Anti-galectin-9 antibodies and their use

Abstract

This invention provides novel human antibodies that bind to human galectin-9, and their therapeutic use in the treatment of cancer. [Solution] Provided are isolated anti-galectin-9 antibodies that bind to epitopes in the glycan recognition domain (CRD) of galectin-9 polypeptides, and methods for using anti-galectin-9 antibodies to inhibit galectin-9-mediated signaling pathways or to eliminate diseased cells expressing galectin-9. Such anti-galectin-9 antibodies may also be used to diagnose and / or treat galectin-9-related diseases, such as autoimmune diseases and solid tumors.

Description

[Background technology]

[0001] Immune checkpoint blockade has demonstrated unprecedented success as a cancer treatment in recent years. Often, antibodies are used to block immunosuppressive pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) pathways. While therapies targeting these two pathways have shown success in treating some cancer types, anti-CTLA-4 and anti-PD-1 therapies have response rates of 10-60% of treated patients, depending on the cancer type, and have yet to demonstrate the ability to exceed a 60% response rate even when used in combination (Kyvistborg et al., Enhancing responses to cancer immunotherapy; Science. 2018 Feb 2;359(6375):516-517). Furthermore, numerous types of cancer are refractory to these therapies. As part of efforts to improve existing immunotherapies in clinical practice, this field has begun to focus on the role of abnormalities in interferon signaling and the upregulation of alternative checkpoints as potential causes of limitations in current treatments. One such potential alternative checkpoint is T-cell immunoglobulin mucin-3 (Tim-3) / galectin-9 (see, for example, Yang and Hung; The role of T-cell immunoglobulin mucin-3 and its ligand galectin-9 in antitumor immunity and cancer immunotherapy; Cancer biology and cancer treatment; Oct 2017, Vol.60 No.10: 1058-1064, and the references therein).

[0002] Galectin-9 is a tandem repeat lectin consisting of two carbohydrate recognition domains (CRDs) and was first discovered and described in 1997 in patients with Hodgkin's lymphoma (HL) (Tureci et al., J. Biol. Chem. 1997, 272, 6416-6422). Three isoforms exist and can be located intracellularly or extracellularly. Elevated galectin-9 levels have been observed in a wide range of cancers, including melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, pancreatic cancer, gastric cancer, colon cancer, and renal clear cell carcinoma (Wdowiak et al. Int. J. Mol. Sci. 2018, 19, 210). In renal cancer, patients with high galectin-9 expression showed larger tumor size and more advanced disease progression with necrosis. Kawashima et al.;BJU Int. 2014;113:320-332In melanoma (considered one of the most deadly cancers due to its invasive metastasis and treatment resistance), galectin-9 is expressed in 57% of tumors and is significantly increased in the plasma of patients with advanced melanoma compared to healthy controls (Enninga et al., Melanoma Res. 2016 Oct;26(5): 429-441). Numerous studies have demonstrated the usefulness of Gal-9 as a prognostic marker, and more recently, its usefulness as a potential novel drug target (Enninga et al., 2016; Kawashima et al. BJU Int 2014;113: 320-332; Kageshita et al., Int J Cancer. 2002 Jun 20;99(6):809-16, and references therein). Galectin-9 has been described as playing an important role in many cellular processes, including adhesion, cancer cell aggregation, apoptosis, and chemotaxis. Recent studies have shown the role of galectin-9 in immunomodulation in tumor support (e.g., through negative regulation of Th1-type responses, Th2 polarization, and polarization of macrophages to the M2 phenotype). This research also includes studies showing that galectin-9 is involved in the direct inactivation of T cells through interactions with T-cell immunoglobulin and mucin protein 3 (TIM-3) receptors (Dardalhon et al., J Immunol., 2010, 185, 1383-1392; Sanchez-Fueyo et al., Nat Immunol., 2003, 4, 1093-1101). Furthermore, galectin-9 is known to play a role in polarizing T cell differentiation into a tumor suppressor phenotype, as well as in promoting immunotolerogenic macrophage programming and adaptive immunosuppression (Daley et al., Nat Med., 2017, 23, 556-567).In a mouse model of pancreatic ductal adenocarcinoma (PDA), blocking the checkpoint interaction between galectin-9 and its receptor dectin-1 (found on innate immune cells in the tumor microenvironment (TME)) has been shown to increase the antitumor immune response in the TME and slow tumor progression (Daley et al., Nat Med., 2017, 23, 556-567). Galectin-9 has also been found to bind to CD206, a surface marker of M2 macrophages, and reduce the secretion of CVL22 (MDC), a macrophage-derived chemokine associated with longer survival and a lower risk of recurrence in lung cancer (Enninga et al, J Pathol. 2018 Aug;245(4):468-477).

[0003] Therefore, modulating the activity of one or more galectin-9 and / or its receptors may provide novel cancer therapeutic approaches, either alone or in combination with existing therapies. Novel human antibodies that bind to human galectin-9 and their therapeutic use in the treatment of cancer are described herein. [Overview of the Initiative]

[0004] This disclosure is based, at least in part, on the development of anti-galectin-9 antibodies that potently suppress galectin-9-induced signaling. Such antibodies can suppress galectin-9 signaling and / or eliminate galectin-9-positive pathological cells, thereby benefiting the treatment of galectin-9-related diseases.

[0005] Accordingly, one aspect of this disclosure provides isolated anti-galectin-9 antibodies that bind to epitopes in the carbohydrate recognition domain (CRD) of galectin-9 polypeptides (e.g., human galectin-9 polypeptides). In some embodiments, the anti-galectin-9 antibodies described herein may bind to both human galectin-9 polypeptides and non-human galectin-9 polypeptides (e.g., mouse galectin-9, rat galectin-9, or primate galectin-9). In some embodiments, the anti-galectin-9 antibody binds exclusively to one of the galectin-9 CRDs. In some embodiments, the anti-galectin-9 antibody binds to multiple galectin-9 CRDs, for example, with similar or different affinities. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to epitopes within the CRD1 region. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the CRD1 region, which may have the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the CRD1 region having the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-galectin-9 antibodies are G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1- The anti-galectin-9 antibody binds to the same epitope as a reference antibody selected from the group consisting of antibodies 8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, G9.1-8m14, G9.1-9, G9.1-10, and G9.1-11, and / or competes with the reference antibody for binding to the CRD1 region. In some embodiments, the anti-galectin-9 antibody binds to the same epitope as antibody G9.1-8 or antibody G9.1-8m13, and / or competes with antibody G9.1-8 or antibody G9.1-8m13 for binding to the CRD1 region.

[0006] In some embodiments, the anti-galectin-9 antibodies disclosed herein are antibodies selected from the group consisting of G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, G9.1-8m14, G9.1-9, G9.1-10, and G9.1-11 antibodies. In some embodiments, the anti-galectin-9 antibody is a G9.1-8 antibody. In some embodiments, the antibody is a G9.1-8m13 antibody. In some examples, the anti-galectin-9 antibody may contain the same heavy chain complementation determining region (CDR) and the same light chain CDR as the reference antibody (e.g., any of the reference antibodies provided herein). In one particular example, the anti-galectin-9 antibody contains the same heavy chain variable region and the same light chain variable region as the reference antibody (e.g., any of the reference antibodies provided above and elsewhere herein).

[0007] In some embodiments, the anti-galectin-9 antibody contains SEQ ID NO: 21, or consists essentially of SEQ ID NO: 21, or consists solely of SEQ ID NO: 21. L It has a sequence. In some embodiments, the anti-galectin-9 antibody contains SEQ ID NO: 86, or consists essentially of SEQ ID NO: 86, or consists only of SEQ ID NO: 86. H It has a sequence. In some embodiments, the anti-galectin-9 antibody is V, which includes SEQ ID NO: 21. L V containing the sequence and sequence number 86 H It has a sequence. In some embodiments, the anti-galectin-9 antibody is essentially V, consisting of SEQ ID NO: 21. L V consisting of the sequence and essentially sequence number 86. H It has a sequence. In some embodiments, the anti-galectin-9 antibody consists only of SEQ ID NO: 21. L V consisting only of the sequence and sequence number 86. H It has an array.

[0008] In some embodiments, the anti-galectin antibody comprises SEQ ID NO: 22, or consists essentially of SEQ ID NO: 22, or consists of only SEQ ID NO: 22 V H sequence. In some embodiments, the anti-galectin-9 antibody comprises V of SEQ ID NO: 21 L sequence, and V of SEQ ID NO: 22 H sequence. In some embodiments, the anti-galectin-9 antibody consists essentially of V of SEQ ID NO: 21 L sequence, and consists essentially of V of SEQ ID NO: 22 H sequence. In some embodiments, the anti-galectin-9 antibody consists of only V of SEQ ID NO: 21 L sequence, and consists of only V of SEQ ID NO: 22 H sequence.

[0009] In some embodiments, the anti-galectin-9 antibody comprises V containing one or more of the sequences set forth in SEQ ID NOs: 328, 329, and 337 L sequence. In some embodiments, the anti-galectin-9 antibody comprises V containing one or more of the sequences set forth in SEQ ID NOs: 361, 364, 374, 366, and 383 H sequence. In some embodiments, the anti-galectin-9 antibody comprises V containing one or more of the sequences set forth in SEQ ID NOs: 328, 329, and 337 L sequence, and V containing one or more of the sequences set forth in SEQ ID NOs: 361, 364, and 374 H sequence. In some embodiments, the anti-galectin-9 antibody comprises V containing one or more of the sequences set forth in SEQ ID NOs: 328, 329, and 337 L sequence, and V containing one or more of the sequences set forth in SEQ ID NOs: 361, 366, and 383 H sequence.

[0010] In some embodiments, the anti-galectin-9 antibody disclosed herein binds to an epitope within the galectin-9 CRD2 region. In some embodiments, the anti-galectin-9 antibody disclosed herein binds to an epitope within the galectin-9 CRD2 region, which may have the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-galectin-9 antibody disclosed herein binds to an epitope within the CRD2 region having the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-galectin-9 antibody binds to an epitope within the galectin-9 CRD2 region containing a tryptophan residue corresponding to residue W309 of SEQ ID NO: 1. In some embodiments, the anti-galectin-9 antibody binds to an epitope within the galectin-9 CRD2 region that does not contain one or more residues corresponding to R253, R271, Y330, R334, R341 and Y236 of SEQ ID NO: 1. In some embodiments, the anti-galectin-9 antibody may bind to an epitope within the galectin-9 CRD2 region that contains a tryptophan residue corresponding to residue W309 of SEQ ID NO: 1, and further does not contain one or more residues corresponding to R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO: 1. In some embodiments, the anti-galectin-9 antibody may bind to G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9 The anti-galectin-9 antibody binds to the same epitope as a reference antibody selected from the group consisting of G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binding antibodies, and / or competes with the reference antibody for binding to the CRD2 region. In some embodiments, the anti-galectin-9 antibody binds to the same epitope as antibody G9.2-17 or antibody G9.2-17mut6, and / or competes with antibody G9.2-17 or antibody G92-17mut6 for binding to the CRD2 region.In some embodiments, the anti-galectin-9 antibody is an antibody selected from the group consisting of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, and G9.2-26 antibodies. In some embodiments, the anti-galectin-9 antibody is G9.2-17 antibody or G9.2-17mut6 antibody. In some embodiments, the anti-galectin-9 antibody includes SEQ ID NO: 54, consists essentially of SEQ ID NO: 54, or consists solely of SEQ ID NO: 54. L It has a sequence. In some embodiments, the anti-galectin-9 antibody contains SEQ ID NO: 55, or consists essentially of SEQ ID NO: 55, or consists only of SEQ ID NO: 55. H It has a sequence. In some embodiments, the anti-galectin-9 antibody is V, which includes SEQ ID NO: 54. L V containing sequence and sequence number 55 H It has a sequence. In some embodiments, the anti-galectin-9 antibody is essentially V, consisting of SEQ ID NO: 54. L V consists of an array and essentially sequence number 55. H It has a sequence. In some embodiments, the anti-galectin-9 antibody consists only of SEQ ID NO: 54. L V consisting only of the sequence and sequence number 55 H It has a sequence. In some embodiments, the antibody is V, which includes SEQ ID NO: 56. H It has a sequence. In some embodiments, the antibody consists essentially of SEQ ID NO: 56 or only SEQ ID NO: 56. H It has a sequence. In some embodiments, the isolated antibody contains V, which includes SEQ ID NO: 54. L V containing sequence and sequence number 56 H It has a sequence. In some embodiments, the isolated antibody is essentially V consisting of SEQ ID NO: 54. LV consists of sequence and essentially sequence number 56. H It has a sequence. In some embodiments, the isolated antibody consists only of SEQ ID NO: 54. L V consisting only of the sequence and sequence number 56. H It has an array.

[0011] In some embodiments, the anti-galectin-9 antibody contains one or more of the sequences described in SEQ ID NOs: 328, 329, and 352. L It has a sequence. In some embodiments, the anti-galectin-9 antibody contains one or more of the sequences described in SEQ ID NOs: 361, 388, 406, and 407. H It has a sequence. In some embodiments, the anti-galectin-9 antibody contains one or more of the sequences described in SEQ ID NOs: 328, 329, and 352. L V containing the sequence and one or more of the sequences described in sequence numbers 361, 388, and 406. H It has a sequence. In some embodiments, the anti-galectin-9 antibody contains one or more of the sequences described in SEQ ID NOs: 328, 329, and 352. L V containing the sequence and one or more of the sequences described in sequence numbers 361, 388, and 407. H It has an array.

[0012] In some examples, an anti-galectin-9 antibody may contain the same heavy chain complementarity-determining region (CDR) and the same light chain CDR as a reference antibody, e.g., one of the reference antibodies provided herein. In one particular example, the anti-galectin-9 antibody contains the same heavy chain variable region and the same light chain variable region as a reference antibody (e.g., one of the reference antibodies provided herein). In some embodiments, the anti-galectin-9 antibody contains heavy chain complementarity-determining region 1 (CDR1), heavy chain complementarity-determining region 2 (CDR2), and heavy chain complementarity-determining region 3 (CDR3), which together are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the heavy chain CDR of a reference antibody (e.g., one of the reference antibodies provided herein). In some embodiments, the anti-galectin-9 antibody comprises light chain CDR1, light chain CDR2, and light chain CDR3, which, as a whole, are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the light chain CDR of a reference antibody (e.g., any of the reference antibodies provided herein).

[0013] In some embodiments, the anti-galectin-9 antibody comprises all of the heavy chain complementarity-determining regions 1 (CDR1), 2 (CDR2), and 3 (CDR3), which together are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the heavy chain CDR of a reference antibody (e.g., any of the reference antibodies provided herein), and further comprises light chain CDR1, CDR2, and CDR3, which together are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the light chain CDR of a reference antibody (e.g., any of the reference antibodies provided herein). In some cases, an anti-galectin-9 antibody may contain the same heavy chain CDR and the same light chain CDR as the reference antibody described above. In one particular case, an anti-galectin-9 antibody may contain the same heavy chain variable region and the same light chain variable region as the reference antibody (e.g., one of the reference antibodies provided herein). In some embodiments, exemplary isolated anti-galectin 9 antibodies that bind to CRD1 include G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14. In some embodiments, exemplary isolated anti-galectin 9 antibodies that bind to CRD2 include G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder.

[0014] In some embodiments, the isolated anti-galectin 9 antibody, or its antigen-binding moiety, comprises a heavy chain and a light chain variable region, the light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. In some embodiments, the light chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. In some embodiments, the isolated anti-galectin 9 antibody, or its antigen-binding moiety, comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some embodiments, the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73.

[0015] In some embodiments, the isolated anti-galectin 9 antibody or its antigen-binding moiety comprises a heavy chain and a light chain variable region, the light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71, and the heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some embodiments, the isolated anti-galectin 9 antibody or its antigen-binding moiety comprises a heavy chain and a light chain variable region, the light chain variable region consisting of an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71, and the heavy chain variable region consisting of an amino acid sequence selected from 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73.

[0016] In some embodiments, the isolated anti-galectin 9 antibody, or its antigen-binding moiety, comprises a heavy chain and a light chain variable region, the light chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the light chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the isolated anti-galectin 9 antibody, or its antigen-binding moiety, comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the heavy chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. Accordingly, in some embodiments, an isolated anti-galectin 9 antibody or its antigen-binding moiety is provided, comprising a heavy chain and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the light chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and the heavy chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.

[0017] In some embodiments, any anti-galectin-9 antibody disclosed herein is V of the reference antibody disclosed herein. HThe heavy chain variable region (V) is at least 85% identical to it. H ) may also be included. Alternatively or in addition, the anti-galectin-9 antibody may be V of the reference antibody. L The light chain variable region (V) is at least 85% identical to it. L ) may include.

[0018] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region containing SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region containing SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody includes a VL region consisting of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region consisting of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions, each containing SEQ ID NOs: 54 and 55. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes VL and VH regions, each consisting of SEQ ID NOs: 54 and 55. In some embodiments, the anti-galectin-9 antibody is clone 9.2-17. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region containing SEQ ID NO: 56. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions, each containing SEQ ID NOs: 54 and 56. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises the VL and VH regions, respectively, consisting of SEQ ID NOs. 54 and 56. In some embodiments, the anti-galectin-9 antibody is clone 9.2-17 mut6.

[0019] In some embodiments, the anti-galectin-9 antibody includes a VL region containing SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody includes a VL region consisting of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody includes a VH region containing SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region consisting of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions, each containing SEQ ID NO: 21 and 86. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions, each consisting of SEQ ID NO: 21 and 86. In some embodiments, the anti-galectin-9 antibody is clone G9.1-8m13. In some embodiments, the anti-galectin-9 antibody includes a VH region containing SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region consisting of SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions, each containing SEQ ID NO: 21 and 22. In some embodiments, the anti-galectin-9 antibody includes the VL and VH regions, respectively, consisting of SEQ ID NOs. 21 and 22. In some embodiments, the anti-galectin-9 antibody is clone G9.1-8.

[0020] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region having the same amino acid sequence as the VL region of antibody 9.1-8m13 (SEQ ID NO: 21). In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region having the same amino acid sequence as the VH region of antibody 9.1-8m13 (SEQ ID NO: 86). In some embodiments, the anti-galectin-9 antibody includes VL and VH regions having the same amino acid sequences as the VL and VH regions of antibody 9.1-8m13 (SEQ ID NOs: 21 and 86, respectively).

[0021] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region having the same amino acid sequence as the VL region of antibody 9.2-17 (SEQ ID NO: 54). In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region having the same amino acid sequence as the VH region of antibody 9.2-17 (SEQ ID NO: 55). In some embodiments, the anti-galectin-9 antibody includes VL and VH regions having the same amino acid sequences as the VL and VH regions of 9.2-17 (SEQ ID NOs: 54 and 55, respectively).

[0022] In some embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL regions described in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH regions described in SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the anti-galectin-9 antibody comprises a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region described in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.

[0023] In some embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL regions described in SEQ ID NOs: 13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. In some embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH regions described in SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some embodiments, the anti-galectin-9 antibody has at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VL region described in SEQ ID NOs: 13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. The VH region includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the VH region described in sequence numbers 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73.

[0024] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VL region described in SEQ ID NO: 21.

[0025] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VH region described in SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety each includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VL and VH regions described in SEQ ID NOs: 21 and 86.

[0026] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment includes a VL having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region described in SEQ ID NO: 54. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NO: 55. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment each includes a VL and / or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and / or VH region described in SEQ ID NOs. 54 and 55. In some specific embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region of G9.1-8m13. In some specific embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region of G9.1-8m13. In some specific embodiments, the anti-galectin-9 antibody includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and VH regions of G9.1-8m13. In some specific embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region of G9.2-17.In some specific embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VH region of G9.2-17. In some specific embodiments, the anti-galectin-9 antibody includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VL and VH regions of G9.2-17.

[0027] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes (a) the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360; (d) the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 427, 428, 431, 435, 436, 437; (d) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362, 363, 387-389 and 446-466; and (e) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417. Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes (a) the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340; (d) the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 424-434; (e) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362-366 and 438-445; and (f) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386.

[0028] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, and the light chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, and the light chain variable region CDR2 includes X1X2X3X4X5SX6X7X8SYADSVKG (SEQ ID NO: 467) (wherein X1=Y or S, X2=I or S, X3=Y or S, X4=P or S, X5=Y or S, X6=G or S, X7=Y or S, and X8=T or S). In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, and the light chain variable region CDR3 includes X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13 Includes GMDY (Scorecard No. 468) (wherein X1=Y or S, X2=T, S, or missing, X3=Y, S, or missing, X4=S or missing, X5=W, S, or missing, X6=S or missing, X7=G, S, or missing, X8=G, T, S, or missing, X9=I, Y, S, or missing, X 10 =G, S, or Y, X 11 =W or S, X 12 =V or S, and X 13 (=W or S). In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 is represented by SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 is represented by X1X2X3X4X5SX6X7X8SYADSVKG (SEQ ID NO: 467) (wherein X1=Y or S, X2=I or S, X3=Y or S, X4=P or S, X5=Y or S, X6=G or S, X7=Y or S, and X8=T or S). In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR3 is represented by X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13Consists of GMDY (Picture Code 468) (wherein X1=Y or S, X2=T, S, or missing, X3=Y, S, or missing, X4=S or missing, X5=W, S, or missing, X6=S or missing, X7=G, S, or missing, X8=G, T, S, or missing, X9=I, Y, S, or missing, X 10 =G, S, or Y, X 11 =W or S, X 12 =V or S, and X 13 (=W or S).

[0029] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 includes SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 consists of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 consists of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR3 consists of SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each contain SEQ ID NOs. 328, 329, and 337, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 337, respectively. In some embodiments, the antibody contains the same VL CDR as G9.1-8m13. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where heavy chain variable region CDR1 contains SEQ ID NOs. 361. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where heavy chain variable region CDR2 contains SEQ ID NOs. 366. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where heavy chain variable region CDR3 contains SEQ ID NOs. 383. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the heavy chain variable region CDR1 is sequence number 361. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the heavy chain variable region CDR2 is sequence number 366.In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, and the heavy chain variable region CDR3 region comprises SEQ ID NO: 383. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, and the heavy chain variable regions CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the anti-galectin-9 antibody contains the same VH CDR as G9.1-8m13. In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 366, and 383, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 366, and 383, respectively. In one particular embodiment, the anti-galectin-9 antibody comprises the same VL and VH CDRs as G9.1-8m13.

[0030] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 includes SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 consists of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 consists of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety consists of a heavy chain and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, with the light chain variable regions CDR1, CDR2, and CDR3 comprising SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the anti-galectin-9 antibody contains the same VL CDR as G9.2-17. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, with the heavy chain variable regions CDR1, CDR2, and CDR3 comprising SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-17. In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs: 361, 388, and 406, respectively.In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs. 328, 329, and 352, and SEQ ID NOs. 361, 388, and 406, respectively. In one particular embodiment, the anti-galectin-9 antibody contains the same VL and VH CDRs as G9.2-17.

[0031] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety is: (a) a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340; (d) VH CDR1 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequences shown in SEQ ID NOs. 361, 427, 428, 431, 436, 437; (e) VH CDR2 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to VH CDR2 amino acid sequences selected from SEQ ID NOs. 362-366 and 438-445; (f) VH CDR3 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to VH CDR3 amino acid sequences selected from SEQ ID NOs. 367-386 Contains the CDR3 amino acid sequence.Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety is: (a) a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360. (d) CDR3 amino acid sequence; (d) VH CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequence shown in SEQ ID NOs. 361, 424-434; (e) VH CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR2 amino acid sequence selected from SEQ ID NOs. 362, 363, 387-389 and 446-466; (e) VH CDR2 amino acid sequence selected from SEQ ID NOs. 390-417 It includes a VH CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the CDR3 amino acid sequence.

[0032] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 337, respectively. In some embodiments, the antibody VL CDR1, CDR2, and CDR3 amino acid sequences have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VL CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy and light chain variable regions whose heavy chain variable regions CDR1, CDR2, and CDR3 amino acid sequences have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the heavy chain variable regions CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs. 361, 366, and 383, respectively. In some embodiments, the antibody VH CDR1, CDR2, and CDR3 amino acid sequences have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13.In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 337, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 361, 366, and 383. In one particular embodiment, the amino acid sequences of the antibody VL CDR1, CDR2, and CDR3 and VH CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1, CDR2, and CDR3 and VH CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the antibody VL CDR1, CDR2, and CDR3 amino acid sequences have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VL CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy and light chain variable regions whose heavy chain variable regions CDR1, CDR2, and CDR3 amino acid sequences have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain variable regions CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the antibody VH CDR1, CDR2, and CDR3 amino acid sequences have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17. In some embodiments, the anti-galectin-9 antibody or its binding portion includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 352, respectively, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 361, 388, and 406. In one particular embodiment, the amino acid sequences of the antibody VL CDR1, CDR2, and CDR3, as well as the VH CDR1, CDR2, and CDR3, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1, CDR2, and CDR3, as well as the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.

[0033] In some embodiments of any anti-galectin antibody provided herein, the heavy chain constant region of the anti-galectin-9 antibody is derived from human IgG (gamma heavy chain) of any IgG subfamily described herein (e.g., IgG1 or IgG4).

[0034] In some embodiments, the amino acid sequences of exemplary anti-galectin antibody light chains correspond to the sequences described in SEQ ID NOs: 88-98 and 99-115. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 108. In some embodiments, the light chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the light chain sequence (or its variable region) described in SEQ ID NO: 95. In some embodiments, the light chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the light chain sequence (or its variable region) described in SEQ ID NO: 108. In some embodiments, the amino acid sequences of the exemplary anti-galectin antibody heavy chains correspond to the sequences described in SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibodies that bind to CRD1) and SEQ ID NOs: 141-168; 194-220; 247-274; 300-327 (anti-galectin-9 antibodies that bind to CRD2). In some embodiments, the heavy chain constant region of the anti-galectin-9 antibody is derived from human IgG1. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 136. In some embodiments, IgG1 is a variant having minimal Fc receptor engagement. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 189. In some embodiments, the heavy chain constant region of the anti-galectin-9 antibody is derived from human IgG4. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 242. In some embodiments, IgG4 is an IgG4 exchange variant. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 295.

[0035] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 157. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 210. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 263. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 316.

[0036] In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 136. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 189. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 242. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 295. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 157. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the heavy chain sequence (or its variable region) described in SEQ ID NO: 210. In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the heavy chain sequence (or its variable region) described in SEQ ID NO: 263.In some embodiments, the heavy chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the heavy chain sequence (or its variable region) described in SEQ ID NO: 316. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 95 and the heavy chain sequence of SEQ ID NO: 136. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 95 and the heavy chain sequence of SEQ ID NO: 189. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 95 and the heavy chain sequence of SEQ ID NO: 242.

[0037] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 95 and the heavy chain sequence of SEQ ID NO: 295. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 108 and the heavy chain sequence of SEQ ID NO: 157.

[0038] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 108 and the heavy chain sequence of SEQ ID NO: 210.

[0039] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 108 and the heavy chain sequence of SEQ ID NO: 263.

[0040] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 108 and the heavy chain sequence of SEQ ID NO: 316.

[0041] In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 95, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 136. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 95, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 189. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 95, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 242. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with SEQ ID NO: 95, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with SEQ ID NO: 295.

[0042] In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 108, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 157. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 108, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 210. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 108, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 263. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 108, and a heavy chain amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 316.

[0043] Any of the anti-galectin-9 antibodies provided herein may comprise a heavy chain variable region framework of VH 3-48; and / or a light chain variable region framework of Vκ 1-39. In some embodiments, any of the VH and / or VL frameworks described herein are germline VH and / or VL genes. In some embodiments, the anti-galectin-9 antibodies described herein are full-length antibodies (e.g., IgG molecules) or antigen-binding fragments thereof. In some examples, the antibody is a Fab or a single-chain antibody. In any case, the antibody may be a human antibody or a humanized antibody.

[0044] In another embodiment, the Disclosure provides isolated nucleic acids or sets of nucleic acids encoding any or all of the anti-galectin-9 antibodies disclosed herein. In some examples, the heavy and light chains of the antibody are encoded by two separate nucleic acid molecules (sets of nucleic acids). In other examples, the heavy and light chains of the antibody are encoded by a single nucleic acid molecule, which may be in a multicistronic format or under the control of separate promoters. In some embodiments, the nucleic acid or sets of nucleic acids are located on one or two vectors. In some examples, the one or two vectors may be one or two expression vectors. Furthermore, the Disclosure provides host cells containing any of the isolated nucleic acids or sets of nucleic acids encoding the anti-galectin-9 antibodies described herein.

[0045] A method for producing an anti-galectin-9 antibody is also provided herein, which comprises culturing host cells described herein under suitable conditions that enable antibody expression, and collecting the antibody thus produced from the cell culture (e.g., from the culture medium).

[0046] Furthermore, this disclosure provides a pharmaceutical composition comprising either an anti-galectin-9 antibody or a nucleic acid encoding such an antibody, and a pharmaceutically acceptable carrier.

[0047] In yet another embodiment, the Disclosure features a method for inhibiting galectin-9 mediated cellular signaling in a subject, the method comprising administering to a subject requiring such inhibition an effective amount of an anti-galectin-9 antibody or a pharmaceutical composition comprising an anti-galectin-9 antibody. In some embodiments, the anti-galectin-9 antibody is one of the anti-galectin-9 antibodies disclosed herein or a pharmaceutical composition comprising such an antibody. In some embodiments, the subject requiring such inhibition is a human patient who has, is suspected of having, or is at risk of having, an autoimmune disease, a solid tumor, a microbial disease, a hematological malignancy, or an allergic disease. Exemplary autoimmune diseases include, but are not limited to, rheumatoid arthritis (e.g., rheumatoid arthritis), autoimmune respiratory diseases, autoimmune metabolic disorders and / or endocrine disorders (e.g., type 1 diabetes mellitus), or fibrotic diseases. Exemplary solid tumors include, but are not limited to, pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, cholangiocarcinoma, breast cancer, small cell and non-small cell lung cancer, upper and lower gastrointestinal malignancies, gastric cancer, squamous cell head and neck cancer, non-genitourinary cancers, hepatocellular carcinoma, ovarian cancer, sarcoma, mesothelioma, glioblastoma, esophageal cancer, bladder cancer, urothelial carcinoma, renal cancer, cervical cancer, and endometrial cancer. Exemplary hematological malignancies include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, and acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasms, as well as other myeloproliferative and myelodysplastic disorders. In some examples, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galectin-9 and dectin-1. In some embodiments, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galectin-9 and CD206. Alternatively, in addition, but not limited to, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galactin-9 and Tim-3.

[0048] Furthermore, this disclosure provides methods for modifying, eliminating, and / or reducing diseased cells expressing galectin-9 (e.g., via antibody-dependent cell-mediated cytotoxicity or ADCC), the methods comprising administering an effective amount of an anti-galectin-9 antibody (e.g., any of the anti-galectin-9 antibodies described herein) or a pharmaceutical composition thereof to a subject having diseased cells expressing galectin-9. In some embodiments, the subject is a human patient having cancer cells expressing galectin-9 and / or diseased immune cells expressing galectin-9. In some embodiments, an effective amount of the pharmaceutical composition is sufficient to initiate antibody-dependent cell-mediated cytotoxicity (ADCC) and / or block diseased cells expressing galectin-9.

[0049] Any therapeutic method described herein may further include administering to a subject a checkpoint molecule inhibitor, a costimulatory receptor activator, or an inhibitor of a congenital immune cell target. Examples of checkpoint molecules include, but are not limited to, PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, and A2aR. Examples of costimulatory receptors include, but are not limited to, OX40, GITR, CD137, CD40, CD27, and ICOS. Examples of congenital immune cell targets include, but are not limited to, KIR, NKG2A, CD96, TLR, and IDO.

[0050] This disclosure also provides pharmaceutical compositions for use in treating galectin-9-related diseases (e.g., those described herein), wherein the pharmaceutical composition comprises an anti-galectin-9 antibody (e.g., any of the anti-galectin-9 antibodies described herein), or a nucleic acid encoding such an antibody, and a pharmaceutically acceptable carrier. This disclosure also provides the use of anti-galectin-9 antibodies or encoding nucleic acids for manufacturing agents for use in treating the target diseases described herein.

[0051] Details of one or more embodiments of the present invention are described below. Other features or advantages of the present invention will become apparent from the following drawings and detailed descriptions of some embodiments, as well as from the appended claims. [Brief explanation of the drawing]

[0052] The following drawings form part of this specification and are included to further demonstrate certain aspects of this disclosure, which can be better understood by referring to the drawings in conjunction with the detailed description of the specific embodiments presented herein.

[0053] [Figure 1A-1B] Figures 1A and 1B include charts showing the binding characteristics of Fabs to galectin-9 CRD2 using phage ELISA. Figure 1A: Binding to human and mouse galectin-9 as shown by phage ELISA. Figure 1B: Affinity of Fabs clones to galectin-9 CRD2 as determined by competitive phage ELISA.

[0054] [Figure 2A-2B] Figures 2A-2B include charts showing the binding characteristics of Fab clones to galectin-9 CRD1 using phage ELISA. Figure 2A: Binding of Fab clones to human and mouse galectin-9 CRD1 as shown by phage ELISA. Figure 2B: Affinity of Fab clones to galectin-9 CRD1 as determined by competitive phage ELISA.

[0055] [Figure 3A-3B] Figures 3A-3B include charts showing epitope binding (binding to CRD2) of the G.9-2 Fab clone using competitive phage ELISA. Figure 3A: Mouse galectin-9 CRD2-coated wells pre-incubated with purified G9.2-1 or G9.2-3 Fab before adding the phage-display galectin-9 CRD2-conjugated Fab clone. Figure 3B: Human galectin-9 CRD2-coated wells pre-incubated with purified G9.2-15 or G9.2-17 Fab before adding the phage-display galectin-9 CRD2-conjugated Fab clone.

[0056] [Figure 4] Figure 4 includes a diagram showing the affinity of purified G9.2 Fab to galectin-9 CRD2, characterized using a bead-based binding assay. The curves represent the best fit of the one-to-one binding model. Top left: G9.2-1 Fab Top right: G9.2-3 Fab Bottom left: G9.2-15 Fab Bottom right: G9.2-17 Fab The apparent Kd values ​​are shown in the table.

[0057] [Figure 5] Figure 5 includes a diagram showing the affinity of purified G9.1 Fab to galectin-9 CRD1, characterized using a bead-based binding assay. The experiment was performed in the same manner as in Figure 4. Top left: G9.1-6 Fab Top right: G9.1-5 Fab Bottom left: G9.1-8 Fab Bottom right: G9.1-11 Fab The apparent Kd values ​​are shown in the table.

[0058] [Figure 6] Figure 6 includes a diagram showing surface plasmon resonance analysis of Fab G9.2-15 and Fab G9.2-17 bound to human (top) and mouse (bottom) galectin-9 CRD2. The binding and dissociation phases of the experiment are indicated in the top panel. Left: G9.2-15 Fab Right: G9.2-17 Fab

[0059] [Figure 7] Figure 7 includes a diagram showing the SPR analysis of G9.2-17 human IgG4 bound to CRD2 of human (top) and mouse (bottom) galectin-9. The gray line shows the sensorgram for G9.2-iso human IgG4, which is an unbound negative control.

[0060] [Figure 8] Figure 8 includes a diagram showing the staining of cell line samples using Fab for galectin-9 CRD2. A histogram of flow cytometry data is shown. Top left: G9.2-1 Fab, Top right: G9.2-3 Fab, Bottom left: G9.2-15 Fab, Bottom right: G9.2-17 Fab.

[0061] [Figure 9] Figure 9 is a chart showing the inhibitory effects of G9.2-17 and G9.1-8 on galectin-9-mediated activation of dectin-1 signaling.

[0062] [Figure 10A-10B] Figures 10A–10B include diagrams showing epitope mapping of G.9-2.17 on human galectin-9 CRD2 by phylogenetic mutagenesis. Figure 10A: Diagram showing the binding activity of G9.2-17 to galectin-9 CRD2 mutants as determined by phage ELISA. The decrease in ELISA signal indicates a site on galectin-9 CRD2 that is important for G9.2-17 binding. Figure 10B shows the location of W309 mapped onto the crystal structure of human galectin-9 CRD2 (PDB ID 3NV2), which is opposite to the binding site of the glycoligand mapped onto the crystal structure (W309 corresponds to W277 in UniProt ID 000182-2; PDB ID 3NV2).

[0063] [Figure 11] Figure 11 includes a chart showing the size exclusion chromatography analysis of Fab G9.2-17 (top), Fab G9.2-17mut6 (center), and Fab G9.2-Iso (bottom). Purified Fab samples were electrophoresed on a TOSOH TSK Bioassist G2WXL column in PBS and detected using absorbance at 280 nm.

[0064] [Figure 12] Figure 12 includes a chart showing surface plasmon resonance analysis of Fab G9.2-17 (top) and Fab G9.2.17mut6 (bottom) bound to human (left) and mouse (right) galectin-9 CRD2. Human or mouse galectin-9 CRD2 was immobilized on an Avicap tip pre-loaded with neutraavidin on a Pall ForteBio Pioneer instrument. The Fab samples were then run using the OneStep method. The binding and dissociation phases of the experiment are indicated in the top panel.

[0065] [Figure 13] Figure 13 is a graph showing the binding characteristics of G9.2 Fab clones to wild-type galectin-9 CRD2 or the W3039K mutant, as analyzed using phage ELISA. The binding of Fab clones to human galectin-9 CRD2 was analyzed using phage ELISA. Either biotinylated wild-type human galectin-9 CRD2, the W309K galectin-9 CRD2 mutant, or galectin-9 CRD2 pre-incubated with G9.2-17 IgG was immobilized in neutraavidin-coated wells and incubated with individual phage-display Fab clones.

[0066] [Figure 14] Figure 14 is a Kaplan-Meier plot showing that blocking galectin-9 results in a significant extension of survival in an animal model of pancreatic cancer (KPC mice).

[0067] [Figure 15] Figure 15 is a photograph of a mouse tumor showing that blocking galectin-9 and anti-PD1 elicits a superior response.

[0068] [Figure 16] Figure 16 is a bar graph showing the tumor mass of mice treated with G9.2-17 mIgG1. Mice with orthotopically transplanted KPC tumors (n=10 / group) were treated with commercially available isotype (200 μg), commercially available αGal9 (200 μg) mAb, G9.2-Iso mIgG1 (200 μg), or G9.2-17 mIgG1 once a week for 3 weeks at two doses (200 μg or 400 μg). Tumors were removed, weighed, processed, and stained for flow cytometry.

[0069] [Figure 17] Figure 17 shows a bar graph of tumor weights in mice treated with G9.2-17 mIgG2a alone or in combination with αPD1 mAb. Mice with orthotopically transplanted KPC tumors (n=10 / group) were treated once a week for 3 weeks with commercially available αPD-1 (200 μg) mAb, G9.2-17 mIgG2a (200 μg), a combination of G9.2-17 and αPD-1, or a matched isotype. Tumors were removed, weighed, processed, and stained for flow cytometry. Each point represents one mouse; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; independent Student's t-test.

[0070] [Figures 18A-18C] Figures 18A-18C show graphs illustrating the binding of purified G9.1-8m1-5 mIgG1 to human galectin-9 CRD1, characterized using a bead-based binding assay.

[0071] [Figures 19A-19G] Figures 19A-19G show graphs illustrating the binding of purified G9.1-8m6-11 Fab to human galectin-9 CRD1, characterized using a bead-based binding assay.

[0072] [Figures 20A-20C] Figures 20A-20C show graphs illustrating the affinity of purified G9.1-8m8, 9, and 11 mIgG2a antibodies to human galectin-9 CRD1, characterized using a bead-based binding assay.

[0073] [Figures 21A-21D] Figures 21A-21D show graphs illustrating the binding of purified G9.1-8m11-14 Fab to human galectin-9 CRD1, characterized using a bead-based binding assay.

[0074] [Figures 22A-22D] Figures 22A-22D show graphs illustrating the binding of purified G9.1-8m12-14 mIgG2a antibody to human galectin-9 CRD1, characterized using a bead-based binding assay.

[0075] [Figure 23] Figure 23 is a graph showing the results of an apoptosis assay demonstrating that the Gal-9 antibody inhibits galectin-9-induced apoptosis in Jurkat cells. Jurkat cells were treated for 6 hours with or without galectin-9 (280 nM), G9.2-17 IgG (1 μM), and / or G9.1-8m13 IgG (1 μM) (Figure 23). The cells were then stained with annexin-V and PI and subsequently analyzed by flow cytometry. Annexin-V positive cells represent both early and late apoptotic cells. Bars represent the mean of three replicates and are represented as individual data points. Statistical analysis was performed by independent Student's t-tests (*p<0.05; **p<0.01; ***p<0.001; ****p<0.0001).

[0076] [Figure 24] Figure 24 is a graph showing the readout of an assay demonstrating that the anti-galectin-9 antibodies disclosed herein disrupt the interaction between galectin-9 and CD206. Figure 24A is a graph showing an ELISA measuring the interaction between immobilized human galectin-9 and soluble CD206 in the absence and presence of G9.1-8m13 or G9.2-17 antibodies. The isotype antibody wells were used as controls. Wells coated with galectin-9 were incubated with CD206 in the presence and absence of G9.1-8m13, G9.2-17, a combination of both antibodies, or the isotype (experiments were performed in triple replication; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; by non-paired Student's t-test). These results indicate that both the G9.1-8m13 and G9.2-17 antibodies inhibit the interaction between galectin-9 and CD206, and that their effects are additive.

[0077] [Figure 25] Figure 25 is a line graph showing the binding of purified G9.1-8m12-14 mIgG2a antibody to human galectin-9 CRD2 compared to G9.18(WT), as characterized using a bead-based binding assay.

[0078] [Figures 26A and 26B] Figures 26A and 26B are bar graphs showing TNF-α (Figure 26A) and IFNγ (Figure 26B) expression in CD3+ T cells in organotype tumor spheroids (PDOTs) derived from patients with primary pancreatic adenocarcinoma treated with 9.2-17 IgG4 (100 nM), compared to an isotype control (100 nM).

[0079] [Figures 27A-27C] Figures 27A-27C are bar graphs showing the expression of CD44 (Figure 27A), TNF-α (Figure 27B), and IFNγ (Figure 27C) in CD3+ T cells in organotype tumor spheroids (PDOTS) derived from patients with primary tumor samples of pancreatic adenocarcinoma treated with 9.2-17 IgG1 (100 nM) or 9.2-17 IgG4 (100 nM), compared to IgG1 or IgG4 isotype controls (100 nM).

[0080] [Figures 28A-28F] Figures 28A–28F show bar graphs illustrating the immune profile expression in gallbladder cancer tumor samples (PDOTS) treated with 9.2–17 IgG4 (100 nM) compared to an IgG4 isotype control (100 nM); showing CD44 in CD3+ T cells (Figure 28A), TNF-α in CD3+ T cells (Figure 28B), CD44 in CD4+ T cells (Figure 28C), TNF-α in CD4+ T cells (Figure 28D), CD44 in CD8+ T cells (Figure 28E), and TNF-α in CD8+ T cells (Figure 28F).

[0081] [Figures 29A-29C] Figures 29A-29C show bar graphs comparing the expression of CD44 (Figure 29A), TNF-α (Figure 29B), and IFNγ (Figure 29C) in CD3+ T cells in liver metastasis samples from colorectal cancer patients (PDOT) treated with 9.2-17 IgG1 (100 nM) or 9.2-17 IgG4 (100 nM) with that of IgG1 (100 nM) or untreated control (Utx).

[0082] [Figure 30] Figure 30 shows a line graph illustrating the effect of 9.2-17 in a B16F10 subcutaneous syngeneic model. Tumors were subcutaneously transplanted and treated with G9.2-17 IgG1 mouse mAb. Unless otherwise specified in the description, the drug was administered intravenously (iv) to animals on days 0 and 4.

[0083] [Figure 31] Figure 31 shows a line graph illustrating the effect of 9.2-17 in a B16F10 subcutaneous syngeneic model. Tumors were subcutaneously transplanted and treated with the G9.2-17 IgG2a mouse mAb. Animals received the drug once on day 0 and every 4 days thereafter until the end of the experiment. Unless otherwise specified in the description, the mAb was administered intravenously.

[0084] [Figure 32] Figure 32 is a graph showing a cell-based binding assay in which the CRL-2134 cell line was incubated with biotinylated Fab, and the binding Fab was detected using neutraavidin conjugated with DyLight 650. The samples were then analyzed using flow cytometry. A strong signal was observed for galectin-9 antibody 9.2-17, but not for the isotype control. The K of the Gal-9 antibody in the two formats... D The (nM) values ​​were as follows: G9.2-17 hIgG1: 0.41±0.07; G9.2-17 mIgG1: 2.91±0.66.

[0085] [Figures 33A and 33B] Figures 33A and 33B show graphs illustrating the thermal stability measurement of the anti-galectin-9 antibody. The first derivative of fluorescence emission (-dF / dT) is plotted as a function of temperature. The melting temperature is expressed as the temperature at which a peak is observed. The thermal transition was measured using the change in binding of the fluorophore SYPRO Orange (ThermoFisher) with a real-time PCR instrument at a heating rate of 1°C / min, essentially following the method described in "Vedadi et al., Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination; Proc Natl Acad Sci US A. 2006 Oct 24; 103(43): 15835-40". [Modes for carrying out the invention]

[0086] This specification provides antibodies that can bind to galectin-9 (e.g., human, mouse, or both). In some embodiments, the anti-galectin-9 antibody binds to one or more epitopes in the CRD1 and / or CRD2 domains. Such anti-galectin-9 antibodies can suppress galectin-9-mediated signaling (e.g., signaling pathways mediated by galectin-9 / dectin-1 or galectin-9 / Tim-3) or eliminate pathological cells expressing galectin-9, for example, via ADCC. Thus, the anti-galectin-9 antibodies described herein can be used to inhibit any of the galectin-9 signaling pathways and / or eliminate galectin-9-positive pathological cells, thereby benefiting the treatment of galectin-9-related diseases (e.g., autoimmune diseases, solid tumors, allergic diseases, or hematological diseases such as hematological malignancies).

[0087] Galectin-9 (tandem repeat lectin) is a β-galactoside-binding protein that has been shown to play a role in regulating cell-cell and cell-matrix interactions. It has been found to be strongly overexpressed in Hodgkin's disease tissue and other pathological conditions. It may also be found circulating in the tumor microenvironment (TME).

[0088] Galectin-9 has been found to interact with Dectin-1, an innate immune receptor highly expressed on macrophages in PDA and on cancer cells (Daley D, et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance; Nat Med. 2017; 23(5):556-6). Regardless of the source of galectin-9, disruption of its interaction with Dectin-1 has been shown to lead to the reprogramming of CD4+ and CD8+ cells into essential mediators of antitumor immunity. Therefore, galectin-9 serves as a valuable therapeutic target for blocking Dectin-1-mediated signaling. Accordingly, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and Dectin-1.

[0089] Galectin-9 has also been found to interact with TIM-3 (a type I cell surface glycoprotein expressed on the surface of leukemia stem cells in all types of acute myeloid leukemia (excluding M3 [acute promyelocytic leukemia]) but not in normal human hematopoietic stem cells (HSCs)). TIM-3 signaling resulting from galectin-9 ligation has been found to have multifaceted effects on immune cells, inducing apoptosis in Th1 cells (Zhu et al., Nat Immunol., 2005, 6:1245-1252), stimulating tumor necrosis factor-α (TNF-α) secretion, leading to monocyte maturation into dendritic cells, and resulting in innate immune inflammation (Kuchroo et al., Nat Rev Immunol., 2008, 8:577-580). Further galectin-9 / TIM-3 signaling has been found to co-activate NF-κB and β-catenin signaling (two pathways that promote LSC self-renewal) (Kikushige et al., Cell Stem Cell, 2015, 17(3):341-352). Anti-galectin-9 antibodies that interfere with galectin-9 / TIM-3 binding may have therapeutic effects, particularly with respect to leukemia and other hematological malignancies. Therefore, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and TIM-3.

[0090] Galectin-9 has also been found to interact with CD206, a mannose receptor highly expressed on M2 polarized macrophages, thereby promoting tumor survival (Enninga et al., CD206-positive myeloid cells bind galectin-9 and promote a tumor-supportive microenvironment. J Pathol. 2018 Aug; 245(4):468-477). Tumor-associated macrophages expressing CD206 are mediators of tumor immunosuppression, angiogenesis, metastasis, and recurrence (see, for example, Scodeller et al., Precision Targeting of Tumor Macrophages with a CD206 Binding Peptide. M1 and M2 had been described as the functional states of macrophages; Sci Rep. 2017 Nov 7; 7(1):14655, and its references). In particular, M1 macrophages (also known as classically activated macrophages) are triggered by Th1-related cytokines and bacterial products, express high levels of IL-12, and are tumor-killing. In contrast, M2 macrophages (so-called alternatively activated macrophages) are activated by Th2-related factors, express high levels of anti-inflammatory cytokines (e.g., IL-10), and promote tumor progression (Biswas and Mantovani; Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm; Nat Immunol. 2010 Oct; 11(10):889-96).The tumor-proliferative effects of M2 include promoting angiogenesis, advancing invasion and metastasis, and protecting tumor cells from chemotherapy-induced apoptosis (Hu et al., Functional significance of macrophages in pancreatic cancer biology; Tumour Biol. 2015 Dec; 36(12): 9119-9126, and its references). Tumor-associated macrophages are thought to have an M2-like phenotype and play a tumor-promoting role. Galectin-9 has been shown to mediate the differentiation of myeloid cells into the M2 phenotype (Enninga et al., Galectin-9 modulates immunity by promoting Th2 / M2 differentiation and impacts survival in patients with metastatic melanoma; Melanoma Res. 2016 Oct;26(5):429-41). Galectin-9-bound CD206 can reprogram TAMs toward the M2 phenotype, similar to what has been previously shown for dectin. While we do not wish to be bound by theory, one mechanism may be provided by blocking the interaction between galectin-9 and CD206 in which anti-galectin antibodies (e.g., those listed in Tables 1 and 2 herein, e.g., antibodies 9.1-8m13 and / or antibodies 9.2-17) may be therapeutically beneficial. Thus, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and CD206.

[0091] Galectin-9 has also been shown to interact with protein disulfide isomerase (PDI) and 4-1BB (Bi S, et al. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry; Proc Natl Acad Sci US A. 2011;108(26):10650-5; Madireddi et al. Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibody. J Exp Med. 2014;211(7):1433-48).

[0092] Anti-galectin-9 antibodies may be useful as therapeutic agents for treating galectin-9-related diseases (e.g., diseases in which galectin-9 signaling plays a role). While not theoretically bound, anti-galectin-9 antibodies may block galectin-9-mediated signaling pathways. For example, antibodies may interfere with the interaction between galectin-9 and its binding partner (e.g., Dectin-1, TIM-3, or CD206), thereby blocking signaling induced by galectin-9 / ligand interactions. Alternatively, or in addition to this, anti-galectin-9 antibodies may also exert their therapeutic effect by inducing blockade and / or cytotoxicity (e.g., ADCC, CDC, or ADCP) against diseased cells expressing galectin-9. Pathogenic cells are defined as cells that directly or indirectly contribute to the onset and / or development of a disease.

[0093] Accordingly, this specification describes anti-galectin-9 antibodies and their therapeutic uses for treating galectin-9-related diseases.

[0094] Antibodies that bind to galectin-9 This disclosure provides antibodies that bind to galectin-9, for example, human and / or mouse galectin-9.

[0095] In some cases, the anti-galectin antibodies described herein bind to epitopes in the glycan recognition domain (CRD) of galectin-9, e.g., CRD1 or CRD2. In some cases, the anti-galectin antibodies may bind to CRD1 and CRD2. Galectin-9 is a protein well known in the art. For example, NCBI GenBank access numbers BAB83625.1 and NP_034838.2 provide information on human and mouse galectin-1, respectively. Exemplary human and mouse galectin-9 polypeptides are provided herein; human galectin-9 (isoform 1; aka “long;”) is provided as SEQ ID NO: 1; human CRD1 and CRD2 are provided as SEQ ID NO: 3 and SEQ ID NO: 4, respectively; mouse galectin-9 (isoform 1; aka “long;”) is provided as SEQ ID NO: 2; and human and mouse CRD1 and CRD2 are provided as SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

[0096] The CRD1 domain of human galectin-9 (SEQ ID NO: 3) encompasses residues 1-148 of SEQ ID NO: 1, and the CRD2 domain (SEQ ID NO: 4) extends from residues 218-355 of SEQ ID NO: 1. Similarly, the CRD1 domain of mouse galectin-9 (SEQ ID NO: 5) extends from residues 1-147 of SEQ ID NO: 2, and the CRD2 domain (SEQ ID NO: 6) extends from residues 226-353 of SEQ ID NO: 2.

[0097] Galectin-9 polypeptides from other species are known in the art and can be obtained from publicly available gene databases (e.g., GenBank) using either human or mouse sequences as queries. The CRD1 and CRD2 domains of a galectin-9 polypeptide can be identified by aligning the sequence of the galectin-9 polypeptide with the sequence of human or mouse galectin-9, as described herein.

[0098] The antibodies described herein bind to galectin-9 or its fragments (e.g., CRD1 or CRD2). As used herein, the term “anti-galectin-9 antibody” refers to any antibody capable of binding to galectin-9 polypeptides from a suitable source, e.g., human or non-human mammals (e.g., primates such as mice, rats, rabbits, and monkeys). In some embodiments, anti-galectin-9 antibodies can be used therapeutically to suppress the biological activity of galectin-9. In some embodiments, anti-galectin-9 antibodies may be used in studies or for the detection of cells expressing galectin-9 in diagnostic / predictive methods, e.g., in the evaluation of eligibility and / or efficacy of treatment. Alternatively, or in addition to the above, anti-galectin-9 antibodies may block the interaction of galectin-9 with its ligands (e.g., dectin-1, TIM-3), thereby suppressing signaling pathways triggered by, for example, galectin-9 / dectin-1 or galectin-9 / TIM-3 interactions. Anti-galectin-9 antibodies can also induce cell death of galectin-9-expressing cells, for example, through antibody-dependent cytotoxicity (ADCC) mechanisms.

[0099] An antibody (single or plural form is used interchangeably) is an immunoglobulin molecule capable of specifically binding to a target (e.g., carbohydrates, polynucleotides, lipids, polypeptides, etc.) via at least one antigen-recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” (e.g., anti-galectin-9 antibody) encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also their antigen-binding fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv), mutants thereof, fusion proteins containing the antibody portion, humanized antibodies, chimeric antibodies, diabodies, nanobodies, linear antibodies, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies), and any other modified configuration of an immunoglobulin molecule containing an antigen-recognition site of the required specificity (including glycosylated variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies). Antibodies, such as anti-galectin-9 antibodies, include antibodies of any class, such as IgD, IgE, IgG, IgA, or IgM (or their subclasses), and the antibody does not need to be of any particular class. Immunoglobulins can be assigned to different classes depending on the antibody amino acid sequence of the constant domain of their heavy chain. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional structures of various classes of immunoglobulins are well known.

[0100] Typical antibody molecules usually have a heavy chain variable region (V) involved in antigen binding. H ) and light chain variable region (V L ) includes. V H and V L The region can be further subdivided into hyper-variable regions, also known as complementary determination regions (CDRs), which are dotted with more conserved regions known as "framework regions" (FRs).H and V L It typically consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The framework region and the scope of the CDRs can be precisely identified using methodologies known in the art (e.g., Kabat definition, Chothia definition, AbM definition, and / or contact definition (all of which are well known in the art)). (For example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242, Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs).

[0101] The anti-galectin-9 antibodies described herein may be full-length antibodies comprising two heavy chains and two light chains, each comprising a variable domain and a constant domain. Alternatively, the anti-galectin-9 antibody may be an antigen-binding fragment of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of a full-length antibody include (i) Fab fragments (V L , V H , C L , and C H (ii) A monovalent fragment consisting of one domain; (ii) F(ab')2 fragment (a bivalent fragment containing two Fab fragments linked by disulfide bridges in the hinge region); (iii) V H and CH Fd fragment consisting of one domain; (iv) V of a single arm of the antibody L and V H Fv fragment consisting of domains; (v)V H (vi) includes a dAb fragment consisting of domains (Ward et al., (1989) Nature 341:544-546); and an isolated complementarity-determining region (CDR) that preserves functionality. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked using recombination methods by a synthetic linker (which allows the VL and VH regions to be paired and constructed as a single protein chain forming a monovalent molecule known as single-stranded Fv (scFv)). See, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0102] The anti-galectin-9 antibodies described herein (e.g., Table 1 and / or Table 2) can bind to galectin-9 and inhibit its activity (e.g., reduce or eliminate it). In some embodiments, the anti-galectin-9 antibodies described herein can bind to galectin-9 and inhibit its activity by at least 30% (e.g., 31%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). The apparent inhibition constant (Ki) is a measure of the potency of the inhibitor. app or K i,app The inhibitory activity (IQ) is related to the concentration of the inhibitor required to reduce enzyme activity and is independent of the enzyme concentration. The inhibitory activity of the anti-galectin-9 antibodies described herein can be determined by conventional methods known in the art.

[0103] K of antibodies i, appThe value can be determined by measuring the inhibitory effect of different concentrations of the antibody on the degree of the reaction (e.g., enzyme activity), and by fitting the change in the pseudo-first-order rate constant (v) to the modified Morrison equation (Equation 1) as a function of the inhibitor concentration, an estimated value of the apparent Ki value can be obtained. For a competitive inhibitor, K i, app -Ki can be determined from the y-intercept extracted from the linear regression analysis of the plot of - versus - substrate concentration app can be obtained. [Number]

[0104] If A is equivalent to v o / E, it is the initial rate of the enzyme reaction (v o ) divided by the total enzyme concentration (E). In some embodiments, the anti-galectin-9 antibody described herein has a Ki app value of 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 pM or less for the target antigen or antigen epitope. In some embodiments, the anti-galectin-9 antibody may have a lower Ki app value for the first target (e.g., CRD2 of galectin-9) compared to the second target (e.g., CRD1 of galectin-9). The difference in Ki app (e.g., for specificity or other comparisons) is at least 1.5, 2, 3, 4, 5, 10, 15, 20, 37.5, 50, 70, 80, 91, 100, 500, 1000, 10,000 or 10 5It may be twice as strong. In some examples, anti-galectin-9 antibodies inhibit a first antigen (e.g., a first protein or its mimetic in a first three-dimensional structure) more strongly than a second antigen (e.g., the same first protein or its mimetic in a second three-dimensional structure; or a second protein). In some embodiments, any of the anti-galectin-9 antibodies inhibit the Ki of the antibody against the target antigen or its antigenic epitope. app To reduce this, affinity can be further matured.

[0105] In some embodiments, anti-galectin-9 antibodies suppress dectin-1 signaling, for example, in tumor-infiltrating immune cells such as macrophages. In some embodiments, anti-galectin-9 antibodies suppress galectin-9-induced dectin-1 signaling by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 2). Alternatively, or in addition, anti-galectin-9 antibodies may suppress galectin-9-initiated T-cell immunoglobulin mutin-3 (TIM-3) signaling. In some embodiments, anti-galectin-9 antibodies inhibit T-cell immunoglobulin mucin-3 (TIM-3) signaling, for example, in tumor-infiltrating immune cells, by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof) in some embodiments. Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 2).

[0106] In some embodiments, anti-galectin-9 antibodies suppress CD206 signaling, for example, in tumor-infiltrating immune cells. In some embodiments, anti-galectin-9 antibodies suppress galectin-9-induced CD206 signaling by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 13). In some embodiments, anti-galectin-9 antibodies block or prevent galectin-9 from binding to CD206 by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 13).

[0107] In some embodiments, any anti-galectin-9 antibody described herein induces cytotoxicity, such as ADCC, in target cells expressing galectin-9 (e.g., when the target cells are cancer cells or immunosuppressive immune cells). In some embodiments, anti-galectin-9 antibodies induce at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof) apoptosis in immune cells (e.g., T cells) or cancer cells. Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 14). In some embodiments, any anti-galectin-9 antibody described herein induces cytotoxicity, such as complement-dependent cell-mediated cytotoxicity (CDC), against target cells expressing galectin-9.

[0108] Antibody-dependent cell-mediated phagocytosis (ADCP) is an important mechanism of action of antibodies that mediates some or all of its action through phagocytosis. In this case, the antibody mediates the uptake of a specific antigen by antigen-presenting cells. ADCP can be mediated by monocytes, macrophages, neutrophils, and dendritic cells via FcγRIIa, FcγRI, and FcγRIIIa, of which FcγRIIa (CD32a) on macrophages exhibits a dominant pathway.

[0109] In some embodiments, any anti-galectin-9 antibody described herein induces phagocytosis (ADCP) of target cells, such as cancer cells or immunosuppressive immune cells expressing galectin-9. In some embodiments, the anti-galectin-9 antibody increases the phagocytosis of target cells (e.g., cancer cells or immunosuppressive immune cells) by at least 30% (including any increment thereof, e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more).

[0110] In some embodiments, any anti-galectin-9 antibody described herein induces cytotoxicity, such as complement-dependent cytotoxicity (CDC), against target cells, e.g., cancer cells or immunosuppressive immune cells. In some embodiments, the anti-galectin-9 antibody increases CDC against target cells by at least 30% (including any increment thereof, e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more).

[0111] In some embodiments, any anti-galectin-9 antibody described herein induces T cell activation (i.e., directly or indirectly suppresses galectin-9-mediated inhibition of T cell activation) in, for example, tumor-infiltrating T cells. In some embodiments, the anti-galectin-9 antibody promotes T cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). T cell activation can be measured by conventional methods or assays described herein (e.g., Example 6) (e.g., measurement of CD44, OX40, IFNγ, PD-1). In some embodiments, the anti-galectin-9 antibody promotes CD4+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce CD44 expression in CD4+ cells. In some embodiments, anti-galectin-9 antibodies increase CD44 expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce IFNγ expression in CD4+ cells. In some embodiments, anti-galectin-9 antibodies increase IFNγ expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce TNFα expression in CD4+ cells. In some embodiments, anti-galectin-9 antibodies increase TNFα expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment thereof).

[0112] In some embodiments, anti-galectin-9 antibodies promote CD8+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce CD44 expression in CD8+ cells. In some embodiments, anti-galectin-9 antibodies increase CD44 expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce IFNγ expression in CD8+ cells. In some embodiments, anti-galectin-9 antibodies increase IFNγ expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof). In non-limiting examples, anti-galectin antibodies induce TNFα expression in CD8+ cells. In some embodiments, anti-galectin-9 antibodies increase TNFα expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher, including any increment thereof).

[0113] The antibodies described herein may be from mouse, rat, human, or any other source (including chimeric or humanized antibodies). Such antibodies do not exist naturally; that is, they are not produced in animals without human action (e.g., immunizing such animals with a desired antigen or fragment thereof, or isolating them from an antibody library).

[0114] Any antibody described herein (e.g., anti-galectin-9 antibody) may be monoclonal or polyclonal. “Monoclonal antibody” refers to a homogeneous population of antibodies, while “polyclonal antibody” refers to a heterogeneous population of antibodies. These two terms do not limit the source of the antibody or the manner in which it is produced.

[0115] In some embodiments, the anti-galectin-9 antibody is a humanized antibody. In some embodiments, the anti-galectin-9 antibody is a humanized antibody having one or more of the elements or features described below or elsewhere in this specification. A humanized antibody refers to a form of non-human (e.g., mouse) antibody that is a specific chimeric immunoglobulin, immunoglobulin chain, or antigen-binding fragment thereof, containing a minimal sequence derived from a non-human immunoglobulin. Generally, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the recipient's CDR are replaced with residues derived from the CDR of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and capability. In some examples, Fv framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, the humanized antibody may also contain residues that are not found in the recipient antibody or the transferred CDR or framework sequence, but are included to further refine and optimize antibody performance. In some cases, a humanized antibody may contain substantially all of at least one, typically two, variable domains, with all or substantially all of the CDR region corresponding to that of a non-human immunoglobulin, and all or substantially all of the FR region being that of a human immunoglobulin consensus sequence. A humanized antibody may also optimally contain at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have a modified Fc region as described in WO 99 / 58572. Other forms of humanized antibodies may have one or more CDRs (one, two, three, four, five, or six) that have been altered relative to the original antibody, also referred to as one or more CDRs "derived" from one or more CDRs from the original antibody. Humanized antibodies may also include affinity maturation.

[0116] Methods for constructing humanized antibodies are also well known in this field. For example, see Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033 (1989). One example is the V of a parent non-human antibody. Hand V L The variable regions of H and V L are subjected to three-dimensional molecular modeling analysis according to methods known in the art. Next, framework amino acid residues predicted to be important for the formation of the correct CDR structure are identified using the same molecular modeling analysis. In parallel, human V H and V L chains having amino acid sequences homologous to the amino acid sequence of the parental non-human antibody are identified from any antibody gene database using the parental V H and V L sequences as search queries. Then, human V

[0117] acceptor genes are selected. The CDR regions within the selected human acceptor genes can be replaced with CDR regions from the parental non-human antibody or a functional variant thereof. If necessary, residues within the framework region of the parental chain predicted to be important when interacting with the CDR region can be used to replace the corresponding residues in the human acceptor gene.

[0118] In some embodiments, the anti-galectin-9 antibody is a chimeric antibody. In some embodiments, the anti-galectin-9 antibody is a chimeric antibody that may include heavy chain constant regions and light chain constant regions derived from human antibodies. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region from a first species and a constant region from a second species. Typically in these chimeric antibodies, the variable regions of both the light and heavy chains mimic the variable regions of antibodies derived from one species of mammal (e.g., a non-human mammal such as a mouse, rabbit, and rat), while the constant portion is homologous to the sequence in an antibody derived from another mammal such as a human. In some embodiments, amino acid modifications can be made in the variable region and / or the constant region.

[0119] In some embodiments, the anti-galectin-9 antibodies described herein specifically bind to the corresponding target antigen or its epitope (e.g., galectin-9 antigen or epitope). The term “specifically binding” to an antigen or epitope is a well-understood term in the art. A molecule is said to exhibit “specific binding” if it reacts more frequently, more rapidly, for a longer duration, and / or with greater affinity to a particular target antigen than to another target. An antibody “specifically binds” to a target antigen or epitope if it binds with higher affinity, higher binding activity, more readily, and / or for a longer duration than it would to other substances. For example, an antibody that specifically (or preferentially) binds to an antigen (galectin-9) or an antigenic epitope within it is an antibody that binds to this target antigen with higher affinity, higher binding activity, more readily, and / or for a longer duration than it would to other antigens or other epitopes in the same antigen. Furthermore, this definition also means, for example, that an antibody that specifically binds to a first target antigen may or may not specifically or preferentially bind to a second target antigen. Therefore, “specific binding” or “preferential binding” does not necessarily require exclusive binding (but may include exclusive binding). In some examples, an antibody that “specifically binds” to a target antigen or its epitope may not bind to other antigens or other epitopes in the same antigen (i.e., only baseline binding activity can be detected in conventional methods). In some embodiments, the anti-galectin-9 antibodies described herein specifically bind to galectin-9. In some embodiments, the anti-galectin-9 antibodies described herein specifically bind to CRD2 of galectin-9. In some embodiments, the anti-galectin-9 antibodies described herein specifically bind to CRD1 of galectin-9.Alternatively, or in addition to the above, the anti-galectin-9 antibodies described herein either specifically bind to human galectin-9 or its fragments, or vice versa, compared to their mouse counterparts (for example, having at least 10-fold higher binding affinity to one antigen than to the other, as determined in the same assay under the same assay conditions).

[0120] In some embodiments, the anti-galectin-9 antibody binds only to CRD1 (but not to CRD2), and for example, significant binding to CRD2 or binding to CRD2 cannot be detected by routine assays. In some embodiments, the anti-galectin-9 or its fragments bind only to CRD2 (but not to CRD1). In some embodiments, certain antibodies described herein may bind to both CRD1 and CRD2. In some embodiments, certain antibodies or their fragments described herein may bind to both CRD1 and CRD2, but have a lower affinity for CRD2. In some embodiments, certain antibodies or their fragments described herein may bind to both CRD1 and CRD2, but have a lower affinity for CRD1.

[0121] In some embodiments, the effects of CRD1-conjugated Gal-9 antibodies and CRD2-conjugated Gal-9 antibodies may be additive. In some embodiments, the effects of CRD1-conjugated Gal-9 antibodies and CRD2-conjugated Gal-9 antibodies may be synergistic. In some embodiments, a “cocktail,” i.e., a mixture of two or more antibodies, may be used in the composition. Such a composition may include one or more antibodies that conjugate CRD1 as described herein, and one or more antibodies that conjugate CRD2 as described herein. In a non-limiting example, an antibody containing the variable region of clones 9.1-8m13 (e.g., SEQ ID NO: 21 (light chain and SEQ ID NO: 86)) may be combined in the composition with an antibody containing the variable region of clones 9.2-17 (SEQ ID NO: 54 (light chain and SEQ ID NO: 55)). The antibodies may be mixed in equimolar amounts or other ratios as determined to be optimal for performance.

[0122] In some embodiments, the antibody may bind to both CRD1 and CRD2. In other embodiments, the anti-galectin-9 antibodies described herein may cross-react with human and non-human galectin-9 (e.g., mouse), with, for example, a difference in binding affinity between human and non-human galectin-9 being less than 5-fold, e.g., less than 2-fold, or substantially the same.

[0123] In some embodiments, the anti-galectin-9 antibodies described herein have appropriate binding affinity to a target antigen (e.g., galectin-9) or its antigenic epitope. As used herein, “binding affinity” refers to the apparent association constant or K A It refers to K. A The dissociation constant (K D ) is the reciprocal of. The anti-galectin-9 antibodies described herein have a reaction of at least 10 against the target antigen or antigen epitope. -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 M or lower binding affinity (K D ) has increased binding affinity, decreased KD This corresponds to the higher affinity binding of the antibody to the first antigen compared to the second antigen, which is due to the K for binding to the second antigen. A (or numerical value K) D ) is better than a higher K for binding to the first antigen A (or a smaller number K) D This is indicated by ). In such cases, the antibody has specificity for the first antigen (e.g., the first protein or its mimetic in the first three-dimensional structure) compared to the second antigen (e.g., the same first protein or its mimetic in the second three-dimensional structure; or the second protein). In some embodiments, the anti-galectin-9 antibody described herein has a higher binding affinity (higher K) for galectin-9 to CRD1 compared to the binding affinity (higher K) for galectin-9 to CRD2. A or a smaller K D ) has. In some embodiments, the anti-galectin-9 antibodies described herein have a higher binding affinity (higher K) for galectin-9 to CRD2 compared to the binding affinity of galectin-9 to CRD1. A or a smaller K D ) has. The difference in binding affinity (for example, specificity or other comparisons) is at least 1.5, 2, 3, 4, 5, 10, 15, 20, 37.5, 50, 70, 80, 91, 100, 500, 1000, 10,000 or 10 5 It may be doubled. In some embodiments, one of the anti-galectin-9 antibodies can be further affinity-matured to increase the binding affinity of the antibody to the target antigen or its antigenic epitope.

[0124] Binding affinity (or binding specificity) can be determined by various methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopy (e.g., using fluorescence assays). Exemplary conditions for evaluating binding affinity are in HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P20).

[0125] These techniques can be used to measure the concentration of bound protein as a function of the target protein concentration. Under certain conditions, the fractional concentration of bound protein ([bound] / [total]) is generally related to the concentration of the total target protein ([target]) by the following equation:

number

[0126] K A While precise measurement is not always necessary, obtaining quantitative measurements of affinity (determined using methods such as ELISA or FACS analysis) is important for determining K A Because it is proportional to the affinity, it is sometimes sufficient and can therefore be used for comparisons to determine whether there is a higher affinity, for example, twice as high, to obtain a qualitative measurement of affinity or to infer affinity by activity in a functional assay (e.g., an in vitro or in vivo assay). In some cases, an in vitro binding assay is an indicator of in vivo activity. In other cases, an in vitro binding assay is not necessarily an indicator of in vivo activity. In some cases, strong binding is beneficial, but in other cases, strong binding may be undesirable in vivo, and antibodies with lower binding affinity may be more desirable. Numerous exemplary anti-galectin-9 antibodies (specific to CRD1 or CRD2) are provided herein.

[0127] Exemplary antibody clones (reference antibodies) of this disclosure that bind to CRD1 include G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14. Exemplary antibody clones (reference antibodies) of this disclosure that bind to CRD2 include G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder.

[0128] Variable region The exemplary anti-galectin-9 antibodies described herein that bind to CRD1 include antibodies G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, Antibodies having the CDR and / or variable region sequences of G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, such as monoclonal antibodies, recombinant antibodies, and / or human antibodies. The exemplary anti-galectin-9 antibodies described herein that bind to CRD2 are antibodies G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, and G9.2-17mut6. These include antibodies having CDRs and / or variable region sequences of G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder, such as monoclonal antibodies, recombinant antibodies, and / or human antibodies. Exemplary sequences and sequence numbers are listed in Tables 1 and 2. CDRs determined using the Kabat methodology are shown in bold. Table 3 shows the CDRs of selected clones determined using the Kabat methodology. In this specification, the terms "m" and "mut," e.g., "9.1-8m" and "9.1-8mut," are used interchangeably.For example, "G9.1-8m1", "G9.1-8m2", "G9.1-8m3", "G9.1-8m4", "G9.1-8m5", "G9.1-8m6", "G9.1-8m7", "G9.1-8m8", "G9.1-8m9", "G9.1-8m10", "G9.1-8m11", "G9.1-8m12", "G9.1-8m13", and "G9.1-8m14" are respectively "G9.1-8mut1", It is used in compatibility with "G9.1-8mut2", "G9.1-8mut3", "G9.1-8mut4", "G9.1-8mut5", "G9.1-8mut6", "G9.1-8mut7", "G9.1-8mut8", "G9.1-8mut9", "G9.1-8mut10", "G9.1-8mut11", "G9.1-8mut12", "G9.1-8mut13", and "G9.1-8mut14".

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[0144] Such CRD1 and CRD2-conjugated anti-galectin-9 antibodies are isolated and structurally characterized as described herein. This disclosure also intends antibodies having at least 80% identity (e.g., at least 85%, at least 90%, at least 95%, or at least 99% identity) to their variable regions or CDR sequences. G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The VL amino acid sequences of G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder are shown in SEQ ID NOs. 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-1 0, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The VH amino acid sequences of G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder are shown in SEQ ID NOs. 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. Accordingly, isolated anti-galectin-9 antibodies, or antigen-binding moieties thereof, comprising heavy chain and light chain variable regions are provided herein, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71.In some embodiments, the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. Also provided are isolated anti-galectin-9 antibodies comprising the heavy chain and light chain variable region, or the antigen-binding moiety thereof, where the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some embodiments, the heavy chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. Accordingly, isolated anti-galectin-9 antibodies or their antigen-binding moieties, comprising heavy chain and light chain variable regions, are provided herein, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71, and the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. Accordingly, isolated anti-galectin-9 antibodies, or their antigen-binding portions, comprising heavy chain and light chain variable regions are provided herein, wherein the light chain variable region consists of amino acid sequences selected from SEQ ID NOs: 29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71, and the heavy chain variable region consists of amino acid sequences selected from SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73.

[0145] In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody includes a VH region having the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody includes a VH region having the sequence of SEQ ID NO: 56. In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 54 and a VH region having the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 54 and a VH region having the sequence of SEQ ID NO: 56.

[0146] The VL amino acid sequences of G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are represented by sequence number 7. These are shown in 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, respectively. G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, The VH amino acid sequences of G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are shown in SEQ ID NOs. 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. Accordingly, isolated anti-galectin-9 antibodies, or their antigen-binding moieties, including heavy chain and light chain variable regions, are provided herein, where the light chain variable region includes an amino acid sequence selected from SEQ ID NOs. 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. Also provided are isolated anti-galectin-9 antibodies, or their antigen-binding moieties, comprising the heavy chain and light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.In some embodiments, the heavy chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. Accordingly, isolated anti-galectin-9 antibodies, or their antigen-binding portions, comprising heavy chain and light chain variable regions, are provided herein, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the light chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and the heavy chain variable region consists of an amino acid sequence selected from SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.

[0147] In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody includes a VH region having the sequence of SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody includes a VH region having the sequence of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 21 and a VH region having the sequence of SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody includes a VL region having the sequence of SEQ ID NO: 21 and a VH region having the sequence of SEQ ID NO: 86.

[0148] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one of sequence numbers 7-87. In some specific embodiments, the anti-galectin-9 antibody comprises one or more arbitrary sequences selected from sequence numbers 7-87 and any combination thereof.

[0149] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one of the sequence numbers 7-28 and 74-87. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one or more sequences selected from sequence numbers 7-28 and 74-87, and any combination thereof.

[0150] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one of sequence numbers 13, 29-73. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one or more sequences selected from sequence numbers 13, 29-73 and any combination thereof. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one of sequence numbers 54, 55, or 54 and 56. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises one or more sequences selected from sequence numbers 54, 55, or 54 and 56 and any combination thereof.

[0151] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody includes a VH region comprising the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region consisting of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region consisting of the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody includes a VL region and a VH region comprising SEQ ID NOs: 54 and 55. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 54 and 55.

[0152] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region comprising SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region consisting of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region comprising SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region consisting of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region comprising SEQ ID NOs: 21 and 86. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 21 and 86.

[0153] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region or a VH region comprising any of SEQ ID NOs: 21, 22, and 74-87. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region or a VH region comprising SEQ ID NOs: 21, 22, and 74-87. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL and / or VH region comprising a sequence selected from SEQ ID NOs: 21, 22, and 74-87 and any combination thereof. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL and / or VH region comprising a sequence selected from SEQ ID NOs: 21, 22, and 74-87 and any combination thereof.

[0154] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 7 and SEQ ID NOs. 8. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 9 and SEQ ID NOs. 10. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 11 and SEQ ID NOs. 12. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 13 and SEQ ID NOs. 14. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 15 and SEQ ID NOs. 16. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 17 and SEQ ID NOs. 18. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 19 and SEQ ID NOs. 20. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 21 and 22. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 23 and 24. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 25 and 26. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 27 and 28. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 21 and 74. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 21 and 75. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 21 and 76.In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 77. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 78. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 79. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 80. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 81. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 82. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 83. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 84. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 108 and SEQ ID NO: 85. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 21 and SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 29 and SEQ ID NO: 30. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 13 and SEQ ID NO: 31. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 13 and SEQ ID NO: 32. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NO: 13 and SEQ ID NO: 33.In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 34 and 35. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 36 and 37. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 38 and 39. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 40 and 41. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 42 and 43. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 44 and 45. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 46 and 47. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 48 and 49. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 29 and 50. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 13 and 51. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 34 and 52. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 13 and 53. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 54 and 55. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 13 and 57.In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 58 and 59. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 54 and 60. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 61 and 62. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 63 and 64. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 65 and 66. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 54 and 56. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region containing SEQ ID NOs. 67 and 68. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region, including SEQ ID NOs. 69 and SEQ ID NOs. 70. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region, including SEQ ID NOs. 71 and SEQ ID NOs. 72. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region, including SEQ ID NOs. 54 and SEQ ID NOs. 73.

[0155] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 7 and SEQ ID NOs: 8. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 9 and SEQ ID NOs: 10. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 11 and SEQ ID NOs: 12. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 13 and SEQ ID NOs: 14. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 15 and SEQ ID NOs: 16. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 17 and SEQ ID NOs: 18. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs: 19 and SEQ ID NOs: 20. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 21 and 22. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 23 and 24. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 25 and 26. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 27 and 28. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 21 and 74. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 21 and 75. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 21 and 76.In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 77. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 78. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 79. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 80. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 81. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 82. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 83. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 84. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 108 and SEQ ID NO: 85. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 21 and SEQ ID NO: 86. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 29 and SEQ ID NO: 30. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 13 and SEQ ID NO: 31. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 13 and SEQ ID NO: 32. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NO: 13 and SEQ ID NO: 33.In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 34 and 35. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 36 and 37. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 38 and 39. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 40 and 41. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 42 and 43. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 44 and 45. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 46 and 47. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 48 and 49. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 29 and 50. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 13 and 51. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 34 and 52. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 13 and 53. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 54 and 55. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 13 and 57.In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 58 and 59. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 54 and 60. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 61 and 62. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 63 and 64. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 65 and 66. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 54 and 56. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 67 and 68. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 69 and SEQ ID NOs. 70. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 71 and SEQ ID NOs. 72. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region and a VH region consisting of SEQ ID NOs. 54 and SEQ ID NOs. 73.

[0156] In some embodiments, the anti-galectin-9 antibody comprises a sequence having at least 80% sequence identity (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with any of the anti-galectin-9 antibodies described in the preceding paragraph. In some embodiments, the anti-galectin-9 antibody comprises a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with the VL regions described in SEQ ID NOs. 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region described in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. In some embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH regions described in SEQ ID NOs: 7-288 and 74-87.In some embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH regions described in SEQ ID NOs: 7-288 and 74-87 and any combination thereof.

[0157] In some embodiments, the anti-galectin-9 antibody is G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1 It includes a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VL region of an antibody selected from -8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14. In some embodiments, the anti-galectin-9 antibody is G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1 It includes a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH region of an antibody selected from -8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14. In some embodiments, the anti-galectin-9 antibody is G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G The antibody comprises VL and VH regions having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL and VH regions of the antibody selected from 9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14.

[0158] In some specific embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH region described in any of SEQ ID NOs: 21, 22, and 74-87.

[0159] In some specific embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region of G9.1-8m13. In some embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region of G9.1-8m13. In some embodiments, the anti-galectin-9 antibody includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and VH regions of G9.1-8m13.

[0160] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region described in SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and VH regions described in SEQ ID NO: 21 and 86.

[0161] In some embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL regions described in SEQ ID NOs: 13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. In some embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NOs: 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some embodiments, the anti-galectin-9 antibody has at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region described in SEQ ID NOs: 13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71. , and include a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NOs. 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, and 73. In some specific embodiments, the anti-galectin-9 antibody includes a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH region described in SEQ ID NOs. 29-75 and 77-85.In some specific embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH region described in SEQ ID NOs: 13, 29-73 and any combination thereof. In some specific embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL or VH region described in any of SEQ ID NOs: 54, 55, and 56.

[0162] In some embodiments, the anti-galectin-9 antibody is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The VL region includes at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region of an antibody selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder. In some embodiments, the anti-galectin-9 antibody is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The VH region includes at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VH region of an antibody selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder.In some embodiments, the anti-galectin-9 antibody is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The VL and VH regions of the antibody selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity to the VL and VH regions of the antibody.

[0163] In some embodiments, the anti-galectin-9 antibody comprises a sequence selected from any of SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 31, 32, 33, 35, 37, 39, 41, 43, 45, 47, 49, 50, 51, 52, 53, 55, 56, 57, 59, 60, 62, 64, 66, 68, 70, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 and 87, and a heavy chain CDR having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any incremental percentage therein) sequence identity. Alternatively, or in addition to the above, the anti-galectin-9 antibody comprises a light chain CDR having at least 80% sequence identity (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% and any incremental percentage therein) of a sequence selected from any of SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 34, 36, 38, 40, 42, 44, 46, 48, 54, 58, 61, 63, 65, 67, 69, 71, and 73.

[0164] In some specific embodiments, the anti-galectin-9 antibody includes a VL region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region of G9.2-17. In some specific embodiments, the anti-galectin-9 antibody includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region of G9.2-17. In some specific embodiments, the anti-galectin-9 antibody includes VL and VH regions having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and VH regions of G9.2-17.

[0165] In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment includes a VL having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL region described in SEQ ID NO: 54. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment includes a VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH region described in SEQ ID NO: 55. In some specific embodiments, the anti-galectin-9 antibody or its antigen-binding fragment includes a VL and / or VH region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL and / or VH region described in SEQ ID NOs. 54 and 55.

[0166] Complementarity Determination Area (CDR) Anti-galectin-9 antibodies (e.g., those that bind to CRD1) include G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, and G9.1-8 This may include the light and heavy chains CDR1, CDR2, and CDR3 of m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, or combinations thereof. The amino acid sequences of VL CDR1 for G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are shown in Sequence ID No. 328. The amino acid sequences of VL CDR2 for G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are shown in Sequence ID No. 329. The amino acid sequences of VL CDR3 for G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are shown in Sequence IDs 330-340.VH of G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 The amino acid sequences of CDR1 are described in SEQ ID NOs. 361, 427, 428, 431, 435, 436, and 437. The amino acid sequences of VH CDR2 for G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are described in SEQ ID NOs. 362-366 and 438-445. The amino acid sequences of VH CDR3 for G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 are described in Sequence IDs 367-386.

[0167] In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody comprises VL CDR2 having the sequence of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody comprises VL CDR3 having a sequence selected from any of SEQ ID NOs: 330 to 340. In some embodiments, the anti-galectin-9 antibody comprises VL CDR3 having the sequence of SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having a sequence selected from any of SEQ ID NOs: 330 to 340. In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having the sequence of SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having a sequence selected from any of SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody comprises VH CDR2 having a sequence selected from any of SEQ ID NOs: 362-366 and 438-445. In some embodiments, the anti-galectin-9 antibody comprises VH CDR2 having a sequence selected from SEQ ID NOs: 364 or 366. In some embodiments, the anti-galectin-9 antibody comprises VH CDR3 having a sequence selected from any of SEQ ID NOs: 367-386. In some embodiments, the anti-galectin-9 antibody comprises VH CDR3 having the sequence of SEQ ID NO: 374 or 383.In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having a sequence selected from SEQ ID NOs. 361, 427, 428, 431, 435, 436, and 437; VH CDR2 having a sequence selected from SEQ ID NOs. 362-366 and 438-445; and VH CDR3 having a sequence selected from SEQ ID NOs. 367-386. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO. 361; VH CDR2 having the sequence of SEQ ID NO. 364; and VH CDR3 having the sequence of SEQ ID NO. 374. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO. 361; VH CDR2 having the sequence of SEQ ID NO. 366; and VH CDR3 having the sequence of SEQ ID NO. 383. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having a sequence selected from any of SEQ ID NOs: 330 to 340, VH CDR1 having a sequence selected from any of SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437, VH CDR2 having a sequence selected from any of SEQ ID NOs: 362 to 366 and 438 to 445, and VH CDR3 having a sequence selected from any of SEQ ID NOs: 367 to 386. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having the sequence of SEQ ID NO: 337, VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 364, and VH CDR3 having the sequence of SEQ ID NO: 374. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, VL CDR3 having the sequence of SEQ ID NO: 337, VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 366, and VH CDR3 having the sequence of SEQ ID NO: 383.In any of these embodiments, the anti-galectin-9 antibody binds to CRD1.

[0168] In some embodiments, the anti-galectin-9 antibody (e.g., one that binds to CRD2) is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 This includes G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and the light and heavy chains CDR1, CDR2, and CDR3 of the G9.2-low affinity binder, or combinations thereof. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and VL CDR1 of the G9.2-low affinity binder are shown in Sequence ID No. 328. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and the VL CDR2 of the G9.2-low affinity binder are shown in Sequence ID No. 329.The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and VL CDR3 of the G9.2-low affinity binder are shown in SEQ ID NOs. 341-360. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and the VH CDR1 of the G9.2-low affinity binder are shown in SEQ ID NOs. 361, 424-434. VH of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder The amino acid sequences of CDR2 are shown in SEQ ID NOs. 362, 363, 387-389, and 446-466.The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and VH CDR3 of the G9.2-low affinity binder are shown in SEQ ID NOs. 390-417.

[0169] In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody comprises VL CDR2 having the sequence of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody comprises VL CDR3 having a sequence selected from any of SEQ ID NOs: 341 to 360. In some embodiments, the anti-galectin-9 antibody comprises VL CDR3 having the sequence of SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having a sequence selected from any of SEQ ID NOs: 341 to 360. In some embodiments, the anti-galectin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having the sequence of SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having a sequence selected from SEQ ID NOs. 361 and 424-434. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NOs. 361. In some embodiments, the anti-galectin-9 antibody comprises VH CDR2 having a sequence selected from SEQ ID NOs. 362, 363, 387-389 and 446-466. In some embodiments, the anti-galectin-9 antibody comprises VH CDR2 having the sequence of SEQ ID NOs. 388. In some embodiments, the anti-galectin-9 antibody comprises VH CDR3 having a sequence selected from SEQ ID NOs. 390-417. In some embodiments, the anti-galectin-9 antibody comprises VH CDR3 having the sequence of SEQ ID NOs. 406 or 407. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having a sequence selected from SEQ ID NOs. 361 and 424-434, VH CDR2 having a sequence selected from SEQ ID NOs. 362, 363, 387-389 and 446-466, and VH CDR3 having a sequence selected from SEQ ID NOs. 390-417.In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 388, and VH CDR3 having the sequence of SEQ ID NO: 406. In some embodiments, the anti-galectin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 388, and VH CDR3 having the sequence of SEQ ID NO: 407. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, VL CDR3 having a sequence selected from any of SEQ ID NOs: 341-360, VH CDR1 having a sequence selected from any of SEQ ID NOs: 361 and 424-434, VH CDR2 having a sequence selected from any of SEQ ID NOs: 362, 363, 387-389 and 446-466, and VH CDR3 having a sequence selected from any of SEQ ID NOs: 390-417. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, VL CDR3 having the sequence of SEQ ID NO: 352, VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 388, and VH CDR3 having the sequence of SEQ ID NO: 406. In some embodiments, the anti-galectin-9 antibody includes VL CDR1 having the sequence of SEQ ID NO: 328, VL CDR2 having the sequence of SEQ ID NO: 329, and VL CDR3 having the sequence of SEQ ID NO: 352, VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 388, and VH CDR3 having the sequence of SEQ ID NO: 407. In any of these embodiments, the anti-galectin-9 antibody binds to CRD1.

[0170] Since the binding specificity of galectin-9 is essentially determined by the CDR1, CDR2, and CDR3 regions, the VH CDR1, VH CDR2, and VH CDR3 sequences, as well as the VL CDR1, VL CDR2, and VL CDR3 sequences disclosed above, can be mixed and matched to generate novel galectin-9 binding antibodies (inso that each of the resulting novel antibodies has VL CDR1, 2, and 3 as well as VH CDR1, 2, and 3). Such antibodies resulting from novel combinations of CDRs described herein can be tested using the binding assays described herein. In some embodiments, CDR1, CDR2, and / or CDR3 sequences derived from a particular VH or VL sequence are substituted with one or more structurally similar CDR sequences. Novel VH and VL sequences can be prepared by substituting one or more VH and / or VL CDR sequences with structurally similar sequences derived from the CDR sequences disclosed herein, according to methods known in the art.

[0171] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes (a) the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340 and 341-360; (d) the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 427, 428, 431, 435, 436, 437; and SEQ ID NOs: 361, 424-434; (e) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362-366 and 438-445, 362, 363, and 387-389 and 446-466; and (f) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386 and 390-417.

[0172] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR1 amino acid sequence shown in SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR2 amino acid sequence shown in SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR2 amino acid sequence selected from SEQ ID NOs: 362-366 and 438-445. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386. Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes (a) the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340; (d) the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 427, 428, 431, 435, 436, 437; (e) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362-366 and 438-445; and (f) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386.

[0173] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR1 amino acid sequence shown in SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR2 amino acid sequence shown in SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR1 amino acid sequence shown in SEQ ID NOs: 361, 424-434. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR2 amino acid sequence selected from SEQ ID NOs: 362, 363, 387-389 and 446-466. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417.

[0174] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes (a) the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360; (d) the VH CDR1 amino acid sequence shown in SEQ ID NO: 361; (e) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362, 363, 387-389 and 446-466; and (f) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417.

[0175] 9.1 Antibody clones and associated CDRs Light chain variable region derived from clone 9.1 In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 330, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 330, respectively. In some embodiments, the antibody includes the same VL CDR as in G9.1-1.

[0176] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 331, respectively. In some embodiments, the antibody comprises the same VL CDR as in G9.1-2.

[0177] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 332, respectively. In some embodiments, the antibody comprises the same VL CDR as in G9.1-3.

[0178] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as in G9.1-4.

[0179] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 334, respectively. In some embodiments, the antibody includes the same VL CDR as G9.1-5.

[0180] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 335, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 335, respectively. In some embodiments, the antibody includes the same VL CDR as G9.1-6.

[0181] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 336, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-7.

[0182] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-8.

[0183] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 338, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 338, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-9.

[0184] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 339, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 339, respectively. In some embodiments, the antibody includes the same VL CDR as G9.1-10.

[0185] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 340, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 340, respectively. In some embodiments, the antibody includes the same VL CDR as G9.1-11.

[0186] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR2 includes SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR1 consists of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR2 consists of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR3 is sequence number 337. In some embodiments, the antibody contains the same VL CDR as G9.1-8, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, or G9.1-8m14. In some embodiments, the antibody contains the same VL CDR as G9.1-8m12. In some embodiments, the antibody contains the same VL CDR as G9.1-8m13.

[0187] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the heavy chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR2 includes X1X2X3X4X5SX6X7X8SYADSVKG (SEQ ID NO: 467) (where X1=Y or S, X2=I or S, X3=Y or S, X4=P or S, X5=Y or S, X6=G or S, X7=Y or S, and X8=T or S). In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes a heavy chain variable region and a light chain variable region, where the light chain variable region CDR3 includes X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13 Includes GMDY (Scorecard No. 468) (where X1=Y or S, X2=T, S, or missing, X3=Y, S, or missing, X4=S or missing, X5=W, S, or missing, X6=S or missing, X7=G, S, or missing, X8=G, T, S, or missing, X9=I, Y, S, or missing, X 10 =G, S, or Y, X 11 =W or S, X 12 =V or S, and X 13 (=W or S). In some cases, the anti-galectin-9 antibody contains G at X7, Y at X8, and / or T at X9 in the heavy chain CDR2 domain. Alternatively, or in addition, the anti-galectin-9 antibody contains a deletion at one or more of X4-X7 in the heavy chain CDR3 domain. In other cases, the anti-galectin-9 antibody contains S at one or more of X6-X8 in the heavy chain CDR2 domain. Alternatively, or in addition, the anti-galectin-9 antibody contains a deletion at one or more of X5-X7 in the heavy chain CDR3 domain. In further cases, the anti-galectin-9 antibody contains S at one or more of X6-X8 in the heavy chain CDR2 domain. Alternatively, or in addition, the anti-galectin-9 antibody contains a deletion at one or more of X3-X9, and / or X 10 It is Y.

[0188] Heavy chain variable region derived from clone 9.1 In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 431, 438, and 367, respectively. In some embodiments, the antibody comprises the same VH CDR as in G9.1-1.

[0189] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 435, 439, and 368, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-2.

[0190] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 436, 363, and 369, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 436, 363, and 369, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-3.

[0191] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 437, 440, and 370, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 437, 440, and 370, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-4.

[0192] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 437, 441, and 371, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-5.

[0193] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 427, 442, and 372, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 427, 442, and 372, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-6.

[0194] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 443, and 373, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-7.

[0195] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 374, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8.

[0196] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 363, and 384, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-9.

[0197] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 429, 444, and 385, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-10.

[0198] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 428, 445, and 386, respectively. In some embodiments, heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 445, and 386, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-11.

[0199] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 365, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m1.

[0200] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 366, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m2.

[0201] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 375, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m3.

[0202] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 361, 364, and 376, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 361, 364, and 376, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m4.

[0203] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 377, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m5.

[0204] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 378, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m6.

[0205] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 379, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m7.

[0206] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 380, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m8.

[0207] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 361, 364, and 383, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m9.

[0208] In some embodiments, the anti-galectin-9 antibody or an antigen-binding portion thereof comprises a heavy chain and a light chain variable region, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 364, and 381, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NO: 361, 364, and 381, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m10.

[0209] In some embodiments, the anti-galectin-9 antibody or an antigen-binding portion thereof comprises a heavy chain and a light chain variable region, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 364, and 382, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NO: 361, 364, and 382, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m11.

[0210] In some embodiments, the anti-galectin-9 antibody or an antigen-binding portion thereof comprises a heavy chain and a light chain variable region, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 366, and 380, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NO: 361, 366, and 380, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m12.

[0211] In some embodiments, the anti-galectin-9 antibody or an antigen-binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1 comprises SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR2 comprises SEQ ID NO: 366. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR3 region comprises SEQ ID NO: 383. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1 consists of SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR2 consists of SEQ ID NO: 366. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR3 region consists of SEQ ID NO: 383. In some embodiments, the anti-galectin-9 antibody or a binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 each comprise SEQ ID NO: 361, 366, and 383. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions each consist of SEQ ID NO: 361, 366, and 383. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m13.

[0212] In some embodiments, the anti-galectin-9 antibody or an antigen-binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 each comprise SEQ ID NO: 361, 366, and 382. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 each consist of SEQ ID NO: 361, 366, and 382. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m^14.

[0213] Clone 9.1-9.1 Heavy and Light Chain Variable Regions In one particular embodiment, the anti-galectin-9 antibody or its antigen-binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 330, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 431, 438, and 367, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 330, and SEQ ID NOs. 431, 438, and 367, respectively. In some embodiments, the antibody comprises the same VL and VH CDRs as in G9.1-1.

[0214] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 331, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 435, 439, and 368, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 331, and SEQ ID NOs. 435, 439, and 368. In one particular embodiment, the antibody comprises the same VL and VH CDRs as in G9.1-2. In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 332, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 436, 363, and 369, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 332, and SEQ ID NOs. 436, 363, and 369. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-3.

[0215] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 437, 440, and 370, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 437, 440, and 370. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-4.

[0216] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 334, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 437, 441, and 371, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 334, and SEQ ID NOs. 437, 441, and 371. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-5.

[0217] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 335, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 427, 442, and 372, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 335, and SEQ ID NOs. 427, 442, and 372. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-6.

[0218] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 336, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 443, and 373, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 336, and SEQ ID NOs. 361, 443, and 373. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-7.

[0219] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 374. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 374. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8.

[0220] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 338, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 363, and 384. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 338, and SEQ ID NOs. 361, 363, and 384. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-9.

[0221] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 339, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 429, 444, and 385. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 339, and SEQ ID NOs. 429, 444, and 385. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-10.

[0222] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 340, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 428, 445, and 386. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 340, and SEQ ID NOs. 428, 445, and 386. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-11.

[0223] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 365, and 374. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 365, and 374. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m1.

[0224] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 366, and 374. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 366, and 374. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m2.

[0225] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 375. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 375. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m3.

[0226] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 376. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 376. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m4.

[0227] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 377. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, as well as SEQ ID NOs. 361, 364, and 377. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m5.

[0228] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 378. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 378. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m6.

[0229] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 379. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 379. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m7.

[0230] In one particular embodiment, the anti-galectin-9 antibody or a binding portion thereof comprises a heavy chain and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 each comprise SEQ ID NO: 328, 329, and 337, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 364, and 380. In some embodiments, the light chain and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NO: 328, 329, and 337, and SEQ ID NO: 361, 364, and 380. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m8.

[0231] In one particular embodiment, the anti-galectin-9 antibody or a binding portion thereof comprises a heavy chain and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 each comprise SEQ ID NO: 328, 329, and 337, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 364, and 383. In some embodiments, the light chain and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NO: 328, 329, and 337, and SEQ ID NO: 361, 364, and 383. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m9.

[0232] In one particular embodiment, the anti-galectin-9 antibody or a binding portion thereof comprises a heavy chain and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 each comprise SEQ ID NO: 328, 329, and 337, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NO: 361, 364, and 381. In some embodiments, the light chain and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NO: 328, 329, and 337, and SEQ ID NO: 361, 364, and 381. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m10.

[0233] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 364, and 382. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 364, and 382. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m11.

[0234] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 366, and 380. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 366, and 380. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m12.

[0235] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 366, and 383. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 366, and 383. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m13.

[0236] In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 366, and 382. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 337, and SEQ ID NOs. 361, 366, and 382. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m14.

[0237] Sequence identity In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) corresponds to the exemplary antibody V described herein. L Compared to CDRs, the light chain CDRs may contain, individually or as a whole, light chain CDRs having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof). Alternatively, or in addition thereto, an anti-galectin-9 antibody (e.g., specific to CRD1 or CRD2) may be used as the V of the exemplary antibody described herein. H Compared to the CDR, the heavy chain CDR may have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) individually or as a whole.

[0238] In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) is G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1 -8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 - an antibody or its corresponding antigen-binding moiety L Compared to CDRs, the light chain CDRs may have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) individually or as a whole. In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may include G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1 -8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 - an antibody or its corresponding antigen-binding moiety H Compared to the CDR, the heavy chain CDR may have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) individually or as a whole.

[0239] In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) is G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1 -8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 - an antibody or its corresponding antigen-binding moiety L CDR and V H The CDR may include light chain CDRs and heavy chain CDRs having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity, individually or as a whole, compared to the CDR.

[0240] In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 374. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs. 330-340.

[0241] In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequence shown in SEQ ID NOs. 361, 427, 428, 431, 435, 436, and 437. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VH CDR2 amino acid sequence selected from SEQ ID NOs. 362-366 and 438-445. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VH CDR3 amino acid sequence selected from SEQ ID NOs. 367-386.

[0242] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety is: (a) a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340; (d) VH CDR1 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequences shown in SEQ ID NOs. 361, 427, 428, 431, 435, 436, 437; (e) VH CDR2 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to VH CDR2 amino acid sequences selected from SEQ ID NOs. 362-366 and 438-445; (f) VH CDR2 amino acid sequences selected from SEQ ID NOs. 367-386 It includes a VH CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the CDR3 amino acid sequence.

[0243] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 337, respectively. In some embodiments, the VL CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs. 361, 366, and 383, respectively. In some embodiments, the VH CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13.In one particular embodiment, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 337, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 361, 366, and 383. In one particular embodiment, the VL CDR1, CDR2, and CDR3, and VH CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1, CDR2, and CDR3, and VH CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13.

[0244] 9.2 Antibody clones and associated CDRs Light chain variable region derived from clone 9.2 In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 341, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 341, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-1.

[0245] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-2.

[0246] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 333, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-3.

[0247] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 342, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-4.

[0248] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 343, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-5.

[0249] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 344, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-6.

[0250] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 345, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 345, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-7.

[0251] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 346, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 346. In some embodiments, the antibody contains the same VL CDR as G9.2-8.

[0252] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 347, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 347, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-9.

[0253] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 348, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 348, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-10.

[0254] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 349, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 349, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-11.

[0255] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 350, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-12.

[0256] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 341, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 341. In some embodiments, the antibody contains the same VL CDR as G9.2-13.

[0257] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-14.

[0258] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 343, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-15.

[0259] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 333. In some embodiments, the antibody contains the same VL CDR as G9.2-16.

[0260] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 includes SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 includes SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR1 consists of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes a heavy chain and a light chain variable region, where the light chain variable region CDR2 consists of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or its binding moiety consists of a heavy chain and a light chain variable region, where the light chain variable region CDR3 includes SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the antibody includes the same VL CDR as G9.2-17.

[0261] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-17mut6.

[0262] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-18.

[0263] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 354, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-19.

[0264] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-20.

[0265] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 355, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 355, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-21.

[0266] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 356, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-22.

[0267] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 357, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-23.

[0268] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 358, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 328, 329, and 358, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-24.

[0269] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 359, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 359, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-25.

[0270] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 360, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 328, 329, and 360, respectively. In some embodiments, the antibody contains the same VL CDR as G9.2-26.

[0271] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as the G9.2-low affinity binder.

[0272] Heavy chain variable region derived from clone 9.2 In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 424, 446, and 390, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 424, 446, and 390, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-1.

[0273] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 431, 447, and 391, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 431, 447, and 391, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-2.

[0274] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 431, 448, and 392, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 431, 448, and 392, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-3.

[0275] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 431, 449, and 393, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 431, 449, and 393, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-4.

[0276] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 431, 450, and 394, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 431, 450, and 394, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-5.

[0277] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 include SEQ ID NOs. 431, 451, and 395, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 431, 452, and 395. In some embodiments, the antibody contains the same VH CDR as G9.2-6.

[0278] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 425, 453, and 396, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 425, 453, and 396, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-7.

[0279] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 425, 453, and 397, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 425, 453, and 397, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-8.

[0280] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 426, 454, and 398, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 426, 454, and 398, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-9.

[0281] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 426, 387, and 399, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 426, 387, and 399, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-10.

[0282] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 432, 455, and 400, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 432, 455, and 400, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-11.

[0283] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 433, 456, and 401, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 433, 456, and 401, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-12.

[0284] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 434, 362, and 402, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 434, 362, and 402, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-13.

[0285] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 361, 457, and 403, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 361, 457, and 403, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-14.

[0286] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 361, 458, and 404, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 361, 458, and 404, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-15.

[0287] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 361, 459, and 405, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 361, 459, and 405, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-16.

[0288] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 include SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 361, 388, and 406. In some embodiments, the antibody contains the same VH CDR as G9.2-17.

[0289] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs: 361, 388, and 407, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-17mut6.

[0290] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 430, 363, and 408, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 430, 363, and 408, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-18.

[0291] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 430, 460, and 409, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 430, 460, and 409, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-19.

[0292] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 429, 461, and 410, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 each consist of SEQ ID NOs. 429, 461, and 410, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-20.

[0293] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 429, 462, and 411, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-21.

[0294] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise sequence numbers 428, 463, and 412, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-22.

[0295] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 428, 464, and 413, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-23.

[0296] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 428, 465, and 414, respectively. In some embodiments, the antibody includes the same VH CDR as G9.2-24.

[0297] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 427, 466, and 415, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 427, 466, and 415. In some embodiments, the antibody contains the same VH CDR as G9.2-25.

[0298] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 361, 389, and 416, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-26.

[0299] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs: 361, 388, and 417, respectively. In some embodiments, the antibody comprises the same VH CDR as the G9.2-low affinity binder.

[0300] Heavy chain variable region and light chain variable region derived from clone 9.2 In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 341, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 424, 446, and 390, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 341, and SEQ ID NOs. 424, 446, and 390. In one particular embodiment, the antibody comprises the same VL and VH CDRs as in G9.2-1.

[0301] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 431, 447, and 391, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 431, 447, and 391. In one particular embodiment, the antibody comprises the same VL and VH CDRs as in G9.2-2.

[0302] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 333, and the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 431, 448, and 392. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 431, 448, and 392. In one particular embodiment, the antibody includes the same VL and VH CDRs as in G9.2-3.

[0303] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 342, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 431, 449, and 393, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 342, and SEQ ID NOs. 431, 449, and 393. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-4.

[0304] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 343, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 431, 450, and 394, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 343, and SEQ ID NOs. 431, 450, and 394. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-5.

[0305] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 344, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 431, 451, and 395. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 344, and SEQ ID NOs. 431, 451, and 395. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-6.

[0306] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 345, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 425, 452, and 396. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 345, and SEQ ID NOs. 425, 452, and 396. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-7.

[0307] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 346, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 245, 453, and 397. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 346, and SEQ ID NOs. 245, 453, and 397. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-8.

[0308] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 347, and the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 426, 454, and 398. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 347, and SEQ ID NOs. 426, 454, and 398. In one particular embodiment, the antibody includes the same VL and VH CDRs as G9.2-9.

[0309] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 348, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 426, 387, and 399, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 348, and SEQ ID NOs. 426, 387, and 399. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-10.

[0310] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 349, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 432, 455, and 400, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 349, and SEQ ID NOs. 432, 455, and 400. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-11.

[0311] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 350, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 433, 456, and 401, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 350, and SEQ ID NOs. 433, 456, and 401. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-12.

[0312] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 341, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 434, 362, and 402, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 341, and SEQ ID NOs. 434, 362, and 402. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-13.

[0313] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 457, and 403. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 361, 457, and 403. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-14.

[0314] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 343, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 458, and 404, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 343, and SEQ ID NOs. 361, 458, and 404. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-15.

[0315] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 459, and 405. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 361, 459, and 405. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-16.

[0316] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, and SEQ ID NOs. 361, 388, and 406. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-17.

[0317] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 388, and 404, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, and SEQ ID NOs. 361, 388, and 404. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-17mut6.

[0318] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 430, 363, and 408, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 333, and SEQ ID NOs. 430, 363, and 408. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-18.

[0319] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 328, 329, and 354, and the heavy chain variable regions CDR1, CDR2, and CDR3 each include SEQ ID NOs. 430, 460, and 409. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 consist of SEQ ID NOs. 328, 329, and 354, and SEQ ID NOs. 430, 460, and 409. In one particular embodiment, the antibody includes the same VL and VH CDRs as G9.2-19.

[0320] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 429, 461, and 410, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, and SEQ ID NOs. 429, 461, and 410. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-20.

[0321] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 355, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 429, 462, and 411, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 355, and SEQ ID NOs. 429, 462, and 411. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-21.

[0322] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 356, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 428, 463, and 412, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 356, and SEQ ID NOs. 428, 463, and 412. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-22.

[0323] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 357, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 428, 464, and 413, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 357, and SEQ ID NOs. 428, 464, and 413. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-23.

[0324] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 358, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 428, 465, and 414, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 358, and SEQ ID NOs. 428, 465, and 414. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-24.

[0325] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 359, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 427, 466, and 415, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 359, and SEQ ID NOs. 427, 466, and 415. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-25.

[0326] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 360, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 389, and 416, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 360, and SEQ ID NOs. 361, 389, and 416. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-26.

[0327] In some embodiments, the anti-galectin-9 antibody or its binding moiety comprises heavy chain and light chain variable regions, where the light chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 361, 388, and 417, respectively. In some embodiments, the light chain and heavy chain variable regions CDR1, CDR2, and CDR3 each comprise SEQ ID NOs. 328, 329, and 352, and SEQ ID NOs. 361, 388, and 417. In one particular embodiment, the antibody comprises the same VL and VH CDRs as the G9.2-low affinity binder.

[0328] Sequence identity In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The corresponding V of an antibody or its antigen-binding moiety selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder L Compared to CDRs, the light chain CDRs may have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) individually or as a whole. In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The corresponding V of an antibody or its antigen-binding moiety selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder H Compared to the CDR, the heavy chain CDR may have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) individually or as a whole.

[0329] In some embodiments, the anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) is G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The corresponding V of an antibody or its antigen-binding moiety selected from G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-Low Affinity Binder L CDR and V H The CDR may include light chain CDRs and heavy chain CDRs having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity, individually or as a whole, compared to the CDR.

[0330] In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 328. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs. 341-360.

[0331] In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequence shown in SEQ ID NOs. 361, 424-434. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VH CDR2 amino acid sequence selected from SEQ ID NOs. 362, 363, 387-389 and 446-466. In some embodiments, an anti-galectin-9 antibody (e.g., specific to CRD1 and / or CRD2) may contain a VH CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417.

[0332] Accordingly, in some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety is: (a) a VL CDR1 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR1 amino acid sequence shown in SEQ ID NO: 328; (b) a VL CDR2 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VL CDR2 amino acid sequence shown in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to a VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360; (d) VH CDR1 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to the VH CDR1 amino acid sequences shown in SEQ ID NOs. 361, 424-434; (e) VH CDR2 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to VH CDR2 amino acid sequences selected from SEQ ID NOs. 362, 363, 387-389 and 446-466; (f) VH CDR3 amino acid sequences having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to VH CDR1 amino acid sequences selected from SEQ ID NOs. 390-417 Contains the CDR3 amino acid sequence.

[0333] In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with respect to the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 352, respectively. In some embodiments, the VL CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with respect to the VL CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17. In some embodiments, the anti-galectin-9 antibody or its binding moiety includes heavy chain and light chain variable regions, where the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs. 361, 388, and 406, respectively. In some embodiments, the VH CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.In some embodiments, the anti-galectin-9 antibody or its binding portion includes heavy chain and light chain variable regions, where the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 328, 329, and 352, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 each have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NOs. 361, 388, and 406. In one particular embodiment, the VL CDR1, CDR2, and CDR3, and VH CDR1, CDR2, and CDR3 amino acid sequences of the antibody have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1, CDR2, and CDR3, and VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.

[0334] Epitope and constant region In some embodiments, the anti-galectin-9 antibodies described herein bind to the same epitope as any of the exemplary antibodies described herein (e.g., any of SEQ ID NOs. 7-87, or antibodies containing their CDRs), or compete with the exemplary antibodies for binding to the galectin-9 antigen. “Epitope” refers to a site on the target antigen that is recognized and bound by the antibody. The site may consist entirely of amino acid components, entirely of chemical modifications of amino acids in a protein (e.g., glycosyl moieties), or a combination thereof. Overlapping epitopes contain at least one common amino acid residue. Epitopes are typically linear, 6-15 amino acid lengths. Alternatively, epitopes can be three-dimensional structures. The epitopes to which antibodies bind can be determined by common techniques, such as epitope mapping (see, for example, the following description). Antibodies that bind to the same epitopes as the exemplary antibodies described herein may bind to the exact same epitopes as the exemplary antibodies or to substantially overlapping epitopes (e.g., including fewer than 3 non-overlapping amino acid residues, fewer than 2 non-overlapping amino acid residues, or only 1 non-overlapping amino acid residue). Whether the two antibodies compete with each other for binding to a congener antigen can be determined by competition assays well known in the art.

[0335] In some embodiments, an anti-galectin-9 antibody may bind, at least a segment thereof, to an epitope within the CRD1 of the galectin-9 protein (e.g., human galectin-9 or mouse galectin-9). In some embodiments, the antibody may bind completely to an epitope within the CRD1 of the galectin-9 protein. In some embodiments, the antibody may bind partially to an epitope within the CRD1 of the galectin-9 protein. In some embodiments, the epitope to which the anti-galectin antibody binds is a linear epitope. In some embodiments, the epitope to which the anti-galectin antibody binds is a structural epitope.

[0336] In some embodiments, an anti-galectin-9 antibody may bind, at least a segment thereof, to an epitope within the CRD2 of the galectin-9 protein (e.g., human galectin-9 or mouse galectin-9). In some embodiments, an anti-galectin-9 antibody may bind completely to an epitope within the CRD2 of the galectin-9 protein. In some specific embodiments where an anti-galectin-9 antibody partially or completely binds to an epitope within the CDR2, the antibody binds to an epitope containing at least residue W309. In some specific embodiments where an anti-galectin-9 antibody partially or completely binds to an epitope within the CDR2, the epitope to which the anti-galectin-9 antibody binds does not contain one or more of R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO: 1. In some embodiments, the epitope to which the anti-galectin antibody binds is a linear epitope containing residue W309. In some embodiments, the epitope to which the anti-galectin antibody binds is a structural epitope containing W309.

[0337] In some cases, the anti-galectin-9 antibody is the same as the exemplary antigen described herein. H and / or V L Includes CD-R. Same V H and / or V L Two antibodies having a CDR are considered identical if their CDRs are determined by the same approach (e.g., the Kabat or Chothia method known in the art). Such anti-galectin-9 antibodies are considered identical compared to the exemplary antibodies described herein. H , same V L They may have, or both.

[0338] Two heavy-chain variable regions (or two light-chain variable regions) having the same CDR means that the CDRs in those two heavy-chain variable regions (or light-chain variable regions) are identical, as determined by the same numbering scheme. Exemplary numbering schemes for determining antibody CDRs include the "Kabat" numbering scheme (Kabat et al. (1991), 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.), the "Chothia" numbering scheme (Al-Lazikani et al., (1997) JMB 273,927-948), the "Contact" numbering scheme (MacCallum et al., J. Mol. Biol. 262:732-745 (1996)), the "IMGT" numbering scheme (Lefranc MP et al., Dev Comp Immunol, 2003 January; 27(1): 55-77), and the "AHo" numbering scheme (Honegger A and Pluckthun A, J Mol Biol, 2001 Jun. 8; 309(3):657-70). As is known to those skilled in the art, the CDR regions of the exemplary anti-pKal antibodies and anti-FXII antibodies identified herein are determined by the “Chothia” numbering scheme used as an example.

[0339] Furthermore, any functional variant of any of the exemplary anti-galectin-9 antibodies disclosed herein is also within the scope of this disclosure. Such functional variants are substantially similar to the exemplary antibodies both structurally and functionally. The functional variants are substantially the same as the exemplary antibodies. H and V L It includes a CDR. For example, it may contain mutations in as few as five amino acid residues (e.g., 4, 3, 2, or 1) within the entire CDR region of the antibody, and with substantially similar affinity (e.g., K of the same order). DIt binds to the same epitope of galectin-9 (which has the value). Alternatively, or in addition to that, amino acid residue mutations are conserved amino acid residue substitutions. As used herein, “conservative amino acid substitution” means an amino acid substitution that does not change the relative charge or size properties of the protein to which the amino acid substitution is made. Mutants can be prepared according to methods for modifying polypeptide sequences that are known to those skilled in the art, as can be found, for example, in the references compiling such methods (e.g., Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, or Current Protocols in Molecular Biology, FM Ausubel, et al., eds., John Wiley & Sons, Inc., New York). Conservative amino acid substitutions include substitutions made between amino acids in the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D

[0340] The "identity percentage" of two amino acid sequences is determined using the Karlin and Altschul algorithm (Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified by Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-77, 1993). Such algorithms are incorporated into Altschul et al.'s NBLAST and XBLAST programs (version 2.0) (Altschul, et al. J. Mol. Biol. 215:403-10, 1990). BLAST protein search can be performed using the XBLAST program (score=50, word length=3) to obtain amino acid sequences homologous to the target protein molecule. If a gap exists between two sequences, Gapped BLAST can be used, as described by Altschul et al., "Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997". When using the BLAST and Gapped BLAST programs, the default parameters of each program (e.g., XBLAST and NBLAST) can be used. The anti-galectin-9 antibody may also contain a heavy chain variable region framework derived from a subclass of germline VH fragments. Such germline VH regions are well known in the field. See, for example, the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php.For example, the IGHV1 subfamily (e.g., IGHV1-2, IGHV1-3, IGHV1-8, IGHV1-18, IGHV1-24, IGHV1-45, IGHV1-46, IGHV1-58, and IGHV1-69), the IGHV2 subfamily (e.g., IGHV2-5, IGHV2-26, and IGHV2-70), and the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, IGHV3 Examples include IGHV3-33, IGHV3-43, IGHV3-48, IGHV3-49, IGHV3-53, IGHV3-64, IGHV3-66, IGHV3-72, and IGHV3-73, IGHV3-74), the IGHV4 subfamily (e.g., IGHV4-4, IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-59, IGHV4-61, and IGHV4-B), the IGHV subfamily (e.g., IGHV5-51, or IGHV6-1), and the IGHV7 subfamily (e.g., IGHV7-4-1).

[0341] Alternatively, or in addition to the above, the anti-galectin-9 antibody may include a light chain variable region containing a framework derived from germline Vκ fragments. Examples include the IGKV1 framework (e.g., IGKV1-05, IGKV1-12, IGKV1-27, IGKV1-33, or IGKV1-39), the IGKV2 framework (e.g., IGKV2-28), the IGKV3 framework (e.g., IGKV3-11, IGKV3-15, or IGKV3-20), and the IGKV4 framework (e.g., IGKV4-1). In other examples, the anti-galectin-9 antibody may include a light chain variable region containing a framework derived from germline Vλ fragments. For example, the IGλ1 framework (e.g., IGλV1-36, IGλV1-40, IGλV1-44, IGλV1-47, IGλV1-51), the IGλ2 framework (e.g., IGλV2-8, IGλV2-11, IGλV2-14, IGλV2-18, IGλV2-23), the IGλ3 framework (e.g., IGλV3-1, IGλV3-9, IGλV3-10, IGλV3-12, IGλV3-16, IGλV3-19, IGλV3-21, IGλV3-25, IGλV3-27), I Examples include the Gλ4 framework (e.g., IGλV4-3, IGλV4-60, IGλV4-69), the IGλ5 framework (e.g., IGλV5-39, IGλV5-45), the IGλ6 framework (e.g., IGλV6-57), the IGλ7 framework (e.g., IGλV7-43, IGλV7-46), the IGλ8 framework (e.g., IGλV8-61), the IGλ9 framework (e.g., IGλV9-49), or the IGλ10 framework (e.g., IGλV10-54).

[0342] In some embodiments, the heavy chain of any of the anti-galectin-9 antibodies described herein may further include a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region may be of any suitable origin (e.g., human, mouse, rat, or rabbit). In one particular example, the heavy chain constant region is derived from human IgG (gamma heavy chain) of any IgG subfamily described herein.

[0343] In some embodiments, the heavy chain constant region of the antibodies described herein may include a single domain of the constant region (e.g., CH1, CH2, or CH3) or any combination of single domains (e.g., SEQ ID NOs: 419-423). In some embodiments, the light chain constant region of the antibodies described herein may include a single domain of the constant region (e.g., CL) (e.g., SEQ ID NO: 418). Exemplary light and heavy chain sequences are listed below. The hIgG1 LALA sequence contains two mutations (L234A and L235A) that suppress FcgR binding and the P329G mutation, eliminate complement C1q binding, and thereby eliminate all immunoeffector functions. These mutations are indicated in underline and bold in the sequences listed below. The hIgG4 Fab Arm exchange mutant sequence contains a mutation to suppress the Fab Arm exchange (S228P), indicated in underline and bold. The light chain sequences of G9.2-17 are identical in all G9.2-17 constructs. Similarly, the light chain sequence of G9.1-8m13 is identical in all G9.1-8m13 constructs. The residues in bold are the VH and VL regions. The IL2 signal sequence (MYRMQLLSCIALSLALVTNS; SEQ ID NO: 469) is located at the N-terminus of the variable region. It is used in expression vectors that are cleaved during secretion and is therefore not present in mature antibody molecules. Mature proteins (post-secretion) begin with "EVQ" in the heavy chain and "DIM" in the light chain.

[0344] Exemplary heavy and light chain examples. TIFF2026062750000018.tif102169TIFF2026062750000019.tif229169TIFF2026062750000020.tif207169

[0345] In some embodiments, the anti-galectin-9 antibody has a light chain containing, essentially consisting of, or solely consisting of, SEQ ID NO: 108. In some embodiments, the anti-galectin-9 antibody has a heavy chain containing, essentially consisting of, or solely consisting of, one sequence selected from the group consisting of SEQ ID NOs: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galectin-9 antibody has a light chain containing, essentially consisting of, or solely consisting of, SEQ ID NO: 108, and a heavy chain containing, essentially consisting of, or solely consisting of, one sequence selected from the group consisting of SEQ ID NOs: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galectin-9 antibody has a light chain containing SEQ ID NO: 108 and a heavy chain containing one of the sequences selected from the group consisting of SEQ ID NOs: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galectin-9 antibody has a light chain consisting essentially of SEQ ID NO: 108 and a heavy chain consisting essentially of one of the sequences selected from the group consisting of SEQ ID NOs: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galectin-9 antibody has a light chain consisting only of SEQ ID NO: 108 and a heavy chain consisting only of one of the sequences selected from the group consisting of SEQ ID NOs: 295, 242, 189, 157, 210, 263, 316, and 136.

[0346] In some embodiments, the constant region is derived from human IgG4. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region comprising SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region comprising SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) to SEQ ID NO: 421. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region comprising SEQ ID NO: 421.

[0347] In some embodiments, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region containing SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region consisting of SEQ ID NO: 418. In some embodiments, the constant region is derived from human IgG1. In some embodiments, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG1 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 419. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG1 constant region containing SEQ ID NO: 419. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region consisting of SEQ ID NO: 419. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG1 constant region containing SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region consisting of SEQ ID NO: 418.

[0348] In some embodiments, the anti-galectin-9 antibody includes a modified constant region. In some embodiments, the anti-galectin-9 antibody includes a modified constant region that is immunologically inactive, for example, does not trigger complement-mediated lysis or stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC activity can be evaluated using the method disclosed in U.S. Patent No. 5,500,362. In other embodiments, the constant region is modified as described in "Eur. J. Immunol. (1999) 29:2613-2624", PCT application "PCT / GB99 / 01441", and / or UK Patent Application No. 9809951.8. In some embodiments, the IgG4 constant region is a mutant with reduced heavy chain exchange. In some embodiments, the constant region is derived from the human IgG4 Fab Arm exchange mutant S229P. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 422. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region containing SEQ ID NO: 422. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG4 constant region consisting of SEQ ID NO: 422. In several embodiments, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region containing SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region consisting of SEQ ID NO: 418. In several embodiments, the IgG is a variant having minimal Fc receptor engagement. In one example, the constant region is derived from human IgG1 LALA.In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG1 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG1 constant region containing SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody includes a heavy chain IgG1 constant region consisting of SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG1 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG1 constant region containing SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody includes a light chain IgG4 constant region consisting of SEQ ID NO: 418.

[0349] In some embodiments, the anti-galectin-9 antibody has a light chain corresponding to SEQ ID NOs. 88-98 (anti-galectin-9 antibody bound to CRD1) and SEQ ID NOs. 99-115 (anti-galectin-9 antibody bound to CRD2); with respect to the heavy chain, the amino acid sequences of the exemplary heavy chains correspond to SEQ ID NOs. 116-140 (hIgG1); 169-193 (hIgG1 LALA); 222-246 (hIgG4); 275-299 (hIgG4 exchange variant) (anti-galectin-9 antibody bound to CRD1), and SEQ ID NOs. 141-168 (hIgG1); 194-221 (hIgG1 LALA); 247-274 (hIgG4); 300-327 (hIgG4 exchange variant) (anti-galectin-9 antibody bound to CRD2). The IgG LALA, IgG4 exchange variant is located in the heavy chain; therefore, the light chain is the same for all IgG1 and IgG4 sequences described herein. In some embodiments, the amino acid sequences of exemplary anti-galectin antibody light chains correspond to the sequences shown in SEQ ID NOs. 88-98 and SEQ ID NOs. 99-115.

[0350] Light chain derived from clone 9.1 In some embodiments, the light chain of the anti-galectin-9 antibody comprises an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any of the light chains (or their variable regions) shown herein (e.g., the light chain sequences shown in SEQ ID NOs. 88 to 98). In some embodiments, the light chain of the anti-galectin-9 antibody comprises an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any of the light chains (e.g., the light chain sequences shown herein) (e.g., the light chain sequences shown in SEQ ID NOs. 88 to 98). In some embodiments, the light chain of the anti-galectin-9 antibody comprises an amino acid sequence shown in SEQ ID NOs. 88 to 98.

[0351] In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 88. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 89. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 90. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 91. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 92. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 93. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 94. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 95. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 96. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 97. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the light chain sequence of SEQ ID NO: 98.

[0352] In some embodiments, the light chain of the anti-galectin-9 antibody includes an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the light chain sequence (or its variable region) shown in SEQ ID NO: 95. In some embodiments, the light chain of the anti-galectin-9 antibody consists of an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) with respect to the light chain sequence shown in SEQ ID NO: 95. In some embodiments, the light chain of the anti-galectin-9 antibody includes the amino acid sequence shown in SEQ ID NO: 95 (or its variable region). In some embodiments, the light chain of the anti-galectin-9 antibody consists of the amino acid sequence shown in SEQ ID NO: 95.

[0353] Heavy chain derived from clone 9.1 In some embodiments, the amino acid sequences of the heavy chains of exemplary anti-galectin antibodies correspond to the sequences shown in SEQ ID NOs: 116-140 (hIgG1); 169-193 (hIgG1 LALA); 222-246 (hIgG4); 275-299 (hIgG4 exchange variant) (anti-galectin-9 antibody conjugated to CRD1). In some embodiments, the heavy chains of anti-galectin-9 antibodies include amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any of the sequences shown in the heavy chains (or their variable regions) shown herein, for example, SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibody conjugated to CRD1). In some embodiments, the heavy chain of the anti-galectin-9 antibody consists of an amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any of the sequences shown herein, for example, SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibodies that bind to CRD1).

[0354] In some embodiments, the heavy chain of the anti-galectin-9 antibody includes the heavy chain amino acid sequence shown in SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibody that binds to CRD1). In some embodiments, the heavy chain of the anti-galectin-9 antibody consists of the amino acid sequence shown in SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibody that binds to CRD1).

[0355] In some embodiments, the constant region is IgG1. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 116. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 117. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 118. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 119. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 120. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 121. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 122. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 123. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 124. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 125. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 126. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 127. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 128. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 129. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 130. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 131. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 132. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 133.In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 134. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 135. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 136. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 137. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 138. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 139. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 140.

[0356] In some embodiments, the constant region is IgG1 LALA. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 169. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 170. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 171. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 172. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 173. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 174. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 175. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 176. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 177. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 178. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 179. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 180. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 181. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 182. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 183. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 184. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 185. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 186.In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 187. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 188. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 189. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 190. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 191. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 192. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 193.

[0357] In some embodiments, the constant region is IgG4. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 222. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 223. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 224. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 225. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 226. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 227. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 228. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 229. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 230. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 231. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 232. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 233. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 234. In some embodiments, the anti-galectin-9 antibody or its antigen-binding moiety includes the heavy chain sequence of SEQ ID NO: 235. In some embodiments, the anti-galectin...

Claims

1. An isolated anti-galectin-9 antibody that binds to an epitope in the glycan recognition domain (CRD) of the galectin-9 polypeptide.

2. The isolated antibody according to claim 1, wherein the anti-galectin-9 antibody binds to a human galectin-9 polypeptide.

3. The isolated antibody according to claim 1, wherein the anti-galectin-9 antibody binds to both human galectin-9 polypeptide and non-human galectin-9 polypeptide.

4. The isolated antibody according to claim 3, wherein the non-human galectin-9 polypeptide is mouse galectin-9 or rat galectin-9.

5. An isolated antibody according to any one of claims 1 to 4, wherein the CRD is CRD1.

6. The isolated antibody according to claim 5, wherein CRD1 consists of the amino acid sequence of SEQ ID NO:

3.

7. The aforementioned antibodies are G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G The isolated antibody according to claim 6, which binds to the same epitope as a reference antibody selected from the group consisting of 9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, G9.1-8m14, G9.1-9, G9.1-10, and G9.1-11, or competes with the reference antibody for binding to CRD1.

8. The antibody comprises a heavy chain variable domain (V) including heavy chain complementarity determination region 1 (CDR1), heavy chain complementarity determination region 2 (CDR2), and heavy chain complementarity determination region 3 (CDR3). H ) which is at least 90% identical overall to the heavy chain CDR of the reference antibody; and / or, The antibody contains a light chain variable domain (V) comprising light chain CDR1, light chain CDR2, and light chain CDR3. L ) includes, which is at least 90% identical overall to the light chain CDR of the reference antibody. The isolated antibody according to claim 7.

9. The aforementioned antibody has at least 85% the same VH as the aforementioned reference antibody. H , and / or VL that is at least 85% the same as the VL of the reference antibody. L The isolated antibody according to claim 7 or 8, comprising:

10. The isolated antibody according to claim 7, wherein the antibody comprises the same heavy chain CDR and / or the same light chain CDR as the reference antibody.

11. The antibody is the same as the reference antibody. H and / or the same V L The isolated antibody according to claim 10, comprising:

12. The isolated antibody according to claim 6, wherein the antibody is selected from the group consisting of G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-8m1, G9.1-8m2, G9.1-8m3, G9.1-8m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, G9.1-8m14, G9.1-9, G9.1-10, and G9.1-11.

13. The antibody contains the V sample code 21. L Region and V including sequence number 22 H An isolated antibody according to any one of claims 1 to 12, having a region.

14. The antibody has a V region containing SEQ ID NO: 21 and a V region containing SEQ ID NO: 86, and is the isolated antibody according to any one of claims 1 to 12. L region, and a V H region containing SEQ ID NO:

86.

15. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 337 L An isolated antibody according to any one of claims 1 to 12, having CDR3.

16. The antibody contains SEQ ID NO: 361 H V containing CDR1, sequence number 364 H CDR2 and V including sequence number 374 H An isolated antibody according to any one of claims 1 to 12, having CDR3.

17. The antibody contains SEQ ID NO: 361 H V containing CDR1, sequence number 366 H CDR2 and V including sequence number 383 H An isolated antibody according to any one of claims 1 to 12, having CDR3.

18. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 337 L V has CDR3 and includes SEQ ID NO: 361 H V containing CDR1, sequence number 364 H CDR2 and V including sequence number 374 H An isolated antibody according to any one of claims 1 to 12, having CDR3.

19. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 337 L V has CDR3 and includes SEQ ID NO: 361 H V containing CDR1, sequence number 366 H CDR2 and V including sequence number 383 H An isolated antibody according to any one of claims 1 to 12, having CDR3.

20. The isolated antibody according to any one of claims 1 to 4, wherein the CRD is CRD2.

21. The isolated antibody according to claim 20, wherein the CRD2 comprises the amino acid sequence of SEQ ID NO:

4.

22. The isolated antibody according to claim 20 or 21, wherein the antibody binds to an epitope in the CRD2, and the epitope comprises residue W309.

23. The isolated antibody according to claim 22, wherein the epitope does not contain one or more residues selected from R253, R271, Y330, R334, Y236, and R341.

24. The aforementioned antibodies are G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6 The isolated antibody according to claim 21, which binds to the same epitope as a reference antibody selected from the group consisting of G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder, or competes with the reference antibody for binding to CRD2.

25. The antibody comprises a heavy chain variable domain (V) including heavy chain complementarity determination region 1 (CDR1), heavy chain complementarity determination region 2 (CDR2), and heavy chain complementarity determination region 3 (CDR3). H ) which is at least 90% identical overall to the heavy chain CDR of the reference antibody; and / or, The antibody contains a light chain variable domain (V) comprising light chain CDR1, light chain CDR2, and light chain CDR3. L ) includes, which is at least 90% identical overall to the light chain CDR of the reference antibody. The isolated antibody according to claim 24.

26. The antibody is the V of the reference antibody. H and at least 85% identical V H , and / or the V of the reference antibody L and at least 85% identical V L The isolated antibody according to claim 24 or 25, comprising:

27. The isolated antibody according to claim 21, wherein the antibody is selected from the group consisting of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2-low affinity binder.

28. The antibody contains SEQ ID NO: 54 L Region and V including sequence number 55 H An isolated antibody according to any one of claims 20 to 27, having a region.

29. The antibody contains SEQ ID NO: 54 L Region and V including sequence number 56 H An isolated antibody according to any one of claims 20 to 27, having a region.

30. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 352 L An isolated antibody according to any one of claims 20 to 27, having CDR3.

31. The antibody contains SEQ ID NO: 361 H V containing CDR1, sequence number 388 H CDR2 and V including sequence number 406 H An isolated antibody according to any one of claims 20 to 27, having CDR3.

32. The antibody contains SEQ ID NO: 361 H V containing CDR1, sequence number 388 H CDR2 and V including sequence number 407 H An isolated antibody according to any one of claims 20 to 27, having CDR3.

33. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 352 L V has CDR3 and includes SEQ ID NO: 361 H V containing CDR1, sequence number 388 H CDR2 and V including sequence number 406 H An isolated antibody according to any one of claims 20 to 27, having CDR3.

34. The antibody contains SEQ ID NO: 328 L V containing CDR1, Sequence ID 329 L CDR2 and V including sequence number 352 L V has CDR3 and includes SEQ ID NO: 361 H V containing CDR1, sequence number 388 H CDR2 and V including sequence number 407 H An isolated antibody according to any one of claims 20 to 27, having CDR3.

35. The aforementioned antibody, V H 3-48 heavy chain framework; and / or, V κ An isolated antibody according to any one of claims 1 to 34, comprising a light chain framework 1-39.

36. The isolated antibody according to any one of claims 1 to 35, wherein the antibody is a full-length antibody or an antigen-binding fragment thereof.

37. The isolated antibody according to claim 36, wherein the antibody is a full-length antibody and is an IgG molecule.

38. The isolated antibody according to claim 37, wherein the IgG molecule is an IgG1 or IgG4 molecule.

39. The isolated antibody according to claim 38, wherein the antibody includes a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 419, 420, 421, 422, or 423.

40. The isolated antibody according to claim 37, wherein the antibody is a Fab or a single-chain antibody.

41. The isolated antibody according to any one of claims 1 to 40, wherein the antibody is a human antibody or a humanized antibody.

42. An isolated nucleic acid encoding an anti-galectin-9 antibody according to any one of claims 1 to 41, or a set of nucleic acids encoding an anti-galectin-9 antibody as a whole according to any one of claims 1 to 41.

43. The isolated nucleic acid or nucleic acid set according to claim 42, wherein the nucleic acid or set of nucleic acids is arranged on one or two vectors.

44. The isolated nucleic acid or nucleic acid set according to claim 43, wherein the one or two vectors are one or two expression vectors.

45. A host cell comprising an isolated nucleic acid or nucleic acid set according to any one of claims 42 to 44.

46. A pharmaceutical composition comprising an anti-galectin-9 antibody according to any one of claims 1 to 41, or a nucleic acid or nucleic acid set according to any one of claims 42 to 44, and a pharmaceutically acceptable carrier.

47. A method for inhibiting galectin-9 mediated cell signaling in a subject, comprising administering an effective amount of the pharmaceutical composition described in claim 46 to a subject in need thereof.

48. The method according to claim 47, wherein the subject is a human patient who has, is suspected of having, or is at risk of having, an autoimmune disease, a solid tumor, a microbial disease, a hematological malignancy, or an allergic disease.

49. The method according to claim 47, wherein the subject is a human patient having an autoimmune disease selected from the group consisting of rheumatic diseases, autoimmune respiratory diseases, autoimmune metabolic disorders and / or endocrine disorders, and fibrotic diseases.

50. The method according to claim 47, wherein the subject is a human patient having a solid tumor selected from the group consisting of pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, bile duct cancer, breast cancer, lung cancer, upper and lower gastrointestinal malignancies, squamous cell head and neck cancer, non-genitourinary cancer, ovarian cancer, and sarcoma.

51. The method according to claim 47, wherein the subject is a human patient having a hematological malignancy selected from the group consisting of acute lymphoblastic leukemia, chronic lymphoblastic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm.

52. The method according to any one of claims 47 to 51, further comprising administering to the subject an inhibitor of a checkpoint molecule, an activator of a costimulatory receptor, or an inhibitor of an innate immune cell target.

53. The method according to claim 52, wherein the checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM-3, and A2aR.

54. The method according to claim 53, wherein the costimulatory receptor is selected from the group consisting of OX40, GITR, CD137, CD40, CD27, and ICOS.

55. The method according to claim 52, wherein the innate immune cell target is selected from the group consisting of KIR, NKG2A, CD96, TLR, and IDO.

56. The method according to any one of claims 47 to 55, wherein an effective amount of the pharmaceutical composition is sufficient to block the interaction between galectin-9 and dectin-1.

57. The method according to any one of claims 47 to 55, wherein an effective amount of the pharmaceutical composition is sufficient to block the interaction between galectin-9 and Tim-3.

58. A method for eliminating diseased cells expressing galectin-9, comprising administering an effective amount of the pharmaceutical composition described in claim 46 to a subject having diseased cells expressing galectin-9.

59. The method according to claim 58, wherein the subject is a human patient having cancer cells expressing galectin-9 or pathological immune cells expressing galectin-9.

60. The method according to claim 58 or 59, wherein an effective amount of the pharmaceutical composition is sufficient to initiate antibody-dependent cell-mediated cytotoxicity (ADCC) against diseased cells expressing galectin-9.

61. A method for producing an anti-galectin-9 antibody, (i) culturing the host cells according to claim 45 under conditions that enable the expression of an anti-galectin-9 antibody; and (ii) Collect the anti-galectin-9 antibody produced in this manner from the cell culture. A method that includes this.

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