FCRN antibodies and methods of use thereof

文档序号：1102037 发布日期：2020-09-25 浏览：8次中文

阅读说明：本技术 Fcrn抗体及其使用方法 (FCRN antibodies and methods of use thereof ) 是由 L·E·凌 D·尼克斯 N·A·克利丰于 2018-12-13 设计创作，主要内容包括：本发明的特征在于结合人新生儿Fc受体(FcRn)的抗体。这些抗-FcRn抗体可用于,例如,促进受试者中自身抗体的清除,抑制受试者中的抗原呈递,阻断免疫应答,例如阻断受试者中免疫应答的基于免疫复合物的激活,和治疗受试者中的免疫性疾病(例如,自身免疫疾病)。这些抗-FcRn抗体也可用于,例如,减少经怀孕受试者的胎盘的病原性抗体运输,增加怀孕受试者中的病原性抗体分解代谢,和治疗胎儿或新生儿中抗体介导的病毒性疾病增强。(The invention features antibodies that bind to human neonatal Fc receptor (FcRn). These anti-FcRn antibodies are useful, for example, to promote clearance of autoantibodies in a subject, inhibit antigen presentation in a subject, block an immune response, e.g., block immune complex-based activation of an immune response in a subject, and treat an immune disease (e.g., an autoimmune disease) in a subject. These anti-FcRn antibodies may also be used, for example, to reduce pathogenic antibody trafficking through the placenta of a pregnant subject, to increase pathogenic antibody catabolism in a pregnant subject, and to treat antibody-mediated viral disease enhancement in a fetus or neonate.)

1. a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDR L1 comprises a sequence having NO more than two amino acid substitutions compared to the sequence of TGTGSDVGSYNLVS (SEQ ID NO:1),

The CDR L2 comprises a sequence having NO more than one amino acid substitution compared to the sequence of GDSERPS (SEQ ID NO:2),

the CDR L3 comprises a sequence having NO more than one amino acid substitution compared to the sequence of SSYAGSGIYV (SEQ ID NO:3),

the CDR H1 comprises a sequence having NO more than one amino acid substitution compared to the sequence of TYAMG (SEQ ID NO:4), DYAMG (SEQ ID NO:5), or NYAAMG (SEQ ID NO:6),

the CDR H2 comprises a sequence having NO more than two amino acid substitutions compared to the sequence of SIGSSGAQTRYADS (SEQ ID NO:7), SIGASGSQTRYADS (SEQ ID NO:8), SIGASGAQTRYADS (SEQ ID NO:9) or SIGASGGQTRYADS (SEQ ID NO:10), and

the CDR H3 comprises a sequence having NO more than one amino acid substitution compared to the sequence of LAIGDSY (SEQ ID NO: 11).

2. The method of claim 1, wherein the antibody is raised to a K less than or equal to that of antibody N026_DBinds human FcRn.

3. The method of claim 1, wherein

The CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDRL2 comprises the sequence GDSERPS (SEQ ID NO:2),

the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO:3),

the CDRH1 comprises the sequence TYAMG (SEQ ID NO:4),

the CDRH2 comprises the sequence SIGSSGAQTRYADS (SEQ ID NO:7), and

The CDRH3 comprises the sequence LAIGDSY (SEQ ID NO: 11).

4. The method of claim 1, wherein

The CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDRL2 comprises the sequence GDSERPS (SEQ ID NO:2),

the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO:3),

the CDRH1 comprises the sequence DYAMG (SEQ ID NO:5),

the CDRH2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO:8), and

the CDRH3 comprises the sequence LAIGDSY (SEQ ID NO: 11).

5. The method of claim 1, wherein

The CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDRL2 comprises the sequence GDSERPS (SEQ ID NO:2),

the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO:3),

the CDRH1 comprises the sequence NYAMG (SEQ ID NO:6),

the CDRH2 comprises the sequence SIGASGAQTRYADS (SEQ ID NO:9), and

the CDRH3 comprises the sequence LAIGDSY (SEQ ID NO: 11).

6. The method of claim 1, wherein

The CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDRL2 comprises the sequence GDSERPS (SEQ ID NO:2),

the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO:3),

the CDRH1 comprises the sequence TYAMG (SEQ ID NO:4),

the CDRH2 comprises the sequence SIGASGGQTRYADS (SEQ ID NO:10), and

The CDRH3 comprises the sequence LAIGDSY (SEQ ID NO: 11).

7. The method of claim 1, wherein

The CDRL1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDRL2 comprises the sequence GDSERPS (SEQ ID NO:2),

the CDRL3 comprises the sequence SSYAGSGIYV (SEQ ID NO:3),

the CDRH1 comprises the sequence TYAMG (SEQ ID NO:4),

the CDRH2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO:8), and

the CDRH3 comprises the sequence LAIGDSY (SEQ ID NO: 11).

8. The method of any one of claims 1-7, wherein the subject has a history of prior fetal and neonatal alloimmune and/or autoimmune disorders.

9. The method of any one of claims 1-8, wherein the subject is at risk of having a fetal and neonatal alloimmune and/or autoimmune disorder.

10. The method of any one of claims 1-9, wherein the fetal and neonatal alloimmune and/or autoimmune disorder is selected from the group consisting of: foetal and neonatal alloimmune thrombocytopenia, foetal and neonatal hemolytic disease, alloimmune pan-thrombocytopenia, congenital heart block, foetal joint contracture, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid 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 diabetes.

11. The method of claim 10, wherein the fetal and neonatal autoimmune and/or autoimmune disorder is a hemolytic disease of the fetus and neonate.

12. The method of claim 10, wherein the fetal and neonatal autoimmune and/or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia.

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

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

15. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Are polar or hydrophobic amino acids and are, in particular,

X₂Is a hydrophobic amino acid, and is,

X₃is a polar amino acid, and is,

X₄is a polar or acidic amino acid, and is,

X₅are polar or hydrophobic amino acids and are, in particular,

X₆is a hydrophobic amino acid, and is,

Z₁is a polar or acidic amino acid, and is,

Z₂are polar or hydrophobic amino acids and are, in particular,

Z₃is G, S or is a-a,

Z₄is a basic amino acid, and is,

Z₅is a hydrophobic or basic amino acid, and

Z₆is G, S, D, Q or H, and

wherein the antibody has a K of less than 200, 150, 100, 50 or 40pM_DBinds human FcRn.

16. The method of claim 15, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

17. The method of claim 15 or 16, wherein

The CDR L1 comprises a sequence having NO more than two amino acid substitutions compared to the sequence of TGTGSDVGSYNLVS (SEQ ID NO:1),

the CDR L2 comprises a sequence having NO more than one amino acid substitution compared to the sequence of GDSERPS (SEQ ID NO:2),

The CDR L3 comprises a sequence having NO more than one amino acid substitution compared to the sequence of SSYAGSGIYV (SEQ ID NO:3),

the CDR H1 comprises a sequence having NO more than one amino acid substitution compared to the sequence of TYAMG (SEQ ID NO:4), DYAMG (SEQ ID NO:5), or NYAAMG (SEQ ID NO:6),

the CDR H3 comprises a sequence having NO more than one amino acid substitution compared to the sequence of LAIGDSY (SEQ ID NO: 11).

18. The method of any one of claims 15-17, wherein the subject has a prior history of having fetal and neonatal alloimmune and/or autoimmune disorders.

19. The method of any one of claims 15-18, wherein the subject is at risk of having a fetal and neonatal alloimmune and/or autoimmune disorder.

20. The method of any one of claims 15-19, wherein the fetal and neonatal alloimmune and/or autoimmune disorder is selected from the group consisting of: foetal and neonatal alloimmune thrombocytopenia, foetal and neonatal hemolytic disease, alloimmune pan-thrombocytopenia, congenital heart block, foetal joint contracture, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid 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 diabetes.

21. The method of claim 20, wherein the fetal and neonatal autoimmune and/or autoimmune disorder is a hemolytic disease of the fetus and neonate.

22. The method of claim 20, wherein the fetal and neonatal autoimmune and/or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia.

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

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

25. A method of treating fetal and neonatal alloimmune and/or autoimmune disorders, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain variable region comprising CDR L1 having the sequence TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDRL2 having the sequence GDSERPS (SEQ ID NO:2), and CDR L3 having the sequence SSYAGSGIYV (SEQ ID NO:3), and a heavy chain variable region comprising CDR H1, CDRH2 and CDRH3, wherein

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ ₂SGZ₃QTRYADS (SEQ ID NO:18), and

the CDRH3 comprises the sequence LAIGDSY (SEQ ID NO:11), and wherein

Z₁Is T, D or is a derivative of N,

Z₂is S or A, and

Z₃is G, S or A.

26. The method of any one of claims 1-25, wherein the light chain comprises a sequence having at least 90% identity to

QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS(SEQ IDNO:19)。

27. The method of any one of claims 1-26, wherein the heavy chain comprises a sequence having at least 90% identity to

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:20)。

28. The method of any one of claims 1-26, wherein the heavy chain comprises a sequence having at least 90% identity to

EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:21)。

29. The method of any one of claims 1-26, wherein the heavy chain comprises a sequence having at least 90% identity to

EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:22)。

30. The method of any one of claims 1-26, wherein the heavy chain comprises a sequence having at least 90% identity to

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:23)。

31. The method of any one of claims 1-26, wherein the heavy chain comprises a sequence having at least 90% identity to

EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:24)。

32. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence having at least 90% identity to

The heavy chain comprises a sequence having at least 90% identity to

33. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence having at least 90% identity to

The heavy chain comprises a sequence having at least 90% identity to

34. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence having at least 90% identity to

The heavy chain comprises a sequence having at least 90% identity to

35. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence having at least 90% identity to

The heavy chain comprises a sequence having at least 90% identity to

36. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence having at least 90% identity to

The heavy chain comprises a sequence having at least 90% identity to

37. The method of any one of claims 27-36, wherein the heavy chain comprises a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of any one of SEQ ID NOs 20-24.

38. The method of claims 27-37, wherein the light chain comprises a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID No. 19.

39. The isolated antibody of any one of claims 1-38, wherein the antibody further comprises the amino acid substitution N297A as compared to the sequence of any one of seq id NOs 20-24.

40. The isolated antibody of any one of claims 1-38, wherein the antibody further comprises the amino acid substitutions D355E and L357M as compared to the sequence of any one of seq id NOs 20-24.

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

42. The isolated antibody of any one of claims 1-41, wherein the antibody does not contain a C-terminal lysine at residue 446 compared to the sequence of any one of SEQ ID Nos. 20-24.

43. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence

The heavy chain comprises the sequence

44. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence

The heavy chain comprises the sequence

45. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence

The heavy chain comprises the sequence

46. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence

The heavy chain comprises the sequence

47. A method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein

The light chain comprises a sequence

The heavy chain comprises the sequence

48. A method of treating fetal anemia associated with hemolytic diseases of a fetus and a neonate, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄Is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

49. A method of treating fetal anemia associated with hemolytic diseases of a fetus and a neonate, the method comprising administering to a pregnant subject an antibody, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises a sequence having at least 90% identity to the sequence of SEQ id No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

50. A method of treating fetal anemia associated with hemolytic diseases of the fetus and neonate, the method comprising administering to a pregnant subject an antibody, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

51. The method of any one of claims 48-50, wherein the method treats a pregnant subject, a fetus of a pregnant subject, and/or a combination thereof.

52. A method of treating an autoimmune disorder, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

53. A method of treating an autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

54. A method of treating an autoimmune disorder, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

55. The method of any one of claims 52-54, wherein the autoimmune disorder is selected from the group consisting of: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Cupid syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, lupus disklike, idiopathic 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff man's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo or Wegener's granulomatosis.

56. The method of any one of claims 52-55, wherein the treatment reduces the risk of miscarriage/loss of the fetus.

57. A method of reducing the risk of or reducing the risk of developing an autoimmune or alloimmune disorder, the method comprising administering an FcRn antibody to a pregnant subject, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

58. A method of reducing the risk of or developing an autoimmune or alloimmune disorder, the method comprising administering an FcRn antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

59. A method of reducing the risk of or developing an autoimmune or alloimmune disorder, the method comprising administering an FcRn antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

60. The method of any one of claims 57-59, wherein the autoimmune disorder is selected from the group consisting of: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Cupid syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, lupus disklike, idiopathic 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff man's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo or Wegener's granulomatosis.

61. The method of any one of claims 57-60, wherein the treatment reduces the risk of miscarriage/loss of the fetus.

62. A method of increasing antibody catabolism in a subject, the method comprising administering an antibody to a pregnant subject, wherein the administered antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

63. A method of increasing antibody catabolism in a subject, the method comprising administering an antibody to a pregnant subject, wherein the administered antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

64. A method of increasing antibody catabolism in a subject, the method comprising administering an antibody to a pregnant subject, wherein the administered antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID NO 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

65. The method of any one of claims 62-64, wherein increasing antibody catabolism comprises increasing pathogenic antibody catabolism.

66. The method of claim 65, wherein the pathogenic antibody is pathogenic to the mother, the fetus, or both the mother and the fetus.

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

68. The method of any one of claims 62-67, wherein the antibody causes a fetal and neonatal alloimmune and/or autoimmune disorder in a fetus of the pregnant subject.

69. The method of claim 68, wherein the fetal and neonatal alloimmune and/or autoimmune disorder is selected from the group consisting of: foetal and neonatal alloimmune thrombocytopenia, foetal and neonatal hemolytic disease, alloimmune pan-thrombocytopenia, congenital heart block, foetal joint contracture, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid 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 diabetes.

70. A method of reducing autoantibodies in a subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDRH2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

71. A method of reducing autoantibodies in a subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

72. A method of reducing autoantibodies in a subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

73. A method of reducing immune complex-based activation of an immune response in a subject, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

74. A method of reducing immune complex-based activation of an immune response in a subject, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

75. A method of reducing immune complex-based activation of an immune response in a subject, the method comprising administering to a pregnant subject an antibody, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID NO 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

76. The method of any one of claims 73-75, wherein the immune response is an acute or chronic immune response in the subject.

77. The method of claim 76, wherein the acute immune response is activated by a medical condition selected from the group consisting of: pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channel disorders, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy and seropathy.

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

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

80. The method of claim 77, wherein the acute immune response is activated by catastrophic anti-phospholipid antibody syndrome.

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

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

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

84. The method of claim 76, wherein the chronic immune response is activated by a medical condition selected from the group consisting of: chronic Inflammatory Demyelinating Polyneuropathy (CIDP), systemic lupus erythematosus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and anti-neutrophil cytoplasmic antibody-associated vasculitis.

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

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

87. The method of claim 86, wherein the autoimmune disease is selected from the group consisting of: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, heparin-induced thrombocytopenia (sensitized grafts, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churg-strauss syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, idiopathic mixed cryoglobulinemia, fibromyalgia, fibromyositis, Grave's disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, lupus erythematosus, inflammatory bowel disease, inflammatory, 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and wegener's granulomatosis.

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

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

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

91. The method of claim 87, wherein the autoimmune disease is a sensitized graft.

92. A method of reducing antibody trafficking across the placenta of a pregnant subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆Is G, S, D, Q or H.

93. A method of reducing antibody trafficking across the placenta of a pregnant subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

94. A method of reducing antibody trafficking across the placenta of a pregnant subject, the method comprising administering an antibody to a pregnant subject, wherein the antibody comprises a light chain and a heavy chain, wherein the light chain comprises the sequence of SEQ ID No. 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

95. A method of treating an enhancement of an antibody-mediated viral disease in a fetus or neonate, comprising administering to a pregnant subject an antibody, wherein said antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3, and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein

The CDRL1 comprises the sequence X₁GTGSDVGSYNX₂VS(SEQ ID NO:12)，

The CDRL2 comprises the sequence GDX₃X₄RPS(SEQ ID NO:13)，

The CDRL3 comprises the sequence X₅SYX₆GSGIYV(SEQ ID NO:14)，

The CDRH1 comprises the sequence Z₁YAMG(SEQ ID NO:15)，

The CDRH2 comprises the sequence SIGZ₂SGZ₃QTZ₄YADS(SEQ ID NO:16)，

The CDRH3 comprises the sequence LAZ₅Z₆DSY (SEQ ID NO:17), wherein

X₁Is T, A, S or I, and the ratio is,

X₂is a group of compounds represented by the general formula (I),

X₃is S, N or T, and is,

X₄is Q, E or is a derivative of N,

X₅is C, S, I or Y, and has the following structure,

X₆is a group A or a group V,

Z₁is E, T, D or is a derivative of N,

Z₂is a group of one of the groups S or A,

Z₃is G, S or is a-a,

Z₄is a group of compounds represented by the general formula (I),

Z₅is I, L or H, and

Z₆is G, S, D, Q or H.

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

97. A method of treating an enhancement of an antibody-mediated viral disease in a fetus or neonate, comprising administering to a pregnant subject an antibody, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO 19; and the heavy chain comprises a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23 and SEQ ID NO 24.

98. The method of any one of claims 95-97, wherein the viral disease is caused by a virus selected from the group consisting of: alpha virus 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 virus infection, respiratory syncytial virus infection, Hantaan virus infection, lattice virus infection, Sindbis virus infection, bunyavirus infection, West Nile virus infection, Japanese encephalitis virus B infection, Leporpox virus infection, lactate dehydrogenase-raised virus infection, Rio virus infection, rabies virus infection, foot and mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection, HIV infection, caprine arthritis virus infection, African swine fever virus infection, lentivirus infection, BK milk-induced polycystic virus infection, ink accumulated valley encephalitis virus infection, enterovirus infection, cytomegalovirus infection, pneumovirus infection, measles virus infection and syphilis virus infection.

99. The method of any one of claims 1-98, wherein the pregnant subject has or is at risk of having a medical condition that activates an immune response in the pregnant subject.

100. The method of claim 99, wherein the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, tunnel disease, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, seropathy, chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive joint disease, primary biliary cirrhosis, ulcerative colitis, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, addison's disease, hemolytic anemia, autoimmune hepatitis, Hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churg-strauss syndrome, cicatricial pemphigoid, localized scleroderma (scleroderma acridum syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, idiopathic 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 hypogammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis.

101. The method of any one of claims 1-100, wherein the pregnant subject has a history of having previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune and/or autoimmune disorder.

102. The method of any one of claims 1-101, wherein antibodies associated with an immune disease are detected in a biological sample obtained from the pregnant subject.

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

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

105. The method of any one of claims 1-104, wherein the administered antibody is a monoclonal antibody.

106. The method of any one of claims 1-105, wherein the administered antibody is IgG 1.

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

108. The method of any one of claims 1-106, wherein the administered antibody is a deglycosylated antibody.

109. The method of any one of claims 1-9 and 12-47, wherein the fetus or neonate is at risk for developing anemia.

110. The method of any one of the preceding claims, wherein the administered antibody comprises SEQ ID NO 19 and SEQ ID NO 24(NO 27).

111. A method for treating or reducing the risk of developing fetal and neonatal alloimmune and/or autoimmune disorders, the method comprising administering to a pregnant woman a composition comprising an antibody comprising a light chain having the amino acid sequence of SEQ ID NO:19 and a heavy chain having the amino acid sequence of SEQ ID NO:24 (N027).

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

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

114. The method of claim 112 or 113, wherein the dose is a dose per administration and is based on the weight of the pregnant woman at the time of the first administration and is not adjusted upward based on an increase in weight of the pregnant woman.

115. The method of claim 112 or 113, wherein the dose is a dose per administration and is adjusted upward based on the weight of the pregnant woman at the time of the first administration and based on the weight gain of the pregnant woman.

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

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

118. The method of any one of claims 111-115, wherein the composition is administered at least weekly.

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

120. The method of any one of claims 111-119 wherein administration is initiated during the first trimester of pregnancy.

121. The method of any one of claims 111-119 wherein administration is initiated during the second trimester of pregnancy.

122. The method of any one of claims 111-119 wherein administration is initiated during the third trimester of pregnancy.

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

124. The method of any one of claims 111-123 wherein the pregnant woman has an obstetric history of severe fetal anemia.

125. The method of any one of claims 111-124, wherein the pregnant woman has increased anti-RhD, anti-Rhc, or anti-Kell immunoglobulin alloantibody titers.

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

127. The method as set forth in any one of claims 111-125,wherein the pregnant woman has an elevated immunoglobulin alloantibody titer of one or more antibodies selected from the group consisting of: anti-Lu^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^aDiego, P and Mi^a/Mur。

128. The method of any one of claims 111-127, wherein the pregnant woman has an obstetric history of severe fetal anemia or miscarriage at ≤ 24 weeks gestation and elevated anti-D or anti-Kell IgG alloantibody titers and is pregnant with an antigen-positive fetus.

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

130. The method of claim 129, wherein the first metered dose administration is during week 14 of pregnancy.

131. A method for treating or reducing the risk of developing fetal and neonatal alloimmune and/or autoimmune disorders, the method comprising administering to a pregnant woman a composition comprising an antibody (M281) comprising a light chain having the amino acid sequence of SEQ ID NO:19 and a heavy chain having the amino acid sequence of SEQ ID NO:24, wherein the administration of M281 is stopped after gestational age 34.

132. The method of claim 131, wherein IVIG is administered to the pregnant woman after administration of M281 is discontinued and before birth.

133. The method of claim 131, wherein IVIG is administered to the pregnant woman 40-100 hours prior to birth.

134. The method of claim 131, wherein administration of M281 is stopped after week 35 of gestation.

135. The method of claim 131 wherein administration of M281 is stopped prior to gestation week 36, 37 or 38.

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

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

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

139. The method of claim 137 or 138, wherein the dose is a dose administered at a time, and is based on the weight of the pregnant woman at the time of the first administration, and is not adjusted upward based on an increase in weight of the pregnant woman.

140. The method of claim 137 or 138, wherein the dose is a dose per administration and is adjusted upward based on the weight of the pregnant woman at the time of the first administration and based on the weight gain of the pregnant woman.

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

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

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

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

145. The method of any one of claims 131-144 wherein administration is initiated during the first trimester of pregnancy.

146. The method of any one of claims 131-144 wherein administration is initiated during the second trimester of pregnancy.

147. The method of any one of claims 131-144 wherein administration is initiated during the third trimester of pregnancy.

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

149. The method as set forth in any one of claims 131-148, wherein the pregnant woman has an obstetrical history of severe fetal anemia.

150. The method as set forth in any one of claims 131-148, wherein the pregnant woman has elevated anti-RhD, anti-Rhc or anti-Kell immunoglobulin alloantibody titers.

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

152. The method of any one of claims 131-148, wherein the pregnant woman has an elevated immunoglobulin alloantibody titer of one or more antibodies selected from the group consisting of: anti-Lu^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^aDiego, P and Mi^a/Mur。

153. The method of any one of claims 131-148, wherein the pregnant woman has an obstetric history of severe fetal anemia or miscarriage at ≤ 24 weeks gestation and elevated anti-D or anti-Kell IgG alloantibody titers and is pregnant with an antigen-positive fetus.

154. The method of any one of claims 131-144 and 149-153, wherein the first quantitative administration is at weeks 12 to 16 of pregnancy.

155. The method of claim 154, wherein the first dosing is during week 14 of pregnancy.

156. The method of any one of claims 131-144 wherein administration is initiated during the first trimester of pregnancy.

157. A method for treating or reducing the risk of developing fetal and neonatal alloimmune and/or autoimmune disorders, the method comprising administering to a pregnant woman a composition comprising an antibody (M281) comprising a light chain having the amino acid sequence of SEQ ID NO:19 and a heavy chain having the amino acid sequence of SEQ ID NO:24, wherein the administration of the M281 is stopped at least one week before birth.

158. The method of claim 132, wherein IVIg administration is initiated 1-15 days after administration of M281 is discontinued.

Background

Therapeutic proteins (e.g., therapeutic antibodies) have rapidly become a clinically important class of drugs for patients with immune diseases. Many autoimmune and alloimmune diseases are mediated by pathogenic antibodies. New methods for treating immune diseases are needed.

Disclosure of Invention

The present invention features novel antibodies against human neonatal Fc receptor (FcRn). These anti-FcRn antibodies can be used, for example, to promote clearance of autoantibodies in a subject, inhibit antigen presentation in a subject, block an immune response, e.g., block immune complex-based activation of an immune response in a subject, or treat an immune disease (e.g., an autoimmune disease) in a subject.

In one aspect, the invention features an isolated antibody that binds human FcRn. The isolated antibody comprises: (1) a light chain variable region comprising CDR L1, CDRL2 and CDR L3 and (2) a heavy chain variable region comprising CDR H1, CDR H2 and CDR H3, wherein said CDR L1 comprises a sequence having NO more than two amino acid substitutions as compared to the sequence of tgtgtgsdvgsynlvs (SEQ ID NO:1), said CDR L2 comprises a sequence having NO more than one amino acid substitution as compared to the sequence of GDSERPS (SEQ ID NO:2), said CDR L3 comprises a sequence having NO more than one amino acid substitution as compared to the sequence of ssyagiyv (SEQ ID NO:3), said CDR H1 comprises a sequence having NO more than one amino acid substitution as compared to the sequence of TYAMG (SEQ ID NO:4), dyacg (SEQ ID NO:5) or NYAMG (SEQ ID NO:6), said CDR H2 comprises a sequence having NO more than two amino acid substitutions as compared to the sequence of SIGSSGAQTRYADS (SEQ ID NO:7), SIGASGSQTRYADS (SEQ ID NO:8), SEQ ID NO SIGASGAQTRYADS (SEQ ID NO: 469) or SEQ ID No. 68510) Substituted sequence and the CDR H3 comprises a sequence having NO more than one amino acid substitution compared to the sequence of LAIGDSY (SEQ ID NO: 11).

In certain embodiments, the antibody has a K of less than 200, 150, 100, 50, or 40pM _DBinds human FcRn.

In certain embodiments, the antibody binds K of human FcRn_DAn antibody having less than or equal to the light chain variable region and the heavy chain variable region of N022, N023, N024, N026, or N027 and further having the same Fc region as the antibody to which it is compared. In another aspect, the invention features an isolated antibody that includes: (1) a light chain variable region comprising CDR L1, CDR L2, and CDRL3 and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein said CDR L₁Comprising X1GTGSDVGSYNX₂Sequence of VS (SEQ ID NO:12), the CDR L2 comprising GDX₃X₄Sequence of RPS (SEQ ID NO:13), the CDR L3 comprising X₅SYX₆The sequence of GSGIYV (SEQ ID NO:14), the CDRH1 comprising Z₁YAMG (SEQ ID NO:15) sequence, the CDR H2 comprising SIGZ₂SGZ₃QTZ₄YADS (SEQ ID NO:16) and the CDR H3 comprises LAZ₅Z₆Sequence of DSY (SEQ ID NO:17), wherein X₁Is a polar or hydrophobic amino acid, X₂Is a hydrophobic amino acid, X₃Is a polar amino acid, X₄Is a polar or acidic amino acid, X₅Is a polar or hydrophobic amino acid, X₆Is a hydrophobic amino acid, Z₁Is a polar or acidic amino acid, Z₂Is a polar or hydrophobic amino acid, Z₃Is G, S or A, Z₄Is a basic amino acid, Z ₅Is a hydrophobic or basic amino acid, and Z₆Is G, S, D, Q or H, and wherein the antibody binds K of human FcRn_DAn antibody having less than or equal to the light chain variable region and the heavy chain variable region of N026 and further having the same Fc region as the compared antibody. In certain embodiments, X₁Is T, A, S or I. In other embodiments, X₂Is L or I. In certain embodiments, X₃Is S, N or T. In other embodiments, X₄Is Q, E or N, X₅Is C, S, I or Y. In certain embodiments, X₆Is A or V, Z₁Is E, T, D or N. In other embodiments, Z₂Is S or A. In certain embodiments, Z₄Is K or R. In other embodiments, Z₅Is I, L or H.

In another aspect, the invention features an isolated antibody containing a light chain variable region comprising CDR L1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2) and CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), and a heavy chain variable region comprising CDR L3 having the sequence of Z₁CDR H1 of the sequence of YAMG (SEQ ID NO:15), having SIGZ₂SGZ₃CDR H2 of the sequence of QTRYADS (SEQ ID NO:18), and CDR H3 of the sequence of LAIGDSY (SEQ ID NO:11), wherein Z ₁Is T, D or N, Z₂Is S or A, and Z₃Is G, S or A.

In certain embodiments, the isolated antibody contains CDRL1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR H1 having the sequence of TYAMG (SEQ ID NO:4), CDR H2 having the sequence of SIGSSGAQTRYADS (SEQ ID NO:7), and CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In certain embodiments, the isolated antibody contains CDRL1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR H1 having the sequence of DYAMG (SEQ ID NO:5), CDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO:8), and CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In certain embodiments, the isolated antibody contains CDRL1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR H1 having the sequence of NYAMG (SEQ ID NO:6), CDR H2 having the sequence of SIGASGAQTRYADS (SEQ ID NO:9), and CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In other embodiments, the isolated antibody contains CDRL1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR H1 having the sequence of TYAMG (SEQ ID NO:4), CDR H2 having the sequence of SIGASGGQTRYADS (SEQ ID NO:10), and CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In other embodiments, the isolated antibody contains CDRL1 having the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 having the sequence of GDSERPS (SEQ ID NO:2), CDR L3 having the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR H1 having the sequence of TYAMG (SEQ ID NO:4), CDR H2 having the sequence of SIGASGSQTRYADS (SEQ ID NO:8), and CDRH3 having the sequence of LAIGDSY (SEQ ID NO: 11).

In certain embodiments, the light chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In certain embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In other embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In certain embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In other embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In another aspect, the invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to

In yet another aspect, the invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to

In certain embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of any one of SEQ ID NOs 20-24. In other embodiments, the light chain of an isolated antibody of the invention comprises a sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of SEQ ID NO. 19.

In certain embodiments, the isolated antibody of the invention further comprises the amino acid substitution N297A as compared to the sequence of any one of SEQ ID NOs 20-24.

In other embodiments, the isolated antibody further comprises the amino acid substitutions D355E and L357M as compared to the sequence of any one of SEQ ID NOs 20-24.

In other embodiments, the isolated antibodies of the invention further comprise any one or more of the following amino acid substitutions: A23V, S30R, L80V, A84T, E85D, A93V as compared to the sequence of any one of SEQ ID NOS 20-24, and Q38H, V58I, and G99D as compared to the sequence of SEQ ID NO 19.

In other embodiments, the isolated antibody of the invention does not contain a C-terminal lysine at residue 446, as compared to the sequence of any of SEQ ID NOS 20-24.

In certain embodiments, the antibody of any of the above aspects binds K of human FcRn_DAn antibody having less than or equal to the light chain variable region and the heavy chain variable region of N022, N023, N024, N026, or N027 and also having the same Fc region as the compared antibody. For example, at a particular K_DIn the assay, the K of the antibody_DLess than 200, 150, 100, 50 or 40 pM.

The amino acid positions of the Complementarity Determining Regions (CDRs) and Framework Regions (FRs) assigned to any of the isolated antibodies described herein are defined according to the EU index of Kabat (Sequences of Proteins of Immunological Interest, 5 th edition published Health Service, National Institutes of Health, Bethesda, Md. (1991)).

In another aspect, the invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence

In yet another aspect, the invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence

In certain embodiments of any of the above aspects, the isolated antibody of the invention is a monoclonal antibody. In certain embodiments, the isolated antibody is IgG 1. In certain embodiments, the isolated antibody comprises a lambda light chain. In certain embodiments, the isolated antibody comprises a kappa light chain.

In certain embodiments of any of the above aspects, the isolated antibody of the invention is a humanized or fully human antibody.

In certain embodiments, the isolated antibody has a K of 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, or 10-40pM_DBinds human FcRn.

In certain embodiments, an isolated antibody of the invention binds to a rodent (e.g., mouse or rat) FcRn. In certain embodiments, an isolated antibody of the invention has a K of less than 200, 150, 100, 50, or 40pM _DBinding to rodent (e.g., mouse or rat) FcRn.

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

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

In another aspect, the invention features a host cell that expresses any of the isolated antibodies described herein. The host cell comprises a nucleic acid molecule encoding any of the isolated antibodies described herein or a vector containing a nucleic acid molecule encoding any of the isolated antibodies described herein, wherein the nucleic acid molecule or vector is expressed by the host cell.

In certain embodiments, the host cell is a Chinese Hamster Ovary (CHO) cell. In certain embodiments, the host cell is an Sp2 cell or an NS0 cell.

In another aspect, the invention features a method of making any of the isolated antibodies described herein. The method comprises the following steps: a) providing a host cell comprising a nucleic acid molecule encoding any of the isolated antibodies described herein or a vector comprising a nucleic acid molecule encoding any of the isolated antibodies described herein, and b) expressing said nucleic acid molecule or vector in said host cell under conditions that allow the formation of said antibody.

In certain embodiments, the method comprises the step of recovering the antibody from the host cell, e.g., at a concentration of about 1-100, 1-50, 1-25, 2-50, 5-50, or 2-20 mg/ml.

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

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

In certain embodiments, the pharmaceutical composition comprises a therapeutically effective dose of the antibody.

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

In certain embodiments, the immune response in the subject is an acute or chronic immune response.

In certain embodiments, the subject has or the acute immune response is activated by a medical condition selected from the group consisting of: pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune hearing loss, Idiopathic Thrombocytopenic Purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated cardiomyopathy and seropathy.

In certain embodiments, the subject has or the chronic immune response is activated by a medical condition selected from the group consisting of: chronic Inflammatory Demyelinating Polyneuropathy (CIDP), systemic lupus, chronic forms of disorders indicative of acute treatment, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis.

In certain embodiments, the subject has an autoimmune disease or the immune response is activated by an autoimmune disease. In particular, the autoimmune disease is selected from alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, addison's disease, hemolytic anemia, autoimmune hepatitis, behcet's disease, bullous pemphigoid, cardiomyopathy, celiac-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churg-strauss syndrome, cicatricial pemphigoid, localized scleroderma (scleroderma acridum syndrome), cold agglutinin disease, crohn's disease, dermatomyositis, discoid lupus, idiopathic mixed cryoglobulinemia, fibromyalgia, fibromyositis, graves ' disease, hashimoto ' thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin dependent diabetes mellitus, juvenile arthritis, lichen planus, chronic inflammatory disease, chronic inflammatory bowel disease, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary, Lupus, meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff man's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis.

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering to, consisting of or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein the CDR L1 comprises, consists of, or consists essentially of a sequence having NO more than two amino acid substitutions as compared to the sequence of tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDR L2 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of SSYAGSGIYV (SEQ ID NO:3), the CDR H1 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of TYAMG (SEQ ID NO:4), dymg (SEQ ID NO:5), or NYAMG (SEQ ID NO:6) A CDR H2 comprising, consisting of, or consisting essentially of a sequence having NO more than two amino acid substitutions as compared to the sequence of SIGSSGAQTRYADS (SEQ ID NO:7), SIGASGSQTRYADS (SEQ ID NO:8), SIGASGAQTRYADS (SEQ ID NO:9), or SIGASGGQTRYADS (SEQ ID NO:10), and a CDR H3 comprising, consisting of, or consisting essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the antibody binds human FcRn with a KD less than or equal to that of antibody N026.

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDR L2 comprises, consists of, or consists essentially of the sequence GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of the sequence SSYAGSGIYV (SEQ ID NO:3), the CDRH1 comprises, consists of, or consists essentially of the sequence TYAMG (SEQ ID NO:4), the CDRH2 comprises, consists of, or consists essentially of the sequence SIGSSGAQTRYADS (SEQ ID NO:7), and the CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDR L2 comprises, consists of, or consists essentially of the sequence GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of the sequence SSYAGSGIYV (SEQ ID NO:3), the CDR H1 comprises, consists of, or consists essentially of the sequence dyacmg (SEQ ID NO:5), the CDR H2 comprises, consists of, or consists essentially of the sequence SIGASGSQTRYADS (SEQ ID NO:8), and the CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDR L2 comprises, consists of, or consists essentially of the sequence GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of the sequence SSYAGSGIYV (SEQ ID NO:3), the CDR H1 comprises, consists of, or consists essentially of the sequence NYAMG (SEQ ID NO:6), the CDRH2 comprises, consists of, or consists essentially of the sequence SIGASGAQTRYADS (SEQ ID NO:9), and the CDRH3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDRL2 comprises, consists of, or consists essentially of the sequence GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of the sequence SSYAGSGIYV (SEQ ID NO:3), the CDRH1 comprises, consists of, or consists essentially of the sequence TYAMG (SEQ ID NO:4), the CDRH2 comprises, consists of, or consists essentially of the sequence SIGASGGQTRYADS (SEQ ID NO:10), and the CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDR L2 comprises, consists of, or consists essentially of the sequence GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of the sequence SSYAGSGIYV (SEQ ID NO:3), the CDRH1 comprises, consists of, or consists essentially of the sequence TYAMG (SEQ ID NO:4), the CDRH2 comprises, consists of, or consists essentially of the sequence SIGASGSQTRYADS (SEQ ID NO:8), and the CDR H3 comprises, consists of, or consists essentially of the sequence LAIGDSY (SEQ ID NO: 11).

In certain embodiments of all aspects, the subject has a prior history of having fetal and neonatal alloimmune and/or autoimmune disorders. For example, in certain embodiments, the pregnant subject has previously been pregnant, wherein the fetus or neonate has suffered from a fetal and neonatal alloimmune and/or autoimmune disorder. In certain embodiments of all aspects, the subject is at risk for having a fetal and neonatal alloimmune and/or autoimmune disorder.

In certain embodiments of all aspects, the fetal and neonatal alloimmune and/or autoimmune disorders are selected from the group consisting of: foetal and neonatal alloimmune thrombocytopenia, foetal and neonatal hemolytic disease, alloimmune pan-thrombocytopenia, congenital heart block, foetal joint contracture, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid 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 diabetes. In certain embodiments of all aspects, the fetal and neonatal autoimmune and/or autoimmune disorder is a hemolytic disease of the fetus and neonate. In certain embodiments of all aspects, the fetal and neonatal autoimmune and/or autoimmune disorder is fetal and neonatal alloimmune thrombocytopenia. In certain embodiments of all aspects, the fetal and neonatal autoimmune and/or autoimmune disorder is congenital heart block.

In certain embodiments of all aspects, the treatment reduces the risk of miscarriage.

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to, consisting of or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of or consists essentially of: (1) a light chain variable region comprising, consisting of or consisting essentially of CDR L1, CDR L2 and CDR L3 and (2) a heavy chain variable region comprising, consisting of or consisting essentially of CDR H1, CDR H2 and CDR H3, wherein said CDR L1 comprises, consists of or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO:12), said CDR L2 comprises, consists of or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO:13), said CDR L3 comprises, consists of or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO:14), said yacrh 1 comprises, consists of or consists essentially of the sequence of Z1 mg (SEQ ID NO:15), said CDR H2 comprises, SIGZ 2Z 3QTZ4 (SEQ ID NO:16), said CDR H3 consists essentially of the sequence of said CDR 5 giy 3917, said CDR H16 consists of the sequence of said sequence of SGZ 6 dsz 16, said CDR 17, Consisting of or consisting essentially of, wherein X1 is a polar or hydrophobic amino acid, X2 is a hydrophobic amino acid, X3 is a polar amino acid, X4 is a polar or acidic amino acid, X5 is a polar or hydrophobic amino acid, X6 is a hydrophobic amino acid, Z1 is a polar or acidic amino acid, Z2 is a polar or hydrophobic amino acid, Z3 is G, S or a, Z4 is a basic amino acid, Z5 is a hydrophobic or basic amino acid, and Z6 is G, S, D, Q or H, and wherein the antibody binds human FcRn with a KD of less than 200, 150, 100, 50, or 40 pM.

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO:12), the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO:13), the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO:14), the CDR H1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO:15), the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO:16), the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO:17), wherein X1 is or T, A, S; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In certain embodiments of all aspects, the CDR L1 comprises, consists of, or consists essentially of a sequence having NO more than two amino acid substitutions as compared to the sequence of tgtgtgsdvgsynlvs (SEQ ID NO:1), the CDRL2 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of GDSERPS (SEQ ID NO:2), the CDR L3 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of SSYAGSGIYV (SEQ ID NO:3), the CDR H1 comprises, consists of, or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of TYAMG (SEQ ID NO:4), dyacg (SEQ ID NO:5), or NYAMG (SEQ ID NO:6), the CDR H2 comprises, consists essentially of, or consists of a sequence having NO more than one amino acid substitution as compared to the sequence of TYAMG (SEQ ID NO:7), SIGASGSQTRYADS (SEQ ID NO:8), SIGASGAQTRYADS (SEQ ID NO:9) or SIGASGGQTRYADS (SEQ ID NO:10) having, consisting of or consisting essentially of a sequence having NO more than two amino acid substitutions as compared to the sequence and the CDRH3 comprises, consists of or consists essentially of a sequence having NO more than one amino acid substitution as compared to the sequence of LAIGDSY (SEQ ID NO: 11).

In another aspect, the invention features a method of treating fetal and neonatal alloimmune and/or autoimmune disorders, comprising administering to, consisting of or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of or consists essentially of a light chain variable region comprising, consisting of or consisting essentially of CDR L1 having the sequence tgtgtgsdvgsynlvs (SEQ ID NO:1), CDR L2 having the sequence GDSERPS (SEQ ID NO:2) and CDR L3 having the sequence SSYAGSGIYV (SEQ ID NO:3), and a heavy chain variable region comprising, consisting of or consisting essentially of CDR H1, CDR H2 and CDR H3, wherein the CDRH1 comprises, consists of or consists essentially of the sequence of Z1 mg (SEQ ID NO:15), the CDR H2 comprises, consists of or consists of the sequence of SIGZ2SGZ3 (qtz 18) yads, Consisting of or consisting essentially of, and the CDR H3 comprises, consists of or consists essentially of the sequence LAIGDSY (SEQ ID NO:11), and wherein Z1 is T, D or N; z2 is S or A; and Z3 is G, S or a.

In certain embodiments of all aspects, the light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19).

In certain embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 20).

In certain embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to

In certain embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 23).

In certain embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 24).

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to a pregnant subject, consisting or consisting essentially of an antibody, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19); and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGSSGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 20).

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to a pregnant subject, consisting or consisting essentially of an antibody, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19); and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to a pregnant subject, consisting or consisting essentially of an antibody, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19); and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMGWVRQAPGKGLEWVSSIGASGAQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 22).

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to a pregnant subject, consisting or consisting essentially of an antibody, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19); and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGGQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 23).

In another aspect, the invention features a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising administering to a pregnant subject, consisting or consisting essentially of an antibody, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to: QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 19); and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 24).

In certain embodiments of all aspects, the heavy chain comprises, consists of, or consists essentially of a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of any one of SEQ ID NOs 20-24. In certain embodiments of all aspects, the light chain comprises, consists of, or consists essentially of a sequence having at least 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID No. 19.

In certain embodiments of all aspects, the antibody further comprises, consists of, or consists essentially of the amino acid substitution N297A as compared to the sequence of any of SEQ ID NOs 20-24. In certain embodiments of all aspects, the antibody further comprises, consists of, or consists essentially of the amino acid substitutions D355E and L357M as compared to the sequence of any one of SEQ ID NOs 20-24. In certain embodiments of all aspects, the antibody further comprises, consists of, or consists essentially of any one or more of the following amino acid substitutions: A23V, S30R, L80V, A84T, E85D, A93V compared to the sequence of any one of SEQ ID NOS 20-24 and Q38H, V58I and G99D compared to the sequence of SEQ ID NO 19.

In certain embodiments of all aspects, the antibody does not contain a C-terminal lysine at residue 446, as compared to the sequence of any of SEQ ID NOS 20-24.

In another aspect, the invention features a method of treating fetal anemia associated with hemolytic diseases of the fetus and neonate, comprising administering, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein said antibody comprises, consists of, or consists essentially of the following regions: (1) a light chain comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1 gtgsdvgsinnx 2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO:15), the CDRH2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDRH3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In another aspect, the invention features a method of treating fetal anemia associated with fetal and neonatal hemolytic diseases, comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In another aspect, the invention features a method of treating fetal anemia associated with hemolytic diseases of the fetus and neonate, comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein said antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein said light chain comprises, consists of, or consists essentially of the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In certain embodiments of all aspects, the method treats a pregnant subject, a fetus of a pregnant subject, and/or combinations thereof.

In another aspect, the invention features a method of treating an autoimmune disorder, comprising, consisting of, or consisting essentially of administering to a pregnant subject an antibody, wherein the antibody comprises, consists of, or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDR H1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I;

X2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In certain embodiments of all aspects, the autoimmune disorder is selected from: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Cupid syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, lupus disklike, idiopathic 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff man's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo or Wegener's granulomatosis.

In certain embodiments of all aspects, the treatment reduces the risk of miscarriage/loss of the fetus.

In another aspect, the invention features a method of reducing the risk of or developing an autoimmune or alloimmune disorder, the method comprising administering to, consisting of, or consisting essentially of a pregnant subject an FcRn antibody, wherein the antibody comprises, consists of, or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDR H1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In certain embodiments of all aspects, the treatment reduces the risk of miscarriage/loss of the fetus.

In another aspect, the invention features a method of increasing antibody catabolism in a subject, the method comprising, consisting of, or consisting essentially of administering to a pregnant subject an antibody, wherein the administered antibody comprises, consists of, or consists essentially of the following regions: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDRH2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDRH3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In certain embodiments of all aspects, increasing antibody catabolism comprises increasing pathogenic antibody catabolism. In certain embodiments of all aspects, the pathogenic antibody is pathogenic to the mother, the fetus, or both the mother and the fetus. In certain embodiments of all aspects, the pathogenic antibody is an IgG antibody. In certain embodiments of all aspects, the antibody causes a fetal and neonatal alloimmune and/or autoimmune disorder of a fetus in the pregnant subject.

In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising, consisting or consisting essentially of administering to a pregnant subject an antibody, wherein the antibody comprises, consists or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO:17), wherein X1 is T, A, S or I;

X2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

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

In another aspect, the invention features a method of reducing autoantibodies in a subject, the method comprising, consisting of, or consisting essentially of administering to a pregnant subject an antibody, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In another aspect, the invention features a method of reducing immune response-based activation in a subject, the method comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In another aspect, the invention features a method of reducing immune complex-based activation of an immune response in a subject, the method comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In certain embodiments of all aspects, the immune response is an acute or chronic immune response in the subject.

In certain embodiments of all aspects, the acute immune response is activated by a medical condition selected from the group consisting of: pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channel disorders, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy and seropathy. For example, in certain embodiments, the acute immune response is activated by a medical condition in a pregnant subject. For example, in certain embodiments, the acute immune response is activated in a fetus or neonate by a medical condition in a pregnant subject. In certain embodiments of all aspects, the acute immune response is activated by a medical condition in the pregnant subject. In certain embodiments of all aspects, the acute immune response is activated in the fetus or neonate by a medical condition in the pregnant subject. In certain embodiments of all aspects, the acute immune response is activated by idiopathic thrombocytopenic purpura. In certain embodiments of all aspects, the acute immune response is activated by pemphigus vulgaris. In certain embodiments of all aspects, the acute immune response is activated by catastrophic anti-phospholipid antibody syndrome. In certain embodiments of all aspects, the acute immune response is activated by neuromyelitis optica. In certain embodiments of all aspects, the acute immune response is activated by antibody-mediated rejection. In certain embodiments of all aspects, the acute immune response is activated by myasthenia gravis.

Also described herein is a method of treating a fetal and neonatal alloimmune and/or autoimmune disorder, comprising, consisting of or consisting essentially of the steps of: m281 is administered to a pregnant subject (e.g., at a dose of 15mg/kg or 30mg/kg, e.g., weekly dose), and administration is discontinued if the subject exhibits hypoalbuminemia (e.g., serum albumin levels below 30g/l, 25g/l, 20 g/l). Also described are methods comprising, consisting of, or consisting essentially of treating fetal and neonatal alloimmune and/or autoimmune disorders, the method comprising administering M281 to a pregnant subject (e.g., at a dose of 15mg/kg or 30mg/kg, e.g., a weekly dose), and administering albumin if the subject exhibits hypoalbuminemia (e.g., serum albumin levels below 30g/l, 25g/l, 20 g/l). Also described are methods comprising, consisting of, or consisting essentially of treating fetal and neonatal alloimmune and/or autoimmune disorders, the methods comprising administering M281 to a pregnant subject (e.g., at a dose of 15mg/kg or 30mg/kg, e.g., a weekly dose), and administering a hypertonic solution (e.g., mannitol or other solution known in the art) if the subject exhibits hypoalbuminemia (e.g., serum albumin levels below 30g/l, 25g/l, 20 g/l). Also described is a method comprising, consisting of, or consisting essentially of treating a fetal and neonatal alloimmune and/or autoimmune disorder, the method comprising administering M281 (e.g., at a dose of 15mg/kg or 30mg/kg, e.g., a weekly dose) to a pregnant subject, and testing the subject for serum albumin levels at least once before or after M281 administration. In some cases of this method, administration of M281 may or may not be continued.

In certain embodiments of all aspects, the chronic immune response is activated by a medical condition selected from the group consisting of: chronic Inflammatory Demyelinating Polyneuropathy (CIDP), systemic lupus erythematosus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and anti-neutrophil cytoplasmic antibody-associated vasculitis. In certain embodiments of all aspects, the chronic immune response is activated by chronic inflammatory demyelinating polyneuropathy.

In certain embodiments of all aspects, the subject has an autoimmune disease. In certain embodiments of all aspects, the autoimmune disease is selected from alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia, anti-factor antibodies, heparin-induced thrombocytopenia (sensitized grafts, autoimmune hepatitis, behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, church syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, crohn's disease, dermatomyositis, discoid lupus, idiopathic mixed cryoglobulinemia, fibromyalgia, fibromyositis, graves disease, hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, rheumatoid arthritis, hypothyroidism, and hypothyroidism, 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Lauter syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff person syndrome, Takayasu's disease, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis. In certain embodiments of all aspects, the autoimmune disease is warm autoimmune hemolytic anemia. In certain embodiments of all aspects, the autoimmune disease is an anti-factor antibody. In certain embodiments of all aspects, the autoimmune disease is heparin-induced thrombocytopenia. In certain embodiments of all aspects, the autoimmune disease is a sensitized graft.

In another aspect, the invention features a method of reducing antibody trafficking across the placenta of a pregnant subject, the method comprising administering, consisting or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists or consists essentially of the following regions: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO:15),

the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO: 17); wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In another aspect, the invention features a method of reducing antibody trafficking across the placenta of a pregnant subject, the method comprising administering, consisting or consisting essentially of an antibody to a pregnant subject, wherein the antibody comprises, consists or consists essentially of a light chain and a heavy chain, wherein the light chain comprises, consists or consists essentially of a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In another aspect, the invention features a method of treating an enhancement of an antibody-mediated viral disease in a fetus or neonate, the method comprising, consisting of, or consisting essentially of administering to a pregnant subject an antibody, wherein said antibody comprises, consists of, or consists essentially of: (1) a light chain variable region comprising, consisting of, or consisting essentially of CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising, consisting of, or consisting essentially of CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises, consists of, or consists essentially of the sequence of X1GTGSDVGSYNX2VS (SEQ ID NO: 12); the CDR L2 comprises, consists of, or consists essentially of the sequence of GDX3X4RPS (SEQ ID NO: 13); the CDR L3 comprises, consists of, or consists essentially of the sequence of X5SYX6GSGIYV (SEQ ID NO: 14); the CDRH1 comprises, consists of, or consists essentially of the sequence of Z1YAMG (SEQ ID NO: 15); the CDR H2 comprises, consists of, or consists essentially of the sequence of SIGZ2SGZ3QTZ4YADS (SEQ ID NO: 16); the CDR H3 comprises, consists of, or consists essentially of the sequence of LAZ5Z6DSY (SEQ ID NO:17), wherein X1 is T, A, S or I; x2 is L or I; x3 is S, N or T; x4 is Q, E or N; x5 is C, S, I or Y; x6 is A or V; z1 is E, T, D or N; z2 is S or A; z3 is G, S or A; z4 is K or R; z5 is I, L or H; and Z6 is G, S, D, Q or H.

In another aspect, the invention features a method of treating an enhancement of an antibody-mediated viral disease in a fetus or neonate, the method comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein said antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein said light chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In another aspect, the invention features a method of treating an enhancement of an antibody-mediated viral disease in a fetus or neonate, the method comprising administering to, consisting of, or consisting essentially of an antibody to a pregnant subject, wherein said antibody comprises, consists of, or consists essentially of a light chain and a heavy chain, wherein said light chain comprises, consists of, or consists essentially of the sequence of SEQ ID No. 19; and the heavy chain comprises, consists of, or consists essentially of a sequence selected from the group consisting of SEQ ID NO 20, SEQ ID NO 21, SEQ ID NO 22, SEQ ID NO 23, and SEQ ID NO 24.

In certain embodiments of all aspects, the viral disease is caused by a virus selected from the group consisting of: alpha virus 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 virus infection, respiratory syncytial virus infection, Hantaan virus infection, lattice virus infection, Sindbis virus infection, bunyavirus infection, West Nile virus infection, Japanese encephalitis virus B infection, Leporpox virus infection, lactate dehydrogenase-raised virus infection, Rio virus infection, rabies virus infection, foot and mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection, HIV infection, caprine arthritis virus infection, African swine fever virus infection, lentivirus infection, BK milk-induced polycystic virus infection, ink accumulated valley encephalitis virus infection, enterovirus infection, cytomegalovirus infection, pneumovirus infection, measles virus infection and syphilis virus infection.

In certain embodiments of all aspects, the pregnant subject has or is at risk of having a medical condition that activates an immune response in the pregnant subject. In certain embodiments of all aspects, the medical condition is pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channel disorders, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, seropathy, chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive joint disease, primary biliary cirrhosis, ulcerative colitis, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, addison's disease, hemolytic anemia, autoimmune hepatitis, Hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churg-strauss syndrome, cicatricial pemphigoid, localized scleroderma (scleroderma acridum syndrome), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, idiopathic 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 hypogammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis.

In certain embodiments of all aspects, the pregnant subject has a history of prior pregnancy with a fetus or neonate having a fetal and neonatal alloimmune and/or autoimmune disorder. For example, in certain embodiments, the pregnant subject has had a prior pregnancy in which the fetus or neonate has a fetal and neonatal alloimmune and/or autoimmune disorder.

In certain embodiments of all aspects, antibodies associated with an immune disease are detected in a biological sample obtained from the pregnant subject. In certain embodiments of all aspects, the biological sample is a blood or urine sample. In certain embodiments of all aspects, the biological sample is a blood sample.

In certain embodiments of all aspects, the administered antibody is a monoclonal antibody. In certain embodiments of all aspects, the administered antibody is IgG 1. In certain embodiments of all aspects, the administered antibody comprises, consists of, or consists essentially of a lambda light chain.

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

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

In a different aspect of the two methods, the method comprises: after cessation of administration of M281 and before birth (e.g., 40-100 hours or 1-15 days before birth), IVIG is administered to the pregnant woman; administration of M281 was stopped after week 35 of gestation; administration of M281 was stopped before gestation week 36, 37 or 38; administering IVIG at 200mg/kg to 1000mg/kg based on the weight of the pregnant woman; m281 was administered at 30mg/kg, based on the weight of the pregnant woman; m281 was administered at 15mg/kg, based on the weight of the pregnant woman; the dose is a dose per administration and is adjusted upward based on the weight of the pregnant woman at the first administration and not based on weight gain of the pregnant woman; the dose is a dose per administration and is adjusted upward based on the weight of the pregnant woman at the first administration and based on the weight gain of the pregnant woman; administering the composition at least every other week; administering the composition every other week;

Administering the composition at least weekly; administering the composition weekly; administration is initiated during the first trimester of pregnancy; administration is initiated during the second trimester of pregnancy; administration is initiated during the third trimester of pregnancy; the route of administration is intravenous; the pregnant woman has an obstetric history of severe fetal anemia; the pregnant woman has increased anti-RhD, anti-Rhc or anti-Kell immunoglobulin alloantibody titers; the pregnant woman has an increased anti-Rhc or anti-Kell immunoglobulin alloantibody titer; the pregnant woman has an elevated immunoglobulin isotype antibody titer of one or more antibodies selected from the group consisting of: 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; the pregnant woman has an obstetric history of severe fetal anemia or stillbirth at less than or equal to 24 weeks gestation and elevated anti-D or anti-Kell IgG alloantibody titers and is pregnant with an antigen positive fetus; the first dosing is at weeks 12 to 16 of pregnancy; the first dosing is during week 14 of pregnancy; and administration is initiated during the first trimester of pregnancy.

Definition of

The term "antibody" is used herein in the broadest sense and includes a variety of antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit FcRn antigen binding activity.

An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding or variable region of an intact antibody. Examples of antibody fragments include Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, straight chain antibodies, single chain antibody molecules and multispecific antibodies.

The term "isolated antibody" as used herein refers to an antibody that has been isolated and/or recovered from a component of its host cell environment in which it was prepared. Contaminant components of the environment of the host cell in which it is produced are substances that would interfere with the research, diagnostic or therapeutic use of the antibody. Contaminant components may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In certain embodiments, the antibody is purified (1) to greater than 95% by weight of the antibody, e.g., as determined by the Lowry method, and in certain embodiments, to greater than 99% by weight; (2) to the extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence, as determined by SDS-PAGE under reducing or non-reducing conditions using, for example, Coomassie blue or silver staining, using, for example, a rotary cup sequencer, or (3) to homogeneity. Isolated antibodies include antibodies in situ within recombinant cells. Typically, however, the isolated antibody will be prepared by at least one purification step. Pharmaceutical preparations of the isolated antibodies typically have less than 250ppm (e.g., less than 200ppm, 150ppm.100ppm) of Host Cell Proteins (HCPs), as determined by ELISA-based HCP assays performed according to the recommendations of the FDA "guide for industry" document.

The term "monoclonal antibody" as used herein means an antibody obtained from a population of substantially homogeneous antibodies, i.e., each antibody in the population has the same basic sequence, except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and are directed against a single antigenic site (i.e., an epitope on human FcRn). Unlike polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody is directed against a single epitope on the antigen. The modifier "monoclonal" indicates that the antibody is characterized as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

The terms "variable region" and "variable domain" as used herein refer to portions of the light and heavy chains of an antibody that include the amino acid sequences of the complementarity determining regions (CDRs, e.g., CDR L1, CDR L2, CDR L3, CDR H1, CDR H2 and CDR H3) and the Framework Regions (FRs). According to the method used in the present invention, the amino acid positions assigned to the CDRs and FRs are defined according to Kabat (Sequences of Proteins of immunological Interest, 5 th edition, Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to a shortening of or insertion into a CDR (further defined herein) or FR (further defined herein) of the variable region. For example, the heavy chain variable region may include a single intervening residue after residue 52 of CDR H2 (i.e., residue 52a according to Kabat) and an intervening residue after residue 82 of the heavy chain FR (i.e., residues 82a, 82b, 82c, etc. according to Kabat). By alignment at regions of homology of antibody sequences to "standard" Kabat numbered sequences, Kabat numbering of residues can be determined for a given antibody.

The terms "complementarity determining regions" and "CDRs" as used herein refer to regions of antibody variable domains that are hypervariable in sequence and/or form structurally defined loops. CDRs are also called hypervariable regions. The light and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR L1, CDR L2 and CDR L3. The heavy chain variable region contains CDR H1, CDR H2 and CDRH 3. Each CDR may comprise amino acid residues from the complementarity determining regions defined by Kabat (i.e., about residues 24-34(CDR L1), 50-56(CDR L2) and 89-97(CDR L3) in the light chain variable region and about residues 31-35(CDRH1), 50-65(CDRH2) and 95-102(CDRH3) in the heavy chain variable region).

The term "FcRn" as used herein denotes a neonatal Fc receptor that binds to the Fc region of an IgG antibody (e.g., an IgG1 antibody). An exemplary FcRn is a human FcRn having UniProt ID No. p 55899. It is believed that human FcRn is responsible for maintaining the half-life of IgG as follows: constitutively internalized IgG is bound and transported back to the cell surface for recycling of IgG.

The terms "affinity" and "binding affinity" as used herein refer to the strength of a binding interaction between two molecules. In general, binding affinity represents the strength of the sum of non-covalent interactions between a single binding site of a molecule and its binding partners such as an isolated antibody and its targets (e.g., an isolated anti-FcRn antibody of the invention and human FcRn). Unless otherwise indicated, binding affinity refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair. Dissociation constant (K) is generally used _D) Or affinity constant (K)_A) The binding affinity between two molecules is described. Two molecules with low binding affinity for each other typically bind slowly, tend to dissociate easily, and exhibit large ks_D. Two molecules with high affinity for each other generally bind easily, tend to remain bound longer, and exhibit small Ks_D. In example 2, a method for determining K for antibodies against human FcRn is described_DMethod of (1) ("SPR method"). K of N022, N023, N024, N026 and N027 Using this method_D31, 31.4, 35.5, 36.5 and 19.3pM, respectively.

The term "inhibiting binding of IgG to FcRn" as used herein refers to the ability of an anti-FcRn antibody of the invention to block or inhibit binding of IgG (e.g., IgG1) to human FcRn. In certain embodiments, an anti-FcRn antibody of the invention binds to FcRn, e.g., at a site on human FcRn to which IgG binds. Thus, the anti-FcRn antibodies of the invention are capable of inhibiting binding of IgG (e.g., autoantibodies from a subject) to FcRn. In certain embodiments, the molecule (e.g., an anti-FcRn antibody of the invention) substantially or completely inhibits binding to IgG. In certain embodiments, IgG binding is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

The term "inhibiting binding of a pathogenic antibody to FcRn" as used herein refers to the ability of an anti-FcRn antibody to block or inhibit binding of a pathogenic antibody (e.g., a pathogenic IgG antibody) to human FcRn. In certain embodiments, the anti-FcRn antibody binds FcRn, e.g., at a site on human FcRn to which a pathogenic antibody binds. Thus, anti-FcRn antibodies are capable of inhibiting binding of pathogenic antibodies (e.g., pathogenic IgG antibodies) to FcRn. In certain embodiments, the molecule (e.g., an anti-FcRn antibody) substantially or completely inhibits binding to a pathogenic antibody. In certain embodiments, binding of a pathogenic antibody to FcRn is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

The term "hydrophobic amino acid" as used herein means an amino acid having relatively low water solubility. Hydrophobic amino acids include, but are not limited to, leucine, isoleucine, alanine, phenylalanine, valine, and proline. Particularly preferred hydrophobic amino acids in the present invention are alanine, leucine, isoleucine and valine.

The term "polar amino acid" as used herein denotes an amino acid having in its side chain a chemical polarity induced by atoms having different electronegativities. The polarity of a polar amino acid depends on the electronegativity between atoms in the side chain of the amino acid and the asymmetry of the side chain structure. Polar amino acids include, but are not limited to, serine, threonine, cysteine, methionine, tyrosine, tryptophan, asparagine, and glutamine. Particularly preferred polar amino acids in the context of the present invention are serine, threonine, asparagine, glutamine, cysteine and tyrosine.

The term "acidic amino acid" as used herein denotes an amino acid whose side chain contains a carboxylic acid group having a pKa between 3.5 and 4.5. In certain embodiments, the acidic amino acids are aspartic acid and glutamic acid.

The term "basic amino acid" as used herein denotes an amino acid whose side chain contains an amino group having a pKa between 9.5 and 13. In certain embodiments, basic amino acids are histidine, lysine, and arginine.

The term "percent (%) identity" as used herein refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence (e.g., an anti-FcRn antibody of the invention) that are identical to the amino acid (or nucleic acid) residues of a reference sequence (e.g., a wild-type anti-FcRn antibody) after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment, and non-homologous sequences can be discarded for comparison purposes). Alignment for the purpose of determining percent identity can be accomplished in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, ALIGN, or megalign (dnastar) software. One skilled in the art can determine suitable parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the full length of the sequences being aligned. In certain embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence relative to a given reference sequence (which may alternatively be expressed as a given candidate sequence having or comprising a particular percentage of amino acid (or nucleic acid) sequence identity relative to a given reference sequence) is calculated as follows:

100x (fraction of A/B)

Wherein a is the number of amino acid (or nucleic acid) residues scored as identical in an alignment of the candidate sequence and the reference sequence, and wherein B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In certain embodiments where the length of the candidate sequence is not equal to the length of the reference sequence, the percent amino acid (or nucleic acid) sequence identity of the candidate sequence relative to the reference sequence will not be equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence relative to the candidate sequence.

In particular embodiments, a reference sequence aligned for comparison to a candidate sequence may indicate that the candidate sequence exhibits 50% to 100% identity over the full length of the candidate sequence or over a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of a candidate sequence aligned for comparison purposes is at least 30%, e.g., at least 40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100% of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid (or nucleic acid) residue as the corresponding position in the reference sequence, then the molecules are identical at that position. The position may be changed by substitution, deletion or insertion. Substitutions, deletions or insertions can comprise a specific number of amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more). When a substitution, deletion or insertion of no more than n amino acids is described, this means that the substitution, deletion or insertion comprises, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, … or n amino acids. When the number of substitutions, deletions or insertions alters 5%, 10%, 15%, 20% or more of the amino acids in the total sequence, the number of substitutions, deletions or insertions can be a certain percentage of the total sequence (e.g., 1%, 5%, 10%, 15%, 20% or more).

The term "fetal and neonatal alloimmune and/or autoimmune disorder" as used herein denotes an immune disorder in a fetus and/or neonate caused by transplacental transfer of maternal antibodies (e.g., pathogenic maternal antibodies) against fetal and/or neonatal antigens. For example, antibodies (e.g., pathogenic antibodies) of a pregnant subject may react with antigens in the fetus (e.g., antigens of the fetus inherited from the father of the fetus). Examples of fetal and neonatal alloimmune and/or autoimmune disorders are provided herein.

The term "pathogenic antibody" as used herein refers to an antibody that causes one or more immune diseases or disorders in a subject (e.g., a pregnant subject), a fetus and/or a neonate of a pregnant subject. In certain embodiments, the pathogenic antibody is an autoantibody raised in a subject (e.g., a pregnant subject) against one or more of the subject's self-proteins, thereby causing an autoimmune disease or disorder in the subject. In certain embodiments, the pathogenic antibodies in the pregnant subject can be transferred to the fetus through the placenta and react with antigens from the fetus (e.g., antigens of the fetus that are inherited from the father of the fetus), thereby causing, for example, a fetal and neonatal alloimmune and/or autoimmune disorder.

The term "antibody-mediated viral disease enhancement" as used herein denotes a viral disease: wherein the antibody facilitates entry of the virus into a host cell, resulting in increased or enhanced infectivity in the cell. In certain embodiments, the antibody can bind to a viral surface protein, and the antibody/viral complex can bind to an FcRn receptor on the surface of a cell through an interaction between the antibody and the receptor. Subsequently, the antibody/virus complex may be internalized into the cell.

The term "host cell" as used herein denotes a vehicle which comprises the necessary cellular components, e.g., organelles, required for expression of a protein from its corresponding nucleic acid. The nucleic acid is typically contained in a nucleic acid vector, which can be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, etc.). The host cell can be a prokaryotic cell, such as a bacterial cell, or a eukaryotic cell, such as a mammalian cell (e.g., a CHO cell). As described herein, host cells are used to express one or more polypeptides encoding anti-FcRn antibodies of the present invention.

The term "vector" as used herein denotes a nucleic acid molecule capable of transporting another nucleic acid molecule to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "recombinant vectors"). In general, expression vectors of utility in recombinant DNA techniques are typically in the form of plasmids.

The term "subject" as used herein means a mammal, e.g., preferably a human. Mammals include, but are not limited to, humans and domestic and farm animals such as monkeys (e.g., cynomolgus monkeys), mice, dogs, cats, horses, and cows, among others.

The term "gestational age" as used herein describes how long a pregnancy is. Gestational age can be described in terms of weeks. Methods of determining gestational age are known in the art (e.g.,Committee on Obstetric Practice American institute of Ultrasound in Medicine Society for the mother-Fetal Medicine, Committee Number 700.2017 month 5 of opinion(ii) a Which is incorporated herein in its entirety). In some cases, gestational age may be determined by ultrasound, number of weeks since the first day of the Last Menstrual Period (LMP), or a combination thereof.

The term "pharmaceutical composition" as used herein denotes a medicament or pharmaceutical formulation: which contains the active ingredient together with one or more excipients and diluents to render the active ingredient suitable for the method of administration. The pharmaceutical compositions of the invention include pharmaceutically acceptable components compatible with the anti-FcRn antibody. The pharmaceutical composition may be in an aqueous form for intravenous or subcutaneous administration, or in the form of a tablet or capsule for oral administration.

The term "pharmaceutically acceptable carrier" as used herein means an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In the present invention, the pharmaceutically acceptable carrier must provide sufficient drug stability to the Fc construct. The nature of the carrier will vary with the mode of administration. For example, for intravenous administration, aqueous carriers are typically used; for oral administration, solid carriers are preferred.

The term "therapeutically effective amount" as used herein means an amount, e.g., a pharmaceutical dose, effective in inducing a desired biological effect in a subject or patient or treating a patient suffering from a condition or disorder described herein. It is also understood herein that a "therapeutically effective amount" may be construed as an amount that produces a desired therapeutic effect, either in one dose or in any dose or route, either alone or in combination with other therapeutic agents.

The term "not more than" as used herein means an amount of less than or equal to. This may be an integer number. For example, no more than two permutations may represent 0, 1, or 2 permutations.

The term "treating" as used herein means reducing a particular disease or condition, reducing the risk of a particular disease or condition, or alleviating a side effect of a particular disease or condition. Reducing a particular disease or condition, reducing the risk of a particular disease or condition, or alleviating a side effect of a particular disease or condition is relative to an untreated subject, e.g., a control, baseline, or known control level or measurement.

Drawings

Figure 1 includes two graphs and a table showing that antibodies N022-N024, N026 and N027 competitively bind to IgG of human or cynomolgus FcRn at pH 6.0.

Figure 2 includes graphs showing the effect of antibodies N023, N024, N026 and N027 on IgG catabolism in mice.

Figure 3 includes a graph showing the dose-dependent effect of antibody N027 on IgG levels and target occupancy in mice.

Figures 4A-4C include graphs showing selective induction of IgG catabolism and target occupancy in cynomolgus monkeys after administration of different doses of antibody N027.

Fig. 5 includes a graph showing the biodistribution of N027 in mice.

Fig. 6 includes an experimental timeline and graph showing the efficacy of N027 in a mouse collagen antibody-induced arthritis model.

Figure 7 includes an experimental timeline and two graphs showing the efficacy of N027 in the mouse model of chronic Idiopathic Thrombocytopenic Purpura (ITP).

Figures 8A-8C show graphs showing dose-dependent FcRn occupancy achieved by N027 in aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively.

Figures 9A-9C show graphs showing that 100% FcRn occupancy by N027 results in increased intracellular IgG accumulation in aortic endothelial cells, venous endothelial cells, and placental trophoblasts, respectively.

Figure 10 shows a graph showing the amount of time required for N027 to reach 100% FcRn occupancy.

Figures 11A and 11B show graphs showing that N027 treatment does not alter FcRn turnover in human endothelial cells and villous trophoblast cells, respectively.

Figures 12A and 12B show images of FcRn in endosomes located in human endothelial and villous trophoblast cells.

Figures 13A and 13B show graphs showing the effect of N027 treatment on the kinetics of IgG transport in human endothelial cells and human placental trophoblasts, respectively.

FIGS. 13C and 13D show that N027 increases intracellular IgG and co-localization of IgG to lysosomes (lysosomal markers: Lamp-1 and dextran).

Figure 14 is a graph showing the transplacental transfer of antipyrine (n-14) over four hours of perfusion. Data represent the antipyrine concentration at 100 μ g/ml in fetal (squares) and maternal (circles) circulation after maternal administration at t-0 as mean ± Standard Deviation (SD).

Figure 15 is a graph showing the transplacental transfer of N027 over four hours of perfusion. Data represent N027 concentrations in fetal and maternal circulation after maternal administration at t ═ 0 for the indicated concentrations, as mean ± SD.

Figure 16 is a graph showing maternal IgG concentrations following treatment with N027 during pregnancy.

Fig. 17 is a graph showing fetal IgG levels after treatment of mothers with N027 during pregnancy.

Figure 18 is a graph showing mean (SD) FcRn receptor occupancy in circulating monocytes after single doses of 0.3, 3, 10, 30 and 60mg/kg N027.

Figure 19 is a graph showing mean (SD) serum IgG levels after single doses of 0.3, 3, 10, 30 and 60mg/kg N027.

Figures 20A and 20B are graphs showing mean (SD) FcRn receptor occupancy by monocytes in 30 and 15mg/kg MAD cohorts according to the number of accumulations administered.

Figures 21A and 21B are graphs showing mean (SD) serum IgG in 30 and 15mg/kg MAD cohorts according to the number of accumulations administered.

FIG. 22 is a graph showing the transplacental transfer of antipyrine (A)In the parent reservoir; n-8). Data represent the concentration of antipyrine at 100 μ g/ml in fetal (filled squares) and maternal (filled circles) circulation after maternal administration at t ═ 0 as mean ± SD.

The diagram of FIG. 23 showsPlacental transfer within 6 hours of perfusion (n ═ 8). Data represent 270. mu.g/ml

In fetal and maternal circulation following maternal administration of t-0

Concentration as mean ± SD.

FIG. 24 is a pictorial representationTransplacental transfer of antipyrine (In the parent reservoir; n-9). Data represent the concentration of antipyrine at 100 μ g/ml in fetal (filled squares) and maternal (filled circles) circulation after maternal administration at t ═ 0 as mean ± SD.

FIG. 25 is a graph showing the presence of N027 at various concentrations

Placental transfer of (4). Data represent 270. mu.g/ml

In fetal and maternal circulation following maternal administration of t-0

Concentration as mean ± SD.

FIG. 26 is a graph showing the trans-placental transfer of antipyrine (A)In the parent reservoir; n-5). Data represent the concentration of antipyrine at 100 μ g/ml in fetal (filled squares) and maternal (filled circles) circulation after maternal administration at t ═ 0 as mean ± SD.

FIG. 27 is a graph showing the presence of IVIgPlacental transfer of (4). Data represent 270. mu.g/ml

In fetal (filled squares) and maternal (filled circles) circulation following maternal administration at t ═ 0Concentration as mean ± SD.

FIG. 28 is a graph showing the transplacental transfer of antipyrine (A)

In the parent reservoir; n-4). Data represent the concentration of antipyrine at 100 μ g/ml in fetal (filled squares) and maternal (filled circles) circulation after maternal administration at t ═ 0 as mean ± SD.

FIG. 29 is a graph showing that IVIg + N027 is presentPlacental transfer of (4). Data represent 270. mu.g/mlIn fetal (filled squares) and maternal (filled circles) circulation following maternal administration at t ═ 0

Concentration as mean ± SD.

Figure 30 is a graph showing the effect on serum albumin in subjects treated with 15mg/kg or 30mg/kg of 3 doses of N027.

Figure 31 is a graph showing the effect on serum albumin in cynomolgus monkeys treated with N027 in a 26 week repeat dose toxicity study.

Figure 32 is a table showing the effect on serum albumin in pregnant cynomolgus monkeys treated with N027 during pregnancy at the EFD and ePPND stages.

Detailed Description

The invention features isolated antibodies that bind human neonatal Fc receptor (FcRn) with high affinity. The invention features anti-FcRn antibodies, methods and compositions for making anti-FcRn antibodies, and methods for blocking FcRn activity, reducing immune response, immune complex-based activation, and treating immune diseases. The present disclosure features anti-FcRn antibodies, methods and compositions for making anti-FcRn antibodies, and methods for blocking FcRn activity, reducing immune response, immune complex-based activation, and treating immune diseases. In addition, anti-FcRn antibodies may be used to reduce the trafficking of pathogenic antibodies through the placenta of a pregnant subject, increase the catabolism of pathogenic antibodies in a pregnant subject, and treat antibody-mediated viral disease enhancement in a fetus or neonate.

I. anti-FcRn antibodies

In general, the invention features isolated antibodies that bind human FcRn with high affinity. An anti-FcRn antibody of the present invention refers to an antibody that can bind human FcRn and inhibit binding of IgG (e.g., IgG autoantibody) to FcRn. In certain embodiments, the antibody is a monoclonal antibody. In other embodiments, the antibody is a polyclonal antibody. In certain embodiments, the antibody is selected from the group consisting of a chimeric antibody, an affinity matured antibody, a humanized antibody, and a human antibody. In certain embodiments, the antibody is an antibody fragment, e.g., Fab-SH, F (ab)₂Or a scFv.

In certain embodiments, the antibody is a chimeric antibody. For example, an antibody contains antigen binding sequences from a non-human donor grafted to heterologous non-human, or humanized sequences (e.g., framework and/or constant domain sequences). In one embodiment, the non-human donor is a mouse. In another embodiment, the antigen binding sequence is synthetic, for example, by mutagenesis (e.g., phage display screening, etc.). In another embodiment, a chimeric antibody has a non-human (e.g., mouse) variable region and a human constant region. In one embodiment, the mouse light chain variable region is fused to a human kappa light chain. In another example, the mouse heavy chain variable region is fused to a human IgG1 constant region.

In one aspect, the invention features an isolated antibody that is capable of binding to human FcRn. The isolated antibody comprises: (1) a light chain variable region comprising CDR L1, CDR L2, and CDR L3 and (2) a heavy chain variable region comprising CDR H1, CDR H2, and CDR H3, wherein said CDR L1 comprises a sequence at least 92% identical to the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), said CDR L2 comprises a sequence at least 85% identical to the sequence of GDSERPS (SEQ ID NO:2), said CDR L3 comprises a sequence at least 85% identical to SSGSYAGIYV (SEQ ID NO:2)3), the CDR H1 comprising a sequence having at least 80% identity to the sequence of TYAMG (SEQ ID NO:4), DYAMG (SEQ ID NO:5) or NYAAMG (SEQ ID NO:6), the CDR H2 comprising a sequence having at least 92% identity to the sequence of SIGSSGAQTRYADS (SEQ ID NO:7), SIGASGSQTRYADS (SEQ ID NO:8), SIGASGAQTRYADS (SEQ ID NO:9) or SIGASGGQTRYADS (SEQ ID NO:10), and the CDR H3 comprising a sequence having at least 85% identity to the sequence of LAIGDSY (SEQ ID NO: 11). In certain embodiments, the antibody has a K of less than 200, 150, 100, 50, or 40pM_DBinds human FcRn. In certain embodiments, the antibody binds K of human FcRn _DAn antibody having less than or equal to the light chain variable region and the heavy chain variable region of N022, N023, N024, N026, or N027 and further having the same Fc region as the compared antibody.

In certain embodiments, an isolated antibody of the invention comprises: comprising X₁GTGSDVGSYNX₂CDR L1 of the sequence of VS (SEQ ID NO:12), comprising GDX₃X₄CDR L2 of the sequence of RPS (SEQ ID NO:13) comprising X₅SYX₆CDR L3 of the sequence of GSGIYV (SEQ ID NO:14) comprising Z₁CDRH1 of the sequence of YAMG (SEQ ID NO:15) comprising SIGZ₂SGZ₃QTZ₄CDR H2 of the sequence of YADS (SEQ ID NO:16), and a CDR comprising LAZ₅Z₆CDR H3 of the sequence of DSY (SEQ ID NO:17), where X₁Is a polar or hydrophobic amino acid (e.g., preferably T, A, S or I), X₂Is a hydrophobic amino acid (e.g., preferably L or I), X₃Is a polar amino acid (e.g., preferably S, N or T), X₄Is a polar or acidic amino acid (e.g., preferably Q, E or N), X₅Is a polar or hydrophobic amino acid (e.g., preferably C, S, I or Y), X₆Is a hydrophobic amino acid (e.g., preferably A or V), Z₁Is a polar or acidic amino acid (e.g., preferably E, T, D or N), Z₂Is a polar or hydrophobic amino acid (e.g., preferably S or A), Z₃Is G, S or A, Z₄Is a basic amino acid (e.g., preferably K or R), Z ₅Is a hydrophobic or basic amino acid (e.g., preferablyI. L or H), and Z)₆Is G, S, D, Q or H, and wherein the antibody has a K of less than 200, 150, 100, 50 or 40pM_DBinds human FcRn.

In other embodiments, the isolated antibody of the invention comprises: CDR L1 comprising the sequence of TGTGTGSDVGSYNLVS (SEQ ID NO:1), CDR L2 comprising the sequence of GDSERPS (SEQ ID NO:2), CDR L3 comprising the sequence of SSYAGSGIYV (SEQ ID NO:3), CDR L1 comprising the sequence of Z₁CDR H1 of the sequence of YAMG (SEQ ID NO:15), comprising SIGZ₂SGZ₃CDR H2 of the sequence of QTRYADS (SEQ ID NO:18), and CDR H3 comprising the sequence of LAIGDSY (SEQ ID NO:11), wherein Z₁Is T, D or N, Z₂Is S or A, and Z₃Is G, S or A.

Table 1 shows the amino acid sequences of the light and heavy chain Complementarity Determining Regions (CDRs) of some exemplary anti-FcRn antibodies of the present invention.

TABLE 1

Table 2 shows the SEQ ID NOs of the light and heavy chains of these exemplary anti-FcRn antibodies of the present invention.

TABLE 2

In certain embodiments, the light chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In certain embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In other embodiments, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

In yet another embodiment, the heavy chain of an isolated antibody of the invention comprises a sequence having at least 90% identity to

The invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence having at least 90% identity to

Furthermore, in any of the anti-FcRn antibodies described herein, the heavy chain of the antibody comprises a sequence having at least 95%, 97%, 99% or 100% identity to the sequence of any one of SEQ ID NOs 20-24. In any of the anti-FcRn antibodies described herein, the light chain comprises a sequence having at least 95%, 97%, 99% or 100% identity to the sequence of SEQ ID No. 19.

The antibodies of the present invention may further contain amino acid substitutions, additions and/or deletions outside the CDRs (i.e., in the Framework Regions (FRs)). In certain embodiments, the antibodies of the invention may further comprise any one or more of the following amino acid substitutions: A23V, S30R, L80V, A84T, E85D, A93V as compared to the sequence of any one of SEQ ID NOS 20-24, and Q38H, V58I, and G99D as compared to the sequence of SEQ ID NO 19.

The antibodies may further contain amino acid substitutions, additions and/or deletions outside the CDRs (i.e., in the Framework Regions (FRs)). The amino acid substitutions, additions and/or deletions may be of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more). Amino acid substitutions, additions and/or deletions may be substitutions, additions and/or deletions of eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, three or fewer or two or fewer individual amino acids. In certain embodiments, the antibody may further comprise any one or more of the following amino acid substitutions: A23V, S30R, L80V, A84T, E85D, A93V as compared to the sequence of any one of SEQ ID NOS 20-24, and Q38H, V58I, and G99D as compared to the sequence of SEQ ID NO 19.

In certain embodiments, the antibodies of the invention may comprise amino acid substitutions, additions and/or deletions in the constant region (e.g., Fc region) of the antibody, which result, for example, in reduced effector function, e.g., reduced complement-dependent cell lysis (CDC), antibody-dependent cell-mediated cell lysis (ADCC), and/or antibody-dependent cell-mediated phagocytosis (ADCP) and/or reduced B-cell killing. The constant regions are not directly involved in binding of the antibody to its target, but rather exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity. In certain embodiments, the antibodies of the invention are characterized by reduced binding (i.e., absence of binding) to human complement factor C1q and/or a human Fc receptor on Natural Killer (NK) cells. In other embodiments, the antibodies of the invention are characterized by reduced binding (i.e., absence of binding) to human Fc γ RI, Fc γ RIIA, and/or Fc γ RIIIA. To alter or reduce antibody-dependent effector functions such as CDC, ADCC, ADCP and/or B-cell killing, the antibodies of the invention may be of the IgG class and contain one or more amino acid substitutions E233, L234, G236, D265, D270, N297, E318, K320, K322, a327, a330, P331 and/or P329 (numbering according to the EU index of Kabat (Sequences of proteins of immunological Interest, 5 th edition. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). In certain embodiments, the antibody contains the mutations L234A/L235A or D265A/N297A. Preferably, the anti-FcRn antibody of the invention contains the amino acid hdfn substitution N297A compared to the sequence of any of SEQ ID NOs 20-24, such that the antibody of the invention becomes deglycosylated. The resulting null response antibodies showed very little binding to complement or Fc receptors (i.e., complement C1q binding), indicating low CDC potential.

In other embodiments, antibodies of the invention may include antibodies with specific amino acid changes that improve antibody stability.

Furthermore, in other embodiments, to minimize potential immunogenicity, certain antibodies of the invention, e.g., N024, N026, and N027, can undergo allotypic changes from G1m17.1 to G1m17 by replacing amino acids D355 and L357 (as compared to the sequence of any of SEQ ID NOS: 20-24) with glutamic acid and methionine, respectively.

In other embodiments, antibodies of the invention, e.g., N022-N024, N026, and N027, do not contain a C-terminal lysine at residue 446 compared to the sequence of any of SEQ ID NOS 20-24.

The invention features an isolated antibody comprising a light chain and a heavy chain, wherein the light chain comprises a sequence

In any of the anti-FcRn antibodies described herein, in certain embodiments, the antibody has a K of less than 200, 150, 100, 50, or 40pM_DBind mouse or rat FcRn.

In any of the anti-FcRn antibodies described herein, in certain embodiments, the antibody binds human FcRn with an affinity of between 1-100, 5-150, 5-100, 5-75, 5-50, 10-50, or 10-40 pM.

The anti-FcRn antibodies of the present invention may be of the immunoglobulin antibody isotype IgG, IgE, IgM, IgA or IgD. Preferably, the anti-FcRn antibody belongs to the immunoglobulin antibody isotype IgG. The anti-FcRn antibody may also belong to any immunoglobulin antibody isotype subclass. For example, the anti-FcRn antibody may belong to IgG subclass IgG1, IgG2, IgG3, or IgG 4. Preferably, the anti-FcRn antibody belongs to subclass IgG 1. Specifically, the anti-FcRn antibodies of the present invention comprise IgGG1m17 or g1m17.1 allotype heavy chains. In certain embodiments, the light chain of the anti-FcRn antibody may be a kappa light chain, a lambda light chain, or a kappa-lambda chimeric light chain. In a preferred embodiment, the anti-FcRn antibody of the invention comprises a full-length lambda light chain.

In certain embodiments, the antibodies of the invention are monoclonal. The antibodies of the invention may also be polyclonal, chimeric, humanized or fully human. In certain embodiments, the antibodies of the invention may be affinity matured. In other embodiments, the antibodies of the invention may be antibody fragments.

Without being bound by theory, it is believed that the anti-FcRn antibodies of the present invention compete with IgG and inhibit binding of IgG to human FcRn. Epitope mapping by hydrogen-deuterium exchange of the antibodies of the invention indicates that the antibodies bind to an epitope on FcRn located at and/or adjacent to the Fc-FcRn interaction interface, suggesting that the antibodies of the invention block binding of IgG to FcRn by direct inhibition. Furthermore, the epitope-mapped binding site is remote from the albumin binding site of FcRn. Thus, serum albumin binding is not inhibited and serum albumin levels are not reduced. Indeed, experimental evidence suggests that mouse albumin levels remain constant following anti-FcRn antibody administration, indicating that albumin recycling is not interfered by antibody binding to FcRn.

FcRn inhibition

FcRn is a type I transmembrane protein that functions as an intracellular vesicle transporter that binds IgG and serum albumin. FcRn is expressed in endothelial cells, luminal epithelial cells, hepatocytes, podocytes, granulocytes, monocytes, macrophages, dendritic cells, and NK cells, but not on B or T cells. FcRn maintains the half-life of IgG by binding and transporting constitutively internalized IgG back to the cell surface. Binding of FcRn to Fc and serum albumin occurs in the primary endosome at pH 6.0, then sorting FcRn into vesicles, and then transporting FcRn-bound IgG or albumin back to the cell surface where FcRn rapidly releases IgG or albumin at pH 7.4. This transport cycle maintains the half-lives of IgG and albumin as follows: both are recycled and prevented from being transported to lysosomes for degradation. FcRn also captures IgG Fc internalized in epithelial cells and transports them bi-directionally to the opposite apical or basolateral membrane. This function allows transport of IgG to the lumen of organs such as the gastrointestinal tract, or transport of IgG or IgG antigen complexes from the lumen to the vasculature of the interstitial layer or lymphoid tissue.

To investigate the contribution of FcRn to IgG homeostasis, mice have been engineered so that portions of the FcRn light and heavy chains are "knocked out" so that these proteins are not expressed (junghas et al, Proc natl acad SciUSA 93:5512,1996). In these mice, serum half-life and concentration of IgG decreased dramatically, suggesting an FcRn-dependent mechanism of IgG homeostasis. Studies in rodent models (e.g., the models discussed above) suggest that blockade of FcRn can increase IgG catabolism, including that of pathogenic autoantibodies, thereby inhibiting disease (e.g., autoimmune disease) progression. FcRn may also facilitate antigen presentation through the transport of immune complexes to antigen degradation and MHC loading compartments.

The present invention provides isolated anti-FcRn antibodies that bind human FcRn with high affinity. The anti-FcRn antibodies of the invention compete with other anti-FcRn antibodies (e.g., IgG autoantibodies) and effectively inhibit their binding to FcRn, thereby increasing catabolism and reducing the half-life of other anti-FcRn antibodies (e.g., IgG autoantibodies). The anti-FcRn antibodies of the invention may be used in methods of treating or reducing immune complex-based activation of an immune response in a subject, e.g., an immune response caused by an autoantibody in an autoimmune disease.

Maternal IgG antibody transfer to the placenta of the fetus is an important FcRn-dependent mechanism that provides protection for the newborn, while his/her humoral response is ineffective. During fetal life, FcRn in the synctrophoblast of the placenta is responsible for the transfer of maternal IgG antibodies to the fetus. Pathogenic maternal antibodies (e.g., pathogenic maternal IgG antibodies) can also cross the placenta by binding to FcRn and cause alloimmune and/or autoimmune disorders in the fetus and neonate. In certain embodiments, the pathogenic antibodies in the pregnant subject cause fetal and neonatal alloimmune and/or autoimmune disorders of the fetus in the pregnant subject. anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) can compete with and inhibit binding to the parent pathogenic antibodies (e.g., parent pathogenic IgG antibodies), thereby increasing the catabolism and decreasing the half-life of these pathogenic antibodies.

The present disclosure provides isolated anti-FcRn antibodies that bind human FcRn. The anti-FcRn antibody can compete with other anti-FcRn antibodies (e.g., IgG autoantibodies) and inhibit its binding to FcRn, thereby increasing the catabolism and decreasing the half-life of the other anti-FcRn antibodies (e.g., IgG autoantibodies). The anti-FcRn antibodies may be used in methods of treating or reducing immune complex-based activation of an immune response in a subject, such as an immune response elicited by autoantibodies in autoimmune diseases. Reducing an immune response can be described as reducing an immune response as compared to a subject not receiving treatment (e.g., a control subject). The anti-FcRn antibodies may also be used in methods of reducing pathogenic antibody trafficking (e.g., pathogenic maternal IgG antibody trafficking) through the placenta of a pregnant subject, increasing pathogenic antibody catabolism in a pregnant subject, and treating an antibody-mediated enhancement of viral disease in a fetus or neonate, comprising administering to a pregnant subject an isolated antibody that binds human FcRn. Reducing the trafficking of pathogenic antibodies by the placenta of a pregnant subject can be described as reducing the trafficking of pathogenic antibodies as compared to a subject not receiving treatment (e.g., a control subject).

Vectors, host cells and antibody production

anti-FcRn antibodies of the invention may be produced from host cells. Host cells represent such vectors: which comprise the necessary cellular components, e.g., organelles, required for expression of the polypeptides and constructs described herein from the corresponding nucleic acids. The nucleic acid may be contained in a nucleic acid vector, which may be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.). The choice of nucleic acid vector will depend, in part, on the host cell to be used. Generally, preferred host cells are of prokaryotic (e.g., bacterial) or eukaryotic (e.g., mammalian) origin.

Nucleic acid vector construction and host cells

Nucleic acid sequences encoding the amino acid sequences of the anti-FcRn antibodies of the present invention can be prepared by a variety of methods known in the art. These methods include, but are not limited to, oligonucleotide-mediated (or site-directed) mutagenesis and PCR mutagenesis. Nucleic acid molecules encoding the anti-FcRn antibodies of the invention can be obtained using standard techniques, such as gene synthesis. Alternatively, standard techniques in the art are used, e.g., QuikChange ^TMMutagenesis, a nucleic acid molecule encoding a wild-type anti-FcRn antibody may be mutated to contain specific amino acid substitutions. Nucleic acid molecules can be synthesized using nucleotide synthesizers or PCR techniques.

The nucleic acid sequence encoding the anti-FcRn antibody of the invention may be inserted into a vector capable of replicating and expressing the nucleic acid molecule in prokaryotic or eukaryotic host cells. Many vectors are available in the art and can be used for the purposes of the present invention. Each vector may contain various components that may be adjusted and optimized for compatibility with the particular host cell. For example, the vector components may include, but are not limited to, an origin of replication, a selectable marker gene, a promoter, a ribosome binding site, a signal sequence, a nucleic acid sequence encoding a protein of interest, and a transcription termination sequence.

In certain embodiments, mammalian cells are used as host cells of the invention. Examples of mammalian cell types include, but are not limited to, Human Embryonic Kidney (HEK) (e.g., HEK293F), Chinese Hamster Ovary (CHO), HeLa, COS, PC3, Vero, MC3T3, NS0, Sp2/0, VERY, BHK, MDCK, W138, BT483, Hs578T, HTB2, BT20, T47D, NS0 (murine myeloma cell line that does not endogenously produce any immunoglobulin chain), CRL7O3O, and HsS78 6378 Bst cells. In other embodiments, E.coli cells are used as host cells for the invention. Examples of E.coli strains include, but are not limited to, E.coli 294( 31,446), Escherichia coli λ 1776 (C.coli)

31,537, E.coli BL21(DE3) (II)BAA-1025), and E.coli RV308(31,608). Different host cells have characteristic and unique mechanisms for post-translational processing and modification of protein products. Appropriate cell lines or host systems may be selected to ensure proper modification and processing of the expressed anti-FcRn antibody. The expression vector can be introduced into a suitable host using techniques conventional in the art, e.g., transformation, transfection, electroporation, calcium phosphate precipitation, and direct microinjectionIn the host cell. Once the vector is introduced into a host cell for protein production, the host cell is cultured in conventional nutrient media, suitably modified to induce promoters, select transformants, or amplify the genes encoding the desired sequences. Methods for expressing therapeutic proteins are known in the art, see, e.g., Paulina Balbas, Argelia Lorence (eds.) Recombinant Gene expression: Reviews and Protocols (Methods in Molecular Biology), Humana Press; 2 nd edition 2004 (20/7/2004) and Vladimir Voynov and Justin A. Caravella (eds.) Therapeutic Proteins Methods and protocols (Methods in molecular biology) HumanaPress; year 2012, version 2 (6 months and 28 days 2012).

Protein production, recovery and purification

Host cells for producing anti-FcRn antibodies of the invention can be cultured in media known in the art and suitable for culturing the selected host cells. Examples of suitable media for mammalian host cells include Minimal Essential Medium (MEM), Dulbecco's Modified Eagle's Medium (DMEM), Expi293^TMExpression medium, DMEM supplemented with Fetal Bovine Serum (FBS) and RPMI-1640. Examples of suitable media for bacterial host cells include Luria Broth (LB) plus necessary supplements such as a selective agent, e.g., ampicillin. At a suitable temperature (such as from about 20 ℃ to about 39 ℃, e.g., from 25 ℃ to about 37 ℃, preferably 37 ℃) and CO₂The host cell is cultured at a level such as 5 to 10% (preferably 8%). The pH of the medium is typically about 6.8 to 7.4, e.g., 7.0, depending primarily on the host organism. If an inducible promoter is used in the expression vector of the present invention, protein expression is induced under conditions suitable for promoter activation.

Protein recovery typically involves the destruction of host cells, usually by methods such as osmotic shock, sonication, or lysis. Once the cells are disrupted, the cell debris can be removed by centrifugation or filtration. The protein may be further purified. The anti-FcRn antibodies of the present invention may be purified by any method known in the art of protein Purification, for example, by protein a affinity, other chromatography (e.g., ion exchange, affinity, and size exclusion column chromatography), centrifugation, differential solubility, or by any other standard technique for purifying proteins (see Process Scale Purification of antibodies, Uwe Gottschalk (eds.) John Wiley & Sons, inc., 2009). In certain instances, anti-FcRn antibodies may be conjugated to marker sequences (such as peptides) to facilitate purification. An example of a marker amino acid sequence is a hexa-histidine peptide (His-tag) that binds with micromolar affinity to a nickel-functionalized agarose affinity column. Other peptide tags that may be used for purification include, but are not limited to, the hemagglutinin "HA" tag, which corresponds to an epitope derived from the influenza hemagglutinin protein.

Alternatively, the anti-FcRn antibodies of the invention can be produced by cells of a subject (e.g., a human), e.g., in a therapeutic context, by administering vectors (e.g., retroviral vectors, adenoviral vectors, poxvirus vectors (e.g., Vaccinia virus vectors such as Modified Vaccinia virus Ankara (MVA)), adeno-associated viral vectors, and alphaviral vectors) containing nucleic acid molecules encoding the anti-FcRn antibodies of the invention. Once the vector enters the cells of the subject (e.g., by transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.), expression of the anti-FcRn antibody will be promoted, followed by secretion of the antibody from the cells. If treatment of the disease or disorder is the desired result, no other measures may be required. If protein collection is desired, blood can be collected from the subject and the protein purified from the blood by methods known in the art.

Pharmaceutical compositions and preparation

The invention features pharmaceutical compositions comprising one or more anti-FcRn antibodies described herein. In certain embodiments, the pharmaceutical compositions of the invention comprise one or more antibodies of the invention (e.g., N022-N024, N026, and N027) as therapeutic proteins. In other embodiments, a pharmaceutical composition of the invention comprising one or more antibodies of the invention (e.g., N022-N024, N026, and N027) can be used in therapy in combination with other 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 further comprise one or more pharmaceutically acceptable carriers or excipients, which may be formulated by methods known to those skilled in the art.

Acceptable carriers and excipients in pharmaceutical compositions are non-toxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates. The pharmaceutical compositions of the present invention may be administered parenterally in the form of injectable preparations. Pharmaceutical compositions for injection (i.e., intravenous injection) may be formulated using sterile solutions or any pharmaceutically acceptable liquid as the vehicle. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco's Modified Eagle's Medium (DMEM), alpha-modified eagle's medium (alpha-MEM), F-12 medium). Formulation methods are known in the art, see, for example, Banga (eds.) Therapeutic Peptides and Proteins: Formulation, processing and Delivery Systems (2 nd edition) Taylor & Francis Group, CRC Press (2006).

The pharmaceutical composition may be formed in unit dosage form as desired. The amount of active ingredient (e.g., one or more anti-FcRn antibodies of the invention (e.g., N022-N024, N026 and N027, preferably N027 and/or N024)) included in the pharmaceutical formulation is such as to provide a suitable dose within the specified range (e.g., a dose within the range of 0.01-500mg/kg body weight).

Route, dose and administration

Pharmaceutical compositions of the invention comprising one or more anti-FcRn antibodies (e.g., N022-N024, N026 and N027, preferably N027 and/or N024) as therapeutic proteins can be formulated for intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, intraarterial administration, intrathecal administration, or intraperitoneal administration. In particular, intravenous administration is preferred. The pharmaceutical composition may also be formulated for oral, nasal, spray, aerosol, rectal or vaginal administration or administration by the routes described. For injectable formulations, a variety of effective pharmaceutical carriers are known in the art.

The dosage of the pharmaceutical composition of the invention depends on a variety of factors including the route of administration, the disease to be treated and the physical characteristics of the subject, e.g., age, weight, overall health. Generally, the amount of an anti-FcRn antibody of the invention (e.g., any of N022-N024, N026 and N027, preferably N027 or N024) contained within a single dose may be an amount effective to prevent, delay or treat the disease without inducing significant toxicity. The pharmaceutical compositions of the invention may include a dose of an anti-FcRn antibody of the invention in the range of 0.01 to 500mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500mg/kg), in a more particular embodiment, from about 1 to about 100mg/kg, and in a more particular embodiment, from about 1 to about 50 mg/kg. The physician may adjust the dosage in accordance with conventional factors such as the degree of disease and various parameters of the subject. In addition, the physician may adjust the dosage depending on factors such as the age of pregnancy, preparation for delivery, weight gain of the woman and/or length of pregnancy.

In certain instances, the compositions and pharmaceutical compositions described herein are administered to a pregnant woman during pregnancy. In certain instances, the compositions and pharmaceutical compositions described herein are administered to a pregnant woman between about 5-25 weeks of gestation (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 weeks). In certain instances, administration of the compositions and pharmaceutical compositions is discontinued after about gestational age 34 (week 34) (e.g., after weeks 34, 35, 36, or 37). In certain instances, IVIG is administered to the pregnant woman after administration of the composition and pharmaceutical composition is discontinued. In certain instances, IVIG is administered about 3-15 days (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days) after administration of the composition and pharmaceutical composition is discontinued. In certain instances, the time of IVIG administration after cessation of administration of the compositions and pharmaceutical compositions is adjusted according to factors such as female weight gain. In certain instances, the compositions and pharmaceutical compositions described herein are administered for the first time after gestational age 12 (e.g., after 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30). In some cases, they are administered during pregnancy between gestational ages 14 to 26 (e.g., 14 to 25; 15 to 25; or 15 to 26, etc.). In some cases, they are administered during pregnancy between gestational ages 12 to 36 (e.g., 12 to 36; 12 to 35; 12 to 34; 13 to 36; 13 to 35; 13 to 34; 14 to 36; 14 to 35; 14 to 34; 15 to 36; 15 to 35; 15 to 34; 16 to 36; 16 to 35; or 16 to 34; etc.).

The pharmaceutical compositions are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount to result in amelioration or remediation of the symptoms. The pharmaceutical compositions are administered in a variety of dosage forms, for example, intravenous dosage forms, subcutaneous dosage forms, and oral dosage forms (e.g., ingestible solutions, drug release capsules). Typically, the dose of therapeutic protein is 1-100mg/kg, e.g., 1-50 mg/kg. A pharmaceutical composition of the invention containing an anti-FcRn antibody (e.g., any of N022-N024, N026, and N027, preferably N027 or N024) can be administered to a subject in need thereof, e.g., daily, weekly, monthly, semi-annually, once or more times per year (e.g., 1-10 or more times), or as medically needed. The dosage may be provided in a single dose or multiple dose regimen. The timing between administrations may decrease as the medical condition improves, or increase as the patient's health decreases.

Methods of treatment and indications

Blockade of human FcRn by the anti-FcRn antibodies of the invention may have therapeutic benefit in diseases driven by IgG autoantibodies. The ability of FcRn blockade to induce global IgG catabolism and clear multiple autoantibodies without interfering with serum albumin, small amounts of circulating metabolites or lipoproteins provides a means to expand the utility and accessibility of autoantibody removal strategies to patients with autoantibody driven autoimmune disease pathologies. Although the present invention is not bound by theory, the primary mechanism of action of the anti-FcRn antibodies of the present invention may be to increase the catabolism of pathogenic autoantibodies in the circulation and reduce autoantibody and immune complex deposition in affected tissues.

The pharmaceutical compositions and methods of the invention comprising one or more anti-FcRn antibodies (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) are useful for promoting catabolism and clearance of pathogenic antibodies (e.g., IgG and IgG autoantibodies) in a subject, reducing an immune response, e.g., blocking immune complex-based activation of an immune response in a subject, and treating an immunological disorder or disease in a subject. In particular, the pharmaceutical compositions and methods of the invention are useful for reducing or treating immune complex-based activation of acute or chronic immune responses. The acute immune response may be activated by a medical condition selected from: pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channelopathy, neuromyelitis optica, autoimmune hearing loss, Idiopathic Thrombocytopenic Purpura (ITP), autoimmune hemolytic anemia (AIHA), immune neutropenia, dilated cardiomyopathy and seropathy. The chronic immune response may be activated by a medical condition selected from: chronic Inflammatory Demyelinating Polyneuropathy (CIDP), systemic lupus, chronic forms of disorders indicative of acute treatment, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, and anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis.

In certain embodiments, the pharmaceutical compositions and methods of the invention are useful for alleviating or treating immune responses activated by autoimmune diseases. The autoimmune disease may be selected from: alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, Addison's disease, hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, Cupid syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, lupus disklike, idiopathic 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, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff man's syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis.

In particular, the pharmaceutical compositions and methods of the invention are useful for reducing or treating an immune response activated by systemic lupus erythematosus, antiphospholipid syndrome, pemphigus vulgaris/bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, myasthenia gravis, or neuromyelitis optica.

In certain embodiments, the pharmaceutical compositions and methods are useful for reducing the risk of developing anemia in a fetus. In certain embodiments, the pharmaceutical compositions and methods can be used to reduce or eliminate the need for IUT (intrauterine blood transfusion). In certain embodiments, the pharmaceutical compositions and methods may be used to reduce or eliminate the need for prenatal PP + IVIg, postnatal blood transfusion, IVIg, and/or phototherapy.

In certain embodiments, the pharmaceutical compositions and methods are useful for alleviating or treating an immune response activated by an autoimmune disease. The autoimmune disease may be selected from: alopecia areata, ankylosing spondylitis, antiphospholipid syndromes (e.g., antiphospholipid antibody syndrome), addison's disease, hemolytic anemia (e.g., warm autoimmune hemolytic anemia), autoimmune hepatitis, behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churus syndrome, cicatricial pemphigoid, localized scleroderma (scleroderma acridum syndrome), cold agglutinin disease, crohn's disease, dermatomyositis, discoid lupus, idiopathic mixed cryoglobulinemia, epidermolysis bullosa; fibromyalgia, fibromyositis, Graves ' disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, membranous nephropathy, Meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, glandular syndrome, polymyalgia rheumatica, polymyositis, primary hypogammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, Takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the pharmaceutical compositions and methods can be used to reduce or treat an immune response in a fetus or neonate. In certain embodiments, the pharmaceutical compositions and methods are useful for reducing or treating an immune response in a fetus or neonate in a pregnant mother that is activated by an autoimmune disease.

In particular, the pharmaceutical compositions and methods are useful for reducing or treating an immune response activated by systemic lupus erythematosus, antiphospholipid syndrome, pemphigus vulgaris/bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, myasthenia gravis, or neuromyelitis optica. In certain embodiments, the pharmaceutical compositions and methods can be used to reduce or treat an immune response in a fetus or neonate. In certain embodiments, the pharmaceutical compositions and methods are useful for reducing or treating an immune response in a pregnant mother that is activated by systemic lupus erythematosus, anti-phospholipid syndrome, pemphigus vulgaris/bullous pemphigoid, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, myasthenia gravis, or neuromyelitis optica.

The pharmaceutical compositions and methods may be used in the following methods: reducing pathogenic antibody trafficking (e.g., pathogenic maternal IgG antibody trafficking) through the placenta of a pregnant subject, increasing pathogenic antibody catabolism in a pregnant subject, and treating antibody-mediated enhancement of viral disease in a fetus or neonate, the method comprising administering to a pregnant subject an isolated antibody that binds human FcRn. Diseases and disorders that may benefit from FcRn inhibition by the isolated anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) include diseases and disorders in the fetus and/or neonate that result from transplacental transfer of maternal pathogenic antibodies (e.g., maternal pathogenic IgG antibodies) from a pregnant subject to the fetus and/or neonate.

In certain embodiments, diseases and disorders that may benefit from FcRn inhibition by the isolated anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) are fetal and neonatal alloimmune and/or autoimmune disorders. Fetal and neonatal alloimmune disorders are disorders of the fetus and/or neonate caused by pathogenic antibodies in a pregnant subject. Pathogenic antibodies in a pregnant subject may attack fetal antigens (e.g., antigens inherited by the fetus from the fetus' father), thereby causing the fetus or neonate to suffer from fetal and neonatal alloimmune and/or autoimmune disorders.

Examples of fetal and neonatal alloimmune and/or autoimmune disorders that can be treated by the methods described herein include, but are not limited to: fetal and neonatal alloimmune thrombocytopenia (FNAIT), fetal and neonatal Hemolytic Disease (HDFN), alloimmune pan-thrombocytopenia, congenital heart block, fetal joint contracture, neonatal myasthenia gravis, neonatal autoimmune hemolytic anemia, neonatal antiphospholipid 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 diabetes.

In certain embodiments, diseases and disorders that may benefit from FcRn inhibition by the isolated anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) are viral diseases, wherein the antibodies facilitate viral entry into the host cell, resulting in increased or enhanced infectivity in the cell, e.g., enhanced antibody-mediated viral disease. In certain embodiments, the antibody may bind to a viral surface protein, and the antibody/virus complex may bind to FcRn on the cell surface through the interaction between the antibody and the receptor. Subsequently, the antibody/virus complex may be internalized into the cell. For example, the virus may enter cells and/or tissues of the fetus by forming a complex with a maternal IgG antibody. The maternal IgG antibody can bind to the viral surface protein, while the IgG/virus complex can bind to FcRn in the synctrophoblast of the placenta, which then transfers the complex into the fetus.

In certain embodiments, the methods described herein can be used to treat enhancement of antibody-mediated viral diseases. In certain embodiments, viral diseases that are enhanced by pathogenic antibodies (e.g., pathogenic IgG antibodies) include, but are not limited to, viral diseases caused by: alpha virus 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 virus infection, respiratory syncytial virus infection, Hantaan virus infection, lattice virus infection, Sindbis virus infection, bunyavirus infection, West Nile river virus infection, Japanese encephalitis virus B infection, leporipox virus infection, lactate dehydrogenase-raised virus infection, Rio virus infection, rabies virus infection, foot and mouth disease virus infection, porcine reproductive and respiratory syndrome virus infection, simian hemorrhagic fever virus infection, equine infectious anemia virus infection, HIV infection with HIV infection, HIV infection, Caprine arthritis virus infection, African swine fever virus infection, lentivirus infection, BK milk-induced polycystic virus infection, ink accumulated valley encephalitis virus infection, enterovirus infection, cytomegalovirus infection, pneumovirus infection, measles virus infection and syphilis virus infection.

Blockade of human FcRn by anti-FcRn antibodies may have therapeutic benefits in diseases driven by pathogenic antibodies (e.g., pathogenic IgG antibodies). The ability of FcRn blockade to induce overall pathogenic antibody catabolism and to clear multiple pathogenic antibodies, small amounts of circulating metabolites or lipoproteins provides a means to expand the utility and accessibility of pathogenic antibody removal strategies to patients with pathogenic antibody driven autoimmune disease pathology. While not being bound by theory, the primary mechanism of action of anti-FcRn antibodies may be to increase catabolism of pathogenic antibodies in the circulation and reduce pathogenic antibody and immune complex deposition in affected tissues.

anti-FcRn antibodies described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) can be administered to a pregnant subject having or at risk of having a medical condition that activates an immune response in the pregnant subject. In certain embodiments, the pregnant subject may have had a medical condition in the past that activated an immune response in the pregnant subject. In certain embodiments, the pregnant subject has a history of having previously been pregnant with a fetus or neonate having a fetal and neonatal alloimmune and/or autoimmune disorder. In certain embodiments, an anti-FcRn antibody described herein can be administered to a pregnant subject if pathogenic antibodies associated with an immune disease are detected in a biological sample (e.g., a blood or urine sample) obtained from the pregnant subject. In certain embodiments, the pathogenic antibodies detected in the biological sample of the pregnant subject are known to bind to antigens from the fetus in the pregnant subject (e.g., antigens inherited by the fetus from the father of the fetus).

In certain embodiments, an anti-FcRn antibody described herein (e.g., N022-N024, N026, and N027, preferably N027 and/or N024) can be administered to a subject who is scheduled to be pregnant and has, or is at risk of having, a medical condition that activates an immune response in the pregnant subject, and/or who has, in the past, had a medical condition that activates an immune response in the pregnant subject. In certain embodiments, the subject is planning to become pregnant and has a history of having previously born a fetus or neonate with a fetal and neonatal alloimmune and/or autoimmune disorder. In certain embodiments, an anti-FcRn antibody described herein may be administered to a subject who is planning to become pregnant and whose biological sample contains pathogenic antibodies associated with an immune disease.

In certain embodiments, an anti-FcRn antibody described herein can be administered to a subject (e.g., a pregnant subject) to reduce or treat immune complex-based activation of an acute or chronic immune response in the subject. The acute immune response may be activated by a medical condition (e.g., pemphigus vulgaris, lupus nephritis, myasthenia gravis, guillain-barre syndrome, antibody-mediated rejection, catastrophic anti-phospholipid antibody syndrome, immune complex-mediated vasculitis, glomerulonephritis, channel disorders, neuromyelitis optica, autoimmune hearing loss, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, immune neutropenia, dilated cardiomyopathy, seropathy, chronic inflammatory demyelinating polyneuropathy, systemic lupus, reactive arthropathy, primary biliary cirrhosis, ulcerative colitis, or anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis).

In certain embodiments, an anti-FcRn antibody described herein can be administered to a subject (e.g., a pregnant subject) to reduce or treat an immune response activated by an autoimmune disease. The autoimmune disease can be, for example, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, addison's disease, hemolytic anemia, warm autoimmune hemolytic anemia (wAIHA), anti-factor antibodies, heparin-induced thrombocytopenia (HICT), sensitized grafts, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease-dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, churg-strauss syndrome, cicatricial pemphigoid, localized scleroderma (acral scleroderma), cold agglutinin disease, Crohn's disease, dermatomyositis, discoid lupus, idiopathic mixed cryoglobulinemia, fibromyalgia, fibromyositis, Graves' disease, Hashimoto 'thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, autoimmune lymphoproliferative disorders, Crohn's disease, Graves's disease, Hashimoto's thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome, idiopathic pulmonary fibrosis, IgA nephropathy, insulin dependent diabetes mellitus, juvenile arthritis, lichen planus, lupus, meniere's disease, mixed connective tissue disease, multiple sclerosis, pernicious anemia, polyarteritis nodosa, polychondritis, glandular syndrome, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, raynaud's phenomenon, reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sjogren's syndrome, stiff person syndrome, takayasu's arteritis, temporal arteritis, ulcerative colitis, uveitis, vitiligo or wegener's granulomatosis.

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FCRN antibodies and methods of use thereof

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