Isoform-selective Anti-TGF-beta antibodies and methods of use

Abstract

To provide isoform-selective anti-TGFβ antibodies and methods of using the same.SOLUTION: Isoform-selective anti-TGFβ2, anti-TGFβ3, and anti-TGFβ2 / 3 monoclonal antibodies are provided, e.g., for the treatment of fibrosis and other TGFβ-related disorders.SELECTED DRAWING: Figure 3A

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 044,478, filed June 26, 2020, and U.S. Provisional Patent Application No. 62 / 991,806, filed March 19, 2020, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on March 16, 2021, is named P35791-WO_Sequence_Listing and is 492,334 bytes in size. [Technical Field]

[0003] FIELD OF THE INVENTION The present invention relates to isoform-selective anti-TGFβ antibodies (e.g., monospecific anti-TGFβ2 and anti-TGFβ3 antibodies, and bispecific anti-TGFβ2 / 3 antibodies) and methods of using same, for example, to treat TGFβ-associated disorders. [Background technology]

[0004] background TGF-β comprises a pleiotropic set of three cytokines (TGF-β1, TGF-β2, and TGF-β3) that play critical roles in cell differentiation, tissue development, wound repair, immune regulation, and, if dysregulated, tissue fibrosis. In the case of interstitial lung diseases (ILDs), such as idiopathic pulmonary fibrosis (IPF), TGF-β activity is involved in multiple aspects of disease pathogenesis. Genetic risk for IPF is conferred by mutations in genes expressed in lung epithelial cells that increase susceptibility to injury and / or impair their regenerative capacity. This epithelial stress or injury can activate innate immune cells, such as alveolar macrophages, to produce cytokines that activate mesenchymal cells to initiate a wound healing response through proliferation, migration, differentiation into myofibroblasts, and secretion of extracellular matrix (ECM). TGF-β may contribute to many of these processes, and in particular has been shown to promote the activation, differentiation, and survival of myofibroblasts while promoting the apoptosis of lung epithelial cells. Systemic sclerosis (SSc) / scleroderma is an autoimmune disease that begins with microvascular inflammation and progresses to multiorgan connective tissue dysfunction involving the skin, lungs, heart, kidneys, and intestinal tissues. TGF-β is involved in the dysregulation of vascular, connective tissue, and immune components in SSc (Lafyatis R. Nat Rev Rheumatol. 2014 Dec;10(12):706-19).

[0005] TGFβ signaling also plays a role in cancer pathogenesis, particularly in the peritumoral stroma and immune compartment, where it can inhibit productive antitumor immune responses by both promoting excessive ECM production, which impedes T cell infiltration into tumor tissue, and by promoting the differentiation and activation of regulatory T cells, which can suppress antitumor immunity. Collectively, these findings suggest that TGFβ is a potential therapeutic target for fibrotic diseases and cancer. However, the complexity of TGFβ's diverse homeostatic functions and the context-dependent mechanisms of TGFβ activation contribute to limitations in both safety and efficacy for establishing a favorable therapeutic index in intervention studies of TGFβ inhibitors in human fibrotic disorders. For example, pan-TGFβ inhibitors have been associated with undesirable safety signals. In particular, the small molecule ALK5 inhibitors AZ12601011 and AZ12799734 (Denton et al. (2011) Toxicologic Pathology, 39:916-924) caused microscopic cardiac valve lesions in rats, and the pan-TGFβ 1D11 antibody (Lonning et al. (2011) Current Pharmaceutical Biotechnology, 12, 2176-2189) caused histologic lesions, weight loss, non-neoplastic cystic epithelial hyperplasia and inflammation of the tongue, as well as dental dysplasia and epithelial hyperplasia of the gingiva and esophagus in 1D11-treated mice. Furthermore, CAT-192 (metelimu- mab), an antibody primarily selective for TGFβ1, had a high rate of serious adverse events, with numerous gastric bleeding events observed in a phase 1-2 trial in SSc (Denton A&R 56:323 (2007)).

[0006] Thus, there remains a need in the art for safe and effective molecules that target TGFβ. The present invention provides such molecules and related uses. Summary of the Invention

[0007] overview The present invention provides isoform-selective anti-TGFβ antibodies and methods of using same.

[0008] In one aspect, an isolated anti-TGFβ3 antibody is provided, the antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9. In some aspects, the antibody selectively neutralizes TGFβ3.

[0009] In another embodiment, an anti-TGFβ3 antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) the binding of the anti-TGFβ3 antibody sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; and (c) the binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and prevents the TGFBR1 / TGFBR2 signaling receptors from binding to TGFβ3. (d) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3; (e) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, and residue R394 of TGFβ3 forms an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3, inhibiting the activity of the anti-TGFβ3 antibody against TGFβ1. (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 by direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to the pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to the pan-TGFβ antibody 1D11; (j) reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; (k) reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib; (l) reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) reduced toxicity compared to isoform-selective anti-TGFβ2 antibodies and / or anti-TGFβ2 / 3 antibodies;(n)(n)(i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9. and (p) the antigen-binding domain is within 15 to 8, 8, 8 to 5, 7 to 5, 6 to 5, or 5 angstroms of a TGFβ3 amino acid residue.

[0010] In another embodiment, the antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) the binding of the anti-TGFβ3 antibody sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; (c) the binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and inhibits the TGFBR1 / TGFBR2 signaling receptors from binding to TGFβ3; and (d) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of human TGFβ3. (e) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, with residue R394 of TGFβ3 forming an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3, resulting in isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ1. (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2 is achieved by direct contact of the antigen-binding domain of the anti-TGFβ3 antibody with amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to pan-TGFβ antibody 1D11; (j) pan-TGFβ small molecule inhibitors (k) has reduced toxicity in rodents compared to galunisertib, a pan-TGFβ small molecule inhibitor; (l) has reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) has reduced toxicity compared to an isoform-selective anti-TGFβ2 antibody and / or an anti-TGFβ2 / 3 antibody; (n) (i) a heavy chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4 and CDR-H2 has the amino acid sequence of SEQ ID NO: 5;(ii) a heavy chain CDR, wherein CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR, comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (o) amino acid residues R325, K331, W332, H333 on human TGFβ3. and (p) the antigen binding domain is within 15-8, 8, 8-5, 7-5, 6-5, or 5 angstroms of a TGFβ3 amino acid residue. In some embodiments, the anti-TGFβ3 antibody comprises a heavy chain variable region (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: 23, 37, and 42-50. In some embodiments, the anti-TGFβ3 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 37, and 42-50. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy (H) chain 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: 29, 59, 64, and 65-72. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy (H) chain amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 59, 64, and 65-72. In further embodiments, the anti-TGFβ3 antibody comprises a light chain variable region (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: 22, 36, and 38-41. In yet another embodiment, the anti-TGFβ3 antibody has a sequence identity that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63.The anti-TGFβ3 antibody comprises a complete light (L) chain amino acid sequence having at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity. In some embodiments, the anti-TGFβ3 antibody comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL pair, the VH / VL pair being selected from SEQ ID NOs: 23 / 22 (rat 2A10), SEQ ID NOs: 37 / 36 (v1), SEQ ID NOs: 37 / 38 (v1.1), SEQ ID NOs: 37 / 39 (v1.2), SEQ ID NOs: 37 / 40 (v1.3), SEQ ID NOs: 37 / 41 (v1.4), SEQ ID NOs: 42 / 36 (v1.5), SEQ ID NOs: 43 / 36 (v1.6), SEQ ID NOs: 44 / 36 (v1.7), SEQ ID NOs: 45 / 46 (v1.8), SEQ ID NOs: 47 / 47 (v1.9), SEQ ID NOs: 48 / 49 (v1.10), SEQ ID NOs: 49 / 50 (v1.11), SEQ ID NOs: 51 / 52 (v1.12), SEQ ID NOs: 53 / 54 (v1.13), SEQ ID NOs: 54 / 55 (v1.14), SEQ ID NOs: 55 / 56 (v1.15), SEQ ID NOs: 56 / 57 (v1.16), SEQ ID NOs: 57 / 58 (v1.17), SEQ ID NOs: 58 / 59 (v1.18), SEQ ID NOs: 59 and SEQ ID NO:45 / 36 (v2), SEQ ID NO:45 / 38 (v2.1), SEQ ID NO:45 / 39 (v2.2), SEQ ID NO:45 / 40 (v2.3), SEQ ID NO:45 / 41 (v2.4), SEQ ID NO:46 / 36 (v2.5), SEQ ID NO:47 / 36 (v2.6), SEQ ID NO:48 / 36 (v2.7), SEQ ID NO:49 / 36 (v2.8), and SEQ ID NO:50 / 36 (v2.9). In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain pair, the complete heavy / light chain pair being SEQ ID NO:29 / 28 (rat 2A10), SEQ ID NO:59 / 58 (v1), SEQ ID NO:59 / 60 (v1.1), SEQ ID NO:59 / 61 (v1.2), SEQ ID NO:59 / 62 (v1.3), SEQ ID NO:59 / 63 (v1.4), SEQ ID NO:64 / 58 (v1.5), SEQ ID NO:65 / 58 (v1.6), SEQ ID NO:66 / 58 (v1.7), ), SEQ ID NO:67 / 58(v2), SEQ ID NO:67 / 60(v2.1), SEQ ID NO:67 / 61(v2.2), SEQ ID NO:67 / 62(v2.3), SEQ ID NO:67 / 63(v2.4), SEQ ID NO:68 / 58(v2.5), SEQ ID NO:69 / 58(v2.6), SEQ ID NO:70 / 58(v2.7), SEQ ID NO:71 / 58(v2.8), SEQ ID NO:72 / 58(v2.9) (respectively). In some embodiments, the anti-TGFβ3 antibody comprises an amino acid sequence selected from the group consisting of: 4L or 4M, 38H or 38Q, 43A or 43Q, and 58V. ...The anti-TGFβ3 antibody VL comprises a set of framework modifications selected from the group consisting of: (i) 4L in FR1, 38H and 43Q in FR2, and 58I in FR3 (h2A10.v1 and h2A10.v2), where the mutations are relative to the rat 2A10 VL having SEQ ID NO: 22: (i) 4L in FR1, 38H and 43Q in FR2, and 58I in FR3 (h2A10.v1 and h2A10.v2); (ii) 4M in FR1 (h2A10.v1.1 and h2A10.v2.1); (iii) 38Q in FR2 (h2A10.v1.2 and h2A10.v2.2); (iv) 43A in FR2 (h2A10.v1.3 and h2A10.v2.3). (v) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4); (vii) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); and (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4). In other embodiments, the anti-TGFβ3 antibody comprises a VH of SEQ ID NO: 23 comprising one or more framework modifications selected from the group consisting of: 47L or 47W; 49A, 49S or 49G; 73D or 73N; and 76N, 78D or 78L, 78A, or 78V. In some embodiments, the TGFβ3 antibody VH comprises a set of framework modifications selected from the group consisting of: (i) 47L, 49A in FR2, 78V in FR3 (h2A10.v1); (ii) 47L, 49A in FR2, 73D, 76S, 78V in FR3 (h2A10.v2); (iii) 47W in FR2 (h2A10.v1.5); (iv) 49G in FR2 (h2A10.v1.6); (v) 78A in FR3 (h2A10.v1.7); (vi) 47W in FR2 (h2A10.v2.5); (vii) 49S in FR2 (h2A10.v2.6); (viii) 73N in FR3 (h2A10.v2.7); (ix) 76N in FR3 (h2A10.v2.8); (x) 78L in FR3 (h2A10.v2.9); and (xi) 49S in FR2, 76N, 78L in FR3 (h2A10.v3 and h2A10.v4). ,

[0011] In certain embodiments of the above anti-TGFβ3 antibodies, the VL of the anti-TGFβ3 antibody retains leucine (L) at position 4 of framework I and leucine (L) at position 47 of framework II (relative to rat 2A10 VL having SEQ ID NO: 22). In some embodiments, the VH retains D at position 73 of framework III of the VH from rat 2A10 (relative to rat 2A10 VH having SEQ ID NO: 23).

[0012] In another embodiment, an anti-TGFβ3 antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) the binding of the anti-TGFβ3 antibody sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; and (c) the binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and prevents the TGFBR1 / TGFBR2 signaling receptors from binding to TGFβ3. (d) directly contacts amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3; (e) directly contacts amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, and residue R394 of TGFβ3 forms an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) an anti-TGFβ3 antibody against TGFβ1 by direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3. (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2 is achieved by direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to the pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to the pan-TGFβ antibody 1D11; (j) reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; (k) reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib; (l) reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) reduced toxicity compared to isoform-selective anti-TGFβ2 antibodies and / or anti-TGFβ2 / 3 antibodies;(n) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (o) an antigen-binding domain that directly contacts amino acid residues R325, K331, W332, H334, E335, T387, I388, L389, Y391, V392, G393, R394, P396, K397, and V398 on human TGFβ3;and (p) an isolated anti-TGFβ3 antibody comprising one or more of the anti-TGFβ3 antibodies described in (o), wherein the antigen-binding domain is within 15-8, 8, 8-5, 7-5, 6-5, or 5 angstroms of a TGFβ3 amino acid residue. In some aspects of this embodiment, the anti-TGFβ3 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 the amino acid sequence of SEQ ID NO: 52. In some aspects, the anti-TGFβ3 antibody comprises a VH amino acid sequence of SEQ ID NO: 52. In some aspects, the anti-TGFβ3 antibody comprises a complete H chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74. In some aspects, the anti-TGFβ3 antibody comprises the complete H chain amino acid sequence of SEQ ID NO: 74. In some embodiments, the anti-TGFβ3 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: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprises a complete L chain 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: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In further embodiments, the anti-TGFβ3 antibody comprises a VH / VL pair comprising the amino acid sequences of SEQ ID NOs: 52 / 36 (respectively). In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain pair, wherein the heavy / light chain pair comprises the amino acid sequences of SEQ ID NOs: 74 / 58 (respectively);

[0013] In another embodiment, the antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) the binding of the anti-TGFβ3 antibody sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; (c) the binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and inhibits the TGFBR1 / TGFBR2 signaling receptors from binding to TGFβ3; and (d) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of human TGFβ3. (e) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, with residue R394 of TGFβ3 forming an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3, resulting in isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ1. (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2 is achieved by direct contact of the antigen-binding domain of the anti-TGFβ3 antibody with amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to pan-TGFβ antibody 1D11; (j) pan-TGFβ small molecule inhibitors (k) has reduced toxicity in rodents compared to galunisertib, a pan-TGFβ small molecule inhibitor; (l) has reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) has reduced toxicity compared to an isoform-selective anti-TGFβ2 antibody and / or an anti-TGFβ2 / 3 antibody; (n) (i) a heavy chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4 and CDR-H2 has the amino acid sequence of SEQ ID NO: 5;(ii) a heavy chain CDR, wherein CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR, comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (o) amino acid residues R325, K331, W332, H333 on human TGFβ3. and (p) the antigen binding domain is within 15-8, 8, 8-5, 7-5, 6-5, or 5 angstroms of a TGFβ3 amino acid residue. In some embodiments, the anti-TGFβ3 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 the amino acid sequence of SEQ ID NO: 51 or 55. In some embodiments, the anti-TGFβ3 antibody comprises the VH amino acid sequence of SEQ ID NO: 51 or 55. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 73 or 77. In some embodiments, the anti-TGFβ3 antibody comprises the complete heavy chain amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-TGFβ3 antibody comprises the complete heavy chain amino acid sequence of SEQ ID NO: 77. In some embodiments, the anti-TGFβ3 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: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 28,In some embodiments, the anti-TGFβ3 antibody comprises a complete L chain 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: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL pair, wherein the VH / VL pair comprises the amino acid sequence of SEQ ID NOs: 51 / 36 or SEQ ID NOs: 55 / 54 (respectively). In some embodiments, the anti-TGFβ3 antibody comprises a complete H / L chain pair, wherein the H / L chain pair comprises the amino acid sequence of SEQ ID NOs: 73 / 58 or SEQ ID NOs: 77 / 76 (respectively).

[0014] In another embodiment, the antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) the binding of the anti-TGFβ3 antibody sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; (c) the binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and inhibits the TGFBR1 / TGFBR2 signaling receptors from binding to TGFβ3; and (d) the anti-TGFβ3 antibody specifically binds to the beta6 / beta7 hairpin region of human TGFβ3. (e) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, with residue R394 of TGFβ3 forming an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3, resulting in isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ1. (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2 is achieved by direct contact of the antigen-binding domain of the anti-TGFβ3 antibody with amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to pan-TGFβ antibody 1D11; (j) pan-TGFβ small molecule inhibitors (k) has reduced toxicity in rodents compared to galunisertib, a pan-TGFβ small molecule inhibitor; (l) has reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) has reduced toxicity compared to an isoform-selective anti-TGFβ2 antibody and / or an anti-TGFβ2 / 3 antibody; (n) (i) a heavy chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4 and CDR-H2 has the amino acid sequence of SEQ ID NO: 5;(ii) a heavy chain CDR, wherein CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR, comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (o) amino acid residues R325, K331, W332, H333 on human TGFβ3. and (p) the antigen binding domain is within 15-8, 8, 8-5, 7-5, 6-5, or 5 angstroms of a TGFβ3 amino acid residue. In some embodiments, the anti-TGFβ3 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 the amino acid sequence of SEQ ID NO: 53 or 57. In some embodiments, the anti-TGFβ3 antibody comprises the VH amino acid sequence of SEQ ID NO: 53. In some embodiments, the anti-TGFβ3 antibody comprises the VH amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75 or 79. In some embodiments, the anti-TGFβ3 antibody comprises the complete heavy chain amino acid sequence of SEQ ID NO: 75. In some embodiments, the anti-TGFβ3 antibody comprises the complete heavy chain amino acid sequence of SEQ ID NO: 79. In some embodiments, the anti-TGFβ3 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: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41. In some embodiments, the anti-TGFβ3 antibody comprisesThe anti-TGFβ3 antibody comprises a complete L chain 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: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL pair comprising the amino acid sequences of SEQ ID NOs: 53 / 36 or SEQ ID NOs: 57 / 56 (respectively). In some embodiments, the anti-TGFβ3 antibody comprises a complete H / L chain pair, wherein the H / L chain pair comprises the amino acid sequences of SEQ ID NOs: 75 / 58 or SEQ ID NOs: 79 / 78 (respectively).

[0015] In another aspect, (a) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; and CDR-L2 has the amino acid sequence of SEQ ID NO: 8. and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (b) a VH / VL pair, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO: 57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO: 56; or (c) a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 78.

[0016] In another aspect, the antibody selectively neutralizes TGFβ2 and TGFβ3 and has the following characteristics: (a) the selectivity of the anti-TGFβ2 / 3 antibody for TGFβ2 and TGFβ3 is achieved for selective neutralization by direct contact of the antigen-binding domain of the antibody with amino acid residue E373 (human TGFβ2 numbering) of TGFβ2 or TGFβ3, which is greater than the selectivity of the anti-TGFβ2 / 3 antibody for human TGFβ1; (b) neutralizes TGFβ2 and / or TGFβ3 via an allosteric mechanism; and (c) causes a conformational change in TGFβ2 and / or TGFβ3 homodimers. (d) induces a conformational change in a TGFβ2 and / or TGFβ3 homodimer, the conformational change involving two monomers pinching together several times; (e) is a bivalent antibody or a monovalent antibody; (f) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-L3. (g) comprises a light chain CDR, 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) specifically binds to a TGFβ2 homodimer, wherein the TGFβ2 homodimer has a first and a second TGFβ2 monomer, and wherein the TGFβ2 homodimer binds to (i) amino acid residues V313, Q314, D315, R320, L322, Y323, R328, D329, F345, and A347 of the first TGFβ2 monomer, and (ii) amino acid residue N368 of the second TGFβ2 monomer. , T369, I370, N371, P372, E373, A374, S375, A376 and S377 (human TGFβ2 numbering); (h) an anti-TGFβ2 / 3 antibody described in (g), wherein the antigen-binding domain is within 5 angstroms of a TGFβ2 and / or TGFβ3 amino acid residue; (i) specifically binds to the same epitope on TGFβ3 as (g); and (j) does not neutralize TGFβ2 and / or TGFβ3 in a monovalent form.In one aspect, an anti-TGFβ2 / 3 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: 27, 81, 83, 86-88, 93-100, and 102-105. In one aspect, an anti-TGFβ2 / 3 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 81, 83, 86-88, 93-100, and 102-105. In one aspect, an anti-TGFβ2 / 3 antibody comprises a complete H-chain 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: 33, 107, 109, 112-114, and 119-130. In one aspect, the anti-TGFβ2 / 3 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. In one aspect, the anti-TGFβ2 / 3 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 80, 82, 84, 85, 89-92, and 101. In one aspect, the anti-TGFβ2 / 3 antibody comprises a complete L chain 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: 32, 106, 108, 110, 111, 115-118, and 186. In one aspect, the anti-TGFβ2 / 3 antibody comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 106, 108, 110, 111, 115-118, and 186.In one aspect, the anti-TGFβ2 / 3 antibody comprises a VH / VL pair, wherein the VH / VL pair is 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) (respectively).In one embodiment, the anti-TGFβ2 / 3 antibody comprises a complete heavy / light chain pair, the complete heavy / light chain pair being 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:1 14 / 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) (respectively). In one aspect, the anti-TGFβ2 / 3 antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 26 comprising one or more framework modifications selected from the group consisting of: 2A or 2I, 4L, 36F or 36Y, 43P or 43A, and 58V or 58I.In one aspect, the anti-TGFβ2 / 3 antibody VL comprises a set of framework modifications selected from the group consisting of: (i) 2A and 4L in FR1, 36F in FR2 (h4A11.v1 and h4A11.v3); (ii) 2A and 4L in FR1, 36F and 43P in FR2 (h4A11.v2 and h4A11.v4); (iii) 2A in FR1, 36F and 43P in FR2, 58F in FR3 V (h4A11.v5 and h4A11.v7); (iv) 2A and 4L in FR1, 36F in FR2 (h4A11.v6 and h4A11.v8); (v) 2I in FR1 (h4A11.v7.4); (vi) 36Y in FR2 (h4A11.v7.5); (vii) 3A in FR24 (h4A11.v7.6); (viii) 58I in FR3 (h4A11.v7.7); and (ix) 2I in FR1, 43A in FR2, 58I in FR3 (h4A11.v7.16-19). In one embodiment, the anti-TGFβ2 / 3 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 27 comprising one or more framework modifications selected from the group consisting of deletion 1E, 2Q or 2V, 24V, 37V or 37I, 48I, 49G, 67F or 67V, 71K or 71V, deletion 73S or 73T, deletion 75K and 76N, 78V or 78F, 91F or 91Y, deletion 105P or 105Q.In one aspect, the anti-TGFβ2 / 3 antibody VL comprises a set of framework 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.v1, h4A11.v2, h4A11.v5, h4A11.v6); h4A11.v3, h4A11.v4, h4A11.v7, h4A11.v8; (iii) deletion of 1E in FR1 (h4A11.v7.1); (iv) deletion of 75K and 76N in FR3 (h4A11.v7.2); (v) deletion of 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 (h4A11.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.v 7.14); (xii) 105Q in FR4 (h4A11.v7.15); (xiii) 2V in FR1, 37I in FR2, 67V in FR3, 73T, 78F, 105Q in FR4 ((h4A11.v7.16); (xiv) FR1 (xv) 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, 105Q in FR4 (h4A11.v7.18); (xvi) 2V in FR1, 37I in FR2, 67V, 73T, 75K deletion and 76N, 105Q in FR4 (h4A11.v7.19). The mutations are to a VH comprising the amino acid sequence of SEQ ID NO: 27.

[0017] In another aspect, an isolated anti-TGFβ2 antibody is provided, comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (d) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one embodiment, the anti-TGFβ2 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. In one embodiment, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142. In one aspect, the anti-TGFβ2 antibody comprises a complete heavy chain amino acid sequence that has 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 to 156. In one aspect, the anti-TGFβ2 antibody comprises a complete heavy chain amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 146, and 152 to 156.In one aspect, the anti-TGFβ2 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. In another aspect, the anti-TGFβ2 antibody comprises a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 131, 133-137, 143, and 144. In one aspect, the anti-TGFβ2 antibody comprises a complete L chain 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: 30, 145, 147-151, 157, and 158. In one aspect, the anti-TGFβ2 antibody comprises a complete L chain amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 145, 147-151, 157, and 158. In one aspect, the anti-TGFβ2 antibody comprises a VH / VL pair, wherein the VH / VL pair comprises an amino acid sequence 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).In one aspect, the anti-TGFβ2 antibody comprises a complete heavy / light chain pair, wherein the complete heavy / light chain pair comprises an amino acid sequence 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). In one aspect, an anti-TGFβ2 antibody comprises a VL comprising the amino acid sequence of SEQ ID NO: 24, which comprises one or more framework mutations selected from the group consisting of 43S or 43A, 66G, 69T, 71F, and 87Y. In one aspect, the anti-TGFβ2 antibody VL comprises a set of framework mutations selected from the group consisting of: (i) 43S in FR2, 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); (vii) 87Y in FR3 (h6F12.v1.5), wherein the mutations are relative to a VL comprising the amino acid sequence of SEQ ID NO: 24. In one aspect, the anti-TGFβ2 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 25, comprising one or more framework mutations selected from the group consisting of 37V or 37I, 48M or 48L, 49G or 49A, 67L, 71K and 78V, and 105P or 105R.In one aspect, the anti-TGFβ2 antibody VH comprises a set of framework mutations selected from the group consisting of: (i) 37V, 48M, and 49G in FR2, 105P in FR4 (h6F12.v1 and h6F12.v3); (ii) 37V and 48M in FR2, 67L, 71K, and 78V in FR3, 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 (h6F 12.v1.9); (vii) 37V, 48M and 49G in FR2, 105P in FR4 (h6F12.v1 and h6F12.v3); (viii) 37V and 48M in FR2, 67L, 71K and 78V in FR3, 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); (xii) 105R in FR4 (h6F12.v1.9), and the mutations are relative to the VH comprising the amino acid sequence of SEQ ID NO: 25.

[0018] In certain embodiments of any of the above aspects, the anti-TGFβ3 antibody and / or anti-TGFβ2 / 3 antibody specifically binds to human TGFβ3. In some embodiments of any of the above aspects, the anti-TGFβ3 antibody specifically binds to both the immature and mature forms of TGFβ3. In some aspects of any of the above embodiments, the anti-TGFβ2 / 3 antibody and / or anti-TGFβ2 specifically binds to human TGFβ2. In some embodiments of any of the above aspects, the antibody is a monoclonal antibody. In some embodiments of any of the above aspects, the antibody is a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments of any of the above aspects, the antibody is an antibody fragment. In some embodiments of any of the above aspects, the antibody comprises a human Fc region that is an IgG1 or IgG4 isotype. In some embodiments of any of the above aspects, the antibody comprises a human Fc region that is an IgG1 isotype. In some embodiments of any of the above aspects, the Fc region of the antibody has been modified to remove effector function. In some aspects, the Fc region comprises a modification to remove a glycosylation site at amino acid residue position N297 (EU numbering as per Kabat). In some aspects, the modification is a mutation selected from N297G or N297A. In some aspects, the modification is a mutation N297G. In some embodiments of any of the above aspects, the antibody has a Cmax of about 230-260 μg / ml and / or a half-life (t) of about 15-16 days. 1 / 2 )

[0019] Also provided are isolated nucleic acids encoding antibodies according to any of the above aspects and embodiments, and host cells comprising the nucleic acids. In some aspects, methods of producing antibodies are provided. The methods may include culturing the host cells provided herein so that the antibody is produced. In some aspects, the methods further include recovering the antibody from the host cells. Antibodies produced by the above methods of producing antibodies are also provided.

[0020] In another aspect, an immunoconjugate is provided comprising an antibody, such as any of the above antibodies, and a cytotoxic agent. In some embodiments, the antibody comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7 and CDR-L2 has the amino acid sequence of SEQ ID NO: 8. (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7. wherein CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a3) (i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) CDR-L1, CDR-L2 and CDR-L3 (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) an anti-TGFβ3 antibody comprising a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In some embodiments, the antibody is an anti-TGFβ2 antibody, and the antibody comprises: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In some embodiments, the antibody is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

[0021] In another aspect, there is provided a pharmaceutical formulation or immunoconjugate comprising the antibody of any one of the above aspects and embodiments and a pharmaceutically acceptable carrier. In some embodiments, the antibody comprises: (a1)(i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7 and CDR-L2 has the amino acid sequence of SEQ ID NO: 8. (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7. wherein CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a3) (i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) CDR-L1, CDR-L2 and CDR-L3 (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) an anti-TGFβ3 antibody comprising a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In some embodiments, the antibody is an anti-TGFβ2 antibody, and the antibody comprises: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In some embodiments of the pharmaceutical formulation or conjugate, the antibody is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

[0022] In some embodiments, the pharmaceutical formulation further comprises an additional therapeutic agent, hi some embodiments, the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, an IL-6 inhibitor (e.g., tocilizumab), an anti-CTFG antibody (e.g., FG-3019), an autotaxin inhibitor, a JAK inhibitor, an IL-11 inhibitor, and PTX2.

[0023] Also provided is an antibody according to any of the above aspects and embodiments for use as a medicament. In some embodiments, the antibody for use as a medicament comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, and CDR-L3 has the amino acid sequence of SEQ ID NO: 8; (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:8. (a3)(i) a light chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:35 and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR consisting of CDR-L1, CDR-L2 and CDR (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; or (b) an anti-TGFβ3 antibody comprising a light chain CDR comprising CDR-L1, CDR-L2, and CDR-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. In some embodiments, the antibody for use as a pharmaceutical is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

[0024] Also provided is an antibody according to any of the above aspects and embodiments for use in treating a TGFβ-associated disorder. In some embodiments, the antibody for use in treating a TGFβ-associated disorder comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:8, CDR-L2 has the amino acid sequence of SEQ ID NO:9, (a3)(i) light chain CDRs consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) heavy chain CDRs consisting of CDR-L1, CDR-L2 and CDR-H3. (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) an anti-TGFβ3 antibody comprising a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In some embodiments, the antibody for use in treating a TGFβ-associated disorder is an anti-TGFβ2 antibody, comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In some embodiments, the antibody for use in treating a TGFβ-related disorder is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

[0025] In one aspect, there is provided an anti-TGFβ3 antibody according to any of the above aspects and embodiments, and an anti-TGFβ2 antibody according to any of the above aspects and embodiments, for use in combination to treat a TGFβ-related disorder. In one embodiment, the anti-TGFβ3 antibody for use in such combination comprises: (a1)(i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:8, CDR-L2 has the amino acid sequence of SEQ ID NO:9, (a3)(i) a light chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR consisting of CDR-L1, CDR-L2 and CDR-H3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; or (a4)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In another embodiment, the anti-TGFβ2 antibody comprises: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (d) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one embodiment, the anti-TGFβ2 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. In one embodiment, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142.

[0026] Also provided is an antibody according to any of the above aspects and embodiments for use in the manufacture of a medicament for treating a TGFβ-related disorder, inhibiting TGFBR-dependent SMAD signaling, inhibiting assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the TGFBR2 / ALK1 complex promoted by endoglin, and / or inhibiting new collagen synthesis. In one embodiment, the antibody to such a medicament comprises: (a1)(i) heavy chain CDRs comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a2)(i) heavy chain CDRs comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 34 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6 and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a3)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9;or (a4)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, and CDR-L2 has the amino acid sequence of SEQ ID NO: 8. and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO: 57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO: 56; or (c) a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 78. In another embodiment, the antibody against such a medicament is an anti-TGFβ2 antibody comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib;and / or (d) reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one aspect, the anti-TGFβ2 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. In one aspect, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142. In another aspect, the antibody is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

[0027] In some embodiments of the above uses and medicaments for treating a TGFβ-associated disorder, the TGFβ-associated disorder is fibrosis. In some embodiments, the fibrosis is a fibrotic condition of the lung, liver, heart, kidney, pancreas, eye, and / or skin. In some aspects, the fibrosis is idiopathic pulmonary fibrosis (IPF), idiopathic upper lobe pulmonary fibrosis (Amitani disease), familial pulmonary fibrosis, pulmonary fibrosis (e.g., pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, idiopathic fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), or chronic asthma), cystic fibrosis, nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COPD), progressive massive fibrosis, scleroderma / systemic sclerosis (limited cutaneous type (lc)), or idiopathic pulmonary fibrosis (IPF), ... and pulmonary fibrosis selected from the group consisting of SSc, including diffuse cutaneous sclerosis (SSc) and diffuse cutaneous sclerosis (dcSSc), and SSc-related interstitial lung disease (SSc-ILD), bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), hypersensitivity pneumonitis, pulmonary hypertension, pulmonary tuberculosis, silicosis, asbestosis, acute lung injury, and acute respiratory distress (ARD, including bacterial pneumonia-induced, trauma-induced, and viral pneumonia-induced, ventilator-induced, and non-pulmonary sepsis-induced ARD). In some embodiments, the fibrosis is a fibrotic condition of the liver selected from the group consisting of cirrhosis, congenital hepatic fibrosis, obesity, fatty liver, alcohol-induced hepatic fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), infectious or virally induced liver fibrosis (e.g., chronic hepatitis B and C virus infection), cystic fibrosis, autoimmune hepatitis, necrotizing hepatitis, primary sclerosing cholangitis, hemochromatosis, disorders of the biliary system, and liver dysfunction due to infection. In some aspects, the fibrosis is a cardiac and / or pericardial fibrotic condition 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 artery infarction, varicose veins, coronary artery stenosis and other post-ischemic conditions, and idiopathic retroperitoneal fibrosis.In some aspects, the fibrosis is selected from the group consisting of glomerulonephritis (including membranoproliferative, diffuse proliferative, rapidly progressive or sclerosing, post-infectious and chronic), diabetic glomerulosclerosis, focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, ischemic nephropathy, tubulointerstitial renal fibrosis, 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 (affecting the kidneys among other tissues), autoimmune nephritis, renal tubulointerstitial fibrosis, renal arteriosclerosis, Alport syndrome, nephropathy, chronic renal failure, chronic kidney disease, periglomerular fibrosis / atubular glomeruli, combined apical fibrosis syndrome In some embodiments, the fibrosis is a fibrotic condition of the kidney selected from the group consisting of emphysema and basal fibrosis syndrome, glomerular hypertension, nephrogenic fibrosing dermopathy, polycystic kidney disease, Fabry disease, and renal hypertension. In some embodiments, the fibrosis is a fibrotic condition of the pancreas selected from the group consisting of interstitial remodeling pancreatitis and interstitial fibrosis. In some embodiments, 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, healing gastric ulcer, and microscopic colitis. In some aspects, the fibrosis is an ocular fibrotic condition 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, scarring of the cornea and conjunctiva, fibrosis of the corneal endothelium, anterior subcapsular cataract and posterior capsule opacification, fibrotic diseases of the anterior segment of the eye, fibrosis of the corneal stroma (e.g., associated with corneal opacification), fibrosis of the trabecular meshwork (e.g., associated with glaucoma), fibrotic diseases of the posterior segment of the eye, fibrovascular scarring (e.g., of the retinal or choroidal vasculature of the eye), retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis (e.g., associated with age-related macular degeneration), traction retinal detachment associated with tissue contraction in diabetic retinopathy, congenital orbital fibrosis, lacrimal gland fibrosis, epicorneal fibrosis, and Graves' ophthalmopathy.In some embodiments, the fibrosis is selected from fibrosis resulting from spinal cord injury / fibrosis or central nervous system fibrosis, such as post-stroke fibrosis; fibrosis associated with neurodegenerative disorders, such as Duchenne muscular dystrophy, Alzheimer's disease, or multiple sclerosis; fibrosis resulting from vascular restenosis, uterine fibrosis, endometriosis, ovarian fibroids, Peyronie's disease, polycystic ovary syndrome, disease-related apical pulmonary fibrosis in ankylosing spondylitis, scarring, and fibrosis associated with microbial (e.g., bacterial, viral, parasitic, fungal) infection. In specific embodiments, the fibrosis is SSc. In specific embodiments, the fibrosis is IPF. In specific embodiments, the fibrosis is chronic obstructive pulmonary disease (COPD). In specific embodiments, the fibrosis is advanced fibrosing interstitial lung disease (PF-ILD). In specific embodiments, the PF-ILD is a disease or condition selected from the group consisting of nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP), progressive massive fibrosis, complications of coal workers' pneumoconiosis, scleroderma / systemic sclerosis, bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), and hypersensitivity pneumonitis. In specific embodiments, the fibrosis is cirrhosis or chronic liver fibrosis. In specific embodiments, the fibrosis is GI tract fibrosis. In specific embodiments, the fibrosis is an ocular fibrotic condition, fibrosis due to spinal cord injury, fibrosis or central nervous system fibrosis, or fibrosis associated with a neurodegenerative disorder.

[0028] In another aspect, methods are provided for treating a subject having a TGFβ-associated disorder. In some embodiments, the methods comprise administering an effective amount of an antibody or pharmaceutical formulation according to any of the above aspects and embodiments to a subject in need thereof. In another aspect, methods are provided for inhibiting TGFBR-dependent SMAD signaling, inhibiting assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the endoglin-promoted TGFBR2 / ALK1 complex, and / or inhibiting de novo collagen synthesis in a subject. In some aspects, the methods comprise administering to a subject in need thereof an effective amount of an antibody according to any of the above aspects and embodiments, thereby inhibiting TGFBR-dependent SMAD signaling, inhibiting assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the endoglin-promoted TGFBR2 / ALK1 complex, and / or inhibiting de novo collagen synthesis in the subject. In some aspects, the methods comprise administering an additional therapeutic agent to the subject. In some aspects, the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, an IL-6 inhibitor (e.g., tocilizumab, sarilumab), an anti-CTFG antibody (e.g., FG-3019), an autotaxin inhibitor, and PTX2. In one embodiment of such a method, the antibody comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9;(a2) (i) heavy chain CDRs, including CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 34, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs, including CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7 and CDR-L2 has the amino acid sequence of SEQ ID NO: 8. (a3) (i) a heavy chain CDR consisting of CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3. (a4)(i) a light chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; or (a4)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6. heavy chain CDRs; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57, and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56;or (c) an anti-TGFβ3 antibody comprising a complete H / L chain pair, wherein the H chain of the H / L chain pair comprises the amino acid sequence of SEQ ID NO: 79 and the L chain of the H / L chain pair comprises the amino acid sequence of SEQ ID NO: 78. In another embodiment of such a method, the antibody is an anti-TGFβ2 antibody comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some aspects, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (d) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one aspect, the anti-TGFβ2 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. In one aspect, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142. In another embodiment of such a method, the antibody comprises: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 13;an anti-TGFβ2 / 3 antibody comprising a light chain CDR, wherein 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;

[0029] In a further aspect of the above method, the method may comprise administering to a subject an effective amount of an anti-TGFβ3 antibody and an effective amount of an anti-TGFβ2 antibody. In one embodiment, the anti-TGFβ3 antibody for use in such combination comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:8, CDR-L2 has the amino acid sequence of SEQ ID NO:9, (a3)(i) a light chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR consisting of CDR-L1, CDR-L2 and CDR-H3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; or (a4)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In another embodiment, the anti-TGFβ2 antibody comprises: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (d) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one embodiment, the anti-TGFβ2 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. In one embodiment, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142.

[0030] In further embodiments of the above methods for treating a TGFβ-associated disorder, the TGFβ-associated disorder can be fibrosis. In some embodiments, the fibrosis is a fibrotic condition of the lung, liver, heart, kidney, pancreas, eye, and / or skin. In some aspects, the fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), idiopathic upper lobe pulmonary fibrosis (Amitani disease), familial pulmonary fibrosis, pulmonary fibrosis (e.g., pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, idiopathic fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), or chronic asthma), cystic fibrosis, nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COPD), progressive massive fibrosis, scleroderma / systemic sclerosis (limited cutaneous type (lc)), and / or idiopathic pulmonary fibrosis (IPF). and pulmonary fibrosis selected from the group consisting of SSc, including diffuse cutaneous sclerosis (SSc) and diffuse cutaneous sclerosis (dcSSc), and SSc-related interstitial lung disease (SSc-ILD), bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), hypersensitivity pneumonitis, pulmonary hypertension, pulmonary tuberculosis, silicosis, asbestosis, acute lung injury, and acute respiratory distress (ARD, including bacterial pneumonia-induced, trauma-induced, and viral pneumonia-induced, ventilator-induced, and non-pulmonary sepsis-induced ARD). In some embodiments, the fibrosis is a fibrotic condition of the liver selected from the group consisting of cirrhosis, congenital hepatic fibrosis, obesity, fatty liver, alcohol-induced hepatic fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), infectious or virally induced liver fibrosis (e.g., chronic hepatitis B and C virus infection), cystic fibrosis, autoimmune hepatitis, necrotizing hepatitis, primary sclerosing cholangitis, hemochromatosis, disorders of the biliary system, and liver dysfunction due to infection. In some aspects, the fibrosis is a cardiac and / or pericardial fibrotic condition 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 artery infarction, varicose veins, coronary artery stenosis and other post-ischemic conditions, and idiopathic retroperitoneal fibrosis.In some aspects, the fibrosis is selected from the group consisting of glomerulonephritis (including membranoproliferative, diffuse proliferative, rapidly progressive or sclerosing, post-infectious and chronic), diabetic glomerulosclerosis, focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, ischemic nephropathy, tubulointerstitial renal fibrosis, 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 (affecting the kidneys among other tissues), autoimmune nephritis, renal tubulointerstitial fibrosis, renal arteriosclerosis, Alport syndrome, nephropathy, chronic renal failure, chronic kidney disease, periglomerular fibrosis / atubular glomeruli, combined apical fibrosis syndrome In some embodiments, the fibrosis is a fibrotic condition of the kidney selected from the group consisting of emphysema and basal fibrosis syndrome, glomerular hypertension, nephrogenic fibrosing dermopathy, polycystic kidney disease, Fabry disease, and renal hypertension. In some embodiments, the fibrosis is a fibrotic condition of the pancreas selected from the group consisting of interstitial remodeling pancreatitis and interstitial fibrosis. In some embodiments, 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, healing gastric ulcer, and microscopic colitis. In some aspects, the fibrosis is an ocular fibrotic condition 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, scarring of the cornea and conjunctiva, fibrosis of the corneal endothelium, anterior subcapsular cataract and posterior capsule opacification, fibrotic diseases of the anterior segment of the eye, fibrosis of the corneal stroma (e.g., associated with corneal opacification), fibrosis of the trabecular meshwork (e.g., associated with glaucoma), fibrotic diseases of the posterior segment of the eye, fibrovascular scarring (e.g., of the retinal or choroidal vasculature of the eye), retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis (e.g., associated with age-related macular degeneration), traction retinal detachment associated with tissue contraction in diabetic retinopathy, congenital orbital fibrosis, lacrimal gland fibrosis, epicorneal fibrosis, and Graves' ophthalmopathy.In some embodiments, the fibrosis is selected from fibrosis resulting from spinal cord injury / fibrosis or central nervous system fibrosis, such as post-stroke fibrosis; fibrosis associated with neurodegenerative disorders, such as Duchenne muscular dystrophy, Alzheimer's disease, or multiple sclerosis; fibrosis resulting from vascular restenosis, uterine fibrosis, endometriosis, ovarian fibroids, Peyronie's disease, polycystic ovary syndrome, disease-related apical pulmonary fibrosis in ankylosing spondylitis, scarring, and fibrosis associated with microbial (e.g., bacterial, viral, parasitic, fungal) infection. In specific embodiments, the fibrosis is SSc. In specific embodiments, the fibrosis is IPF. In specific embodiments, the fibrosis is chronic obstructive pulmonary disease (COPD). In specific embodiments, the fibrosis is advanced fibrosing interstitial lung disease (PF-ILD). In specific embodiments, the PF-ILD is a disease or condition selected from the group consisting of nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP), progressive massive fibrosis, complications of coal workers' pneumoconiosis, scleroderma / systemic sclerosis, bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), and hypersensitivity pneumonitis. In specific embodiments, the fibrosis is liver cirrhosis or chronic liver fibrosis. In specific embodiments, the fibrosis is GI tract fibrosis, e.g., 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, healing gastric ulcer, and microscopic colitis. In specific embodiments, the fibrosis is an ocular fibrotic condition, fibrosis due to spinal cord injury, fibrosis or central nervous system fibrosis, or fibrosis associated with a neurodegenerative disorder.

[0031] In another aspect, a method for diagnosing a subject with SSc is provided. In some embodiments, the method comprises detecting the expression levels of genes in an 18-gene signature set consisting of PRSS23, PXDN, COL8A1, COL6A3, SERPINE2, TNC, COMP, THBS1, COL11A1, COL1A1, COL5A2, COL1A2, COL4A1, COL4A2, SFRP4, ALPK2, COL5A1, and TAGLN, and diagnosing the subject with SSc if the level of the gene is determined to be elevated compared to the gene level in a healthy control set or reference gene signature. In some embodiments, a gene level is elevated if the increase in expression compared to the healthy control set or reference gene signature is statistically significant, optionally, if the increase is at least two-fold, at least three-fold, or at least four-fold compared to the healthy control set or reference gene signature. In some embodiments, the gene expression level is detected using qPCR, microarray, or RNA sequencing.

[0032] In another aspect, methods for monitoring a subject's response to treatment with an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody are provided. In some aspects, the methods include 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 doses of an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody. In some aspects, the subject is determined to be responsive to treatment with an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody if the expression level of one or more TGFβ-inducible genes is significantly reduced compared to the pre-treatment level of the one or more TGFβ-inducible genes, and optionally further comprising administering an additional anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody if the expression level of one or more TGFβ-inducible genes is determined to be significantly reduced. In some aspects, the anti-TGFβ2 antibody is administered to the subject as monotherapy. In some embodiments, the anti-TGFβ3 antibody is administered to the subject as monotherapy. In some embodiments, the expression level of one or more TGFβ-inducible genes is determined by qPCR or microarray analysis. In one embodiment of the above method, the antibody comprises: (a1)(i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a2)(i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 34, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a3)(i) a heavy chain CDR consisting of CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; or (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3 an anti-TGFβ3 antibody comprising: (i) a heavy chain CDR consisting of CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO: 57, and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO: 56; or (c) a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 79, and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO: 78. In another embodiment of the above method, the antibody is an anti-TGFβ2 antibody comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 19;a light chain CDR, wherein 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. In one embodiment, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (d) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one embodiment, the anti-TGFβ2 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. In one aspect, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142;

[0033] In any of the above aspects and embodiments for the uses, medicaments, and methods of treatment and diagnosis, and methods of monitoring response to treatment, the subject may be a human, e.g., a human patient.

[0034] In another aspect, a kit is provided comprising the antibody of any of the above aspects and embodiments. In one embodiment of the kit, the antibody comprises: (a1) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 5, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7 and CDR-L2 has the amino acid sequence of SEQ ID NO: 8; (a2)(i) a light chain CDR comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO:4, CDR-H2 has the amino acid sequence of SEQ ID NO:34, and CDR-H3 has the amino acid sequence of SEQ ID NO:6; and (ii) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7. wherein CDR-L2 has the amino acid sequence of SEQ ID NO: 8 and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a3) (i) a heavy chain CDR consisting of CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 35 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) CDR-L1, CDR-L2 and CDR-L3 (a4)(i) a light chain CDR comprising CDR-H1, CDR-H2 and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of SEQ ID NO: 159 and CDR-H3 has the amino acid sequence of SEQ ID NO: 6;and (ii) a light chain CDR comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO:7, CDR-L2 has the amino acid sequence of SEQ ID NO:8, and CDR-L3 has the amino acid sequence of SEQ ID NO:9; (b) a VH / VL, wherein the VH of the VH / VL pair has the amino acid sequence of SEQ ID NO:57 and the VL of the VH / VL pair has the amino acid sequence of SEQ ID NO:56; or (c) an anti-TGFβ3 antibody comprising a complete H / L chain pair, wherein the H chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:79 and the L chain of the H / L chain pair has the amino acid sequence of SEQ ID NO:78. In another embodiment of the kit, the antibody is an anti-TGFβ2 antibody comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. In one aspect, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In some embodiments, the anti-TGFβ2 antibody (a) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (b) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib;and / or (d) reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib. In one aspect, the anti-TGFβ2 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. In one aspect, the anti-TGFβ2 antibody comprises a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142. In another embodiment of the kit, the antibody is an anti-TGFβ2 / 3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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. [Brief explanation of the drawings]

[0035] [Figure 1]Figure 1 shows the primary amino acid sequence alignment of human TGFβ1, 2, and 3 with the following accession numbers: huTGFβ1: XP_011525544.1, huTGFβ2: NP_003229.1, and huTGFβ3: ABQ59024.1, along with the domains of TGFβ1 (α-sheet and β-strand, latency lasso, fastener, integrin binding, furin cleavage, and cytokine) as indicated by Shi et al., Nature 474:343 (2011). Residues are numbered from the predicted ATG (methionine) start site; the Shi et al. numbering begins at L30 at the start of the α1 helix. The black arrow below the sequence indicates the start of the receptor-binding domain. Frameshift, premature stop, and splice site mutations reported for TGFβ2 and TGFβ3 have been omitted for clarity. The sequences shown correspond to SEQ ID NOs: 1-3, respectively. [Figure 2A] FIG. 2A shows the pharmacokinetic profile of 6F12 muIgG2a antibody given as a single 1 or 10 mg / kg IV and 10 mg / kg IP dose in C57BL6 mice (n=3 / time point). [Figure 2B] Figure 2B shows the pharmacokinetic profiles of 16C10 muIgG2a, 15A7 muIgG2a, 18B5 muIgG2a, 2A10 muIgG2a and a non-binding anti-gD huIgG1 control antibody given as a single 10 mg / kg IV dose in C57BL6 mice (n=3 / time point). [Figure 2C] Figure 2C shows the pharmacokinetic profiles of 4A11 muIgG2a given as a single dose of 1 or 10 mg / kg IV and 10 mg / kg IP, and 6F12 muIgG2a antibody given as a single dose of 10 mg / kg IV in C57BL6 mice (n=3 / time point). [Figure 3A]Figure 3A is a graph showing expression levels determined from microarray analysis of TGFβ isoforms in bulk lung biopsy tissue from control (n=8) and IPF (n=40) lungs. The data show elevated expression of TGFβ2 and TGFβ3, but not TGFβ1, in IPF. **P<0.01; ****P<0.0001 (unpaired, two-tailed Student's t-test). [Figure 3B] FIG. 3B is an image of pSMAD2 / 3 immunohistochemistry (IHC) of control and IPF lung tissues showing increased nuclear pSMAD staining in fibroblastic foci in IPF lung tissue. [Figure 4A] Figure 4A shows a t-SNE plot representing single-cell RNA-seq data (n = 3, total) from IPF lungs, demonstrating the expression of multiple labeled epithelial, mesenchymal, and hematopoietic cell lineages. Expression of individual TGFβ isoforms showed widespread expression of TGFβ1, primarily in hematopoietic and endothelial cells; TGFβ2 expression primarily in epithelial cells; and TGFβ3, primarily present in mesenchymal cells. Expression of TGFβ target genes showed strong overlap between TGFβ3 expression in fibroblasts and myofibroblasts and that of SERPINE1, COL1A1, POSTN, and COMP. SERPINE1 also overlaps with TGFβ1 expression in endothelial cells and macrophages, as well as with POSTN in endothelial cells. [Figure 4B] Figure 4B is an image of double IHC for pSMAD3 and in situ hybridization (ISH) for TGFβ3, showing colocalization of TGFβ3 mRNA and nuclear pSMAD3 in multiple cells in fibroblastic foci in IPF lung tissue. [Figure 5A] Figure 5A contains plots showing the expression of TGFβ isoforms determined from microarray analysis of skin biopsies taken from healthy controls (HCs) and patients with systemic sclerosis (SSc) at baseline enrolled in the FaSScinate trial. [Figure 5B]Figure 5B shows the TGFβR signaling-dependent skin gene expression signature derived by comparing genes induced in fibroblasts treated in vitro with recombinant TGFβ1 receptor-binding domain with genes significantly upregulated in SSc compared with control skin biopsies. Genes significantly elevated in both conditions were selected as candidate TGFβ signatures in SSc skin. [Figure 6A] Figure 6A is a plot showing principal component 1 of the signature defined in Figure 5B, derived as a continuous variable for the magnitude of TGFβR-dependent gene expression across all signature genes in SSc skin biopsies and compared with TGFβ isoform expression levels in those biopsies. Both "TGFβ-high" and "TGFβ-low" SSc patients had higher levels of this gene signature than healthy controls, and the skin biopsy TGFβ gene signature was highly correlated with TGFβ3 but not with TGFβ1 or TGFβ2 expression. [Figure 6B] Figure 6B is a table showing the cross-correlation between the TGFβ-induced skin gene signature metrics as determined in Figure 4C and skin gene expression levels of TGFβ isoforms, POSTN and COMP; and with serum levels of POSTN and COMP protein in the FaSScinate study. [Figure 6C] FIG. 6C is a table summarizing the correlation between serum periostin and COMP levels and the modified Rodan skin score (MRSS), a clinical measure of generalized dermal fibrosis used in the FaSScinate study. [Figure 7] Figure 7 includes plots showing the distribution of change in MRSS from baseline to 48 weeks for patients in the FaSScinate study, stratified by baseline TGFβ skin gene signature cluster. PBO: placebo; TCZ: tocilizumab treatment; Cum Prob: cumulative probability of change in MRSS. [Figure 8A-F]Figures 8A–F show microarray-derived expression of TGFβ1 (Figure 8A), TGFβ2 (Figure 8B), TGFβ3 (Figure 8C), COL1A1 (Figure 8D), Serpine1 (Figure 8E), and Fn1 (Figure 8F) at the indicated times after it bleomycin instillation. Expression of TGFβ2, TGFβ3, COL1A1, Serpine1, and Fn1 followed similar kinetics, peaking between days 7 and 14 after bleomycin. *, P<0.05; **, P<0.01; ***, P<10; ****, P<10 by unpaired, two-tailed Student's t-test. Data represent the mean ± SEM. [Figure 9A] Figure 9A is a schematic diagram of an in vivo IT bleomycin experiment to assess the efficacy of TGFβ antibodies. Separate cohorts of animals were sacrificed on days 14 or 24 to assess lung gene expression during peak TGFβ2 / 3 expression or lung collagen toward the end of the "fibrotic" phase, respectively. Animals were provided with deuterated drinking water from days 9 to 23, and the rate of new collagen production (deuterated hydroxyproline) was assessed during that period. [Figure 9B] Figure 9B is a plot showing the reduction in the level of deuterated lung fraction relative to total hydroxyproline by prophylactic administration of anti-TGFβ2 and / or TGFβ3 antibodies (10 mpk, TIW) on day 24. Each dot represents an individual animal. [Figure 9C] Figure 9C is a plot showing the reduction in pulmonary gene expression levels of FN1 at 14 days after it bleomycin instillation with prophylactic administration of anti-TGFβ2 and / or TGFβ3 antibodies (10 mpk, TIW). **P<0.01; ***P<0.001; ****P<0.0001 (one-way ANOVA with Dunnett's test). [Figure 9D-E]Figures 9D and 9E are plots showing the effect of coadministration of 6F12 and 2A10 (10 mpk, TIW) or 4A11 at 10 mpk TIW, 10 mpk QW, or 2.5 mpk QW on total hydroxyproline (Figure 9D) and deuterated hydroxyproline (Figure 9E) at 24 days after it bleomycin. Similar reductions were observed with 10 mpk 4A11 QW versus TIW, but the effect was reduced with 2.5 mpk QW. **P<0.01; ***P<0.001; ****P<0.0001 (one-way ANOVA with Dunnett's test). [Figure 10] FIG. 10 is a schematic diagram showing attempts to express various humanized variants of the 2A10b mAb. [Figure 11] FIG. 11 is a table showing the loss of expression and stability of most h2A10v1 variants during framework and CDR polishing. [Figure 12] Figure 12 is a diagram containing an amino acid sequence alignment of the light chain variable region sequences (upper panel) and heavy chain variable region sequences (lower panel) of the rat 2A10 antibody and its humanized variants v1 to v4; the amino acid sequences shown in the figure are SEQ ID NOs: 22, 36, 36, 54, and 56 (upper panel, from top to bottom in the alignment), and SEQ ID NOs: 23, 37, 45, 55, and 57 (lower panel, from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 13] Figure 13 includes an amino acid sequence alignment of the light chain variable regions of rat 2A10 and humanized h2A10 v2 variants, v2-v2.9; the sequences shown correspond to SEQ ID NOs: 22, 36, 38, 39, 40, 41, 36, 36, 36, 36, and 36 (from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 14]Figure 14 includes an amino acid sequence alignment of the heavy chain variable regions of rat 2A10 and humanized h2A10 v2 variants, v2-v2.9; the sequences shown correspond to SEQ ID NOS: 23, 45, 45, 45, 45, 45, and 46-50 (from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 15] Figure 15 includes an amino acid sequence alignment of the light chain variable region sequences (upper panel) and heavy chain variable region sequences (lower panel) of the rat 2A10 antibody and the humanized v2 variant; the amino acid sequences shown are SEQ ID NOs: 22, 36, 36, 36, and 36 (upper panel, from top to bottom in the alignment), and SEQ ID NOs: 23, 45, and 51-53 (lower panel, from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 16] Figure 16 includes an amino acid sequence alignment of the light chain variable region sequence (upper panel) and the heavy chain variable region sequence (lower panel) of the rat 2A10 antibody and its humanized v4 variant; the amino acid sequences shown in the figure are SEQ ID NOs: 22 and 56 (upper panel, from top to bottom in the alignment), and SEQ ID NOs: 23 and 57 (lower panel, from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 17] FIG. 17 is a line graph showing the mean (±SD) serum concentrations of h2A10v3 and h2A10v4 after a single IV dose of 10 mg / kg in a cynomolgus monkey PK study (n=4 / group). [Figure 18]Figure 18 contains an amino acid sequence alignment of the light chain variable regions of rabbit 4A11 mAb and its humanized variants v1-v8; the sequences shown correspond to SEQ ID NOs: 26, 80, 82, 80, 82, 84, 85, 84, and 84 (from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 19] Figure 19 contains an amino acid sequence alignment of the heavy chain variable regions of rabbit 4A11 and humanized variants v1-v8; the sequences shown correspond to SEQ ID NOs: 27, 81, 81, 83, 83, 81, 81, 83, and 83 (from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 20] Figure 20 includes an amino acid sequence alignment of the light chain variable regions of humanized 4A11 variants v7-v7.19; the sequences shown correspond to SEQ ID NOs: 84, 84, 84, 84, 89-92, 101, 101, 101, and 101 (from top to bottom in the alignment). Residue numbering is according to Kabat; * indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 21] Figure 21 includes an amino acid sequence alignment of the heavy chain variable regions of humanized 4A11 variants v7-v7.19; the sequences shown correspond to SEQ ID NOs: 83, 86, 87, 88, 83, 83, 83, 83, 93-100, and 102-105 (from top to bottom in the alignment). Residue numbering is according to Kabat; * indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 22]Figure 22 includes an amino acid sequence alignment of the light chain variable region sequences (upper panel) and heavy chain variable region sequences (lower panel) of rabbit 6F12 antibody and humanized variants v1 to v4; the amino acid sequences shown in the figure are SEQ ID NOs: 24, 131, 131, 143, and 144 (upper panel, from top to bottom in the alignment), and SEQ ID NOs: 25, 132, 142, 132, and 142 (lower panel, from top to bottom in the alignment). Residue numbering is according to Kabat; "*" indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 23] Figure 23 contains an amino acid sequence alignment of the light chain variable regions of humanized 6F12 v1 variants v1-v1.9. The sequences shown correspond to SEQ ID NOs: 131, 133-137, 131, 131, 131, and 131 (from top to bottom in the alignment). Residue numbering is according to Kabat; * indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 24] Figure 24 contains an amino acid sequence alignment of the heavy chain variable regions of humanized 6F12 v1 variants v1-v1.9. The sequences shown correspond to SEQ ID NOs: 132, 132, 132, 132, 132, 132, and 138-141 (from top to bottom in the alignment). Residue numbering is according to Kabat; * indicates a Vernier zone. CDR regions according to Chothia or Kabat (as designated) are boxed; mutated residues are highlighted. [Figure 25] FIG. 25 is an image of the crystal structure of 2A10 in complex with human TGFβ3. [Figure 26] Figure 26 is an image of TGFβ3 bound to 2A10, compared to TGFβ1 and the TGFBR1 / TGFBR2 complex, indicating that 2A10 likely sterically blocks the recruitment of TGFBR2, but not TGFBR1. [Figure 27]Figure 27 is an image comparing the pan-TGFβ antibody fresolimumab ("freso") with 2A10. Fresolimumab blocks binding to both TGFβ3 and TGFBR1 / TGFBR2, whereas 2A10 blocks binding only to TGFBR2 due to a different binding angle. [Figure 28] Figure 28 shows the epitope on TGFβ3 bound by 2A10. 2A10 binds to the beta hairpin at the tip of the beta6-beta7 "finger" of TGFβ3 via R394. Polar contacts are also made between R325 and K331. [Figure 29] FIG. 29 shows the epitope on TGFβ3 bound by 2A10; residues involved in binding of TGFβ3 by 2A10 within 5.0 Å are labeled. [Figure 30] Figure 30 shows the 2A10 antibody paratope (residue numbering according to Kabat). R394 on TGFβ3 makes contact with D50 of 2A10. [Figure 31] Figure 31 shows the TGFβ3 / 2A10 epitope and comparison with TGFβ1. TGFβF1 has three changes in epitope residues compared to TGFβ3. The P387T, L389V, and T395K substitutions slightly alter the conformation of the β-hairpin and β6-β7 fingers of TGFβ2 and may remove some beneficial contacts with 2A10. [Figure 32] Figure 32 shows the TGFβ3 / 2A10 epitope and comparison with TGFβ2. TGFβ2 has four changes in epitope residues when compared to TGFβ3. The primary reason for TGFβ3 versus TGFβ2 specificity is likely due to the R394K change, which removes an optimized salt bridge in the epitope R394-D50 and V398I and adds a potential steric clash. [Figure 33] Figure 33 shows a comparison of TGFβ2 binding for 4A11v2 (left panel) and 4A11v7 (right panel). The antigen-antibody complexes are very similar. Upon binding, the heavy chains are brought into close proximity, but the elbow angle for binding of the second Fab is different. [Figure 34]Figure 34 shows a comparison of 4A11v2 / TGFβ2 and TGFβ3 / receptor complexes. 4A11v2 does not directly compete with the TGFBR1 / 2 binding site; rather, 4A11v2 slightly alters the structure of TGFβ2, "sandwiching" the fingers. This may be the result of a steric clash between 4A11v2 Fabs. [Figure 35] Figure 35 shows the TGFβ2 epitope bound by 4A11. The glutamic acid at position E373 of the amino acid sequence of TGFβ2 (TGFβ2 numbering) is located in the center of the contact interface. Like TGFβ2, TGFβ3 also has a glutamic acid at this position, while TGFβ1 has a glycine. [Figure 36] Figure 36 includes diagrams showing conformational changes in TGFβ2 (right panel) and TGFβ2 (left panel) from fresolimumab ("freso") complexes induced by 4A11v2. Conformational changes in TGFβ2 structure may alter the ability of signaling receptors to bind to TGFβ2. 4A11 may also block access of membrane-tethered receptors by binding to the membrane-proximal side of TGFβ2 or TGFβ3. [Figure 37] Figure 37 is a cartoon showing TGFβ2 from the 4A11v2 complex (left image) and TGFβ3 from the TGFβR1 / TGFβR2 complex. Conformational changes in the TGFβ2 structure can alter the ability of TGFBR1 to bind to one monomer. [Figure 38] FIG. 38 shows heavy chain interactions of 4A11v2 (left structure) and 4A11v7 (right structure) residues; VH framework interactions are complementary in both structures. [Figure 39] Figure 39 shows a comparison of the 4A11v2 and 4A11v7 VH frameworks. In 4A11v2, Q81 is packed against R19 in a high-energy rotator and awkward position. In 4A11v7, K81 forms a weak H-bond to S79, so the framework residues of v2 are likely repulsive, while the v7 residues are more tolerant. [Figure 40] FIG. 40 includes pictures showing monovalent (left panel) and bivalent (right panel) 4A11 binding to TGFβ2. [Figure 41]Figure 41 is a graph plotting the relative luciferase activity of MLEC reporter cells after coculture with 293T cells transfected with plasmids encoding FL-TGFβ1 or FL-TGFβ3 (wild-type or RGE mutant), with or without plasmids encoding integrins αv and β6. **, P<0.01; ***, P<10-3; ****, P<10-4; NS, P>0.05 by unpaired, two-tailed Student's t-test. [Figure 42] Figure 42 is a graph plotting relative luciferase activity in supernatants (SN) from MLEC reporter cells (measuring TGFβ activity). SN was collected from cells transfected with plasmids encoding FL-TGFβ1, FL-TGFβ2, FL-TGFβ3, or empty vector (control). Supernatants were acidified (HCl treatment) as indicated. **, P<0.01; ***, P<10-3; ****, P<10-4; NS, P>0.05 by unpaired, two-tailed Student's t-test. [Figure 43A-B] Figures 43A and 43B are graphs plotting TGFβ activity as assessed by alkaline phosphatase released by HEK-Blue TGFβ reporter cells (Figure 43A) or in an MLEC reporter cell assay (relative luciferase activity) (Figure 43B). In Figure 43A, supernatants (SN) were collected from 293T cells transfected with plasmids encoding FL-TGFβ1, FL-TGFβ2, FL-TGFβ3, or an empty vector (control). In Figure 43B, SN was collected from COS-7 cells transfected with plasmids encoding FL-TGFβ1, FL-TGFβ3, or an empty vector (control). **, P<0.01; ***, P<0.001; ****, P<10-4; NS, P>0.05 by unpaired, two-tailed Student's t-test. Data are mean ± SEM from triplicate experiments. Error bars are not shown if they are shorter than the size of their corresponding symbols. [Figure 44]Figure 44 is a graph plotting TGFβ activity (relative luciferase activity) assessed by MLEC reporter cell assay. 293T cells were transfected with plasmids encoding various forms of FL-TGFβ and integrins αv and β6. TGFβ activity was measured using MLEC reporter cells after co-culture. Where indicated ("Cyto D"), cytochalasin D (30 μM) was added at the initiation of co-culture. "MLE" is the control. **, P<0.01; ***, P<0.001; ****, P<10-4; NS, P>0.05 by unpaired, two-tailed Student's t-test. [Figure 45] Figure 45 is a graph plotting TGFβ activity assessed by MLEC reporter cell assay (relative luciferase activity) in supernatants collected from 293T cells transfected with plasmids encoding wild-type or furin-site mutant FL-TGFβ proteins, demonstrating loss of TGFβ activity by the mutant proteins. **, P<0.01; ***, P<0.001; ****, P<10-4; NS, P>0.05 by unpaired, two-tailed Student's t-test. Data are means ± SEM from experiments performed in triplicate. Error bars are not shown if they are shorter than the size of their corresponding symbols. [Figure 46] Figure 46 shows images of Western blots showing the kinetics of Smad2 phosphorylation in NHLF cells treated with recombinant protein or supernatant. As a control, NHLF cells were also treated with supernatant from non-transfected cells (SN.ctr1) or recombinant BMP2 for 1 hour. To control for loading between different samples, the protein concentration of the supernatant was measured by BCA, and 20 μg of protein was loaded per lane. [Figure 47]Figure 47 is a graph plotting TGFβ activity (relative luciferase activity) measured in MLEC reporter cells after incubation with a range of concentrations of human Fc-FL-TGFβ isoform fusion protein. "Background" means no fusion protein was added. Data are means ± SEM from triplicate experiments; error bars are not shown if they are shorter than the size of their corresponding symbols. [Figure 48] Figure 48 is a graph plotting TGFβ activity (relative luciferase activity) measured in MLEC reporter cells after incubation with human Fc-FL-TGFβ2 or Fc-FL-TGFβ3 fusion proteins (30 ng / ml) and isoform-specific antibodies: 19D8 (anti-TGFβ1); 6F12 (anti-TGFβ2); 2A10 (anti-TGFβ3); and 1D11 (pan-anti-TGFβ) at 3 μg / ml. "Background" means no fusion protein was added. "None" means no antibody was added. Data are means ± SEM from experiments performed in triplicate; error bars are not shown if they are shorter than the size of their corresponding symbols. [Figure 49] FIG. 49 is a table showing the primary amino acid sequence similarity (%) between the latency-associated peptide (LAP) and mature domain (active) human TGFβ isoforms. [Figure 50A-C] Figures 50A, 50B, and 50C are graphs showing titration curves from MLEC reporter cell assays (TGFβ activity) after incubation of mature peptides (1 ng / ml) of TGFβ1, TGFβ2, or TGFβ3 (left to right graphs) with a range of concentrations of human Fc-LAP fusion protein as indicated. Data are means ± SEM from experiments performed in triplicate; error bars are not shown if they are shorter than the size of their corresponding symbols. [Figure 51] FIG. 51 is a table showing IC50s based on the titration curves shown in FIG. [Figure 52A-B]Figures 52A and 52B are graphs showing the percentage (%) of de novo hydroxyproline (mean ± SEM) measured as an index of newly synthesized collagen in WT or TGFβ isoform CKO mice. In Figure 52A, n = 5 (each saline group), n = 20 (WT, bleomycin-treated ("BLM")), and n = 24 mice (β2.cKO, BLM); in Figure 52B, n = 7 (WT, saline), n = 14 (WT, BLM), n = 13 (β3.cKO, BLM), and n = 13 (β2 / 3.cDKO, BLM); *P < 0.05, ***P < 0.001 by one-way ANOVA with Dunnett's test. [Figure 53A-B] Figures 53A and 53B are bar graphs plotting whole lung gene expression of Serpine1, Fn1, and Col1a1 as determined by quantitative RT-PCR 14 days after IT saline or bleomycin instillation and treatment with isotype control antibody, anti-TGFβ2 antibody (6F12) (Figure 53A) or anti-TGFβ3 antibody (2A10) (Figure 53B). In Figure 53A, n=5 (saline), n=15 (control, bleomycin ("BLM")), and n=14 (6F12, BLM); in Figure 53B, n=5 (saline), n=19 (control, BLM), and n=20 mice (2A10, BLM). By one-way ANOVA with Dunnett's test, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, NS, P>0.05. [Figure 53C]Figure 53C is a bar graph plotting newly synthesized collagen levels determined 24 days after instillation of saline (n=10) or bleomycin ("BLM"). Animals were treated with either an isotype control (n=21), a combination of 6F12 and 2A10 (n=23), or an anti-TGFβ2 / 3 antibody (4A11). 4A11 dose levels were high (10 mg / kg; 3 times / week, n=23); intermediate (10 mg / kg; 1 time / week, n=24); or low (2.5 mg / kg; 1 time / week, n=23). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, NS, P>0.05 by one-way ANOVA with Dunnett's test. [Figure 53D] Figure 53D is a bar graph plotting disease scores determined by pathology analysis. Mouse lungs were harvested 24 days after either saline (n=5) or bleomycin ("BLM") instillation and treated with either isotype control (n=7) or 4A11 (high dose, n=12). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, NS, P>0.05 by one-way ANOVA with Dunnett's test. [Figure 53E] Figure 53E contains representative mouse lung images of immunohistochemical staining for collagen III. [Figure 54A] Figure 54A contains a bar graph plotting the relative gene expression levels of TGFβ isoforms in livers from NASH patients with mild fibrosis (F0 and F1) (N=40) versus severe fibrosis (F3 and F4) (N=32). [Figure 54B] FIG. 54B contains dot plots showing the relative gene expression levels of TGFβ isoforms in mouse liver as determined by quantitative RT-PCR 6 weeks after the initiation of vehicle or CCl4 treatment; n=8 for both groups. [Figure 54C]Figure 54C contains bar graphs plotting hepatic gene expression of Col1a1 and Col3a1 as determined by quantitative RT-PCR 6 weeks after the initiation of vehicle or CCl4 treatment; animals were treated prophylactically with either isotype control or 4A11; n=8 for all groups. *P<0.05 by unpaired, two-tailed Student's t-test; **, P<0.01; ****, P<10-4; NS, P>0.05 (A and B); **P<0.01 by one-way ANOVA with Dunnett's test. [Figure 54D] Figure 54D is a bar graph plotting liver pathology scores determined by histopathological analysis; mouse livers were harvested 6 weeks after vehicle or CCl4 treatment; n = 8 for all groups. *P < 0.05 by unpaired, two-tailed Student's t-test; **, P < 0.01; ****, P < 10-4; NS, P > 0.05 (A and B); **P < 0.01 by one-way ANOVA with Dunnett's test. [Figure 55A] FIG. 55A is a table showing the binding affinities (KD) of antibodies 6F12 and 4A11 for human TGFβ2 and mouse TGF2 as determined by Biacore SPR. [Figure 55B] Figure 55B includes a line graph plotting TGFβ activity as measured in MLEC reporter cells. Human or mouse TGFβ2 mature peptide (1 ng / ml) was incubated with a range of concentrations of 6F12 or 4A11 antibodies. The curves are best fitted to a dose-response inhibition model. BKGD (background), no mature peptide was added. [Figure 56A] FIG. 56A is a schematic diagram of a colitis model for assessing the enhanced inflammatory response associated with anti-TGFβ antibodies. [Figure 56B] Figure 56B provides colon weights (grams) measured on day 24 in the colitis model of Figure 56A. N=10 for all groups except the untreated group (n=6). [Figure 56C]Figure 56C provides the relative expression of inflammatory genes (analyzed from colonic RNA) in the colitis model in Figure 56A. Three to five mice from each group were analyzed, as indicated. [Figure 56D] Figure 56D summarizes the number of immune cells in the lamina propria of the remaining mice in each group (3-5 / group) in the colitis model shown in Figure 56A, as determined by flow cytometry using these surface markers. DETAILED DESCRIPTION OF THE INVENTION

[0036] I. Definition As used herein, the terms "tumor necrosis factor β" and "TGFβ" are used interchangeably and, unless otherwise specified, refer to any naturally occurring TGFβ isoform from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). This term encompasses "full-length," unprocessed TGFβ and any form of TGFβ resulting from processing in cells. This term also encompasses naturally occurring variants of TGFβ, such as splice variants or allelic variants. TGFβ isoforms have precursor (immature) and mature forms. As shown in Figure 1, the latency-associated peptide is cleaved intracellularly by the furin protease and forms a noncovalent interaction with the receptor-binding domain. This complex is secreted from cells either alone or covalently bound via the latency-associated peptide to "environmental" molecules such as GARP, LRRC33, or latent TGFβ-binding proteins (LTBPs) 1-4. The complex of LAP and the receptor-binding domain is called the small latent complex (SLC), and the complex of LAP, the receptor-binding domain, and environmental molecules is called the large latent complex (LLC).

[0037] The amino acid sequences of TGFβ1, TGFβ2, and TGFβ3 are as follows:

[0038] Human TGFβ1 MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSELREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSNRLLAPSDSPEWLSFDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLATIHGMNRPFLLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS (SEQ ID NO: 1).

[0039] Human TGFβ2 MHYCVLSAFLILHLVTVALSLSTCSTLDMDQFMRKRIEAIRGQILSKLKLTSPPEDYPEPEEVPPEVISIYNSTRDLLQEKASRRAAACERERSDEEYYAKEVYKIDMPPFFPSENAIPPTFYRPYFRIVRFDVSAMEKNASNLVKAEFRVFRLQNPKARVPEQRIELYQILKSKDLTSPTQRYIDSKVVKTRAEGEWLSFDVTDAVHEWLHHKDRNLGFKISLHCPCCTFVPSNNYIIPNKSEELEARFAGIDGTSTYTSGDQKTIKSTRKKNSGKTPHLLLMLLPSYRLESQQTNRRKKRALDAAYCFRNVQDNCCLRPLYIDFKRDLGWKWIHEPKGYNANFCAGACPYLWSSDTQHSRVLSLYNTINPEASASPCCVSQDLEPLTILYYIGKTPKIEQLSNMIVKSCKCS (SEQ ID NO: 2).

[0040] Human TGFβ3 MKMHLQRALVVLALLNFATVSLSLSTCTTLDFGHIKKKRVEAIRGQILSKLRLTSPPEPTVMTHVPYQVLALYNSTRELLEEMHGEREEGCTQENTESEYYAKEIHKFDMIQGLAEHNELAVCPKGITSKVFRFNVSSVEKNRTNLFRAEFRVLRVPNPSSKRNEQRIELFQILRPDEHIAKQRYIGGKNLPTRGTAEWLSFDVTDTVREWLLRRESNLGLEISIHCPCHTFQPNGDILENIHEVMEIKFKGVDNEDDHGRGDLGRLKKQKDHHNPHLILMMIPPHRLDNPGQGGQRKKRALDTNYCFRNLEENCCVRPLYIDFRQDLGWKWVHEPKGYYANFCSGPCPYLRSADTTHSTVLGLYNTLNPEASASPCCVPQDLEPLTILYYVGRTPKVEQLSNMVVKSCKCS (SEQ ID NO: 3).

[0041] As used herein, the term "TGFβ1," unless otherwise indicated, refers to any native TGFβ1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed TGFβ1 and any form of TGFβ1 that results from processing in cells. The term also encompasses naturally occurring variants of TGFβ1, such as splice variants or allelic variants. The amino acid sequence of an exemplary human TGFβ1 is shown in Figure 1 (SEQ ID NO: 1).

[0042] As used herein, the term "TGFβ2," unless otherwise indicated, refers to any native TGFβ2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed TGFβ2 and any form of TGFβ2 that results from processing in a cell. The term also encompasses naturally occurring variants of TGFβ2, such as splice variants or allelic variants. The amino acid sequence of an exemplary human TGFβ2 is shown in Figure 1 (SEQ ID NO: 2).

[0043] As used herein, the term "TGFβ3," unless otherwise indicated, refers to any native TGFβ3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed TGFβ3 and any form of TGFβ3 that results from processing in cells. The term also encompasses naturally occurring variants of TGFβ3, such as splice variants or allelic variants. The amino acid sequence of an exemplary human TGFβ3 is shown in Figure 1 (SEQ ID NO: 3).

[0044] As used herein, the term "TGFβ" refers to any one, two or all three of the TGFβ isoforms TGFβ1, TGFβ2 and TGFβ3, as defined above.

[0045] As used herein, the terms "specifically binds" and "specifically binds to" refer to an antibody that selectively or preferentially binds to its target antigen. Preferably, the binding affinity for the antigen is greater than or equal to 10 -9 mol / l or less (e.g., 10 -10 K (mol / l) D value, preferably 10 -10 mol / l or less (e.g., 10 -12 K in mol / l D The binding affinity is determined by standard binding assays such as surface plasmon resonance technology (BIACORE®).

[0046] As used herein, the term "anti-TGFβ antibody" refers to an antibody that specifically binds to one or more TGFβ isoform(s). Thus, as used herein, the term "anti-TGFβ3 antibody" refers to a monospecific antibody that specifically binds to TGFβ3, the term "anti-TGFβ2 antibody" refers to a monospecific antibody that specifically binds to TGFβ2 (e.g., human TGFβ2), the term "anti-TGFβ2 / 3 antibody" refers to a bispecific antibody that specifically binds to TGFβ2 (e.g., human TGFβ2) and TGFβ3 (e.g., human TGFβ3), the term "anti-TGFβ1 antibody" refers to a monospecific antibody that specifically binds to TGFβ1 (e.g., human TGFβ1), and the term "pan-specific TGFβ antibody" refers to an antibody that binds to all three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3, e.g., human TGFβ1, TGFβ2, and TGFβ3). Anti-TGFβ antibodies described herein that are mono- or bispecific for a TGFβ isoform(s) are also referred to herein as "isoform-selective anti-TGFβ antibodies." In one embodiment, the extent of binding of an isoform-selective anti-TGFβ antibody (e.g., an anti-TGFβ1 antibody, an anti-TGFβ2 antibody, an anti-TGFβ2 / 3 antibody, or an anti-TGFβ3 antibody) to the TGFβ isoform(s) for which the antibody is not specific is less than about 10% of the binding of the antibody to its target TGFβ isoform(s), as measured, for example, by radioimmunoassay (RIA) or surface plasmon resonance (SPR). In another embodiment, the extent of binding of an isoform-selective anti-TGFβ antibody to a TGFβ isoform(s) for which the antibody is not specific is less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or preferably less than about 1% of the binding of the antibody to its target TGFβ isoform(s), as measured, for example, by RIA or SPR. In one embodiment, an isoform-selective anti-TGFβ antibody refers to an antibody that can bind to the TGFβ isoform(s) for which it is specific with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic in targeting TGFβ isoform(s).In one embodiment, the extent of binding of an isoform-selective anti-TGFβ antibody to unrelated proteins is less than about 10%, or less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or preferably less than about 1% of the binding of the isoform-selective anti-TGFβ antibody, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the anti-TGFβ antibody has a binding activity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In a preferred embodiment, the isoform-selective anti-TGFβ antibody has a K D It has.

[0047] As used herein, with respect to the isoform-selective anti-TGFβ antibodies described herein, the term "selectively neutralizes" and grammatical variations thereof means that the antibody specifically binds to and neutralizes an isoform(s) selectively but does not neutralize other isoform(s). Thus, for example, an anti-TGFβ1 antibody that selectively neutralizes TGFβ1 will not neutralize TGFβ2 or TGFβ3; an anti-TGFβ2 antibody that selectively neutralizes TGFβ2 will not neutralize TGFβ1 or TGFβ3; an anti-TGFβ3 antibody that selectively neutralizes TGFβ3 will not neutralize TGFβ1 or TGFβ2; and an anti-TGFβ2 / 3 antibody that selectively neutralizes TGFβ2 and TGFβ3 will not neutralize TGFβ1. In certain embodiments, isoform-selective anti-TGFβ antibodies as described herein specifically bind to an epitope of a TGFβ isoform that is conserved across different species. In some embodiments, the ability of an antibody (e.g., an isoform-selective anti-TGFβ antibody described herein) to selectively neutralize one or more TGFβ isoforms can be measured in an in vitro inhibition assay, such as the cell-based inhibitory TGFβ assay described herein below.

[0048] As used herein, "TGFBR" refers to the TGFβ receptor. The dimeric receptor binding domains of all three TGFβ isoforms bind to a pair of heterodimeric receptor complexes, TGFBR1 and TGFBR2, and the tetrameric receptor complex then activates intracellular signaling through the receptor tyrosine kinase (RTK) activity of TGFBR1, also known as ALK5 (Weiss et al., Wiley Interdiscip. Rev. Dev. Biol. 2:47-63 (2013)). In canonical TGFBR signaling, ALK5 phosphorylates SMAD2 and SMAD3, which then associate with SMAD4, translocate to the nucleus, and direct gene transcription. Smad complexes activate the transcription of myofibroblast genes, including αSMA, calponin, and collagen (Usuki et al., J. Nippon Med. Sch. 79:46-59 (2012); Carthy et al., PloS one 6:e19809 (2011); and Gu et al., Acta Pharmacol. Sin. 28:382-391 (2007)). There are additional non-SMAD-dependent signaling pathways that can be activated by TGFβ under certain circumstances, including MAP kinase, AKT, JAK-STAT, and NFκB. Biochemical and structural studies have shown that the assembly of TGFβ-TGFβR signaling complexes can have subtle isoform-specific differences: TGFβ1 and TGFβ3 bind more strongly to TGFβR2 and form strong interactions with TGFβR1 only when complexed with TGFβR2, whereas TGFβ2 binds weakly to both TGFβ1 and TGFBR2 alone, and the binding activity can drive full complex formation (Radaev JBC 2009;285,14806-14814).While TGF-β1 and TGF-β2 crystallize in a "closed" conformation that promotes binding to TGFBR1 and TGFBR2, TGF-β3 can adopt a similar "closed" or less ordered "open" conformation in crystalline form, potentially resulting in differences in the binding activity of the ligand-receptor complex assembly (Hinck, AP et al. 2016; Cold Spring Harb Perspect Biol doi:10.1101 / cshperspect.a02210). Furthermore, the non-signaling receptor TGFBR3 (betaglycan) can promote TGF-β2 binding to the TGF-βR1 / 2 complex, but does not appear to play a similar role in TGF-β1 or TGF-β3 receptor binding (del Re, JBC 2004;279,22765-22772). In most cells (including endothelial cells), TGFβ signals through the TGF-BR1 / 2 complex; however, in endothelial cells, TGFβ1 and TGFβ3 can also signal through the TGF-BR2 / ALK1 complex, which is promoted by endoglin, contributing to SMAD1 / 5-dependent vascular endothelial proliferation and angiogenesis (EMBO J. 2004 Oct 13;23(20):4018-28). Finally, despite these differences in signaling complex organization, recombinant receptor-binding domains of TGFβ1, 2, and 3 can all induce TGFβR-dependent SMAD signaling to the same extent in cell-based in vitro assays. Therefore, any biological differences in the activities of endogenous TGFβ isoforms are more likely to result from differences in their expression patterns and release mechanisms from SLCs or LLCs than from differences in their receptor-binding domains.

[0049] As used herein, with respect to the isoform-selective anti-TGFβ antibodies described herein, the term "neutralizing" and grammatical variations thereof means that the antibody measurably inhibits its target TGFβ isoform(s) from inducing signaling through the TGFBR complex.

[0050] As used herein, the term "directly contact" and grammatical variations thereof, with respect to the antigen-binding domain of an anti-TGFβ antibody, means that the antigen-binding domain is within 15 to 8, 8, 8 to 5 angstroms, or preferably within 5 angstroms, of an amino acid residue in its corresponding epitope.

[0051] "TGFβ disorder" or "TGFβ-associated disorder" refers to any disorder, disease, or condition that would benefit from treatment with the isoform-selective anti-TGFβ antibodies provided herein. This includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question. Disorders treated herein include diseases characterized by the accumulation of extracellular matrix, diseases caused by circulating TGFβ or locally activated TGFβ, including one or more TGFβ isoforms, conditions caused by suppression of the immune system due to endogenous TGFβ production, acute immunodeficiency resulting from diseases such as severe injury, burns, and viral or bacterial infections, multi-organ systemic diseases due to TGFβ production or overproduction, and TGFβ-producing tumors.

[0052] As used herein, the terms "fibrosis," "fibrotic condition," and "fibrotic condition" are intended to have the same meaning. In certain embodiments, the fibrotic condition is one mediated by a fibrotic stimuli. Exemplary fibrotic stimuli include, but are not limited to, TGFβ, endothelin, lactate (via lactate dehydrogenase), IL-1, Thy-1 (CD 90), connective tissue growth factor ("CTGF"), and combinations thereof. In certain embodiments, the fibrotic condition is a condition mediated by TGFβ. In certain embodiments, the fibrotic condition is a condition mediated by one or more of TGFβ1, TGFβ2, and TGFβ3. In certain embodiments, the fibrotic condition is a condition mediated by one or both of TGFβ2 and TGFβ3. In certain embodiments, the fibrotic condition is a condition mediated by TGFβ2. In certain embodiments, the fibrotic condition is a condition mediated by TGFβ3. Exemplary fibrotic conditions are described in more detail herein below.

[0053] "Systemic sclerosis" (SSc) or "scleroderma" is a complex and heterogeneous disease characterized by skin and tissue fibrosis, vascular changes, and autoantibodies against various cellular antigens. The clinical presentation of systemic sclerosis can range from limited skin involvement to severe visceral dysfunction. Visceral organ involvement is a major factor contributing to the morbidity of the disease, with the kidneys, esophagus, heart, and lungs most frequently involved. The generally accepted classification of SSc includes two major subgroups: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). Gabrielli et al. Mechanisms of disease. Scleroderma. N Engl J Med 360:1989-2003 (2009). In one embodiment, patients with systemic sclerosis are classified according to the American College of Rheumatology (formerly the American College of Rheumatology) criteria for the classification of systemic sclerosis, which are based on the following: major criterion: diffuse (truncal) sclerosis (skin tightness, thickening, and non-pitting sclerosis); and minor criteria: (1) sclerodactyly (fingers and / or toes only), (2) digital pitting scars or loss of material on the digital pulp pads (loss of digital pulp), and (3) bilateral basilar fibrosis; patients with systemic sclerosis must meet either the major criterion or two of the three minor criteria. See Subcommittee for Scleroderma Criteria of the American Rheumatism Association, Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581-90 (1980).

[0054] As used herein, chronic obstructive pulmonary disease ("COPD") is an umbrella term used to describe a group of airway diseases generally characterized by airflow obstruction or airflow limitation. This condition may also be known by the terms chronic obstructive respiratory disease (CORD), chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COLD), or chronic airway limitation (CAL). As used herein, the term COPD is intended to encompass all such references. The clinical course of COPD is characterized by chronic impairment, with intermittent acute exacerbations occurring more frequently during the winter months. An acute exacerbation of COPD can be defined as a sustained deterioration of a patient's condition beyond normal day-to-day fluctuations and from the patient's usual stable state that is acute in onset. When acute exacerbations occur, they typically manifest as increased sputum production, more purulent sputum, changes in sputum color, increased coughing, upper respiratory conditions (e.g., colds and sore throat), increased wheezing, chest tightness, decreased exercise tolerance, increased fatigue, fluid retention, acute confusion, and worsening dyspnea. Infectious etiologies account for most exacerbations, but exposure to allergens, pollutants, or inhaled irritants may also play a role. Infectious agents known to cause acute exacerbations of COPD include rhinovirus, influenza, parainfluenza, coronavirus, adenovirus, respiratory syncytial virus, Chlamydia pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Mycoplasma pneumoniae, and Pseudomonas aeruginosa. Pollutants known to cause acute exacerbations include nitrogen dioxide, fine particles, sulfur dioxide, and ozone. Despite these known causes, the exact cause of an exacerbation may not be identified in up to 30% of diagnosed COPD cases. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as a disease state characterized by airflow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal inflammatory response of the lungs to harmful particles or gases.The American Thoracic Society (ATS) defines COPD as a disease process involving progressive, chronic airflow obstruction due to chronic bronchitis, emphysema, or both. Chronic bronchitis is clinically defined as excessive coughing and phlegm production on most days for at least three months over at least two consecutive years. Emphysema is characterized by chronic dyspnea (shortness of breath) due to destruction of lung tissue and enlargement of air spaces. Another condition typically encompassed by the term COPD is bronchiectasis, which is the abnormal dilation and enlargement of airways caused by mucus accumulation and blockage. Under such conditions, weakened passages can scar and deform, allowing more mucus and bacteria to accumulate, potentially leading to a cycle of infection and airway blockage.

[0055] As used herein, the term "ILD" refers to interstitial lung disease. Interstitial lung disease includes a large and diverse group of over 200 lung diseases and respiratory conditions characterized by inflammation and fibrosis of the interstitium, the tissue and spaces between the air sacs of the lung (see, e.g., du Bois, Nat. Rev. Drug Discov. 2010, 9, 129-140). In "progressive fibrosing interstitial lung disease (PF-ILD)," the response to lung injury in fibrotic ILD includes the development of fibrosis, which is progressive and self-sustaining, and becomes unrelated to the original clinical association or trigger.

[0056] As used herein, the terms "idiopathic pulmonary fibrosis" and "IPF" refer to a restrictive lung disease characterized by progressive interstitial fibrosis of the lung parenchyma, affecting approximately 100,000 patients in the United States (Raghu et al., Am J Respir Crit Care Med 174:810-816 (2006)). This interstitial fibrosis associated with IPF leads to progressive loss of lung function and death from respiratory failure in most patients. The median survival from time of diagnosis is 2-3 years (Raghu et al., Am J Respir Crit Care Med 183:788-824 (2011)). The etiology and key molecular and pathophysiological factors of IPF are unknown. In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. Diagnostic criteria for IPF are known. Ryu et al. (1998) Mayo Clin. Proc. 73:1085-1101.

[0057] As used herein, "GI tract fibrosis" refers to fibrosis of the digestive tract, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and anus. Thus, "GI tract fibrosis" includes intestinal fibrosis. "Intestinal fibrosis" is a common complication of inflammatory bowel disease (IBD) and is typically defined as the excessive accumulation of scar tissue in the intestinal wall. Intestinal fibrosis can occur in both forms of IBD: ulcerative colitis and Crohn's disease. "GI tract fibrosis" includes, but is not limited to, fibrosis associated with Crohn's disease, ulcerative colitis, collagenous colitis, colorectal fibrosis, villous atrophy, crypt hyperplasia, polyp formation, healing gastric ulcers, and microscopic colitis.

[0058] As used herein, "monitoring disease progression" refers to assessing a subject (e.g., a subject suffering from a TGFβ-associated disorder, e.g., a subject receiving treatment with an anti-TGFβ antibody as described elsewhere herein) at successive time intervals to determine whether the disease state has worsened, stabilized, or improved (i.e., become less severe). For example, monitoring the progression of fibrosis (e.g., SSc or IPF, or other fibrosis) in a subject may, in certain cases, include monitoring changes in the 18-gene TGFβ signature set described in Table 2 below, overall response rate, duration of response, quality of life, expression and / or activity of disease markers (e.g., expression of certain other genes and / or proteins), or other criteria known in the art. Additional approaches for monitoring disease progression in patients with TGFβ-associated disorders can be used, including, for example, measuring response to treatment by imaging techniques as described in more detail elsewhere herein.

[0059] As used herein, the terms "monitoring the progress of treatment" or "monitoring the response to treatment" are used interchangeably and refer to assessing a subject (e.g., a subject suffering from a TGFβ-associated disorder, e.g., a subject receiving treatment with an anti-TGFβ antibody as described elsewhere herein) at successive time intervals during or after treatment to determine whether the disease state has worsened, stabilized, or improved (i.e., become less severe) as a result of the treatment. For example, the progress of treatment in a subject (e.g., a subject receiving or having received treatment with an immunotherapeutic agent, such as, but not limited to, an anti-TGFβ antibody as described herein) can be monitored using the same criteria as those used to monitor disease progression.

[0060] As used herein, the term "detection" includes any means of detecting, including direct and indirect detection.

[0061] As used herein, the term "diagnosis" is used herein to refer to the identification or classification of a molecular or pathological state, disease, or condition. For example, "diagnosis" can refer to the identification of a particular type of fibrosis (e.g., SSc, IPF, etc.) or other TGFβ-mediated disorder. "Diagnosis" can also refer to the classification of a particular subtype of a fibrotic condition, for example, by histopathological or radiological criteria or molecular features (e.g., a subtype characterized by the expression of one or a combination of particular genes or proteins encoded by said genes).

[0062] The term "prognosis" is used herein to refer to the likelihood of survival over time, as well as the prediction of one or more TGFβ-driven disease states worsening over time.

[0063] As used herein, a "control subject" refers to a healthy subject who has not been diagnosed with a disease or condition of interest, e.g., fibrosis, e.g., IPF, SSc, etc., and who is not suffering from symptoms or conditions associated with the disease or condition.

[0064] As used herein, the term "sample" refers to a composition obtained or derived from a subject of interest that contains cellular and / or other molecular elements to be characterized and / or identified based on, for example, physical, biochemical, chemical, and / or physiological characteristics. For example, the phrase "disease sample" and variations thereof refers to any sample obtained from a subject of interest that is expected to contain or known to contain the cellular and / or molecular entities to be characterized.

[0065] "Tissue" or "cell sample" refers to a collection of similar cells obtained from a subject's or patient's tissue. The source of the tissue or cell sample can be a freshly collected, frozen, and / or preserved organ or tissue sample, or a biopsy or aspirate; blood or any blood component; a bodily fluid such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or solid tissue from cells at any time during a subject's gestation or development. The tissue sample may be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue / organ. The tissue sample may contain compounds not naturally mixed with natural tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, or antibiotics. As used herein, "reference sample," "reference cell," "reference tissue," "control sample," "control cell," or "control tissue" refers to a sample, cell, or tissue obtained from a source known or believed to be free of the disease or condition that the methods or compositions of the present invention are being used to identify. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell or control tissue is obtained from a healthy part of the body of the same subject or patient in whom a disease or condition has been identified using a composition or method of the invention. In one embodiment, the reference sample, reference cell, reference tissue, subject sample, control cell or control tissue is obtained from a healthy part of the body of an individual who is not the subject or patient in whom a disease or condition has been identified using a composition or method of the invention.

[0066] As used herein, the term "gene signature" is used interchangeably with "gene expression signature" and refers to one or a combination of genes whose expression is indicative of a subject, or a tissue or other sample isolated from a subject, having elevated TGFβ activity and / or is indicative of a subject that is likely to benefit from treatment with an inhibitor of a TGFβ isoform characterized by particular molecular, pathological, histological, radiological, and / or clinical properties. In certain embodiments, the expression of one or more genes comprising the gene signature is elevated compared to its expression in a control subject.

[0067] As used herein, the term "increased expression level" or "increased level" refers to increased mRNA or protein expression in a subject (e.g., a subject, e.g., a patient, suspected of or diagnosed with a TGFβ-associated disorder, e.g., fibrosis, e.g., IPF, COPD, PF-ILD (e.g., SSc), liver fibrosis (e.g., cirrhosis or chronic liver fibrosis)) compared to a control, e.g., an individual not suffering from a TGFβ-associated disorder.

[0068] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0069] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by methods common in the art, including those described herein. Specific illustrative examples and exemplary embodiments for measuring binding affinity are described below.

[0070] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs), which alterations improve the affinity of the antibody for antigen, compared to a parent antibody that does not possess such alterations.

[0071] The term "antibody" is used herein in the broadest sense and encompasses 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 the desired antigen-binding activity.

[0072] An "antibody fragment" is a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0073] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the reference antibody from binding to its antigen by 50% or more in a competition assay, and conversely, a reference antibody that blocks the antibody from binding to its antigen by 50% or more in a competition assay. Exemplary competition assays are provided herein.

[0074] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0075] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, several of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0076] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof); and various anti-tumor or anti-cancer agents disclosed below.

[0077] "Effector functions" refer to biological activities attributable to the Fc region of an antibody and vary depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0078] An "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

[0079] The term "therapeutically effective amount" refers to, for example, an amount of an immunotherapeutic agent (such as an immunotherapeutic agent described elsewhere herein) effective to "treat" a disease or disorder in a subject (e.g., a mammal such as a human).

[0080] As used herein, "tocilizumab" is a recombinant humanized monoclonal antibody that binds to the human interleukin-6 receptor (IL-6R). It is an IgG1κ (gamma 1, kappa) antibody with two heavy chains and two light chains that form two antigen-binding sites. In a preferred embodiment, the light and heavy chain amino acid sequences of tocilizumab comprise SEQ ID NOs: 187 and 188, respectively.

[0081] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated herein, numbering of amino acid residues in an Fc region or constant region is according to the EU numbering system, also known as the EU index, as described by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0082] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0083] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0084] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived from the host cell regardless of the number of passages. The progeny may not have completely identical nucleic acid content as the parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included in the present invention.

[0085] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody obtained from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences. This definition of human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues.

[0086] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (supra).

[0087] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues derived from non-human HVRs and amino acid residues derived from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to the variable domains of a non-human antibody and all or substantially all of the FRs correspond to the variable domains of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0088] The term "hypervariable region" or "HVR," as used herein, refers to each region of an antibody variable domain that is hypervariable in sequence ("complementarity determining region" or "CDR") and / or forms structurally distinct loops ("hypervariable loops") and / or contains residues that contact the antigen ("antigen contacts"). Generally, antibodies contain six HVRs (e.g., CDRs), three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs of the invention include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

[0089] In one embodiment, the HVR residues include those identified in Figures 12-16 and 18-24 or elsewhere herein.

[0090] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0091] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including, but not limited to, a cytotoxic agent.

[0092] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, horses, etc.), primates (e.g., humans and non-human primates such as monkeys), rabbits, rodents (e.g., mice, rats, etc.), etc. In certain embodiments, the individual or subject is human.

[0093] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0094] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes nucleic acid molecules that are contained in cells that originally contained the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0095] An "isolated nucleic acid encoding an isoform-selective anti-TGFβ antibody" refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present in one or more locations within a host cell.

[0096] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, with the exception of possible variant antibodies that contain, for example, naturally occurring mutations or that arise during production of the monoclonal antibody preparation, and such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0097] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. Naked antibodies may be present in a pharmaceutical formulation.

[0098] "Native antibodies" refer to naturally occurring immunoglobulin molecules with diverse structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, comprising two identical light chains and two identical heavy chains disulfide-linked. From the N-terminus to the C-terminus, each heavy chain contains a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain contains a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0099] The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product, including information regarding the indications, uses, dosages, administration, concomitant therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0100] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California), or can be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0101] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored by the sequence alignment program ALIGN-2 as identical matches in the program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is different from the length of amino acid sequence B, the % amino acid sequence identity of A to B will differ from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0102] The term "pharmaceutical formulation" refers to a formulation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain additional ingredients that have unacceptable toxicity to the subject to whom the formulation will be administered.

[0103] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0104] As used herein, "treatment" (and grammatical variations thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be carried out prophylactically or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating the condition, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, remission or palliation of the condition, and recovery or improved prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of disease or to slow the progression of disease.

[0105] A "variable region" or "variable domain" is a domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, and each domain contains four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antigen-binding antibody to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0106] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This term includes vectors as autonomously replicating nucleic acid structures as well as vectors that are integrated into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0107] As used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, regardless of the presence or absence of the other. For example, "A and / or B" should be interpreted as a specific disclosure of each of (i) A, (ii) B, and (iii) A and B, as if each were individually set forth herein.

[0108] II. Compositions and Methods In one aspect, the present invention is based in part on the provision of isoform-selective anti-TGFβ antibodies (e.g., monospecific anti-TGFβ2 and anti-TGFβ3 antibodies, and bispecific anti-TGFβ2 / 3 antibodies) and methods of use thereof. TGFβs are involved in regulating several important cellular functions, including cell proliferation, differentiation, migration, apoptosis, and extracellular matrix production. As a result, growth factors influence many biological processes, including embryonic development, wound repair, immune function, malignant transformation, and aging. Thus, the isoform-selective anti-TGFβ antibodies of the present invention are useful for the diagnosis or treatment of TGFβ-associated disorders, such as, but not limited to, fibrotic diseases and cancer.

[0109] In some embodiments, epitopes bound by isoform-selective anti-TGFβ antibodies are provided. The antigen-binding domains of isoform-selective anti-TGFβ antibodies were determined based on their crystal structures. As an example, the binding epitopes of the 2A10 and 4A11 antibodies were mapped by solving the crystal structures of their antibody / TGFβ complexes. See Example 10 below. As will be understood by those skilled in the art, the results from Example 10 demonstrate that the anti-TGFβ2 / 3 antibody 4A11 interacts with TGFβ2 (presumably also binding to the same highly conserved region of TGFβ3), and the anti-TGFβ3 antibody 2A10 interacts with TGFβ3. Therefore, antibodies that interact with or block any of these residues in TGFβ2 or TGFβ3 may be useful as neutralizing antibodies for TGFβ2 or TGFβ3, respectively. In some embodiments, antibodies that, when bound to their target TGFβ isoform(s), interact with or block residues on the TGFβ isoform, or are within 15-8, 8, 8-7, 8-6, 8-5, or 5 angstroms of residues on the TGFβ isoform(s), are believed to provide useful neutralization of the TGFβ isoform(s). As a non-limiting example, the anti-TGFβ3 antibody 2A10 was determined to bind to an epitope on TGFβ3 comprising amino acid residues R325, K331, W332, H334, E335, T387, I388, L389, Y391, V392, G393, R394, P396, K397, and V398 on human TGFβ3 (i.e., the antigen binding domain made direct contact with these residues on TGFβ3), and this binding resulted in neutralization of TGFβ3. Thus, in some embodiments, antibodies that, when bound to TGFβ3, interact with, block, or are within 15 to 8, 8, 8 to 5, or preferably 5 angstroms of those residues on TGFβ3 are believed to provide useful neutralization of TGFβ3.As a further non-limiting example, the anti-TGFβ2 / 3 antibody 4A11 has been determined to bind to TGFβ2 homodimers and directly contact amino acid residues V313, Q314, D315, R320, L322, Y323, R328, D329, F345, and A347 in the first TGFβ2 monomer of the homodimer, and amino acid residues N368, T369, I370, N371, P372, E373, A374, S375, A376, and S377 in the second TGFβ2 monomer. Thus, in some embodiments, antibodies that, when bound to TGFβ2, interact with, block, or are within 15-8, 8, 8-5, or preferably 5 angstroms of those residues on TGFβ2 are believed to provide useful neutralization of TGFβ2. In some embodiments, the antigen-binding domain binds within 30, 30-25, 25-20, 20-15, 15-8, 8, 8-5, 5, 5-4, 4 angstroms or less of one or more of the above residues. In some embodiments, the antigen-binding domain is within at least one of the above distances for one or more of the above residues when bound to a TGFβ isoform. For example, in some embodiments, the antigen-binding domain is within one of the recited distances (e.g., 30, 30-25, 25-20, 20-15, 15-8, 8, 8-5, 5, 5-4, 4 or less) for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75 or more of the above residues. In some embodiments, the antigen-binding domain is within one of the recited distances for at least 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, 99-100% of the residues identified in each group of that subgroup (e.g., only the surface residues in that group).Unless otherwise specified, the distance between the antigen-binding domain and a TGFβ isoform is the shortest distance between a covalently bonded atom on the TGFβ isoform and the covalently bonded atom of the antigen-binding domain that is the closest atom of the TGFβ isoform and the antigen-binding domain. Similarly, unless otherwise specified, the distance between a residue on the antigen-binding domain and the TGFβ isoform for which it is specific is the distance from the closest point on the identified residue to the closest covalently bonded portion of the TGFβ isoform, or vice versa. In some embodiments, the distance can be measured from the backbone of the amino acid chain. In some embodiments, the distance can be measured between the edge of the paratope and the edge of the epitope (closest to each other). In some embodiments, the distance can be measured between the center of the surface of the paratope and the center of the surface of the epitope. As will be understood by those skilled in the art, this specification is applicable to each individual set of residues listed herein. For example, the above ranges are generally and specifically contemplated for the epitope and paratope residues listed in Example 10.

[0110] A. Exemplary Isoform-Selective Anti-TGFβ Antibodies Anti-TGFβ2 antibody In one aspect, the invention provides isolated antibodies that bind to TGFβ2. In certain embodiments, the anti-TGFβ2 antibody selectively neutralizes TGFβ2. In certain embodiments, the anti-TGFβ2 antibody has one or more of the following properties: (a) selectively neutralizes TGFβ2; (b) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (c) has reduced toxicity compared to the pan-TGFβ antibody 1D11; (d) has reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (e) has reduced toxicity compared to the pan-TGFβ small molecule inhibitor galunisertib; and / or (f) has reduced toxicity in rodents compared to the pan-TGFβ small molecule inhibitor galunisertib.

[0111] In certain embodiments, the anti-TGFβ2 antibodies provided herein have a K Dand / or a cell-based IC of less than 250 pM 50 In one aspect, the anti-TGFβ2 antibodies provided herein bind to TGFβ2 with a K of about 5 pM, about 4 pM, about 3 pM, about 2 pM, or about 1 pM or less. D In one aspect, the anti-TGFβ2 antibodies provided herein bind to TGFβ2 with a K of less than 1 pM. D In one aspect, the anti-TGFβ2 antibodies provided herein bind to TGFβ2 with a cell-based IC of about 250 pM, about 200 pM, about 150 pM, about 100 pM, about 75 pM, or about 50 pM or less. 50 In one aspect, the anti-TGFβ2 antibodies provided herein have a cell-based IC50 for inhibition (neutralization) of TGFβ2 of 40 pM. 50 It has.

[0112] In one aspect, the invention provides an anti-TGFβ2 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0113] In one aspect, the invention provides an anti-TGFβ2 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In another aspect, the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18.

[0114] In another aspect, the invention provides an anti-TGFβ2 antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0115] In another embodiment, the anti-TGFβ2 antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In a further embodiment, the anti-TGFβ2 antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17.

[0116] In another aspect, the TGFβ2 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0117] In another aspect, the present invention provides an anti-TGFβ2 antibody comprising: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0118] In any of the above embodiments, the anti-TFGβ2 antibody is humanized. In one embodiment, the anti-TFGβ2 antibody comprises an HVR as in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework. In any of the above embodiments, the humanized anti-TGFβ2 antibody comprises one or more mutations in the VH framework selected from the group consisting of 37V or 37I, 48M or 48L, 49G or 49A, 67L, 71K and 78V, and 105P or 105R. In some embodiments, the anti-TGFβ2 antibody comprises a VH, wherein the VH comprises the amino acid sequence of SEQ ID NO: 25, and the VH comprises a set of framework mutations selected from the group consisting of: (i) 37V, 48M, and 49G in FR2, 105P in FR4 (h6F12.v1 and h6F12.v3); (ii) 37V and 48M in FR2, 67L, 71K, and 78V in FR3, 105P in FR4 (h6F12.v2 and h6F12.v4); (iii) 37I in FR2 (h6F12.v1.6); (iv) 48L in FR2 (h6F12.v1.7); (v) 48L in FR2 (h6F12.v1.8); 9A (h6F12.v1.8); (vi) 105R in FR4 (h6F12.v1.9); (vii) 37V, 48M and 49G in FR2, 105P in FR4 (h6F12.v1 and h6F12.v3); (viii) 37V and 48M in FR2, 67L, 71K and 78V in FR3, 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). In any of the above embodiments, the humanized anti-TGFβ2 antibody comprises one or more mutations in the VL framework selected from the group consisting of 43S or 43A, 66G, 69T, 71F and 87Y.In some embodiments, the anti-TGFβ2 antibody comprises a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO: 24, and the VL comprises a set of framework mutations selected from the group consisting of: (i) 43S in FR2, 66E, 69P, 71Y, and 87F in FR3 (h6F12.v1 and h6F12.v2); (ii) 43S in FR2, 58V in FR3, 66 E, 69P, 71Y and 87F (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).

[0119] In another aspect, the anti-TGFβ2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an isoform-selective anti-TGFβ2 antibody comprising that sequence retains the ability to bind to and selectively neutralize TGFβ2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 25. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ2 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17, or (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18.

[0120] In another aspect, an anti-TGFβ2 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 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. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, although an anti-TGFβ2 antibody comprising that sequence retains the ability to bind to PRO. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 24. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ2 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 24, 131, 133-137, 143, and 144, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0121] In another aspect, an anti-TGFβ2 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the antibody comprises a VH / VL sequence 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) (respectively), including post-translational modifications of those sequences.

[0122] In another aspect, an anti-TGFβ2 antibody is provided, which comprises a complete H chain amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 146, and 152-156, and / or a complete L chain amino acid sequence having an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 145, 147-151, 157, and 158. In some embodiments, the anti-TGFβ2 antibody comprises a complete heavy / light chain pair, wherein the complete heavy / light chain pair comprises an amino acid sequence (respectively) 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).

[0123] In a further aspect, the present invention provides antibodies that bind to the same epitope as the anti-TGFβ2 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as the anti-TGFβ2 antibodies provided herein, comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 16; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 17; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0124] Anti-TGFβ2 / 3 antibody In another aspect, the invention provides isolated antibodies that bind to both TGFβ2 and TGFβ3 (anti-TGFβ2 / 3 antibodies). In particular aspects, the antibodies selectively neutralize TGFβ2 and TGFβ3 and have one or more of the following characteristics: (a) direct contact between the antigen-binding domain of the antibody and amino acid residue E373 (human TGFβ2 numbering) of TGFβ2 or TGFβ3 achieves the selectivity of the anti-TGFβ2 / 3 antibody for TGFβ2 and TGFβ3 with respect to selective neutralization, which is greater than the selectivity of the anti-TGFβ2 / 3 antibody for human TGFβ1; (b) neutralizing TGFβ2 and / or TGFβ3 via an allosteric mechanism; (c) induce conformational changes in TGFβ2 and / or TGFβ3 homodimers; (d) induce a conformational change in TGFβ2 and / or TGFβ3 homodimers, the conformational change involving two monomers pinching together several times; (e) is a bivalent or monovalent antibody; (f) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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) specifically binds to a TGFβ2 homodimer, the TGFβ2 homodimer having a first and a second TGFβ2 monomer and comprising 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 (human TGFβ2 numbering) of the second TGFβ2 monomer; (h) The anti-TGFβ2 / 3 antibody according to (g), wherein the antigen-binding domain is located within 5 angstroms of a TGFβ2 and / or TGFβ3 amino acid residue; (i) specifically binds to the same epitope on TGFβ3 as (g); and (j) does not neutralize TGFβ2 and / or TGFβ3 in a monovalent form;

[0125] In certain embodiments, the anti-TGFβ2 / 3 antibodies selectively neutralize TGFβ2 and TGFβ3. In certain aspects, the anti-TGFβ2 / 3 antibodies provided herein have a K D and / or a cell-based IC of less than 250 pM 50 In one aspect, the anti-TGFβ2 / 3 antibodies provided herein bind to TGFβ2 / 3 with a K of less than about 10 pM, about 9 pM, about 8 pM, about 7 pM, about 6 pM, about 5 pM, about 4 pM, about 3 pM, about 2 pM, or about 1 pM. DIn one aspect, the anti-TGFβ2 / 3 antibodies provided herein bind to TGFβ2 and / or TGFβ3 with a K of about 5 pM. D In one aspect, the anti-TGFβ2 / 3 antibodies provided herein bind to TGFβ2 with a cell-based IC50 of about 250 pM, about 200 pM, about 150 pM, about 100 pM, about 75 pM, or about 50 pM for inhibition of TGFβ2. 50 In one aspect, the anti-TGFβ2 / 3 antibodies provided herein have a cell-based IC of about 250 pM, about 200 pM, about 150 pM, about 100 pM, about 75 pM, about 50 pM, about 40 pM, about 30 pM, or less than about 30 pM for inhibition of TGFβ3. 50 In one aspect, the anti-TGFβ2 / 3 antibodies provided herein have a cell-based IC for inhibition of TGFβ2 of about 250 pM. 50 and / or a cell-based IC for inhibition (neutralization) of TGFβ3 of approximately 30 pM 50 It has.

[0126] In one aspect, the present invention provides an HVR comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-H2 comprising the amino acid anti-TGFβ2 / 3 antibody sequence of SEQ ID NO: 11, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15.

[0127] In one aspect, the invention provides an anti-TGFβ2 / 3 antibody comprising at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-H2 comprising the amino acid anti-TGFβ2 / 3 antibody sequence of SEQ ID NO: 11, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12. In one embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12. In another embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15. In a further embodiment, the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12.

[0128] In another aspect, the invention provides an anti-TGFβ2 / 3 antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15. In one embodiment, the anti-TGFβ2 / 3 antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15.

[0129] In another aspect, an anti-TGFβ2 / 3 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 12; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15.

[0130] In another aspect, the present invention provides an anti-TGFβ2 / 3 antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 15.

[0131] In any of the above embodiments, the anti-TFGβ2 / 3 antibody is humanized. In one embodiment, the anti-TFGβ2 / 3 antibody comprises an HVR as in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework. In another embodiment, the anti-TGFβ2 / 3 antibody comprises an HVR of any of the above embodiments and further comprises a VH comprising FR modifications selected from the group consisting of deletions 1E, 2Q or 2V, 24V, 37V or 37I, 48I, 49G, 67F or 67V, 71K or 71V, 73S or 73T, 75K and 76N, 78V or 78F, 91F or 91Y, and 105P or 105Q.In some embodiments, the anti-TGFβ2 / 3 antibody comprises a VH, wherein the VH comprises the amino acid sequence of SEQ ID NO: 27, and the VH comprises a set of framework 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, 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, F (iii) deletion of 1E in FR1 (h4A11.v7.1); (iv) deletion of 75K and 76N in FR3 (h4A11.v7.2); (v) deletion of 1E in FR1 and 75K76N in FR3 (h4A11.v7.3); (vi) deletion of 2V in FR1 (h4A11.v7.8); (vi) deletion of 37I in FR2 (h4A11.v7.9); (vii) deletion of 67V in FR3 (h4A11.v7.10); (viii) deletion of 71V in FR3 (h4A 11.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); (xii i) 2V in FR1, 37I in FR2, 67V in FR3, 73T, 78F, 105Q in FR4 ((h4A11.v7.16);(xiv) 2V in FR1, 37I in FR2, 67V in FR3, 73T, 91Y, 105Q in FR4 (h4A11.v7.17);( (xv) 2V in FR1, 37I in FR2, 67V, 73T in FR3, 105Q in FR4 (h4A11.v7.18); (xvi) 2V in FR1, 37I in FR2, 67V, 73T, deletion of 75K and 76N in FR3, 105Q in FR4 (h4A11.v7.19). In another embodiment, an anti-TGFβ2 / 3 antibody comprises the HVR of any of the above embodiments and further comprises a VL comprising a FR modification selected from the group consisting of: 2A or 2I, 4L, 36F or 36Y, 43P or 43A, and 58V or 58I.In some embodiments, the anti-TGFβ2 / 3 antibody comprises a VL, wherein the VL comprises the amino acid sequence of SEQ ID NO: 26, and the VL comprises a set of framework modifications selected from the group consisting of: (i) 2A and 4L in FR1, 36F in FR2 (h4A11.v1 and h4A11.v3); (ii) 2A and 4L in FR1, 36F and 43P in FR2 (h4A11.v2 and h4A11.v4); (iii) 2A in FR1, 36F and 43P in FR2, 43P in FR3 58V in FR1 (h4A11.v5 and h4A11.v7); (iv) 2A and 4L in FR1, 36F in FR2 (h4A11.v6 and h4A11.v8); (v) 2I in FR1 (h4A11.v7.4); (vi) 36Y in FR2 (h4) A11.v7.5); (vii) 3A in FR24 (h4A11.v7.6); (viii) 58I in FR3 (h4A11.v7.7); (ix) 2I in FR1, 43A in FR2, 58I in FR3 (h4A11.v7.16-19).

[0132] In another aspect, the anti-TGFβ2 / 3 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 81, 83, 86-88, 93-100, and 102-105. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-TGFβ2 / 3 antibody comprising that sequence retains the ability to bind to TGFβ2 and TGFβ3. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 27. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ2 / 3 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 27, 81, 83, 86-88, 93-100, and 102-105, including post-translational modifications of the sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12.

[0133] In another aspect, provided are anti-TGFβ2 / 3 antibodies, comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 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. In specific embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-TGFβ2 / 3 antibody comprising that sequence retains the ability to bind to TGFβ2 and TGFβ3. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 26. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ2 / 3 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 26, 80, 82, 84, 85, 89-92, and 101, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15.

[0134] In another aspect, an anti-TGFβ2 / 3 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the anti-TGFβ2 / 3 antibody is 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 / 85 (v7.14), SEQ ID NO:99 / 86 (v7.15), SEQ ID NO:99 / 87 (v7.16), SEQ ID NO:99 / 88 (v7.17), SEQ ID NO:99 / 89 (v7.18), SEQ ID NO:99 / 89 (v7.19), SEQ ID NO:99 / 90 (v7 (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), including post-translational modifications of these sequences.

[0135] In another aspect, an anti-TGFβ2 / 3 antibody is provided, comprising a complete H-chain amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 107, 109, 112-114, and 119-130, and / or a complete L-chain amino acid sequence having an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 106, 108, 110, 111, 115-118, and 186. In some embodiments, the anti-TGFβ2 / 3 antibody comprises a complete heavy / light chain pair, the complete heavy / light chain pair being 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:115 / 118 (v7.7), SEQ ID NO:116 / 119 (v7.8), SEQ ID NO:117 / 120 (v7.9), SEQ ID NO:121 / 122 (v7.10), SEQ ID NO:122 / 123 (rabbit 4A11), SEQ ID NO:123 / 124 (v7.11), SEQ ID NO:124 / 125 (v7.12), SEQ ID NO:125 / 126 (v7.13), SEQ ID NO:126 / 127 (v7.14), SEQ ID NO:127 / 128 (v7.15), SEQ ID NO:128 / 129 (v7.16), SEQ ID NO:129 / 130 (v7.17), SEQ ID NO:129 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) (respectively).

[0136] In a further aspect, the present invention provides anti-TGFβ2 / 3 antibodies that bind to the same epitope as the anti-TGFβ2 / 3 antibodies provided herein. For example, in certain embodiments, antibodies are provided that bind to the same epitope as an anti-TGFβ2 / 3 antibody, comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14; or (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 15. In certain embodiments, an anti-TGFβ2 / 3 antibody is provided that binds to an epitope spanning a TGFβ2 homodimer, the TGFβ2 homodimer having a first and a second TGFβ2 monomer, and the anti-TGFβ2 / 3 antibody comprises an antigen-binding domain that directly contacts amino acid residues V313, Q314, D315, R320, L322, Y323, R328, D329, F345, and A347 of the first TGFβ2 monomer and amino acid residues N368, T369, I370, N371, P372, E373, A374, S375, A376, and S377 of the second TGFβ2 monomer, and in some embodiments, the anti-TGFβ2 / 3 antibody binds to the same epitope in TGFβ3. TGFβ2 and TGFβ3 are highly conserved in the region including amino acid positions 368 to 377 (TGFβ2 numbering), and therefore anti-TGFβ2 / 3 antibodies bind to the same region in both TGFβ2 and TGFβ3.

[0137] Anti-TGFβ3 antibody In one aspect, the present invention provides isolated antibodies that bind to TGFβ3. In certain embodiments, the anti-TGFβ3 antibodies selectively neutralize TGFβ3. Furthermore, the anti-TGFβ3 antibodies described herein have now been discovered to have an improved safety profile (e.g., reduced toxicity) compared to pan-TGFβ inhibitors, as well as compared to isoform-selective antibodies specific for TGFβ2 (Example 2) and anti-TGFβ1-selective antibodies. Several inhibitors of TGFβ signaling have been investigated in preclinical toxicology studies, including both small molecule inhibitors of the kinase activity of TGFBR1 (ALK5), e.g., galunisertib, and antibody-based inhibitors of TGFβ-TGFBR interactions, e.g., the pan-TGFβ antibody fresolimumab. Rat toxicology studies of ALK5 small molecule inhibitors from different chemical series have consistently demonstrated hemorrhagic, inflammatory, and degenerative cardiac valve lesions and epiphyseal dysplasia (Frazier Toxicol Pathol 35, 284-95, 2007; Anderton Toxicol Pathol 39:916, 2011). In early clinical studies, galunisertib was administered at levels that did not completely inhibit ALK5 activity for relatively short periods, and cardiac findings have not yet been observed in clinical settings. Mice treated with the pan-TGFβ antibody 1D11 (Lonning et al. (2011) Current Pharmaceutical Biotechnology, 12, 2176-2189) developed histologic lesions, weight loss, non-neoplastic cystic epithelial hyperplasia and inflammation of the tongue, as well as dental dysplasia and epithelial hyperplasia of the gingiva and esophagus. Fresolimumab (a humanized form of the GC1008 antibody that binds to and inhibits the activity of all three TGFβ isoforms with equal affinity for these isoforms as the 1D11 antibody) was tested in cynomolgus monkeys and produced dose-dependent bleeding, anemia, and hyperplasia in the urinary, nasal, and bladder epithelium.In humans, fresolimumab treatment resulted in anemia and bleeding (gingival, nasal, and subconjunctival), as well as an increased rate of keratoacanthoma (a precancerous squamous skin lesion) that resolved with discontinuation of treatment (Rice, JCI 125:2795 (2015); Lacouture, Cancer Immunol Immunother 64:437 (2015)). CAT-192, an antibody primarily selective for TGF-β1, had a high rate of serious adverse events, with numerous gastric bleeding events observed in a phase 1-2 trial in SSc (Denton A&R 56:323 (2007); see also the World Wide Web at tripod.nih.gov / ginas / app / substance / 4AR6718OL0). Collectively, these findings suggest that bleeding, cardiac involvement, and epithelial hyperplasia are important concerns with long-term chronic pharmacological TGF-β inhibition.

[0138] In contrast to the safety concerns observed in previous attempts to neutralize TGFβ in vivo, in certain embodiments, the present invention provides anti-TGFβ3 antibodies with improved safety profiles (e.g., reduced toxicity). For example, in Example 2 below, mice treated with anti-TGFβ3 antibodies at doses up to 50 mg / kg, administered three times a week for a total of four weeks, experienced no or very mild side effects (epiphyseal dysplasia at the highest dose), and none of the serious side effects caused by small molecule inhibitors, anti-TGFβ1 antibodies, or pan-TGFβ antibodies discussed above were observed. The anti-TGFβ3 antibodies described herein were also found to have an improved safety profile compared to isoform-selective anti-TGFβ2 / 3 and anti-TGFβ2 antibodies (see Example 2, Table 8).

[0139] In certain embodiments, an anti-TGFβ3 antibody selectively neutralizes TGFβ3 and has the following characteristics: (a) Specific binding to the beta6 / beta7 hairpin region of TGFβ3; (b) binding of anti-TGFβ3 antibodies sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; (c) The binding of anti-TGFβ3 antibodies to TGFβ3 blocks the binding of TGFΒR2 and inhibits the binding of TGFBR1 / TGFBR2 signaling receptors to TGFβ3; (d) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3; (e) direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, and residue R394 of TGFβ3 makes an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3 achieves isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ1; (g) direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3 achieves isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2; (h) reduced toxicity compared with the pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to the pan-TGFβ antibody 1D11; (j) reduced toxicity compared with the pan-TGFβ small molecule inhibitor galunisertib; (k) reduced toxicity in rodents compared with galunisertib, a pan-TGFβ small molecule inhibitor; (l) reduced toxicity compared with the anti-TGFβ1 antibody CAT-192; (m) reduced toxicity compared to isoform-selective anti-TGFβ2 antibodies and / or anti-TGFβ2 / 3 antibodies; (n) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (o) an antigen-binding domain that directly contacts amino acid residues R325, K331, W332, H334, E335, T387, I388, L389, Y391, V392, G393, R394, P396, K397, and V398 on human TGFβ3; and (p) the anti-TGFβ3 antibody according to (o), wherein the antigen-binding domain is located within 15 to 8, 8, 8 to 5, 7 to 5, 6 to 5, or 5 angstroms of a TGFβ3 amino acid residue; Anti-TGFβ3 antibodies are provided, comprising one or more of:

[0140] In certain embodiments, the anti-TGFβ3 antibodies provided herein have a K D and / or a cell-based IC of less than 250 pM 50 In one aspect, the anti-TGFβ3 antibodies provided herein bind to TGFβ3 with a K of less than about 5 pM, about 4 pM, or about 3 pM. D In one aspect, the anti-TGFβ3 antibodies provided herein bind to TGFβ3 with a K of less than about 2 pM. D In one aspect, the anti-TGFβ3 antibodies provided herein bind to TGFβ3 with a cell-based IC of less than about 200 pM, about 150 pM, about 100 pM, about 75 pM, or about 50 pM. 50 In one aspect, the anti-TGFβ3 antibodies provided herein have a cell-based IC 50 is less than about 20 pM.

[0141] In another aspect, the anti-TGFβ3 antibodies provided herein selectively neutralize TGFβ3 and have reduced toxicity in mice compared to the pan-TGFβ antibody 1D11 (see Lonning et al. (2011)). In another aspect, the anti-TGFβ3 antibodies provided herein selectively neutralize TGFβ3 and have an improved safety profile compared to pan-TGFβ inhibitors, such as the ALK5 inhibitors described in Anderton et al. and / or the 1D11 antibody described in Lonning et al. (2011). In another aspect, the anti-TGFβ3 antibodies provided herein selectively neutralize TGFβ3 and have reduced toxicity in mice compared to the anti-TGFβ1 antibody CAT-192 / metelimumab.

[0142] In a particular embodiment, the CAT-192 antibody has the following heavy and light chain variable amino acid sequences: VH EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PSCPAPEFLGGPSVFLFPPKPKPTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 184) VL EIVLTQSPSSLSASVGDRVTITCRASQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSPVTKSFNRGEC (SEQ ID NO: 185)

[0143] In any of the above aspects, the anti-TGFβ3 antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 5, 34, 35, and 159; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.

[0144] In one aspect, the invention provides an anti-TGFβ3 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another aspect, the invention provides an anti-TGFβ3 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another aspect, the invention provides an anti-TGFβ3 antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another aspect, the invention provides an anti-TGFβ3 antibody comprising at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6.

[0145] In one embodiment, the antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another embodiment, the antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9. In a further embodiment, the antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5. In a further embodiment, the anti-TGFβ3 antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34. In a further embodiment, the anti-TGFβ3 antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35. In a further embodiment, the anti-TGFβ3 antibody comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159. In a further embodiment, the anti-TGFβ3 antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, the anti-TGFβ3 antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, the anti-TGFβ3 antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, the anti-TGFβ3 antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159, and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6.

[0146] In another aspect, the invention provides an anti-TGFβ3 antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.

[0147] In another aspect, an anti-TGFβ3 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 6; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9. In another aspect, an anti-TGFβ3 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 6; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9. In another aspect, an anti-TGFβ3 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 6; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.In another aspect, an anti-TGFβ3 antibody of the invention comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 6; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.

[0148] In another aspect, the present invention provides an anti-TGFβ2 / 3 antibody comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (f) an HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 9. In another aspect, the present invention provides an anti-TGFβ2 / 3 antibody comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (f) an HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 9. In another aspect, the present invention provides an anti-TGFβ2 / 3 antibody comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (f) an HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 9. In another aspect, the present invention provides an anti-TGFβ2 / 3 antibody comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159, (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6, (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (f) an HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 9.

[0149] In certain embodiments, any one or more amino acids of the anti-TGFβ3 antibodies provided above are substituted at the following HVR positions: - in HVR-H2 (SEQ ID NO: 5): at position N54 (e.g., N54S, N54Q) or T56 (e.g., T56A).

[0150] In certain embodiments, the substitutions are conservative substitutions, as provided herein.

[0151] In any of the above embodiments, the anti-TFGβ3 antibody is humanized. In some aspects, anti-TFGβ3 antibodies provided herein that have undergone one or more humanization steps may have TGFβ blocking ability similar to the parent antibody, and / or have human TGFβ binding similar to the parent antibody, and / or maintain solubility and / or be capable of expression, although such abilities may potentially or actually be unknown or absent in other TGFβ3 antibody-derived variants (Example 6, Tables 9 and 10; Figures 10 and 11). In one embodiment, the anti-TFGβ3 antibody comprises an HVR as in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework. In another embodiment, an anti-TGFβ3 antibody comprises an HVR of any of the above embodiments and further comprises a VH comprising FR modifications selected from the group consisting of: 47L or 47W, 49A, 49S or 49G; 73D or 73N; and 76N, 78D or 78L, 78A or 78V. In some embodiments, the anti-TGFβ3 antibody comprises a VH, wherein the VH comprises the amino acid sequence of SEQ ID NO: 23, and the VH comprises a set of framework modifications selected from the group consisting of: (i) 47L, 49A in FR2, 78V in FR3 (h2A10.v1); (ii) 47L, 49A in FR2, 73D, 76S, 78V in FR3 (h2A10.v2); (iii) 47W in FR2 (h2A10.v1.5); (iv) 49G in FR2 (h2A10.v1.6); A10.v1.6); (v) 78A in FR3 (h2A10.v1.7); (vi) 47W in FR2 (h2A10.v2.5); (vii) 49S in FR2 (h2A10.v2.6); (viii) FR3 (h2A10.v2. 7) 73N; (ix) 76N in FR3 (h2A10.v2.8); (x) 78L in FR3 (h2A10.v2.9); and (xi) 49S in FR2, 76N, 78L in FR3 (h2A10.v3 and h2A10.v4).In another embodiment, an anti-TGFβ3 antibody comprises the HVR of any of the above embodiments and further comprises a VL comprising FR modifications selected from the group consisting of: 4L or 4M, 38H or 38Q, 43A or 43Q, and 58V (relative to the VL amino acid sequence of SEQ ID NO: 22). In another embodiment, the antibody comprises a VL of SEQ ID NO: 22, wherein the VL comprises a set of framework modifications selected from the group consisting of: (i) 4L in FR1, 38H and 43Q in FR2, and 58I in FR3 (h2A10.v1 and h2A10.v2); (ii) 4M in FR1 (h2A10.v1.1 and h2A10.v2.1); (iii) 38Q in FR2 (h2A10.v1.2 and h2A10.v2.2); (iv) FR (v) 43A in FR2 (h2A10.v1.3 and h2A10.v2.3); (v) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4); (vii) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); and (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4).

[0152] In another aspect, the anti-TGFβ3 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 37, 42-50, 55, and 57. In another aspect, the anti-TGFβ3 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 37, and 42-50. In some aspects, the anti-TGFβ3 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-TGFβ3 antibody comprising that sequence retains the ability to bind to TGFβ3. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 23. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ3 antibody comprises a VH sequence, including post-translational modifications of the sequence, selected from the group consisting of SEQ ID NOs: 23, 37, 42-50, 55, and 57. Optionally, the anti-TGFβ3 antibody comprises a VH sequence, including post-translational modifications of the sequence, selected from the group consisting of SEQ ID NOs: 23, 37, and 42-50. In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6.In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In certain embodiments, the VH comprises one, two, or three HVRs selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6.

[0153] In another aspect, an anti-TGFβ3 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, 38-41, 54 and 56. In another aspect, an anti-TGFβ3 antibody is provided, the antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41. In some aspects, anti-TGFβ3 antibodies are provided, which comprise a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 56. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but an anti-TGFβ3 antibody comprising that sequence retains the ability to bind to TGFβ3. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 22. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-TGFβ3 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 22, 36, 38-41, 54, and 56, including post-translational modifications of that sequence. Optionally, the anti-TGFβ3 antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 8, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 9.

[0154] In another aspect, an anti-TGFβ3 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the anti-TGFβ3 antibody is selected from the group consisting of SEQ ID NO:23 / 22 (rat 2A10), SEQ ID NO:37 / 36 (v1), SEQ ID NO:37 / 38 (v1.1), SEQ ID NO:37 / 39 (v1.2), SEQ ID NO:37 / 40 (v1.3), SEQ ID NO:37 / 41 (v1.4), SEQ ID NO:42 / 36 (v1.5), SEQ ID NO:43 / 36 (v1.6), SEQ ID NO:44 / 36 (v1.7), SEQ ID NO:45 / 36 (v2), SEQ ID NO:45 / 38 (v2.1), SEQ ID NO: SEQ ID NO:45 / 39 (v2.2), SEQ ID NO:45 / 40 (v2.3), SEQ ID NO:45 / 41 (v2.4), SEQ ID NO:46 / 36 (v2.5), SEQ ID NO:47 / 36 (v2.6), SEQ ID NO:48 / 36 (v2.7), SEQ ID NO:49 / 36 (v2.8), SEQ ID NO:50 / 36 (v2.9), SEQ ID NO:55 / 54 (v3), and SEQ ID NO:57 / 56 (v4), respectively, including post-translational modifications of these sequences. In one embodiment, the anti-TGFβ3 antibody is selected from the group consisting of SEQ ID NO:23 / 22 (rat 2A10), SEQ ID NO:37 / 36 (v1), SEQ ID NO:37 / 38 (v1.1), SEQ ID NO:37 / 39 (v1.2), SEQ ID NO:37 / 40 (v1.3), SEQ ID NO:37 / 41 (v1.4), SEQ ID NO:42 / 36 (v1.5), SEQ ID NO:43 / 36 (v1.6), SEQ ID NO:44 / 36 (v1.7), SEQ ID NO:45 / 36 (v2), SEQ ID NO:46 In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL sequence selected from the group consisting of SEQ ID NOs: 5 / 38 (v2.1), 45 / 39 (v2.2), 45 / 40 (v2.3), 45 / 41 (v2.4), 46 / 36 (v2.5), 47 / 36 (v2.6), 48 / 36 (v2.7), 49 / 36 (v2.8), and 50 / 36 (v2.9), respectively, including post-translational modifications of these sequences. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL sequence selected from the group consisting of SEQ ID NOs: 57 / 56 (v2.1), 5 / 38 (v2.2), 45 / 39 (v2.2), 45 / 40 (v2.3), 45 / 41 (v2.4), 46 / 36 (v2.5), 47 / 36 (v2.6), 48 / 36 (v2.7), 49 / 36 (v2.8), and 50 / 36 (v2.9), respectively, including post-translational modifications of these sequences.

[0155] In another aspect, an anti-TGFβ3 antibody is provided, the antibody comprising a complete H chain amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 59, 64, 65-72, 77, and 79, and / or a complete L chain amino acid sequence having an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, 60-63, 76, and 78. In another aspect, an anti-TGFβ3 antibody is provided, the antibody comprising a complete H chain amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 59, 64, and 65-72, and / or a complete L chain amino acid sequence having an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the antibody comprises a complete H chain amino acid sequence having at least 95% sequence identity to SEQ ID NO: 79 and / or the complete L chain amino acid sequence of SEQ ID NO: 78. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain pair, the complete heavy / light chain pair being SEQ ID NO:29 / 28 (rat 2A10), SEQ ID NO:59 / 58 (v1), SEQ ID NO:59 / 60 (v1.1), SEQ ID NO:59 / 61 (v1.2), SEQ ID NO:59 / 62 (v1.3), SEQ ID NO:59 / 63 (v1.4), SEQ ID NO:64 / 58 (v1.5), SEQ ID NO:65 / 58 (v1.6), SEQ ID NO:66 / 58 (v1.7), SEQ ID NO:67 / 58 (v2). , SEQ ID NO:67 / 60 (v2.1), SEQ ID NO:67 / 61 (v2.2), SEQ ID NO:67 / 62 (v2.3), SEQ ID NO:67 / 63 (v2.4), SEQ ID NO:68 / 58 (v2.5), SEQ ID NO:69 / 58 (v2.6), SEQ ID NO:70 / 58 (v2.7), SEQ ID NO:71 / 58 (v2.8), SEQ ID NO:72 / 58 (v2.9), SEQ ID NO:77 / 76 (v3), and SEQ ID NO:79 / 78 (v4) (respectively).In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain pair, the complete heavy / light chain pair being selected from the group consisting of SEQ ID NO:29 / 28 (rat 2A10), SEQ ID NO:59 / 58 (v1), SEQ ID NO:59 / 60 (v1.1), SEQ ID NO:59 / 61 (v1.2), SEQ ID NO:59 / 62 (v1.3), SEQ ID NO:59 / 63 (v1.4), SEQ ID NO:64 / 58 (v1.5), SEQ ID NO:65 / 58 (v1.6), SEQ ID NO:66 / 58 (v1.7), SEQ ID NO:67 / 58 (v1.8), SEQ ID NO:68 / 58 (v1.9), SEQ ID NO:69 / 59 (v1.10), SEQ ID NO:69 / 59 (v1.11), SEQ ID NO:69 / 59 (v1.12), SEQ ID NO:69 / 59 (v1.13), SEQ ID NO:69 / 59 (v1.14), SEQ ID NO:69 / 59 (v1.15), SEQ ID NO:69 / 59 (v1.16), SEQ ID NO:69 / 59 (v1.17), SEQ ID NO:69 / 59 (v1.18), SEQ ID NO:69 / 59 (v1.19), SEQ ID NO:69 / 59 (v1.20), SEQ ID NO:69 / 59 (v1.21), SEQ ID NO:69 / 59 (v1.22), SEQ ID NO:69 / 59 (v1.23), SEQ ID NO:69 / 59 (v1.24), SEQ ID NO:69 / 59 (v1.25), SEQ ID NO:69 / 59 (v1.26), SEQ ID NO:69 / 59 7), SEQ ID NO:67 / 58 (v2), SEQ ID NO:67 / 60 (v2.1), SEQ ID NO:67 / 61 (v2.2), SEQ ID NO:67 / 62 (v2.3), SEQ ID NO:67 / 63 (v2.4), SEQ ID NO:68 / 58 (v2.5), SEQ ID NO:69 / 58 (v2.6), SEQ ID NO:70 / 58 (v2.7), SEQ ID NO:71 / 58 (v2.8), SEQ ID NO:72 / 58 (v2.9) (respectively).

[0156] In another embodiment, an anti-TGFβ3 antibody is provided, the antibody comprising a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52. In some aspects, the anti-TGFβ3 antibody comprises a VL amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38-41. In some aspects, the antibody comprises a VH / VL sequence (respectively) comprising the amino acid sequence of SEQ ID NO: 52 / 36 (h2A10.v2.N54Q). In some embodiments, the antibody comprises an entire heavy chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the anti-TGFβ3 antibody comprises an entire light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, and a complete light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60-63. In some embodiments, the antibody comprises a complete heavy / light chain sequence comprising the amino acid sequences of SEQ ID NOs: 74 / 58 (respectively).

[0157] In another embodiment, an anti-TGFβ3 antibody is provided, the antibody comprising a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 51 or 55. In some aspects, the anti-TGFβ3 antibody comprises a VL amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, 38-41 and 54. In some aspects, the anti-TGFβ3 antibody comprises a VH / VL sequence (respectively) comprising the amino acid sequence of SEQ ID NO: 51 / 36 or SEQ ID NO: 55 / 54 (h2A10.v3). In some embodiments, the antibody comprises a complete heavy chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 73 or 77, and / or the anti-TGFβ3 antibody comprises a complete light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, 60-63, and 76. In some embodiments, the antibody comprises a complete heavy / light chain sequence comprising the amino acid sequence of SEQ ID NO: 73 / 58 or SEQ ID NO: 77 / 76 (respectively).

[0158] In another embodiment, an anti-TGFβ3 antibody is provided, the antibody comprising a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 53 or 57. In some aspects, the anti-TGFβ3 antibody comprises a VL amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, 38-41 and 56. In some aspects, the anti-TGFβ3 antibody comprises a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57. In other embodiments, the anti-TGFβ3 antibody comprises a VL having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the anti-TGFβ3 antibody comprises a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57, and a VL amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL sequence comprising the amino acid sequence of SEQ ID NO:53 / 36 or SEQ ID NO:57 / 56 (h2A10.v4), respectively. In some embodiments, the anti-TGFβ3 antibody comprises a VH / VL sequence comprising the amino acid sequence of SEQ ID NO:57 / 56 (h2A10.v4), respectively. In some embodiments, the antibody comprises an entire heavy chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:74 or 79, and / or an entire light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs:28, 58, 60-63, 76, and 78.In some embodiments, the anti-TGFβ3 antibody comprises an entire heavy chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79. In other embodiments, the anti-TGFβ3 antibody comprises an entire light chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78. In still further embodiments, the anti-TGFβ3 antibody comprises an entire heavy chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79, and an entire light chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the antibody comprises an entire heavy chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 79, and / or an entire light chain amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain sequence comprising the amino acid sequence of SEQ ID NO: 75 / 58 or SEQ ID NO: 79 / 78 (respectively). In particular embodiments, the anti-TGFβ3 antibody comprises a complete heavy / light chain sequence comprising the amino acid sequence of SEQ ID NO: 79 / 78 (respectively).

[0159] In a further aspect, the present invention provides anti-TGFβ3 antibodies that bind to the same epitope as the anti-TGFβ3 antibodies provided herein. For example, in a specific embodiment, an antibody is provided that binds to the same epitope as an anti-TGFβ3 antibody comprising: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In one embodiment, an antibody is provided that binds to the same epitope as an anti-TGFβ3 antibody comprising: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another embodiment, an antibody is provided that binds to the same epitope as an anti-TGFβ3 antibody comprising: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 35; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6. In another embodiment, an antibody is provided that binds to the same epitope as an anti-TGFβ3 antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 159; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6.

[0160] In another aspect, SEQ ID NO: 53 / 36 (h2A10.v2.t56A), SEQ ID NO: 57 / 56 (h2A10.v4), SEQ ID NO: 51 / 36 (h2A10.v2.N54S), SEQ ID NO: 57 / 56 (h2A10.v3), SEQ ID NO: 52 / 36 (h2A10.v2.N54Q), SEQ ID NO: 23 / 22 (rat 2A10), SEQ ID NO: 37 / 36 (v1), SEQ ID NO: 37 / 38 (v1.1), SEQ ID NO: 37 / 39 (v1.2), SEQ ID NO: 37 / 40 (v1.3), SEQ ID NO: 37 / 41 (v1.4), SEQ ID NO: 42 / 36 (v1.5), SEQ ID NO: 43 / 36 (v1.6), SEQ ID NO: 44 / 36 (v1.7), SEQ ID NO: 45 / 36 (v1.8), SEQ ID NO: 46 / 36 (v1.9), SEQ ID NO: 47 / 36 (v1.10), SEQ ID NO: 48 / 36 (v1.11), SEQ ID NO: 49 / 37 (v1.12), SEQ ID NO: 40 / 41 (v1.13), SEQ ID NO: 41 / 42 (v1.14), SEQ ID NO: 42 / 36 (v1.15), SEQ ID NO: 43 / 36 (v1.16), SEQ ID NO: 44 / 36 (v1.17), SEQ ID NO: 45 / 36 (v1.18), SEQ ID NO: 46 / 36 (v1.19), SEQ ID NO: 47 / 36 (v1.20), S and SEQ ID NO: 36 (v1.7), SEQ ID NO: 45 / 36 (v2), SEQ ID NO: 45 / 38 (v2.1), SEQ ID NO: 45 / 39 (v2.2), SEQ ID NO: 45 / 40 (v2.3), SEQ ID NO: 45 / 41 (v2.4), SEQ ID NO: 46 / 36 (v2.5), SEQ ID NO: 47 / 36 (v2.6), SEQ ID NO: 48 / 36 (v2.7), SEQ ID NO: 49 / 36 (v2.8), SEQ ID NO: 50 / 36 (v2.9), SEQ ID NO: 55 / 54 (v3), and SEQ ID NO: 57 / 56 (v4).In another embodiment, SEQ ID NO: 53 / 36 (h2A10.v2.t56A), SEQ ID NO: 57 / 56 (h2A10.v4), SEQ ID NO: 51 / 36 (h2A10.v2.N54S), SEQ ID NO: 55 / 54 (h2A10.v3), SEQ ID NO: 52 / 36 (h2A10.v2.N54Q), SEQ ID NO: 23 / 22 (rat 2A10), SEQ ID NO: 37 / 36 (v1), SEQ ID NO: 37 / 38 (v1.1), SEQ ID NO: 37 / 39 (v1.2), SEQ ID NO: 37 / 40 (v1.3), SEQ ID NO: 37 / 41 (v1.4), SEQ ID NO: 42 / 36 (v1.5), SEQ ID NO: 43 / 3 and SEQ ID NO: 50 / 36 (v2.9).

[0161] In one embodiment, an anti-TGFβ3 antibody is provided that binds to the same epitope as an anti-TGFβ3 antibody comprising the VH / VL sequences (respectively) of SEQ ID NOs: 57 / 56 (h2A10.v4).

[0162] In a specific embodiment, an isolated anti-TGFβ3 antibody is provided, which comprises an antigen-binding domain that directly contacts amino acid residues R325, K331, W332, H334, E335, T387, I388, L389, Y391, V392, G393, R394, P396, K397 and V398 on human TGFβ3, and which selectively neutralizes TGFβ3.

[0163] In some aspects, provided herein is an isolated anti-TGFβ3 antibody comprising: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7, CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9. In some embodiments, CDR-H2 has the amino acid sequence of SEQ ID NO: 35. In certain embodiments, the isolated anti-TGFβ3 antibody further comprises a VH having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57. In some embodiments, the anti-TGFβ3 antibody further comprises a VL having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 56. In certain embodiments, the anti-TGFβ3 antibody further comprises a complete H chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 79. In other embodiments, the anti-TGFβ3 antibody further comprises an intact light chain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:78.

[0164] In another embodiment, an isolated anti-TGFβ3 antibody is provided that selectively neutralizes TGFβ3 and has reduced toxicity in mice compared to the pan-TGFβ antibody 1D11. In some embodiments, the anti-TGFβ3 antibody provided herein has reduced toxicity in mice compared to the pan-TGFβ antibody 1D11 at a dose of 50 mg / kg. The 1D11 antibody is described in Lonning et al. (Current Pharmaceutical Biotechnology, 2011, 12, 2176-2189) and has the following amino acid sequence: VH:QVQLQQSGPELVRPGASVKLSCKASGYIFITYWMNWVKQRPGQGLEWIGQIFPASGSTNYNEMFEGKATLTVDTSSSTAYMQLSSLTSEDSAVYYCARGDGNYALDAMDYWGQGTSVTVSS (SEQ ID NO: 160) VL:DIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKSGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPLTFGAGTKLEIK (SEQ ID NO: 161)

[0165] In a further aspect of the invention, the isoform-selective anti-TGFβ antibody according to any of the above embodiments (e.g., monospecific anti-TGFβ2 and anti-TGFβ3 antibodies, and bispecific anti-TGFβ2 / 3 antibodies described herein) is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the isoform-selective anti-TGFβ antibody; the antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG1 or IgG4 antibody, preferably a human IgG1, even more preferably a human IgG1 comprising an N297 mutation (EU numbering as in Kabat), such as N297A or N297G, preferably N297G, or other antibody class or isotype as defined herein.

[0166] In a further aspect, an isoform-selective anti-TGFβ antibody according to any of the above embodiments can incorporate any of the features described in Sections 1-7 below, either alone or in combination.

[0167] 1. Antibody affinity In certain embodiments, the antibodies provided herein have a cytotoxicity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D )

[0168] In one embodiment, K D is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed using a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is determined by measuring the binding affinity of the Fab to the antigen at the lowest concentration ( 125 I) Fab is equilibrated with labeled antigen, followed by capturing the bound antigen on a plate coated with an anti-Fab antibody (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish assay conditions, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / mL of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), followed by blocking with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In non-adsorbent plates (Nunc #269620), 100 pM or 26 pM [ 125[I]-antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, incubation may be continued for a longer period (e.g., about 65 hours) to reach equilibrium. The mixture is then transferred to a capture plate for incubation at room temperature (e.g., 1 hour). The solution is then removed, and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate has dried, 150 μl / well of scintillant (MICROSCINT-20™, Packard) is added, and the plate is counted for 10 minutes on a TOPCOUNT™ gamma counter (Packard). Concentrations of each Fab that result in 20% or less of maximal binding are selected for use in competitive binding assays.

[0169] According to another embodiment, K Dis measured using a BIACORE® surface plasmon resonance assay. For example, assays using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) are performed at 25°C using an immobilized antigen CM5 chip at approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE) is activated with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to instructions in the art. The antigen is diluted in 10 mM sodium acetate, pH 4.8, to 5 μg / ml (approximately 0.2 μM) before injection at a flow rate of 5 μl / min to achieve approximately 10 response units (RU) of bound protein. Following antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS containing 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25°C at a flow rate of approximately 25 μl / min. Association rates (k) and dissociation rates (k) are calculated by simultaneously fitting the association and dissociation sensorgrams using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2). The equilibrium dissociation constant (K D) is calculated as the ratio koff / kon. See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the association rate by the surface plasmon resonance assay described above exceeds 106 M-1 s-1, the association rate can be determined using a fluorescence quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing antigen concentrations, as measured in a spectrometer such as a spectrophotometer equipped with stopped-flow (Aviv Instruments) or an 8000 series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0170] 2. Antibody fragments In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. For a review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthuen, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93 / 16185 and U.S. Pat. Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a description of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased in vivo half-lives.

[0171] Diabodies are antibody fragments with two antigen-binding sites that can be bivalent or bispecific. See, e.g., EP 404,097, WO 1993 / 01161, Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

[0172] Single-domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, single-domain antibodies are human single-domain antibodies (Domantis, Inc. (Waltham, Massachusetts) see, e.g., U.S. Patent No. 6,248,516 B1).

[0173] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0174] 3. Chimeric and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0175] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody and the FRs (or portions thereof) are derived from human antibody sequences. Optionally, a humanized antibody also comprises at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0176] Humanized antibodies and methods for their production are reviewed by Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (description of specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (description of resurfacing); Dall'Acqua et al., Methods 36:43-60 (2005) (description of FR shuffling); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (description of a "guided selection" approach to FR shuffling).

[0177] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of particular subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996).

[0178] 4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0179] Human antibodies can be prepared by administering immunogens to transgenic animals that have been engineered to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of human immunoglobulin loci that replace endogenous immunoglobulin loci, or that are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Patent No. 5,770,429, which describes HUMAB® technology; U.S. Patent No. 7,041,870, which describes KM MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining with different human constant regions.

[0180] Human antibodies can also be produced by hybridoma-based methods. Human myeloma cell lines and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies generated via human B cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include those described, for example, in U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (which describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0181] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. These variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0182] 5. Library-derived antibodies Antibodies of the invention can be isolated by screening combinatorial libraries for antibodies with one or more desired activities. For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding characteristics. Such methods are reviewed, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and are also described, for example, by McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al. al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

[0183] In some phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR), randomly recombined into phage libraries, and then screened for antigen-binding phage, as described by Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phage typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources provide high-affinity antibodies against the immunogen without the need for hybridoma construction. Alternatively, naive repertoires can be cloned (e.g., from humans) without immunization to provide a single source of antibodies against a wide range of non-self and also self antigens, as described by Griffiths et al., EMBO J., 12:725-734 (1993). Finally, naive libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions to achieve rearrangement in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0184] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments herein.

[0185] 6. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for a TGFβ isoform (e.g., TGFβ1, TGFβ2, TGFβ3, or TGFβ2 / 3) and the other is for any other antigen. In certain embodiments, one of the binding specificities is for one TGFβ isoform (e.g., TGFβ1, TGFβ2, or TGFβ3) and the other is for a different TGFβ isoform. In certain embodiments, bispecific antibodies can bind to two different epitopes within a single TGFβ isoform. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing one or more TGFβ isoform(s). Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0186] Techniques for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983), WO 93 / 08829, and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-into-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies have also been developed using techniques such as the manipulation of electrostatic steering effects to create antibody Fc heterodimeric molecules (WO 2009 / 089004 A1); cross-linking of two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al., Science, 229:81 (1985)); the use of leucine zippers to create bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); the use of "diabody" technology to create bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and the use of single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 148(5):1547-1553 (1992)). al., J. Immunol., 152:5368 (1994)); and, for example, by the preparation of trispecific antibodies as described in Tutt et al. J. Immunol. 147:60 (1991).

[0187] Engineered antibodies with three or more functional antigen-binding sites, including "octopus antibodies," are also included herein (see, e.g., U.S. Patent Publication No. 2006 / 0025576 A1).

[0188] The antibodies or fragments herein also include "dual acting FAbs" or "DABs" that contain antigen binding sites that bind to one or more TGFβ isoform(s) (e.g., TGFβ1, TGFβ2 and / or TGFβ3) and another distinct antigen (see, e.g., U.S. Patent Application Publication No. 2008 / 0069820).

[0189] 7. Antibody Variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, so long as the final construct possesses the desired characteristics (e.g., antigen binding).

[0190] a) Substitution, insertion, and deletion mutants In certain embodiments, antibody variants are provided that have one or more amino acid substitutions. Sites of interest for substitutional mutagenesis include HVRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "Preferred Substitutions." More substantial changes are shown in Table 1 under the heading of "Exemplary Substitutions" and are further described below with respect to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the products screened for the desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 1] Amino acids can be classified according to general side chain properties: (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0191] Non-conservative substitutions involve exchanging a member of one of these classes for another class.

[0192] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., an improvement) in a particular biological property (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody and / or will substantially retain a particular biological property of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which may be conveniently generated using, for example, phage-display-based affinity maturation techniques as described herein. Briefly, one or more HVR residues are mutated and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0193] Alterations (e.g., substitutions) may be made in HVRs, for example, to improve antibody affinity. Such alterations may be made within HVR "hotspots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or residues that contact the antigen, and the resulting mutant VH or VL are tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries is described, for example, in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then generated. This library is then screened to identify antibody variants with the desired affinity. Another method for introducing diversity involves an HVR-directed approach, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified using, for example, alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0194] In certain embodiments, substitutions, insertions, or deletions may be made within one or more HVRs so long as such changes do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such changes may, for example, be outside of antigen-contact residues within the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unaltered or contains no more than one, two, or three amino acid substitutions.

[0195] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues, e.g., Arg, Asp, His, Lys, and Glu) is identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Further substitutions may be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of the antigen-antibody complex may be used to identify contact points between the antibody and antigen. Such contact and neighboring residues may be targeted or eliminated as candidates for substitution. Mutants may be screened to determine whether they possess the desired properties.

[0196] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0197] b) Glycosylation variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0198] If the antibody contains an Fc region, the carbohydrate attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are commonly attached to Asn297 in the CH2 domain of the Fc region via an N-linkage. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharides in the antibodies of the invention can be performed to generate antibody variants with specific improved properties.

[0199] In one embodiment, antibody variants are provided that have carbohydrate structures lacking fucose attached (directly or indirectly) to the Fc region. The amount of fucose in such antibodies may be, for example, 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycans at Asn297 relative to the sum of all glycan structures attached to Asn297 (e.g., complex, hybrid, and high-mannose structures) as measured by MALDI-TOF mass spectrometry, e.g., as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located upstream or downstream of position 297, i.e., approximately ±3 amino acids between positions 294 and 300, due to minor antibody sequence variations. Such fucosylation variants may have improved ADCC function. See, e.g., U.S. Patent Application Publication Nos. 2003 / 0157108 (Presta, L.); 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: U.S. Patent Application Publication Nos. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. Patent Application Publication Nos. 2003 / 0115614; 2002 / 0164328; 2004 / 0093621; and U.S. Patent Application Publication Nos. 2004 / 0115614 and 2002 / 0164328. 32140; 2004 / 0110704; 2004 / 0110282; 2004 / 0109865; WO 2003 / 085119; 2003 / 084570; 2005 / 035586; 2005 / 035778; 2005 / 053742; 2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., especially Example 11), and knockout cell lines, such as α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003 / 085107).

[0200] In certain embodiments, the N-glycosylation site in the CH2 domain of an isoform-selective anti-TGFβ antibody of the present invention is mutated to prevent glycosylation. For example, an isoform-selective anti-TGFβ antibody having an aglycosylated Fc region can be generated by mutating the amino acid residue at position 297 (e.g., N297) as per the EU index in the CH2 domain of the Fc region. In certain embodiments, glycosylation in the CH2 domain of the Fc region can be removed by modifying the glycosylation consensus site, i.e., Asn at position 297, followed by any amino acid residue (Ser in the case of human IgG) and Thr. The glycosylation site can be modified by amino acid insertion, deletion, and / or substitution. For example, one or more amino acid residues can be inserted between Asn and Ser or between Ser and Thr to alter the original glycosylation site; the insertion does not regenerate an N-glycosylation site. In certain specific embodiments, the amino acid residue at position 297 of the EU index in the CH2 domain of human IgG Fc (e.g., the N-glycosylation site of Fc) is mutated to eliminate the glycosylation site. In certain specific embodiments, the amino acid residue at position 297 as in the EU index (e.g., N297) is changed to Gly, Ala, Gln, Asp, or Glu. In some specific embodiments, the amino acid residue at position 297 of the EU index (e.g., N297) is changed to Gly or Ala. In other specific embodiments, the amino acid residue at position 297 of the EU index (e.g., N297) is changed to Gly. In certain other embodiments, the amino acid residue at position 299 of the EU index can be substituted with another amino acid, e.g., Ala, Val, or Gly. In certain specific embodiments, the mutation resulting in an aglycosylated Fc does not affect the structure and / or stability of the isoform-selective anti-TGFβ antibody.

[0201] In certain embodiments, isoform-selective anti-TGFβ antibodies of the invention comprise an Fc region in which the amino acid residue at position 297 of the EU index in the CH2 domain is mutated. In certain embodiments, the amino acid residue at position 297 of the EU index is changed to Gly or Ala, preferably Gly. In certain other embodiments, the amino acid residue at position 297 of the EU index is deleted. In other embodiments, the N-glycan attached to the wild-type amino acid residue at position 297 of the EU index (e.g., N297) can be enzymatically removed, for example, by deglycosylation. Suitable glycolytic enzymes include, but are not limited to, peptide-N-glycosidase (PNGase).

[0202] Further provided are antibody variants having bisected oligosaccharides, for example, biantennary oligosaccharides attached to the Fc region of the antibody, bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); and U.S. Patent Application Publication No. 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0203] c) Fc region mutants In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0204] In certain embodiments, the present invention contemplates antibody variants that retain some, but not all, effector functions, making them desirable candidates for uses in which in vivo antibody half-life is important but certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / absent CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to confirm that the antibody lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express FcRIII only, whereas monocytes express FcR1, FcR1I, and FcR1I. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest include those described in U.S. Pat. No. 5,500,362 (e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); (See, e.g., Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays may be employed (see, e.g., ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA) and CytoTox 96® Non-Radioactive Cytotoxicity Test (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.Alternatively, or additionally, ADCC activity of a molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, e.g., the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0205] Antibodies with reduced effector function include those containing one or more substitutions at residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant in which residues 265 and 297 are substituted with alanine (U.S. Patent No. 7,332,581).

[0206] Certain antibody variants have been described that have improved or diminished binding to FcRs (see, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0207] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0208] In some embodiments, alterations are made in the Fc region that result in altered (i.e., improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0209] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in U.S. Patent Application Publication No. 2005 / 0014934 A1 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions in one or more of the following Fc region residues: :238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, for example, substitution of Fc region residue 434 (U.S. Patent No. 7,371,826).

[0210] For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94 / 29351.

[0211] d) Cysteine Engineered Antibody Variants In certain embodiments, it may be desirable to generate cysteine-engineered antibodies, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with a cysteine residue. In certain embodiments, the substituted residues are located at accessible sites of the antibody. By substituting these residues with cysteine, reactive thiol groups are thereby placed at accessible sites on the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine-engineered antibodies can be generated, for example, as described in U.S. Pat. No. 7,521,541.

[0212] e) Antibody derivatives In certain embodiments, the antibodies provided herein can be further modified to contain additional nonproteinaceous moieties known in the art and readily available. Suitable sites for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone), polyethylene glycol, polypropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde can be advantageous during manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and when multiple polymers are attached, they can be the same molecule or different molecules. Generally, the number and / or type of polymers used for derivatization can be determined based on considerations such as, but not limited to, the particular property or function of the antibody to be improved and whether the antibody derivative will be used therapeutically under defined conditions.

[0213] In another embodiment, a conjugate of an antibody and a non-protective moiety is provided that can be selectively heated by exposure to radiation. In one embodiment, the non-protective moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may be of any wavelength, including, but not limited to, wavelengths that are not harmful to normal cells but heat the non-protective moiety to temperatures that kill cells proximal to the antibody non-protective moiety.

[0214] B. Recombinant Methods and Compositions Antibodies may be produced using recombinant methods and compositions described, for example, in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an isoform-selective anti-TGFβ antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL of the antibody and / or an amino acid sequence constituting the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In a further embodiment, a host cell comprising such nucleic acids is provided. In one such embodiment, the host cell comprises (e.g., transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a nucleic acid encoding an amino acid sequence comprising the VH of the antibody, or (2) a vector comprising a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphocytic cell (e.g., a Y0, NS0, Sp20 cell). In one embodiment, a method of making an isoform-selective anti-TGFβ antibody is provided, the method comprising culturing a host cell comprising nucleic acid encoding the antibody under conditions suitable for expression of the antibody, as described above, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0215] For recombinant production of an isoform-selective anti-TGFβ antibody, nucleic acid encoding the antibody, such as those described above, is isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of binding specifically to genes encoding the antibody heavy and light chains).

[0216] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly if glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) Following expression, the antibody may be isolated in a soluble fraction from the bacterial cell paste or further purified.

[0217] In addition to prokaryotes, eukaryotic organisms such as filamentous fungi and yeast are suitable cloning or expression hosts for antibody-encoding vectors, including bacterial and yeast strains that have been "humanized" in their glycosylation pathways to produce antibodies with partially or fully human glycosylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0218] Suitable host cells for expressing glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified and can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0219] Plant cell cultures can also be used as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0220] Vertebrate cells may also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include SV40 (COS-7) transformed monkey kidney CV1 line, human embryonic kidney lines (e.g., 293 or 293 cells as described in Graham et al., J Gen Virol., 36:59 (1977)), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells as described in Mather, Biol Reprod., 23:243-251 (1980)), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical carcinoma cells (HELA), canine kidney cells (MDCK), buffalo rat liver cells (BRL 3A), human lung cells (W138), human liver cells (Hep G2), mouse mammary tumor cells (MMT 060562), TRI cells (e.g., Mather et al., Annals NY Acad. Sci., 383:44-68 (1982); MRC5 cells; and FS4 cells...

Claims

1. 1. An isolated anti-tumor necrosis factor beta 3 (TGFβ3) antibody, which selectively neutralizes TGFβ3 and has the following characteristics: (n) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (a) specifically binds to the beta6 / beta7 hairpin region of TGFβ3; (b) binding of anti-TGFβ3 antibodies sterically blocks the ability of TGFβR2 to bind to TGFβ3, but does not sterically block the ability of TGFβR1 to bind to TGFβ3; (c) binding of the anti-TGFβ3 antibody to TGFβ3 blocks the binding of TGFβR2 and inhibits the binding of TGFBR1 / TGFBR2 signaling receptors to TGFβ3; (d) makes direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3; (e) makes direct contact with amino acid residue R394 in the beta6 / beta7 hairpin region of human TGFβ3, and residue R394 of TGFβ3 makes an ionic salt bridge with the anti-TGFβ3 antibody in the heavy chain CDR2; (f) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ1 is achieved by direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues T387, L389, and T395 (human TGFβ3 numbering) of TGFβ3; (g) isoform selectivity of the anti-TGFβ3 antibody for TGFβ3 that exceeds the isoform selectivity of the anti-TGFβ3 antibody for TGFβ2 is achieved by direct contact between the antigen-binding domain of the anti-TGFβ3 antibody and amino acid residues R325, R394, and V398 (human TGFβ3 numbering) of TGFβ3; (h) reduced toxicity compared to pan-TGFβ antibody 1D11; (i) reduced toxicity in rodents or cynomolgus monkeys compared to the pan-TGFβ antibody 1D11; (j) reduced toxicity compared to galunisertib, a pan-TGFβ small molecule inhibitor; (k) reduced toxicity in rodents compared to galunisertib, a pan-TGFβ small molecule inhibitor; (l) reduced toxicity compared to the anti-TGFβ1 antibody CAT-192; (m) reduced toxicity compared to isoform-selective anti-TGFβ2 antibodies and / or anti-TGFβ2 / 3 antibodies; (o) an antigen-binding domain that directly contacts amino acid residues R325, K331, W332, H334, E335, T387, I388, L389, Y391, V392, G393, R394, P396, K397, and V398 on human TGFβ3; and (p) The anti-TGFβ3 antibody according to (o), wherein the antigen-binding domain is within 15 to 8, 8, 8 to 5, 7 to 5, 6 to 5, or 5 angstroms of TGFβ3 amino acid residues.

1. An isolated anti-tumor necrosis factor beta 3 (TGFβ3) antibody comprising one or more of:

2. An isolated anti-TGFβ3 antibody, comprising: (i) heavy chain CDRs including CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 5, 34, 35, and 159, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs including CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO:

9.

3. The anti-TGFβ3 antibody of claim 1 or claim 2, comprising a heavy chain variable region (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: 23, 37, 42 to 53, 55, and 57.

4. The anti-TGFβ3 antibody of any one of claims 1 to 3, comprising a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 37, 42-53, 55 and 57.

5. The anti-TGFβ3 antibody of any one of claims 1 to 4, comprising a complete heavy (H) chain 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: 29, 59, 64, 65-75, 77, and 79.

6. The anti-TGFβ3 antibody of any one of claims 1 to 5, comprising a complete heavy (H) chain amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 59, 64, 65-75, 77 and 79.

7. The anti-TGFβ3 antibody of any one of claims 1 to 6, comprising a light chain variable region (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: 22, 36, 38-41, 54, and 56.

8. The anti-TGFβ3 antibody of any one of claims 1 to 7, comprising a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, 38-41, 54 and 56.

9. The anti-TGFβ3 antibody of any one of claims 1 to 8, comprising a complete light (L) chain 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: 28, 58, 60-63, 76, and 78.

10. The anti-TGFβ3 antibody of any one of claims 1 to 9, comprising a complete light chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, 60-63, 76 and 78.

11. and VH / VL pairs, wherein the VH / VL pairs are selected from the group consisting of SEQ ID NOs: 23 / 22 (rat 2A10), 37 / 36 (v1), 37 / 38 (v1.1), 37 / 39 (v1.2), 37 / 40 (v1.3), 37 / 41 (v1.4), 42 / 36 (v1.5), 43 / 36 (v1.6), 44 / 36 (v1.7), 45 / 36 (v2), 45 / 38 (v2.1), 45 / 39 (v2.2), 45 / 40 (v2.3), and 45 / 41 (v2.4).

11. The TGFβ3 antibody of any one of claims 1 to 10, comprising an amino acid sequence (respectively) selected from the group consisting of: SEQ ID NO:46 / 36 (v2.5), SEQ ID NO:47 / 36 (v2.6), SEQ ID NO:48 / 36 (v2.7), SEQ ID NO:49 / 36 (v2.8), SEQ ID NO:50 / 36 (v2.9), SEQ ID NO:51 / 36 (h2A10.v2.N54S), SEQ ID NO:52 / 36 (h2A10.v2.N54Q), SEQ ID NO:53 / 36 (h2A10.v2.T56A), SEQ ID NO:55 / 54 (v3), and SEQ ID NO:57 / 56 (v4).

12. The complete H / L chain pair may be selected from the group consisting of SEQ ID NOs: 29 / 28 (rat 2A10), 59 / 58 (v1), 59 / 60 (v1.1), 59 / 61 (v1.2), 59 / 62 (v1.3), 59 / 63 (v1.4), 64 / 58 (v1.5), 65 / 58 (v1.6), 66 / 58 (v1.7), 67 / 58 (v2), 67 / 60 (v2.1), 67 / 61 (v2.2), and SEQ ID NOs:

12. The anti-TGFβ3 antibody of any one of claims 1 to 11, comprising an amino acid sequence (respectively) selected from the group consisting of SEQ ID NOs:67 / 62 (v2.3), 67 / 63 (v2.4), 68 / 58 (v2.5), 69 / 58 (v2.6), 70 / 58 (v2.7), 71 / 58 (v2.8), 72 / 58 (v2.9), 73 / 58 (h2A10.v2.N54S), 74 / 58 (h2A10.v2.N54Q), 75 / 58 (h2A10.v2.T56A), 77 / 76 (v3), and 79 / 78 (v4).

13. 11. The anti-TGFβ3 antibody of any one of claims 1 to 10, comprising a VL of SEQ ID NO: 22 comprising one or more framework modifications selected from the group consisting of 4L or 4M, 38H or 38Q, 43A or 43Q, and 58V.

14. VL is, (i) 4L in FR1, 38H and 43Q in FR2, and 58I in FR3 (h2A10.v1 and h2A10.v2); (ii) 4M in FR1 (h2A10.v1.1 and h2A10.v2.1); (iii) 38Q in FR2 (h2A10.v1.2 and h2A10.v2.2); (iv) 43A in FR2 (h2A10.v1.3 and h2A10.v2.3); (v) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4); (vii) 58V in FR3 (h2A10.v1.4 and h2A10.v2.4); and (vi) 38Q, 43A in FR2, 58V in FR3 (h2A10.v3 and h2A10.v4) The anti-TGFβ3 antibody of any one of claims 1 to 10, comprising a set of framework modifications selected from the group consisting of:

15. 15. The anti-TGFβ3 antibody of any one of claims 1 to 10, 13 and 14, comprising a VH of SEQ ID NO: 23 comprising one or more framework modifications selected from the group consisting of: 47L or 47W; 49A, 49S or 49G; 73D or 73N; and 76N, 78D or 78L, 78A, or 78V.

16. VH, (i) 47L, 49A in FR2, 78V in FR3 (h2A10.v1); (ii) 47L, 49A in FR2, 73D, 76S, 78V in FR3 (h2A10.v2); (iii) 47W in FR2 (h2A10.v1.5); (iv) 49G in FR2 (h2A10.v1.6); (v) 78A in FR3 (h2A10.v1.7); (vi) 47W in FR2 (h2A10.v2.5); (vii) 49S in FR2 (h2A10.v2.6); (viii) 73N in FR3 (h2A10.v2.7); (ix) 76N of FR3 (h2A10.v2.8); (x) 78L in FR3 (h2A10.v2.9); and (xi) 49S in FR2, 76N, 78L in FR3 (h2A10.v3 and h2A10.v4) 16. The anti-TGFβ3 antibody of claim 15, comprising a set of framework modifications selected from the group consisting of:

17. 16. The antibody of claim 13 or claim 15, comprising a VL, wherein the VL retains a leucine (L) at position 4 of framework I and a leucine (L) at position 47 of framework II.

18. 18. The antibody of claim 15 or claim 17, wherein the VH retains D at position 73 of framework III of the VH derived from r2A10.

19. The anti-TGFβ3 antibody according to any one of claims 1 to 12, comprising a CDR-H2 having the amino acid sequence of SEQ ID NO:

5.

20. The anti-TGFβ3 antibody of any one of claims 1 to 12, comprising a CDR-H2 having the amino acid sequence of SEQ ID NO:

159.

21. 21. The anti-TGFβ3 antibody of claim 20, comprising 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 the amino acid sequence of SEQ ID NO:

52.

22. 22. The anti-TGFβ3 antibody of claim 20 or claim 21, comprising the VH amino acid sequence of SEQ ID NO:

52.

23. The anti-TGFβ3 antibody of any one of claims 20 to 22, comprising a complete heavy chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

74.

24. The anti-TGFβ3 antibody of any one of claims 20 to 23, comprising the complete heavy chain amino acid sequence of SEQ ID NO:

74.

25. The anti-TGFβ3 antibody of any one of claims 20 to 24, comprising 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: 22, 36, and 38 to 41.

26. The anti-TGFβ3 antibody of any one of claims 20 to 25, comprising a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 22, 36, and 38 to 41.

27. The anti-TGFβ3 antibody of any one of claims 20 to 26, comprising a complete light chain 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: 28, 58, and 60 to 63.

28. The anti-TGFβ3 antibody of any one of claims 20 to 27, comprising a complete light chain amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 58, and 60 to 63.

29. 21. The anti-TGFβ3 antibody of claim 20, comprising a VH / VL pair comprising the amino acid sequences of SEQ ID NOs: 52 / 36 (respectively).

30. 21. The anti-TGFβ3 antibody of claim 20, comprising a complete H / L chain pair, wherein the H / L chain pair comprises the amino acid sequences of SEQ ID NOs: 74 / 58 (respectively).

31. The anti-TGFβ3 antibody according to any one of claims 1 to 12, comprising a CDR-H2 having the amino acid sequence of SEQ ID NO:

34.

32. 32. The anti-TGFβ3 antibody of claim 31, comprising 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 the amino acid sequence of SEQ ID NO:

55.

33. 33. The anti-TGFβ3 antibody of claim 31 or claim 32, comprising the VH amino acid sequence of SEQ ID NO:

55.

34. The anti-TGFβ3 antibody of any one of claims 31 to 33, comprising a complete heavy chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

77.

35. The anti-TGFβ3 antibody of any one of claims 31 to 34, comprising the complete heavy chain amino acid sequence of SEQ ID NO:

77.

36. The anti-TGFβ3 antibody of any one of claims 31 to 35, comprising 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 the amino acid sequence of SEQ ID NO:

54.

37. The anti-TGFβ3 antibody of any one of claims 31 to 36, comprising the VL amino acid sequence of SEQ ID NO:

54.

38. The anti-TGFβ3 antibody of any one of claims 31 to 37, comprising a complete light chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

76.

39. The anti-TGFβ3 antibody of any one of claims 31 to 38, comprising the complete light chain amino acid sequence of SEQ ID NO:

76.

40. 32. The anti-TGFβ3 antibody of claim 31, comprising a VH / VL pair, wherein the VH / VL pair comprises the amino acid sequences of SEQ ID NOs: 55 / 54 (respectively).

41. 32. The anti-TGFβ3 antibody of claim 31, comprising a complete H / L chain pair, wherein the H / L chain pair comprises the amino acid sequences of SEQ ID NOs: 77 / 76 (respectively).

42. The anti-TGFβ3 antibody according to any one of claims 1 to 12, comprising a CDR-H2 having the amino acid sequence of SEQ ID NO:

35.

43. 43. The anti-TGFβ3 antibody of claim 42, comprising 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 the amino acid sequence of SEQ ID NO:

57.

44. 44. The anti-TGFβ3 antibody of claim 42 or claim 43, comprising the VH amino acid sequence of SEQ ID NO:

57.

45. The anti-TGFβ3 antibody of any one of claims 42 to 44, comprising a complete heavy chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

79.

46. The anti-TGFβ3 antibody of any one of claims 42 to 45, comprising the complete heavy chain amino acid sequence of SEQ ID NO:

79.

47. The anti-TGFβ3 antibody of any one of claims 42 to 46, comprising 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 the amino acid sequence of SEQ ID NO:

56.

48. 48. The anti-TGFβ3 antibody of any one of claims 42 to 47, comprising the VL amino acid sequence of SEQ ID NO:

56.

49. The anti-TGFβ3 antibody of any one of claims 42 to 48, comprising a complete light chain amino acid sequence having at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:

76.

50. 50. The anti-TGFβ3 antibody of any one of claims 42 to 49, comprising the complete light chain amino acid sequence of SEQ ID NO:

76.

51. 43. The anti-TGFβ3 antibody of claim 42, comprising a VH / VL pair comprising the amino acid sequences of SEQ ID NOs: 57 / 56 (respectively).

52. 43. The anti-TGFβ3 antibody of claim 42, comprising a complete H / L chain pair, wherein the H / L chain pair comprises the amino acid sequences of SEQ ID NOs: 79 / 78 (respectively).

53. (a) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (b) a VH / VL pair, wherein the VH of the VH / VL pair comprises the amino acid sequence of SEQ ID NO: 57 and the VL of the VH / VL pair comprises the amino acid sequence of SEQ ID NO: 56; or (c) a complete heavy / light chain pair, wherein the heavy chain of the heavy / light chain pair comprises the amino acid sequence of SEQ ID NO: 79 and the light chain of the heavy / light chain pair comprises the amino acid sequence of SEQ ID NO:

78. An anti-TGFβ3 antibody comprising:

54. 1. An isolated anti-TGF2 / 3 antibody that selectively neutralizes TGFβ2 and TGFβ3 and has the following characteristics: (a) the selectivity of the anti-TGFβ2 / 3 antibody for TGFβ2 and TGFβ3 over the selectivity of the anti-TGFβ2 / 3 antibody for human TGFβ1 in terms of selective neutralization is achieved by direct contact between the antigen-binding domain of the antibody and amino acid residue E373 (human TGFβ2 numbering) of TGFβ2 or TGFβ3; (b) neutralizing TGFβ2 and / or TGFβ3 via an allosteric mechanism; (c) inducing a conformational change in TGFβ2 and / or TGFβ3 homodimers; (d) inducing a conformational change in TGFβ2 and / or TGFβ3 homodimers, the conformational change involving the two monomers pinching together several times; (e) is a bivalent antibody or a monovalent antibody; (f) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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) specifically binds to a TGFβ2 homodimer, the TGFβ2 homodimer having a first and a second TGFβ2 monomer and comprising 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 (human TGFβ2 numbering) of the second TGFβ2 monomer; (h) the anti-TGFβ2 / 3 antibody according to (g), wherein the antigen-binding domain is within 5 angstroms of a TGFβ2 and / or TGFβ3 amino acid residue; (i) specifically binds to the same epitope on TGFβ3 as (g); and (j) does not neutralize TGFβ2 and / or TGFβ3 in a monovalent form An anti-TGFβ2 / 3 antibody comprising one or more of:

55. 55. The anti-TGFβ2 / 3 antibody of claim 54, comprising 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: 27, 81, 83, 86-88, 93-100, and 102-105.

56. 56. The anti-TGFβ2 / 3 antibody of claim 54 or claim 55, comprising a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 81, 83, 86-88, 93-100, and 102-105.

57. The anti-TGFβ2 / 3 antibody of any one of claims 54 to 56, comprising a complete heavy chain 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: 33, 107, 109, 112-114, and 119-130.

58. 58. The anti-TGFβ2 / 3 antibody of any one of claims 54 to 57, comprising 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.

59. 57. The anti-TGFβ2 / 3 antibody of any one of claims 54 to 56, comprising a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 80, 82, 84, 85, 89-92, and 101.

60. The anti-TGFβ2 / 3 antibody of any one of claims 54 to 59, comprising a complete light chain 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: 32, 106, 108, 110, 111, 115-118, and 186.

61. 61. The anti-TGFβ2 / 3 antibody of any one of claims 54 to 60, comprising a complete light chain amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 106, 108, 110, 111, 115-118, and 186.

62. and a VH / VL pair, wherein the VH / VL pair is 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.

55. The anti-TGFβ2 / 3 antibody of claim 54, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 94 / 84 (v7.8), 94 / 84 (v7.9), 95 / 84 (v7.10), 96 / 84 (v7.11), 97 / 84 (v7.12), 98 / 84 (v7.13), 99 / 84 (v7.14), SEQ ID NOs: 100 / 84 (v7.15), SEQ ID NOs: 102 / 101 (v7.16), SEQ ID NOs: 103 / 101 (v7.17), SEQ ID NOs: 104 / 101 (v7.18), SEQ ID NOs: 105 / 101 (v7.19), and SEQ ID NOs: 83 / 85 (v8) (respectively).

63. The complete H / L chain pair is 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 55. The anti-TGFβ2 / 3 antibody of claim 54, comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:114 / 111 (v8), 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).

64. 55. The anti-TGFβ2 / 3 antibody of claim 54, comprising a VL comprising the amino acid sequence of SEQ ID NO: 26, wherein the VL comprises one or more framework modifications selected from the group consisting of 2A or 2I, 4L, 36F or 36Y, 43P or 43A, and 58V or 58I.

65. VL is, (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) 2I in FR1 (h4A11.v7.4); (vi) 36Y in FR2 (h4A11.v7.5); (vii) 43A in FR2 (h4A11.v7.6); (viii) 58I in FR3 (h4A11.v7.7); and (ix) 2I in FR1, 43A in FR2, 58I in FR3 (h4A11.v7.16-19) 55. The anti-TGFβ2 / 3 antibody of claim 54, comprising a set of framework modifications selected from the group consisting of:

66. 55. The anti-TGFβ2 / 3 antibody of claim 54, comprising a VH comprising the amino acid sequence of SEQ ID NO: 27 comprising one or more framework 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, deletion 105P or 105Q.

67. VL is, (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 of 1E in FR1 (h4A11.v7.1); (iv) deletion of 75K and 76N in FR3 (h4A11.v7.2); (v) deletion of 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 (h4A11.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) deletion of 2V in FR1, 37I, 67V, 73T in FR2, 75K and 76N in FR3, and 105Q in FR4 (h4A11.v7.19) 67. The anti-TGFβ2 / 3 antibody of claim 54 or claim 66, comprising a set of framework modifications selected from the group consisting of:

68. 1. An isolated anti-TGFβ2 antibody, comprising: (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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) a light chain CDR comprising CDR-L1, CDR-L2, and CDR-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; 1. An isolated anti-TGFβ2 antibody comprising:

69. 69. The anti-TGFβ2 antibody of claim 68, which selectively neutralizes TGFβ2.

70. (a) Reduced toxicity compared to pan-TGFβ antibody 1D11; (b) reduced toxicity in rodents compared to the pan-TGFβ antibody 1D11; (c) reduced toxicity compared to galunisertib, a pan-TGFβ small molecule inhibitor; and / or (d) reduced toxicity in rodents compared to galunisertib, a pan-TGFβ small molecule inhibitor; 70. The anti-TGFβ2 antibody of claim 69.

71. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising 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.

72. 72. The anti-TGFβ2 antibody of claim 71, comprising a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 132, and 138-142.

73. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a complete heavy chain 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: 31, 146, and 152-156.

74. 74. The anti-TGFβ2 antibody of claim 73, comprising a complete heavy chain amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 146, and 152-156.

75. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising 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.

76. 76. The anti-TGFβ2 antibody of claim 75, comprising a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 24, 131, 133-137, 143, and 144.

77. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a complete light chain 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: 30, 145, 147-151, 157, and 158.

78. 78. The anti-TGFβ2 antibody of claim 77, comprising a complete light chain amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 145, 147-151, 157, and 158.

79. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a VH / VL pair, wherein the VH / VL pair comprises an amino acid sequence 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).

80. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a complete heavy / light chain pair, wherein the complete heavy / light chain pair comprises an amino acid sequence 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).

81. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a VL comprising the amino acid sequence of SEQ ID NO: 24, comprising one or more framework mutations selected from the group consisting of 43S or 43A, 66G, 69T, 71F, and 87Y.

82. VL is, (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) 82. The anti-TGFβ2 antibody of claim 81, comprising a set of framework mutations selected from the group consisting of:

83. 70. The anti-TGFβ2 antibody of claim 68 or claim 69, comprising a VH comprising the amino acid sequence of SEQ ID NO: 25, wherein the VH comprises one or more framework mutations selected from the group consisting of 37V or 37I, 48M or 48L, 49G or 49A, 67L, 71K and 78V, and 105P or 105R.

84. VH, (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) 84. The anti-TGFβ2 of claim 83, comprising a set of framework mutations selected from the group consisting of:

85. An anti-TGFβ3 antibody according to any one of claims 1 to 53, or an anti-TGFβ2 / 3 antibody according to any one of claims 54 to 66, which specifically binds to human TGFβ3.

86. 54. The anti-TGFβ3 antibody of any one of claims 1 to 53, which specifically binds to both immature and mature forms of TGFβ3.

87. An anti-TGFβ2 / 3 antibody according to any one of claims 54 to 66, or an anti-TGFβ2 antibody according to any one of claims 68 to 81, which specifically binds to human TGFβ2.

88. An antibody described in any one of claims 1 to 87, which is a monoclonal antibody.

89. An antibody according to any one of claims 1 to 87, which is a human antibody, a humanized antibody or a chimeric antibody.

90. An antibody described in any one of claims 1 to 87, which is an antibody fragment.

91. An antibody according to any one of claims 1 to 87, comprising a human Fc region of the IgG1 or IgG4 isotype.

92. 92. The antibody of claim 91, comprising a human Fc region of the IgG1 isotype.

93. 93. The antibody of claim 91 or claim 92, wherein the Fc region comprises a modification to remove a glycosylation site at amino acid residue position N297 (EU numbering as per Kabat).

94. 94. The antibody of claim 93, wherein the modification is a mutation selected from N297G or N297A.

95. 95. The antibody of claim 94, wherein the modification is the mutation N297G.

96. An antibody according to any one of claims 91 to 95, wherein the Fc region has been modified to remove effector function.

97. Cmax of about 230-260 μg / ml and / or a half-life (t １／２ 97. The antibody of any one of claims 1 to 96, having the following structure:

98. An isolated nucleic acid encoding the antibody of any one of claims 1 to 97.

99. A host cell comprising the nucleic acid of claim 98.

100. 100. A method of producing an antibody, comprising culturing the host cell of claim 99 so that the antibody is produced.

101. 101. The method of claim 100, further comprising recovering the antibody from the host cell.

102. 102. An antibody produced by the method of claim 100 or claim 101.

103. An immunoconjugate comprising the antibody of any one of claims 1 to 97 and a cytotoxic agent.

104. A pharmaceutical formulation comprising the antibody of any one of claims 1 to 97 or the immunoconjugate of claim 103 and a pharmaceutically acceptable carrier.

105. 105. A pharmaceutical formulation comprising the antibody of claim 104, further comprising an additional therapeutic agent.

106. 106. The pharmaceutical formulation of claim 105, wherein the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, an IL-6 inhibitor (e.g., tocilizumab), an anti-CTFG antibody (e.g., FG-3019), an autotaxin inhibitor, a JAK inhibitor, an IL-11 inhibitor, and PTX2.

107. An antibody according to any one of claims 1 to 97 for use as a medicament.

108. 98. The antibody of any one of claims 1 to 97 for use in the treatment of a TGFβ-associated disorder.

109. 69. The antibody of claim 1 and the antibody of claim 68 for use in combination to treat a TGFβ-associated disorder.

110. 110. The antibody of claim 108 or claim 109, wherein the TGFβ-associated disorder is fibrosis.

111. 111. The antibody of claim 110, wherein the fibrosis is a fibrotic condition of the lung, liver, heart, kidney, pancreas, eye and / or skin.

112. An antibody described in any one of claims 1 to 97 for use in the manufacture of a medicament for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling via the TGFBR1 / R2 complex, inhibiting TGFβ signaling via the TGFBR2 / ALK1 complex promoted by endoglin, and / or inhibiting new collagen synthesis.

113. 98. Use of an antibody according to any one of claims 1 to 97 in the manufacture of a medicament for treating a TGFβ-associated disorder in a subject.

114. 114. The use of claim 113, wherein the TGFβ-related disorder is fibrosis, and optionally the fibrosis is a fibrotic condition of the lung, liver, heart, kidney, pancreas, eye and / or skin.

115. Use of an antibody described in any one of claims 1 to 97 in the manufacture of a medicament for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the TGFBR2 / ALK1 complex promoted by endoglin, and / or inhibiting new collagen synthesis.

116. 104. A method of treating a subject having a TGFβ-associated disorder, comprising administering to a subject in need thereof an effective amount of an antibody of any one of claims 1 to 97, or administering to a subject the pharmaceutical formulation of claim 104.

117. A method for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the TGFBR2 / ALK1 complex promoted by endoglin, and / or inhibiting new collagen synthesis in a subject, comprising administering an effective amount of an antibody described in any one of claims 1 to 97 to a subject in need thereof for inhibiting TGFBR-dependent SMAD signaling, inhibiting the assembly of the TGFβ-TGFBR signaling complex, inhibiting TGFβ signaling through the TGFBR1 / R2 complex, inhibiting TGFβ signaling through the TGFBR2 / ALK1 complex promoted by endoglin, and / or inhibiting new collagen synthesis in a subject.

118. 118. The method of claim 116 or 117, further comprising administering to the subject an additional therapeutic agent.

119. 119. The method of claim 118, wherein the additional therapeutic agent is selected from the group consisting of pirfenidone, nintedanib, mycophenylate mofetil, IL-6 inhibitors (e.g., tocilizumab, sarilumab), anti-CTFG antibodies (e.g., FG-3019), autotaxin inhibitors, and PTX2.

120. A method according to any one of claims 116 to 119, comprising administering to a subject an effective amount of an anti-TGFβ3 antibody according to claim 1 and an effective amount of an anti-TGFβ2 antibody according to claim 68.

121. 121. The method of any one of claims 116 to 120, wherein the subject has a TGFβ-associated disorder that is fibrosis.

122. The fibrosis may be idiopathic pulmonary fibrosis (IPF), idiopathic upper lobe pulmonary fibrosis (Amitani disease), familial pulmonary fibrosis, pulmonary fibrosis (e.g., pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, idiopathic fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), or chronic asthma), cystic fibrosis, nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP), progressive massive fibrosis, scleroderma / systemic sclerosis (limited cutaneous (lcSSc) and diffuse cutaneous (d 122. The method of claim 121, wherein the pulmonary fibrosis is selected from the group consisting of SSc, including forms of SSc (cSSc), and SSc-related interstitial lung disease (SSc-ILD), bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), hypersensitivity pneumonitis, pulmonary hypertension, pulmonary tuberculosis, silicosis, asbestosis, acute lung injury, and acute respiratory distress (ARD, including bacterial pneumonia-induced, trauma-induced, and viral pneumonia-induced, ventilator-induced, and non-pulmonary sepsis-induced ARD).

123. 122. The method of claim 121, wherein the fibrosis is a fibrotic condition of the liver selected from the group consisting of cirrhosis, congenital hepatic fibrosis, obesity, fatty liver, alcohol-induced hepatic fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), infectious or virally induced liver fibrosis (e.g., chronic hepatitis B and C virus infection), cystic fibrosis, autoimmune hepatitis, necrotizing hepatitis, primary sclerosing cholangitis, hemochromatosis, biliary system disorders, and liver dysfunction due to infection.

124. 122. The method of claim 121, 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 artery infarction, varicose veins, coronary artery stenosis and other post-ischemic conditions, and idiopathic retroperitoneal fibrosis.

125. Fibrosis includes glomerulonephritis (including membranoproliferative, diffuse proliferative, rapidly progressive or sclerosing, post-infectious and chronic), diabetic glomerulosclerosis, focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, ischemic nephropathy, tubulointerstitial renal fibrosis, 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 (affecting the kidney among other tissues), autoimmune nephritis, renal tubulointerstitial fibrosis, renal arteriosclerosis, Alport syndrome, nephropathy, chronic renal failure, chronic kidney disease, periglomerular fibrosis / atubular glomeruli, combined basal fibrosis syndrome with cardiac emphysema 122. The method of claim 121, wherein the renal fibrotic condition is selected from the group consisting of apical emphysema and basal fibrosis syndrome, glomerular hypertension, nephrogenic fibrosing dermopathy, polycystic kidney disease, Fabry disease, and renal hypertension.

126. 122. The method of claim 121, wherein the fibrosis is a pancreatic fibrotic condition selected from the group consisting of interstitial remodeling pancreatitis and interstitial fibrosis.

127. 122. The method of claim 121, 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, healing gastric ulcer, and microscopic colitis.

128. 122. The method of claim 121, wherein the fibrosis is an ocular fibrotic condition 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, scarring of the cornea and conjunctiva, fibrosis of the corneal endothelium, anterior subcapsular cataract and posterior capsule opacification, fibrotic diseases of the anterior segment of the eye, fibrosis of the corneal stroma (e.g., associated with corneal opacification), fibrosis of the trabecular meshwork (e.g., associated with glaucoma), fibrotic diseases of the posterior segment of the eye, fibrovascular scarring (e.g., of the retinal or choroidal vasculature of the eye), retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis (e.g., associated with age-related macular degeneration), traction retinal detachment associated with tissue contraction in diabetic retinopathy, congenital orbital fibrosis, lacrimal gland fibrosis, epicorneal fibrosis, and Graves' ophthalmopathy.

129. 122. The method of claim 121, wherein the fibrosis is selected from central nervous system fibrosis such as fibrosis resulting from spinal cord injury / fibrosis or post-stroke fibrosis, fibrosis associated with neurodegenerative disorders such as Duchenne muscular dystrophy, Alzheimer's disease or multiple sclerosis, fibrosis resulting from vascular restenosis, uterine fibrosis, endometriosis, ovarian fibroids, Peyronie's disease, polycystic ovary syndrome, disease-related apical pulmonary fibrosis in ankylosing spondylitis, scarring, and fibrosis associated with microbial (e.g., bacterial, viral, parasitic, fungal) infection.

130. The method of claim 121, wherein the fibrosis is SSc.

131. 122. The method of claim 121, wherein the fibrosis is IPF.

132. 122. The method of claim 121, wherein the fibrosis is chronic obstructive pulmonary disease (COPD).

133. 122. The method of claim 121, wherein the fibrosis is progressive fibrotic interstitial lung disease (PF-ILD).

134. 134. The method of claim 133, wherein the PF-ILD is a disease or condition selected from the group consisting of nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), progressive massive fibrosis, coal worker's pneumoconiosis complications, scleroderma / systemic sclerosis, bronchiolitis obliterans organizing pneumonia, connective tissue disease-associated ILD (CT-ILD), and hypersensitivity pneumonitis.

135. 122. The method of claim 121, wherein the fibrosis is cirrhosis or chronic liver fibrosis.

136. 122. The method of claim 121, wherein the fibrosis is GI tract fibrosis, e.g., 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, healing gastric ulcers, and microscopic colitis.

137. 122. The method of claim 121, wherein the fibrosis is an ocular fibrotic condition, fibrosis resulting from spinal cord injury, fibrosis or central nervous system fibrosis, or fibrosis associated with a neurodegenerative disorder.

138. The method of any one of claims 116 to 137, wherein the antibody is an anti-TGFβ2 antibody.

139. The anti-TGFβ2 antibody (a) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

139. The method of claim 138, comprising:

140. The method of any one of claims 116 to 137, wherein the antibody is an anti-TGFβ3 antibody.

141. The anti-TGFβ2 / 3 antibody (a) (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-H3, wherein CDR-H1 has the amino acid sequence of SEQ ID NO: 4, CDR-H2 has the amino acid sequence of one of SEQ ID NOs: 35, and CDR-H3 has the amino acid sequence of SEQ ID NO: 6; and (ii) light chain CDRs comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-L1 has the amino acid sequence of SEQ ID NO: 7; CDR-L2 has the amino acid sequence of SEQ ID NO: 8, and CDR-L3 has the amino acid sequence of SEQ ID NO: 9; (b) a VH / VL pair, wherein the VH of the VH / VL pair comprises the amino acid sequence of SEQ ID NO: 57 and the VL of the VH / VL pair comprises the amino acid sequence of SEQ ID NO: 56; or (c) a complete H / VL chain pair, wherein the H chain of the H / L chain pair comprises the amino acid sequence of SEQ ID NO: 79 and the L chain of the H / L chain pair comprises the amino acid sequence of SEQ ID NO:

78.

141. The method of claim 140, comprising:

142. The method of any one of claims 116 to 137, wherein the antibody is an anti-TGFβ2 / 3 antibody.

143. The method of claim 142, wherein the anti-TGFβ2 / 3 antibody comprises: (i) heavy chain CDRs comprising CDR-H1, CDR-H2, and CDR-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, CDR-L2, and CDR-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.

144. 1. A method of diagnosing a subject as having SSc, comprising detecting expression levels of genes in an 18-gene signature set consisting of PRSS23, PXDN, COL8A1, COL6A3, SERPINE2, TNC, COMP, THBS1, COL11A1, COL1A1, COL5A2, COL1A2, COL4A1, COL4A2, SFRP4, ALPK2, COL5A1, and TAGLN; and diagnosing the subject as having SSc if the levels of the genes are determined to be elevated compared to the gene levels in a healthy control set or reference gene signature.

145. 145. The method of claim 144, wherein the gene level is elevated if the increase in expression compared to a healthy control set or reference gene signature is statistically significant, optionally at least 2-fold increased, or at least 3-fold increased, or at least 4-fold increased compared to a healthy control set or reference gene signature.

146. A method for monitoring a subject's response to treatment with an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody, comprising 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 doses of an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody.

147. The method of claim 146, wherein the subject is determined to be responsive to treatment with an anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody if the expression level of one or more TGFβ-inducible genes is significantly reduced compared to the pre-treatment level of the one or more TGFβ-inducible genes, and optionally further comprises administering an additional anti-TGFβ2 antibody and / or an anti-TGFβ3 antibody if the expression level of one or more TGFβ-inducible genes is determined to be significantly reduced.

148. The method of claim 146 or claim 147, wherein the subject is administered an anti-TGFβ2 antibody as monotherapy.

149. The method of claim 146 or claim 147, wherein the subject is administered an anti-TGFβ3 antibody as monotherapy.

150. 147. The method of claim 146, wherein the expression level of one or more TGFβ-inducible genes is determined by qPCR or microarray analysis.

151. 151. The method or use of any one of claims 98 to 150, wherein the subject is a human.

152. A kit comprising an antibody according to any one of claims 1 to 97.

Images