FcRn-Binding Polypeptides and Uses Thereof

1 . A polypeptide comprising at least one VHH domain that binds FcRn, wherein at least one VHH domain that binds FcRn comprises a CDR1 sequence selected from SEQ ID NOs: 80-81, a CDR2 sequence selected from SEQ ID NOs: 83-84, and a CDR3 sequence of SEQ ID NO: 85.

2 . The polypeptide of claim 1 , wherein each VHH domain that binds FcRn comprises, independently, a CDR1 sequence selected from SEQ ID NOs: 80-81, a CDR2 sequence selected from SEQ ID NOs: 83-84, and a CDR3 sequence of SEQ ID NO: 85.

3 . The polypeptide of claim 1 or claim 2 , wherein at least one VHH domain that binds FcRn comprises CDR1, CDR2, and CDR3 sequences selected from: SEQ ID NOs: 80, 83, and 85 SEQ ID NOs: 81, 83, and 85; and SEQ ID NOs: 81, 84, and 85.

4 . The polypeptide of claim 3 , wherein each VHH domain that binds FcRn comprises, independently, CDR1, CDR2, and CDR3 sequences selected from: SEQ ID NOs: 80, 83, and 85 SEQ ID NOs: 81, 83, and 85; and SEQ ID NOs: 81, 84, and 85.

5 . The polypeptide of any one of claims 1-4 , wherein at least one VHH domain that binds FcRn is humanized.

6 . The polypeptide of claim 5 , wherein each VHH domain that binds FcRn is humanized.

7 . The polypeptide of any one of claims 1-6 , wherein at least one VHH domain that binds FcRn comprises a sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence selected from SEQ ID NOs: 86-93.

8 . The polypeptide of claim 7 , wherein each VHH domain that binds FcRn comprises a sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence selected from SEQ ID NOs: 86-93.

9 . The polypeptide of any one of claims 1-7 , wherein at least one VHH domain that binds FcRn comprises a sequence selected from SEQ ID NOs: 86-93.

10 . The polypeptide of any one of claims 1-9 , wherein each VHH domain that binds FcRn comprises a sequence selected from SEQ ID NOs: 86-93.

11 . The polypeptide of any one of claims 1-10 , wherein at least one VHH domain that binds FcRn binds human FcRn with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

12 . The polypeptide of any one of claims 1-11 , wherein each VHH domain that binds FcRn binds human FcRn with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

13 . The polypeptide of any one of claims 1-12 , wherein at least one VHH domain that binds FcRn binds human FcRn at pH 6 and at pH 7.4.

14 . The polypeptide of any one of claims 1-13 , wherein each VHH domain that binds FcRn binds human FcRn at pH 6 and at pH 7.4.

15 . The polypeptide of any one of claims 1-14 , wherein at least one VHH domain that binds FcRn blocks binding of human IgG to human FcRn.

16 . The polypeptide of any one of claims 1-15 , wherein each VHH domain that binds FcRn blocks binding of human IgG to human FcRn.

17 . The polypeptide of any one of claims 1-16 , wherein the polypeptide comprises at least one VHH domain that binds albumin.

18 . The polypeptide of claim 17 , wherein at least one VHH domain that binds albumin comprises a CDR1 sequence selected from SEQ ID NOs: 5-8, a CDR2 sequence selected from SEQ ID NOs: 9-21, and a CDR3 sequence of SEQ ID NO: 22.

19 . That polypeptide of claim 17 , wherein each VHH domain that binds albumin comprises, independently, a CDR1 sequence selected from SEQ ID NOs: 5-8, a CDR2 sequence selected from SEQ ID NOs: 9-21, and a CDR3 sequence of SEQ ID NO: 22.

20 . The polypeptide of claim 17 or claim 18 , wherein at least one VHH domain that binds albumin comprises CDR1, CDR2, and CDR3 sequences selected from: SEQ ID NOs: 5, 9, and 22; SEQ ID NOs: 5, 10, and 22; SEQ ID NOs: 5, 11, and 22; SEQ ID NOs: 5, 12, and 22; SEQ ID NOs: 5, 13, and 22; SEQ ID NOs: 5, 14, and 22; SEQ ID NOs: 5, 15, and 22; SEQ ID NOs: 6, 15, and 22; SEQ ID NOs: 7, 15, and 22; SEQ ID NOs: 8, 15, and 22; SEQ ID NOs: 6, 16, and 22; SEQ ID NOs: 6, 17, and 22; SEQ ID NOs: 6, 18, and 22; SEQ ID NOs: 6, 19, and 22; SEQ ID NOs: 6, 20, and 22; and SEQ ID NOs: 6, 21, and 22.

21 . The polypeptide of claim 17 or claim 18 , wherein each VHH domain that binds albumin comprises, independently, CDR1, CDR2, and CDR3 sequences selected from: SEQ ID NOs: 5, 9, and 22; SEQ ID NOs: 5, 10, and 22; SEQ ID NOs: 5, 11, and 22; SEQ ID NOs: 5, 12, and 22; SEQ ID NOs: 5, 13, and 22; SEQ ID NOs: 5, 14, and 22; SEQ ID NOs: 5, 15, and 22; SEQ ID NOs: 6, 15, and 22; SEQ ID NOs: 7, 15, and 22; SEQ ID NOs: 8, 15, and 22; SEQ ID NOs: 6, 16, and 22; SEQ ID NOs: 6, 17, and 22; SEQ ID NOs: 6, 18, and 22; SEQ ID NOs: 6, 19, and 22; SEQ ID NOs: 6, 20, and 22; and SEQ ID NOs: 6, 21, and 22.

22 . The polypeptide of any one of claims 17-21 , wherein at least one VHH domain that binds albumin is humanized.

23 . The polypeptide of claim 22 , wherein each VHH domain that binds albumin is humanized.

24 . The polypeptide of any one of claims 17-23 , wherein at least one VHH domain that binds albumin comprises a sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence selected from SEQ ID NOs: 23-43 and 97-100.

25 . The polypeptide of any one of claims 17-23 , wherein each VHH domain that binds albumin comprises a sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence selected from SEQ ID NOs: 23-43 and 97-100.

26 . The polypeptide of any one of claims 17-23 , wherein at least one VHH domain that binds albumin comprises a sequence selected from SEQ ID NOs: 23-43 and 97-100.

27 . The polypeptide of any one of claims 17-23 , wherein each VHH domain that binds albumin comprises a sequence selected from SEQ ID NOs: 23-43 and 97-100.

28 . The polypeptide of any one of claims 17-27 , wherein the polypeptide comprises a sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence selected from SEQ ID NOs: 69-77.

29 . The polypeptide of any one of claims 17-27 , wherein the polypeptide comprises a sequence selected from SEQ ID NOs: 69-77.

30 . The polypeptide of any one of claims 17-29 , wherein at least one VHH domain that binds albumin binds human albumin and at least one albumin selected from cynomolgus monkey, mouse, and rat albumin.

31 . The polypeptide of any one of claims 17-29 , wherein each VHH domain that binds albumin binds human albumin and at least one albumin selected from cynomolgus monkey, mouse, and rat albumin.

32 . The polypeptide of any one of claims 17-29 , wherein at least one VHH domain that binds albumin binds human, cynomolgus monkey, mouse, and rat albumin.

33 . The polypeptide of any one of claims 17-29 , wherein each VHH domain that binds albumin binds human, cynomolgus monkey, mouse, and rat albumin.

34 . The polypeptide of any one of claims 17-33 , wherein at least one VHH domain that binds albumin binds human albumin with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

35 . The polypeptide of any one of claims 17-34 , wherein at least one VHH domain that binds albumin binds each of human, cynomolgus monkey, mouse, and rat albumin with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

36 . The polypeptide of any one of claims 17-35 , wherein each VHH domain that binds albumin binds human albumin with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

37 . The polypeptide of any one of claims 17 - 63 , wherein each VHH domain that binds albumin binds each of human, cynomolgus monkey, mouse, and rat albumin with an affinity of less than 5 nM, less than 2 nM, less than 1 nM, or less than 0.5 nM.

38 . The polypeptide of any one of claims 17-37 , wherein the each VHH domain that binds albumin does not bind albumin domain 3.

39 . The polypeptide of any one of claims 17-38 , wherein the each VHH domain that binds albumin does not interfere with binding of albumin to FcRn.

40 . The polypeptide of any one of the preceding claims , wherein the polypeptide comprises at least two, at least three, or at least four VHH domains that bind FcRn and at least one VHH domain that binds albumin.

41 . The polypeptide of claim 40 , wherein the polypeptide comprises two, three, or four VHH domains that bind FcRn and one VHH domain that binds albumin.

42 . The polypeptide of any one of claims 1-41 , wherein the polypeptide comprises at least one binding domain that binds a protein other than albumin or FcRn.

43 . The polypeptide of claim 42 , wherein at least one binding domain that binds a protein other than albumin or FcRn is a VHH.

44 . The polypeptide of claim 43 , wherein each binding domain that binds a protein other than albumin or FcRn is a VHH.

45 . The polypeptide of claim 42 or claim 43 , wherein at least one binding domain that binds a protein other than albumin or FcRn comprises a heavy chain variable region and a light chain variable region.

46 . The polypeptide of claim 45 , wherein each binding domain that binds a protein other than albumin or FcRn comprises a heavy chain variable region and a light chain variable region.

47 . The polypeptide of any one of claims 42-46 , wherein at least one binding domain that binds a protein other than albumin or FcRn is a binding domain of a therapeutic antibody.

48 . The polypeptide of claim 47 , wherein each binding domain that binds a protein other than albumin is a binding domain of a therapeutic antibody.

49 . The polypeptide of claim 47 or claim 48 , wherein the therapeutic antibody is useful for treating a disease or disorder selected from an autoimmune disease or disorder, an inflammatory disease or disorder, an infection, and cancer.

50 . The polypeptide of any one of claims 1-41 , wherein the polypeptide comprises an amino acid sequence of a therapeutic protein.

51 . The polypeptide of claim 50 , wherein the therapeutic protein is useful for treating a disease or disorder selected from an autoimmune disease or disorder, an inflammatory disease or disorder, an infection, and cancer.

52 . The polypeptide of any one of the preceding claims , wherein the half-life of the polypeptide is greater than the half-life of the same polypeptide lacking a VHH domain that binds albumin.

53 . A pharmaceutical composition comprising the polypeptide of any one of claims 1-52 and a pharmaceutically acceptable carrier.

54 . An isolated nucleic acid that encodes the polypeptide of any one of claims 1-52 .

55 . A vector comprising the nucleic acid of claim 54 .

56 . A host cell comprising the nucleic acid of claim 54 or the vector of claim 55 .

57 . A host cell that expresses the polypeptide of any one of claims 1-52 .

58 . A method of producing the polypeptide of any one of claims 1-52 , comprising incubating the host cell of claim 56 or claim 57 under conditions suitable for expression of the polypeptide.

59 . The method of claim 58 , further comprising isolating the antibody or polypeptide.

60 . A method comprising administering to a subject the polypeptide of any one of claims 1-52 , or the pharmaceutical composition of claim 53 .

61 . A method of treating a disease or disorder comprising administering to a subject with the disease or disorder a pharmaceutically effective amount of the polypeptide of any one of claims 1-52 , or the pharmaceutical composition of claim 53 .

62 . The method of claim 61 , wherein the disease or disorder is selected from an autoimmune disease or disorder, an inflammatory disease or disorder, an infection, and cancer.

63 . The method of claim 61 or claim 62 , wherein the disease or disorder is an autoantibody-mediated disease or disorder.

64 . The method of any one of claims 61-63 , wherein the disease or disorder is pemphigus vulgaris, lupus nephritis, myasthenia gravis, Guillain-Barré syndrome, antibody-mediated rejection, antiphospholipid antibody syndrome, chronic inflammatory demyelinating polyneuropathy, immune complex-mediated vasculitis, glomerulitis, a channelopathy, neuromyelitis optica, autoimmune encephalitis, autoimmune Grave's disease, idiopathic thrombocytopenia purpura, autoimmune haemolytic anaemia, immune neutropenia, dilated cardiomyopathy, or serum sickness.

65 . The method of any one of claims 60-64 , wherein the polypeptide is administered subcutaneously.