Fcrn antibodies and methods of use thereof

Abstract

To provide a pharmaceutical composition for use in a method for treating an alloimmune and / or autoimmune disorder.SOLUTION: A pharmaceutical composition comprises an antibody against a human neonatal Fc receptor (anti-FcRn antibody), wherein the treatment comprises intravenous infusion of the anti-FcRn antibody to a subject, the dose of the anti-FcRn antibody being 30 to 60 mg / kg, and the intravenous infusion being carried out over 15 to 30 minutes, the anti-FcRn 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.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claims This application is a continuation of U.S. Provisional Patent Application No. 62 / 881,897, filed August 1, 2019. No. 60 / 699,999, filed on Oct. 1, 2003, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Therapeutic proteins, such as therapeutic antibodies, are rapidly becoming available to patients with immunological disorders. Many autoimmune and alloimmune diseases are caused by pathogenic antibodies. There is a need for new methods of treating immunological diseases. do. Summary of the Invention [Means for solving the problem]

[0003] The present disclosure provides a method for intravenous administration of antibodies against the human neonatal Fc receptor (FcRn). The anti-FcRn antibody is characterized by, for example, promoting clearance of autoantibodies in a subject. to suppress antigen presentation in a subject, to block an immune response, e.g., to block activation of immune complex-based immune responses in a subject, or to inhibit the immune response in a subject It is useful for treating epidemiological diseases (eg, autoimmune diseases).

[0004] 1. A method of treating an alloimmune and / or autoimmune disorder, comprising administering to a subject 5-60 mg or more of an alloimmune or autoimmune disorder. The study involved intravenous infusion of anti-FcRn antibodies at a dose of 30-60 mg / kg, and the intravenous infusion was The antibody was tested for 10 minutes or less, and the anti-FcRn antibody was tested for: (1) CDR L1, CD (1) a light chain variable region comprising CDRs H1, H2, and L3; and (2) a light chain variable region comprising CDRs H1, H2, and L3. a heavy chain variable region comprising CDR H1, H2, and CDR H3, and CDR L1 is Contains no more than two amino acid substitutions relative to the sequence of DVGSYNLVS (SEQ ID NO: 1) and CDR L2 has one or more sequences corresponding to the sequence of GDSERPS (SEQ ID NO: 2). CDR L3 contains a sequence with a non-repeating amino acid substitution, and 3) a sequence having no more than one amino acid substitution relative to the sequence of CDR H1 is TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or NYAMG (SEQ ID NO: 6) a sequence having no more than one amino acid substitution relative to the sequence of CDR H2 is SIGSSGAQTRYADS (SEQ ID NO: 7), SIGASGSQTRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), or SIGASGG Contains no more than two amino acid substitutions relative to the sequence of QTRYADS (SEQ ID NO: 10) The CDR H3 has one sequence different from the sequence of LAIGDSY (SEQ ID NO: 11). Methods are described herein that involve sequences with non-rotating amino acid substitutions.

[0005] In various embodiments, CDR L1 has the sequence TGTGSDVGSYNLVS (sequence CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), and CDR L3 contains the sequence SSYAGSGIYV (SEQ ID NO: 3) and CDR H1 contains the sequence TYA MG (SEQ ID NO: 4), and CDR H2 contains the sequence SIGASGSQTRYADS (sequence No. 8), and CDR H3 contains the sequence LAIGDSY (SEQ ID NO: 11); , 7-90 minutes, 7-60 minutes, 7-45 minutes, 7-30 minutes, 10-90 minutes, 10- It can be performed for 60 minutes, 10-45 minutes, 10-30 minutes, or 15-30 minutes. The Fc domain of the antibody is non-fucosylated; The Fc domain of the antibody is glycosylated alloimmune and / or autoimmune disorders are not classified as fetal and neonatal alloimmune disorders. Thrombocytopenia, hemolytic disease of the fetus and newborn, alloimmune panthrombocytopenia, congenital heart disease Lock, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antimyelitis Phospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, neonatal scleroderma, bech Neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and Neonatal type I diabetes mellitus.

[0006] In various embodiments, the alloimmune and / or autoimmune disorder is thrombocytopenia, pancreatic cancer, or thyroid cancer. Thrombocytopenia, congenital heart block, arthrogryposis, myasthenia gravis, autoimmune hemolytic anemia, Warm autoimmune hemolytic anemia, antiphospholipid syndrome, polymyositis, dermatomyositis, lupus, scleroderma Behçet's disease, Graves' disease, Kawasaki disease, autoimmune thyroid disease, and type I euthyroidism Diarrhea is selected from the group consisting of:

[0007] In various embodiments, the injection is of a composition containing 5-60 mg / ml of antibody. injection is of a composition containing 30 mg / ml of antibody; the heavy chain is SEQ ID NO: 20 At least 95%, 97%, 99%, or 1% of the 24 sequences and the light chain comprises a sequence having at least 900% identity to the sequence of SEQ ID NO: 19. the antibody heavy chain comprises a sequence having 5%, 97%, 99%, or 100% identity to the sequence Any of SEQ ID NOs: 20 to 24 having an amino acid other than N at position 296 of SEQ ID NOs: 20 to 24 injections of 10-60 mg / ml of antibody, 20-30 mM of Sodium phosphate, 20-30 mM sodium chloride, 80-100, and 0.1-0. 0.05% weight / volume polysorbate 80; the antibody heavy chain is The following amino acid substitutions relative to sequence number 24: A23V, S30R, L80V, A84T 24, having one or more of the following amino acid sequences: E85D, A93V, E85C, E85D, A93V. The antibody light chain contains the following amino acid substitutions with respect to the sequence of SEQ ID NO: 19: Q38H, V58I and G99D; The antibody heavy chain does not contain a C-terminal lysine; the administered antibody has a light chain comprising SEQ ID NO: 19, and SEQ ID NO: 24 or a variant of SEQ ID NO: 24 in which the amino acid at position 296 is other than N. The antibody is administered at 5-30 mg / kg; the antibody is administered intravenously The concentration is 10 mg / ml to 30 mg / ml.

[0008] In various embodiments, the subject is a pregnant woman; the dose is Based on the weight of the pregnant woman and not upregulated based on the weight gain of the pregnant woman The dose is per administration and is based on the weight of the pregnant woman at the time of the first dose. The dose should be adjusted upward based on the woman's weight gain during pregnancy; the dose is administered every other week; the dose is administered at least weekly; the dose is Administered weekly; subjects are pregnant women, and the first dose is administered during the first trimester of pregnancy. The subjects are pregnant women, and the first dose is administered during the middle trimester of pregnancy. subjects are pregnant women and the first dose is administered during the last trimester of pregnancy The subject is a pregnant woman who has an obstetric history of severe fetal anemia. The subject is a pregnant woman who is at risk of hemolytic disease of the fetus and newborn. obstetric history; the subject is a pregnant woman who has elevated anti-RhD , anti-Rhc, or anti-Kell immunoglobulin alloantibody titers; subjects are pregnant The pregnant woman had elevated anti-Rhc or anti-Kell immunoglobulin levels. the subject is a pregnant woman, and the pregnant woman has anti-Lua, L ub, Bg, Kna, Yta, E, c, K, Cw, Fya, cE, ce, D, Ce, cE ,K,Kpa,Kpb,Fya,M,N,S,Lea,Leb,Fy,Jka,Dieg For one or more antibodies selected from the group consisting of o, P, and Mia / Mur , have elevated immunoglobulin alloantibody titers; the subject is a pregnant woman, and Pregnant women should be monitored for obstetric history of severe fetal anemia or stillbirth within 24 weeks of gestation, as well as elevated blood pressure. have high anti-D or anti-Kell IgG alloantibody titers and are pregnant with an antigen-positive fetus; The subjects are pregnant women, and the first dose is administered between 12 and 16 weeks of pregnancy; and the subjects are , pregnant women, and the first dose is administered during the 14th week of pregnancy.

[0009] In one embodiment, the isolated antibody comprises: (1) CDR L1, CDR L2, and CDR L3; (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; RH3, and CDR L1 is TGTGSDVGSYNLVS (SEQ ID NO: 1) RL2 has no more than one amino acid substitution relative to the sequence of GDSERPS (SEQ ID NO: 2). CDR L3 has the sequence of SSYAGSGIYV (SEQ ID NO: 3) and CDR H1 comprises a sequence having no more than one amino acid substitution relative to TYAMG. (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or NYAMG (SEQ ID NO: 6) and CDR H2 comprises a sequence having no more than one amino acid substitution relative to SIGSS. GAQTRYADS (SEQ ID NO: 7), SIGASGSQTRYADS (SEQ ID NO: 8), S IGASGAQTRYADS (SEQ ID NO: 9), or SIGASGGQTRYADS (SEQ ID NO: 10) a sequence having no more than two amino acid substitutions relative to the sequence of CDR H3 has no more than one amino acid substitution relative to the sequence of LAIGDSY (SEQ ID NO: 11). It includes sequences with substitutions.

[0010] In some embodiments, the antibody is less than 200 pM, less than 150 pM, less than 100 pM K less than, less than 50 pM, or less than 40 pM D and binds to human FcRn.

[0011] In some embodiments, the isolated antibody has the sequence TGTGSDVGSYNLVS (sequence CDR L1 having the sequence of sequence number 1), GDSERPS having the sequence of sequence number 2 CDR L2, CDR L3 with the sequence SSYAGSGIYV (SEQ ID NO: 3), CDR H1 having the sequence of AMG (SEQ ID NO: 4), CDR H2 having the sequence of SIGSSGAQTRYADS (SEQ ID NO: 5), CDR H2 having the sequence of (sequence number 7), and the sequence of LAIGDSY (SEQ ID NO: 11) It contains a CDR H3 having the following structure:

[0012] In some embodiments, the isolated antibody has the sequence TGTGSDVGSYNLVS (sequence CDR L1 having the sequence of sequence number 1), GDSERPS having the sequence of sequence number 2 CDR L2, CDR L3 having the sequence SSYAGSGIYV (SEQ ID NO: 3), DY CDR H1 having the sequence of AMG (SEQ ID NO: 5), CDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO: 6), CDR H2 having the sequence of (SEQ ID NO: 8), and the sequence of LAIGDSY (SEQ ID NO: 11) It contains a CDR H3 having the following structure:

[0013] In some embodiments, the isolated antibody has the sequence TGTGSDVGSYNLVS (sequence CDR L1 having the sequence of sequence number 1), GDSERPS having the sequence of sequence number 2 CDR L2, CDR L3 having the sequence SSYAGSGIYV (SEQ ID NO: 3), CDR H1 having the sequence of AMG (SEQ ID NO: 6), SIGASGAQTRYADS (sequence CDR H2 having the sequence of (SEQ ID NO: 9), and the sequence of LAIGDSY (SEQ ID NO: 11) It contains a CDR H3 having the following structure:

[0014] In other embodiments, the isolated antibody has the sequence TGTGSDVGSYNLVS (SEQ ID NO: CDR L1 having the sequence of 1), CDR L2 having the sequence of GDSERPS (SEQ ID NO: 2) L2, CDR with sequence SSYAGSGIYV (SEQ ID NO: 3) L3, TYAMG CDR H1 having the sequence of (SEQ ID NO: 4), SIGASGGQTRYADS (SEQ ID NO: 5), 10), and CDR H2 having the sequence of LAIGDSY (SEQ ID NO: 11). It contains CDR H3.

[0015] In yet another embodiment, the isolated antibody is TGTGSDVGSYNLVS (sequence CDR L1 having the sequence of sequence number 1), GDSERPS having the sequence of sequence number 2 CDR L2, CDR L3 with the sequence SSYAGSGIYV (SEQ ID NO: 3), CDR H1 having the sequence of AMG (SEQ ID NO: 4), CDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO: 5), CDR H2 having the sequence of (SEQ ID NO: 8), and the sequence of LAIGDSY (SEQ ID NO: 11) It contains a CDR H3 having the following structure:

[0016] In some embodiments, the light chain of the isolated antibody is QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT At least 90% of the sequence of HEGSTVEKTVAPTECS (SEQ ID NO: 19) It includes sequences that have identity.

[0017] In some embodiments, the heavy chain of the isolated antibody is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 20) The present invention includes sequences having at least 90% identity to the sequence of

[0018] In other embodiments, the heavy chain of the isolated antibody is EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQA PGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 21) The present invention includes sequences having at least 90% identity to the sequence of

[0019] In other embodiments, the heavy chain of the isolated antibody is EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQA PGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 22) The present invention includes sequences having at least 90% identity to the sequence of

[0020] In some embodiments, the heavy chain of the isolated antibody is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 23) The present invention includes sequences having at least 90% identity to the sequence of

[0021] In other embodiments, the heavy chain of the isolated antibody is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 24) The present invention includes sequences having at least 90% identity to the sequence of

[0022] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT at least 90% to the sequence of HEGSTVEKTVAPTECS (SEQ ID NO: 19); 95%, 98%, or 99% identity, and the heavy chain comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 20) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of Includes.

[0023] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS (SEQ ID NO: 19) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of and the heavy chain comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQA PGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 21) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of Includes.

[0024] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS (SEQ ID NO: 19) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of and the heavy chain comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQA PGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 22) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of Includes:

[0025] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS (SEQ ID NO: 19) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of and the heavy chain comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 23) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of Includes.

[0026] In yet another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS (SEQ ID NO: 19) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of and the heavy chain comprises EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 24) A sequence having at least 90%, 95%, 98%, or 99% identity to the sequence of Includes:

[0027] In some embodiments, the antibody is QSALTQPASVSGSPGQSIT ISCTGTGSDVGSYNLLVSWYQQHPGKAPKLMIYGDSERPSG VSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIY At least 95%, 97%, 99%, or 100% homology to VFGTGTKVTVL (SEQ ID NO: X) or a light chain variable region comprising an amino acid sequence that is 100% identical to the amino acid sequence of the first or second nucleotide polynucleotide. In some embodiments, the light chain variable region is TGTGSDVGSYNLVS (SEQ ID NO: CDR L1 having the sequence of GDSERPS (SEQ ID NO: 2) R L2, containing CDR L3 having the sequence SSYAGSGIYV (SEQ ID NO: 3) In some embodiments, the antibody is EVQLLESGGGLVQPGGSLR LSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTR YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARL At least 95% and 97% for AIGDSYWGQGTMVTVSS (sequence number Y) , 99%, or 100% identity to a heavy chain variable region containing an amino acid sequence nothing. In some embodiments, the heavy chain variable region has the sequence TYAMG (SEQ ID NO: 4). CDR H1 having the sequence SIGASGSQTRYADS (SEQ ID NO: 8) H2, and CDR H3 having the sequence of LAIGDSY (SEQ ID NO: 11).

[0028] In some embodiments, the heavy chain of the isolated antibody is selected from the group consisting of SEQ ID NOs: 20-24. At least 95%, 97%, 99%, or 100% identical to any one sequence In another embodiment, the light chain of the isolated antibody comprises a sequence having the sequence of SEQ ID NO: 19. A sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of Contains columns.

[0029] In some embodiments, the heavy chain of the isolated antibody is selected from the group consisting of SEQ ID NOs: 20-24. No more than 5, no more than 4, or no more than 3 for any one amino acid sequence sequences with no, more than two, or more than one single amino acid substitution In some embodiments, the light chain of the isolated antibody corresponds to the sequence of SEQ ID NO: 19. and not more than five, not more than four, not more than three, not more than two, or includes sequences with no more than one single amino acid substitution.

[0030] In some embodiments, the isolated antibody is selected from the group consisting of any of SEQ ID NOs: 20-24. It further contains the amino acid substitution N297A relative to one of the sequences (according to EU numbering).

[0031] In other embodiments, the isolated antibody is selected from the group consisting of any one of SEQ ID NOs: 20-24. It further contains the amino acid substitutions D355E and L357M relative to the sequence of evening).

[0032] In other embodiments, the isolated antibody has the following amino acid substitutions: SEQ ID NOs: 20-24 A23V, S30R, L80V, A84T, E85 for any one of the sequences D, A93V (according to EU numbering), and Q38H for the sequence of SEQ ID NO: 19; V58I, and G99D (EU numbering) This includes:

[0033] In yet other embodiments, the isolated antibody is selected from the group consisting of any of SEQ ID NOs: 20-24. For one sequence, it does not contain a C-terminal lysine at residue 446.

[0034] In some embodiments, the antibody of any of the above aspects is N022, N0 23, N024, N026, or N027, lower than or equal to that of an antibody that also has the same Fc region as that of the antibody being compared Equal K D It binds to human FcRn. For example, specific K D In the assay, the antibody K D is less than 200 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than 40 It is less than pM.

[0035] The complementarity determining regions (CDRs) and frames of any of the isolated antibodies described herein The amino acid positions assigned to the framework regions (FR) are based on the EU index of Kabat. (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service , National Institutes of Health, Bethesda, MD. (1991)). Fc The location of the region sequences is indicated by EU numbering (Edelman et al., Proc Natl Acad USA, 63:78-85 (19 69).

[0036] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT comprising or consisting of the sequence HEGSTVEKTVAPTECS (SEQ ID NO: 19) , the heavy chain is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMG WVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO: 20) The sequence comprises or consists of:

[0037] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT comprising or consisting of the sequence HEGSTVEKTVAPTECS (SEQ ID NO: 19) , the heavy chain is EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMG WVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO: 21) The sequence comprises or consists of:

[0038] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT HEGSTVEKTVAPTECS (SEQ ID NO: 19), and the heavy chain comprises the sequence EVQLL ESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGL EWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 22) The sequence comprises or consists of:

[0039] In another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT comprising or consisting of the sequence HEGSTVEKTVAPTECS (SEQ ID NO: 19) , the heavy chain is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMG WVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO: 23) The sequence comprises or consists of:

[0040] In yet another embodiment, the isolated antibody has a light chain and a heavy chain, wherein the light chain comprises: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQ HPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGL QAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVK AGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVT comprising or consisting of the sequence HEGSTVEKTVAPTECS (SEQ ID NO: 19) , the heavy chain is EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMG WVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPG (SEQ ID NO: 24) The sequence comprises or consists of:

[0041] In another aspect, the disclosure features a method of increasing catabolism of IgG in a subject. In another aspect, the disclosure features a method of reducing autoantibodies in a subject. In yet another aspect, the present disclosure provides a method for inhibiting the activity of an immune complex-based immune response in a subject. The present invention features a method for treating or reducing inflammatory bowel disease in a subject, comprising administering to a subject a therapeutically effective amount of a compound described herein. Any isolated antibody or pharmaceutical composition comprising any isolated antibody described herein This includes administering a substance.

[0042] In some embodiments, the immune response in the subject is an acute or chronic immune response. do.

[0043] In some embodiments, the treatment of pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, and the like. Barre syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome, immune complex-mediated Vasculitis, glomerulitis, channelopathy, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenia oligopurpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilation the subject has a medical condition selected from the group consisting of: cardiomyopathy, idiopathic pulmonary fibrosis, and serum sickness; or An acute immune response is thereby activated.

[0044] In some embodiments, chronic inflammatory demyelinating polyneuropathy (CIDP), Systemic lupus, chronic forms of the disorder for which acute treatment is indicated, reactive arthropathy, primary biliary hepatitis From the group consisting of cirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis The subject has a medical condition selected from the group consisting of, or a chronic immune response is activated by, will be done.

[0045] In some embodiments, the subject has an autoimmune disease or an immune response caused by the disease. Specifically, autoimmune diseases include alopecia areata, ankylosing spondylitis, and antiphospholipids. Chronic hepatitis syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behçet's disease, bullous hepatitis Pemphigus, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory decompensation syndrome Myelogenous polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, localized scleroderma CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential Gender-mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, Hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, I gamma 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 inflammation, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-man syndrome, Takayasu's artery Arteritis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis The compound is selected from the group consisting of:

[0046] In another aspect, the present disclosure provides methods for treating fetal and neonatal alloimmune and / or autoimmune disorders. a method of treating a pregnant subject, the method comprising IV administration of an antibody described herein to the pregnant subject. or a process that consists of, or consists essentially of,

[0047] In some embodiments of all aspects, the subject has received prior fetal and neonatal alloimmunization. have a history of having an illness and / or an autoimmune disorder. For example, in some embodiments In the method, the pregnant subject has been previously pregnant and the fetus or newborn has and had neonatal alloimmune and / or autoimmune disorders. In some embodiments, the subject is a patient with a fetal or neonatal alloimmune and / or autoimmune disorder. There is a risk of having

[0048] In some embodiments of all aspects, fetal and neonatal alloimmunization and / or The autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolysis, Diseases, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myositis Asthenia, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis Dermatomyositis, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Selected from the group consisting of Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes mellitus. In some embodiments of all aspects, fetal and neonatal alloimmunization and The autoimmune and / or immune disorder is hemolytic disease of the fetus and newborn. In some embodiments, the fetal and neonatal alloimmune and / or autoimmune disorder is In some embodiments of all aspects, the present invention relates to neonatal and neonatal alloimmune thrombocytopenia. In this regard, fetal and neonatal alloimmune and / or autoimmune disorders include congenital heart block. do.

[0049] In some embodiments of all aspects, treatment reduces the risk of miscarriage.

[0050] In some embodiments of all aspects, the subject has received prior fetal and neonatal alloimmunization. have a history of having an illness and / or an autoimmune disorder. For example, in some embodiments In the method, the pregnant subject has been previously pregnant and the fetus or newborn has and had neonatal alloimmune and / or autoimmune disorders. In some embodiments, the subject is a patient with a fetal or neonatal alloimmune and / or autoimmune disorder. There is a risk of having

[0051] In some embodiments of all aspects, fetal and neonatal alloimmunization and / or The autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolysis, Diseases, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myositis Asthenia, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis Dermatomyositis, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Selected from the group consisting of Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes mellitus. In some embodiments of all aspects, fetal and neonatal autoimmunity and The autoimmune and / or immune disorder is hemolytic disease of the fetus and newborn. In some embodiments, the fetal and neonatal alloimmune and / or autoimmune disorder is In some embodiments of all aspects, the present invention relates to neonatal and neonatal alloimmune thrombocytopenia. In this regard, fetal and neonatal alloimmune and / or autoimmune disorders include congenital heart block. In some embodiments of all aspects, treatment reduces the risk of miscarriage.

[0052] In some embodiments of all aspects, the method includes administering to a pregnant subject, and / or combinations thereof.

[0053] In some embodiments of all aspects, the autoimmune disorder is alopecia areata, ankylosing vertebrae, or the like. Spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease gallbladder disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome , chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid Acne, localized 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 urinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, Rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff man disease syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, or Wegener's syndrome Granulomatous diseases are selected from the group consisting of:

[0054] Reduce the risk of or reduce the risk of developing an autoimmune or alloimmune disorder IV administration of an FcRn antibody described herein to a pregnant subject. Also described are methods comprising, consisting of, or consisting essentially of.

[0055] In another aspect, the disclosure provides a method of increasing antibody catabolism in a subject, the method comprising administering to a subject a therapeutically effective amount of an antibody to ... comprising or consisting of IV administration of an antibody described herein to a pregnant subject; The method comprises the steps of:

[0056] In some embodiments of all aspects, increasing antibody catabolism reduces pathogenicity. In some embodiments of all aspects, the pathogen Antibodies can be pathogenic to the mother, the fetus, or both the mother and the fetus. In some embodiments, the pathogenic antibody is an IgG antibody. In some embodiments, the antibody is expressed in the fetus of a pregnant subject at both the fetal and neonatal levels. Causing species immune and / or autoimmune disorders.

[0057] In some embodiments of all aspects, fetal and neonatal alloimmunization and / or The autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolysis, Diseases, alloimmune panthrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myositis Asthenia, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis Dermatomyositis, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Selected from the group consisting of Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes mellitus. It is selected.

[0058] In another aspect, the present disclosure provides a method of reducing autoantibodies in a subject, the method comprising administering to a subject a dose of 100 mg ... or comprising, or consisting of, administering to a subject in need thereof an antibody as described herein; characterised in a method consisting essentially of

[0059] In some embodiments of all aspects, the immune response is an acute or chronic immune response in the subject. It is a sexual immune response.

[0060] In some embodiments of all aspects, the acute immune response is pemphigus vulgaris, loop nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, severe antiphospholipid Interstitial antibody syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathies, neuromyelitis optica, Autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia activated by a medical condition selected from the group consisting of: cardiomyopathy, dilated cardiomyopathy, and serum sickness For example, in some embodiments, the acute immune response is For example, in some embodiments, an acute immune response is activated by a biological condition. , is activated in the fetus or newborn due to a medical condition in the pregnant subject. In some embodiments of all aspects, the acute immune response is a medical condition in a pregnant subject. In some embodiments of all aspects, the immune system is activated by an acute immune response. The response is activated in the fetus or newborn by a medical condition in a pregnant subject. In some embodiments of all aspects, the acute immune response is idiopathic thrombocytopenia. In some embodiments of all aspects, acute immune responses are activated by purpura. The response is activated by pemphigus vulgaris. Thus, an acute immune response is activated by fulminant antiphospholipid syndrome. In some embodiments, the acute immune response is activated by neuromyelitis optica. In some embodiments of all aspects, the acute immune response is antibody-mediated rejection. In some embodiments of all aspects, the acute immune response is activated by Activated by myasthenia gravis.

[0061] 1. A method of treating fetal and neonatal alloimmune and / or autoimmune disorders, comprising administering to a subject For example, a pregnant subject is administered M281, e.g., a light chain sequence of SEQ ID NO: 19 and a light chain sequence of SEQ ID NO: 24 (or a variant thereof (e.g., an amino acid at position 296 of SEQ ID NO: 24 other than N) An antibody having a heavy chain sequence of g (e.g., weekly doses) Also described herein are methods for targeting a subject. In some cases, the methods include However, hypoalbuminemia (e.g., blood pressure less than 30 g / L, less than 25 g / L, less than 20 g / L) Fetal and neonatal allogeneic comprising, consisting of, or treating immune and / or autoimmune disorders. administering to a pregnant subject an antibody described herein. (e.g., at a dose of 15 mg / kg or 30 mg / kg, e.g., in a weekly dose), and and the subject has hypoalbuminemia (e.g., less than 30 g / L, less than 25 g / L, less than 20 g / L). and administering albumin if the patient exhibits a serum albumin level below 100 mg / kg / day. The present invention relates to the treatment of fetal and neonatal alloimmune and / or autoimmune disorders. A method comprising, consisting of, or consisting essentially of administering to a pregnant subject administering an antibody described herein (e.g., 15 mg / kg or 30 mg / kg at a dose of 100 mg / kg / day, e.g., at a weekly dose), and if the subject has hypoalbuminemia (e.g., less than 30 g / L serum albumin levels below 25 g / L, or below 20 g / L) administering a solution (e.g., mannitol or other solution known in the art); Also described are methods comprising: 1. A method comprising, consisting of, or consisting essentially of treating Pregnant subjects should be administered M281 (e.g., 15 mg / kg or 30 mg / kg g dose, e.g., in a weekly dose), and at least once before or after administration of M281 Also described are methods that include testing a subject's serum albumin level. In some cases, administration of M281 may or may not be continued. That's fine.

[0062] In some embodiments of all aspects, the chronic immune response is a chronic inflammatory demyelinating polymyelitis. CIDP, systemic lupus erythematosus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and antineutrophil cytoplasmic antibody-associated vasculitis In some embodiments of all aspects, the immune response is activated by a chronic immune response. is activated by chronic inflammatory demyelinating polyneuropathy.

[0063] In some embodiments of all aspects, the subject has an autoimmune disease. In some embodiments of this aspect, the autoimmune disease is alopecia areata, ankylosing spondylitis, anti-inflammatory drugs, or the like. Phospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, hemolytic anemia Thrombocytopenia, sensitization transplantation, autoimmune hepatitis, hepatitis, Behçet's disease, bullous Pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory Demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, localized sclerosing neuropathy CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, Atopic 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 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, rheumatic disease Arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, stiff-man syndrome, hyperactivity From phlebitis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis In some embodiments of all aspects, the autoimmune disease is selected from the group consisting of: In some embodiments of all aspects, the autoimmune hemolytic anemia is warm autoimmune hemolytic anemia. In some embodiments of all aspects, the autoimmune disease is an anti-factor antibody. In some embodiments of all aspects, the disease is heparin-induced thrombocytopenia. , autoimmune diseases are sensitizing transplants.

[0064] In another aspect, the present disclosure provides a method for reducing the transport of an antibody across the placenta of a pregnant subject. The present invention is characterized by a method for reducing the amount of oxidative stress, comprising:

[0065] In another aspect, the present disclosure provides a method for the treatment of antibody-mediated viral infection in fetuses or neonates. A method of treating an increased risk of a disease, comprising administering an antibody to a pregnant subject. and the antibody comprises or consists essentially of a light chain and a heavy chain. and wherein the light chain consists of or consists essentially of a sequence similar to that of SEQ ID NO: 19. comprising, consisting of, or consisting essentially of a sequence having at least 90% identity to the , the heavy chain is SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, and SEQ ID NO:24. 24, which contains a sequence having at least 90% identity to a sequence selected from the group consisting of characterised by a process comprising, consisting of, or consisting essentially of.

[0066] In another aspect, the present disclosure provides a method for the treatment of antibody-mediated viral infection in fetuses or neonates. A method of treating an increased risk of a disease, comprising administering an antibody to a pregnant subject. and the antibody comprises or consists essentially of a light chain and a heavy chain. and wherein the light chain comprises or consists essentially of the sequence of SEQ ID NO: 19. and wherein the heavy chain consists of or consists essentially of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: SEQ ID NO: 22, SEQ ID NO: 23, and SEQ ID NO: 24. The present invention is characterized in that the method comprises or consists essentially of:

[0067] In some embodiments of all aspects, the viral disease is an alphavirus infection. infection, flavivirus infection, Zika virus infection, Chikungunya virus infection, Ross River virus infection, severe acute respiratory syndrome coronavirus infection, Middle East respiratory syndrome, bird flu flu infection, influenza virus infection, human respiratory syncytial virus infection, Ebola virus Virus infection, yellow fever virus infection, dengue virus infection, human immunodeficiency virus infection, respiratory Syncytial virus infection, Hantavirus infection, Getah virus infection, Sindbis virus infection Infection, Bunyamwera virus infection, West Nile virus infection, Japanese encephalitis virus B infection, Heronpox virus infection, lactate dehydrogenase elevated virus infection, reovirus infection, rabies Virus infection, hand, foot and mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection, monkey Blood fever virus infection, equine infectious anemia virus infection, caprine arthritis virus infection, African brown Taba fever virus infection, lentivirus infection, BK papovavirus infection, Murray Valley encephalitis virus Rus infection, enterovirus infection, cytomegalovirus infection, pneumovirus infection, morbillivirus infection, and measles virus infection. This is caused by this.

[0068] In some embodiments of all aspects, the pregnant subject is Have or are at risk of having a medical condition that activates an immune response. In some embodiments of this aspect, the medical condition is pemphigus vulgaris, lupus nephritis, severe rheumatoid arthritis, or rheumatoid arthritis. Myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, fulminant antiphospholipid syndrome Group, immune complex-mediated vasculitis, glomerulitis, channelopathies, neuromyelitis optica, autoimmune Hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated Dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy , systemic lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, antineutrophilic cells Antibody-specific antigen (ANCA)-associated vasculitis, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, adipocyte Hemolytic anemia, autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, Celiac sprue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating multiple neuropathies pemphigoid, Churg-Strauss syndrome, cicatricial pemphigoid, localized scleroderma (CREST syndrome) syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulin Globulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto's thyroiditis, hypothyroidism , inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin Phosphate-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 umatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis , psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis sis, scleroderma, Sjögren's syndrome, stiff-man syndrome, Takayasu's arteritis, temporal arteritis, These are ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis.

[0069] In some embodiments of all aspects, the pregnant subject has previously had a fetus or The neonate had a history of fetal and neonatal alloimmune and / or autoimmune disorders. For example, in some embodiments, the pregnant subject has been previously pregnant. and the fetus or newborn develops fetal and neonatal alloimmune and / or autoimmune disorders. had.

[0070] In some embodiments of all aspects, antibodies associated with an immune disorder are detected in pregnant women. and in biological samples obtained from elephants. In some embodiments, the biological sample is a blood or urine sample. In some embodiments, the biological sample is a blood sample.

[0071] In another aspect, the present disclosure provides methods for treating fetal and neonatal alloimmune and / or autoimmune disorders. 1. A method for treating or reducing the risk of developing uterine ulcers during pregnancy, comprising administering A light chain having the amino acid sequence of SEQ ID NO: 19 and a light chain having the amino acid sequence of SEQ ID NO: 24 for a female and administering to a subject a composition comprising an antibody (M281) comprising a heavy chain having the formula: , is discontinued after 34 weeks of gestation.

[0072] In another aspect, the present disclosure provides methods for treating fetal and neonatal alloimmune and / or autoimmune disorders. 1. A method for treating or reducing the risk of developing uterine ulcers during pregnancy, comprising administering Females were administered a light chain having the amino acid sequence of SEQ ID NO: 19 and a light chain having the amino acid sequence of SEQ ID NO: 24. administering a composition comprising an antibody (M281) comprising a heavy chain having the is discontinued at least one week before delivery.

[0073] In various embodiments of all methods, the method comprises administering M281 after cessation of administration and after delivery. Before delivery (e.g., 40–100 hours or 1–15 days before delivery), pregnant women should administration of VIG; M281 administration is discontinued after 35 weeks of gestation; M2 Administration of 81 is discontinued before 36, 37, or 38 weeks of gestation; IVIG , administered at 200 mg / kg to 1000 mg / kg based on the pregnant woman's weight. ;M281 is administered at 30 mg / kg based on the weight of the pregnant woman;M281 is administered at 15 mg / kg based on the weight of the pregnant woman; the dose is The dose is based on the pregnant woman's weight at the time of the first dose. not upregulated based on weight gain after administration; doses are per administration and are based on the initial dose. Based on the pregnant woman's weight at the time of medication, and upward based on the woman's weight gain during pregnancy The composition is administered at least every other week; the composition is administered every other week; the composition The composition is administered at least weekly; the composition is administered weekly; administration is at least once a week, preferably at least once a week, during the first three or four weeks of pregnancy. Administration begins during the first trimester of pregnancy; administration begins during the second trimester of pregnancy; administration begins during the Initiated during the last trimester of pregnancy; Route of administration is intravenous; Pregnant women should not take have an obstetric history of fetal anemia; pregnant women have elevated anti-RhD, anti-Rhc, or anti- have Kell immunoglobulin alloantibody titers; pregnant women may have elevated anti-Rhc or have anti-Kell immunoglobulin alloantibody titers; pregnant women have anti-Lua, 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, Diego, P, and Mia / Mur, have elevated immunoglobulin alloantibody titers; pregnant women should be monitored for severe fetal anemia or Obstetric history of stillbirth within 24 weeks of gestation and elevated anti-D or anti-Kell IgG alloantibodies Pregnant women with a titered, antigen-positive fetus; first dose administered between 12 and 16 weeks of pregnancy; The first dose is administered at 14 weeks of gestation; and administration is initiated during the first trimester of pregnancy. do.

[0074] In various embodiments of all methods, the infusion time is the same, 90 minutes or less. less than, 60 minutes or less, 45 minutes or less, 30 minutes or less The duration of the test is 15 minutes or less, or 7 minutes or less. In various embodiments of all methods, the initial infusion may be for 90 minutes or less, even 60 minutes. or less, 45 minutes or less, 30 minutes or less, 15 minutes or less In some embodiments, the injection time is reduced. wherein the duration of the second and third infusions is the same and is 60 minutes or less. , 45 minutes or less, 30 minutes or less, 15 minutes or less, or for 7 minutes or less, with subsequent injection times being reduced. In various embodiments of all methods, the time of the first infusion and the second infusion are the same and are 90 minutes or less, 60 minutes or less, 45 minutes or less, 30 minutes 15 minutes or less, and subsequent infusion times are In various embodiments of all methods, the initial infusion is performed over a 60 minute period. and subsequent infusions are given over 45 minutes or less, 30 minutes or less, or 15 minutes or less. minutes or less, or the initial infusion is over 45 minutes. and subsequent infusions are given over 30 minutes or less, or over 15 minutes or less. or the first infusion is given over 30 minutes and subsequent infusions are given over 10 minutes. In various embodiments of all methods, the first The first and second infusions were both given over 60 minutes, and subsequent infusions were given over 45 minutes. for 10 minutes or less, 30 minutes or less, or 15 minutes or less Either the first and second infusions are administered over a 45-minute period, or and subsequent infusions are given over 30 minutes or less, or over 15 minutes or less. or the first and second infusions are both given over a 30-minute period. and subsequent infusions are given over 15 minutes or less.

[0075] In particular, the method comprises administering an anti-FcRn antibody to a subject at a dose of 5 to 60 mg / kg. g of an anti-FcRn antibody, wherein the intravenous infusion is for 90 minutes or less. The anti-FcRn antibody was used to identify (1) CDR L1, CDR L2, and CDR L3. (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; a heavy chain variable region comprising RH3, CDR L1 has two sequences corresponding to the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1). a sequence having a non-rotating amino acid substitution, CDR L2 has no more than one amino acid sequence to the sequence of GDSERPS (SEQ ID NO: 2). including sequences with acid substitutions, CDR L3 does not exceed one for the sequence of SSYAGSGIYV (SEQ ID NO: 3) a sequence having an amino acid substitution, CDR H1 is TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or NYA MG (SEQ ID NO: 6) CDR H2 is SIGSSGAQTRYADS (SEQ ID NO: 7), SIGASGSQTR YADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), or SIG No more than two amino acid substitutions relative to the sequence of ASGGQTRYADS (SEQ ID NO: 10) and a sequence having the formula: CDR H3 has no more than one amino acid sequence to the sequence of LAIGDSY (SEQ ID NO: 11). including sequences with amino acid substitutions, The methods are described herein.

[0076] In some embodiments, CDR L1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1), CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), CDR L3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 3), CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4), CDR H2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO: 8), CDR H3 contains the sequence LAIGDSY (SEQ ID NO: 11).

[0077] In some embodiments of all of the methods described herein, the injection is performed over a period of 7 to 90 minutes. minutes, 7-60 minutes, 7-45 minutes, 7-30 minutes, 10-90 minutes, 10-60 minutes, It can last for 10-45 minutes, 10-30 minutes, or 15-30 minutes.

[0078] In some embodiments of all of the methods described herein, the Fc domain of the antibody The fucosylated polypeptide is non-fucosylated. In some embodiments, the Fc domain of the antibody is aglycosylated. In some embodiments of all of the methods, the antibody is an IgG1 antibody. In some embodiments of all of the methods described, the antibody is a fully human antibody. In some embodiments of all of the methods described herein, the subject is a fetus and Neonatal alloimmune thrombocytopenia, hemolytic disease of the fetus and newborn, alloimmune panthrombocytopenia Hypothyroidism, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune hemolysis anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, neonatal Neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease alloimmune and / or steroid-resistant ... In some embodiments of all of the methods described herein, The subjects are thrombocytopenia, panthrombocytopenia, congenital heart block, arthrogryposis, myasthenia gravis, Asthenia, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, antiphospholipid syndrome, multiple Myositis, dermatomyositis, lupus, scleroderma, Behçet's disease, Graves' disease, Kawasaki disease, autoimmune alloimmune and / or thyroid disease, and type I diabetes mellitus Have an autoimmune disorder.

[0079] In some embodiments of all of the methods described herein, the injection is performed over a period of 5 to 60 minutes. The injection of a composition containing 100 mg / ml of antibody is also an effective treatment for all of the methods described herein. In some embodiments, the injection is administered using a composition containing 30, 45, or 60 mg / ml of antibody. In some embodiments of any of the methods described herein, The strand is at least 95%, 97%, or more preferably 98%, to any one of SEQ ID NOs: 20 to 24. %, 99%, or 100% identity, and the light chain comprises a sequence of SEQ ID NO: 19. containing sequences having at least 95%, 97%, 99%, or 100% identity to In some embodiments of all of the methods described herein, the antibody heavy chain is Any of SEQ ID NOs: 20 to 24 having an amino acid other than N at position 296 of SEQ ID NOs: 20 to 24 It contains either amino acid sequence.

[0080] In some embodiments of all of the methods described herein, the injection is performed at a pH of 6. 5, 10-60 mg / ml (or 10, 20, or 30 mg / ml) of antibody, 2 0-30 mM sodium phosphate, 20-30 mM sodium chloride, 80-100 mM g / ml trehalose, and 0.1–0.005% weight / volume polysorbate 80 and injecting a composition comprising:

[0081] In some embodiments of all of the methods described herein, the antibody heavy chain is The following amino acid substitutions relative to sequence number 24: A23V, S30R, L80V, A84T 24, having one or more of the following amino acid sequences: E85D, A93V, E85C, E85D, A93V. The antibody light chain contains the following amino acid substitutions with respect to the sequence of SEQ ID NO: 19: Q38H, V58I and G99D. In some embodiments of all of the methods described herein, the antibody heavy chain comprises a C-terminal In some embodiments of any of the methods described herein, the method is lysine-free. The antibody administered has a light chain comprising SEQ ID NO: 19 and an amino acid sequence at position 296 or SEQ ID NO: 24. The present invention also includes a heavy chain comprising a variant of SEQ ID NO: 24 in which the amino acid is other than N.

[0082] In some embodiments of all of the methods described herein, the antibody is 5 to 30 In some embodiments of all of the methods described herein, In all of the methods described herein, the antibody is administered at 30-60 mg / kg. In some embodiments, the concentration of the antibody in the intravenous infusion is between 10 mg / ml and 3 0mg / ml. In some embodiments of all of the methods described herein, the subject is a pregnant female. In some embodiments of all of the methods described herein, the dose is Based on the pregnant woman's weight at the time of first dose and based on the woman's weight gain during pregnancy In some embodiments of all of the methods described herein, The dose is per administration and is based on the weight of the pregnant woman at the time of the first administration. Based on the weight gain of pregnant women, it is upregulated.

[0083] In some embodiments of any of the methods described herein, the composition comprises at least In some embodiments of any of the methods described herein, Thus, the composition is administered every other week. In some embodiments, the composition is administered at least weekly. In some embodiments of the method, the composition is administered weekly.

[0084] In some embodiments of all of the methods described herein, the subject is pregnant. and the first injection is administered during the first trimester of pregnancy. In some embodiments of all of the methods, the subject is a pregnant woman and the first infusion is , administered during the second trimester of pregnancy. In one embodiment, the subject is a pregnant woman and the first infusion is administered during the last trimester of pregnancy. In some embodiments of all of the methods described herein, The elephant is a pregnant female with an obstetric history of severe fetal anemia. In some embodiments of all of the methods described herein, the subject is a pregnant woman. and this pregnant woman has an obstetric history of hemolytic disease of the fetus and newborn. In some embodiments of all of the methods described herein, the subject is a pregnant woman. This pregnant woman had elevated anti-RhD, anti-Rhc, or anti-Kell immunoglobulins. In some embodiments of all of the methods described herein, and the subject is a pregnant woman, who has elevated anti-Rhc or anti-K. All immunoglobulin alloantibody titers. In some embodiments, the subject is a pregnant woman, and the pregnant woman is a , Lu b , Bg, Kn a , Yt a ,E,c,K,C w ,Fy a ,cE,ce,D,Ce, cE, K, Kp a , Kp b ,Fy a ,M.,N.,S.,Le a , Le b ,Fy,Jk a , Di ego, P, and Mi a / Mur All of the subjects described herein have elevated immunoglobulin alloantibody titers. In some embodiments of the method, the subject is a pregnant woman, and the pregnant woman is Obstetric history of severe fetal anemia or stillbirth within 24 weeks of gestation, and elevated anti-D or anti- Kell IgG alloantibody titers and are pregnant with an antigen-positive fetus. In some embodiments of all of the methods described herein, the subject is a pregnant woman and Injections are performed between 12 and 16 weeks of gestation. In an embodiment, the subject is a pregnant woman and the first infusion is during the 14th week of pregnancy. In some embodiments of all of the methods described herein, the infusion times are the same. Yes, 90 minutes or less, 60 minutes or less, 45 minutes or less Full, 30 minutes or less, 15 minutes or less, or 7 minutes or less In some embodiments of all of the methods described herein, The first infusion may be over 90 minutes or less, 60 minutes or less, or 45 minutes or less. or less, 30 minutes or less, 15 minutes or less In some implementations of all the methods described herein, In one embodiment, the first infusion is administered over 60 minutes, and subsequent infusions are administered over 45 minutes. for 30 minutes or less, or for 15 minutes or less Alternatively, the first infusion may be given over 45 minutes, with subsequent infusions over 30 minutes. or less, or for 15 minutes or less, or for the first time The first infusion was given over 30 minutes, with subsequent infusions over 15 minutes or less. This is what happens.

[0085] In some embodiments of all of the methods described herein, the second injection and The duration of the third infusion is the same, 60 minutes or less, 45 minutes or less. Full, 30 minutes or less, 15 minutes or less, or 7 minutes or less and subsequent injection times are reduced.

[0086] In some embodiments of all of the methods described herein, the initial injection and the second injection The duration of the two infusions is the same, 90 minutes or less, 60 minutes or less , 45 minutes or less, 30 minutes or less, 15 minutes or less The method described herein is carried out over a period of time, and subsequent injection times are reduced. In some embodiments, the first infusion and the second infusion are both administered over a period of 60 minutes. subsequent infusions may be given over 45 minutes or less, 30 minutes or less, or may be administered over 15 minutes or less, or the first and second injections may be administered over 15 minutes or less. All injections were given over 45 minutes, with subsequent injections lasting 30 minutes or less. or over 15 minutes or less, or a first injection and a second injection Each injection was given over 30 minutes, with subsequent injections over 15 minutes or less. It is carried out over a period of time.

[0087] formulation Compositions for intravenous infusion are physiologically compatible, water-soluble compositions (e.g., (It is buffered at physiological pH and is substantially isotonic.) The composition may be, for example, sodium chloride. thorium, trehalose, and surfactant polysorbate (PS) 80, and buffering The composition may contain an ionic osmolyte stabilizing agent (sodium chloride) and a non- The formulation may contain both an ionic osmolyte stabilizer (trehalose) and an ionic osmolyte stabilizer (trehalose). A suitable formulation is (1) 25 mM sodium phosphate, 25 mM sodium chloride, 90. 5mg ml -1 of trehalose, 0.01% polysorbate (PS) 80, and p Buffered to H6.5, 10 or 30 mg ml -1 antibodies, and (2) 25m M sodium succinate, 25 mM sodium chloride, 90.5 mg ml 1 Trehalo 0.01% polysorbate (PS) 80, and pH 6.6 or pH 6.5. Buffered, 10 or 30 mg ml -1 Contains antibodies to

[0088] definition The term "antibody" is used in a broad sense herein and refers to any antibody that exhibits FcRn antigen-binding activity. As long as the antibody is a monoclonal antibody, a polyclonal antibody, a multispecific antibody (e.g., a bispecific antibody), Various antibody structures, including but not limited to, antibody fragments, are also available. Contains.

[0089] An "antibody fragment" is a portion of an intact antibody, preferably an intact antibody. Examples of antibody fragments include Fab, Fab's, and Fab's. ', F(ab')2, and Fv fragments, diabodies, linear antibodies, single-chain antibodies and multispecific antibodies.

[0090] As used herein, the term "isolated antibody" refers to the antibody produced Refers to an antibody that has been separated and / or recovered from components of the host cell environment. Contaminating components of the host cell environment may interfere with the research, diagnostic, or therapeutic use of the antibody. Contaminants include enzymes, hormones, and other proteinaceous or non-proteinaceous In some embodiments, the antibody can be (1) a soluble solute, e.g., More than 95% of the antibody by weight was detected as determined by the Lowry method, and several experiments In embodiments, the content is greater than 99% by weight. (2) For example, a spinning cup sequence By using a spinning cup sequenator, N-terminal or internal amino acid sequences can be identified. (3) enough to obtain at least 15 residues, or (4) e.g., Coomassieble SDS-PAGE under reducing or non-reducing conditions using β- or silver staining The isolated antibody is purified to homogeneity by in situ synthesis within recombinant cells. Typically, however, isolated antibodies will have undergone at least one purification step. Pharmaceutical preparations of isolated antibodies will typically be prepared by FDA's This is done as recommended by the "Guidance for Industry" document. Less than 250 ppm (e.g., For example, less than 200 ppm, less than 150 ppm, less than 100 ppm) of host cell protein ( HCP).

[0091] As used herein, the term "monoclonal antibody" refers to a substantially homogeneous antibody. refers to antibodies obtained from a high-quality antibody population, i.e., individual antibodies within the population are present in small amounts. They have the same primary sequence except for any naturally occurring mutations that may be present. A monoclonal antibody is highly specific and targets a single antigenic site (i.e., on the human FcRn). epitopes) and typically contain different antibodies directed against different epitopes In contrast to polyclonal antibody preparations, each monoclonal antibody binds to a single antigen. The modifier "monoclonal" means that the antibody is directed against a single epitope. It is characterized as being derived from a high-quality antibody population and is anti- It is not to be construed as requiring bodily production.

[0092] As used herein, the terms "variable region" and "variable domain" , complementarity determining regions (CDRs, for example, CDR L1, CDR L2, CDR L3, C CDR H1, CDR H2, and CDR H3) and framework regions (FR) As used in this disclosure, the term "antibody light chain" refers to portions of the antibody light and heavy chains comprising the amino acid sequence of According to the method, the amino acid positions assigned to the CDRs and FRs are determined by the Kabat Sequence Listing. s of Proteins of Immunological Interest, 5th Ed. Public Health Service, National This numbering system is defined according to the National Institutes of Health, Bethesda, MD. (1991). Using the stem, the actual linear amino acid sequence is determined by the CDRs of the variable region (referred to herein as corresponds to a shortened form of FR (as further defined herein) or FR (as further defined herein). It may contain fewer amino acids than, or additional amino acids corresponding to insertions therein. For example, the heavy chain variable region contains a single inserted residue (i.e., residue 52a according to Kabat) and the inserted residue after residue 82 of the heavy chain FR. (i.e., residues 82a, 82b, 82c, etc. according to Kabat). The residue numbering in t refers to the "number of residues" in the region of homology of the sequence of a given antibody. It can be determined by alignment with the standard Kabat numbered sequences.

[0093] As used herein, the terms "complementarity determining region" and "CDR" refer to , antibody variable domains that are hypervariable in sequence and / or form structurally defined loops CDRs refer to domains or regions of a variable region. CDRs are also known as hypervariable regions. The light chain and heavy chain variable regions each have three CDRs. The heavy chain variable region contains CDR H L1, CDR L2, and CDR L3. Each CDR contains CDR H1, CDR H2, and CDR H3. The amino acid residues derived from the complementarity determining regions defined by Approximately residues 24-34 (CDR L1), 50-56 (CDR L2), and 8 9-97 (CDR L3), and approximately residues 31-35 (C DR H1), 50-65 (CDR H2), and 95-102 (CDR H3) It may include.

[0094] As used herein, the term "FcRn" refers to IgG antibodies, e.g., Refers to the neonatal Fc receptor, which binds to the Fc region of IgG1 antibodies. An exemplary FcRn is U Human FcRn has the niProt identification number P55899. binds constitutively internalized IgG and transports it to the cell surface for recycling. It is believed that this transport and return is responsible for maintaining the half-life of IgG.

[0095] As used herein, the terms "affinity" and "binding affinity" refer to two It refers to the strength of the binding interaction between two molecules. Generally, binding affinity is measured by the binding affinity of a single binding site of a molecule. between an antibody and its binding partner, e.g., between an isolated antibody and its target (e.g., a single antibody) The total strength of non-covalent interactions between the isolated anti-FcRn antibody and human FcRn was calculated by Unless otherwise indicated, binding affinity refers to a 1:1 interaction between members of a binding pair. The binding affinity between two molecules generally reflects the dissociation Constant (K D ) or affinity constant (K A ) are described as: Two molecules generally tend to bind slowly and dissociate easily, with large K D exhibit Two molecules that have a high affinity for each other generally bind more easily and remain bound longer. It tends to be small, D The K D To determine One method for this is described in Example 2 ("SPR Method"). and N022, N023, N024, N026, and N027 K D are respectively 3 1, 31.4, 35.5, 36.5, and 19.3 pM.

[0096] As used herein, the term "inhibiting IgG binding to FcRn" The term refers to an anti-Fc antibody that blocks or inhibits the binding of IgG (e.g., IgG1) to human FcRn. In some embodiments, anti-FcRn antibodies are capable of inhibiting, for example, Ig It binds to FcRn at the site on human FcRn where G binds. The body can inhibit the binding of IgG (eg, a subject's autoantibodies) to FcRn. In some embodiments, the molecule (e.g., an anti-FcRn antibody of the present disclosure) binds to IgG. In some embodiments, the binding of IgG is inhibited by 1 0%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 10 0% reduction.

[0097] As used herein, "inhibiting the binding of pathogenic antibodies to FcRn" refers to The term "antibody" refers to an antibody that blocks or inhibits the binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to human FcRn. refers to the ability of an anti-FcRn antibody to inhibit binds to FcRn, for example, at the site on human FcRn where pathogenic antibodies bind. Therefore, anti-FcRn antibodies prevent the binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to FcRn. In some embodiments, the molecule (e.g., an anti-FcRn antibody) can inhibit binding. The antibody substantially or completely inhibits binding to the pathogenic antibody. In some embodiments, Therefore, the binding of pathogenic antibodies to FcRn was observed at 10%, 20%, 30%, 50%, 70%, and 80%. %, 90%, 95%, or even 100% reduction.

[0098] As used herein, the term "hydrophobic amino acid" refers to an amino acid having relatively low water solubility. Hydrophobic amino acids include leucine, isoleucine, and alanine. amino acids, including, but not limited to, phenylalanine, valine, and proline Particularly preferred hydrophobic amino acids in the present disclosure are alanine, leucine, isoleucine, and valine.

[0099] As used herein, the term "polar amino acid" refers to a group of amino acids with different electronegativities. refers to an amino acid that has chemical polarity in its side chain, derived from an atom having The polarity of an amino acid depends on the electronegativity between atoms in the side chain of the amino acid and the structure of the side chain. The polar amino acids are serine, threonine, cysteine, methionine, and These include tyrosine, tryptophan, asparagine, and glutamine. Particularly preferred polar amino acids in the present disclosure are serine and threonine. , asparagine, glutamine, cysteine, and tyrosine.

[0100] As used herein, the term "acidic amino acid" refers to an amino acid having a side chain of 3.5 to 5.0 carbon atoms. It refers to an amino acid containing a carboxylic acid group with a pKa of 4.5. In the formula (I), the acidic amino acids are aspartic acid and glutamic acid.

[0101] As used herein, the term "basic amino acid" refers to an amino acid having a side chain of 9.5 to 10.5 carbon atoms. It refers to an amino acid containing an amino group with a pKa of 13. In some embodiments, The basic amino acids are histidine, lysine, and arginine.

[0102] As used herein, the term "percent identity" refers to the degree to which a sequence is identical to Align and introduce gaps as necessary to achieve maximum percent identity After the alignment (i.e., gaps are removed), the candidate and reference sequences are aligned for optimal alignment. The non-homologous sequences can be introduced into one or both of the sequences, and the non-homologous sequences can be ignored for comparison purposes. (which can be used as a reference sequence), the amino acid (or nucleic acid) residues of a reference sequence, e.g., a wild-type anti-FcRn antibody candidate sequences, e.g., amino acid (or nucleic acid) residues of the anti-FcRn antibodies of the present disclosure, that are identical to Alignment for purposes of determining percent identity is within the skill of the art. By various means within the skill of the Publicly available computer software such as lign (DNASTAR) software This can be achieved using software. Those skilled in the art will appreciate that the full length of the sequences being compared Alignment, including any algorithms necessary to achieve maximal alignment across In some embodiments, the appropriate parameters for measuring the concentration of In this method, the alignment of a given candidate sequence to, with, or against a given reference sequence is performed. Percent amino acid (or nucleic acid) sequence identity (which can alternatively be expressed as the percentage of a sequence that is identical to a given reference sequence) Percent identity of a particular amino acid (or nucleic acid) sequence with or to that (which may be expressed as a given candidate sequence having or containing 100×(Fraction A / B) where A is the number of sequences scored as identical in the alignment of the candidate and reference sequences. is the number of amino acid (or nucleic acid) residues in the reference sequence, and B is the number of amino acid (or nucleic acid) residues in the reference sequence. The total number of nucleic acid residues. In some implementations, the length of the candidate sequence is not equal to the length of the reference sequence. In the form, the percent amino acid (or nucleic acid) sequence identity of a candidate sequence to a reference sequence The percent identity is equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence. It will not be easy.

[0103] In certain embodiments, the reference sequence to be aligned for comparison to the candidate sequence is: The candidate sequence may be the entire length of the candidate sequence or a selected contiguous amino acid (or nucleic acid) sequence of the candidate sequence. ) residues exhibiting 50% to 100% identity. The length of the candidate sequence to be aligned should be at least 30% of the length of the reference sequence, e.g., at least 100% of the length of the reference sequence. at least 40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100%. A position in the candidate sequence is identical to the corresponding position in the reference sequence. If the molecule is occupied by an amino acid (or nucleic acid) residue, the molecule will have the same The position may be changed by substitution, deletion, or insertion. The input contains a certain number of amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more When describing substitutions, deletions, or insertions of no more than n amino acids, This means that the substitution, deletion, or insertion may be, for example, 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, or n amino acids The number of substitutions, deletions, or insertions is a percentage of the total sequence. may constitute a percentage (e.g., 1%, 5%, 10%, 15%, 20%, or more) of the The number of substitutions, deletions, or insertions is limited to 5%, 10%, 15%, 20%, or 30% of the amino acids in the entire sequence. %, or more.

[0104] As used herein, "fetal and neonatal alloimmunization and / or autoimmunization" refers to The term "immune disorder" refers to maternally derived antibodies directed against fetal and / or neonatal antigens. fetal and / or fetal morbidity caused by transplacental transfer of antibodies (e.g., pathogenic maternal antibodies) Refers to immune disorders in pregnant subjects or newborns. For example, antibodies (e.g., pathogenic antibodies) ) react to antigens in the fetus (e.g., antigens inherited by the fetus from its father) Examples of fetal and neonatal alloimmune and / or autoimmune disorders are provided herein. It has been done.

[0105] As used herein, the term "pathogenic antibody" refers to an antibody that is present in a subject (e.g., a pregnant woman) one or more immune responses in a pregnant subject, a fetus in a pregnant subject, and / or a newborn This refers to an antibody that causes a disease or disorder. In some embodiments, a pathogenic antibody is to a subject (e.g., a pregnant subject) against one or more of the subject's own proteins and the autoantibodies produced in the subject, thereby preventing an autoimmune disease or disorder in the subject. In some embodiments, pathogenic antibodies in a pregnant subject cross the placenta. antigens that can be transferred to the fetus through the and / or other antigens) and thus contribute to, for example, fetal and neonatal alloimmunization and / or Or it may cause an autoimmune disorder.

[0106] As used herein, the term "antibody-mediated enhancement of viral disease" The term refers to antibodies that can facilitate viral entry into host cells and thus increase viral load in the cells. In some embodiments, the term "viral disease" refers to a viral disease that can result in increased or enhanced infectivity. In the method, the antibody can bind to a viral surface protein, and the antibody / virus complex is It can bind to the FcRn receptor on the cell surface through an interaction between the receptor and the antibody. The body / virus complex can be internalized by the cell.

[0107] As used herein, the term "gestational age" refers to how long a pregnancy lasts. Gestational age may be described in weeks. Methods for determining gestational age are well known in the art. These methods are well known in the art (see, for example, the Committee on Obstetric Practice, American Institute of te of Ultrasound in Medicine Society for Maternal-Fetal Medicine, Committee Opin ion. Number 700. May 2017, which is incorporated herein in its entirety. In this case, gestational age was measured by ultrasound, the number of weeks from the first day of the last menstrual period (LMP), , or a combination thereof.

[0108] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition containing an active ingredient, as well as One or more excipients and diluents that can make the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure refers to a medicine or pharmaceutical preparation containing an anti-FcRn antibody and an appropriate inhibitor. The pharmaceutical composition is suitable for intravenous or subcutaneous administration. It may be in a water-soluble form for oral administration or in tablet or capsule form for oral administration. It's okay to have it.

[0109] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutical composition. A pharmaceutically acceptable carrier refers to an excipient or diluent in a formulation. It must be compatible with the human body and must not be deleterious to the recipient. In this regard, the pharmaceutically acceptable carrier should provide adequate pharmaceutical stability to the Fc construct. The nature of the carrier will depend on the mode of administration. For example, for intravenous administration, an aqueous solution A carrier is generally used, and for oral administration, a solid carrier is preferred.

[0110] As used herein, the term "therapeutically effective amount" refers to a dose administered to a subject or patient. Inducing a desired biological effect in, or inducing a condition or refers to an amount, e.g., a pharmaceutical dose, that is effective in treating a patient with a disorder. A "therapeutically effective amount" is a single dose or any dosage or route taken, either alone or It is understood as the amount taken in combination with other therapeutic agents to produce the desired therapeutic effect. It is also understood herein to obtain.

[0111] As used herein, the term "not more than" means less than equal to It refers to a quantity. It can be an integer quantity. For example, no more than two permutations are 0, 1, Or it may refer to two substitutions.

[0112] As used herein, the term "treatment" or "treating" refers specifically to To reduce, decrease, or reduce the risk of a certain disease or condition It refers to reducing the risk of side effects or the risk of side effects. Reducing the side effects of or reducing the side effects of treatment is similar to reducing the side effects of treatment in untreated subjects, e.g. It is relative to a control, baseline, or known control level or measurement. [Brief explanation of the drawings]

[0113] [Figure 1] 1 shows two graphs and a table showing the competitive binding of IgG of antibodies N022-N024, N026, and N027 to human or cynomolgus monkey FcRn at pH 6.0. [Figure 2] 1 is a graph showing the effect of antibodies N023, N024, N026, and N027 on IgG catabolism in mice. [Figure 3] 1 is a graph showing the dose-dependent effect of antibody N027 on IgG levels and target occupancy in mice. [Figures 4A-4C] 1 is a graph showing selective induction of IgG catabolism and target occupancy in cynomolgus monkeys following administration of different doses of antibody N027. [Figure 5]1 is a timeline and two graphs of an experiment showing the efficacy of N027 in a mouse chronic idiopathic thrombocytopenic purpura (ITP) model. DETAILED DESCRIPTION OF THE INVENTION

[0114] Described herein are methods for intravenous (IV) administration of anti-FcRn antibodies. IV administration includes: It can be done relatively quickly yet safely.

[0115] I. Anti-FcRn antibody In general, the present disclosure describes certain isolated antibodies that bind to human FcRn with high affinity. The anti-FcRn antibody binds to human FcRn and induces Ig expression of FcRn. It refers to an antibody that can inhibit the binding of G (e.g., IgG autoantibodies).

[0116] In one aspect, the present disclosure provides an antibody against an isolated antibody capable of binding to human FcRn. In some embodiments, the isolated antibody comprises: (1) a CDR a light chain variable region comprising CDR L1, CDR L2, and CDR L3; and (2) a CDR a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, and CDR L1 contains TGTGSDVGSYNLVS (SEQ ID NO: 1), and CDR L2 contains GDSER PS (SEQ ID NO: 2), and CDR L3 contains SSYAGSGIYV (SEQ ID NO: 3). and CDR H1 is TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or N YAMG (SEQ ID NO: 6), and CDR H2 contains SIGSSGAQTRYADS (sequence No. 7), SIGASGSQTRYADS (SEQ ID NO: 8), SIGASGAQTRYAD S (SEQ ID NO: 9), or SIGASGGQTRYADS (SEQ ID NO: 10), RH3 comprises LAIGDSY (SEQ ID NO: 11). The antibody has a sequence identity of at least 95%, 97%, or 100% with any one of SEQ ID NOs: 20 to 24. %, 99%, or 100% identity to the sequence of SEQ ID NO: 19. Contains a sequence having at least 95%, 97%, 99%, or 100% identity to In some embodiments, the antibody heavy chain comprises a light chain. Contains any one of the amino acid sequences of SEQ ID NOs: 20 to 24, which contains an amino acid other than N In some embodiments, the antibody heavy chain has the following amino acid sequence relative to the sequence of SEQ ID NO:24: Acid substitution: one of A23V, S30R, L80V, A84T, E85D, A93V In some embodiments, the antibody comprises the amino acid sequence of SEQ ID NO: 24 having one or more of the amino acid sequences of SEQ ID NO: 24. The human light chain has the following amino acid substitutions relative to the sequence of SEQ ID NO: 19: Q38H, V58I, and and G99D. In some embodiments, the antibody heavy chain does not contain a C-terminal lysine. wherein the heavy chain is SEQ ID NO: 24 or SEQ ID NO: 24 in which the amino acid at position 296 is other than N. In some embodiments, the antibody has a nucleotide sequence of less than 200 pM, 150 pM, or K less than M, less than 100 pM, less than 50 pM, or less than 40 pM D So, human FcRn In some embodiments, the antibody binds to N022, N023, N024, N0 26, or N027, and the antibody being compared. K lower than or equal to that of an antibody further possessing the same Fc region D So, Human F In some embodiments, the antibody is an IgG1 isotype. In some embodiments, the antibody is fully human. The antibody is not glycosylated at position N297 according to EU numbering. In some cases, the antibody composition to be administered is glycosylated on the Fc domain. The antibody is less than 20%, less than 10%, or less than 5% w / w.

[0117] Table 1 shows the light and heavy chain complementarity determining regions of several exemplary anti-FcRn antibodies of the present disclosure. The amino acid sequences of the CDRs are shown.

[0118] [Table 1] Table 2 shows the light and heavy chain SEQ ID NOs for these exemplary anti-FcRn antibodies of the present disclosure.

[0119] [Table 2]

[0120] Furthermore, in any of the anti-FcRn antibodies described herein, the heavy chain of the antibody may have the following sequence: At least 95%, 97%, or 99% of any one of the sequences from sequence numbers 20 to 24 %, or 100% identity. In any of the above, the light chain has a sequence identity of at least 95%, 97%, or The anti-FcRn sequences described herein include sequences with 99% or 100% identity. In any of the antibodies, the heavy chain variable region of the antibody is selected from the group consisting of SEQ ID NOs: 20 to 24. In any of the anti-FcRn antibodies described herein, the light chain variable region of the antibody The region comprises SEQ ID NO: 19. In some embodiments, the antibody comprises SEQ ID NO: 20-22. At least 95%, 97%, 99%, or 10% for any one of the four sequences The heavy chain comprises a sequence having 0% identity to the sequence of SEQ ID NO: 19, and the light chain comprises a sequence having at least 10% identity to the sequence of SEQ ID NO: 19. Some sequences share at least 95%, 97%, 99%, or 100% identity. In this embodiment, the antibody heavy chain has an amino acid other than N at position 296 of SEQ ID NOs: 20-24. Some embodiments include the amino acid sequence of any one of SEQ ID NOS: 20 to 24. wherein the antibody heavy chain comprises the following amino acid substitutions relative to the sequence of SEQ ID NO: 24: A23V, S A sequence having one or more of 30R, L80V, A84T, E85D, and A93V In some embodiments, the antibody light chain comprises the amino acid sequence of SEQ ID NO: 1. 9, with the following amino acid substitutions: Q38H, V58I, and G99D In some embodiments, the amino acid sequence of SEQ ID NO: 19 includes one or more In some embodiments, the antibody heavy chain does not contain a C-terminal lysine. Includes variants of SEQ ID NO: 24 in which the amino acid at position 24 or 296 is other than N.

[0121] In some embodiments, the light chain variable region comprises CDR L1, CDR L2, and the heavy chain variable region comprises CDR H1, CDR H2, and CDR H3; 3, and CDR L1 corresponds to the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1). CDR L2 comprises a sequence having no more than two amino acid substitutions in the GDSERPS (SEQ ID NO: 2) and having no more than one amino acid substitution with respect to the sequence of RL3 has no more than one amino acid sequence for the sequence SSYAGSGIYV (SEQ ID NO: 3). CDR H1 comprises a sequence having an amino acid substitution, TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), or NYAMG (SEQ ID NO: 6) CDR H2 contains a sequence with a 5'-amino acid substitution SIGSSGAQTRYADS (SEQ ID NO: 1). No. 7), SIGASGSQTRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), or SIGASGGQTRYADS (SEQ ID NO: 10) CDR H3 contains a sequence with no more than two amino acid substitutions, and This includes sequences that have no more than one amino acid substitution relative to the sequence of SEQ ID NO: 11).

[0122] The antibody may contain amino acid substitutions outside the CDRs (i.e., in the framework regions (FR)), In some embodiments, the antibody may further contain additions, and / or deletions. The following amino acid substitution: A23V in any one of SEQ ID NOs: 20 to 24 , S30R, L80V, A84T, E85D, A93V, and the sequence of SEQ ID NO: 19 whereas Q38H, V58I, and G99D (numbered according to the EU system) It may further include one or more of:

[0123] The antibody may contain amino acid substitutions outside the CDRs (i.e., in the framework regions (FR)), It may further contain additions, and / or deletions. The deletion may be one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7 , 8, or more) substitutions, additions, and / or deletions. , additions, and / or deletions may be 8 or less, 7 or less, 6 or more or less, 5 or less, 4 or less, 3 or less or two or less single amino acid substitutions, additions, and / or deletions In some embodiments, the antibody has the following amino acid substitutions: SEQ ID NOs: 20-24 A23V, S30R, L80V, A84T, E85 for any one of the sequences D, A93V, and Q38H, V58I, and G99 relative to the sequence of SEQ ID NO: 19 D (numbering according to the EU system).

[0124] In some embodiments, the antibody may have, for example, a reduced effector function, e.g., reduced complement-dependent cytolysis (CDC), antibody-dependent cell-mediated cytolysis (ADCC), and / or antibody-dependent cell-mediated phagocytosis (ADCP), and / or Amino acids in the constant region of an antibody (e.g., the Fc region) that result in impaired or reduced B-cell killing. The constant region may contain amino acid substitutions, additions, and / or deletions. The constant region controls the binding of the antibody to its target. Although they are not directly involved in the production of antibodies, they are involved in various effects, such as the involvement of antibodies in antibody-dependent cellular cytotoxicity. In some embodiments, the antibody exhibits target function. or reduced binding to human Fc receptors on natural killer (NK) cells (i.e. In other embodiments, the antibody is characterized by a human FcγR binding. Decreased binding to FcγRIA, FcγRIIA, and / or FcγRIIIA (i.e., binding Absence of antibody-dependent effector functions, e.g., CDC, A To alter or reduce DCC, ADCP, and / or B cell killing, the antibody may: It may be of the IgG class and may have one or more amino acid substitutions E233, L234, G2 36, D265, D270, N297, E318, K320, K322, A327, A3 30, P331, and / or P329 (numbering according to the EU system) In some embodiments, the antibody has the mutations L234A / L235A or D26 In some cases, the anti-FcRn antibody contains a nucleotide sequence at position 297. In some cases, the anti-FcRn antibody is Glycosylation at position 297 (EU numbering) of any one of SEQ ID NOs: 20 to 24 In some cases, the nucleotide sequence does not have an N at that position, making it unmodified. , the anti-FcRn antibody is aglycosylated at N at position 297 (EU numbering) The resulting effectorless antibody has a sequence modified to provide a exhibits little binding to complement or Fc receptors (i.e., complement C1q binding), This indicates a decrease in CDC capacity.

[0125] In other embodiments, the antibody has specific amino acid changes that improve the stability of the antibody. This may include:

[0126] Additionally, in other embodiments, to minimize the possibility of immunogenicity, any of the methods of the present disclosure may be used. Some antibodies, e.g., N024, N026, and N027, have amino acids D355 and D360. and L357 (corresponding to any one of SEQ ID NOs: 20 to 24), respectively. G1m17.1 to G1m17 by substitution with glutamic acid and methionine may undergo allotype change to

[0127] In other embodiments, antibodies of the present disclosure, e.g., N022-N024, N026, and and N027 are sequences corresponding to residue 446 of any one of SEQ ID NOs: 20 to 24. Does not contain a C-terminal lysine.

[0128] Without being bound by theory, anti-FcRn antibodies compete with IgG to bind human FcRn. It is thought to inhibit the binding of IgG to cRn. Topography mapping is performed to identify antibodies that are located at the Fc-FcRn interaction interface and / or It has been shown that the antibody binds to an epitope on FcRn adjacent to it, thereby Direct inhibition of IgG binding to FcRn is suggested. The pitope-mapped binding site is distal to the albumin-binding site of FcRn. Therefore, serum albumin binding is not inhibited and serum albumin levels are In fact, experimental evidence suggests that after administration of anti-FcRn antibodies, Mouse albumin levels remain constant, suggesting that albumin recycling is a key factor in the regulation of FcRn It is shown that the binding of the antibody to the

[0129] II. FcRn Inhibition FcRn acts as an intracellular vesicle transport protein that binds IgG and serum albumin. FcRn is a type I transmembrane protein that functions on endothelial cells, luminal epithelial cells, hepatocytes, It is expressed in podocytes, granulocytes, monocytes, macrophages, dendritic cells, and NK cells, but not in B FcRn is not expressed on either IgG or T cells. It constitutively binds internalized IgG. maintains the half-life of IgG by transporting it back to the cell surface. Binding of both Fc and serum albumin by β-glucan was observed in early endosomes at pH 6.0. Subsequently, FcRn is sorted into vesicles, which bind to FcRn-bound IgG or It transports albumin back to the cell surface, where FcRn interacts with IgG or This transport cycle transports both IgG and albumin. By recycling them into the circulation and preventing them from being transported to lysosomes for degradation. FcRn also mediates the uptake of internalized Ig in epithelial cells, maintaining their half-life. Captures G Fc and transports them bidirectionally to opposing apical or basal membranes This function allows IgG to be transported to the lumen of organs, such as the gastrointestinal tract, or Transport of IgG or IgG-antigen complexes from the vasculature to lymphoid tissue within the interstitial layer. Transport becomes possible.

[0130] To study the contribution of FcRn to IgG homeostasis, mice were transfected with FcRn protein. to "knock out" the light and heavy chain portions of FcRn so that the protein is not expressed. (Junghans et al., Proc Natl Acad Sci USA 93:5512, 1996). In this system, the serum half-life and concentration of IgG are dramatically reduced, resulting in the loss of FcR activity in IgG homeostasis. Studies in rodent models, such as those discussed above, have suggested an n-dependent mechanism. In some cases, blockade of FcRn increases the catabolism of IgG, including that of pathogenic autoantibodies. , suggesting that the development of diseases (eg, autoimmune diseases) may be inhibited. FcRn also mediates antigen degradation and transport of immune complexes to MHC loading compartments. It may contribute to antigen presentation through transport.

[0131] The present disclosure provides isolated anti-FcRn antibodies that bind to human FcRn with high affinity. Anti-FcRn antibodies do not compete with other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies). , effectively inhibiting their binding to FcRn, thereby inhibiting other anti-FcRn antibodies (e.g. Increases catabolism of antibodies (e.g., IgG, IgG autoantibodies) and decreases their half-life. n antibodies are used to inhibit immune complex-based immune responses in a subject, e.g., autoimmune diseases. For use in methods of treating or reducing activation of immune responses caused by autoantibodies. It can be used.

[0132] Transplacental transfer of maternal IgG antibodies to the fetus is beneficial while the humoral response of the newborn is ineffective. This is an important FcRn-dependent mechanism that provides protection to the neonate. FcRn in the nutrient layer is responsible for the transfer of maternal IgG antibodies to the fetus. The body (e.g., pathogenic maternal IgG antibodies) also transmit antibodies to the placenta by binding to FcRn. can transcend the immune system and cause alloimmune and / or autoimmune disorders in the fetus and newborn. In some embodiments, pathogenic antibodies in pregnant subjects may cause harm. , causing fetal and neonatal alloimmune and / or autoimmune disorders in the fetus of a pregnant subject. The anti-FcRn antibodies described herein (e.g., N022 to N024, N0 26, and N027, preferably N027 and / or N024) are maternally transmitted pathogens. competes with maternal antibodies (e.g., maternally derived pathogenic IgG antibodies) and inhibits their binding to FcRn. This may impair the immune system, thereby increasing the catabolism of these pathogenic antibodies and decreasing their half-life. This can be done.

[0133] The present disclosure provides isolated anti-FcRn antibodies that bind to human FcRn. The antibody competes with other anti-FcRn antibodies (e.g., IgG, IgG autoantibodies) to target FcRn. inhibits their binding, thereby inhibiting other anti-FcRn antibodies (e.g., IgG, IgG Anti-FcRn antibodies can increase the catabolism of autoantibodies and decrease their half-life. , immune complex-based immune responses in a subject, e.g., autoantibodies in autoimmune diseases. can be used in methods of treating or reducing the activation of immune responses caused by A reduced immune response is a reduction in the immune response compared to a subject not receiving treatment (e.g., a control subject). Anti-FcRn antibodies also induce human FcR in pregnant subjects. Transplacental pathogenicity in pregnant subjects by administering isolated antibodies that bind to n Reduced antibody transport (e.g., transport of pathogenic maternal IgG antibodies) Increased catabolism of pathogenic antibodies in pregnant subjects and increased antibody production in the fetus or newborn The present invention may be used in methods for treating an increase in viral diseases mediated by the virus during pregnancy. The reduction in transport of pathogenic antibodies across the elephant placenta is comparable to that observed in untreated subjects (e.g. This can be explained as a decrease in the transport of pathogenic antibodies compared to controls (e.g., control subjects). .

[0134] III. Vectors, Host Cells, and Antibody Production The anti-FcRn antibody can be produced from a host cell. To express the described polypeptides and constructs from their corresponding nucleic acids. Nucleic acids refer to vehicles that contain essential cellular components, such as organelles, required for the synthesis of a cell. Conventional techniques known in the art (e.g., transformation, transfection, electroporation) can be used. troporation, calcium phosphate precipitation, direct microinjection, infection, etc.) The nucleic acid vector may be included in a nucleic acid vector that can be introduced into a host cell by The choice will depend in part on the host cell used. Generally, preferred host cells are prokaryotic They may be of microbial (e.g., bacterial) or eukaryotic (e.g., mammalian) origin.

[0135] Nucleic acid vector construction and host cells

[0136] Nucleic acid sequences encoding the amino acid sequences of anti-FcRn antibodies are known in the art. They can be prepared by a variety of methods, including the use of oligonucleotides. These include PCR-mediated (or site-directed) mutagenesis and PCR mutagenesis. Nucleic acid molecules encoding anti-FcRn antibodies can be prepared using standard techniques, e.g., but not limited to, For example, it can be obtained using gene synthesis. Alternatively, wild-type anti-FcRn antibodies can be produced by The nucleic acid molecule to be transferred can be prepared using standard techniques in the art, such as QuikChange. ™ mutagenesis to mutate the polypeptide to contain specific amino acid substitutions. Nucleic acid molecules can be synthesized using a nucleotide synthesizer or PCR techniques. can.

[0137] The nucleic acid sequence encoding the anti-FcRn antibody can be expressed in a nuclear medium in a prokaryotic or eukaryotic host cell. The nucleic acid molecule can be inserted into a vector that is capable of replicating and expressing the nucleic acid molecule. are available in the art and can be used for the purposes of this disclosure. Each vector can be adjusted and optimized for compatibility with a particular host cell. For example, vector components may include an origin of replication, a selection vector, and a Marker gene, promoter, ribosome binding site, signal sequence, target protein These sequences may include, but are not limited to, a nucleic acid sequence encoding a protein, and a transcription termination sequence. It will not be done.

[0138] In some embodiments, mammalian cells are used as host cells in the present disclosure. Examples of mammalian cell types include human embryonic kidney (HEK) (e.g., HEK293, HEK 293F), Chinese hamster ovary (CHO), HeLa, COS, PC3, V ero, MC3T3, NS0, Sp2 / 0, VERY, BHK, MDCK, W138, B T483, Hs578T, HTB2, BT20, T47D, NS0 (any immunoglobulin Mouse myeloma cell lines CRL7O3O and HsS78 (which do not endogenously produce phosphoryl chains) In another embodiment, the host cell is a bacterial strain, including, but not limited to, Escherichia coli (E. E. coli cells are used as host cells in the present disclosure. Exemplary E. coli strains include , E. coli 294 (ATCC® 31,446), E. coli λ 1776 (ATCC® 31,537), E. coli BL21 (D E3) (ATCC® BAA-1025), and E. coli RV30 8 (ATCC® 31,608). The host cell in which the recombinant protein is grown has characteristics and specific functions for post-translational processing and modification of protein products. It has a mechanism to ensure the correct modification and processing of the expressed anti-FcRn antibody. For the purpose of expression, an appropriate cell line or host system can be selected. Conventional techniques in the art, such as transformation, transfection, electroporation, Using troporation, calcium phosphate precipitation, and direct microinjection The vector can be used to transform the vector into a host cell for protein production. After introduction into the host cells, the host cells are then either transduced with the promoter or selected for transformants. or conventional genomic DNA appropriately modified to amplify the gene encoding the desired sequence. Methods for the expression of therapeutic proteins are well known in the art. For example, see Paulina Balbas and 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 Protocols (Methods in Molecular Biology) Huma na Press; 2nd ed. 2012 (June 28, 2012).

[0139] Protein production, recovery, and purification Host cells used to produce anti-FcRn antibodies are known in the art. The cells may be grown in a medium suitable for culturing the selected host cells. Examples of media suitable for the host cells include minimal essential medium (MEM), Dulbecco's modified Eagle's medium, and the like. DMEM, Expi293™ Expression Medium, supplemented with fetal bovine serum (FBS) Examples of suitable media for bacterial host cells include DMEM, modified DMEM, and RPMI-1640. Examples include Luria broth (LB) supplements, such as selective agents, e.g., ampicillin The host cells are cultured at a suitable temperature, for example, from about 20°C to about 39°C, For example, 25°C to about 37°C, preferably 37°C, and a CO2 level of, for example, 5 to 10 % (preferably 8%). The pH of the medium generally depends mainly on the host organism. In some cases, the inducible promoter is about 6.8 to 7.4, for example, 7.0. When used in a vector, expression of the protein is regulated by a suitable promoter. It is induced under certain conditions.

[0140] Protein recovery typically involves techniques such as osmotic shock, sonication, or lysis. This involves destroying the host cells by any means. Once the cells are destroyed, the cell debris is removed by It can be removed by centrifugation or filtration. The protein may be further purified. Anti-FcRn antibodies can be purified by any method known in the art for protein purification. by, for example, protein A affinity, other chromatography (e.g., ion exchange , affinity, and size-exclusion column chromatography), centrifugation, differential solubility, or can be purified by any other standard technique for protein purification. (Process Scale Purification of Antibodies, Uwe Gottschalk (ed.) John Wiley & So In some cases, anti-FcRn antibodies can be used to detect markers such as The marker may be conjugated to a specific sequence, such as a peptide, to facilitate purification. An example of an amino acid sequence is a hexa-histidine peptide (His tag), which is Binds to nickel-functionalized agarose affinity columns with micromolar affinity. Useful for purification. Other peptide tags that may be useful include epitope tags derived from influenza hemagglutinin protein. Examples of suitable antibodies include, but are not limited to, the hemagglutinin "HA" tag corresponding to the tope.

[0141] Alternatively, the anti-FcRn antibody may be a nucleic acid molecule encoding the anti-FcRn antibody of the present disclosure. vectors (e.g., retroviral vectors, adenoviral vectors, poxvirus vectors) virus vectors (e.g., vaccinia virus vectors, e.g., modified vaccinia Ankara (Modified Vaccinia Ankara) (MVA), adeno-associated virus vectors, and alveoli In the context of a treatment, for example, by administering a viral vector to a subject ( The vector can be produced by cells of a subject (e.g., a human). (e.g., transformation, transfection, electroporation, phosphate calcification) (by calcium precipitation, direct microinjection, infection, etc.), and the development of anti-FcRn antibodies. The expression of ATP is then secreted from the cell. If the result is positive, no further action may be necessary. In this case, blood may be collected from the subject and the protein may be extracted using methods known in the art. It is purified from blood by

[0142] IV. Pharmaceutical Compositions and Preparations The present disclosure provides pharmaceutical compositions comprising one or more anti-FcRn antibodies described herein. In some embodiments, the pharmaceutical composition comprises one or more of the compounds of the present disclosure. Antibodies, e.g., N022-N024, N026, and N027, are used in combination with therapeutic proteins. In other embodiments, one or more antibodies of the present disclosure, e.g., N02 2-N024, N026, and N027. Use in combination with agents (e.g., therapeutic biologics and / or small molecules) or compositions In addition to a therapeutically effective amount of the antibody, the pharmaceutical composition may be administered by methods known to those skilled in the art. It may contain one or more pharmaceutically acceptable carriers or excipients with which it may be formulated.

[0143] Acceptable carriers and excipients in pharmaceutical compositions are suitable for use in recipes at the dosages and concentrations employed. Acceptable carriers and excipients include buffers, antioxidants, The pharmaceutical composition may include an injectable composition, a soluble fiber ... It can be administered parenterally in the form of a suitable formulation. The pharmaceutical composition can be prepared using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include sterile water, physiological saline, and cell culture medium (e.g., Dulbecco's Modified Eagle's Medium (DMEM), alpha modified Eagle's medium (α-DMSO)). Examples of suitable formulations include, but are not limited to, alpha-MEM, F-12 medium, and F-12 medium. Methods are known in the art and are described, for example, in Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2nd ed.) Taylor & F. See Rancis Group, CRC Press (2006).

[0144] The pharmaceutical composition may be formulated in unit dosage form, if desired. The active ingredient, e.g., one or more anti-FcRn antibodies (e.g., N022-N024, N The amounts of N026, and N027, preferably N027 and / or N024) are as specified. A suitable dose within the range (e.g., a dose within the range of 0.01 to 500 mg / kg body weight) is It is as provided.

[0145] In some embodiments, the formulations contain different concentrations of sodium chloride, trehalose, and surfactant polysorbate (PS) 80, buffering agent, and different p In some embodiments, the composition may be buffered to pH 5-8. Ionic osmolyte stabilizer (sodium chloride) and non-ionic osmolyte stabilizer The stability of the formulation and composition is determined by the appearance, pH, temperature, and Protein concentration, size purity, charge distribution, and thermal stability can be assessed over time. These stability parameters can be determined by pH, UV-Vis, and size exclusion chromatography. including fluorescein, ion exchange chromatography, CE-SDS, and differential scanning calorimetry , can be measured by analytical techniques.

[0146] In various embodiments, the formulation comprises: (1) 25 mM sodium phosphate, 25 mM salt Sodium chloride, 90.5 mg ml -1 of trehalose, 0.01% polysorbate ( PS) 80, and buffered to pH 6.5, 10 or 30 mg ml -1 This specification (2) 25 mM sodium succinate, 25 mM sodium chloride Thorium, 90.5mg ml -1 trehalose, 0.01% polysorbate (PS ) 80, and buffered to pH 6.6, 10 or 30 mg ml -1 This specification The stability of the two aforementioned formulations is characterized by mechanical, thermal, and chemical resistance. In some embodiments, the cells can be further tested in the presence of mechanical stress. The stability of the composition was evaluated using the following formulations: Formulation (1) 25 mM sodium phosphate, 25 mM sodium chloride 90.5 mg ml-1 trehalose, 0.01% polysorbate (PS) 80 , and 3 for 10 or 30 mg ml-1 antibody buffered at pH 6.5. In various embodiments, the formulation contains 25 mM sodium phosphate. thorium, 25 mM sodium chloride, 90.5 mg ml-1 trehalose, and The antibodies disclosed herein, buffered at pH 6.5, were incubated with different amounts of polysorbate 80. In some embodiments, the pharmaceutical composition may comprise up to five single amino acids. 10 or 30 mg / ml of the compounds disclosed herein having insertions, substitutions, or deletions of amino acids. Antibody, 20-30mM sodium phosphate, 20-30mM sodium chloride, 80- 100 mg / ml trehalose and 0.10 to 0.005% weight / volume Polysol It contains bate 80 and is buffered to pH 6.5.

[0147] V. Route, Dosage, and Administration one or more anti-FcRn antibodies (e.g., N022-N024, N026, and N027) N027, preferably N027 and / or N024) as a therapeutic protein. The pharmaceutical composition can be formulated for intravenous administration.

[0148] The dosage of the pharmaceutical composition will depend on the route of administration, the disease to be treated, the physical characteristics of the subject, e.g. The dosage will depend on factors including age, weight, and general health. The anti-FcRn antibodies contained therein (e.g., N022 to N024, N026, and N027) Any one of these, preferably N027 or N024) is sufficient to induce significant toxicity. The pharmaceutical composition may be an amount that effectively prevents, delays, or treats the disease without causing side effects. 0.01 to 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, 6 0, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg / kg), and in a more specific embodiment, about 1 to about 100 mg / kg, In one embodiment, the dose ranges from about 1 to about 50 mg / kg, and in another embodiment, from about 30 to 60 mg / kg. The dosage may be determined based on conventional factors, such as the severity of the disease. and can be adapted by a physician according to different parameters of the subject. may be influenced by factors such as gestational age, preparation for childbirth, female weight gain, and / or length of pregnancy. It may be adapted by a physician accordingly.

[0149] In some cases, the compositions and pharmaceutical compositions described herein are administered during pregnancy. In some cases, the compositions described herein are administered to pregnant women. and the pharmaceutical composition is administered during approximately 5 to 25 weeks of pregnancy (e.g., approximately 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks Between, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks In some cases, it is administered to pregnant women for 14, 24, or 25 weeks. The administration of the compositions and pharmaceutical compositions is generally after about 34 weeks of gestation (e.g., 3 weeks). After 4, 35, 36, or 37 weeks. In the present invention, IVIG is administered to a pregnant woman after cessation of administration of the composition and pharmaceutical composition. In some cases, IVIG may be administered after administration of the composition and pharmaceutical composition is discontinued. 3 to 15 days (e.g., 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th) 1, 2, 13, 14, or 15 days after the initial dose. Therefore, the timing of IVIG administration after cessation of administration of the composition and pharmaceutical composition may be affected by factors such as weight gain in women. In some cases, the compositions and methods described herein may be adapted to suit the individual patient's individual needs. and pharmaceutical compositions may be administered after gestational age 12 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 3 In some cases, they are administered at gestational ages 14 to 26. Administered during pregnancy (e.g., 14-25, 15-25, or 15-26) In some cases, they are preterm births occurring between gestational ages 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, 16-36, 16-35, or 1 It is administered during pregnancy (e.g., 6-34).

[0150] The pharmaceutical composition is administered in a manner compatible with the dosage formulation to bring about improvement or alleviation of symptoms. The anti-FcRn antibody (e.g., N022 to N024, N0 26, and any one of N027, preferably N027 or N024) The pharmaceutical composition may be administered to a subject in need thereof, for example, daily, weekly, every two weeks, every four weeks, or the like. Every week, every month, twice a month, twice a year, yearly, or as medically indicated It can be administered one or more times (e.g., 1 to 10 times, or more). The dosage regimen may be either single or multiple. The timing between doses may vary depending on the medical condition. It may decrease as the patient's condition improves and may increase as the patient's health condition declines.

[0151] Pharmaceutical compositions are administered in a manner and at a rate compatible with the dosage formulation. In this case, subjects received 30 or 60 mg / kg for 90 minutes or less. A single dose of antibody is received by intravenous infusion. In some cases, the intravenous infusion is , 60 minutes or less, 45 minutes or less, 30 minutes or less, It lasts for 15 minutes or less, or 7 minutes or less.

[0152] In some embodiments, subjects receive a dose of 30 mg / kg over 15 minutes. The antibody is received by intravenous infusion. In some embodiments, the subject receives Over the course of several weeks, the animals received a dose of 30 mg / kg of antibody via intravenous infusion. In this regimen, subjects receive an intravenous infusion of antibody at a dose of 45 mg / kg over 15 minutes. In some embodiments, the subject receives 45 minutes of In some embodiments, the patient receives a dose of antibody at a dose of 100 mg / kg by intravenous infusion. Elephants receive a dose of 60 mg / kg of antibody by intravenous infusion over 30 minutes. In some embodiments, subjects receive a 30 mg / kg dose over 60 minutes. The antibody is received by intravenous infusion. In some embodiments, the subject receives 30-60 mg for the first period and 30-60 mg for the second period In some cases, the first period is In some cases, the second infusion is a second administration of the antibody. In some cases, the second infusion is a third administration of the antibody. In the first infusion, subjects were administered 30 minutes of steroids for the first period and 30 minutes of steroids for the second period. A dose of 30 mg / kg was administered intravenously over 15 minutes for the second period of infusion. In some cases, the subject receives over 30 minutes and over 15 minutes for the second period of the second infusion, A dose of 5 mg / kg is received by intravenous infusion. , over 60 minutes for the first period of the first infusion, and over the second period of the second infusion. received a dose of 60 mg / kg over 30 minutes by intravenous infusion. The dosage and rate of administration of the pharmaceutical composition will depend on the prior treatment of the subject, the disease to be treated, and the It depends on factors including the elephant's physical characteristics, such as age, weight and general health.

[0153] [Table 3]

[0154] [Table 4]

[0155] In some embodiments, the anti-FcRn antibody is administered to a subject to prevent a severe adverse event or reaction. The dose is administered at the rates disclosed herein without prior experience.

[0156] VI. Methods and Indications for Treatment Blockade of human FcRn by anti-FcRn antibodies is a potential treatment for diseases driven by IgG autoantibodies Serum albumin, small circulating metabolites, or lipoproteins may be therapeutically useful in Induces global IgG catabolism and clearance of multiple autoantibodies without disrupting protein The ability to block FcRn may provide a therapeutic benefit to patients with autoantibody-driven autoimmune disease pathologies. The present disclosure provides a method for expanding the utility and availability of autoantibody removal strategies. Although not bound by the above, the primary mechanism of action of anti-FcRn antibodies is to inhibit pathogenic autoantibodies in the circulation. Increased autoantibody catabolism, reducing autoantibody and immune complex accumulation in affected tissues It may be possible to make it so.

[0157] one or more anti-FcRn antibodies (e.g., N022-N024, N026, and N027) 027, preferably N027 and / or N024) and pharmaceutical compositions and methods catabolism and clearance of pathogenic antibodies, e.g., IgG and IgG autoantibodies, in a subject. and reducing the immune response, e.g., to immune complexes in a subject. and blocking activation of an immune response based on an immunological condition or disease in a subject. In particular, the pharmaceutical compositions and methods are useful for treating immunoconjugate-based These compounds are useful for reducing or treating the activation of acute or chronic immune responses. Pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated Rejection due to vasculitis, fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, Neuromyelitis optica, autoimmune deafness, idiopathic thrombocytopenic purpura (ITP), autoimmune From immune-mediated hemolytic anemia (AIHA), immune-mediated neutropenia, dilated cardiomyopathy, and serum sickness The chronic immune response may be activated by a medical condition selected from the group consisting of: chronic inflammatory CIDP, systemic lupus erythematosus, disorders for which acute treatment is indicated Chronic forms of cholangiocarcinoma, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and antineutrophilic cells Antibody-mediated vasculitis (ANCA)-associated vasculitis obtain.

[0158] In some embodiments, the pharmaceutical compositions and methods are directed to treating alopecia areata, ankylosing spondylitis, Antiphospholipid syndrome, Addison's disease, warm autoimmune hemolytic anemia (AIHA), hemolytic anemia, Autoimmune hepatitis, hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue Dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy, churg Strauss syndrome, cicatricial pemphigoid, limited scleroderma (CREST syndrome), cold agglutinin Crohn's disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia Myalgia, 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 Elephant, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sheath disease -Gren's syndrome, stiff man syndrome, Takayasu arteritis, temporal arteritis, ulcerative colitis, bud Uveitis, leukoplakia, membranous glomerulonephritis, myasthenia gravis, hemolytic disease of the fetus and newborn (HD) FN), chronic inflammatory demyelinating polyneuropathy (CIDP), membranous nephropathy, Goodpasti syndrome thrombocytopenia, polymyositis, idiopathic thrombocytopenic purpura (ITP, also known as "immune thrombocytopenia"), (discovered), scleroderma, relapsing rheumatoid arthritis, Graves' disease, autoimmune thyroiditis, polyglandular autoimmune leukemia, glomerulonephritis, lupus nephritis, systemic lupus erythematosus (SLE), Sjögren's syndrome and reducing or eliminating disorders selected from the group consisting of: leukemia, type 1 diabetes, and Wegener's granulomatosis. It is useful for treating

[0159] Specifically, the pharmaceutical compositions and methods are useful for treating systemic lupus erythematosus, antiphospholipid syndrome, Pemphigus vulgaris / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis Useful for reducing or treating the immune response activated by asthenia gravis or neuromyelitis optica. It is useful.

[0160] In some embodiments, the pharmaceutical compositions and methods include those that reduce the risk of anemia in a fetus. In some embodiments, the present invention is useful for reducing or reducing the risk of the occurrence of In the present invention, pharmaceutical compositions and methods are provided to reduce or eliminate the need for IUT (intrauterine transfusion). In some embodiments, the pharmaceutical compositions and methods are useful for administering prenatal PP + Reduce or eliminate the need for IVIg, postnatal transfusions, IVIg, and / or phototherapy It is useful to

[0161] In some embodiments, the pharmaceutical compositions and methods involve administering to a subject an autoimmune disease-activated The present invention is useful for reducing or treating an immune response caused by autoimmune diseases such as alopecia areata, severe alopecia, and the like. Orthodontic 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 deficiency syndrome, chronic Inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, Localized scleroderma (CREST syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid loop 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, ulcers, membranous nephropathy, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, nodules Polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, Primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome group, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, Stiff-man syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, and Wegener's granulomatosis. The pharmaceutical compositions and methods are useful for reducing or treating immune responses in fetuses or newborns. In some embodiments, the pharmaceutical compositions and methods are for use in pregnant mothers. and reducing or treating the immune response in the fetus or newborn that is activated by autoimmune diseases associated with It is useful for placing

[0162] Specifically, the pharmaceutical compositions and methods are useful for treating systemic lupus erythematosus, antiphospholipid syndrome, Pemphigus vulgaris / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, myasthenia gravis Useful for reducing or treating the immune response activated by asthenia gravis or neuromyelitis optica. In some embodiments, the pharmaceutical compositions and methods are administered to a fetus or a newborn. In some embodiments, the present invention is useful for reducing or treating an immune response in a patient. Pharmaceutical compositions and methods for treating systemic lupus erythematosus, antiphospholipid syndrome in pregnant mothers group, pemphigus vulgaris / bullous pemphigoid, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, severe and reducing or treating the immune response activated by myasthenia gravis or neuromyelitis optica. It is useful for

[0163] The pharmaceutical compositions and methods comprise administering to a pregnant subject an isolated antibody that binds to human FcRn. Transport of pathogenic antibodies across the placenta of a pregnant subject by administering the Reduces the transport of pathogenic maternal IgG antibodies and reduces pathogenicity in pregnant subjects Increased antibody catabolism, leading to increased antibody-mediated viral disease in the fetus or neonate The isolated anti-FcRn antibodies described herein are useful in methods for treating rheumatoid arthritis. (e.g., N022 to N024, N026, and N027, preferably N027 and Diseases and disorders that may benefit from FcRn inhibition with N024 and / or N025 is the transfer of maternal pathogenic antibodies ( fetal and / or foetal infections caused by transfer of pathogenic maternal IgG antibodies Diseases and disorders in newborns are included.

[0164] In some embodiments, an isolated anti-FcRn antibody described herein (e.g., For example, N022 to N024, N026, and N027, preferably N027 and / or Diseases and disorders that may benefit from FcRn inhibition by N024 include: Fetal and neonatal alloimmune and / or autoimmune disorders. Epidemic disorders are caused by pathogenic antibodies in pregnant subjects and / or fetuses. Disorders in newborns. Pathogenic antibodies in pregnant subjects are directed against fetal antigens (e.g., The fetus attacks the antigens inherited from the fetus's father, and the fetus and newborn This can lead to having alloimmune and / or autoimmune disorders.

[0165] Fetal and neonatal alloimmunization and immunosuppression can be treated by the methods described herein. Examples of immune and / or autoimmune disorders include fetal and neonatal alloimmune thrombocytopenia (F NAIT), hemolytic disease of the fetus and newborn (HDFN), alloimmune pantithrombocytopenia, 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.

[0166] In some embodiments, an isolated anti-FcRn antibody described herein (e.g., For example, N022 to N024, N026, and N027, preferably N027 and / or Diseases and disorders that may benefit from FcRn inhibition by anti-cancer drugs (e.g., N024) include: The body promotes viral entry into host cells, increasing or enhancing infectivity in the cells, e.g. For example, it is a viral disease that results in antibody-mediated enhancement of the viral disease. In this embodiment, the antibody can bind to a viral surface protein, and the antibody / virus complex The body can bind to FcRn on the cell surface through interactions between the antibody and the receptor. Thus, the antibody / virus complex can be internalized by the cell. For example, the virus can be maternally derived. Entry into fetal cells and / or tissues through complex formation with IgG antibodies Maternally derived IgG antibodies can bind to viral surface proteins, resulting in IgG / virus The virus complex binds to FcRn on the syncytiotrophoblasts of the placenta, which then binds to the complex. The complex can be transferred to the fetus.

[0167] In some embodiments, the methods described herein include antibody-mediated viral In some embodiments, the present invention can be used to treat the enhancement of cancer-related diseases. Viral diseases that are enhanced by pathogenic antibodies (e.g., pathogenic IgG antibodies) include: Alphavirus infection, flavivirus infection, Zika virus infection, Chikungunya virus infection, Ross River virus infection, severe acute respiratory syndrome coronavirus infection, Middle East respiratory Syndrome, avian influenza infection, influenza virus infection, human respiratory syncytial virus infection, Ebola virus infection, yellow fever virus infection, dengue virus infection, human immunodeficiency Viral infection, respiratory syncytial virus infection, hantavirus infection, getah virus infection, Bambis virus infection, Bunyamwera virus infection, West Nile virus infection, Japanese encephalitis virus Virus B infection, rabbitpox virus infection, lactate dehydrogenase-elevating virus infection, leukemia virus infection virus infection, rabies virus infection, hand, foot and mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection Rus 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, Leh Valley encephalitis virus infection, enterovirus infection, cytomegalovirus infection, caused by morbillivirus, morbillivirus, and measles virus infections Examples of diseases that may be caused by the virus include, but are not limited to, viral diseases.

[0168] Blockade of human FcRn by anti-FcRn antibodies prevents the production of pathogenic antibodies (e.g., pathogenic IgG antibodies). ) may be therapeutically useful in diseases driven by the overall catabolism of pathogenic antibodies. , and induces clearance of multiple pathogenic antibodies, small circulating metabolites, or lipoproteins The ability of FcRn blockade to inhibit the immune response in patients with autoimmune disease pathologies driven by pathogenic antibodies This provides a method to expand the usefulness and availability of pathogenic antibody removal strategies. Although not bound by the above, the primary mechanism of action of anti-FcRn antibodies is to inhibit the proliferation of circulating pathogenic antibodies. Increases the body's catabolism and reduces the accumulation of pathogenic antibodies and immune complexes in affected tissues. This could be achieved by:

[0169] The anti-FcRn antibodies described herein (e.g., N022 to N024, N026, and and N027, preferably N027 and / or N024) are used to evaluate the immunological status of pregnant subjects. pregnant women who have or are at risk of having a medical condition that activates the immune response In some embodiments, the pregnant subject may have previously received a steroid drug during pregnancy. The subjects may have had a medical condition that activated an immune response. In some embodiments, the pregnant subject is a mother whose previously had a fetus or newborn is a fetus and newborn. In some embodiments, the patient has a history of having an allergic and / or autoimmune disorder. In this regard, the anti-FcRn antibodies described herein are useful in preventing pathogenic antibodies associated with immune disorders during pregnancy. Detected in a biological sample (e.g., a blood or urine sample) obtained from a subject In some embodiments, the compound may be administered to a pregnant subject. Pathogenic antibodies detected in biological samples from elephants originate from the fetus of a pregnant subject. They are known to bind to antigens (e.g., antigens inherited by a fetus from its father).

[0170] In some embodiments, an anti-FcRn antibody described herein (e.g., N02 2 to N024, N026, and N027, preferably N027 and / or N024 ) is intended to treat pregnancy and has a medical condition that activates an immune response in pregnant subjects. in subjects who have or are at risk of having and / or have previously been pregnant It may be administered to a subject who has had a medical condition that activates an immune response. In the method, the subject is planning a pregnancy and has previously had a fetus or newborn. A history of a live-born alloimmune and / or autoimmune disorder. In some embodiments, the anti-FcRn antibodies described herein may be used in combination with other anti-FcRn antibodies. A target sample can be administered to a subject containing pathogenic antibodies associated with an immune disorder.

[0171] In some embodiments, the anti-FcRn antibodies described herein are To reduce or treat the activation of immune complex-based acute or chronic immune responses, a subject (e.g., pregnant subjects). An acute immune response can be observed in a medical condition (e.g., Pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection , fulminant antiphospholipid syndrome, immune complex-mediated vasculitis, glomerulitis, channelopathies , neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, Immune neutropenia, dilated cardiomyopathy, serum sickness, chronic inflammatory demyelinating polyneuropathy, Systemic lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, or antineutrophilic It can be activated by anti-cytoplasmic antibody (ANCA)-associated vasculitis.

[0172] In some embodiments, the anti-FcRn antibodies described herein are used to treat autoimmune diseases. In order to reduce or treat an immune response activated by The autoimmune disease may be, for example, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia (wAIHA), antifactor Heparin-induced thrombocytopenia (HICT), sensitized transplant, autoimmune hepatitis, hepatitis, base Chet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial Pemphigoid, localized 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, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, nodular polyarteritis Phlebitis, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, primary non-cancer Magloglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff neck Mann's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, leukoplakia, or Werner's syndrome It may be Goenner's granulomatosis. [Example]

[0173] The various FcRn antibodies and their properties described herein are disclosed in WO 2019 This is described in detail in PCT Patent Application No. PCT / US2018 / 065568.

[0174] [Example 1] IgG competition Anti-FcRn antibodies that compete with IgG for binding to human or cynomolgus monkey FcRn The ability to express glycophosphatidylinositol (GPI)-linked FcRn on the cell surface was examined by ectopically expressing FcRn. The results were evaluated in human embryonic kidney (HEK) 293 cells expressing α-glucan. The human and crab FcRn alpha amino acid sequences share 97.5% sequence identity. Among the monkey FcRn alphas, 9 out of 355 amino acid residues differ, but the epitope None of the IgG bound to the cells was within the domain-mapped binding region. Determined using 66 nM fluorescent probe-labeled nonspecific IgG. Cell surface FcRn Binding of IgG to FcRn occurs at pH 7.0, which allows the Fc portion of IgG to interact with FcRn. As shown in Figure 1, the amount of IgG bound to the cells was significantly increased by the anti-FcRn antibody. As the concentration of (N022-N024, N026, or N027) increased, IgG binding was reduced by each of the five exemplary anti-FcRn antibodies of the present disclosure. , inhibited in a concentration- and saturation-dependent manner and effectively competed with IgG at pH 6.0. , anti-FcRn antibodies N022 to N024 and N026 that inhibit IgG binding to FcRn; The EC50 values ​​of the antibodies ranged from 2 to 6 nM.

[0175] [Example 2] Effect of anti-FcRn antibodies on IgG catabolism in mice To determine the effect of anti-FcRn antibodies on IgG catabolism in vivo, mouse Although it lacks mouse FcRn, it expresses human FcRn with tissue distribution similar to that of endogenous mouse and human FcRn. Human FcRn transgenic mouse strain FcRn- / -hFcRn expressing FcRn (32) Tg mice were used. On day 0, they were injected with 500 mg / kg of human IgG. Rn- / -hFcRn(32)Tg mice were treated with a single dose of anti-FcRn on days 1 and 4. Rn antibody was administered at 10 mg / kg. As shown in Figure 2, catabolism of IgG was significantly suppressed by anti-Fc Confirmed by low levels of IgG measured over time in mice treated with Rn antibody As shown in Fig. 1, administration of anti-FcRn antibody increased the expression of N024(K D =35.5pM ), N026(K D = 36.5 pM), and N027 (K D =19.4pM) activity , and appeared to be equivalent at 10 mg / kg.

[0176] [Example 3] In vitro and in vivo functional characterization of anti-FcRn antibodies In vitro The cell binding affinity of the antibody was determined by the glycophosphatidylinositol (GPI)-linked structure on the cell surface. Human embryonic kidney (HEK) 293 cells ectopically expressing human or cynomolgus monkey FcRn FcRn is a type I transmembrane protein that binds to IgG and albumin. The transmembrane-binding domain is oriented on the luminal side of the endosomal membrane or is transmembrane-associated with the plasma membrane. When transferred to HEK293 cells at pH 7.4, the ATP is oriented to the cell surface. Binding of anti-FcRn antibodies to membrane-bound FcRn on the cell surface is essential for physiologically relevant environments. At that pH, only the Fab domain of the antibody, not the Fc domain, binds to the antibody. interacts with FcRn. The FcRn extracellular domain is attached via a C-terminal engineered GPI linkage. The anti-FcRn antibody was labeled with a fluorescent probe and displayed on the cell surface at high density. The cells were then washed at 4°C and the bound antibodies were removed by centrifugation with a fluorescent dye. Detection was performed using a secondary antibody specific for human F, e.g., goat anti-human IgG F(ab)2. Binding to cRn was concentration-dependent, with the antibodies exhibiting EC50 values ​​in the range of 4-7 nM. Ta.

[0177] The cell binding affinity of the antibodies was also measured on endogenously expressed human FcRn. Monocytes express the highest levels of FcRn and are the primary Fc receptors in mouse and human blood. The highest percentage of positives for Rn expression was observed using the monocytic cell line THP-1. The binding of anti-FcRn antibodies to endogenous human FcRn was evaluated at pH 7.4. Because FcRn is primarily located in intracellular endosomal vesicles in THP-1 cells, The cells were first permeabilized with a mild detergent, fixed, and then incubated in the presence of bovine serum. and incubated with anti-FcRn antibody at 4°C for 30 minutes to detect nonspecific Fc receptor binding. This assay distinguishes antibodies with better binding to endogenous human FcRn. The binding of anti-FcRn antibodies to THP-1 cells was concentration-dependent. All antibodies of the present disclosure, for example, N022 to N024, N026, and N027 Antibody N027 showed better binding affinity than IgG1 with an EC50 of 3.0 nM. The values ​​presented the highest binding affinities.

[0178] Anti-FcRn antibodies that compete with IgG for binding to human or cynomolgus monkey FcRn The ability to express GPI-linked FcRn on the cell surface was confirmed by human embryonic kidney (HEK) 29 The level of cell-bound IgG was assessed using fluorescent probe-labeled non-specific The binding of IgG to cell surface FcRn was determined by the Fc portion of IgG. The experiments were carried out at pH 6.0, which allows the interaction of FcRn with the FcRn. As shown in Fig. 1, the amount of cell-bound IgG increased with increasing concentration of anti-FcRn antibody. IgG binding was significantly reduced by five exemplary anti-FcRn antibodies of the present disclosure, e.g., For example, N022 to N024, N026, and N027 determine the concentration and saturation. It is inhibited in a saturation-dependent manner and effectively competes with IgG at pH 6.0 to bind to FcRn. The ability of anti-FcRn antibodies to inhibit IgG binding was demonstrated. The EC50 values ​​of the antibodies ranged from 2 to 6 The concentrations were in the nM range.

[0179] Epitope mapping by hydrogen-deuterium exchange of antibodies is a method for determining whether an antibody binds to Fc-FcRn. Binds to epitopes on human FcRn located at and / or adjacent to the interaction interface. This indicates that antibodies can directly inhibit the binding of IgG to FcRn. Furthermore, the epitope-mapped binding site of F Distal to the albumin-binding site of cRn. Enzyme-linked immunosorbent assay (ELISA) was used to confirm that the antibody did not inhibit the binding of serum albumin to FcRn. The soluble His-tagged extracellular domain of human FcRn was bound to the plate surface and incubated at pH 6. The cells were pre-incubated with increasing concentrations of anti-FcRn antibody at 0.0. Peroxidase (HRP)-conjugated human serum albumin was used to prepare soluble His The antibodies bound to the tagged FcRn. None of the antibodies inhibited albumin binding to FcRn. Furthermore, in vivo experimental evidence demonstrated that administration of anti-FcRn antibodies resulted in the development of myeloma. Usual albumin levels remained constant, and albumin recycling was observed to be associated with FcRn. It was also shown that the binding of the antibody was not interfered with.

[0180] In vivo To test the effect of anti-FcRn antibodies on IgG catabolism in vivo, mouse lacking endogenous FcRn but has a tissue distribution similar to that of endogenous mouse and human FcRn Human FcRn transgenic mouse strain FcRn- / -hF expressing human FcRn in the mouse cRn(32) Tg mice were used. FcRn- / - mice were injected with human IgG on day 0. FcRn(32) Tg mice were injected with a single dose of anti-FcRn antibody on days 1 and 4. As shown in Figure 2, IgG catabolism was significantly reduced by treatment with anti-FcRn antibody. as confirmed by the low levels of IgG measured over time in mice treated with , and increased with the administration of anti-FcRn antibody. D =35.5pM), N026 (K D = 36.5 pM), and N027 (K D =19.4 pM) activity is 10 mg / kg appeared to be equivalent.

[0181] [Example 4] Effect of anti-FcRn antibodies on IgG levels and target occupancy in mice Tg32 human FcRn (hFCGRT) transgenic mouse FcRn (mF CGRT) knockout mice were treated with 500 mg / kg IVIg (tracer). 24 hours later, N027 was administered intravenously (iv). Circulating human IgG was measured daily with EL The cells were then immunophenotyped with cell surface markers. After incubation, followed by fixation and permeabilization, cells were analyzed by fluorescence-activated cell sorting (FACS). Target occupancy was measured daily in monocytes derived from whole blood lysed by ELISA. Unreacted FcRn was measured by staining with Dy650-labeled N027 (n=1 (4 males per group). As shown in Figure 3, IgG levels and unoccupied Fc The percentage of Rn was decreased in a dose-dependent manner by administration of N027.

[0182] [Example 5] Selective induction of IgG catabolism and target occupancy in cynomolgus monkeys N027 was administered intravenously to cynomolgus monkeys at time t = 0. Circulating endogenous IgG and The cells were immunophenotyped using cell surface immunoassays. After incubation with markers followed by fixation and permeabilization, FACS Target occupancy was measured in monocytes derived from whole blood lysed by PBS. FcRn was measured by staining with Dy650-labeled N027 (n = 1 per group). As shown in Figure 4, IgG levels and unoccupied FcRn The percentage of plasma arginine was decreased in a dose-dependent manner by administration of N027. Glucocorticoid levels remained unchanged.

[0183] [Example 6] Efficacy of N027 in chronic idiopathic thrombocytopenic purpura (ITP) in mice Tg32 human FcRn (hFCGRT) transgenic mouse FcRn (mFC GRT) knockout mice, anti-platelet antibodies (anti-CD41, MWReg30) Thrombocytopenia was induced by continuous infusion with subcutaneous (sc) miniosmotic pumps. Circulating platelet levels were 300 × 10 by 72 hours (day 3) after pump implantation. 9 / N027 was administered 72 hours after pump implantation (day 3) and and 120 hours later (day 5), the animals were intravenously dosed with therapeutic drugs (A, n = 4 per group; B (n = 7 per group). Figure 5 shows platelet levels in mice with thrombocytopenia. The effect of N027 on

[0184] [Example 7] Safety and Tolerability of Intravenous Infusion of Anti-FcRn Antibody Single-dose, sequential, randomized, double-blind (sponsor-unblinded), placebo-controlled, escalation and a steroid hormone receptor agonist (SEQ ID NO: 19) with a light chain sequence of SEQ ID NO: 24 at increasing doses and escalating infusion rates. A study of antibodies (N027, M281) was conducted. Subjects were randomized and administered 1 day a single dose of 30 or 60 mg / kg antibody or placebo by intravenous infusion Each of the five cohorts consisted of six subjects receiving the antibody and one placebo. Each cohort consisted of two subjects receiving IVF therapy, for a total of 40 subjects. 30 mg / kg antibody (6 subjects) or placebo (2 subjects) for 60 minutes ) and 30 mg / kg of antibody over 30 minutes (6 subjects) or placebo (2 subjects), 30 mg / kg of antibody over 15 minutes (6 subjects), or or placebo (2 subjects), and 30 mg / kg of antibody over 7.5 minutes ( 6 subjects) or placebo (2 subjects), and 60 mg / kg of antibody was administered for 15 minutes. (6 subjects) or placebo (2 subjects) were administered intravenously. The antibody concentration was 30 mg / ml.

[0185] There were no deaths, serious adverse events (SAEs), or adverse events leading to subject withdrawal from the study. The most commonly reported treatment-emergent adverse events were: Headache occurred in 6 (20%) subjects in the active treatment group and 1 (10%) receiving placebo. Nausea was reported by 3 (10%) subjects receiving active treatment. The 30 mg / Kg infusion over 7.5 minutes and the 60 mg / Kg infusion over 15 minutes were Both were well tolerated but appeared to be associated with higher rates of headache and nausea than the lower infusion rates. Ta.

[0186] Other embodiments While this disclosure has been described in connection with specific embodiments thereof, it is capable of further modifications. SUMMARY OF THE INVENTION This application generally follows principles, known or customary in the art to which this disclosure pertains. This invention can be applied to the essential features described hereinabove, which occur within the scope of the present invention. It is intended to cover any variations, uses, or adaptations that deviate from the disclosure. It is understood that.

[0187] All publications, patents, and patent applications are individually identified as separate publications, patents, or patent applications. The referenced application shall be deemed to have been specifically and individually indicated to be incorporated by reference in its entirety. No. 6,239,999, which is incorporated herein by reference in its entirety.

[0188] Other embodiments are within the scope of the following claims.

Claims

1. 1. A method of treating an alloimmune and / or autoimmune disorder, comprising administering to a subject 5 to 60 mg of / kg, wherein the intravenous infusion is for 90 minutes or and the anti-FcRn antibody comprises: (1) CDR L1, CDR L2 and (2) a light chain variable region comprising CDR H1, CDR H2, and CDR L3; and a heavy chain variable region comprising CDR H3; The CDR L1 has two sequences corresponding to the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1). and a sequence having no more than The CDR L2 has no more than one amino acid sequence to the sequence of GDSERPS (SEQ ID NO: 2). a sequence having an amino acid substitution, The CDR L3 has more than one sequence with respect to the sequence of SSYAGSGIYV (SEQ ID NO: 3). a sequence having an amino acid substitution that is not present in the The CDR H1 is selected from the group consisting of TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), and N YAMG (SEQ ID NO: 6) fruit, The CDR H2 is SIGSSGAQTRYADS (SEQ ID NO: 7), SIGASGSQ TRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), or S No more than two amino acids relative to the sequence of IGASGGQTRYADS (SEQ ID NO: 10) including sequences with substitutions, The CDR H3 has no more than one sequence corresponding to the sequence of LAIGDSY (SEQ ID NO: 11). including sequences with amino acid substitutions, The method.

2. said CDR L1 comprising the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1); said CDR L2 comprising the sequence GDSERPS (SEQ ID NO: 2); the CDR L3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 3), the CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4); the CDR H2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO: 8); the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); The method of claim 1.

3. The infusion may be performed over a period of 7 to 90 minutes, 7 to 60 minutes, 7 to 45 minutes, 7 to 30 minutes, 10 to 90 minutes, minutes, 10-60 minutes, 10-45 minutes, 10-30 minutes, or 15-30 minutes The method according to claim 1 or 2, wherein the method is carried out by

4. 4. The antibody of claim 1, wherein the Fc domain of the antibody is non-fucosylated. The method described.

5. 4. The antibody of claim 1, wherein the Fc domain of the antibody is aglycosylated. The method described below.

6. The method of any one of claims 1 to 5, wherein the antibody is an IgG1 antibody.

7. The method of any one of claims 1 to 6, wherein the antibody is a fully human antibody.

8. the alloimmune and / or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia Hemolytic disease of the fetus and newborn, alloimmune pantithrombocytopenia, congenital heart block, fetal Infantile arthrogryposis, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipidosis syndrome, neonatal polymyositis, dermatomyositis, neonatal lupus, neonatal scleroderma, Behcet's disease, Neonatal Graves' disease, neonatal Kawasaki disease, neonatal autoimmune thyroid disease, and neonatal type I The method of any one of claims 1 to 7, wherein the medicament is selected from the group consisting of diabetes mellitus.

9. The alloimmune and / or autoimmune disorder is thrombocytopenia, panthrombocytopenia, congenital Heart block, arthrogryposis, myasthenia gravis, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia Anemia, antiphospholipid syndrome, polymyositis, dermatomyositis, lupus, scleroderma, Behcet's disease, Graves' disease, Kawasaki disease, autoimmune thyroid disease, and type 1 diabetes mellitus. The method according to any one of claims 1 to 7, wherein

10. 10. The method of claim 1, wherein the injection is an injection of a composition containing 5 to 60 mg / ml of the antibody.

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

11. the injection is of a composition containing 30, 45, or 60 mg / ml of the antibody; The method according to any one of claims 1 to 10.

12. the heavy chain has a sequence identity of at least 95% with any one of SEQ ID NOs: 20-24 %, 97%, 99%, or 100% identity to a sequence of SEQ ID NO: 19 sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of The method of any one of claims 1 to 11, comprising a sequence

13. the antibody heavy chain is a sequence number of SEQ ID NO: 20 to 24 having an amino acid other than N at position 296 20 to 24 amino acid sequences according to any one of claims 1 to 12. How to post.

14. the injection comprising 10-60 mg / ml of the antibody, 20-30 mM sodium phosphate; 20-30 mM sodium chloride, 80-100 mg / ml trehalose, and 0.

1. The method of claim 1, wherein the injection comprises administering a composition containing 1 to 0.005% weight / volume of polysorbate 80.

14. The method according to any one of claims 1 to 13.

15. the antibody heavy chain has the following amino acid substitutions with respect to the sequence of SEQ ID NO: 24: A23V, S30 SEQ ID NO: 1 having one or more of the following: R, L80V, A84T, E85D, A93V 24 amino acid sequence, wherein the antibody light chain has the following amino acid sequence with respect to the sequence of SEQ ID NO: 19: SEQ ID NO: 1 with one or more of the following acid substitutions: Q38H, V58I, and G99D The method of any one of claims 1 to 14, comprising a sequence of 19 amino acids.

16. The antibody heavy chain of any one of claims 1 to 14, wherein the antibody heavy chain does not contain a C-terminal lysine. method.

17. the administered antibody comprises a light chain comprising SEQ ID NO: 19 and a sequence encoding a sequence encoding a sequence of SEQ ID NO: 24 or 296 24. A heavy chain comprising a variant of SEQ ID NO: 24 in which the amino acid of SEQ ID NO: 24 is other than N.

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

18. 18. Any of claims 1 to 10 and 12 to 17, wherein the antibody is administered at 5 to 30 mg / kg. The method according to any one of claims 1 to 4.

19. The antibody according to any one of claims 1 to 10 and 12 to 17, wherein the antibody is administered at 30 to 60 mg / kg. The method according to any one of claims 1 to 5.

20. The concentration of the antibody in the intravenous infusion is 10 mg / ml to 30 mg / ml.

10. The method according to claim 9 , wherein

21. 10. The method of any one of the preceding claims, wherein the subject is a pregnant woman.

22. The dose is based on the pregnant woman's weight at the time of first administration, 22. The method of claim 21, which is not upregulated based on weight gain in women.

23. The dose is a dose per administration, and the pregnant woman at the time of first administration 22. The method of claim 21, wherein the amount of the steroid hormone is upregulated based on the weight of the pregnant woman and based on the weight gain of the pregnant woman. The method described.

24. 10. The method of claim 1, wherein the composition is administered at least every other week. method.

25. 10. The method of any one of the preceding claims, wherein the composition is administered every other week.

26. 10. The method of any one of the preceding claims, wherein the composition is administered at least weekly. Law.

27. 10. The method of any one of the preceding claims, wherein the composition is administered weekly.

28. The subject is a pregnant woman and the first infusion is administered during the first trimester of pregnancy.

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

29. The subject is a pregnant woman and the first infusion is administered during the middle trimester of pregnancy.

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

30. The subject is a pregnant woman and the first infusion is administered during the last trimester of pregnancy.

26. The method according to any one of claims 1 to 25.

31. The subject is a pregnant woman, and the pregnant woman has an obstetric history of severe fetal anemia.

10. The method of any one of the preceding claims,

32. The subject is a pregnant woman, and the pregnant woman is diagnosed with fetal and neonatal hemolytic disease.

10. The method of any one of the preceding claims, wherein the patient has an obstetric history.

33. The subject is a pregnant woman, and the pregnant woman has elevated anti-RhD, anti-Rhc or anti-Kell immunoglobulin alloantibody titers. The method described in paragraph .

34. The subject is a pregnant woman, and the pregnant woman has elevated anti-Rhc or anti-K 31. The method of claim 30, wherein the patient has a ll immunoglobulin alloantibody titer.

35. The subject is a pregnant woman, and the pregnant woman is administered an anti-Lu ａ , Lu ｂ , Bg, K N ａ 、Yt ａ ,E,C,K,C ｗ 、Fy ａ ,cE,ce,D,ce,cE,�･ ａ 、 Kp ｂ , Fy ａ ,M.,N.,S.,Le. ａ , Le ｂ , Fy, Jk ａ , Diego, P., and Mi ａ / Mur.

10. The method of any one of the preceding claims, wherein the patient has globulin alloantibody titers.

36. The subject is a pregnant woman, and the pregnant woman has severe fetal anemia or gestational age 2 obstetric history of stillbirth within 4 weeks and elevated anti-D or anti-Kell IgG alloantibody titers 10. The method of any one of the preceding claims, wherein the patient is pregnant with an antigen-positive fetus. 。

37. 1. The method of claim 1, wherein the subject is a pregnant woman and the first injection is administered between 12 and 16 weeks of pregnancy.

26. The method according to any one of claims 1 to 25.

38. 10. The method of claim 1, wherein the subject is a pregnant woman and the first infusion is during the 14th week of pregnancy.

26. The method according to any one of claims 1 to 25.

39. The infusion times are the same, 90 minutes or less, 60 minutes or less , 45 minutes or less, 30 minutes or less, 15 minutes or less, or for 7 minutes or less. How to post.

40. The initial infusion is 90 minutes or less, 60 minutes or less, 45 minutes or less is performed for less than 30 minutes or less, or for 15 minutes or less, 39. The method of any one of claims 1 to 38, wherein subsequent infusion times are reduced.

41. The duration of the second and third infusions is the same, 60 minutes or less, 45 minutes or less, 30 minutes or less, 15 minutes or less, or 41. The method of claim 40, wherein the injection is performed over a period of 7 minutes or less, and subsequent injection times are reduced. The method described below.

42. The duration of the first and second infusions is the same, and is 90 minutes or less, 60 minutes or less 10 minutes or less, 45 minutes or less, 30 minutes or less, 15 minutes 39. The method of claim 1, wherein the injection time is reduced to 100 s or less.

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

43. The first infusion is given over 60 minutes, with subsequent infusions over 45 minutes or less; It lasts for 30 minutes or less, or 15 minutes or less, or Alternatively, the first infusion may be given over 45 minutes, with subsequent infusions over 30 minutes or less. or over 15 minutes or less, or the initial injection is minutes, with subsequent infusions occurring over 15 minutes or less; 41. The method of claim 40.

44. The first and second infusions were both administered over 60 minutes, and subsequent infusions were administered over 4 5 minutes or less, 30 minutes or less, or 15 minutes or less or the first and second injections are both performed over 45 minutes. and subsequent infusions are given over 30 minutes or less, or 15 minutes or less. Either the first and second injections are administered over a 30-minute period, or 5. The method of claim 4, wherein the injection is administered over a period of 15 minutes or less.

2. The method according to claim 2.

45. A method of administering an anti-FcRn antibody to a subject, comprising administering to the subject a dose of 5 to 60 mg / kg. and intravenous infusion of said anti-FcRn antibody, said intravenous infusion being administered over 90 minutes or less. and the anti-FcRn antibody comprises: (1) CDR L1, CDR L2, and CDR L3; (2) a light chain variable region comprising CDR H1, CDR H2, and CDR H3; a heavy chain variable region comprising DR H3; The CDR L1 has two sequences corresponding to the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1). and a sequence having no more than The CDR L2 has no more than one amino acid sequence to the sequence of GDSERPS (SEQ ID NO: 2). a sequence having an amino acid substitution, The CDR L3 has more than one sequence with respect to the sequence of SSYAGSGIYV (SEQ ID NO: 3). a sequence having an amino acid substitution that is not present in the The CDR H1 is selected from the group consisting of TYAMG (SEQ ID NO: 4), DYAMG (SEQ ID NO: 5), and N YAMG (SEQ ID NO: 6) fruit, The CDR H2 is SIGSSGAQTRYADS (SEQ ID NO: 7), SIGASGSQ TRYADS (SEQ ID NO: 8), SIGASGAQTRYADS (SEQ ID NO: 9), or S No more than two amino acids relative to the sequence of IGASGGQTRYADS (SEQ ID NO: 10) including sequences with substitutions, The CDR H3 has no more than one sequence corresponding to the sequence of LAIGDSY (SEQ ID NO: 11). including sequences with amino acid substitutions, The method.

46. said CDR L1 comprising the sequence TGTGSDVGSYNLVS (SEQ ID NO: 1); said CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 2), the CDR L3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 3), the CDR H1 comprises the sequence TYAMG (SEQ ID NO: 4); the CDR H2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO: 8); the CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 11); 46. ​​The method of claim 45.

47. The infusion may be performed over a period of 7 to 90 minutes, 7 to 60 minutes, 7 to 45 minutes, 7 to 30 minutes, 10 to 90 minutes, minutes, 10-60 minutes, 10-45 minutes, 10-30 minutes, or 15-30 minutes 47. The method of claim 45 or 46, wherein the method is carried out by

48. 48. Any one of claims 45 to 47, wherein the Fc domain of the antibody is non-fucosylated. The method described in paragraph .

49. Any of claims 45 to 47, wherein the Fc domain of the antibody is aglycosylated.

10. The method according to claim 1.

50. 50. The method of any one of claims 45 to 49, wherein the antibody is an IgG1 antibody.

51. The method of any one of claims 45 to 50, wherein the antibody is a fully human antibody.

52. The subject is a patient with fetal and neonatal alloimmune thrombocytopenia, fetal and neonatal hemolytic disease, Alloimmune pantithrombocytopenia, congenital heart block, fetal arthrogryposis, neonatal myasthenia gravis Neonatal autoimmune hemolytic anemia, neonatal antiphospholipid syndrome, neonatal polymyositis, dermatomyopathy inflammation, neonatal lupus, neonatal scleroderma, Behçet's disease, neonatal Graves' disease, neonatal Kawasaki disease neonatal type 1 diabetes mellitus, neonatal type 1 thyroid disease, neonatal autoimmune thyroid disease, and neonatal type 1 diabetes mellitus.

52. The method of claim 45, wherein the patient has an alloimmune and / or autoimmune disorder. The method described.

53. The subject is a patient suffering from thrombocytopenia, panthrombocytopenia, congenital heart block, arthrogryposis, myasthenia gravis, Asthenia, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, antiphospholipid syndrome, multiple Myositis, dermatomyositis, lupus, scleroderma, Behçet's disease, Graves' disease, Kawasaki disease, autoimmune alloimmune and / or thyroid disease, and type I diabetes mellitus 52. The method of any one of claims 45 to 51, wherein the patient has an autoimmune disorder.

54. The injection is an injection of a composition containing 5 to 60 mg / ml of the antibody.

53. The method of any one of claims 53 to 53.

55. the injection is of a composition containing 30, 45, or 60 mg / ml of the antibody; 55. The method according to any one of claims 45 to 54.

56. the heavy chain has a sequence identity of at least 95% with any one of SEQ ID NOs: 20-24 %, 97%, 99%, or 100% identity to a sequence of SEQ ID NO: 19 sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of 56. The method of any one of claims 45 to 55, comprising a sequence

57. the antibody heavy chain is a sequence number of SEQ ID NO: 20 to 24 having an amino acid other than N at position 296 57. The method according to claim 45, comprising any one of the amino acid sequences of 20 to 24. The method described.

58. the injection comprising 10-60 mg / ml of the antibody, 20-30 mM sodium phosphate; 20-30 mM sodium chloride, 80-100 mg / ml trehalose, and 0.

4. An injection of a composition containing 1 to 0.005% weight / volume polysorbate 80.

58. The method of any one of claims 5 to 57.

59. the antibody heavy chain has the following amino acid substitutions with respect to the sequence of SEQ ID NO: 24: A23V, S30 SEQ ID NO: 1 having one or more of the following: R, L80V, A84T, E85D, A93V 24 amino acid sequence, wherein the antibody light chain has the following amino acid sequence with respect to the sequence of SEQ ID NO: 19: SEQ ID NO: 1 with one or more of the following acid substitutions: Q38H, V58I, and G99D 59. The method of any one of claims 45 to 58, comprising 19 amino acid sequences.

60. 60. The antibody heavy chain of claim 45, wherein the antibody heavy chain does not contain a C-terminal lysine. How to do it.

61. the administered antibody comprises a light chain comprising SEQ ID NO: 19 and a sequence encoding a sequence encoding a sequence of SEQ ID NO: 24 or 296 45-5. The heavy chain of claim 45, comprising a variant of SEQ ID NO: 24 in which the amino acid 4. The method according to any one of claims 3 to 3.

62. 62. The method of claim 45, wherein the antibody is administered at 5 to 30 mg / kg.

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

63. Claims 45-54 and 56-61, wherein the antibody is administered at 30-60 mg / kg.

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

64. The concentration of the antibody in the intravenous infusion is 10 mg / ml to 30 mg / ml. Item 45 to 63, a method according to any one of items 45 to 63.

65. 65. The method of any one of claims 45 to 64, wherein the subject is a pregnant woman.

66. The dose is based on the pregnant woman's weight at the time of first administration, 66. The method of claim 65, which is not upregulated based on weight gain in women.

67. The dose is a dose per administration, and the pregnant woman at the time of first administration 66. The method of claim 65, wherein the level of the IL-1 receptor is upregulated based on the weight of the pregnant woman and based on the weight gain of the pregnant woman. The method described.

68. 68. The method of any one of claims 45 to 67, wherein the composition is administered at least every other week. How to do it.

69. 68. The method of any one of claims 45 to 67, wherein the composition is administered every other week.

70. 68. The method of any one of claims 45 to 67, wherein the composition is administered at least weekly. method.

71. 68. The method of any one of claims 45 to 67, wherein the composition is administered weekly.

72. The subject is a pregnant woman and the first infusion is administered during the first trimester of pregnancy.

72. The method according to any one of claims 45 to 71.

73. The subject is a pregnant woman and the first infusion is administered during the middle trimester of pregnancy.

72. The method according to any one of claims 45 to 71.

74. The subject is a pregnant woman and the first infusion is administered during the last trimester of pregnancy.

72. The method according to any one of claims 45 to 71.

75. The subject is a pregnant woman, and the pregnant woman has an obstetric history of severe fetal anemia. The method according to any one of claims 45 to 74,

76. The subject is a pregnant woman, and the pregnant woman is diagnosed with fetal and neonatal hemolytic disease.

76. The method of any one of claims 45 to 75, wherein the patient has an obstetric history.

77. The subject is a pregnant woman, and the pregnant woman has elevated anti-RhD, anti-Rhc or any of claims 45 to 76, having anti-Kell immunoglobulin alloantibody titers.

10. The method according to claim 1.

78. The subject is a pregnant woman, and the pregnant woman has elevated anti-Rhc or anti-K 77. The method of claim 45, wherein the antibody has a IgG1 immunoglobulin alloantibody titer. method.

79. The subject is a pregnant woman, and the pregnant woman is administered an anti-Lu ａ , Lu ｂ , Bg, K N ａ 、Yt ａ ,E,C,K,C ｗ 、Fy ａ ,cE,ce,D,ce,cE,�･ ａ 、 Kp ｂ , Fy ａ ,M.,N.,S.,Le. ａ , Le ｂ , Fy, Jk ａ , Diego, P., and Mi ａ / Mur.

79. The method of any one of claims 45 to 78, having globulin alloantibody titers.

80. The subject is a pregnant woman, and the pregnant woman has severe fetal anemia or gestational age 2 obstetric history of stillbirth within 4 weeks and elevated anti-D or anti-Kell IgG alloantibody titers The method according to any one of claims 45 to 79, wherein the patient is pregnant with an antigen-positive fetus. Law.

81. 4. The method of claim 3, wherein the subject is a pregnant woman and the first injection is administered between 12 and 16 weeks of pregnancy.

72. The method of any one of claims 5 to 71.

82. 5. The method of claim 4, wherein the subject is a pregnant woman and the first infusion is during the 14th week of pregnancy.

72. The method of any one of claims 5 to 71.

83. The infusion times are the same, 90 minutes or less, 60 minutes or less , 45 minutes or less, 30 minutes or less, 15 minutes or less, or for 7 minutes or less, The method described.

84. The initial infusion is 90 minutes or less, 60 minutes or less, 45 minutes or less is performed for less than 30 minutes or less, or for 15 minutes or less, 83. The method of any one of claims 45 to 82, wherein subsequent infusion times are reduced.

85. The duration of the second and third infusions is the same, 60 minutes or less, 45 minutes or less, 30 minutes or less, 15 minutes or less, or 84. The method of claim 84, wherein the injection is performed for 7 minutes or less, and subsequent injection times are reduced. The method described below.

86. The duration of the first and second infusions is the same, and is 90 minutes or less, 60 minutes or less 10 minutes or less, 45 minutes or less, 30 minutes or less, 15 minutes or less, and subsequent injection times are reduced.

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

87. The first infusion is given over 60 minutes, with subsequent infusions over 45 minutes or less; It lasts for 30 minutes or less, or 15 minutes or less, or Alternatively, the first infusion may be given over 45 minutes, with subsequent infusions over 30 minutes or less. or over 15 minutes or less, or the initial injection is minutes, with subsequent infusions occurring over 15 minutes or less; 85. The method of claim 84.

88. The first and second infusions were both administered over 60 minutes, and subsequent infusions were administered over 4 5 minutes or less, 30 minutes or less, or 15 minutes or less or the first and second injections are both performed over 45 minutes. and subsequent infusions are given over 30 minutes or less, or 15 minutes or less. Either the first and second injections are administered over a 30-minute period, or 9. The method of claim 8, wherein the injection is administered over a period of 15 minutes or less, and subsequent injections are administered over a period of 15 minutes or less.

6. The method according to claim 6.

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