ISOFORM-SELECTIVE ANTIBODIES TO TGF-BETA AND METHODS OF THEIR USE

Claims

1. An isolated TGFβ2 / 3 antibody, wherein the antibody selectively neutralizes TGFβ2 and TGFβ3, and wherein the antibody is characterized by one or more of the following properties: (a) the selectivity of the TGFβ2 / 3 antibody for TGFβ2 and TGFβ3 over human TGFβ1 for selective neutralization is achieved through direct contact of the antigen-binding domain of the antibody with the amino acid residue E373 of TGFβ2 or TGFβ3 (human TGFβ2 numbering); (b) the TGFβ2 / 3 antibody neutralizes TGFβ2 and / or TGFβ3 via an allosteric mechanism; (c) an antibody to TGFβ2 / 3 induces a conformational change in the TGFβ2 and / or TGFβ3 homodimer; (d) an anti-TGFβ2 / 3 antibody induces a conformational change in a TGFβ2 and / or TGFβ3 homodimer, wherein the conformational change involves a co-compression of the two monomers by several degrees; (d) the anti-TGFβ2 / 3 antibody is a bivalent antibody or a monovalent antibody; (e) an anti-TGFβ2 / 3 antibody comprises (i) a heavy chain CDR comprising CDR-H1, -H2, and -H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 10, CDR-H2 has the amino acid sequence of SEQ ID NO: 11, and CDR-H3 has the amino acid sequence of SEQ ID NO: 12; and (ii) a light chain CDR comprising CDR-L1, -L2, and -L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 13; CDR-L2 has the amino acid sequence of SEQ ID NO: 14, and CDR-L3 has the amino acid sequence of SEQ ID NO: 15; (g) the anti-TGFβ2 / 3 antibody specifically binds to a TGFβ2 homodimer, wherein the TGFβ2 homodimer has a first and a second TGFβ2 monomer, and wherein the anti-TGFβ2 / 3 antibody comprises an antigen-binding domain that directly contacts (i) amino acid residues V313, Q314, D315, R320, L322, Y323, R328, D329, F345, and A347 of the first TGFβ2 monomer, and (ii) amino acid residues N368, T369, I370, N371, P372, E373, A374, S375, A376, and S377 of the second TGFβ2 monomer (human TGFβ2 numbering); (i) an anti-TGFβ2 / 3 antibody as in (g), wherein the antigen-binding domain is within 5 angstroms of amino acid residues of TGFβ2 and / or TGFβ3; (k) in which the TGFβ2 / 3 antibody specifically binds to the same epitope on TGFβ3 as in (g); and (l) The TGFβ2 / 3 antibody does not neutralize TGFβ2 and / or TGFβ3 in a monovalent form.

2. The TGFβ2 / 3 antibody of claim 1, wherein the antibody comprises a VH amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 81, 83, 86-88, 93-100 and 102-105.

3. The TGFβ2 / 3 antibody according to any one of claims 1, 2, wherein the antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NO: 27, 81, 83, 86-88, 93-100 and 102-105.

4. The TGFβ2 / 3 antibody of any one of claims 1 to 3, wherein the antibody comprises a complete amino acid sequence of an H chain having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 107, 109, 112-114, and 119-130.

5. The TGFβ2 / 3 antibody of any one of claims 1 to 4, wherein the antibody comprises a VL amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 80, 82, 84, 85, 89-92, and 101.

6. The TGFβ2 / 3 antibody of any one of claims 1-5, wherein the antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NO: 26, 80, 82, 84, 85, 89-92 and 101.

7. The TGFβ2 / 3 antibody of any one of claims 1 to 6, wherein the antibody comprises a complete amino acid sequence of an L chain having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 106, 108, 110, 111, 115-118, and 186.

8. The TGFβ2 / 3 antibody of any one of claims 1-7, wherein the antibody comprises a complete amino acid sequence of an L chain selected from the group consisting of SEQ ID NO: 32, 106, 108, 110, 111, 115-118 and 186.

9. The TGFβ2 / 3 antibody of claim 1, wherein the antibody comprises a VH / VL pair, wherein the VH / VL pair comprises amino acid sequences (respectively) selected from the group consisting of SEQ ID NO: 27 / 26 (rabbit 4A11), SEQ ID NO: 81 / 80 (v1), SEQ ID NO: 81 / 82 (v2), SEQ ID NO: 83 / 80 (v3), SEQ ID NO: 83 / 82 (v4), SEQ ID NO: 81 / 84 (v5), SEQ ID NO: 81 / 85 (v6), SEQ ID NO: 83 / 84 (v7), SEQ ID NO: 86 / 84 (v7 / 1), SEQ ID NO: 87 / 84 (v7.2), SEQ ID NO: 88 / 84 (v7.3), SEQ ID NO: 83 / 89 (v7.4), SEQ ID NO: 83 / 90 (v7.5), SEQ ID NO: 83 / 91 (v7.6), SEQ ID NO: 83 / 92 (v7.7), SEQ ID NO: 93 / 84 (v7.8), SEQ ID NO: 94 / 84 (v7.9), SEQ ID NO: 95 / 84 (v7.10), SEQ ID NO: 96 / 84 (v7.11), SEQ ID NO: 97 / 84 (v7.12), SEQ ID NO: 98 / 84 (v7.13), SEQ ID NO: 99 / 84 (v7.14), SEQ ID NO: 100 / 84 (v7.15), SEQ ID NO: 102 / 101 (v7.16), SEQ ID NO: 103 / 101 (v7.17), SEQ ID NO: 104 / 101 (v7.18), SEQ ID NO: 105 / 101 (v7.19) and SEQ ID NO: 83 / 85 (v8).

10. The TGFβ2 / 3 antibody of claim 1, wherein the antibody comprises a complete pair of H / L chains, wherein the complete pair of H / L chains comprises amino acid sequences (respectively) selected from the group consisting of SEQ ID NO: 32 / 33 (rabbit 4A11), SEQ ID NO: 107 / 106 (v1), SEQ ID NO: 107 / 108 (v2), SEQ ID NO: 109 / 106 (v3), SEQ ID NO: 109 / 108 (v4), SEQ ID NO: 107 / 110 (v5), SEQ ID NO: 107 / 111 (v6), SEQ ID NO: 109 / 110 (v7), SEQ ID NO: 112 / 110 (v7.1), SEQ ID NO: 113 / 110 (v7.2), SEQ ID NO: 114 / 110 (v7.3), SEQ ID NO: 114 / 115 (v7.4), SEQ ID NO: 114 / 116 (v7.5), SEQ ID NO: 114 / 117 (v7.6), SEQ ID NO: 114 / 118 (v7.7), SEQ ID NO: 119 / 110 (v7.8), SEQ ID NO: 120 / 110 (v7.9), SEQ ID NO: 121 / 110 (v7.10), SEQ ID NO: 122 / 110 (v7.11), SEQ ID NO: 123 / 110 (v7.12), SEQ ID NO: 124 / 110 (v7.13), SEQ ID NO: 125 / 110 (v7.14), SEQ ID NO: 126 / 110 (v7.15), SEQ ID NO: 127 / 186 (v7.16), SEQ ID NO: 128 / 186 (v7.17), SEQ ID NO: 129 / 186 (v7.18), SEQ ID NO: 130 / 186 (v7.19) and SEQ ID NO: 114 / 111 (v8).

11. The TGFβ2 / 3 antibody of claim 1, wherein the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 26, comprising one or more framework region modifications selected from the group consisting of: 2A or 2I, 4L, 36F or 36Y, 43P or 43A, and 58V or 58I.

12. The TGFβ2 / 3 antibody of claim 1, wherein the VL comprises a set of framework region modifications selected from the group consisting of: (i) 2A and 4L in FR1 and 36F in FR2 (h4A11.v1 and h4A11.v3); (ii) 2A and 4L in FR1 and 36F and 43P in FR2 (h4A11.v2 and h4A11.v4); (iii) 2A in FR1, 36F and 43P in FR2 and 58V in FR3 (h4A11.v5 and h4A11.v7); (iv) 2A and 4L in FR1 and 36F in FR2 (h4A11.v6 and h4A11.v8); (v) 21 in FR1 (h4A11.v7.4); (vi) 36Y in FR2 (h4A11.v7.5); (vii) 43A in FR2 (h4Al 1.v7.6); (viii) 581 in FR3 (h4A11.v7.7); and (ix) 21 in FR1, 43A in FR2, 581 in FR3 (h4A11.v7.16-19).

13. The TGFβ2 / 3 antibody of claim 1, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 27, comprising one or more framework region modifications selected from the group consisting of: deletion 1E, 2Q or 2V, 24V, 37V or 37I, 48I, 49G, 67F or 67V, 71K or 71V, 73S or 73T, deletion 75K and 76N, 78V or 78F, 91F or 91Y, 105P or 105Q.

14. The TGFβ2 / 3 antibody of claim 1 or 13, wherein the VL comprises a set of framework region modifications selected from the group consisting of: (i) 2Q and 24V in FR1, 48I and 49G in FR2, 71K, 73S, 78V and 91F in FR3 and 105P in FR4 (h4A11.v1, h4A11.v2, h4A11.v5, h4A11.v6); (ii) 2Q in FR1, 37V in FR2, 67F, 71K, 73S, 78V and 91F in FR3 and 105P in FR4 (h4A11.v3, h4A11.v4, h4A11.v7, h4A11.v8); (iii) deletion 1E in FR1 (h4A11.v7.1); (iv) deletions 75K and 76N in FR3 (h4A11.v7.2); (v) deletions 1E in FR1 and 75K76N in FR3 (h4A11.v7.3); (vi) 2V in FR1 (h4A11.v7.8); (vi) 37I in FR2 (h4A11.v7.9); (vii) 67V in FR3 (h4A 11.v7.10); (viii) 71V in FR3 (h4A11.v7.11); (ix) 73T in FR3 (h4A11.v7.12); (x) 78F in FR3 (h4A11.v7.13); (xi) 91Y in FR3 (h4A11.v7.14); (xii) 105Q in FR4 (h4A11.v7.15); (xiii) 2V in FR1, 37I in FR2, 67V, 73T, 78F in FR3, 105Q in FR4 (h4A11.v7.16); (xiv) 2V in FR1, 37I in FR2, 67V, 73T, 91Y in FR3, 105Q in FR4 (h4A11.v7.17); (xv) 2V in FR1, 37I in FR2, 67V, 73T in FR3, 105Q in FR4 (h4A11,v7.18); and (xvi) 2V in FR1, 37I in FR2, 67V, 73T, deletions 75K and 76N in FR3, 105Q in FR4 (h4A11.v7.19).

15. An isolated antibody to TGFβ2, wherein the antibody comprises: (a) heavy chain CDRs comprising CDR-H1, -H2 and -H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 16, CDR-H2 has the amino acid sequence of SEQ ID NO: 17, and CDR -H3 has the amino acid sequence of SEQ ID NO: 18; and (b) light chain CDRs comprising CDR-L1, -L2 and -L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 19; CDR-L2 has the amino acid sequence of SEQ ID NO: 20, and CDR-L3 has the amino acid sequence of SEQ ID NO:

21.

16. The TGFβ2 antibody of claim 15, wherein the antibody selectively neutralizes TGFβ2.

17. The antibody to TGFβ2 according to claim 16, wherein the antibody: (a) has reduced toxicity compared to the antibody 1D11 to all types of TGFβ; (b) has reduced toxicity in rodents compared to the 1D11 antibody to all TGFβ types; (c) has reduced toxicity compared to the small molecule inhibitor of all TGFβ types galunisertib; and / or (g) has reduced toxicity in rodents compared to the small molecule inhibitor of all TGFβ types galunisertib.

18. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a VH amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132 and 138-142.

19. The TGFβ2 antibody of claim 18, wherein the antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142.

20. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a complete amino acid sequence of an H chain having at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 146 and 152-156.

21. The TGFβ2 antibody of claim 20, wherein the antibody comprises a complete amino acid sequence of an H chain selected from the group consisting of SEQ ID NOs: 31, 146, and 152-156.

22. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a VL amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 131, 133-137, 143, and 144.

23. The TGFβ2 antibody of claim 22, wherein the antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NO: 24, 131, 133-137, 143 and 144.

24. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a complete amino acid sequence of an L chain having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 145, 147-151, 157, and 158.

25. The TGFβ2 antibody of claim 24, wherein the antibody comprises a complete amino acid sequence of an L chain selected from the group consisting of SEQ ID NO: 30, 145, 147-151, 157 and 158.

26. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a VH / VL pair, wherein the VH / VL pair comprises amino acid sequences selected from the group consisting of SEQ ID NO: 25 / 24 (rabbit 6F12), SEQ ID NO: 132 / 131 (v1), SEQ ID NO: 132 / 133 (v1.1), SEQ ID NO: 132 / 134 (v1.2), SEQ ID NO: 132 / 135 (v1.3), SEQ ID NO: 132 / 136 (v1.4), SEQ ID NO: 132 / 137 (v1.5), SEQ ID NO: 138 / 131 (v1.6), SEQ ID NO: 139 / 131 (v1.7), SEQ ID NO: 140 / 131 (v1.8), SEQ ID NO: 141 / 131 (v1.9), SEQ ID NO: 142 / 131 (v2), SEQ ID NO: 132 / 143 (v3) and SEQ ID NO: 142 / 144 (v4).

27. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a complete pair of H / L chains, wherein the complete pair of H / L chains comprises amino acid sequences selected from the group consisting of SEQ ID NO: 31 / 30 (rabbit 6F12), SEQ ID NO: 146 / 145 (v1), SEQ ID NO: 146 / 147 (v1.1), SEQ ID NO: 146 / 148 (v1.2), SEQ ID NO: 146 / 149 (v1.3), SEQ ID NO: 146 / 150 (v1.4), SEQ ID NO: 146 / 151 (v1.5), SEQ ID NO: 152 / 145 (v1.6), SEQ ID NO: 153 / 145 (v1.7), SEQ ID NO: 154 / 145 (v1.8), SEQ ID NO: 155 / 145 (v1.9), SEQ ID NO: 156 / 145 (v2), SEQ ID NO: 146 / 157 (v3) and SEQ ID NO: 156 / 158 (v4).

28. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 24, comprising one or more framework region mutations selected from the group consisting of 43S or 43A, 66G, 69T, 71F and 87Y.

29. The TGFβ2 antibody of claim 28, wherein the VL comprises a set of framework region mutations selected from the group consisting of: (i) 43S in FR2 and 66E, 69P, 71Y and 87F in FR3 (h6F12.v1 and h6F12.v2); (ii) 43S in FR2 and 58V, 66E, 69P, 71Y and 87F in FR3 (h6F12.v3 and h6F12.v4); (iii) 43A in FR2 (h6F12.v1.1); (iv) 66G in FR3 (h6F12.v1.2); (v) 69T in FR3 (h6F12.v1.3); (vi) 71F in FR3 (h6F12.v1.4); and (vii) 87Y in FR3 (h6F12.v1.5).

30. The TGFβ2 antibody of claim 15 or 16, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 25, comprising one or more framework region mutations selected from the group consisting of 37V or 37I, 48M or 48L, 49G or 49A, 67L, 71K and 78V, and 105P or 105R.

31. The TGFβ2 antibody of claim 30, wherein the VH comprises a set of framework region mutations selected from the group consisting of: (i) 37V, 48M and 49G in FR2 and 105P in FR4 (h6F12.v1 and h6F12.v3); (ii) 37V and 48M in FR2, 67L, 71K and 78V in FR3 and 105P in FR4 (h6F12.v2 and h6F12.v4); (iii) 37I in FR2 (h6F12.v1.6); (iv) 48L in FR2 (h6F12.v1.7); (v) 49A in FR2 (h6F12.v1.8); (vi) 105R in FR4 (h6F12.v1.9); (vii) 37V, 48M and 49G in FR2 and 105P in FR4 (h6F12.v1 and h6F12.v3); (viii) 37V and 48M in FR2, 67L, 71K and 78V in FR3 and 105P in FR4 (6F12.v2 and h6F12.v4); (ix) 37I in FR2 (h6F12.v1.6); (x) 48L in FR2 (h6F12.v1.7); (xi) 49A in FR2 (h6F12.v1.8); and (xii) 105R in FR4 (h6F12.v1.9).

32. The TGFβ2 / 3 antibody of any one of claims 1-14 or the TGFβ2 antibody of any one of claims 15-28, wherein the antibody specifically binds to human TGFβ2.

33. The antibody according to any one of claims 1-32, which is a monoclonal antibody.

34. The antibody of any one of claims 1-32, which is a human, humanized or chimeric antibody.

35. The antibody of any one of claims 1-32, which is an antibody fragment.

36. An antibody according to any one of claims 1-32, comprising a human Fc region that is of the IgG1 or IgG4 isotype.

37. The antibody according to claim 36, comprising a human Fc region that belongs to the IgG1 isotype.

38. The antibody of claim 36 or 37, wherein the Fc region comprises a modification that results in the removal of the glycosylation site at amino acid residue position N297 (EU numbering according to Kabat).

39. The antibody of claim 38, wherein the modification is a mutation selected from N297G or N297A.

40. The antibody of claim 39, wherein the modification is the N297G mutation.

41. The antibody of any one of claims 36-40, wherein the Fc region is modified to remove effector function.

42. The antibody of any one of claims 1-41, wherein the antibody has a Cmax of approximately 230-260 μg / ml and / or a half-life amounting to approximately 15 to 16 days.

43. An isolated nucleic acid encoding an antibody according to any one of claims 1-42.

44. A host cell containing the nucleic acid of claim 43.

45. A method for producing an antibody comprising culturing a host cell according to claim 44 so as to produce the antibody.

46. ​​The method of claim 45, further comprising isolating the antibody from the host cell.

47. An antibody obtained using the method according to claim 45 or 46.

48. An immunoconjugate comprising an antibody according to any one of claims 1-42 and a cytotoxic agent.

49. A pharmaceutical composition comprising an antibody according to any one of claims 1-42 or an immunoconjugate according to claim 103 and a pharmaceutically acceptable carrier.

50. A pharmaceutical composition containing an antibody according to claim 49, further containing an additional therapeutic agent.

51. The pharmaceutical composition of claim 50, wherein the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, an IL-6 inhibitor (e.g., tocilizumab), an antibody to CTFG (e.g., FG-3019), an autotaxin inhibitor, a JAK inhibitor, an IL-11 inhibitor, and PTX2.

52. An antibody according to any one of claims 1-42 for use as a medicinal product.

53. The antibody of any one of claims 1-42 for use in the treatment of a TGFβ-associated disorder.

54. The antibody of claim 1 and 15 for use in combination for the treatment of a TGFβ-associated disorder.

55. The antibodies of claim 53 or 54, wherein the TGFβ-associated disorder is fibrosis.

56. The antibodies of claim 55, wherein the fibrosis is a fibrotic condition of the lungs, liver, heart, kidneys, pancreas, eyes and / or skin.

57. The antibody of any one of claims 1-42 for use in the manufacture of a medicinal product for inhibiting TGFBR-dependent SMAD signaling, for inhibiting the assembly of TGFβ-TGFBR signaling complexes, for inhibiting TGFβ signaling via the TGFBR1 / R2 complex, for inhibiting TGFβ signaling via the TGFBR2 / ALK1 complex facilitated by endoglin, and / or for inhibiting the synthesis of new collagen.

58. Use of an antibody according to any one of claims 1-42 in the manufacture of a medicinal product for the treatment of a TGFβ-associated disorder in a subject.

59. The use according to claim 58, wherein the TGFβ-associated disorder is fibrosis, optionally wherein the fibrosis is a fibrotic condition of the lungs, liver, heart, kidneys, pancreas, eyes and / or skin.

60. Use of an antibody according to any one of claims 1-42 in the manufacture of a medicinal product for inhibiting TGFBR-dependent SMAD signaling, for inhibiting the assembly of TGFβ-TGFBR signaling complexes, for inhibiting TGFβ signaling via the TGFBR1 / R2 complex, for inhibiting TGFβ signaling via the TGFBR2 / ALK1 complex facilitated by endoglin, and / or for inhibiting the synthesis of new collagen.

61. A method of treating a subject who has a disorder associated with TGFβ, wherein the method comprises administering to the subject in need thereof an effective amount of an antibody according to any one of claims 1-42 or administering to the subject a pharmaceutical composition according to claim 49.

62. A method for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of TGFβ-TGFBR signaling complexes, inhibiting TGFβ signaling via the TGFBR1 / R2 complex, inhibiting TGFβ signaling via the TGFBR2 / ALK1 complex facilitated by endoglin, and / or inhibiting new collagen synthesis in a subject, comprising administering to a subject in need thereof an effective amount of an antibody according to any one of claims 1-42 for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of TGFβ-TGFBR signaling complexes, inhibiting TGFβ signaling via the TGFBR1 / R2 complex, inhibiting TGFβ signaling via the TGFBR2 / ALK1 complex facilitated by endoglin, and / or inhibiting new collagen synthesis in the subject.

63. The method of claim 61 or 62, further comprising administering to the subject an additional therapeutic agent.

64. The method of claim 63, wherein the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, an IL-6 inhibitor (e.g., tocilizumab, sarilumab), an antibody to CTFG (e.g., FG-3019), an autotaxin inhibitor, and PTX2.

65. The method of any one of claims 61-64, wherein the subject has a TGFβ-related disorder that is fibrosis.

66. The method of claim 65, wherein the fibrosis is pulmonary fibrosis selected from the group consisting of idiopathic pulmonary fibrosis (IPF), idiopathic upper lobe fibrosis (Amitani disease), familial pulmonary fibrosis, pulmonary fibrosis (e.g., pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), or chronic asthma), cystic fibrosis, non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), progressive massive fibrosis, scleroderma / systemic sclerosis (SSc, including limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) forms, and SSc-related interstitial connective tissue disease-associated lung disease (SSc-ILD), bronchiolitis obliterans with organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), hypersensitivity pneumonitis, pulmonary hypertension, tuberculosis,silicosis, pulmonary asbestosis, acute lung injury and acute respiratory distress (ARD, including bacterial pneumonia-induced, injury-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced), 67. The method of claim 65, wherein the fibrosis is a fibrotic condition of the liver selected from the group consisting of liver cirrhosis, congenital liver fibrosis, obesity, fatty liver, alcoholic liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), infectious or viral liver fibrosis (e.g., chronic hepatitis B and C virus infections), cystic fibrosis, autoimmune hepatitis, necrotizing hepatitis, primary sclerosing cholangitis, hemochromatosis, bile duct system disorders, and liver dysfunction due to infections.

68. The method of claim 65, wherein the fibrosis is a fibrotic condition of the heart and / or pericardium selected from the group consisting of endomyocardial fibrosis, cardiac allograft vasculopathy (CAV), myocardial infarction, atrial fibrosis, congestive heart failure, arteriosclerosis, atherosclerosis, vascular stenosis, myocarditis, congestive cardiomyopathy, coronary infarctions, varicose veins, coronary artery stenosis and other post-ischemic conditions, and idiopathic retroperitoneal fibrosis.

69. The method of claim 65, wherein the fibrosis is a fibrotic condition of the kidneys selected from the group consisting of glomerulonephritis (including membranoproliferative, diffuse proliferative, rapidly progressive or sclerosing, post-infectious and chronic forms), diabetic glomerulosclerosis, focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, ischemic nephropathy, tubulointerstitial fibrosis of the kidneys, HIV-associated nephropathy, membranous nephropathy, glomerulonephritis secondary to systemic inflammatory diseases such as lupus, scleroderma and diabetic glomerulonephritis, idiopathic membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, amyloidosis (which affects the kidneys, among other tissues), autoimmune nephritis, renal tubulointerstitial fibrosis, renal atherosclerosis, Alport syndrome, nephrotic syndrome,chronic renal failure, chronic kidney disease, periglomerular fibrosis / atubular glomeruli, combined apical emphysema and basal fibrosis syndrome (emphysema / fibrosis syndrome), glomerular hypertension, nephrogenic fibrosing dermatopathy, polycystic kidney disease, Fabry disease and renal hypertension.

70. The method of claim 65, wherein the fibrosis is a fibrotic condition of the pancreas selected from the group consisting of stromal remodeling pancreatitis and stromal fibrosis.

71. The method of claim 65, wherein the fibrosis is a fibrotic condition of the gastrointestinal tract selected from the group consisting of Crohn's disease, ulcerative colitis, collagenous colitis, colorectal fibrosis, villous atrophy, crypt hyperplasia, polyp formation, gastric ulcer healing, and microscopic colitis.

72. The method of claim 65, wherein the fibrosis is a fibrotic condition of the eye selected from the group consisting of ocular fibrosis, ocular fibrosis, proliferative vitreoretinopathy, vitreoretinopathy of any etiology, fibrosis associated with retinal dysfunction, fibrosis associated with wet or dry macular degeneration, corneal and conjunctival scarring, corneal endothelial fibrosis, anterior subcapsular cataract and posterior lens capsule opacification, fibrotic diseases of the anterior segment of the eye, corneal stromal fibrosis (e.g., associated with corneal opacification), trabecular meshwork fibrosis (e.g., associated with glaucoma), fibrotic diseases of the posterior segment of the eye, fibrovascular scarring (e.g., in the retina or choroidal vasculature of the eye), retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis (eg, associated with age-related macular degeneration),tractional retinal detachment associated with tissue contraction in diabetic retinopathy, congenital orbital fibrosis, lacrimal gland fibrosis, corneal subepithelial fibrosis, and Graves' ophthalmopathy.

73. The method of claim 65, wherein the fibrosis is selected from fibrosis resulting from spinal cord injury / fibrosis or central nervous system fibrosis, such as post-stroke fibrosis, Duchenne muscular dystrophy, fibrosis associated with a neurodegenerative disorder such as Alzheimer's disease or multiple sclerosis, vascular restenosis, uterine fibrosis, endometriosis, ovarian fibroids, Peyronie's disease, polycystic ovary syndrome, apical pulmonary fibrosis associated with ankylosing spondylitis, scarring and fibrosis resulting from microbial infections (e.g., bacterial, viral, parasitic, fungal).

74. The method of claim 65, wherein the fibrosis is SSc.

75. The method of claim 65, wherein the fibrosis is IPF.

76. The method of claim 65, wherein the fibrosis is chronic obstructive pulmonary disease (COPD).

77. The method of claim 65, wherein the fibrosis is progressive fibrosing interstitial lung disease (PF-ILD).

78. The method of claim 77, wherein the PF-ILD is a disease or condition selected from the group consisting of non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), progressive massive fibrosis, a complication of miner's pneumoconiosis, scleroderma / systemic sclerosis, bronchiolitis obliterans with organizing pneumonia; ILD associated with connective tissue disease (CT-ILD), and hypersensitivity pneumonitis.

79. The method of claim 65, wherein the fibrosis is liver cirrhosis or chronic liver fibrosis.

80. The method of claim 65, wherein the fibrosis is gastrointestinal fibrosis, such as intestinal fibrosis, optionally selected from the group consisting of fibrosis associated with Crohn's disease, ulcerative colitis, collagenous colitis, colorectal fibrosis, villous atrophy, crypt hyperplasia, polyp formation, gastric ulcer healing, and microscopic colitis.

81. The method of claim 65, wherein the fibrosis is a fibrotic condition of the eye, fibrosis resulting from spinal cord injury, fibrosis or fibrosis of the central nervous system, or fibrosis associated with a neurodegenerative disorder.

82. The method according to any one of claims 61-81, wherein the antibody is an antibody to TGFβ2.

83. The method according to claim 82, wherein the antibody to TGFβ2 comprises: (a) heavy chain CDRs comprising CDR-H1, -H2 and -H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 16, CDR-H2 has the amino acid sequence of SEQ ID NO: 17 and CDR-H3 has the amino acid sequence of SEQ ID NO: 18; and (b) light chain CDRs comprising CDR-L1, -L2 and -L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 19; CDR-L2 has the amino acid sequence of SEQ ID NO: 20 and CDR-L3 has the amino acid sequence of SEQ ID NO:

21.

84. The method according to any one of claims 61-81, wherein the antibody is an antibody to TGFβ2 / 3.

85. The method of claim 84, wherein the TGFβ2 / 3 antibody comprises: (i) heavy chain CDRs comprising CDR-H1, -H2, and -H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 10, CDR-H2 has the amino acid sequence of SEQ ID NO: 11, and CDR-H3 has the amino acid sequence of SEQ ID NO: 12; and (ii) light chain CDRs comprising CDR-L1, -L2, and -L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 13; CDR-L2 has the amino acid sequence of SEQ ID NO: 14, and CDR-L3 has the amino acid sequence of SEQ ID NO:

15.

86. A method for diagnosing SSc in a subject, wherein the method comprises determining the expression levels of genes in a set of 18 gene signatures consisting of PRSS23, PXDN, COL8A1, COL6A3, SERPINE2, TNC, COMP, THBS1, COL11A1, COL1A1, COL5A2, COL1A2, COL4A1, COL4A2, SFRP4, ALPK2, COL5A1 and TAGLN, and establishing a diagnosis of SSc in the subject if it is determined that the gene levels are elevated compared to the gene levels in a control set from a healthy subject or a reference gene signature.

87. The method of claim 86, wherein the level of a gene is increased if the increase in expression compared to a control set from a healthy subject or a signature of reference genes is statistically significant, optionally at least two times higher, or at least three times higher, or at least four times higher compared to a control set from a healthy subject or a signature of reference genes.

88. A method for monitoring the response to treatment of a subject with an antibody to TGFβ2 and / or an antibody to TGFβ 3, wherein the method comprises determining the expression level of one or more TGFβ-inducible genes selected from the group consisting of serpine1, col1a1, col1a2 and col3a1 in a sample from the subject, wherein the subject has received one or more administrations of an antibody to TGFβ2 and / or an antibody to TGFβ3.

89. The method of claim 88, wherein the subject is determined to have a response to treatment with an antibody to TGFβ2 and / or an antibody to TGFβ3 if the level of expression of one or more TGFβ-inducible genes is significantly reduced compared to the levels of one or more TGFβ-inducible genes before treatment, wherein the method optionally further comprises further administration of an antibody to TGFβ2 and / or an antibody to TGFβ3 if it is determined that the level of expression of one or more TGFβ-inducible genes is significantly reduced.

90. The method of claim 88 or 89, wherein the subject is administered an antibody to TGFβ2 as monotherapy.

91. The method of claim 88, wherein the expression level of one or more genes induced by TGFβ is determined using qPCR or microarray analysis.

92. The method or use according to any of paragraphs 43-91, wherein the subject is a human.

93. A kit containing an antibody according to any one of claims 1-42.