Cd8-specific binding proteins and methods of using the same

Abstract

Binding agents (e.g., antibodies or antigen-binding fragments thereof, binding proteins) that specifically bind to CDS, and their use in the treatment of diseases or disorders, such as an inflammatory disease or an autoimmune disease, are provided.

Description

This invention provides binders (e.g., antibodies or their antigen-binding fragments, binding proteins) that specifically bind to CDS, and their use in treating diseases or conditions such as inflammatory diseases or autoimmune diseases. Abstract

Claims

CLAIMS1. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:55; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:56;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:55; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:56; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:55; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:56.

2. A binding protein comprising: a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to DVQI TQS PS SLSASVGDRVT I TCRTSRS I SQYLAWYQQKPGKVPKLL IYSGS TLQSGVPSRFSGS GSGTDFTLT I S SLQPEDVATYYCQQHNENPLT FGXGTKVE IK (SEQ ID NO: 133), wherein: X = G or C.

3. The binding protein of claim 2, wherein the VL has CDRL1, CDRL2, and CDRL3 amino acid sequences according to RTSRSISQYLA (SEQ ID NO: 1), SGSTLQS (SEQ ID NO:2), and QQHNENPLT (SEQ ID NO:3).

4. The binding protein of claim 2, wherein the VL has CDRL1, CDRL2, and CDRL3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

5. A binding protein comprising: a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according toEVQLVE S GGGLVQPGGS LRLS CAAS GFNXiKDT Y I HFVRQAPGKX2LEW I GRJ DPANDNTL YASK X3QGKX4 T I SX5DTSKNTAYLQMNSLRAEDTAVYYCX6RGYGYYVFDHWGQGTLVTVS S (SEQ ID NO: 134), wherein:(a) Xi = I or F;(b) X2= G or C;(c) X3= F or V;(d) X4 = A or F;(e) X5 = A or R; and(f) Xe = G or A.

6. The binding protein of claim 5, wherein the VH has CDRH1, CDRH2, and CDRH3 amino acid sequences according to GFNIKDT (SEQ ID NO:4), RIDPANDNT (SEQ ID NO:5), and GYYVFDH (SEQ ID NO:6), respectively.

7. The binding protein of claim 5, wherein the VH has CDRH1, CDRH2, and CDRH3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

8. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to DVQI TQS PS SLSASVGDRVT I TCRTSRS I SQYLAWYQQKPGKVPKLL IYSGS TLQSGVPSRFSGS GSGTDFTLT I S SLQPEDVATYYCQQHNENPLT FGXGTKVE IK (SEQ ID NO: 133), wherein: X = G or C; and(b) a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according toEVQLVE S GGGLVQPGGS LRLS CAAS GFNXiKDT Y I HFVRQAPGKX2LEW I GRJ DPANDNTL YASK X3QGKX4 T I SX5DTSKNTAYLQMNSLRAEDTAVYYCX6RGYGYYVFDHWGQGTLVTVS S (SEQ ID NO: 144), wherein:(1) Xi = I or F;(2) X2= G or C;(3) X3= F or V;(4) X4= A or F;(5) X5 = A or R; and(6) X6= G or A.

9. The binding protein of claim 8, wherein the VL has CDRL1, CDRL2, and CDRL3 amino acid sequences according to RTSRSISQYLA (SEQ ID NO: 1), SGSTLQS (SEQ ID NO:2), and (QQHNENPLT) SEQ ID NO:3.

10. The binding protein of claim 8, wherein the VL has CDRL1, CDRL2, and CDRL3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

11. The binding protein of any one of claims 8-10, wherein the VH has CDRH1, CDRH2, and CDRH3 amino acid sequences according to GFNIKDT (SEQ ID NO:4), RIDPANDNT (SEQ ID NO:5), and GYYVFDH (SEQ ID NO:6), respectively.

12. The binding protein of any one of claims 8-10, wherein the VH has CDRH1, CDRH2, and CDRH3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

13. A binding protein compri sing :(a) CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3; and CDRH1, CDRH2, and CDRH3 amino acid sequences according to SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively; and(b) one or more of the following framework regions:(i) a light chain FR4 according to SEQ ID NO: 126;(ii) a heavy chain FR2 according to SEQ ID NO: 128;(iii) a heavy chain FR3 according to SEQ ID NO: 129;(iv) a heavy chain FR3 according to SEQ ID NO: 130;(v) a heavy chain FR3 according to SEQ ID NO: 131;(vi) a heavy chain FR3 according to SEQ ID NO: 132; and(vii) a heavy chain FR3 according to SEQ ID NO: 16 with one or more of the following substitutions: F6V, A10F, A14R, and G39A, according to the position of the amino acid within SEQ ID NO: 16.

14. A binding protein comprising:(a) CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3; and CDRH1, CDRH2, and CDRH3 amino acid sequences according to SEQ ID NO: 127, SEQ ID NO:5, and SEQ ID NO:6, respectively; and(b) one or more of the following framework regions:(i) a light chain FR4 according to SEQ ID NO: 126;(ii) a heavy chain FR2 according to SEQ ID NO: 128;(iii) a heavy chain FR3 according to SEQ ID NO: 129;(iv) a heavy chain FR3 according to SEQ ID NO: 130;(v) a heavy chain FR3 according to SEQ ID NO: 131;(vi) a heavy chain FR3 according to SEQ ID NO: 132;(vii) a heavy chain FR3 according to SEQ ID NO: 16 with one or more of the following substitutions: F6V, A10F, A14R, and G39A, according to the position of the amino acid within SEQ ID NO: 16;(viii) light chain framework regions of the VL according to SEQ ID NO: 7; and(ix) heavy chain framework regions of the VH according to SEQ ID NO: 8.

15. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 17; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 18;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 17; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 18; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO: 17; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 18.

16. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 19; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 20;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO: 19; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 20; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO: 19; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:20.

17. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:21; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 22;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:21; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 22; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:21; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:22.

18. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:23; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 24;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:23; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 24; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:23; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:24.

19. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:25; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 26;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:25; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 26; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:25; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:26.

20. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:27; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:28;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:27; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:28; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:27; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 28.

21. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:29; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 30;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:29; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 30; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:29; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:30.

22. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:31; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:32;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:31; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:32; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:31; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:32.

23. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:33; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:34;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:33; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:34; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:33; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:34.

24. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:35; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 36;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:35; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 36; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:35; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:36.

25. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:37; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:38;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:37; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:38; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:37; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 38.

26. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:39; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 40;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:39; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 40; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:39; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:40.

27. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:41; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 42;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:41; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 42; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:41; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:42.

28. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:43; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 44;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:43; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 44; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:43; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:44.

29. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:45; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 46;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:45; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 46; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:45; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:46.

30. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:47; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:48;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:47; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:48; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:47; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 48.

31. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:49; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 50;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:49; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 50; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:49; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 50.

32. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:51; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 52;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:51; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 52; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:51; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 52.

33. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:53; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 54;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:53; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 54; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:53; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 54.

34. A binding protein comprising:(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 57; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 58;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:57; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 58; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:57; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO: 58.

35. A binding protein compri sing :(a) a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 59; and a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 60;(b) a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:59; and a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO: 60; or(c) a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:59; and a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:60.

36. The binding protein of any one of claims 1-35, wherein the binding protein is an scFv.

37. The binding protein of any one of claims 1-36, wherein the VH and VL are connected by a linker polypeptide.

38. The binding protein of claim 37, wherein the linker polypeptide comprises or consists of the amino acid sequence according to SEQ ID NO:61.

39. The binding protein of any one of claims 36-38, further comprising a constant domain comprising the sequence according to SEQ ID NO:62.

40. The binding protein of any one of claims 1-39, further comprising a polypeptide that binds to a KIR protein.

41. The binding protein of any one of claims 1-39, further comprising a second polypeptide that comprises: CDRL1, CDRL2, and CDRL3 amino acid sequences according to RASQSVSSYLA (SEQ ID NO:63), DASNRAT (SEQ ID NO:64), and QQRSNWMYTF (SEQ ID NO:65), respectively.

42. The binding protein of claim 41, further comprising a third polypeptide that comprises: CDRH1, CDRH2, and CDRH3 amino acid sequences according to FYAIS (SEQ ID NO:66), GFIPIFGAANYAQKF (SEQ ID NO:67), and IPSGSYYYDYDMDV (SEQ ID NO:68), respectively.

43. The binding protein of any one of claims 1-39, further comprising:(a) a second polypeptide comprising a light chain variable region (VL) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 69; and a third polypeptide comprising a heavy chain variable region (VH) comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:70;(b) a second polypeptide comprising a light chain variable region (VL) comprising the amino acid sequence according to SEQ ID NO:69; and third polypeptide comprising a heavy chain variable region (VH) comprising the amino acid sequence according to SEQ ID NO:70; or(c) a second polypeptide comprising a light chain variable region (VL) consisting of the amino acid sequence according to SEQ ID NO:69; and third polypeptide comprising a heavy chain variable region (VH) consisting of the amino acid sequence according to SEQ ID NO:70.

44. The binding protein of claim 43, wherein the VL of the second polypeptide has CDRL1, CDRL2, and CDRL3 amino acid sequences according to SEQ ID NO: 63, SEQ ID NO:64, and SEQ ID NO:65, respectively; and the VH of the third polypeptide has CDRH1, CDRH2, and CDRH3 amino acid sequences according to SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO:68, respectively.

45. The binding protein of claim 43, wherein the VL of the second polypeptide has CDRL1, CDRL2, and CDRL3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

46. The binding protein of claim 43 or claim 45, wherein the VH of the third polypeptide has CDRH1, CDRH2, and CDRH3 amino acid sequences according to any one of Kabat, Chothia, EU, International Immunogenetics Information System (IMGT), and AHo.

47. A binding protein according to Table 3.

48. A binding protein comprising:(a) a polypeptide sequence comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:78, a polypeptide comprising at least 90% identity to the amino acid sequence according to SEQ ID NO:80, and a polypeptide comprising at least 90% identity to the amino acid sequence according to SEQ ID NO: 120;(b) a polypeptide sequence comprising the amino acid sequence according to SEQ ID NO:78, a polypeptide comprising the amino acid sequence according to SEQ ID NO:80, and a polypeptide comprising the amino acid sequence according to SEQ ID NO: 120; or(c) a polypeptide sequence consisting of the amino acid sequence according to SEQ ID NO:78, a polypeptide consisting of the amino acid sequence according to SEQ ID NO:80, and a polypeptide consisting of the amino acid sequence according to SEQ ID NO: 120.

49. A pharmaceutical composition comprising the binding protein of any one of claims 1-48 and a pharmaceutically acceptable carrier.

50. A nucleic acid encoding the binding protein of any one of claims 1-48.

51. A nucleic acid molecule comprising SEQ ID NOs: 139, 141, and 141.

52. A nucleic acid molecule comprising SEQ ID NOs: 138, 140, and 142.

53. A vector comprising the nucleic acid of any one of claims claim 50-52.

54. A cell line comprising the vector of claim 53.

55. A method of treating a disease, comprising administering the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49 to a subject in need thereof.

56. A method of preventing a disease, comprising administering the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49 to a subject in need thereof.

57. The method of claim 55 or claim 56, wherein the disease is an inflammatory disease or an autoimmune disease.

58. The method of claim 55 or claim 66, wherein the disease is a CD4+ T cell-driven inflammatory disease or autoimmune disease.

59. The method of claim 57 or claim 58, wherein the number or activity of pathogenic immune cells in the subject is decreased.

60. The method of any one of claims 55-59, wherein the disease is a rheumatological disorder, fibrotic disorder, gastrointestinal disorder, endocrinological disorder, neurological disorder, or skin disorder.

61. The method of any one of claims 57-59, wherein the autoimmune disease is celiac disease, Crohn's disease, juvenile idiopathic arthritis, inflammatory bowel disease (IBD), insulindependent diabetes mellitus (IDDM or type 1 diabetes), lupus, lupus nephritis, cutaneous lupus, discoid lupus, myasthenia gravis, myocarditis, multiple sclerosis (MS), pemphigus / pemphigoid, rheumatoid arthritis (RA), scleroderma / systemic sclerosis, Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), or ulcerative colitis.

62. The method of any one of claims 57-59, wherein the autoimmune disease is celiac disease.

63. The method of any one of claims 57-59, wherein the autoimmune disease isCrohn's disease.

64. The method of any one of claims 57-59, wherein the autoimmune disease is inflammatory bowel disease (IBD).

65. The method of any one of claims 57-59, wherein the autoimmune disease is ulcerative colitis.

66. The method of any one of claims 55-59, wherein the disease is graft versus host disease (GVHD).

67. The method of any one of claims 55-59, wherein the disease is type 1 diabetes.

68. A method of suppressing an immune response mediated by pathogenic immune cells, comprising contacting CD8+ T regulatory cells (Tregs) with the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49, thereby activating or stimulating CD8+ Tregs.

69. A method of suppressing an immune response to an antigen, such as an autoantigen, comprising administering to a subject in need thereof the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49, thereby activating or stimulating CD8+ Tregs, whereby the number or activity of pathogenic immune cells that are responsive to the antigen or autoantigen is decreased.

70. The method of claim 68 or claim 69, wherein the pathogenic immune cells are autoreactive CD4+ T cells, autoantibody producing B cells, or self antigen presenting dendritic cells.

71. The method of claim 68 or claim 69, wherein the pathogenic immune cells are autoreactive CD4+ T cells.

72. The method of any one of claims 68-71, wherein the CD8+ Tregs are CD8+KIR+Tregs.

73. The method of any one of claims 68-72, wherein the activated CD8+ Tregs are administered to the subject or to a second subject.

74. The method of any one of claims 68-73, wherein the subject and / or the second subject has an inflammatory or autoimmune disease.

75. A method of suppressing, reducing, or preventing an immune response to a viral vector in a subject, the method comprising administering to the subject the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49.

76. The method of claim 75, wherein the viral vector has been, is, or will be administered to the subject and the immune response to the viral vector is induced by administration of the viral vector to the subject.

77. The method of any one of claims 55-76, wherein the binding protein is administered in a dose of from about 0.01 mg / kg to about 20 mg / kg.

78. The method of claim 77, wherein the binding protein is administered in a dose of from about 0.01 mg / kg to about 10 mg / kg.

79. The method of claim 77, wherein the binding protein is administered in a dose of from about 0.05 mg / kg to about 0.1 mg / kg.

80. The method of claim 77, wherein the binding protein is administered in a dose of from about 0.5 mg / kg to about 1.0 mg / kg.

81. The method of claim 77, wherein the binding protein is administered in a dose of from 0.05 mg / kg to 0.1 mg / kg.

82. The method of claim 77, wherein the binding protein is administered in a dose of from 0.5 mg / kg to 1.0 mg / kg.

83. The method of claim 77, wherein the binding protein is administered in a dose up to about 10 mg / kg.

84. The method of claim 77, wherein the binding protein is administered in a dose up to 10 mg / kg.

85. The method of claim 77, wherein the binding protein is administered in a dose of about 10 mg / kg.

86. The method of claim 77, wherein the binding protein is administered in a dose of 10 mg / kg.

87. Use of the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49 in the method of any one of claims 55-86.

88. The binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49 for use in the method of any one of claims 55-86.

89. Use of the binding protein of any one of claims 1-48 or the pharmaceutical composition of claim 49 in the manufacture of a medicament for use in the method of any one of claims 55-86.

90. A method of treating celiac disease in a subject in need thereof, comprising administering the binding protein of claim 48 to the subject.

91. A method of preventing celiac disease in a subject in need thereof, comprising administering the binding protein of claim 48 to the subject.

92. A method of treating celiac disease in a subject in need thereof, comprising administering the pharmaceutical composition of claim 49 to the subject.

93. A method of preventing celiac disease in a subject in need thereof, comprising administering the pharmaceutical composition of claim 49 to the subject.

94. A method of treating type 1 diabetes in a subject in need thereof, comprising administering the binding protein of claim 48 to the subject.

95. A method of preventing type 1 diabetes in a subject in need thereof, comprising administering the binding protein of claim 48 to the subject.

96. A method of treating type 1 diabetes in a subject in need thereof, comprising administering the pharmaceutical composition of claim 49 to the subject.

97. A method of preventing type 1 diabetes in a subject in need thereof, comprising administering the pharmaceutical composition of claim 49 to the subject.

98. Use of the binding protein of claim 48 or the pharmaceutical composition of claim 49 in the method of any one of claims 90-97.

99. The binding protein of claim 48 or the pharmaceutical composition of claim 49 for use in the method of any one of claims 90-97.

100. Use of the binding protein of claim 48 or the pharmaceutical composition of claim 49 in the manufacture of a medicament for use in the method of any one of claims 90-97.

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