated by neuromyelitis optica. In some embodiments of all aspects, the acute immune response is activated by antibody-mediated rejection. In some embodiments of all aspects, the acute immune response is activated by myasthenia gravis. In some embodiments of all aspects, the acute immune response is activated by myasthenia gravis.

[0115] Also described herein is a method of treating alloimmune and / or autoimmune disorders in a fetus and neonate, consisting of, consisting essentially of, or comprising administering M281 (e.g., at a dose of 15 mg / kg or 30 mg / kg, e.g., a weekly dose) to a subject during pregnancy and terminating administration if the subject exhibits hypoalbuminemia (e.g., serum albumin levels less than 30 g / l, 25 g / l, 20 g / l). Also described herein is a method of treating alloimmune and / or autoimmune disorders in a fetus and neonate, consisting of, consisting essentially of, or comprising administering M281 (e.g., at a dose of 15 mg / kg or 30 mg / kg, e.g., a weekly dose) to a subject during pregnancy and terminating administration if the subject exhibits hypoalbuminemia (e.g., serum albumin levels less than 30 g / l, 25 g / l, 20 g / l). administering a dose (e.g., a weekly dose), and, when the subject exhibits hypoalbuminemia (e.g., serum albumin levels of less than 30 g / l, 25 g / l, 20 g / l), administering albumin, including treating alloimmune and / or autoimmune disorders in fetuses and neonates, consisting of or essentially comprising such treatment. Also described is a method of administering M281 (e.g., a dose of 15 mg / k g or 30 mg / kg, e.g., a weekly dose) to a subject during pregnancy, and, when the subject exhibits hypo albuminemia (e.g., serum albumin levels of less than 30 g / l, 25 g / l, 20 g / l), administering a hypertonic solution (e.g., mannitol, or other solutions known in the art ), including treating alloimmune and / or autoimmune disorders in fetuses and neonates, consisting of or essentially comprising such treatment. Also described is a method of administering M281 (e.g., a dose of 15 mg / kg or 30 mg / kg, e.g., a weekly dose) to a subject during pregnancy, and testing the subject's serum albumin level at least once before or after administration of M281, including treating alloimmune and / or autoimmune disorders in fetuses and neonates, consisting of or essentially comprising such treatment. In some instances of the method, administration of M281 may or may not be continued. In some embodiments of all aspects, the chronic immune response is chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus, reactive arthritis, primary biliary cirrhosis, ulcerative colitis .

[0116] In some embodiments of all aspects, the chronic immune response is chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus, reactive arthritis, primary biliary cirrhosis, ulcerative colitis and is activated by a medical condition selected from the group consisting of antineutrophil cytoplasmic antibody - related vasculitis. In some embodiments of all aspects, the chronic immune response is activated by chronic inflammatory demyelinating polyneuropathy. In some embodiments of all aspects, the subject has an autoimmune disease. In some embodiments of all aspects, the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti - factor antibody, heparin - induced thrombocytopenia, sensitized transplantation, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, myopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg - Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease,

[0117] 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, Sjogren's syndrome, stiff - man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments of all aspects, the autoimmune disease is warm autoimmune hemolytic anemia. myopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg - Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff - man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments of all aspects, the autoimmune disease is selected from the group consisting of alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti - factor antibody, heparin - induced thrombocytopenia, sensitized transplantation, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, myopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg - Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff - man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments of all aspects, the autoimmune disease is selected from the group consisting of alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti - factor antibody, heparin - induced thrombocytopenia, sensitized transplantation, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, myopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg - Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, In some embodiments of all aspects, the autoimmune disease is a sensitized transplant.

[0118] In another aspect, the present invention features a method of reducing antibody transfer through the placenta of a subject during pregnancy, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or essentially consisting of administering an antibody to a subject during pregnancy, where the antibody comprises (1) a light chain variable region comprising, consisting of, or essentially consisting of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or essentially consisting of CDR H1, CDR H2, and CDR H3, the light chain variable region and the heavy chain variable region consisting of or essentially consisting of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or essentially consists of the sequence TIFF0007690538000126.tif4128, CDR L2 comprises, consists of, or essentially consists of the sequence GDX3X4RPS (SEQ ID NO:13), CDR L3 comprises, consists of, or essentially consists of the sequence TIFF0007690538000127.tif4128, CDR H1 comprises, consists of, or essentially consists of the sequence Z1YAMG (SEQ ID NO:15), Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, In some embodiments of all aspects, the autoimmune disease is a sensitized transplant. Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, In some embodiments of all aspects, the autoimmune disease is a sensitized transplant. Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, In some embodiments of all aspects, the autoimmune disease is a sensitized transplant. Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, In some embodiments of all aspects, the autoimmune disease is a sensitized transplant. Yes. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. That is, In some embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. That is, Comprising TIFF0007690538000128, consisting of, or consisting essentially of, said array, wherein CDR H3 comprises the sequence LAZ 5Z6DSY (SEQ ID NO:17), consisting of, or consisting essentially of, said array wherein X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N, X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I L, or H, and Z6 is G, S, D, Q, or H.

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

[0120] In another aspect, the invention features a method for reducing antibody transfer across the placenta of a pregnant subject The method, as a feature, comprises administering an antibody to a subject during pregnancy, and consists essentially of administering an antibody to a subject during pregnancy, where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence 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. In another aspect, the invention features a method of treating antibody-mediated enhancement of a viral disease in a fetus or neonate, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, where the antibody comprises, consists of, or consists essentially of (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000129.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence where the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, where the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence 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. where the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence 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. SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24 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 and comprising, consisting of, or consisting essentially of the sequence 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. .

[0121] In another aspect, the invention features a method of treating antibody-mediated enhancement of a viral disease in a fetus or neonate, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, where the antibody comprises, consists of, or consists essentially of (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000129.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence In another aspect, the invention features a method of treating antibody-mediated enhancement of a viral disease in a fetus or neonate, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, where the antibody comprises, consists of, or consists essentially of (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000129.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence In another aspect, the invention features a method of treating antibody-mediated enhancement of a viral disease in a fetus or neonate, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, where the antibody comprises, consists of, or consists essentially of (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence TIFF0007690538000129.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, and comprising, consisting of, or consisting essentially of the light chain variable region and the heavy chain variable region, where CDR L1 comprises, consists of, or consists essentially of the sequence sequence TIFF0007690538000129.tif4128 and comprising, consisting of, or consisting essentially of the sequence TIFF0007690538000129.tif4128, CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence CDR L2 comprises, consists of, or consists essentially of the sequence GDX3X4RPS (SEQ ID NO:13), and CDR L3 comprises, consists of, or consists essentially of the sequence sequence Comprising TIFF0007690538000130.tif4128, consisting of or consisting essentially of said sequence, wherein CDR H1 is the sequence Z1Y Comprising AMG (SEQ ID NO:15), consisting of or consisting essentially thereof, wherein CDR H2 is the sequence Comprising TIFF0007690538000131.tif4128, consisting of or consisting essentially of said sequence, wherein CDR H3 is the sequence LAZ Comprising 5Z6DSY (SEQ ID NO:17), consisting of or consisting from essentially thereof, wherein X1 is T, A, S, or I, X2 is L or I, X3 is S, N, or T, X4 is Q, E, or N, X5 is C, S, I, or Y, X6 is A or V, Z1 is E, T, D, or N, Z2 is S or A, Z3 is G, S, or A, Z4 is K or R, Z5 is I , L, or H, and Z6 is G, S, D, Q, or H.

[0122] In another aspect, the present invention features a method of treating antibody-mediated enhancement of viral diseases in a fetus or neonate The method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially thereof, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain wherein the light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to 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:2 2, SEQ ID NO:23, and SEQ ID NO:24 a sequence having at least 90% identity with the resulting sequence, consisting of the sequence, or consisting essentially of the sequence.

[0123] In another aspect, the present invention features a method of treating antibody-mediated enhancement of a viral disease in a fetus or newborn, the method comprising administering an antibody to a subject during pregnancy, consisting of administering an antibody to a subject during pregnancy, or consisting essentially of administering an antibody to a subject during pregnancy, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID NO:19, and the heavy chain comprises, consists of, or consists essentially of a sequence 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.

[0124] In some embodiments of all aspects, the viral disease is an alphavirus infection, a flavivirus infection, a Zika virus infection, a chikungunya virus infection, a Ross River virus infection, a severe acute respiratory syndrome coronavirus infection, a Middle East respiratory syndrome, an avian influenza infection, an influenza virus infection, a human respiratory syncytial virus infection, an Ebola virus infection, a yellow fever virus infection, a dengue virus infection, a human immunodeficiency virus infection, a respiratory syncytial virus infection, a hantavirus infection, a Getah virus infection, a Sindbis virus infection, a Bunyamwera virus infection, a West Nile virus infection, a Japanese encephalitis virus B infection, a rabbitpox virus infection, a lactate dehydrogenase-elevating virus infection ​​​​​​​​​​​​​​​​ infections, Lassa fever virus infection, rabies virus infection, foot-and-mouth disease virus infection, porcine genital 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 caused by a virus selected from the group consisting of measles virus infection.

[0125] In some embodiments of all aspects, the pregnant subject has, or is at risk of having, a medical condition that activates an immune response in the pregnant subject. In some embodiments of all aspects, the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis , Guillain-Barré syndrome, antibody-mediated rejection, catastrophic antiphospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive arthritis, 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, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic scleroderma (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, polychondritis, polyglandular syndrome, rheumatoid poly myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , 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, rheumatoid poly myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , 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, rheumatoid poly myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, rheumatoid poly myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, rheumatoid poly myalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. , Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. uveitis, vitiligo, and Wegener's granulomatosis.

[0126] In some embodiments of all aspects, the subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. For example, in some embodiments, the subject during pregnancy has had a previous pregnancy with a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. In some embodiments of all aspects, the subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. For example, in some embodiments, the subject during pregnancy has had a previous pregnancy with a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. In some embodiments of all aspects, the subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. For example, in some embodiments, the subject during pregnancy has had a previous pregnancy with a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. In some embodiments of all aspects, the subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. For example, in some embodiments, the subject during pregnancy has had a previous pregnancy with a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. In some embodiments of all aspects, the subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. For example, in some embodiments, the subject during pregnancy has had a previous pregnancy with a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate.

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

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

[0129] In another aspect, the present invention features a method for treating fetal and neonatal alloimmune and / or autoimmune disorders or reducing the risk of developing fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to a pregnant woman a composition comprising an antibody (M281) having a light chain with the amino acid sequence of SEQ ID NO: 19 and a heavy chain with the amino acid sequence of SEQ ID NO: 24, wherein administration of M281 is completed after 34 weeks of gestation.

[0130] In another aspect, the present invention features a method for treating fetal and neonatal alloimmune and / or autoimmune disorders or reducing the risk of developing fetal and neonatal alloimmune and / or autoimmune disorders, the method comprising administering to a pregnant woman a composition comprising an antibody (M281) having a light chain with the amino acid sequence of SEQ ID NO: 19 and a heavy chain with the amino acid sequence of SEQ ID NO: 24, wherein administration of M281 is completed at least 1 week before birth.

[0131] In various embodiments of both methods, the method includes the following: administering IVIG to the pregnant woman after completion of M281 administration and before birth (e.g., 40-100 hours or 1-15 days before birth); terminating administration of M281 after 35 weeks Discontinue administration of M281 8 weeks prior; administer IVIG at 200 mg / kg to 100 mg / kg based on the weight of the pregnant woman; administer M281 at 30 mg / kg based on the weight of the pregnant woman ; administer M281 at 15 mg / kg based on the weight of the pregnant woman; the dose is the dose per administration and is based on the weight of the pregnant woman at the first administration and based on the increase in the weight of the pregnant woman and is not adjusted upward; the dose is the dose per administration and is based on the weight of the pregnant woman at the first administration and is adjusted upward based on the increase in the weight of the pregnant woman; 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 started in the first trimester of pregnancy ; administration is started in the second trimester of pregnancy; administration is started in the third trimester of pregnancy ; the route of administration is intravenous; the pregnant woman has an obstetric history of severe fetal anemia; the pregnant woman has elevated anti RhD, anti-Rhc, or anti-Kell immunoglobulin alloantibody titers; the pregnant woman has elevated anti-Rhc or anti-Kell immunoglobulin alloantibody titers ; the pregnant woman has elevated immunoglobulin alloantibody titers for one or more antibodies selected from the group consisting of anti-Lu a, Lub, Bg, Kna, Yta, E.c.K.Cw, Fya, cE, ce, D, Ce , cE, K, Kpa, Kpb, Fya, M, N, S, Lea, Leb, Fy, Jka.D iego, P, and Mia / Mur; the pregnant woman has severe fetal anemia, or an obstetric history of stillbirth at ≤ 24 weeks of gestation, and elevated anti-D or anti-Kell IgG alloantibody titers and is pregnant with an antigen-positive fetus; the first administration is at 12 - 16 weeks of pregnancy; the first administration is at 14 weeks of pregnancy; and administration is started in the first trimester of pregnancy.

[0132] ​​Definition As used herein, the term "antibody" is used in the broadest sense and includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and various antibody structures including, but not limited to, antibody fragments that exhibit FcRn antigen-binding activity.

[0133] "Antibody fragment" includes a portion of an intact antibody, preferably the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments, bispecific antibodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies.

[0134] As used herein, the term "isolated antibody" refers to an antibody that has been separated and / or recovered from the components of its production host cell environment. The contaminant components of its production host cell environment are substances that interfere with the research, diagnostic, or therapeutic use of the antibody. The contaminant components can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is (1) greater than 95% by weight of the antibody, as determined, for example, by the Lowry method, and in some embodiments greater than 99% by weight, (2) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence, for example, by the use of a spinning cup sequenator, or (3) homogeneous and purified by SDS-PAGE under reducing or non-reducing conditions using, for example, Coomassie blue or silver staining. Isolated antibodies include antibodies contained in recombinant cells in situ. However, usually isolated antibodies are prepared by at least one purification step. ​​​​​​​​​​​​​​​ It is carried out. The pharmaceutical preparation of the isolated antibody is typically determined by an ELISA-based HCP assay as recommended by the FDA "Industrial Guidance" literature The host cell protein (HCP) is less than 250 ppm (e.g., less than 200 ppm, 150 ppm, 100 ppm) as determined by an ELISA-based HCP assay carried out as per the recommendation below).

[0135] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical in primary sequence except for naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and are directed against a single antigenic site (i.e., an epitope on human FcRn). In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different epitopes, each monoclonal antibody is directed against a single epitope on the antigen. The modifying factor "monoclonal" indicates the property of the antibody obtained from a substantially homogeneous population of antibodies and should not be construed to require the production of the antibody by a particular method.

[0136] As used herein, the terms "variable region" and "variable domain" refer to portions of the light and heavy chains of an antibody that include the amino acid sequences of the complementarity determining regions (CDRs, e.g., CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, and CDR H3), and the framework regions (FRs). According to the methods used in the present invention, the amino acid positions assigned to the CDRs and FRs are defined according to Kabat (Sequences of Proteins of Immunological Intere 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 may contain fewer or additional amino acids corresponding to truncations of the variable region C DR (as further defined herein) or FR (as further defined herein), or insertions into the CDR (as further defined herein) or FR (as further defined herein) of the variable region. For example, the heavy chain variable region may contain a single inserted residue (i.e., residue 52a according to Kabat) after residue 52 of CDR H2 and after residue 82 of the heavy chain FR inserted residues (i.e., residues 82a, 82b, 82c, etc. according to Kabat). The Kabat numbering of residues can be determined for a given antibody by aligning the antibody sequence in the region of sequence homology with the "standard" Kabat numbering sequence in the region of sequence homology of the antibody sequence ). As used herein, "complementary determining region" and "CDR" refer to regions of the antibody variable domain that are regions of high frequency variability in the sequence and / or form structurally defined loops. CDRs are also known as high frequency variable regions. The light and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR L1, CDR L2 , and CDR L3. The heavy chain variable region contains CDR H1, CDR H2, and CDR H3. Each CDR is a complementary determining region defined by Kabat

[0137] variability and / or form structurally defined loops. CDRs are also known as high frequency variable regions. The light and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR L1, CDR L2 variability and / or form structurally defined loops. CDRs are also known as high frequency variable regions. The light and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR L1, CDR L2 and CDR L3. The heavy chain variable region contains CDR H1, CDR H2, and CDR L3. The heavy chain variable region contains CDR H1, CDR H2, and , and CDR L3. The heavy chain variable region contains CDR H1, CDR H2, and and CDR H3. Each CDR is a complementary determining region defined by Kabat may contain amino acid residues from the domain (i.e., in the light chain variable region, 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 (C DR H2), and 95-102 (CDR H3).

[0138] As used herein, the term "FcRn" refers to the neonatal Fc receptor that binds to the Fc region of an IgG antibody, such as an IgG1 antibody. An exemplary FcRn is the human FcRn having UniPro t ID number P55899. Human FcRn is thought to be responsible for maintaining the half-life of IgG by constantly binding to and transporting endogenous IgG back to the cell surface .

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

[0140] As used herein, "inhibiting IgG binding to FcRn" means the anti-F of the present invention for blocking or inhibiting the binding of IgG (e.g., IgG1) to human F cRn. Refers to the ability of the cRn antibody. In some embodiments, the anti-FcRn antibody of the present invention binds to FcRn, for example at the site on human FcRn to which IgG binds. Thus the anti-FcRn antibody of the present invention can inhibit the binding of IgG (e.g., the subject's autoantibody) to FcRn . In some embodiments, the molecule (e.g., the anti-FcRn antibody of the present invention ) substantially or completely inhibits binding to IgG. In some embodiments, the binding of IgG is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 1 up to 00%.

[0141] As used herein, "inhibiting the binding of pathogenic antibodies to FcRn" means blocking or inhibiting the binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to human FcRn Refers to the ability of the anti-FcRn antibody of the present invention. In some embodiments, the anti-FcRn antibody binds to FcRn, for example, at the site on human FcRn to which the pathogenic antibody binds . Thus, the anti-FcRn antibody is a pathogenic antibody against FcRn (e.g., pathogenic IgG ​can inhibit the binding of an antibody). In some embodiments, the molecule (e.g., an anti-Fc Rn antibody) substantially or completely inhibits binding to pathogenic antibodies. In some embodiments the binding of the pathogenic antibody to FcRn is reduced by 10%, 20%, 30%, 50%, 70%, 8 0%, 90%, 95%, or even 100%.

[0142] As used herein, the term "hydrophobic amino acid" refers to an amino acid having a relatively low water solubility . Hydrophobic amino acids include, but are not limited to, leucine, isoleucine, alanine, phe nylalanine, valine, and proline. Particularly preferred hydrophobic amino acids in the present invention are alanine, leucine, isoleucine, and valine .

[0143] As used herein, the term "polar amino acid" refers to an amino acid having a chemical polarity in its side chain induced by atoms having different electronegativities . The polarity of polar amino acids depends on the electronegativity between atoms within the side chain of the amino acid and the asymmetry of the side chain structure . Polar amino acids include, but are not limited to, serine, threonine, cysteine, methionine, tyr rosine, tryptophan, asparagine, and glutamine. Particularly preferred polar amino acids in 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 containing a carboxylic acid group having a pKa of 3.5 - 4 .5. In some embodiments the acidic amino acids are aspartic acid and glutamic acid.

[0145] As used herein, the term "basic amino acid" means an amino acid containing an amino group having a pKa of 9.5 to 1 3. In some embodiments, the basic amino acids are histidine, lysine, and arginine.

[0146] As used herein, the term "percent (%) identity" refers to the alignment of sequences and, if necessary, the introduction of gaps (i.e., it is possible to introduce gaps in one or both of the candidate and reference sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes) to achieve the maximum percent identity, and then, for example, the percentage of amino acid (or nucleic acid) residues of a candidate sequence, such as an anti-FcRn antibody of the present invention, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, such as a wild-type anti-FcRn antibody. Alignment for determination of percent identity can be achieved by various methods within the art using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for measuring alignment, including any algorithm necessary to achieve maximum alignment over the entire length of the sequences being compared. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (the specific percent amino acid sequence identity of a given candidate sequence to, with, or against a given reference sequence) to a given reference sequence, with a given reference sequence, or against a given reference sequence is determined after alignment and introduction of gaps as necessary to achieve maximum percent identity, and ignoring non-homologous sequences for comparison purposes. For example, the percentage of amino acid (or nucleic acid) residues of a candidate sequence, such as an anti-FcRn antibody of the present invention, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, such as a wild-type anti-FcRn antibody. The alignment for determination of percent identity can be achieved by various methods within the art using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for measuring alignment, including any algorithm necessary to achieve maximum alignment over the entire length of the sequences being compared. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (the specific percent amino acid sequence identity of a given candidate sequence to, with, or against a given reference sequence) to a given reference sequence, with a given reference sequence, or against a given reference sequence is determined after alignment and introduction of gaps as necessary to achieve maximum percent identity, and ignoring non-homologous sequences for comparison purposes. For example, the percentage of amino acid (or nucleic acid) residues of a candidate sequence, such as an anti-FcRn antibody of the present invention, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, such as a wild-type anti-FcRn antibody. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (the specific percent amino acid sequence identity of a given candidate sequence to, with, or against a given reference sequence) to a given reference sequence, with a given reference sequence, or against a given reference sequence As an alternative representation, a given candidate sequence having (or containing) sequence identity to the (or nucleic acid) sequence can be. ) is calculated as follows: 100×(fraction of A / B) wherein A is the number of amino (or nucleic acid) residues scored as identical within the alignment of the candidate sequence and the reference sequence, and B is the total number of amino acid (or nucleic acid) residues in the reference sequence is. 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 the candidate sequence to the reference sequence is not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence.

[0147] In certain embodiments, the reference sequence aligned for comparison to the candidate sequence is a candidate sequence showing 50% to 100% identity over the entire length of the candidate sequence, or a selected portion of consecutive amino (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purposes is at least 30% of the length of the reference sequence, such as at least 40%, such as at least 50%, 60%, 70%, 80%, 90%, or 100%. When the position of the candidate sequence is occupied by the same amino acid (or nucleic acid) residue as the corresponding position of the reference sequence, the molecule is identical at that position. The position may be altered by substitution, deletion, or insertion . Substitutions, deletions, or insertions may include a certain number of amino acids, (e.g., including 1, 2, 3, 4 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more) . When describing substitutions, deletions, or insertions of n amino acids or less, this is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,... or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,... or ​​​means a substitution, deletion, or insertion comprising n amino acids. The number or substitution, deletion, or insertion can comprise a percentage of the total sequence (e.g., 1%, 5%, 10%, 15%, 20%, or more), where the number of substitutions, deletions, or insertions varies by 5%, 10%, 15%, 20% or more of the total sequence of amino acids

[0148] As used herein, the term "fetal and neonatal alloimmune and / or autoimmune disorders" refers to immune disorders in a fetus and / or neonate caused by the transplacental transfer of maternal antibodies (e.g., pathogenic maternal antibodies) against fetal antigens. For example, antibodies (e.g., pathogenic antibodies) in a subject during pregnancy can react with antigens in the fetus (e.g., antigens that the fetus has inherited from the fetus's father). Examples of fetal and neonatal alloimmune and / or autoimmune disorders are provided herein

[0149] As used herein, the term "pathogenic antibody" refers to an antibody that causes one or more immune diseases or disorders in a subject (e.g., a subject during pregnancy), a fetus within the subject during pregnancy, and / or a neonate. In some embodiments, the pathogenic antibody is an autoantibody produced in a subject (e.g., a subject during pregnancy) against one or more of the subject's own proteins, thus causing an autoimmune disease or disorder in the subject. In some embodiments, the pathogenic antibody in a subject during pregnancy migrates through the placenta to the fetus and reacts against an antigen from the fetus (e.g., an antigen that the fetus has inherited from the fetus's father), and thus, for example, fetal and neonatal alloimmune and / or autoimmune disorders occur

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

[0151] As used herein, the term "host cell" refers to a vehicle that contains the necessary cellular components, such as an organelle, necessary for expressing proteins from their corresponding nucleic acids. The nucleic acid is typically contained in a nucleic acid vector that can be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, etc.). The host cell may be a prokaryotic cell, such as a bacterial cell, or a eukaryotic cell, such as a mammalian cell (e.g., a CHO cell). As described herein, the host cell is used to express one or more polypeptides encoding the anti-FcRn antibody of the invention.

[0152] As used herein, the term "vector" refers to a nucleic acid molecule that can transport another nucleic acid molecule to which it is ligated. One type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, where the additional DNA segment is ligated within the viral genome. They may be transfected. Certain vectors can self-replicate in the host cells into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of the host cell upon introduction into the host cell, thereby replicating with the host genome. Further, certain vectors have the ability to direct the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "recombinant vectors"). Generally, useful expression vectors in recombinant DNA technology are often in the form of plasmids. When 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), mice, dogs, cats, horses, and livestock such as cows. When used herein, the term "gestational age" describes how much time has elapsed since conception. Gestational age can be described in weeks. Methods for determining gestational age are known in the art (e.g., incorporated herein by reference in their entirety). In some examples, gestational age can be determined by ultrasound, by weeks from the first day of the last menstrual period (LMP), or by a combination thereof.

[0153]

[0154] Committee on Obstetric Practice American Institute of Ultrasoun d in Medicine Society for Maternal-Fetal Medicine、Committee Opinion.Number 700.2 May 2017;

[0155] ​​​​​​​​​​​​​​ As used herein, the term "pharmaceutical composition" refers to a pharmaceutical product or pharmaceutical formulation containing an active ingredient, as well as one or more excipients and diluents to render the active ingredient suitable for the method of administration. The pharmaceutical compositions of the present invention include pharmaceutically acceptable components that are compatible with anti-FcRn

[0156] antibodies. The pharmaceutical compositions may be in an aqueous form for intravenous or subcutaneous administration, or may be in the form of tablets or capsules for oral administration. As used herein, the term "pharmaceutically acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. A pharmaceutically acceptable carrier must be compatible with the other components of the

[0157] formulation and not harmful to the recipient. In the present invention, the pharmaceutically acceptable carrier must provide appropriate pharmaceutical stability for the Fc construct. The nature of the carrier will vary depending on the mode of administration. For example, for intravenous administration, aqueous carriers are commonly used, and solid carriers are preferred for oral administration.

[0158] As used herein, the term "less than" refers to an amount that is less than or Yes. This can be an integer amount. For example, two or fewer substitutions can refer to 0, 1, or 2 substitutions.

[0159] As used herein, the terms "treat" or "treating" refer to reducing a particular disease or condition, decreasing the risk of a particular disease or condition, or reducing the side effects of a particular disease or condition. Reducing, decreasing, reducing the risk, or reducing the side effects is relative to a subject that has not received treatment, e.g., a control, baseline, or known control level, or a subject that has not received a measurement. BRIEF DESCRIPTION OF THE DRAWINGS

[0160]

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[0161] DETAILED DESCRIPTION OF THE INVENTION The present invention features an isolated antibody that binds with high affinity to the human neonatal Fc receptor (FcRn). The present invention features anti-FcRn antibodies, methods and compositions for preparing anti-FcRn antibodies, as well as methods for blocking FcRn activity, reducing the activation of immune complex-based immune responses, and treating immune diseases. The present disclosure features anti-FcRn antibodies, methods and compositions for preparing anti-Fc Rn antibodies, as well as methods for blocking FcRn activity, reducing the activation of immune complex-based immune responses, and treating immune diseases. Further, anti-FcRn antibodies can be used to reduce the transfer of pathogenic antibodies across the placenta of a subject during pregnancy, enhance the catabolism of pathogenic antibodies in a subject during pregnancy, and treat antibody-mediated enhancement of viral diseases in a fetus or neonate.

[0162] I. Anti-FcRn Antibodies Generally, the present invention features isolated antibodies that bind to human FcRn with high affinity. The anti-FcRn antibodies of the present invention refer to antibodies that can bind to human FcRn and inhibit the binding of IgG (e.g., IgG autoantibodies) 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 selected from the group consisting of chimeric antibodies, affinity matured antibodies, humanized antibodies, and human antibodies. In certain embodiments, the antibody is an antibody fragment, e.g., Fab, Fab', Fab'-SH, F(ab′) 2 , or scFv.

[0163] In some embodiments, the antibody is a chimeric antibody. For example, the antibody contains an antigen-binding sequence from a non-human donor that has been transplanted into a heterologous non-human, murine, or humanized sequence (e.g., a framework and / or constant domain sequence). In one embodiment, the non-human donor is a mouse. In another embodiment, the antigen-binding sequence is synthetic and is obtained, for example, by mutagenesis (e.g., phage display screening, etc.). In a further embodiment, the chimeric antibody has a non-human (e.g., murine) variable region and a human constant region. In one example, the murine light chain variable region is fused to a human κ light chain. In another example, the murine heavy chain variable region is fused to a human IgG1 constant region.

[0164] In one aspect, the present invention features an isolated antibody that can bind to human FcRn. The isolated antibody has a light chain variable region that includes (1) CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3 having, wherein CDR L1 comprises a sequence having at least 92% identity with the sequence of TIFF0007690538000132.tif4128, and CDR L2 is GDSERP comprises a sequence having at least 85% identity with the sequence of S(SEQ ID NO:2), and CDR L3 comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000133.tif4128, and CDR H1 comprises a sequence having at least 80% identity with the sequence of TIFF0007690538000134.tif4128, and CDR H2 comprises a sequence having at least 92% identity with the sequence of TIFF0007690538000135.tif9149, and CDR H3 is LAIG comprises a sequence having at least 85% identity with the sequence of DSY(SEQ ID NO:11) In some embodiments, the antibody has a K less than 200 pM, less than 150 pM, less than 100 pM D and binds to human FcRn. In some embodiments, the antibody has the light chain variable region and heavy chain variable region of N022, N023, N024, N026, or N027 and further binds to human FcRn with a K that is D less than or equal to the K D of an antibody having the same Fc region as the antibody being compared.

[0165] In some embodiments, the isolated antibody of the invention has CDR L1 comprising the sequence of TIFF0007690538000136.tif4128, GDX 3 X 4 has CDR L2 comprising the sequence of RPS(SEQ ID NO:13) and CDR L3, Z containing the sequence of TIFF0007690538000137.tif4128 1 C containing the sequence of YAMG (SEQ ID NO:15) DR H1 CDR H2 containing the sequence of TIFF0007690538000138.tif4128, and LAZ 5 Z 6 DSY (SEQ ID NO:17) including CDR H3 containing the sequence, where 1 X is a polar or hydrophobic amino acid (e.g., preferably T, A, S, or I), X 2 is a hydrophobic amino acid (e.g., preferably L, or I), X 3 is a polar amino acid (e.g., preferably S, N, or T ), X 4 is a polar or acidic amino acid (e.g., preferably Q, E, or N), X 5 is a polar or hydrophobic amino acid (e.g., preferably C, S, I, or Y), X 6 is a hydrophobic amino acid (e.g., preferably A, or V), Z 1 is a polar or acid ic amino acid (e.g., preferably E, T, D, or N), Z 2 is a polar or hydro phobic amino acid (e.g., preferably S, or A), Z 3 is G, S, or A and Z 4 is a basic amino acid (e.g., preferably K, or R), Z 5 is a hydrophobic or basic amino acid (e.g., preferably I, L, or H), as well as Z 6 is G, S, D, Q, or H, and here, the antibody binds to human FcRn with a K of less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 pM and D binds to human FcRn Do it.

[0166] In other embodiments, the isolated antibody of the invention contains CDR L1 containing the sequence of TIFF0007690538000139.tif4128, C containing the sequence of GDSERPS (SEQ ID NO:2) DR L2, contains CDR L3 containing the sequence of TIFF0007690538000140.tif4128, Z 1 C containing the sequence of YAMG (SEQ ID NO:15) DR H1, contains CDR H2 containing the sequence of TIFF0007690538000141.tif4128, and the sequence of LAIGDSY (SEQ ID NO:11) and contains CDR H3, where Z 1 is E, D, or N, Z 2 is S or A and Z 3 is G, S, or A.

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

[0168] (Table 1) TIFF0007690538000142.tif64158

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

[0170] (Table 2) TIFF0007690538000143.tif52128

[0171] In some embodiments, the light chain of the isolated antibody of the invention contains a sequence having at least 90% identity with the sequence of TIFF0007690538000144.tif21160.

[0172] In some embodiments, the heavy chain of the isolated antibody of the present invention comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000145.tif38160.

[0173] In some embodiments, the heavy chain of the isolated antibody of the present invention comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000146.tif38160.

[0174] In some embodiments, the heavy chain of the isolated antibody of the present invention comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000147.tif38160.

[0175] In other embodiments, the heavy chain of the isolated antibody of the present invention comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000148.tif38160.

[0176] In still other embodiments, the heavy chain of the isolated antibody of the present invention comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000149.tif38160.

[0177] The present invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000150.tif21160, and the heavy chain comprises a sequence having at least 90% identity with the sequence of TIFF0007690538000151.tif38160.

[0178] The present invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain It includes an array having at least 90% identity with the array of TIFF0007690538000152, and the heavy chain is It includes an array having at least 90% identity with the array of TIFF0007690538000153.

[0179] The present invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain It includes an array having at least 90% identity with the array of TIFF0007690538000154, and the heavy chain is It includes an array having at least 90% identity with the array of TIFF0007690538000155.

[0180] The present invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain It includes an array having at least 90% identity with the array of TIFF0007690538000156, and the heavy chain is It includes an array having at least 90% identity with the array of TIFF0007690538000157.

[0181] The present invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain It includes an array having at least 90% identity with the array of TIFF0007690538000158, and the heavy chain is It includes an array having at least 90% identity with the array of TIFF0007690538000159.

[0182] Furthermore, in any of the anti-FcRn antibodies described herein, the heavy chain of the antibody comprises an array having at least 95 %, 97%, 99%, or 100% identity with any one of the sequences of SEQ ID NO: 20-24. As described herein In any of the anti-FcRn antibodies, the light chain has a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:19 and includes a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:19 .

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

[0184] The antibodies may further contain amino acid substitutions, additions, and / or deletions outside the CDRs (i.e., in the framework regions (FRs)). The amino acid substitutions, additions, and / or deletions can be substitutions, additions, and / 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 can be substitutions, additions, and / or deletions of single amino acids of 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments the antibodies may further contain any one or more of the following amino acid substitutions: A23V, S30R, L80V, A84T, E85D, A93V, with respect to any one of the sequences of SEQ ID NOs: 20-24 and Q38H, V58I, and G99D with respect to the sequence of SEQ ID NO:19 .

[0185] ​In some embodiments, the antibodies of the invention are capable of, e.g., reducing effector function, e.g. , complement-dependent cell lysis (CDC), antibody-dependent cell-mediated cell lysis (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 an antibody that result in a reduced The constant regions may include deletions 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., the 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 / It contains L235A or D265A / N297A. The anti-FcRn antibody of the present invention is SE For any one of the sequences of SEQ ID NOs: 20 to 24, the amino acid hdfn substitution N2 Contains 97A, and as a result, the antibody of the present invention is preferably changed to a non-glycosylated form. The resulting antibody without effector shows very little binding to complement or Fc receptors (i.e., complement C1q binding), indicating a low possibility of CDC.

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

[0187] Furthermore, in other embodiments, to minimize potential immunogenicity, amino acids D355 and L357 (relative to any one of the sequences of SEQ ID NOs: 20 to 24) are each Substituted with glutamic acid and methionine, respectively, so that some antibodies of the present invention, such as For example, N024, N026, and N027 may undergo an allotype change from G1m17.1 to G1m17.

[0188] In other embodiments, the antibodies of the present invention, such as N022 to N024, N026, and N0 27 do not contain a C-terminal lysine for any one of the sequences of SEQ ID NOs: 20 to 24.

[0189] The present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain Contains the sequence of TIFF0007690538000160.tif21160, and the heavy chain Contains the sequence of TIFF0007690538000161.tif38160.

[0190] ​​​The present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain includes the sequence of TIFF0007690538000162.tif21160, and the heavy chain includes the sequence of TIFF0007690538000163.tif38160.

[0191] The present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain includes the sequence of TIFF0007690538000164.tif21160, and the heavy chain includes the sequence of TIFF0007690538000165.tif38160.

[0192] The present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain includes the sequence of TIFF0007690538000166.tif21160, and the heavy chain includes the sequence of TIFF0007690538000167.tif38160.

[0193] The present invention features an isolated antibody containing a light chain and a heavy chain, where the light chain includes the sequence of TIFF0007690538000168.tif21160, and the heavy chain includes the sequence of TIFF0007690538000169.tif38160.

[0194] In any of the anti-FcRn antibodies described herein, in some embodiments, the antibody binds to mouse or rat FcRn with a K less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 D pM.

[0195] In any of the anti-FcRn antibodies described herein, in some embodiments, the antibody has a Kd of 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, or It binds to human FcRn with an affinity of 10 - 40 pM.

[0196] The anti - FcRn antibody of the present invention may be an immunoglobulin antibody isotype IgG, IgE, IgM , IgA, or IgD. The anti - FcRn antibody is preferably of the immunoglobulin antibody isotype IgG. The anti - FcRn antibody may also be a subclass of any immunoglobulin antibody isotype. For example, the anti - FcRn antibody may be of the IgG subclass IgG1, IgG2, IgG3, or IgG4. The anti - FcRn antibody is preferably of subclass IgG1. In particular, the anti - FcRn antibody of the present invention contains an allotype heavy chain of IgG G1m17 or G1m17.1. In some embodiments the light chain of the anti - FcRn antibody may be 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 .

[0197] In some embodiments, the antibody of the present invention is monoclonal. The antibody of the present invention may also be polyclonal, chimeric, humanized or fully human. In some embodiments the antibody of the present invention may be affinity - matured. In other embodiments, the antibody of the present invention may be an antibody fragment .

[0198] Without being bound by theory, the anti - FcRn antibody of the present invention is thought to compete with and inhibit the binding of IgG to human FcRn. Hydrogen - deuterium exchange - based epitope mapping of the antibody of the present invention indicates that the antibody binds to epitopes on FcRn that are located at and / or adjacent to the Fc - FcRn interaction interface, which indicates that the antibody of the present invention is in the direction ​ suggests blocking the binding of IgG to FcRn by inhibition. Furthermore, the epitope-mapped binding site is distant from the albumin binding site of FcRn. Thus, serum albumin binding should not be inhibited and serum albumin levels should not be decreased. Indeed, experimental evidence shows that mouse albumin levels remain constant after anti-FcRn antibody administration, indicating that albumin recycling is not inhibited by antibody binding to

[0199] II. FcRn Inhibition FcRn is a type I transmembrane protein that functions as an IgG- and serum albumin-binding, intracellular vesicular transport protein. FcRn is expressed in endothelial cells, luminal epithelial cells, hepatocytes, podocytes, granulocytes, monocytes, macrophages, dendritic cells, and NK cells, but not on B cells or T cells. FcRn constitutively binds endogenous IgG and transports it back to the cell surface, thereby maintaining the half-life of IgG. The binding of both Fc and serum albumin by FcRn occurs in early endosomes at pH 6.0, followed by sorting of FcRn within the vesicle, and this vesicle transports FcRn-bound IgG or albumin back to the cell surface where FcRn rapidly releases IgG or albumin at pH 7.4. This transport cycle maintains the half-life of IgG and albumin by recycling them within the circulation and by preventing their transport to G is transported into the lumen of an organ such as the gastrointestinal tract, or from the lumen of the stroma of IgG or an IgG antigen complex to the vascular system or lymphoid tissue becomes transportable. It becomes possible to transport to the vascular system or lymphoid tissue from the lumen of the stroma.

[0200] To examine the contribution of FcRn to IgG homeostasis, mice were engineered so that the light and heavy chain portions of FcRn were "knocked out" and these proteins were not expressed (Junghans et al., Proc Natl Acad Sci USA 93:5512, 1996). In these mice, the serum half-life and IgG concentrations decreased dramatically, suggesting a FcRn-dependent mechanism for IgG homeostasis. Studies in rodent models such as those described above have shown that blockade of FcRn can enhance the catabolism of IgG, including that of pathogenic autoantibodies, thereby inhibiting the development of disease (e.g., autoimmune diseases). FcRn may also contribute to antigen presentation through antigen degradation and transport of immune complexes to MHC loading compartments. USA 93:5512, 1996). In these mice, the serum half-life and IgG concentrations decreased dramatically, suggesting a FcRn-dependent mechanism for IgG homeostasis. Studies in rodent models such as those described above have shown that blockade of FcRn can enhance the catabolism of IgG, including that of pathogenic autoantibodies, thereby inhibiting the development of disease (e.g., autoimmune diseases). FcRn may also contribute to antigen presentation through antigen degradation and transport of immune complexes to MHC loading compartments. USA 93:5512, 1996). In these mice, the serum half-life and IgG concentrations decreased dramatically, suggesting a FcRn-dependent mechanism for IgG homeostasis. Studies in rodent models such as those described above have shown that blockade of FcRn can enhance the catabolism of IgG, including that of pathogenic autoantibodies, thereby inhibiting the development of disease (e.g., autoimmune diseases). FcRn may also contribute to antigen presentation through antigen degradation and transport of immune complexes to MHC loading compartments. USA 93:5512, 1996). In these mice, the serum half-life and IgG concentrations decreased dramatically, suggesting a FcRn-dependent mechanism for IgG homeostasis. Studies in rodent models such as those described above have shown that blockade of FcRn can enhance the catabolism of IgG, including that of pathogenic autoantibodies, thereby inhibiting the development of disease (e.g., autoimmune diseases). FcRn may also contribute to antigen presentation through antigen degradation and transport of immune complexes to MHC loading compartments. USA 93:5512, 1996). In these mice, the serum half-life and IgG

[0201] The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. The present invention provides an isolated anti-FcRn antibody that binds to human FcRn with high affinity. The anti-FcRn antibody of the present invention competes with and effectively inhibits the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibody of the present invention can be used in methods for treating or reducing the activation based on immune complexes of immune responses in a subject, such as immune responses caused by autoantibodies in autoimmune diseases.

[0202] Transplacental transfer of maternal IgG antibodies to the fetus is an important FcRn-dependent mechanism that provides protection to the neonate while the neonate's humoral response is inefficient. During gestation, FcRn in the syncytiotrophoblast layer of the placenta is involved in the transfer of maternal IgG antibodies to the fetus. Pathogenic maternal antibodies (e.g., pathogenic maternal IgG antibodies) also cross the placenta by binding to FcRn and can cause alloimmune and / or autoimmune disorders in the fetus and neonate. In some embodiments, pathogenic antibodies in a subject during pregnancy cause alloimmune and / or autoimmune disorders in the fetus within the subject during pregnancy and in the neonate. The anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and / or N024) compete with and inhibit the binding of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) to FcRn, thereby enhancing the catabolism and decreasing the half-life of these pathogenic antibodies. This is an important FcRn-dependent mechanism that provides protection to the neonate while the neonate's humoral response is inefficient. During gestation, FcRn in the syncytiotrophoblast layer of the placenta is involved in the transfer of maternal IgG antibodies to the fetus. Pathogenic maternal antibodies (e.g., pathogenic maternal IgG antibodies) also cross the placenta by binding to FcRn and can cause alloimmune and / or autoimmune disorders in the fetus and neonate. In some embodiments, pathogenic antibodies in a subject during pregnancy cause alloimmune and / or autoimmune disorders in the fetus within the subject during pregnancy and in the neonate. The anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and / or N024) compete with and inhibit the binding of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) to FcRn and thereby enhance the catabolism and decrease the half-life of these pathogenic antibodies. This can be done by competing with and inhibiting the binding of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) to FcRn, thereby enhancing the catabolism and decreasing the half-life of these pathogenic antibodies.

[0203] The present disclosure provides isolated anti-FcRn antibodies that bind to human FcRn. The anti-FcRn antibodies compete with and inhibit the binding of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to FcRn, thereby enhancing catabolism and decreasing the half-life of other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). The anti-FcRn antibodies can be used in methods for treating or reducing the activation of immune responses based on immune complexes in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing the immune response compared to a subject not receiving treatment (e.g., a control subject). The anti-FcR n antibodies can be used in methods for treating or reducing the activation of immune responses based on immune complexes in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing the immune response compared to a subject not receiving treatment (e.g., a control subject). The anti-FcR n antibodies can be used in methods for treating or reducing the activation of immune responses based on immune complexes in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing the immune response compared to a subject not receiving treatment (e.g., a control subject). The anti-FcR n antibodies can be used in methods for treating or reducing the activation of immune responses based on immune complexes in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing the immune response compared to a subject not receiving treatment (e.g., a control subject). The anti-FcR n antibodies can be used in methods for treating or reducing the activation of immune responses based on immune complexes in a subject, such as immune responses caused by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing the immune response compared to a subject not receiving treatment (e.g., a control subject). The anti-FcR ​n antibodies also play a role in pathogenic antibody transfer across the placenta in pregnant subjects (e.g., pathogenic maternal Ig Methods for reducing IgG antibody transfer and for 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 symptoms of a given condition. and reducing pathogenic antibody transfer compared to a non-treated subject (e.g., a control subject). It can be described as:

[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 acids Nucleic acid refers to a vehicle that contains necessary cellular components, such as organelles. The method can be carried out by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate depletion, etc.). in a nucleic acid vector that can be introduced into a host cell by intracellular transport (e.g., by precipitation with ethanol, 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) The origin of the term is either

[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 are known in the art. These methods include oligonucleotide-mediated These include site-directed mutagenesis and PCR mutagenesis. There is no limitation. The nucleic acid molecule encoding the anti-FcRn antibody of the present invention can be obtained using standard techniques, such as , gene synthesis. Alternatively, the nucleic acid molecule encoding the wild-type anti-FcRn antibody may be mutated to contain specific amino acid substitutions using standard techniques in the art, such as QuikChange™ mutagenesis. The nucleic acid molecule can be synthesized using a nucleotide synthesizer or PCR technology.

[0206] The nucleic acid sequence encoding the anti-FcRn antibody of the present invention can be inserted into a vector capable of replicating and expressing the nucleic acid molecule of a prokaryotic or eukaryotic host cell. Many vectors are available in the art and can be used for the purposes of the present invention. Each vector may contain various components that can be adjusted and optimized for compatibility with a specific host cell. For example, , the vector components may 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 the protein of interest, and a transcription termination sequence.

[0207] In some embodiments, mammalian cells are used as the host cells of the present invention. Examples of mammalian 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 (a mouse myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7O3O, and H There are sS78Bst cells. In other embodiments, E. coli cells are used as the host cells of 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 RV308 (ATCC® 31,608). Different host cells have characteristics and specific mechanisms related to post-translational processing and modification of protein products. An appropriate cell line or host system can be selected to ensure the correct modification and processing of the expressed anti-FcRn antibody. The above-described expression vectors can be introduced into appropriate host cells using conventional techniques in the art, such as transformation, transfection, electroporation, calcium phosphate precipitation, and direct microinjection. When the vector is introduced into the host cell for protein production, the host cell is cultured in a conventional nutrient medium modified to be appropriate for inducing the promoter, selecting the transformant, or amplifying the gene encoding the desired sequence. Methods for the expression of therapeutic proteins are known in the art, for example, Paulina Balbas, Argelia Lorence (eds.) Recombinant Gene Expression: Reviews and Protocols (Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto are used. 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 have characteristics and specific mechanisms related to post-translational processing and modification of protein products. An appropriate cell line or host system can be selected to ensure the correct modification and processing of the expressed anti-FcRn antibody. The above-described expression vectors can be introduced into appropriate host cells using conventional techniques in the art, such as transformation, transfection, electroporation, calcium phosphate precipitation, and direct microinjection. When the vector is introduced into the host cell for protein production, the host cell is cultured in a conventional nutrient medium modified to be appropriate for inducing the promoter, selecting the transformant, or amplifying the gene encoding the desired sequence. Methods for the expression of therapeutic proteins are known in the art, for example, Paulina Balbas, Argelia Lorence (eds.) Recombinant Gene Expression: Reviews and Protocols (Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ocols(Methods in Molecular Biology), Humana Press; 2nd ed. 2004 (July 20, 2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins: Methods and Proto ) Therapeutic Proteins: Methods and Proto cols (Methods in Molecular Biology) Humana Press; see 2nd ed. 2012 (June 28, 2012). Please refer to it.

[0208] Protein Production, Recovery, and Purification The host cells used to produce the anti-FcRn antibody of the present invention are known in the art and may be grown in a medium suitable for culturing the selected host cells. Examples of media suitable for mammalian host cells include Minimal Essential Medium (MEM), Dulbecco's Modified Eagle Medium (D MEM), Expi293™ Expression Medium, DMEM supplemented with fetal bovine serum (FBS), and RPMI-1640. Examples of media suitable for bacterial host cells include Luria-Bertani (LB) medium supplemented with necessary adjuvants such as ampicillin. Host cells are cultured at an appropriate temperature, for example, about 20°C to about 39°C, such as 25°C to about 37°C, preferably 37°C, and at a CO level of, for example, 5-10% (preferably 8%). 2 The pH of the medium is generally about 6.8-7.4, for example 7.0, mainly depending on the host organism. When an inducible promoter is used in the expression vector of the present invention, protein expression is induced under conditions suitable for activation of the promoter.

[0209] Protein recovery typically involves disrupting the host cells by means such as osmotic shock, sonication, or lysis. Once the cells are disrupted, cell debris can be removed by centrifugation or filtration. The protein may be further purified. The anti-FcRn antibody of the present invention can be purified by any method known in the art of protein purification, for example, Protein A affinity chromatography. ​​​Sex, other chromatography (e.g., ion exchange, affinity, and size exclusion column chromatography), centrifugation, absorption rate differential solubility, or any other standard technique related to protein purification (see Process Scale Purification of Antibodies, Uwe Gottschalk (ed.) John Wiley & Sons, Inc., 2009). In some examples, the anti-FcRn antibody can be conjugated to a marker sequence such as a peptide to facilitate purification. Examples of marker amino acid sequences are hexahistidine peptides (His tags), which bind to nickel-functionalized agarose affinity columns with micromolar affinity. Other peptide tags useful for purification include, but are not limited to, the "HA" tag of hemagglutinin, which corresponds to an epitope derived from the influenza hemagglutinin protein. Chromatography), centrifugation, absorption rate differential solubility, or any other standard technique related to protein purification can be purified (see Process Scale Purific ation of Antibodies, Uwe Gottschalk (ed.) J ohn Wiley & Sons, Inc., 2009). In some examples, the anti-FcRn antibody can be conjugated to a marker sequence such as a peptide to facilitate purification of. Examples of marker amino acid sequences are hexahistidine peptides (H is tag), which binds to nickel-functionalized agarose affinity columns with micromolar affinity. Other peptide tags useful for purification include, but are not limited to, the "HA" tag of hemagglutinin, which corresponds to an epitope derived from the influenza hemagglutinin protein .

[0210] Alternatively, the anti-FcRn antibody of the present invention can be produced by cells of a subject (e.g., a human) in a therapeutic context, for example, by administering a vector (e.g., a retroviral vector, an adenoviral vector, a poxvirus vector (e.g., a vaccinia virus vector such as modified vaccinia Ankara (MVA)), an adeno-associated virus vector, and an alphavirus vector) containing a nucleic acid molecule encoding the anti-FcRn antibody of the present invention. Once the vector enters the cells of the subject (e.g., by transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), it then promotes the expression of the anti-FcRn antibody secreted from the cells. Treatment of a disease or disorder is desired by, for example, a vaccinia virus vector such as modified vaccinia Ankara (MVA)), an adeno-associated virus vector, and an alphavirus vector) administered to promote the expression of the anti-FcRn antibody secreted from the cells. Treatment of a disease or disorder is desired by, for example, administering a vector (e.g., a retroviral vector, an adenoviral vector, a poxvirus vector (e.g., a vaccinia virus vector such as modified vaccinia Ankara (MVA)), an adeno-associated virus vector, and an alphavirus vector) containing a nucleic acid molecule encoding the anti-FcRn antibody of the present invention to a subject (e.g., a human) in a therapeutic context. Once the vector enters the cells of the subject (e.g., by transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), it then promotes the expression of the anti-FcRn antibody secreted from the cells. Treatment of a disease or disorder is desired Once the vector enters the cells of the subject (e.g., by transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), it then promotes the expression of the anti-FcRn antibody secreted from the cells. Treatment of a disease or disorder is desired If the result is satisfactory, no further measures are necessary. If protein collection is desired, blood is collected from the subject and the protein purified from the blood by methods known in the art.

[0211] V. Pharmaceutical Compositions and Preparations The present 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 therapeutic proteins, one or more antibodies of the present invention, such as N022 - N024, N026, and N027. In other embodiments, the pharmaceutical compositions of the present invention containing one or more antibodies of the present invention, such as N022 - N024, N026, and N027, may be used in combination with other agents (e.g., therapeutic biologics and / or small molecules) or compositions during therapy. In addition to a therapeutically effective amount of the antibody, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients that can be formulated by methods known to those skilled in the art.

[0212] The acceptable carriers and excipients in the pharmaceutical composition are non-toxic to the recipient at the dosages and concentrations used. Acceptable carriers and excipients can include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates. The pharmaceutical compositions of the present invention can be administered parenterally in the form of injectable formulations. Pharmaceutical compositions for injection (i.e., intravenous injection) can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles can include sterile water, physiological saline, and cell culture media (e.g., Dulbecco's Modified Eagle Medium (DMEM), α - modified Eagle Medium ​- Eagle's medium (α-MEM), F-12 medium), but not limited to these. Formulations Methods are known in the art. For example, Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Proc essing and Delivery Systems (2nd ed.) Tayl or & Francis Group, CRC Press (2006) for reference .

[0213] The pharmaceutical composition can be formed in unit doses as needed. The active ingredient contained in the pharmaceutical preparation , 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) is provided in an appropriate dose within the specified range (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 as therapeutic proteins (e.g., N022 to N024, N026, and N027, preferably N027 and / or N024) of the present invention The pharmaceutical composition may be formulated for intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, intraarterial administration, spinal administration, or intraperitoneal administration. In particular, intravenous administration is preferred. Pharmaceutical The composition may also be formulated for oral, nasal, spray, aerosol, rectal, or vaginal administration well, or administered via them. For injectable formulations, various effective pharmaceutical carriers are known in the art.

[0215] The dosage of the pharmaceutical composition of the present invention depends on the route of administration, the disease to be treated, and the age of the subject, for example depends on factors including physical characteristics such as age, weight, and relative health. Typically, within a single administration the amount of the anti-FcRn antibody of the present invention contained (e.g., N022 - N024, N026, and N 027, preferably N027 or N024) can be an amount that effectively prevents, delays, or treats the disease without inducing significant toxicity. The pharmaceutical composition of the present invention is 0.01 - 500 mg / 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 more specific embodiments, the dosage of the anti-FcRn antibody of the present invention ranges from about 1 to about 10 0 mg / kg, and in more specific embodiments, can include a dosage of the anti-FcR n antibody of the present invention from about 1 to about 50 mg / kg. The dosage can be adjusted by a physician according to conventional factors such as the degree of the disease and various parameters of the subject . Further, the dosage can be adjusted by a physician according to factors such as gestational age, birth preparation , weight gain of the female, and / or length of pregnancy .

[0216] In some cases, the compositions and pharmaceutical compositions described herein are administered to pregnant women throughout pregnancy . In some cases, the compositions and pharmaceutical compositions described herein are administered to pregnant women during approximately 5 - 25 weeks of gestation (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 weeks). In some examples, the administration of the composition and pharmaceutical composition is after approximately gestational age 34 (week 34) (e.g., week 34, week 35, week 36, or ends after the 37th week). In some examples, IVIG is administered to pregnant women after the administration of the composition and the pharmaceutical composition ends. In some examples, after the administration of the composition and the pharmaceutical composition, IVIG is administered for about 3 to 15 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days). In some cases, the IVIG administration time after the administration of the composition and the pharmaceutical composition is adapted according to factors such as the weight gain of the woman. In some examples, the composition and pharmaceutical composition described herein are first administered after a gestational age of 1 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 administered during pregnancy between a gestational age of 14 and 26 (e.g., 14 - 25, 15 - 25, or 15 - 26, etc.). In some cases, during pregnancy between a gestational age of 12 and 36 ( e.g., 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, etc.). The pharmaceutical composition is administered in a therapeutically effective amount in a manner compatible with the dosage formulation, resulting in symptom improvement or treatment. The pharmaceutical composition is administered in various dosage forms, e.g., intravenous dosage form, subcutaneous dosage form, and oral dosage form (e.g., ingestible solution, drug - release capsule). Generally, therapeutic proteins are administered at 1 - 100 mg / kg, e.g., 1 - 50 mg / kg. Anti - FcRn antibodies (e.g., N022 - N024, N026, and N027,

[0217] ​​​​​The pharmaceutical composition of the present invention containing preferably N027 or N024) is, for example, administered daily, weekly, monthly, semi-annually, annually, one or more times (e.g., 1 to 10 times or more), or according to medical necessity to a subject in need thereof. The dosage may be provided in either a single or multiple dosing regimen. When the medical condition improves, the timing between administrations may decrease, and when the patient's health deteriorates, it may increase.

[0218] VII. Treatment methods and indications Blocking of human FcRn by the anti-FcRn antibody of the present invention may be for the therapeutic benefit in diseases driven by IgG autoantibodies. Without disturbing serum albumin, small circulating metabolites, or lipoproteins, the ability of FcRn blockade to induce the catabolism of overall IgG and the removal of multiple types of autoantibodies provides a way to broaden the public welfare and availability of the autoantibody removal strategy for patients with autoimmune disease pathologies driven by autoantibodies. Although the present invention is not bound by theory, the main mechanism of action of the anti-FcRn antibody of the present invention may be to enhance the catabolism of pathogenic autoantibodies in circulation and to reduce the deposition of autoantibodies and immune complexes in diseased tissues.

[0219] The pharmaceutical composition and method of the present invention containing one or more anti-FcRn antibodies (e.g., N022 to N024, N026, and N027 preferably N027 and / or N024) are used to promote the catabolism and removal of pathogenic antibodies (e.g., IgG and autoantibodies of IgG) in a subject, to reduce the immune response, for example, to block the activation of the immune response based on immune complexes in the subject, and to treat the immunological state or immune disease of the subject ​​​In particular, the pharmaceutical compositions and methods of the present invention are useful for immunoconjugate-based rapid The present invention is 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, channelopathies, Neuromyelitis optica, autoimmune deafness, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic Anemia (AIHA), immune neutropenia, dilated cardiomyopathy omyopathy, 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 joint disorders, 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 target a compound active against an autoimmune disease. The present invention is useful for reducing or treating an impaired immune response. disease, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune Dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial Pemphigus, Limited systemic sclerosis (CREST syndrome), Cold agglutinin disease, Crohn's disease, Skin and muscle fibromyalgia, fibromyositis, grepatocellular carcinoma, discoid lupus, essential mixed cryoglobulinemia, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome a 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, 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, Sjogren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener granulomatosis, and may be selected from the group consisting of.

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

[0222] In some embodiments, the pharmaceutical compositions and methods are useful for reducing the risk of anemia in the fetus or reducing the risk of its development. In some embodiments the pharmaceutical compositions and methods are useful for reducing or avoiding the need for IUT (intrauterine transfusion) . In some embodiments, the pharmaceutical compositions and methods are useful for reducing or avoiding the need for prenatal PP+IVI g, postnatal transfusions, IVIg, and / or phototherapy. In some embodiments, the pharmaceutical compositions and methods are useful for reducing or treating an immune response activated by an autoimmune disease. The autoimmune disease is alopecia areata, ankylosing

[0223] In some embodiments, the pharmaceutical compositions and methods are useful for reducing or treating an immune response activated by an autoimmune disease. spondylitis, Ankylosing spondylitis, antiphospholipid syndrome (e.g., antiphospholipid antibody syndrome), Addison's disease, hemolytic anemia (e.g., warm autoimmune hemolytic anemia), autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited systemic 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, Ménière'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, Sjögren's syndrome, stiff man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate activated by an autoimmune disease of a pregnant mother. In particular, the pharmaceutical composition and method are useful for systemic lupus erythematosus, antiphospholipid syndrome, psoriasis vulgaris, and the like. and the like. and the like. and the like. and the like. and the like. and the like. and the like. and the like. and the like. and the like. and may be selected from the group consisting of. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate activated by an autoimmune disease of a pregnant mother. In particular, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating the immune response of a fetus or neonate activated by an autoimmune disease of a pregnant mother. and the like.

[0224] In particular, the pharmaceutical composition and method are useful for systemic lupus erythematosus, antiphospholipid syndrome, psoriasis vulgaris, Pemphigus / bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis, or is useful for reducing or treating an immune response activated by neuromyelitis optica. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating an immune response in a fetus or neonate. In some embodiments, the pharmaceutical composition and method are useful for reducing or treating an immune response activated by systemic lupus erythematosus, antiphospholipid syndrome, pemphigus vulgaris / bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis, or neuromyelitis optica in a pregnant mother. The pharmaceutical composition and method are useful for reducing or treating pathogenic antibody transfer (e.g., pathogenic maternal IgG antibody transfer) through the placenta of a pregnant subject, enhancing catabolism of pathogenic antibodies in a pregnant subject, and treating antibody-mediated enhancement of viral diseases in a fetus or neonate by administering an isolated antibody that binds to human FcRn to a pregnant subject. The diseases and disorders that can benefit from FcRn inhibition by the isolated anti-FcRn antibodies described herein (e.g., N022-N0 24, N026, and N027, preferably N027 and / or N024) include diseases and disorders in a fetus and / or neonate caused by transfer of maternal pathogenic antibodies (e.g., maternal pathogenic IgG

[0225] antibodies) from a pregnant subject through the placenta. In some embodiments, the isolated anti-FcRn antibodies described herein (e.g., N02 are useful for treating antibody-mediated enhancement of viral diseases in a fetus or neonate by reducing pathogenic antibody transfer (e.g., pathogenic maternal IgG antibody transfer) through the placenta of a pregnant subject, enhancing catabolism of pathogenic antibodies in a pregnant subject, and administering an isolated antibody that binds to human FcRn to a pregnant subject. antibodies) through the placenta of a pregnant subject, enhancing catabolism of pathogenic antibodies in a pregnant subject, and administering an isolated antibody that binds to human FcRn to a pregnant subject. For example, N022-N024, N026, and N027, preferably N027 and / or N024) The diseases and disorders that can benefit from FcRn inhibition by the isolated anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and / or N024) include diseases and disorders in a fetus and / or neonate caused by transfer of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) from a pregnant subject through the placenta. In some embodiments, the isolated anti-FcRn antibodies described herein (e.g., N02 antibodies) from a pregnant subject through the placenta. include.

[0226] In some embodiments, the isolated anti-FcRn antibodies described herein (e.g., N02 2 to N024, N026, and N027, preferably N027 and / or N024 Diseases and disorders that can benefit from FcRn inhibition by ( are alloimmune and / or autoimmune disorders of the fetus and newborn. Alloimmune disorders of the fetus and newborn are disorders of the fetus and / or newborn caused by pathogenic antibodies of a pregnant subject There is. Pathogenic antibodies of a pregnant subject attack fetal antigens (e.g., antigens inherited by the fetus from the fetus's father antigens), which can cause the fetus or newborn to have alloimmune and / or autoimmune disorders.

[0227] Examples of alloimmune and / or autoimmune disorders of the fetus and newborn that can be treated by the methods described herein include, but are not limited to, fetal and neonatal alloimmune thrombocytopenia (FNAIT), fetal and neonatal hemolytic disease (HDFN), alloimmune thrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal auto immune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus erythematosus, neonatal scleroderma. Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I diabetes.

[0228] In some embodiments, the isolated anti-FcRn antibodies described herein (e.g., N02 2 to N024, N026, and N027, preferably N027 and / or N024 ) Diseases and disorders that can benefit from FcRn inhibition are viral diseases wherein the antibody promotes viral entry into host cells, e.g., antibodies against viral diseases result in an increase or enhancement of infectivity within cells, such as enhanced intermediacy. In some embodiments , the antibody binds to the viral surface protein, and the antibody / virus complex can bind to FcRn on the cell surface through the interaction between the antibody and the receptor. Subsequently, the antibody / virus complex may be internalized into the cell. For example, a virus may gain entry into fetal cells and / or tissues by forming a complex with maternal IgG antibodies. Maternal I gG antibodies bind to viral surface proteins, and the IgG / virus complex can bind to FcRn of syncytiotrophoblasts of the placenta, which then transfers the complex into the fetus.

[0229] In some embodiments, the methods described herein can be used to treat antibody-mediated enhancement of viral diseases. In some embodiments, viral diseases enhanced by pathogenic antibodies (e.g., pathogenic IgG antibodies) include, but are not limited to, alphavirus infections , flavivirus infections, Zika virus infections, chikungunya virus infections, Ross River virus infections, severe acute respiratory syndrome coronavirus infections, Middle East respiratory syndrome, avian influenza infections, influenza virus infections, human respiratory syncytial virus infections, Ebola virus infections, yellow fever virus infections, dengue virus infections, human immunodeficiency virus infections, respiratory syncytial virus infections, hantavirus infections, Getah virus infections, Sindbis virus infections, Bunyamwera virus infections, West Nile virus infections, Japanese encephalitis virus B infections, rabbitpox virus infections, lactate dehydrogenase-elevating virus infections, reovirus infections, rabies virus infections, foot-and-mouth disease virus infections, b ​​​​​​​​​​​Genital respiratory syndrome virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection, 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 measles virus infection, including viral diseases caused thereby.

[0230] Blocking of human FcRn by an anti-FcRn antibody may be for the therapeutic benefit in diseases driven by pathogenic antibodies (e.g., pathogenic IgG antibodies ). Without disturbing, the catabolism of overall pathogenic antibodies, and the FcRn blocking ability to induce the removal of multiple types of autoantibodies, small circulating metabolites, or lipoprotein proteins, provides a way to broaden the public welfare and availability of pathogenic antibody removal strategies for patients with pathogenic antibody-driven autoimmune diseases. Without being bound by theory, the main mechanism of action of the anti-FcRn antibody may be to enhance the catabolism of pathogenic antibodies in circulation, and to reduce the deposition of pathogenic antibodies and immune complexes in diseased tissues.

[0231] The anti-FcRn antibodies described herein (e.g., N022~N024, N026, and N027, preferably N027 and / or N024) may be administered to a pregnant subject having or at risk of having a medical condition that activates the immune response of the subject during pregnancy. In some embodiments, the pregnant subject may have had in the past a medical condition that activates the immune response in a pregnant subject. In some embodiments The subject during pregnancy has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate. In some embodiments wherein a pathogenic antibody associated with an immune disease is detected in a biological sample obtained from a subject during pregnancy (e.g., a blood sample or a urine sample), the anti-FcRn antibody described herein can be administered to the subject during pregnancy. In some embodiments, the pathogenic antibody detected in the biological sample of the subject during pregnancy is known to bind to a fetal antigen (e.g., an antigen that the fetus has inherited from the fetus's father) in the subject during pregnancy.

[0232] In some embodiments, the anti-FcRn antibodies described herein (e.g., N022~ N024, N026, and N027, preferably N027 and / or N024) are administered to a subject planning pregnancy, and to a subject having or at risk of having a medical condition that activates an immune response during pregnancy and / or to a subject who has had a medical condition that activated an immune response in a previous pregnancy of the subject during pregnancy. In some embodiments, the subject has a history of having had a fetus or neonate with alloimmune and / or autoimmune disorders of the fetus and neonate and is planning pregnancy. In some embodiments, the anti-FcRn antibodies described herein are administered to a subject planning pregnancy and whose biological sample contains a pathogenic antibody associated with an immune disease

[0233] In some embodiments, the anti-FcRn antibodies described herein are used to reduce or treat activation based on immune complexes of acute or chronic immune responses in a subject (e.g., ​ For example, it can be administered to a subject during pregnancy. The acute immune response can be activated by a medical condition (e.g., psoriasis vulgaris, lupus nephritis, myasthenia gravis, Guillain - Barré syndrome, antibody - mediated rejection, severe type anti - phospholipid antibody syndrome, immune complex - mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia reduction, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive arthritis, primary biliary cirrhosis, ulcerative colitis, or anti - neutrophil cytoplasmic antibody (ANCA) - associated vasculitis).

[0234] In some embodiments, the anti - FcRn antibodies described herein can be administered to a subject (e.g., a subject during pregnancy) to reduce or treat an immune response activated by an autoimmune disease. Autoimmune diseases include, for example, alopecia areata, ankylosing spondylitis, anti - phospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia (wAIHA), anti - factor antibodies, heparin - induced thrombocytopenia (HICT), sensitized transplantation, autoimmune hepatitis, hepatitis, Behçet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg - Strauss syndrome, cicatricial pemphigoid, limited cutaneous 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, 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 Hemolysis, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis Arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff man syndrome, Arteritis of the thorax, temporal arteritis, ulcerative colitis, uveitis, vitiligo, or Wegener's granulomatosis It's possible. EXAMPLES

[0235] Example 1 - Antibody Production IgG heavy and light chain nucleic acid molecules were engineered into vectors using the osteonectin secretion signal. The HEK 293F cells were cultured at 37°C with 8% O 2 Cells were grown in Expi293 medium at 100°C for 1 h .... Cells were grown at 1 mg total DNA per liter. Using 3x10 6 The cells were transfected at a density of 2 Add enhancer on days 1 and 2 before cell viability drops below 50%-60%. The cells were cultured for 5 or 6 days. The cells were then 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 first was isolated from the second, whereas the second was isolated from the first, which removed heavy chain dimers, light chain dimers, and half antibodies, and The high molecular weight species were removed by SDS-P. Stored based on AGE gel analysis to maximize the purity of the full-length antibody. The collected fractions were placed on a Sephadex G50 buffer exchange column equilibrated in PBS at pH 7.2. The peak fractions were stored and concentrated to 10 mg / ml using a 30 kDa spin concentrator and frozen at -30 °C in aliquots of 2 mg and 5 mg. The final protein sample was checked for purity by SDS-PAGE.

[0236] Example 2 - Binding Affinity Through affinity maturation, the inventors identified over 100 anti-FcRn antibodies with binding affinities to human FcRn in the sub-micromolar range of K D d. Five antibodies (N022 ~N024, N026, and N027) were selected for further characterization. Surface plasmon resonance (SPR) was used to determine the on-rate and off-rate (k , and k respectively) for each of these five antibodies. Briefly, a Bio-Rad GLC sensor chip was inserted into a ProteOn XPR 36 and air was initialized. After initialization, the running buffer was switched appropriately to either freshly prepared buffer, HBSP+ (0.01 a M HEPES, 0.15 M NaCl, 0.05% P20, pH 7.4) or d sodium phosphate buffer (0.02 M sodium phosphate, 0.15 M NaCl, 0.05% P20, pH 6.0), which was used for the remainder of the assay and for all dilutions. The chip was regenerated with 0.5% SDS, 50 mM NaOH and 10 mM HCl, each at 30 μl / min for 60 seconds (s) once It was pretreated using injection. Mice from GE Healthcare (BR100839) The anti-human Fc mAb was diluted to 10 μg / ml in 10 mM acetate buffer pH 5.0 and approximately 5,700 response units (RU) were immobilized horizontally on a GL C sensor chip using standard amine coupling chemistry. The anti-hFcRn mAb to be tested was immobilized on the surface vertically with the goal of immobilizing approximately 200 response units (RU) per interaction spot rhFcRn was diluted in a 5-point 3-fold dilution series starting at 1.25 μg / ml, and one lane was left as buffer only for double reference. The analyte was flowed horizontally across the sensor surface at 100 μl / min for 240 seconds with a dissociation time of 3600 seconds rhFcRn was diluted in a 5-point 3-fold dilution series starting at 1.25 μg / ml, and one lane was left as buffer only for double reference. The analyte was flowed horizontally across the sensor surface at 100 μl / min for 240 seconds with a dissociation time of 3600 seconds For double reference, one lane was left as buffer only. The analyte was flowed horizontally across the sensor surface at 100 μl / min for 240 seconds with a dissociation time of 3600 seconds For double reference, one lane was left as buffer only. The analyte was flowed horizontally across the sensor surface at 100 μl / min for 240 seconds with a dissociation time of 3600 seconds MmgCl 2 Regeneration was achieved by injecting at 100 μl / min for 30 seconds in both the horizontal and vertical directions These procedures were repeated for all ligands

[0237] Data analysis was performed using ProteOn Manager software. Each interaction step was adjusted in the Y and X directions using an automated process tool, and then non-specific interactions were removed with inter-spot channel reference and assay lift was removed with blank lane double reference Data analysis was performed using ProteOn Manager software. Each interaction step was adjusted in the Y and X directions using an automated process tool, and then non-specific interactions were removed with inter-spot channel reference and assay lift was removed with blank lane double reference Data analysis was performed using ProteOn Manager software. Each interaction step was adjusted in the Y and X directions using an automated process tool, and then non-specific interactions were removed with inter-spot channel reference and assay lift was removed with blank lane double reference The data was grouped and fit to the Langmuir 1:1 rapid kinetics model to match Rmax. The k a , k d and K D values obtained from ProteOn Manager in one run were averaged, and when N was 3 or more, the percent CV was calculated in Microsoft Excel The k, k and K values obtained from ProteOn Manager in one run were averaged, and when N was 3 or more, the percent CV was calculated in 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 as shown. The equilibrium dissociation constant, K D of the anti-FcRn antibody of the present invention for binding to human F cRn at pH 7.4 was in the range of 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, for binding to human FcRn, the on-rates were in the range of 0.93 to 1. 42 X 10 6 1 / Ms. The off-rates were in the range of 2.31 to 4.44 X 10 6 1 / s.

[0239] (Table 3) TIFF0007690538000170.tif72128

[0240] Example 3 - IgG Competition The ability of the anti-FcRn antibodies of the present invention to compete with IgG for binding to human or cynomolgus monkey FcRn was evaluated on human embryonic kidney (HEK) 293 cells heterologously expressing cell surface, glycosylphosphatidylinositol (GPI)-anchored Fc Rn. The alpha amino acid sequences of human and cynomolgus monkey FcRn show 97.5% sequence identity. Nine of the 355 amino acid residues differ between human and cynomolgus monkey FcRn alpha, but are not in the epitope mapping binding region. The level of cell-bound IgG was determined using 66 nM of a fluorescent probe-labeled non-specific IgG. Binding of IgG to cell surface FcRn was performed at pH 6.0, which allows the Fc portion of IgG to interact with FcRn and is not. The level of cell-bound IgG was determined using 66 nM of a fluorescent probe-labeled non-specific IgG. Binding of IgG to cell surface FcRn was performed at pH 6.0, which allows the Fc portion of IgG to interact with FcRn enabled. As shown in Figure 1, as the concentration of anti-FcRn antibodies (N022 - N024, N026, or N027) increased, the amount of cell-bound IgG decreased significantly. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The EC50 values of the antibodies were in the range of 2 - 6 nM. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The binding of IgG was inhibited in a concentration- and saturation-dependent manner by each of the five exemplary anti-FcRn antibodies of the present invention, and the anti-FcRn antibodies, N022 - N024, N026, and N027, effectively competed with the binding of IgG to FcRn at pH 6.0 and demonstrated the ability to inhibit the binding of IgG to FcRn. The EC50 values of the antibodies were in the range of 2 - 6 nM.

[0241] Example 4 - Effect of Anti-FcRn Antibodies on IgG Catabolism in Mice To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. On day 0, FcRn- / -hFcRn(32)Tg mice injected with 500 mg / kg of human IgG were administered 10 mg / kg of anti-FcRn antibody once on days 1 and 4. As shown in Figure 2, IgG catabolism was increased by the administration of anti-FcRn antibody, as seen in the lower levels of IgG measured over time in anti-FcRn antibody-treated mice. The activities of N024 (K = 35.5 pM), N026 (K = 36.5 pM), and N027 (K = 19.4 pM) were considered similar at 10 mg / kg. To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. On day 0, FcRn- / -hFcRn(32)Tg mice injected with 500 mg / kg of human IgG were administered 10 mg / kg of anti-FcRn antibody once on days 1 and 4. To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. On day 0, FcRn- / -hFcRn(32)Tg mice injected with 500 mg / kg of human IgG were administered 10 mg / kg of anti-FcRn antibody once on days 1 and 4. To measure the effect of the anti-FcRn antibodies of the present invention on IgG catabolism in vivo, human FcRn transgenic mouse strain FcRn- / -hFcRn(32)Tg mice that lack murine FcRn but express human FcRn with a tissue distribution similar to endogenous murine and human FcRn were used. On day 0, FcRn- / -hFcRn(32)Tg mice injected with 500 mg / kg of human IgG were administered 10 mg / kg of anti-FcRn antibody once on days 1 and 4. As shown in Figure 2, IgG catabolism was increased by the administration of anti-FcRn antibody, as seen in the lower levels of IgG measured over time in anti-FcRn antibody-treated mice. As shown in Figure 2, IgG catabolism was increased by the administration of anti-FcRn antibody, as seen in the lower levels of IgG measured over time in anti-FcRn antibody-treated mice. D =35.5pM), N02 6(K D =36.5pM), and N027(K D =19.4pM) of the activities were considered similar at 10 mg / kg.

[0242] Example 5 - Functional Characteristics of Anti-FcRn Antibodies In Vitro and In Vivo In vitro The cell-binding affinity of the antibodies of the present invention was measured in human embryonic kidney (HEK) 293 cells that ectopically express cell surface, glycosylphosphatidylinositol (G PI)-anchored human or cynomolgus FcRn. FcRn is a type I transmembrane protein that has IgG and albumin-binding domains and is directed to the cell surface when transported to the luminal side of the endosomal membrane or the plasma membrane . Binding of anti-FcRn antibodies to membrane-associated FcRn on the cell surface, HEK293 cells, at pH 7.4 mimics binding in a physiologically relevant environment and pH where only the Fab domain of the antibody, not the Fc domain , interacts with FcRn. The FcRn extracellular domain was displayed on the cell surface at high density through C-terminal engineered GPI linkage . The anti-FcRn antibodies of the present invention were labeled with a fluorescent probe. Antibodies were allowed to bind for 30 minutes on ice. Cells were then washed at 4°C and bound antibodies were detected using a fluorophore-labeled secondary antibody, e.g., goat anti-human IgG F(ab) . Binding to human FcRn was concentration-dependent and the antibodies of the present invention showed EC50 values in the range of 4 - 7 nM . 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 show the highest percentage positivity for FcRn expression in mouse and human blood. Using the monocyte cell line THP-1, the binding of anti-FcRn antibodies to endogenous human FcRn at pH 7.4 was evaluated. Since endogenous FcRn is mainly in intracellular endosomal vesicles within THP-1 cells, the cells were first made permeable with a neutral detergent and then washed at 4°C and bound antibodies were detected using a fluorophore-labeled secondary antibody, e.g., goat anti-human IgG F(ab) . 2 Human Binding to FcRn was concentration-dependent and the antibodies of the present invention showed EC50 values in the range of 4 - 7 nM .

[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 show the highest percentage positivity for FcRn expression in mouse and human blood. Using the monocyte cell line THP-1, the binding of anti-FcRn antibodies to endogenous human FcRn at pH 7.4 was evaluated. Since endogenous FcRn is mainly in intracellular endosomal vesicles within THP-1 cells, the cells were first made permeable with a neutral detergent and then washed at 4°C and bound antibodies were detected using a fluorophore-labeled secondary antibody, e.g., goat anti-human IgG F(ab) . Endogenous FcRn is mainly in intracellular endosomal vesicles within THP-1 cells, so the cells were first made permeable with a neutral detergent and then washed at 4°C and bound antibodies were detected using a fluorophore-labeled secondary antibody, e.g., goat anti-human IgG F(ab) The non-human lysates were fixed and 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 results showed that the anti-FcRn antibodies bound to THP-1 cells were significantly different from those with good binding. Binding is concentration dependent. All of the 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 was determined to bind to human or cynomolgus monkey FcRn. The ability of FcRn to compete with G was examined in human embryonic kidney cells ectopically expressing cell surface, GPI-linked FcRn. The levels of cell-bound IgG were assessed using fluorescent probe-labeled nonspecific IgG. The binding of IgG to cell surface FcRn was determined at pH 6.0. This allows the Fc portion of IgG to interact with FcRn. 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, in a concentration- and saturation-dependent manner and anti-FcRn antibodies effectively compete with the binding of IgG to FcRn at pH 6.0. 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 antibody of the present invention by hydrogen-deuterium exchange shows that the antibody binds to Fc-FcR Binds to epitopes on human FcRn that are located at and / or adjacent to the FcRn interaction interface showed that this indicates that the antibody of the present invention blocks the binding of Ig G to FcRn by direction inhibition. Furthermore, the epitope-mapped binding site is away from the albumin binding site of FcRn. Using an enzyme-linked immunosorbent assay (ELI SA), it was confirmed that the antibody of the present invention does not inhibit serum albumin binding to FcRn . The soluble His-tagged extracellular domain of human FcRn was bound to the plate surface and pre-incubated with increasing concentrations of anti-FcRn antibody at pH 6.0. Horseradish peroxidase (HRP)-conjugated human serum albumin was bound to soluble His-tagged F cRn. None of the antibodies inhibited albumin binding to FcRn . Furthermore, in vivo experimental evidence also showed that mouse albumin levels remained constant after administration of anti-FcRn antibody , indicating that albumin recycling is not inhibited by antibody binding to FcRn .

[0246] In vivo To test the in vivo effect of the anti-FcRn antibody of the present invention on IgG catabolism, a human FcRn transgenic mouse strain FcRn- / -hF cRn(32)Tg mice that lack mouse FcRn but express human FcRn with a tissue distribution similar to that of endogenous mouse and human FcRn were used . On day 0, human IgG was injected into FcRn- / - hFcRn(32)Tg mice, and on days 1 and 4, a single dose of 10 mg / kg of anti-FcRn antibody was administered. As shown in Example 3 and Figure 2, IgG catabolism was seen at lower levels of IgG measured over time in anti-FcRn antibody-treated mice . Increased by administration of anti-FcRn antibody. N024 (K D = 35.5 pM), N026( K D = 36.5 pM), and N027 (K D = 19.4 pM) activities were considered similar at 10 mg / k g.

[0247] Example 6 - Effect of Anti-FcRn Antibody on IgG Levels and Target Occupancy in Mice After administration of 500 mg / kg IVIg (tracer) to Tg32 human FcRn (hFCGRT ) transgenic, mouse FcRn (mFCGRT) knockout mice , N027 was administered intravenously (i.v.) for 24 hours. Circulating human IgG was detected daily by ELI SA. After incubation of cells using immunophenotyping cell surface markers followed by fixation and permeabilization, target occupancy was measured daily in monocytes from lysed whole blood by fluorescence-activated cell sorting (FACS). Unoccupied FcRn was measured by staining with Dy 650-labeled N027 (n = 4 males / group). As shown in Figure 3 , the percentage of IgG levels and unoccupied FcRn decreased following administration of N027 in a dose-dependent manner.

[0248] Example 7 - Selective Induction of IgG Catabolism and Target Occupancy in Cynomolgus Monkeys N027 was administered intravenously to cynomolgus monkeys at t = 0. Circulating endogenous IgG and al bumin were detected by ELISA. After incubation of cells using immunophenotyping cell surface markers followed by fixation and permeabilization, target occupancy was measured by FACS in monocytes from lysed whole blood. Unoccupied FcRn was measured by staining with Dy650-labeled N02 ​​​​Measured by staining with 7 (male / group, n = 3). As shown in Figure 4, IgG levels and the percentage of unoccupied FcRn were decreased by the administration of N027 in a dose-dependent manner while plasma albumin levels remained unchanged.

[0249] Example 8 - In Vivo Distribution of N027 in Mice N027 labeled with fluorophore (VT680) or isotype human IgG1 control antibody was intravenously administered at 30 mg / kg to Tg32 human FcRn transgenic, mouse FcRn knock - out mice. The levels of labeled antibody were measured in individual organs by quantitative ex vivo optical imaging. Figure 5 shows the in vivo distribution of N027 in various organs of the mouse.

[0250] Example 9 - Efficacy of N027 in Mouse Collagen - Antibody - Induced Arthritis Collagen - antibody - induced arthritis was induced in Tg32 human FcRn transgenic, mouse FcRn knock - out mice by intraperitoneal (i.p.) injection of ArthritoMab™ cocktail (MD Biosciences) on day 1 and inflammatory disease activity was induced by intraperitoneal (i.p.) administration of 100 μg LPS on day 4 . N027 was therapeutically intravenously administered at 5 mg / kg (arrow) on day 6 after disease induction and randomization . 1 g / kg of IVIG (positive control group) or vehicle PBS (negative control) was administered on day 6 after randomization (n = 5 / group). As shown in Figure 6, N027 effectively inhibits collagen - antibody - induced arthritis in human transgenic FcRn mice when therapeutically administered .

[0251] ​​​​ Example 10 - Efficacy of N027 in chronic idiopathic thrombocytopenic purpura (ITP) in mice Thrombocytopenia was treated with subcutaneous (sc) miniimmunotherapy using antiplatelet antibodies (anti-CD41, MWReg30). Continuous infusion of osmotic pumps was used to express Tg32 human FcRn (hFCGRT) transgenes. Nicks, 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 therapeutically intravenously (A, n=4 / group; B, n=7 / group). 1 shows the effect of N027 on platelet levels in mice with pulmonary tuberculosis.

[0252] Example 11 - Concentration-dependent FcRn occupancy is achieved by N027 in target cell types was Receptor occupancy by N027 was observed in primary human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs). in different cell types, including human endothelial (HUVEC) cells and placental trophoblasts (HVTs). Cells were grown in complete EBM-2 medium (Lonza, Waterville) or Cells were grown to confluency in lophoblast medium (ScienCell). The monolayers were inked 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 The cells were then rinsed with cold HyQTase before incubation with 100 mM NaCl for 30 min at 4 °C in the dark. After incubation, the cells were resuspended in FACS buffer. Prior to transfection, 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 FcRn occupancy across N027 concentrations for HAEC, HUVEC, and HVT, respectively. The results summarized in Table 4 show that human EC (HAEC, HUVEC) and placental HVT exhibit similar concentration-dependent receptor occupancy by N027.

[0253] (Table 4) TIFF0007690538000171.tif30143

[0254] The concentration of N027 that achieved 100% receptor occupancy in Example 12 increased the accumulation of intracellular IgG The relationship between the level of receptor occupancy by N027 and the change in IgG intracellular transport was compared in different cell types. Human endothelial cells (HAEC and HUVEC) were cultured in endothelial cell medium (EBM -2, Lonza), while human placental trophoblasts (HVT) were cultured in trophoblast medium (ScienCell). Next, the cell monolayers were pulsed in 1 mL of medium containing any of the following at 37 °C for 4 - 5 hours: 1. Various concentrations of N027 + VivoTag645-IgG (50 μg / mL) 2. Various concentrations of isotype control IgG + VivoTag645-IgG (50 μg / mL) The cell monolayers were then washed with cold medium and cell dissociation was performed by HyQtase treatment. Cell-associated VivoTag645-N027 was measured by flow cytometry. Values are geometric mean fluorescence intensity (gMFI) ± SD (n = 2). Figures 9A, 9B, and 9C represent the intracellular IgG levels of HAEC, HUVEC, and H VT respectively corresponding to various dosages of N027. The N027 dosage corresponding to >100% FcRn occupancy resulted in significantly higher IgG accumulation compared to the isotype control. The results demonstrate that the effective N027 concentration required to saturate the IgG accumulation level is similar among these target cell types and is in the range of 4.99 - 2.43 μg / mL as summarized in Table 5 .

[0255] (Table 5) TIFF0007690538000172.tif30155

[0256] Example 13 - Measurement of Time to 100% FcRn Occupancy To determine the time taken by N027 to saturate FcRn and block IgG transport, confluent vascular endothelial cell (HUVEC) monolayers were incubated at 37°C for the indicated times in EBM - 2 medium in the presence or absence of a saturating concentration of N027 (16.6 μg / ml) (Figure 10). At the end of the incubation, the cells were washed clean, harvested using cold HyQtase, and then fixed and permeabilized. Subsequently, these cells were incubated in permeation buffer + 10% human serum and VivoTag645 - labeled N0 27 (10 μg / mL) in the dark at 4°C for 30 minutes. Next, the cells were washed with permeation buffer, resuspended in FACS buffer, and cell - associated VivoTag645 - N027 was measured by FACS. The values represent mean gMFI ± SD (n = 2). The results shown in Figure 10 indicate that 100% FcRn - occupancy by N027 was achieved in this endothelial cell type in approximately 30 minutes.

[0257] Example 14 - Human vascular endothelial cells and placental trophoblasts exhibit similar FcRn metabolic turnover rates that are not altered by N027 The FcRn metabolic turnover rates of human vascular endothelial cells (HUVEC) and placental trophoblasts (HVT) were compared in the presence and absence of N027. Cells were cultured for 3 days in 75 cm flasks in medium containing 25% D 2O (deuterium oxide, Aldrich). After 3 2 days, the medium was replaced with normal medium containing N027 (100 μg / mL), or control IgG (100 μg / ml), or mock treatment. Next, at the indicated time points after medium change, the cells were harvested from the flasks (Figure 11A and Figure 11B). The cell monolayers were washed, the cells were harvested 2 and pelleted, individual pellets were lysed and digested separately. Shotgun proteomics mix and targeted proteomics were performed. The isotopic relative intensities were extracted using Qual Browser and the fractional abundances for each isotopomer were calculated by dividing each intensity by the sum. Using the fractional abundance values, the percentage of D 2O-labeled FcRn remaining in the system was calculated. Figures 11A and 11B show that the FcRn metabolic turnover rates are similar between human vascular endothelial cells (HUVEC) and placental trophoblasts (HVT). Furthermore, treatment with N027 did not change the FcRn metabolic turnover rate. 2

[0258] Example 15 - Localization of FcRn in target cells The localization of N027 was examined in human vascular endothelial cells (HUVEC) and placental trophoblasts ​​​​​​​​​​were compared with those in human vascular endothelial cells (HUVEC) and placental trophoblasts (HVT). Cells were grown on glass coverslips in EBM-2 / TM medium and incubated with live cells at 37 °C for 1 hour in medium containing DyLight594-N027 (2 μg / mL). Cells were then washed and imaged live on a fluorescence microscope in confocal mode using a 60X dry objective lens using an appropriate filter. Representative single-cell images showed similar localization patterns of N027 bound to the endosomal compartments of FcRn in both cell types (Figures 12A and 12B) . The circles in the center of the cells indicate the position of the nuclei .

[0259] Example 16 - Effect of N027 treatment on the kinetics of IgG transport: Intracellular IgG accumulation and co-localization with lysosomes The effect of N027 treatment on the kinetics of intracellular IgG accumulation was compared between target cell types expressing FcRn, such as human umbilical vein endothelial cells (HUVEC) and placental trophoblasts (HVT). Cells were grown to confluence in EBM-2 medium (Lonza, Waterville) or TM1 medium (ScienCell). The confluent cell monolayers were then pulsed at 37 °C for 20 hours in 1 ml of medium containing either N027 (2 μg / ml) + VivoTag645-IgG (50 μg / mL) or isotype control IgG (2 μg / mL) + VivoTag 645-IgG (50 μg / ml). The cell monolayers were then washed and then chased at 37 °C for 0 minutes , 30 minutes, and 90 minutes in chase medium containing either N027 (2 μg / mL), or isotype control (2 μg / ml). After each chase period, cells were washed, detached, and Hy ​​​​​Collected by Qtase treatment. Cell-associated VivoTag645-N027 was measured by flow -cytometry. Values are expressed as 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 dynamics of intracellular IgG accumulation was similar between the two cell types tested as shown in Figures 13A and 13B.

[0260] Also, in primary human umbilical vein endothelial cells (HUVECs), it was determined whether N027 increased the co-localization of intracellular IgG with lysosomes. Cells were grown on glass coverslips and incubated at 37 °C for 2 h in medium containing 10 μg / ml Alexa Fluor 594 dextran (10,000 MW, anionic, fixable). After incubation, cells were washed and pulsed at 37 °C for 20 h in medium containing N027 (2 μg / ml) + DyLight 488-IgG (50 μg / ml), or medium containing isotype control IgG (2 μg / ml) + DyLight 488-IgG (50 μg / ml), or medium containing no IgG treatment. Plates were washed with cold medium and then chased at 37 °C for 0 or 30 min. The following chase conditions were used: the N027 + DyLight 488-IgG pulse set was chased in the presence of N02 7 (2 μg / mL); the isotype + DyLight 488-IV IG pulse set was chased in the presence of isotype control IgG (2 μg / mL), and the set containing no IgG treatment was chased in medium only. Cells were washed and BD Cy ​​​​Incubate in tofix / Cytoperm solution at 4 °C for 30 minutes in the dark, palm Wash with perm wash buffer, followed by palm wash buffer + Incubate overnight at 4 °C in the dark in 10% normal mouse serum + 5 μg / ml mouse anti-human Lamp1 antibody. Then wash the cells with palm wash buffer and PBS, and then Mounted on glass slides. Using the confocal mode of an Olympus fluorescence microscope, cell imaging was performed with a 60X dry objective lens at 2 X magnification. As shown in Figures 13C and 13D, N027 treatment was shown to increase the accumulation of IgG in the lysosomal compartment compared to isotype control IgG-treated cells. Example 17 - Inhibition 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 administered weekly from gestational day 45 (GD45) until cesarean section at gestational day 100 (mid-gestation) or gestational day 140 (late gestation). A cohort of animals capable of delivering pups was also included in the study (birth date [BD1]). The study design is shown in Table 8.

[0261] Example 17 - Inhibition 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 administered weekly from gestational day 45 (GD45) until cesarean section at gestational day 100 (mid-gestation) or gestational day 140 (late gestation). A cohort of animals capable of delivering pups was also included in the study (birth date [BD1]). The study design is shown in Table 8. Pregnant female cynomolgus monkeys were administered weekly from gestational day 45 (GD45) until cesarean section at gestational day 100 (mid-gestation) or gestational day 140 (late gestation). A cohort of animals capable of delivering pups was also included in the study (birth date [BD1]). The study design is shown in Table 8. A cohort of animals capable of delivering pups was also included in the study (birth date [BD1]). The study design is shown in Table 8. Shown.

[0262] (Table 8) Study design TIFF0007690538000173.tif42160 a Twenty-four pregnant females were initially enrolled in the study (8 per group). Four pregnancies per group were assigned to the cesarean section cohort at gestational day 1 40 ± 2 days, and the remaining pregnancies of four per group were assigned to the cohort at gestational day 100 ± 2 days days.

[0263] Using a standard validated total IgG ELISA, maternal and neonatal blood samples were used The IgG concentration was measured (Table 9). Briefly, polystyrene plates (96-well ) were coated with a commercially available anti-human IgG antigen. The coated plates were washed to remove unbound samples, then blocked with a blocking buffer, and then washed to remove residual blocking buffer . Serum samples were diluted and added to wells coated with anti-human IgG, and incubated at room temperature for 60 ± 5 minutes. Each well was washed, and then a secondary (detection) antibody conjugated with horseradish peroxidase ( HRP) was added and incubated at room temperature for 60 ± 5 minutes . Then, tetramethylbenzidine (TMB) substrate was added to each well and incubated at room temperature for 20 ± 5 minutes on a plate shaker, and then 2N H 2 SO4 was added to stop the enzyme reaction. Absorbance of each well was read at 450 nm using a SpectraMax® 190 microplate reader . Any commercially available or proprietary pair of an anti-human IgG capture antibody and an HRP-conjugated anti-human I gG detection antibody that recognizes total I gG and cross-reacts with cynomolgus IgG can be used to measure total cynomolgus Ig G during ELISA. The IgG detection antibody can be, for example, intact Ig G, a polyclonal serum antibody, a monoclonal antibody, or a Fab(2) fragment .

[0264] (Table 9) Method TIFF0007690538000174.tif87150

[0265] For all pregnant adult females assigned to the study, blood was collected by venipuncture from the femoral vein (preferred ) or the radial cutaneous / medial vein according to Table 10. On gestational day 100 ± 2 Alternatively, for all fetuses obtained by cesarean section on gestational day 140 ± 2, blood was collected from the umbilical cord according to Table 10. The sample (1 mL) was allowed to clot for at least 60 minutes, centrifuged, and the resulting serum was separated and transferred to a properly labeled (e.g., IgG) polypropylene tube and immediately frozen in a freezer set to maintain -80°C.

[0266] (Table 10) Time points for sample collection for evaluation TIFF0007690538000175.tif224156 a Time points were collected only from animals in the cesarean section cohort on gestational day 100. b Collection ranges listed based on potential dosing days on gestational days 44 - 46. All time points were based on the dosing day.

[0267] Suppression of endogenous maternal IgG Administration of N027 resulted in a dose - dependent decrease in serum IgG levels in adult females starting 72 hours after administration, and in both animals dosed at 100 and 300 mg / kg, on gestational days 51 - 53: the maximum decrease in serum IgG concentration was observed at the pre - dosing time point (Figure 16). The serum IgG values of the second group (100 mg / kg) tended to return to pre - dosing levels in a dose - dependent manner, and on gestational days 65 - 67: starting from the pre - dosing time point, it continued until gestational days 65 - 95 and the next dosing on gestational days 135 - 137, and then a decrease of similar magnitude was present within 72 hours of dosing. Animals in the third group (300 mg / kg) were maintained at the nadir IgG values at all pre - dosing time points throughout the dosing period (refer to in Table 10) until. In animals treated with vehicle, no change in IgG from baseline was observed (Group 1).

[0268] The dose-dependent increase in serum IgG concentration was present 2 hours after administration at gestational days 44-46, 93-95, and 135-137. These increases were thought to be the result of detection of N027 by the total IgG assay and were not considered to be related to the pharmacology of N027. A dose-dependent decrease in fetal serum IgG levels was present compared to control values at gestational day 100 and gestational day 140 and was also present in neonates at the time of birth (Figure 17).

[0269] Absence of N027 transfer from mother to fetal circulation Transfer of N027 from the maternal circulation to the fetal circulation was evaluated by measuring the level of N027 FcRn occupation in fetal circulating monocytes. N027 receptor occupancy was measured by flow cytometry (FACS) assay to measure the binding of fluorescently labeled N027 to free / unbound FcRn in the presence and absence of a saturating concentration of N027 on monocytes, granulocytes, B lymphocytes, and T lymphocytes. Unsaturated samples showed the percentage of free or unbound FcRn receptors present on each leukocyte subset at each pre-dose and post-dose time point. Saturated samples were spiked with an unlabeled N027 concentration determined to completely saturate any FcRn receptors remaining free / unbound at each post-dose time point. N027 receptor occupancy was not detected in fetal whole blood at gestational day 100 and gestational day 140 or in neonates at the time of birth in the context of the unsaturated sample analysis described above.

[0270] Example 18 - Evaluation of transplacental transfer of N027 Human placentas obtained from uncomplicated term pregnancies were used in an ex vivo double-perfused single placental The placental transfer of N027 was evaluated using the leaf method. Briefly, the rupture of each placenta was examined, and two chorionic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in an perfusion chamber with the maternal surface facing upwards. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. The flow rates of the perfusion media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusate was equilibrated with a gas mixture consisting of approximately 95% O and 5% CO 2 , and the fetal perfusate was equilibrated with a mixture of 95% N 2 and 5% CO . All experiments were conducted at a temperature of 37 °C. 2 2 Each placental lobe was perfused for an initial control period of 1 hour to allow the tissue to stabilize in the new environment using an open-open configuration of the perfusion system. Perfusion was terminated if any of the

[0271] following occurred during the control period: a volume loss in the fetal circulation exceeding 3 mL / hour, or an inadequate perfusion overlap between the two circulations, indicated by a pO difference of less than 60 mmHg between the fetal vein and artery. After the control period, an experimental period of 4 hours ensued using a closed-closed configuration (i.e., recirculation of the media) of the perfusion system. The latter was initiated by replacement of the media in the maternal and fetal reservoirs and addition of 2 3 mg / ml of BSA.

[0272] ​​​​The transfer of N027 across the lobules of the human placenta was tested at three different concentrations, 0.3 mg / ml, 3 mg / ml, and 30 mg / ml. Fourteen individual placentas were perfused for 4 hours with N027 added to the maternal perfusate at 0.3 mg / ml , 3 mg / ml, and 30 mg / ml. Samples from the maternal artery and fetal vein were taken at 0 , 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes during the experimental period in aliquots of 0.5 mL . Antipyrine was used as a positive control to confirm the integrity of the circulation (Figs. 14 -15). A highly sensitive Meso Scale Discovery (MSD) immuno assay with a lower limit of quantification of 5 ng / ml (meso scale discovery(MSD)immunoass ay) was used to determine the concentration of N027 in the maternal and fetal samples. This assay includes a sandwich format using an anti-idiotype antibody pair, where the MSD plate is coated with the anti-idiotype Ab, followed by incubation with the sample , and then visualized with a second biotinylated anti-idiotype Ab, followed by detection with streptavidin tagged with an MSD tag and addition of the read buffer. The concentration of antipyrine was determined using an HPLC assay with UV detection at 26 0 nm after liquid-liquid extraction. The mean fetal transfer rate of antipyrine across 14 experiments was 41 ± 2.8%. The mean fetal transfer rate of N027 across 14 experiments was 0.0027 ± 0.0021%, indicating a very low level of transfer . The results suggest that N027 can be used in a method for treating pregnant patients without causing fetal exposure .

[0273] ​​ Pharmacokinetics and pharmacodynamics data of Example 19 - N027 Phase 1, single - center, randomized, double - blind, placebo - controlled SAD / MA in NHV A D study was conducted to evaluate the safety, tolerability, PK, and PD of N027. In the SAD study five cohorts received a single IV injection of placebo (n = 2 / cohort), or escalating doses of N027 at 0.3 (n = 3), 3 (n = 3), 10 (n = 6), 30 (n = 6), or 60 (n = 6) mg / kg and were followed for safety, PK, and PD for 8 weeks (Figures 18 and 19). (Figures 18 and 19).

[0274] In the MAD part of the study, subjects received up to 4 weekly IV injections of N027 or placebo and were followed for safety, PK, and PD for 10 weeks after dosing. Subjects in the first cohort received 30 mg / kg N027 or placebo. Results showed that complete FcRn RO was achieved and maintained at 30 mg / kg (Figure 20A). The second cohort of subjects was enrolled to receive 15 mg / kg of N027 (or placebo), and complete RO was determined not to be maintained at 15 mg / kg (Figure 20B).

[0275] Mean serum N027 concentration data (Cmax and trough on day 1) for subjects in the 30 mg / kg and 15 mg / kg cohorts are summarized in Figure 18 using graphs. For 30 mg / kg of N027, the 2 - hour (Cmax) value after the first dose was within the expected range of 500 - 700 μg / m L (based on SAD data), and the trough values on days 7, 14, and 21 were in the range of 4 0 - 140 μg / mL. With repeated dosing, it was 100 - 200 μg / mL As the steady state was established, the variability of the group decreased. With 15 mg / kg of N027 the Cmax value 2 hours after the first dose was 200 - 400 μg / mL, and there was variability to consider in trough concentrations, with most of this data falling below 10 μg / mL, providing a possible explanation for the inability to maintain complete RO at 15 mg / kg.

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

[0277] Both the 15 mg / kg dose and the 30 mg / kg dose were safe and well - tolerated in this first - stage study.

[0278] Example 20 - Effect of M281 (N027) and IVIg on the transplacental transfer of an IgG1 monoclonal antibody In this example, the average maternal - to - fetal transfer of Humira®, a representative IgG1 monoclonal antibody known to cross the placenta, was studied, and the potential of M281 (i.e., M281) to inhibit this transplacental transfer of Humira® was evaluated. The effect of M281 on IgG transfer was close to the threshold for increased M281 clearance due to its target - mediated nature, and related to the M281 pharmacokinetics at a time frame when complete loss of FcRn receptor occupation occurred, from 10 μg / ml to concentrations up to 3000 μg / ml, which are 2 - 3 times the Cmax of 60 mg / kg M281, the highest dose first evaluated in studies in healthy volunteers who are subjects. Further, I​ This blockade of IgG trafficking was also evaluated using positive control IVIg (a polyclonal IgG mixture), which is a known competitive inhibitor of FcRn for IgG trafficking. It was evaluated using positive control IVIg (a polyclonal IgG mixture), which is a known competitive inhibitor of FcRn for IgG trafficking.

[0279] Placental perfusion Placentas from pregnancies of normal healthy duration (38 - 40 weeks) were collected immediately after cesarean section delivery according to an approved study protocol. Placentas with any evidence of maternal infection, systemic disease, and drug or alcohol abuse during pregnancy were excluded from this study. Placentas from pregnancies of normal healthy duration (38 - 40 weeks) were collected immediately after cesarean section delivery according to an approved study protocol. Placentas with any evidence of maternal infection, systemic disease, and drug or alcohol abuse during pregnancy were excluded from this study. Placentas with any evidence of maternal infection, systemic disease, and drug or alcohol abuse during pregnancy were excluded from this study.

[0280] The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The technique of double perfusion of human placental lobules (DPPL) was used according to a defined protocol (Nanovskaya T, Deshmukh S, Brooks M, Ahmed MS. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300(1):26 - 33). Briefly, each placenta was examined for rupture and two chorioangiotic vessels (one artery and one vein) supplying a single intact peripheral placental lobe were cannulated using umbilical catheters of 3F and 5F respectively. The placental lobe was trimmed and placed in the perfusion chamber with the maternal surface facing up. The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The intervillous space on the maternal side was perfused by two catheters penetrating the basal plate. A large venous drain was connected to a peristaltic pump, which continuously removed fluid from the chamber and returned it either to a maternal reservoir (closed circulation) or to a separate container (open circulation). The flow rates of the perfusion fluid media for the fetal and maternal circulations were 3.0 and 12 mL / min respectively. The maternal perfusion The effluent was equilibrated with a gas mixture made of approximately 95% O2 and 5% CO2, and the fetal perfusate was equilibrated with a mixture of 95% N2 and 5% CO2. All experiments were performed at 37 °C .

[0281] Each placental lobe was perfused during an initial control period of 1 hour to allow the tissue to stabilize in the new environment using the open-open configuration. Perfusion was terminated if any of the following quality criteria were not met during the control period: i) a volume loss in the fetal circulation of more than 3 mL / hour, or ii) a pressure difference between the fetal vein and artery of less than 60 mmHg indicating inadequate perfusion overlap between the two circulations . At the end of the control period, 10 ml of effluent was collected from the mother and 10 ml from the fetal vein to determine the baseline level of endogenous IgG. At the end of the control period, the perfusion system was converted to a closed-closed configuration (medium recirculation). The medium was replaced in both the maternal and fetal reservoirs, and then 3 mg / ml of BSA was added to both 2 reservoirs. The test substance (Humira®, or Humira® + M281, or Humira® + IVIg, or Humira® + IVIg + M281) was then added to the maternal reservoir, and an aliquot ( 1 mL) was withdrawn and stored as T = 0 before starting the experimental period. The test substance was co-transfused with a positive control, antipyrine (AP), at 10

[0282] 0 μg / ml. Samples were taken from the maternal artery and fetal vein at 0, 30, 60 at 0.5 mL aliquots during the experimental period . The medium was replaced in both the maternal and fetal reservoirs, and then 3 mg / ml of BSA was added to both reservoirs. The test substance (Humira®, or Humira® + M281, or Humira® + IVIg, or Humira® + IVIg + M281) was then added to the maternal reservoir, and an aliquot ( 1 mL) was withdrawn and stored as T = 0 before starting the experimental period. The test substance was co-transfused with a positive control, antipyrine (AP), at 10 0 μg / ml. Samples were taken from the maternal artery and fetal vein at 0, 30, 60 at 0.5 mL aliquots during the experimental period . mL aliquots from the maternal artery and fetal vein were taken at 0, 30, 60 , were collected at 120, 180, 240, 270, 300, 330, and 360 minutes. At the end of the experiment, the perfused area was cut from the adjacent placental tissue, weighed, and one piece of the perfused lobe was placed in 4% PFA for IHC analysis. The perfused area was cut from the adjacent placental tissue, weighed, and one piece of the perfused lobe was placed in 4% PFA for IHC analysis. The perfused area was cut from the adjacent placental tissue, weighed, and one piece of the perfused lobe was placed in 4% PFA for IHC analysis.

[0283] The concentration of Humira® in aliquots of all maternal and fetal samples was determined using a sandwich ELISA with a lower limit of quantification (LLOQ) of approximately 1 ng / ml. The transfer of Humira® from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000176.tif9140. The concentration of Humira® in aliquots of all maternal and fetal samples was determined using a sandwich ELISA with a lower limit of quantification (LLOQ) of approximately 1 ng / ml. The transfer of Humira® from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000176.tif9140. The transfer of Humira® from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000176.tif9140. The transfer of Humira® from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000176.tif9140.

[0284] The concentration of M281 in aliquots of all maternal and fetal samples was determined. The transfer of M281 from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000177.tif8132. The transfer of M281 from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000177.tif8132. The transfer of M281 from the mother to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000177.tif8132.

[0285] (Table 11) Composition of maternal and fetal compartments TIFF0007690538000178.tif60148

[0286] Antipyrine analysis Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments. Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments. Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments. Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments. Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments. Antipyrine (AP) is a small molecule (188 Da), non-ionizable at pH 7.4 (pKa 1.4), and as a result freely crosses the placenta via passive diffusion. Furthermore, AP preferentially distributes in the aqueous maternal and fetal circulations with minimal retention in tissues due to its low octanol / water partition coefficient of 0.33 and its minimal binding to plasma proteins and serum albumin. It has been widely used in perfusion models as an internal permeability positive control to account for variations within the placenta across various experiments.

[0287] The antipyrine concentration was measured in samples using the modified HPLC method described in the previous report (Morck T.J., Sorda G., Be chi N., Rasmussen B.S., Nielsen J.B., Ietta F., Rytting E., Mathiesen L., Paulesu L, Kn udsen L.E.Placental transport and in vit ro effects of Bisphenol A.Reproductive T oxicol.2010;30: 131~137). The transfer of antipyrine from the maternal to the fetal reservoir was determined by the fetal transfer rate (FTR) calculated as TIFF0007690538000179.tif9134.

[0288] FTRs of antipyrine of 35 - 45%, considered to represent a high degree of perfusion overlap, were used to validate and compare the respective experiments. Furthermore, the fetal - to - maternal (FTM) ratio for the transfer of AP was calculated at each time point to confirm the equilibrium between the maternal and fetal sides. The F TM ratio was expected to exceed 0.75 and to be approximately 60 - 120 minutes, and thus it is ideal to confirm the integrity of the placenta.

[0289] Briefly, proteins were precipitated from each 200 μl sample with 200 μl of ice - cold acetonitrile containing 10 μl / ml of the internal standard phenacetin. The samples were centrifuged at 8000 rpm for 25 minutes and the supernatants were analyzed by HPLC. Briefly, antipyrine and phenacetin were analyzed by an Agilent 1200 HP equipped with a UV detector ​Analysis was performed using an LC system. The stationary phase used was a reversed-phase C18-based column (W aters Atlantis T3, Atlantis T3 Column, 100 Å, 3 μm, 3 mm × 150 mm). The column was also equipped with a guard cartridge (Waters T3, 3 μm, 2.1 mm X 150 mm ) that was changed before the start of each sample set. The temperatures of the column and the sample were maintained at 25 °C and 4 °C, respectively. The sample was run at a flow rate of 0.3 mL / min for 14 minutes with a linear gradient in the range of 25 - 95% methanol-water, the injection volume was 10 μL, and detection was performed using absorbance at 260 nm.

[0290] Transfer of Humira® The transplacental transfer of Humira® was studied at a fixed concentration of 270 μg / ml. All eight experiments that met the quality criteria for good perfusion, such as maintaining placental integrity throughout the experimental period, an antipyrine FTM ratio of greater than 0.75, and a volume loss from the fetal reservoir of 3 ml / hour or less, are reported in Table 12. For these experiments, oxygen transfer levels and consumption were also monitored as markers of perfusion duplication and tissue viability, respectively.

[0291] (Table 12) Transplacental transfer of Humira® TIFF0007690538000180.tif74128 1 Ratio of fetal perfusate concentration to maternal perfusate concentration x 100% 2 Antipyrine transfer range of 35 - 45%

[0292] The transplacental transfer of antipyrine during the course of these experiments is shown in Figure 22 and also each In the experiment, the fetal-to-maternal (FTM) concentration ratio was calculated at each time point and at the end time point. All experiments achieved equilibrium (FTM ratio, 0.9 - 1.0) within 60 - 180 minutes. In eight experiments, the mean ± SD FTM ratio of the fetus to the mother at the end time point was calculated to be 1.03 ± 0.11, indicating appropriate placental integrity over the experimental period. The level of antipyrine transfer from the mother to the fetus was observed to be > 35% in all experiments, showing a high degree of perfusion overlap compared to the reported experiments. The transfer of Humira® across the placenta in eight experiments is shown in Figure 23. As shown in Table 2, the mean ± SD fetal transfer rate was calculated to be approximately 0.23 ± 0.21% on average, while the approximate mean ± SD fetal concentration at the end of the experiment was in the range of 0.49 ± 0.49 μg / mL.

[0293] The transfer of Humira® in the presence of M281

[0294] The Humira® concentration constant was kept constant at 270 μg / ml, and the concentration of M281 in the maternal reservoir was varied to study the transplacental transfer of Humira® in the presence of M281. All experiments maintained placental integrity over the experimental period and met quality criteria for favorable perfusion such as an FTM ratio of antipyrine from the fetus to the mother > 0.75 and a volume loss from the fetal reservoir of 3 ml / hour or less. An overview of the studies and results is shown in Table 3. As mentioned above, oxygen transfer levels were also monitored as a marker of tissue viability for these experiments (note: experiment PP 75 was conducted in the absence of antipyrine, but other parameters such as fetal volume and oxygen transfer were measured and they indicated good perfusion quality). ​​​​​​​​​​​​​​​ was in accordance with the standard).

[0295] (Table 13) Transplacental transfer of Humira (registered trademark) in the presence of M281 TIFF0007690538000181.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 in each experiment, the transfer ratio of the fetus to the mother (FTM) was calculated at each time point and at the end time point. In 8 experiments with antipyrine, the average ±SD FTM ratio at the end time point was 1.1 ± 0.11 (equilibrium was achieved in the maternal and fetal circulations) and was calculated, indicating appropriate placental integrity over the experimental period. The transfer level of antipyrine from the mother to the fetus was observed to be >35%, showing a high degree of perfusion overlap compared to the reported experiments .

[0297] The transplacental transfer of Humira (registered trademark) in the presence of M281 in 9 experiments is shown in Figure 2 5. The fetal transfer rate (mean ± SD) of Humira (registered trademark) in the presence of 300 μg / ml of M281 was calculated to be 0.06 ± 0.01% (n = 5), while the experiment of Humira (registered trademark) in the presence of 10 μg / mL of M281 (n = 3) showed an average fetal transfer rate of 0.07 ± 0.01% (mean ± SD). Similarly, the fetal transfer rate of Humira (registered trademark) in the presence of 3000 μg / ml of M281 was 0.06 (n = 1). For all 9 experiments reported in Table 13, the fetal transfer rate of Humira (registered trademark) was calculated, collectively, to be approximately 0.07 ± 0.01% on average, whil...

Claims

1. A pharmaceutical composition for use in a method for treating or reducing the risk of developing alloimmune and / or autoimmune disorders in fetuses and neonates, wherein the pharmaceutical composition comprises an antibody comprising a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 24, wherein the method comprises administering the pharmaceutical composition to a pregnant woman, the administration being initiated between about 12 weeks of gestation and about 16 weeks of gestation and terminated after 34 weeks of gestation, wherein the alloimmune and / or autoimmune disorders in the fetus and neonate are hemolytic diseases of the fetus and neonate, the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the antibody is used to be administered at a dose per administration, the dose being based on the weight of the pregnant woman at the time of the first administration and being upregulated based on the weight gain of the pregnant woman.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is used such that IVIG (polyclonal IgG mixture) is administered to the pregnant woman after the end of the administration of the antibody and before birth.

4. The pharmaceutical composition according to claim 3, wherein the IVIG is administered to the pregnant woman 40 to 100 hours before birth.

5. The pharmaceutical composition according to claim 3 or 4, wherein the IVIG is administered at 200 mg / kg to 1000 mg / kg based on the weight of the pregnant woman.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is used to be administered from 16 weeks of gestation to 35 weeks of gestation.

7. A pharmaceutical composition for use in a method for treating or reducing the risk of developing alloimmune and / or autoimmune disorders in fetuses and neonates, wherein the pharmaceutical composition comprises an antibody comprising a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 24, wherein the method comprises administering the pharmaceutical composition to a pregnant woman, the administration being initiated between about 12 weeks of gestation and about 16 weeks of gestation and terminated after 34 weeks of gestation, wherein the alloimmune and / or autoimmune disorders in the fetus and neonate are fetal and neonatal alloimmune thrombocytopenia (FNAIT), the pharmaceutical composition.

8. The pharmaceutical composition is one in which the antibody is used to be administered at a dose per administration, the dose is based on the weight of the pregnant woman at the time of the first administration, and is adjusted upward based on the increase in the weight of the pregnant woman, the pharmaceutical composition according to claim 7.

9. The pharmaceutical composition is one in which IVIG (polyclonal IgG mixture) is used to be administered to the pregnant woman after the end of the administration of the antibody and before birth, the pharmaceutical composition according to claim 7 or 8.

10. The pharmaceutical composition according to claim 9, wherein the IVIG is administered to the pregnant woman 40 to 100 hours before birth.

11. The pharmaceutical composition according to claim 9 or 10, wherein the IVIG is administered at 200 mg / kg to 1000 mg / kg based on the weight of the pregnant woman.

12. The pharmaceutical composition is one in which the pharmaceutical composition is used to be administered from 13 weeks of pregnancy to 38 weeks of pregnancy, the pharmaceutical composition according to any one of claims 7 to 11.

13. The pharmaceutical composition is one in which the pharmaceutical composition is used to be administered from 14 weeks of pregnancy to 38 weeks of pregnancy, the pharmaceutical composition according to any one of claims 7 to 11.

14. The pharmaceutical composition is one in which the pharmaceutical composition is used to be administered from 15 weeks of pregnancy to 38 weeks of pregnancy, the pharmaceutical composition according to any one of claims 7 to 11.

15. The pharmaceutical composition is one in which the pharmaceutical composition is used to be administered from 16 weeks of pregnancy to 38 weeks of pregnancy, the pharmaceutical composition according to any one of claims 7 to 11.

16. A pharmaceutical composition for use in a method for treating fetal and neonatal alloimmune disorders and / or autoimmune disorders or for reducing the risk of their onset, wherein the pharmaceutical composition comprises an antibody comprising a light chain having the amino acid sequence of SEQ ID NO: 19 and a heavy chain having the amino acid sequence of SEQ ID NO: 24, the method comprising administering the pharmaceutical composition to a pregnant woman, the administration being initiated from about 12 weeks of pregnancy to about 16 weeks of pregnancy and terminated after 34 weeks of pregnancy, wherein the fetal and neonatal alloimmune disorders and / or autoimmune disorders are congenital heart block, the pharmaceutical composition.

17. The pharmaceutical composition is used such that the antibody is administered at a dose per administration, the dose being based on the weight of the pregnant woman at the time of the first administration and being adjusted upward based on the weight gain of the pregnant woman, the pharmaceutical composition according to claim 16.

18. The pharmaceutical composition is used such that IVIG (polyclonal IgG mixture) is administered to the pregnant woman after the completion of the administration of the antibody and before birth, the pharmaceutical composition according to claim 16 or 17.

19. The pharmaceutical composition according to claim 18, wherein the IVIG is administered to the pregnant woman 40 to 100 hours before birth.

20. The pharmaceutical composition according to claim 18 or 19, wherein the IVIG is administered at 200 mg / kg to 1000 mg / kg based on the weight of the pregnant woman.

21. The pharmaceutical composition is used such that it is administered from 16 weeks of pregnancy to 35 weeks of pregnancy, the pharmaceutical composition according to any one of claims 16 to 20.

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