Anti-galectin-9 antibodies and uses thereof

Abstract

To provide anti-Galectin-9 antibodies, and methods of using anti-Galectin-9 antibodies for inhibiting a signaling pathway mediated by Galectin-9 or eliminating pathologic cells expressing Galectin-9.SOLUTION: The present invention provides an isolated anti-Galectin-9 antibody, wherein the antibody binds to an epitope in a carbohydrate recognition domain (CRD) of a Galectin-9 polypeptide.SELECTED DRAWING: None

Description

[Background technology]

[0001] Immune checkpoint blockade has demonstrated unprecedented success as a cancer treatment over the past few years. Antibodies are often used to block immune inhibitory pathways, such as the 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 several cancer types, anti-CTLA-4 and anti-PD-1 treatments have a response rate of 10–60% in treated patients, depending on the cancer type, and even when used in combination, they have yet to achieve a response rate of more than 60% (Kyvistborg et al., Enhancing Responses to Cancer Immunotherapy; Science. 2018 Feb 2;359(6375):516–517). Furthermore, many types of cancer are refractory to these treatments. As part of efforts to improve existing immunotherapies in the clinic, the field has begun to focus on the role of abnormalities in interferon signaling and upregulation of alternative checkpoints as potential causes of current treatment limitations. One such potential alternative checkpoint is T-cell immunoglobulin mucin-3 (Tim-3) / galectin-9 (see, e.g., 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 references therein).

[0002] Galectin-9 is a tandem repeat lectin consisting of two carbohydrate recognition domains (CRDs). It was first discovered and described in 1997 in patients with Hodgkin's lymphoma (HL) (Tureci et al., J. Biol. Chem. 1997, 272, 6416-6422). It exists in three isoforms and can be located intracellularly or extracellularly. Elevated levels of galectin-9 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 carcinoma, patients with high galectin-9 expression showed more advanced disease progression with larger tumor size and necrosis (Kawashima et al.; BJU Int. 2014;113:320-332). In melanoma (considered one of the most lethal cancers due to its aggressive metastasis and treatment resistance), galectin-9 was expressed in 57% of tumors and was significantly increased in the plasma of patients with advanced melanoma compared with healthy controls (Enninga et al., Melanoma Res. 2016 Oct;26(5):429-441). Numerous studies have demonstrated the utility of Gal-9 as a prognostic marker and, more recently, 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 to play an important role in many cellular processes, such as adhesion, cancer cell aggregation, apoptosis, and chemotaxis. Recent studies have demonstrated the role of galectin-9 in immune regulation in tumor support (e.g., through negative regulation of Th1-type responses, Th2 polarization, and macrophage polarization toward an M2 phenotype).This research also includes studies demonstrating that galectin-9 is involved in direct T cell inactivation through its interaction with the T-cell immunoglobulin and mucin protein 3 (TIM-3) receptor (Dardalhon et al., J Immunol., 2010, 185, 1383-1392; Sanchez-Fueyo et al., Nat Immunol., 2003, 4, 1093-1101). Galectin-9 has also been shown to play a role in polarizing T cell differentiation toward a tumor-suppressor phenotype, as well as promoting tolerogenic macrophage programming and adaptive immune suppression (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 antitumor immune responses 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 to 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] Thus, modulating the activity of galectin-9 and / or one or more of its receptors may provide a novel approach to cancer treatment, either alone or in combination with existing therapies. Described herein are novel human antibodies that bind to human galectin-9 and their therapeutic use in the treatment of cancer. Summary of the Invention

[0004] The present disclosure is based, at least in part, on the development of anti-galectin-9 antibodies that potently inhibit galectin-9-induced signaling. Such antibodies can inhibit galectin-9 signaling and / or eliminate galectin-9-positive pathological cells, thereby providing benefits in the treatment of galectin-9-associated diseases.

[0005] Accordingly, one aspect of the present disclosure provides isolated anti-galectin-9 antibodies that bind to an epitope in the carbohydrate recognition domain (CRD) of a galectin-9 polypeptide (e.g., a human galectin-9 polypeptide). In some embodiments, the anti-galectin-9 antibodies described herein can bind to both a human galectin-9 polypeptide and a non-human galectin-9 polypeptide (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, e.g., with similar or different affinities. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the CRD1 region. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the CRD1 region, which CRD1 region 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 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- 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 antibody disclosed herein is an antibody 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 comprise the same heavy chain complementarity determining regions (CDRs) and the same light chain CDRs as a reference antibody (e.g., any of the reference antibodies provided herein). In one particular example, the anti-galectin-9 antibody comprises the same heavy chain variable region and the same light chain variable region as a reference antibody (e.g., any of the reference antibodies provided above and elsewhere herein).

[0007] In some embodiments, the anti-galectin-9 antibody comprises, consists essentially of, or consists of SEQ ID NO:21. L In some embodiments, the anti-galectin-9 antibody has the sequence V that comprises, consists essentially of, or consists of SEQ ID NO:86. H In some embodiments, the anti-galectin-9 antibody has the sequence V comprising SEQ ID NO: 21. L V comprising the sequence SEQ ID NO: 86 H In some embodiments, the anti-galectin-9 antibody has the sequence V consisting essentially of SEQ ID NO:21. L and V consisting essentially of SEQ ID NO: 86 H In some embodiments, the anti-galectin-9 antibody has the V sequence consisting solely of SEQ ID NO: 21. L V consisting only of sequence and SEQ ID NO: 86 H It has an array.

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

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

[0010] In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the galectin-9 CRD2 region. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the galectin-9 CRD2 region, which CRD2 region may have the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-galectin-9 antibodies disclosed herein bind to an epitope within the CRD2 region having the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-galectin-9 antibodies bind to an epitope within the galectin-9 CRD2 region that includes a tryptophan residue corresponding to residue W309 of SEQ ID NO: 1. In some embodiments, the anti-galectin-9 antibodies bind to an epitope within the galectin-9 CRD2 region that does not include 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 includes a tryptophan residue corresponding to residue W309 of SEQ ID NO: 1, but does not include one or more residues corresponding to R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO: 1. ... one or more of the following: 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, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, G9.2-27, G9.2-28, G9.2-29, G9.2-30, G9.2-31, G9.2-32, G9.2-33, G9. and 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. 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 G9.2-17mut6 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 a G9.2-17 antibody or a G9.2-17mut6 antibody. In some embodiments, the anti-galectin-9 antibody comprises, consists essentially of, or consists of SEQ ID NO:54. L In some embodiments, the anti-galectin-9 antibody has the sequence V that comprises, consists essentially of, or consists of SEQ ID NO:55. H In some embodiments, the anti-galectin-9 antibody has a V comprising SEQ ID NO: 54. L V comprising the sequence SEQ ID NO: 55 H In some embodiments, the anti-galectin-9 antibody has the sequence V consisting essentially of SEQ ID NO: 54. L and V consisting essentially of SEQ ID NO: 55 H In some embodiments, the anti-galectin-9 antibody has a V sequence consisting solely of SEQ ID NO: 54. L V consisting only of sequence and SEQ ID NO: 55 H In some embodiments, the antibody has a V comprising SEQ ID NO: 56. H In some embodiments, the antibody has the sequence V consisting essentially of or consisting only of SEQ ID NO:56. H In some embodiments, the isolated antibody has a V comprising SEQ ID NO: 54. L V comprising the sequence SEQ ID NO: 56 H In some embodiments, the isolated antibody has the sequence V consisting essentially of SEQ ID NO:54. Land V consisting essentially of SEQ ID NO: 56 H In some embodiments, the isolated antibody has a V consisting solely of SEQ ID NO:54. L V consisting only of sequence and SEQ ID NO: 56 H It has an array.

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

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

[0013] In some embodiments, the anti-galectin-9 antibody comprises heavy chain complementarity determining region 1 (CDR1), heavy chain complementarity determining region 2 (CDR2), and heavy chain complementarity determining region 3 (CDR3), all of which, taken together, are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the heavy chain CDRs of a reference antibody (e.g., any of the reference antibodies provided herein), and further comprises light chain CDR1, light chain CDR2, and light chain CDR3, which, taken together, are at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to the light chain CDRs of a reference antibody (e.g., any of the reference antibodies provided herein). In some examples, the anti-galectin-9 antibody may comprise the same heavy chain CDRs and the same light chain CDRs as the reference antibody described above. In one particular example, the anti-galectin-9 antibody may comprise 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 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 antigen-binding portion thereof, comprises 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: 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 antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein 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.

[0015] In some embodiments, the isolated anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, 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, 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. In some embodiments, the isolated anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain and a light chain variable region, wherein 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; and 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.

[0016] In some embodiments, the isolated anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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. 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 antigen-binding portion thereof, comprises a heavy chain and a 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. Thus, in some embodiments, an isolated anti-galectin-9 antibody, or antigen-binding portion thereof, 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 has a V Ha heavy chain variable region (V) that is at least 85% identical to H Alternatively or additionally, the anti-galectin-9 antibody may comprise a V L a light chain variable region (V) that is at least 85% identical to L ).

[0018] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region comprising SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody comprises a VL region consisting of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region consisting of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions comprising SEQ ID NOs: 54 and 55, respectively. In some specific embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises VL and VH regions comprising SEQ ID NOs: 54 and 55, respectively. In some embodiments, the anti-galectin-9 antibody is clone 9.2-17. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region comprising SEQ ID NO: 56. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions comprising SEQ ID NOs: 54 and 56, respectively. In some specific embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, 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 comprises a VL region comprising SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody comprises a VL region consisting of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody comprises a VH region comprising SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody, or an antigen-binding portion thereof, comprises a VH region consisting of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions comprising SEQ ID NOs: 21 and 86, respectively. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions comprising SEQ ID NOs: 21 and 86, respectively. In some embodiments, the anti-galectin-9 antibody is clone G9.1-8m13. In some embodiments, the anti-galectin-9 antibody comprises a VH region comprising SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody, or an antigen-binding portion thereof, comprises a VH region consisting of SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions comprising SEQ ID NOs: 21 and 22, respectively. In some embodiments, the anti-galectin-9 antibody comprises VL and VH regions consisting of SEQ ID NOs: 21 and 22, respectively. In some embodiments, the anti-galectin-9 antibody is clone G9.1-8.

[0020] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 comprises 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, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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, an anti-galectin-9 antibody comprises 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 comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galectin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27; and a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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 comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth 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 comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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 comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth 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 a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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.

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

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

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

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

[0028] In some embodiments, an anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, an anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises 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, an anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13 GMDY (SEQ ID NO: 468) (wherein X1 = Y or S, X2 = T, S, or deletion, X3 = Y, S, or deletion, X4 = S or deletion, X5 = W, S, or deletion, X6 = S or deletion, X7 = G, S, or deletion, X8 = G, T, S, or deletion, X9 = I, Y, S, or deletion, 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 binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 consists of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 consists of 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 binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 consists of X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13GMDY (SEQ ID NO: 468) (wherein X1 = Y or S, X2 = T, S, or deletion, X3 = Y, S, or deletion, X4 = S or deletion, X5 = W, S, or deletion, X6 = S or deletion, X7 = G, S, or deletion, X8 = G, T, S, or deletion, X9 = I, Y, S, or deletion, 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 binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 337, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-8m13. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the heavy chain variable region CDR1 comprises SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the heavy chain variable region CDR2 comprises SEQ ID NO: 366. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy 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 binding portion thereof, comprises heavy and light chain variable regions, and the heavy chain variable region CDR1 consists of SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the heavy chain variable region CDR2 consists of SEQ ID NO: 366.In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the heavy chain variable region CDR3 region consists of SEQ ID NO: 383. In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the anti-galectin-9 antibody comprises the same VH CDRs as G9.1-8m13. In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, respectively, and SEQ ID NOs: 361, 366, and 383, respectively. In one specific 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 binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 352. In some embodiments, an anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the anti-galectin-9 antibody comprises the same VL CDRs as G9.2-17. In some embodiments, an anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 388, and 406, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 388, and 406, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-17. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 388, and 406, respectively.In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively, and SEQ ID NOs: 361, 388, and 406, respectively. In one particular embodiment, the anti-galectin-9 antibody comprises the same VL and VH CDRs as G9.2-17.

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

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

[0033] In some embodiments of any of the anti-galectin antibodies provided herein, the heavy chain constant region of the anti-galectin-9 antibody is derived from human IgG (gamma heavy chain) of any of the IgG subfamilies 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 set forth in SEQ ID NOs: 88-98 and 99-115. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the light chain sequence of SEQ ID NO: 108. 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 therein) sequence identity to the light chain sequence set forth in SEQ ID NO: 95 (or the variable region thereof). 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 therein) sequence identity to the light chain sequence set forth in SEQ ID NO: 108 (or the variable region thereof). In some embodiments, the amino acid sequences of exemplary anti-galectin antibody heavy chains correspond to the sequences set forth 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 antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 136. In some embodiments, the IgG1 is a variant with minimal Fc receptor engagement. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 242. In some embodiments, the IgG4 is an IgG4 exchange mutant. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 295.

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

[0036] In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 136 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 189 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 242 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 295 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 157 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 210 (or the variable region thereof). In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 263 (or a variable region thereof).In some embodiments, the heavy 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 therein) sequence identity to the heavy chain sequence set forth in SEQ ID NO: 316 (or the variable region thereof). In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 95 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 136. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 95 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 189. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 95 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 242. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 95 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 295.

[0042] In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 108 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 157. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 108 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 210. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 108 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 263. In one embodiment, the anti-galectin-9 antibody comprises a light chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 108 and a heavy chain amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity 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 antibodies are Fab or single-chain antibodies. In any case, the antibodies may be human or humanized.

[0044] In another aspect, the present disclosure provides an isolated nucleic acid or set of nucleic acids encoding, or entirely encoding, any 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 (set 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 set of nucleic acids is located on one or two vectors. In some examples, the one or two vectors may be one or two expression vectors. Furthermore, the present disclosure provides a host cell comprising any of the isolated nucleic acids or set of nucleic acids encoding the anti-galectin-9 antibodies described herein.

[0045] Also provided herein is a method for producing an anti-galectin-9 antibody, the method comprising culturing a host cell described herein under appropriate conditions that allow expression of the antibody, and collecting the antibody thus produced from the cell culture (e.g., from the culture medium).

[0046] Additionally, the present disclosure provides pharmaceutical compositions comprising either an anti-galectin-9 antibody or a nucleic acid encoding such an antibody and a pharmaceutically acceptable carrier.

[0047] In yet another aspect, the disclosure features a method of inhibiting galectin-9-mediated cell signaling in a subject, the method comprising administering to a subject in need thereof 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 any of the anti-galectin-9 antibodies disclosed herein, or a pharmaceutical composition comprising such. In some embodiments, the subject in need thereof is a human patient having, suspected of having, or at risk of having an autoimmune disease, a solid cancer, 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), an autoimmune respiratory disease, an autoimmune metabolic and / or endocrine disorder (e.g., type 1 diabetes), or a fibrotic disease. 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 cancer, hepatocellular carcinoma, ovarian cancer, sarcoma, mesothelioma, glioblastoma, esophageal cancer, bladder cancer, urothelial carcinoma, renal cancer, cervical cancer, and endometrial cancer. Exemplary hematologic malignancies include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, and acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndromes or myeloproliferative neoplasms, and 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, the effective amount of the pharmaceutical composition is sufficient to block the interaction between galectin-9 and CD206. Alternatively or additionally, but not limited to, the effective amount of the pharmaceutical composition is sufficient to block the interaction between galactin-9 and Tim-3.

[0048] Furthermore, the present disclosure provides methods for modifying, eliminating, and / or reducing pathological cells that express galectin-9 (e.g., via antibody-dependent cellular cytotoxicity or ADCC), the methods comprising administering to a subject having pathological cells that express galectin-9 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. In some embodiments, the subject is a human patient having cancer cells that express galectin-9 and / or pathological immune cells that express galectin-9. In some embodiments, the effective amount of the pharmaceutical composition is sufficient to initiate antibody-dependent cellular cytotoxicity (ADCC) and / or block the pathological cells that express galectin-9.

[0049] Any of the therapeutic methods described herein may further comprise administering to a subject an inhibitor of a checkpoint molecule, an activator of a costimulatory receptor, or an inhibitor of an innate 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 innate immune cell targets include, but are not limited to, KIR, NKG2A, CD96, TLR, and IDO.

[0050] The present disclosure also provides pharmaceutical compositions for use in treating a galectin-9-associated disease (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. The present disclosure also provides use of an anti-galectin-9 antibody or encoding nucleic acid for the manufacture of a medicament for use in treating a target disease described herein.

[0051] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the invention will be apparent from the following drawings and detailed description of some embodiments, as well as from the appended claims. [Brief explanation of the drawings]

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

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

[0054] [Figure 2A-2B] Figures 2A-2B contain charts showing the binding properties of Fabs for 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 contain charts showing epitope binding (CRD2 binding) of the G.9-2 Fab clone using competitive phage ELISA. Figure 3A: Mouse galectin-9 CRD2-coated wells preincubated with purified G9.2-1 or G9.2-3 Fab before adding the phage-displayed galectin-9 CRD2-binding Fab clone. Figure 3B: Human galectin-9 CRD2-coated wells preincubated with purified G9.2-15 or G9.2-17 Fab before adding the phage-displayed galectin-9 CRD2-binding Fab clone.

[0056] [Figure 4] Figure 4 contains a diagram showing the affinity of purified G9.2 Fab for galectin-9 CRD2, characterized using a bead-based binding assay. The curves represent the best fit of a 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 contains a diagram showing the affinity of purified G9.1 Fab for galectin-9 CRD1, characterized using a bead-based binding assay. The experiment was performed 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 diagrams showing surface plasmon resonance analysis of Fab G9.2-15 and Fab G9.2-17 binding to the CRD2 of human (top) and mouse (bottom) galectin-9. The association and dissociation phases of the experiment are depicted in the top panel. Left: G9.2-15 Fab. Right: G9.2-17 Fab.

[0059] [Figure 7] 7 includes diagrams showing SPR analysis of G9.2-17 human IgG4 binding to the CRD2 of human (top) and mouse (bottom) galectin-9. The gray line shows the sensorgram for the non-binding negative control, G9.2-iso human IgG4.

[0060] [Figure 8] Figure 8 includes an illustration showing staining of cell line samples with Fabs directed against galectin-9 CRD2. Histograms of flow cytometry data are 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] FIG. 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 the epitope mapping of G.9-2.17 on human galectin-9 CRD2 by systematic mutagenesis. Figure 10A: Diagram showing the binding activity of G9.2-17 to galectin-9 CRD2 mutants as determined by phage ELISA. The reduction 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 the carbohydrate ligand binding site mapped onto the crystal structure (W309 corresponds to W277 in UniProt ID 000182-2; PDB ID 3NV2).

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

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

[0065] [Figure 13] Figure 13 is a graph showing the binding characteristics of G9.2 Fab clones for wild-type galectin-9 CRD2 or the W3039K mutant using phage ELISA. Binding of Fab clones to human galectin-9 CRD2 analyzed using phage ELISA. Biotinylated wild-type human galectin-9 CRD2, the W309K galectin-9 CRD2 mutant, or galectin-9 CRD2 preincubated with G9.2-17 IgG was immobilized on neutravidin-coated wells and incubated with individual phage-displayed Fab clones.

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

[0067] [Figure 15] FIG. 15 is a photograph of mouse tumors showing that galectin-9 and anti-PD1 blockade produces a superior response.

[0068] [Figure 16] Figure 16 is a bar graph showing tumor mass in mice treated with G9.2-17 mIgG1. Mice (n=10 / group) bearing orthotopically implanted KPC tumors were treated weekly for 3 weeks with commercial isotype (200 μg) or commercial αGal9 (200 μg) mAb, or G9.2-Iso mIgG1 (200 μg), or G9.2-17 mIgG1 in two doses (200 μg or 400 μg). Tumors were removed, weighed, and then processed and stained for flow cytometry.

[0069] [Figure 17] Figure 17 shows a bar graph depicting tumor weights in mice treated with G9.2-17 mIgG2a alone or in combination with αPD1 mAb. Mice (n=10 / group) bearing orthotopically implanted KPC tumors were treated weekly for 3 weeks with commercially available αPD-1 (200 μg) mAb or G9.2-17 mIg2a (200 μg), or a combination of G9.2-17 and αPD-1, or matched isotypes. Tumors were removed, weighed, and then processed and stained for flow cytometry. Each point represents one mouse; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; by unpaired Student's t-test.

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

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

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

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

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

[0075] [Figure 23] Figure 23 is a graph showing the results of an apoptosis assay demonstrating that Gal-9 antibody inhibits galectin-9-induced apoptosis of Jurkat cells. Jurkat cells were treated with or without galectin-9 (280 nM), G9.2-17 IgG (1 μM), and / or G9.1-8m13 IgG (1 μM) for 6 hours (Figure 23). 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 presented as individual data points. Statistical analysis was performed by unpaired Student's t-test (*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 anti-galectin-9 antibodies disclosed herein disrupt the interaction between galectin-9 and CD206. Figure 24A shows a graph showing an ELISA measuring the interaction between immobilized human galectin-9 and soluble CD206 in the absence and presence of added G9.1-8m13 or G9.2-17 antibodies. Isotype antibody wells serve as controls. Galectin-9-coated wells were incubated with CD206 in the presence or absence of G9.1-8m13, G9.2-17, a combination of both antibodies, or isotype antibodies (experiments performed in triplicate; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001; by unpaired 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] FIG. 25 is a line graph showing 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 organotypic tumor spheroids (PDOT) derived from pancreatic adenocarcinoma primary tumor samples treated with 9.2-17 IgG4 (100 nM) compared to isotype control (100 nM).

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

[0080] [Figure 28A-28F] Figures 28A-28F show bar graphs depicting immune profile expression in gallbladder cancer tumor samples (PDOTS) treated with 9.2-17 IgG4 (100 nM) compared to the IgG4 isotype control (100 nM); 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] [Figure 29A-29C] Figures 29A-29C show bar graphs depicting CD44 (Figure 29A), TNF-α (Figure 29B), and IFNγ (Figure 29C) expression 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) compared to IgG1 (100 nM) or untreated control (Utx).

[0082] [Figure 30] Figure 30 shows a line graph demonstrating the effect of 9.2-17 in a B16F10 subcutaneous syngeneic model. Tumors were implanted subcutaneously and treated with G9.2-17 IgG1 murine mAb. Animals were dosed intravenously (iv) on days 0 and 4 unless otherwise noted in the legend.

[0083] [Figure 31] Figure 31 shows a line graph demonstrating the effect of 9.2-17 in a B16F10 subcutaneous syngeneic model. Tumors were implanted subcutaneously and treated with the G9.2-17 IgG2a murine mAb. Animals were dosed on day 0 and once every four days thereafter until the end of the experiment. mAbs were administered i.v. unless otherwise specified in the legend.

[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 bound Fab was detected using neutravidin conjugated to DyLight 650. Samples were then analyzed using flow cytometry. A strong signal was observed for the galectin-9 antibody 9.2-17 but not for the isotype control. The K values ​​of the Gal-9 antibodies in the two formats were D The (nM) values ​​were as follows: G9.2-17 hIgG1: 0.41 ± 0.07; G9.2-17 mIgG1: 2.91 ± 0.66.

[0085] [Figure 33A-33B] Figures 33A and 33B show graphs illustrating thermal stability measurements of anti-galectin-9 antibodies. 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 the peak is observed. Thermal transitions were measured using changes in binding of the fluorophore SYPRO Orange (ThermoFisher) in a real-time PCR instrument at a heating rate of 1°C / min, essentially according to 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 U S A. 2006 Oct 24; 103(43): 15835-40." DETAILED DESCRIPTION OF THE INVENTION

[0086] Provided herein are antibodies capable of binding 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 domain. Such anti-galectin-9 antibodies can inhibit galectin-9-mediated signaling (e.g., galectin-9 / Dectin-1 or galectin-9 / Tim-3-mediated signaling pathways) or eliminate pathological cells expressing galectin-9, e.g., via ADCC. Thus, the anti-galectin-9 antibodies described herein can be used to inhibit either galectin-9 signaling and / or eliminate galectin-9-positive pathological cells, thereby providing benefit in the treatment of galectin-9-associated 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 can 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 as well as 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 reprogramming of CD4+ and CD8+ cells into essential mediators of antitumor immunity. Thus, galectin-9 serves as a valuable therapeutic target for blocking dectin-1-mediated signals. Thus, 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 leukemic stem cells in all types of acute myeloid leukemia (except M3 [acute promyelocytic leukemia]), but not on normal human hematopoietic stem cells (HSCs). TIM-3 signaling resulting from galectin-9 ligation has been found to have pleiotropic effects on immune cells, inducing apoptosis in Th1 cells (Zhu et al., Nat Immunol., 2005, 6:1245-1252) and stimulating the secretion of tumor necrosis factor-α (TNF-α), leading to the maturation of monocytes into dendritic cells and contributing to innate immune inflammation (Kuchroo et al., Nat Rev Immunol., 2008, 8:577-580). Additionally, galectin-9 / TIM-3 signaling has been found to coactivate 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 disrupt galectin-9 / TIM-3 binding may have therapeutic benefits, particularly with respect to leukemia and other hematological malignancies. Thus, 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). CD206-expressing tumor-associated macrophages are mediators of tumor immunosuppression, angiogenesis, metastasis, and recurrence (see, e.g., 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 references therein). In particular, M1 (also called classically activated macrophages) are triggered by Th1-associated cytokines and bacterial products, express high levels of IL-12, and are tumoricidal. In contrast, M2 (alternatively activated macrophages) are activated by Th2-associated 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 growth effects of M2 include promoting angiogenesis, invasion and metastasis, and protecting tumor cells from chemotherapy-induced apoptosis (Hu et al., Functional significance of macrophages in pancreatic cancer biology; Tumor Biol. 2015 Dec; 36(12): 9119-9126, and references therein). Tumor-associated macrophages are thought to have an M2-like phenotype and have a tumor-promoting role. Galectin-9 has been shown to mediate the differentiation of myeloid cells toward 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-binding CD206 can reprogram TAMs toward the M2 phenotype, similar to what has previously been shown for dectin. Without wishing to be bound by theory, blocking the interaction between galectin-9 and CD206 may provide one mechanism by which anti-galectin antibodies (e.g., those described in Tables 1 and 2 herein, e.g., antibody 9.1-8m13 and / or antibody 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 U S A. 2011;108(26):10650-5; Madireddi et al. Galectin-9 controls the therapeutic activity of 4-1BB-targeting antibodies. 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). Without being bound by theory, anti-galectin-9 antibodies may block signaling pathways mediated by galectin-9. For example, the antibodies may interfere with the interaction between galectin-9 and its binding partners (e.g., Dectin-1, TIM-3, or CD206), thereby blocking signaling induced by galectin-9 / ligand interactions. Alternatively, or in addition, anti-galectin-9 antibodies may exert their therapeutic effect by inducing blocking and / or cytotoxicity (e.g., ADCC, CDC, or ADCP) against pathological cells expressing galectin-9. Pathological cells refer to cells that directly or indirectly contribute to the initiation and / or development of disease.

[0093] Thus, described herein are anti-galectin-9 antibodies and their therapeutic uses for treating diseases associated with galectin-9.

[0094] Antibodies that bind to galectin-9 The present disclosure provides antibodies that bind to galectin-9, eg, human and / or mouse galectin-9.

[0095] In some examples, the anti-galectin antibodies described herein bind to an epitope in the carbohydrate recognition domain (CRD) of galectin-9, e.g., CRD1 or CRD2. In some examples, the anti-galectin antibody may bind to CRD1 and CRD2. Galectin-9 is a protein well known in the art. For example, NCBI GenBank accession numbers BAB83625.1 and NP_034838.2 provide information about human and mouse galectin-1, respectively. Exemplary human and mouse galectin-9 polypeptides are provided herein: human galectin-9 (isoform 1; also known as "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; also known as "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) spans residues 218-355 of SEQ ID NO: 1. Similarly, the CRD1 domain of mouse galectin-9 (SEQ ID NO: 5) spans residues 1-147 of SEQ ID NO: 2, and the CRD2 domain (SEQ ID NO: 6) spans 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 the human or mouse sequence as a query. 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 a fragment thereof (e.g., CRD1 or CRD2). As used herein, the term "anti-galectin-9 antibody" refers to any antibody capable of binding to a galectin-9 polypeptide from a suitable source, such as a human or non-human mammal (e.g., a primate, such as a mouse, rat, rabbit, or monkey). In some embodiments, anti-galectin-9 antibodies can be used therapeutically to inhibit the biological activity of galectin-9. In some embodiments, anti-galectin-9 antibodies can be used in research or diagnostic / prognostic methods, such as for detecting cells expressing galectin-9, in assessing the eligibility and / or efficacy of a treatment. Alternatively, or in addition, anti-galectin-9 antibodies can block the interaction of galactin-9 with its ligand (e.g., dectin-1, TIM-3), thereby inhibiting signaling pathways triggered by, for example, galectin-9 / dectin-1 or galectin-9 / TIM-3 interaction. Anti-galectin-9 antibodies can also induce the death of cells expressing galectin-9, for example, via antibody-dependent cellular cytotoxicity (ADCC) mechanisms.

[0099] An antibody (the singular and plural forms are used interchangeably) is an immunoglobulin molecule capable of specifically binding to a target (e.g., a carbohydrate, a polynucleotide, a lipid, a polypeptide, 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., an anti-galectin-9 antibody) encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising antibody portions, 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 that contains an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. Antibodies, e.g., anti-galectin-9 antibodies, include antibodies of any class, such as IgD, IgE, IgG, IgA, or IgM (or subclasses thereof); antibodies need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of various classes of immunoglobulins are well known.

[0100] A typical antibody molecule typically contains a heavy chain variable region (V H ) and the light chain variable region (V L ) included. V H and V L The regions can be further subdivided into regions of hypervariability, also known as "complementarity-determining regions" (CDRs), interspersed with more conserved regions known as "framework regions" (FRs).H and V L is typically composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methodologies known in the art, such as the Kabat definition, the Chothia definition, the AbM definition, and / or the 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 antibodies may be antigen-binding fragments of full-length antibodies. 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) F(ab')2 fragment (a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region); (iii) V H and CH (iv) a single-arm V of an antibody; L and V H Fv fragment consisting of domains; (v) V H and (vi) isolated complementarity-determining regions (CDRs) that retain functionality. Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker, which allows the VL and VH domains to be produced as a single protein chain that pairs to form a monovalent molecule known as a single-chain Fv (scFv). See, e.g., 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., in Table 1 and / or Table 2) can bind to galectin-9 and inhibit (e.g., reduce or eliminate) its activity. In some embodiments, the anti-galectin-9 antibodies described herein can bind to galectin-9 and inhibit the activity of galectin-9 by at least 30% (e.g., 31%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). The apparent inhibition constant (Ki), which is a measure of the potency of the inhibitor, can be used to determine the inhibitory activity. app or K i,app ) is related to the concentration of inhibitor required to reduce enzyme activity and is independent of enzyme concentration. The inhibitory activity of the anti-galectin-9 antibodies described herein can be determined by routine methods known in the art.

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

number

[0104] A is v o / E, the initial velocity (v o ) divided by the total enzyme concentration (E). In some embodiments, the anti-galectin-9 antibodies described herein have a Ki 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 antigenic epitope. app In some embodiments, the anti-galectin-9 antibody may have a lower Ki value for a first target (e.g., CRD2 of galectin-9) compared to a second target (e.g., CRD1 of galectin-9). app It may have a value Ki app The difference in (e.g., for specificity or other comparison) 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 5In some instances, the anti-galectin-9 antibody inhibits a first antigen (e.g., a first protein or mimetic thereof in a first conformation) more potently than a second antigen (e.g., the same first protein or mimetic thereof in a second conformation; or a second protein). In some embodiments, any of the anti-galectin-9 antibodies inhibits a target antigen or antigenic epitope thereof more potently than the K app Further affinity maturation can be performed to reduce the

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

[0106] In some embodiments, the anti-galectin-9 antibody inhibits CD206 signaling, e.g., in tumor-infiltrating immune cells. In some embodiments, the anti-galectin-9 antibody inhibits 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 therein). Such inhibitory activity can be determined by conventional methods or assays described herein (e.g., Example 13). In some embodiments, the anti-galectin-9 antibody blocks or prevents galectin-9 binding to CD206 by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). 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 that express galectin-9 (e.g., when the target cells are cancer cells or immunosuppressive immune cells). In some embodiments, the anti-galectin-9 antibody induces at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein) apoptosis in immune cells (e.g., T cells) or cancer cells. Such inhibitory activity can be determined by conventional methods or by assays described herein (e.g., Example 14). In some embodiments, any anti-galectin-9 antibody described herein induces cytotoxicity, such as complement-dependent cytotoxicity (CDC), against target cells that express galectin-9.

[0108] Antibody-dependent cell-mediated phagocytosis (ADCP) is an important mechanism of action of antibodies, which mediate some or all of their actions through phagocytosis. In this case, antibodies mediate the uptake of specific antigens 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 represents the predominant pathway.

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

[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% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein).

[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), e.g., in tumor-infiltrating T cells. In some embodiments, the anti-galectin-9 antibody enhances T cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). T cell activation can be measured by conventional methods or by assays described herein (e.g., Example 6) (e.g., measuring CD44, OX40, IFNγ, PD-1). In some embodiments, the anti-galectin-9 antibody enhances CD4+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, an anti-galectin antibody induces CD44 expression in CD4+ cells. In some embodiments, an anti-galectin-9 antibody increases CD44 expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, an anti-galectin antibody induces IFNγ expression in CD4+ cells. In some embodiments, an anti-galectin-9 antibody increases IFNγ expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, an anti-galectin antibody induces TNFα expression in CD4+ cells. In some embodiments, the anti-galectin-9 antibody increases 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 therein).

[0112] In some embodiments, the anti-galectin-9 antibody stimulates CD8+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces CD44 expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases CD44 expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces IFNγ expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases IFNγ expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces TNFα expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases TNFα expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, including any increment therein).

[0113] The antibodies described herein may be murine, rat, human, or of any other origin (including chimeric or humanized antibodies). Such antibodies are non-naturally occurring, i.e., not produced in an animal without human action (e.g., immunizing such an animal with the desired antigen or a fragment thereof or isolating it from an antibody library).

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

[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 characteristics described below or elsewhere herein. Humanized antibodies refer to forms of non-human (e.g., murine) antibodies that are specific chimeric immunoglobulins, immunoglobulin chains, or antigen-binding fragments thereof that contain minimal sequence derived from non-human immunoglobulin. In general, humanized antibodies are human immunoglobulins (recipient antibodies) in which residues from the recipient CDRs are replaced by residues from the CDRs of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. In some examples, a humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. A humanized antibody also optimally comprises at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have an altered Fc region as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six) that are 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 undergo affinity maturation.

[0116] Methods for constructing humanized antibodies are also well known in the art. See, e.g., Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033 (1989). In one example, the V of a parent non-human antibody is Hand V L The variable regions of the V1000A-V2000A-V3000A-V4000A-V5000A-V6000A-V7000A-V8000A-V9000A-V ...11000A-V12000A-V13000A-V14000A-V15000A-V16000A-V17000A-V18000A-V19000A-V2000A-V21000A-V22000A-V23000A-V24000A-V31000A-V42000A-V5000A-V6000A-V7000A-V18000A-V19000A-V21000A-V22000A-V32000A-V43000A-V5000A-V6000A-V7000A-V19000A-V21000A-V22000A-V32000A-V43000A-V5000A-V6000A-V7000A-V18000A-V19000A-V21000A-V22000A-V32000A-V43000A-V5000A-V6000A-V7000A-V19000A-V21000A-V22000A-V3 H and V L The chain is the parent V as a search query. H and V L The sequence is then used to identify the human V H and V L An acceptor gene is selected.

[0117] The CDR regions in the selected human acceptor gene can be replaced with CDR regions from the parent non-human antibody or a functional variant thereof. Where necessary, residues in the framework regions of the parent chain that are predicted to be important in interacting with the CDR regions 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 contain heavy and light chain constant regions derived from a human antibody. A chimeric antibody refers to an antibody having a variable region or a portion of a variable region derived from a first species and a constant region derived 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 mouse, rabbit, or rat), while the constant portions are homologous to sequences in antibodies derived from another mammal, such as a human. In some embodiments, amino acid modifications may be made in the variable and / or constant regions.

[0119] In some embodiments, the anti-galectin-9 antibodies described herein specifically bind to a corresponding target antigen or epitope thereof (e.g., a galectin-9 antigen or epitope). An antibody that "specifically binds" to an antigen or epitope is a term well understood in the art. A molecule is said to exhibit "specific binding" if it reacts more frequently, more rapidly, with a longer duration, and / or with greater affinity with a particular target antigen than with another target. An antibody "specifically binds" to a target antigen or epitope if it binds with higher affinity, with higher avidity, more readily, and / or with a longer duration than it binds to other substances. For example, an antibody that specifically (or preferentially) binds to an antigen (galectin-9) or an antigenic epitope therein is an antibody that binds to this target antigen with higher affinity, with higher avidity, more readily, and / or with a longer duration than it binds to other antigens or other epitopes within the same antigen. It is also understood that, for example, an antibody that specifically binds to a first target antigen may or may not specifically or preferentially bind to a second target antigen. Thus, "specific binding" or "preferential binding" does not necessarily require (but can include) exclusive binding. In some instances, an antibody that "specifically binds" to a target antigen or epitope thereof may not bind to other antigens or other epitopes within the same antigen (i.e., conventional methods may only detect baseline binding activity). 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, the anti-galectin-9 antibodies described herein specifically bind to human galectin-9 or a fragment thereof compared to their murine counterparts, or vice versa (e.g., have at least a 10-fold higher binding affinity for one antigen than 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 (and not to CRD2), e.g., significant or no binding to CRD2 is detectable by routine assays. In some embodiments, the anti-galectin-9 or fragment thereof binds only to CRD2 (and not to CRD1). In some embodiments, certain antibodies described herein may bind to both CRD1 and CRD2. In some embodiments, certain antibodies or fragments thereof described herein may bind to both CRD1 and CRD2 but have lower affinity for CRD2. In some embodiments, certain antibodies or fragments thereof described herein may bind to both CRD1 and CRD2 but have lower affinity for CRD1.

[0121] In some embodiments, the effects of the CRD1-binding Gal-9 antibody and the CRD2-binding Gal-9 antibody may be additive. In some embodiments, the effects of the CRD1-binding Gal-9 antibody and the CRD2-binding Gal-9 antibody may be synergistic. In some embodiments, a "cocktail," i.e., a mixture of two or more antibodies, can be used in a composition. Such a composition can include one or more antibodies that bind to CRD1 described herein and one or more antibodies that bind to CRD2 described herein. In a non-limiting example, an antibody comprising the variable region of clone 9.1-8m13 (e.g., SEQ ID NO: 21 (light chain and SEQ ID NO: 86)) can be combined in a composition with an antibody comprising the variable region of clone 9.2-17 (SEQ ID NO: 54 (light chain and SEQ ID NO: 55)). Antibodies can 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 examples, the anti-galectin-9 antibodies described herein may cross-react with human and non-human galectin-9 (e.g., murine), e.g., the difference in binding affinity for human and non-human galectin-9 is less than 5-fold, e.g., less than 2-fold, or substantially similar.

[0123] In some embodiments, the anti-galectin-9 antibodies described herein have suitable binding affinity for 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 K A is the dissociation constant (K D The anti-galectin-9 antibodies described herein have a binding affinity of at least 10 to the target antigen or antigen epitope. -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 M or lower binding affinity (K D ) The increased binding affinity is due to the decreased KD The higher affinity binding of an antibody to a first antigen compared to a second antigen corresponds to a K A (or number K D ) for binding to the first antigen. A (or a smaller number K D ) in a first conformation. In such cases, the antibody has specificity for a first antigen (e.g., a first protein or mimetic thereof in a first conformation) compared to a second antigen (e.g., the same first protein or mimetic thereof in a second conformation; or a second protein). In some embodiments, the anti-galectin-9 antibodies described herein have a higher binding affinity (higher K A or smaller K D In some embodiments, the anti-galectin-9 antibodies described herein have a higher binding affinity (higher K) for CRD2 of galectin-9 compared to the binding affinity for CRD1 of galectin-9. A or smaller K D The difference in binding affinity (e.g., for specificity or other comparison) 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 In some embodiments, any of the anti-galectin-9 antibodies can be further affinity matured to increase the binding affinity of the antibody for the target antigen or antigenic epitope thereof.

[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 a fluorescence assay). Exemplary conditions for assessing 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 binding protein as a function of target protein concentration. Under certain conditions, the fractional concentration of bound binding protein ([bound] / [total]) is generally related to the concentration of total target protein ([target]) by the following formula:

number

[0126] K A While it is not necessary to perform an exact measurement of affinity, obtaining a quantitative measurement of affinity (e.g., determined using methods such as ELISA or FACS analysis) can provide a good indication that it is a K A It is sometimes sufficient for the binding affinity to be proportional to the binding affinity of the galectin-9 antibody, and thus can be used for comparison, such as to determine whether a higher affinity, e.g., two-fold higher, is obtained, providing a qualitative measure of affinity, or an inference of affinity can be obtained, for example, by activity in a functional assay (e.g., an in vitro or in vivo assay). In some cases, an in vitro binding assay is indicative of in vivo activity. In other cases, an in vitro binding assay is not necessarily indicative of in vivo activity. While tight binding is beneficial in some cases, in other cases tight binding may be undesirable in vivo, and an antibody with a lower binding affinity may be more desirable. A number of exemplary anti-galectin-9 antibodies (specific for CRD1 or CRD2) are provided herein.

[0127] Exemplary antibody clones (reference antibodies) of the 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 the 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 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, such as monoclonal antibodies, recombinant antibodies, and / or human 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. Exemplary anti-galectin-9 antibodies described herein that bind to CRD2 include 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, 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. Exemplary sequences and SEQ ID NOs 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. The terms "m" and "mut," e.g., "9.1-8m" and "9.1-8mut," are used interchangeably herein.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 "G9.1-8mut1", "G9.1-8mut2", "G9.1-8mut3", "G9.1-8mut4", "G9.1-8mut5", "G9.1-8mut6", "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", respectively. Used interchangeably 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-binding anti-galectin-9 antibodies are isolated and structurally characterized as described herein. The present disclosure also contemplates 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 region 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, G9.2-18mut6, G9.2-19mut6, G9.2-20mut6, G9.2-21mut6, G9.2-22mut6, G9.2-23mut6, G9.2-24mut6, G9.2-25mut6, G9.2-26mut6, G9.2-27mut6, G9.2-28mut6, G9.2-29mut6, G9.2-30mut6, G9.2-31mut6, G9.2-32mut6, G9.2-33mut6, G9.2-34mut6, G9.2-35mut6, G9.2-36mut6, G9.2-37mut6, G9.2-38mut6, G9.2-39mut6, G9.2-40mut6, G9.2-41mut6, G9.2-42mut6, G9.2-43mut6, G9.2-44mut6, G9.2-45mut6, G9.2-46 , 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, G9.2-low affinity binder VL amino acid sequences 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 , 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, G9.2-low affinity binder VH amino acid sequences 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, provided herein is an isolated anti-galectin-9 antibody, or an antigen-binding portion thereof, 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: 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 consists of 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 is an isolated anti-Galectin-9 antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain variable region, wherein 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, provided herein is an isolated anti-galectin-9 antibody, or antigen-binding portion thereof, 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: 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, provided herein is an isolated anti-galectin-9 antibody, or antigen-binding portion thereof, comprising a heavy chain and a light chain variable region, wherein 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, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69, and 71; and 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.

[0145] In some embodiments, the anti-galectin-9 antibody comprises a VL region having the sequence of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody comprises a VH region having the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody comprises a VH region having the sequence of SEQ ID NO: 56. In some embodiments, the anti-galectin-9 antibody comprises 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 comprises 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 set forth in SEQ ID NOs: 7, 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 set forth 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, provided herein is an isolated anti-Galectin-9 antibody, or an antigen-binding portion thereof, 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. 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. Also provided is an isolated anti-Galectin-9 antibody, or antigen-binding portion thereof, comprising a heavy chain and a 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, provided herein is an isolated anti-galectin-9 antibody, or antigen-binding portion thereof, 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.

[0147] In some embodiments, the anti-galectin-9 antibody comprises a VL region having the sequence of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody comprises a VH region having the sequence of SEQ ID NO: 22. In some embodiments, the anti-galectin-9 antibody comprises a VH region having the sequence of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody comprises 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 comprises 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 certain embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises any of SEQ ID NOs: 7 to 87. In certain embodiments, the anti-galectin-9 antibody comprises one or more of any sequence(s) selected from SEQ ID NOs: 7 to 87, and any combination(s) thereof.

[0149] In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises any of SEQ ID NOs: 7 to 28 and 74 to 87. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises one or more of any of the sequences selected from SEQ ID NOs: 7 to 28 and 74 to 87, and any combination thereof.

[0150] In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises any of SEQ ID NOs: 13, 29-73. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises any one or more sequences selected from SEQ ID NOs: 13, 29-73, and any combination thereof. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises any of SEQ ID NOs: 54, 55, or 54 and 56. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises any one or more sequences selected from SEQ ID NOs: 54, 55, or 54 and 56, and any combination thereof.

[0151] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region comprising the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region consisting of SEQ ID NO: 54. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region consisting of the sequence of SEQ ID NO: 55. In some embodiments, the anti-galectin-9 antibody comprises a VL region and a VH region comprising SEQ ID NOs: 54 and 55. In some specific embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises 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 antigen-binding portion thereof, comprises a VL region comprising SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region consisting of SEQ ID NO: 21. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region comprising SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH region consisting of SEQ ID NO: 86. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region and a VH region comprising SEQ ID NOs: 21 and 86. In some specific embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL region and a VH region consisting of SEQ ID NOs: 21 and 86.

[0153] In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises a VL region or a VH region comprising any of SEQ ID NOs: 21, 22, and 74 to 87. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises a VL region or a VH region consisting of SEQ ID NOs: 21, 22, and 74 to 87. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises a VL and / or VH region comprising a sequence selected from SEQ ID NOs: 21, 22, and 74 to 87, and any combination thereof. In certain embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises a VL and / or VH region consisting of a sequence selected from SEQ ID NOs: 21, 22, and 74 to 87, and any combination thereof.

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

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

[0156] In some embodiments, the anti-galectin-9 antibody comprises a sequence having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galectin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL region set forth in SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27, and a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH region set forth 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL or VH region set forth 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to a VL or VH region set forth in SEQ ID NOs: 7-288 and 74-87, and any combination thereof.

[0157] In some embodiments, the anti-galectin-9 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, G9.1-9, 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 and a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL region of an antibody selected from 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, the anti-galectin-9 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, G9.1-9, 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, the anti-galectin-9 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, G9.1-9, 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, G9.1-8m ...8m10, G9.1-11, G9.1-8m11, G9.1-8m12, G9.1-8m13, G9.1-8m14, G9.1-8m15, G9.1-8m16, G9.1-8m17, G9.1-8m18, G9.1-8m19, G9.1-8m20, G9.1-8m21, G9.1-8m22, G9.1-8m23, G9.1-8m24, G9.1-8m25, G9.1-8m26, G9.1-8m27, G9.1-8m28, G9.1-8m29, G9.1-8m29, G9.1-8m29, G9.1-8 and G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14.

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

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

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

[0161] In some embodiments, the anti-galectin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth 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 comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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 comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL regions set forth 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 a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH regions set forth 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 comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL or VH regions set forth in SEQ ID NOs: 29-75 and 77-85.In certain embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL or VH region set forth in SEQ ID NOs: 13, 29-73, and any combination thereof. In certain embodiments, the anti-galectin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL or VH region set forth 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 , 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 binders. 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 , 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 binders.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 , 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 binders.

[0163] In some embodiments, the anti-galectin-9 antibody comprises heavy chain CDRs having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to 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. Alternatively, or in addition, the anti-galectin-9 antibody comprises a light chain CDR having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment therein) sequence identity to 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 comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL region of G9.2-17. In some specific embodiments, the anti-galectin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH region of G9.2-17. In some specific embodiments, the anti-galectin-9 antibody comprises a VL region and a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL region and VH region of G9.2-17.

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

[0166] Complementarity-Determining Regions (CDRs) Anti-galectin-9 antibodies (e.g., 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 G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, or a combination thereof. The amino acid sequences of the VL CDR1 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 shown in sequence number 328. The amino acid sequences of the VL CDR2 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 shown in sequence number 329. The amino acid sequences of the VL CDR3 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 shown in SEQ ID NOs: 330 to 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 set forth in SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437. The amino acid sequences of the VH CDR2 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 set forth in SEQ ID NOs: 362 to 366 and 438 to 445. The amino acid sequences of the VH CDR3 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 set forth in SEQ ID NOs: 367 to 386.

[0167] In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR2 having the sequence of SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR3 having a sequence selected from any of SEQ ID NOs: 330-340. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR3 having the sequence of SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328, a VL CDR2 having the sequence of SEQ ID NO: 329, and a VL CDR3 having a sequence selected from any of SEQ ID NOs: 330-340. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328, a VL CDR2 having the sequence of SEQ ID NO: 329, and a VL CDR3 having the sequence of SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody comprises a 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 a VH CDR1 having the sequence of SEQ ID NO: 361. In some embodiments, the anti-galectin-9 antibody comprises a 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 a VH CDR2 having a sequence selected from SEQ ID NOs: 364 or 366. In some embodiments, the anti-galectin-9 antibody comprises a VH CDR3 having a sequence selected from any of SEQ ID NOs: 367-386. In some embodiments, the anti-galectin-9 antibody comprises a VH CDR3 having the sequence of SEQ ID NO: 374 or 383.In some embodiments, the anti-galectin-9 antibody comprises a VH CDR1 having a sequence selected from any of SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437, a VH CDR2 having a sequence selected from any of SEQ ID NOs: 362 to 366 and 438 to 445, and a VH CDR3 having a sequence selected from any of SEQ ID NOs: 367 to 386. In some embodiments, the anti-galectin-9 antibody comprises a VH CDR1 having the sequence of SEQ ID NO: 361, a VH CDR2 having the sequence of SEQ ID NO: 364, and a VH CDR3 having the sequence of SEQ ID NO: 374. In some embodiments, the anti-galectin-9 antibody comprises a VH CDR1 having the sequence of SEQ ID NO: 361, a VH CDR2 having the sequence of SEQ ID NO: 366, and a VH CDR3 having the sequence of SEQ ID NO: 383. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328, a VL CDR2 having the sequence of SEQ ID NO: 329, and a VL CDR3 having a sequence selected from any of SEQ ID NOs: 330 to 340, a VH CDR1 having a sequence selected from any of SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437, a VH CDR2 having a sequence selected from any of SEQ ID NOs: 362 to 366 and 438 to 445, and a VH CDR3 having a sequence selected from any of SEQ ID NOs: 367 to 386. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328, a VL CDR2 having the sequence of SEQ ID NO: 329, and a VL CDR3 having the sequence of SEQ ID NO: 337, a VH CDR1 having the sequence of SEQ ID NO: 361, a VH CDR2 having the sequence of SEQ ID NO: 364, and a VH CDR3 having the sequence of SEQ ID NO: 374. In some embodiments, the anti-galectin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO: 328, a VL CDR2 having the sequence of SEQ ID NO: 329, and a VL CDR3 having the sequence of SEQ ID NO: 337, a VH CDR1 having the sequence of SEQ ID NO: 361, a VH CDR2 having the sequence of SEQ ID NO: 366, and a 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., that binds to CRD2) 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-comprises the light and heavy chain CDR1, CDR2 and CDR3 of a low affinity binder, or a combination thereof. The amino acid sequences of the VL CDR1 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 are shown in SEQ ID NO: 328. The amino acid sequences of the VL CDR2 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 are shown in SEQ ID NO: 329.The amino acid sequences of the VL CDR3 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 are shown in SEQ ID NOs: 341 to 360. The amino acid sequences of VH CDR1 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 are shown in SEQ ID NOs: 361, 424 to 434. 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 VHs The amino acid sequences of CDR2 are shown in SEQ ID NOs: 362, 363, 387 to 389, and 446 to 466.The amino acid sequences of the VH CDR3 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 are shown in SEQ ID NOs: 390 to 417.

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

[0170] Because 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, and VL CDR1, VL CDR2, and VL CDR3 sequences disclosed above can be mixed and matched to generate new galectin-9-binding antibodies (as long as each resulting new antibody has VL CDR1, 2, and 3 and VH CDR1, 2, and 3). Such antibodies resulting from new combinations of CDRs described herein can be tested using the binding assays described herein. In some embodiments, the CDR1, CDR2, and / or CDR3 sequence from a particular VH or VL sequence is replaced with a structurally similar CDR sequence(s). Novel VH and VL sequences can be generated by replacing one or more VH and / or VL CDR sequences with structurally similar sequences from the CDR sequences disclosed herein, according to methods known in the art.

[0171] Thus, in some embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises: (a) the VL CDR1 amino acid sequence set forth in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence set forth 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 sequences set forth 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, 438-445, 362, 363, 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, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the VL CDR1 amino acid sequence set forth in SEQ ID NO: 328. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the VL CDR2 amino acid sequence set forth in SEQ ID NO: 329. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330-340. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the VH CDR1 amino acid sequence set forth in SEQ ID NOs: 361, 427, 428, 431, 435, 436, or 437. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362-366 and 438-445. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386. Thus, in some embodiments, the anti-galectin-9 antibody or antigen-binding portion thereof comprises: (a) the VL CDR1 amino acid sequence set forth in SEQ ID NO: 328; (b) the VL CDR2 amino acid sequence set forth in SEQ ID NO: 329; (c) a VL CDR3 amino acid sequence selected from SEQ ID NOs: 330 to 340; (d) the VH CDR1 amino acid sequence set forth in SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437; (e) a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362 to 366 and 438 to 445; and (f) a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367 to 386.

[0173] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the VL CDR1 amino acid sequence set forth in SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the VL CDR2 amino acid sequence set forth in SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VL CDR3 amino acid sequence selected from SEQ ID NOs: 341-360. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a VH CDR1 amino acid sequence set forth in SEQ ID NOs: 361, 424-434. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a 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 antigen-binding portion thereof, comprises a VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417.

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

[0175] 9.1 Antibody Clones and Associated CDRs Light chain variable region from clone 9.1 In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 330, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 330, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-1.

[0176] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 331, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 331, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-2.

[0177] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 332, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 332, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-3.

[0178] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-4.

[0179] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 334, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 334, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-5.

[0180] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 335, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 335, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-6.

[0181] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 336, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 336, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-7.

[0182] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 337, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-8.

[0183] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 338, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 338, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-9.

[0184] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 339, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 339, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-10.

[0185] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 340, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 328, 329, and 340, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.1-11.

[0186] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 comprises SEQ ID NO: 337. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 consists of SEQ ID NO: 337. In some embodiments, the antibody comprises 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 comprises the same VL CDR as G9.1-8m12. In some embodiments, the antibody comprises the same VL CDRs as G9.1-8m13.

[0187] In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 comprises 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, an anti-galectin-9 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 comprises X1SX2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13 GMDY (SEQ ID NO: 468) (wherein X1 = Y or S, X2 = T, S, or deletion, X3 = Y, S, or deletion, X4 = S or deletion, X5 = W, S, or deletion, X6 = S or deletion, X7 = G, S, or deletion, X8 = G, T, S, or deletion, X9 = I, Y, S, or deletion, X 10 = G, S, or Y, X 11 =W or S, X 12 = V or S, and X 13 =W or S). In some examples, the anti-galectin-9 antibody comprises 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 comprises a deletion at one or more of X4 to X7 in the heavy chain CDR3 domain. In other examples, the anti-galectin-9 antibody comprises S at one or more of X6 to X8 in the heavy chain CDR2 domain. Alternatively, or in addition, the anti-galectin-9 antibody comprises a deletion at one or more of X5 to X7 in the heavy chain CDR3 domain. In a further example, the anti-galectin-9 antibody comprises S at one or more of X6 to X8 in the heavy chain CDR2 domain. Alternatively, or in addition, the anti-galectin-9 antibody comprises a deletion at one or more of X3 to X9 and / or X 10 is Y.

[0188] Heavy chain variable region from clone 9.1 In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 431, 438, and 367, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 431, 438, and 367, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-1.

[0189] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 435, 439, and 368, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 435, 439, and 368, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-2.

[0190] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 436, 363, and 369, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 436, 363, and 369, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-3.

[0191] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 437, 440, and 370, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 437, 440, and 370, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-4.

[0192] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 437, 441, and 371, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 437, 441, and 371, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-5.

[0193] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 427, 442, and 372, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 427, 442, and 372, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-6.

[0194] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 443, and 373, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 443, and 373, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-7.

[0195] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 374, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 374, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8.

[0196] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 363, and 384, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 363, and 384, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-9.

[0197] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 429, 444, and 385, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 429, 444, and 385, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-10.

[0198] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 428, 445, and 386, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 445, and 386, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-11.

[0199] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 365, and 374, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 365, and 374, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m1.

[0200] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 374, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 366, and 374, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m2.

[0201] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 375, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 375, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m3.

[0202] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 376, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 364, and 376, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m4.

[0203] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 377, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 377, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m5.

[0204] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 378, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 378, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m6.

[0205] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 379, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 379, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m7.

[0206] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 380, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 380, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m8.

[0207] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 383, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 364, and 383, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m9.

[0208] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 381, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 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 antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 382, ​​respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 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 antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 380, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 366, and 380, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m12.

[0211] In some embodiments, an anti-galectin-9 antibody, or 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, an anti-galectin-9 antibody, or 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, an anti-galectin-9 antibody, or 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, an anti-galectin-9 antibody, or 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, an anti-galectin-9 antibody, or 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, an anti-galectin-9 antibody, or 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 binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 366, and 383, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m13.

[0212] In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 382, ​​respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 consist of SEQ ID NOs: 361, 366, and 382, ​​respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.1-8m14.

[0213] Clone 9.1-9.1 heavy and light chain variable regions In one specific embodiment, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 330, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 431, 438, and 367, respectively. In some embodiments, the light and heavy chain variable regions CDR1, CDR2, and CDR3 consist of 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 G9.1-1.

[0214] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 331, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 435, 439, and 368, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 331, and SEQ ID NOs: 435, 439, and 368. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-2. In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 332, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 436, 363, and 369, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 332, and SEQ ID NOs: 436, 363, and 369. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-3.

[0215] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 437, 440, and 370, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, and SEQ ID NOs: 437, 440, and 370. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-4.

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

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

[0218] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 336, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 443, and 373, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 336, and SEQ ID NOs: 361, 443, and 373. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-7.

[0219] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 374. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 374. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8.

[0220] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 338, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 363, and 384. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 338, and SEQ ID NOs: 361, 363, and 384. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-9.

[0221] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 339, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 429, 444, and 385. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 339, and SEQ ID NOs: 429, 444, and 385. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-10.

[0222] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 340, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 428, 445, and 386. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 340, and SEQ ID NOs: 428, 445, and 386. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-11.

[0223] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 365, and 374. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 365, and 374. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m1.

[0224] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 374. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 366, and 374. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m2.

[0225] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 375. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 375. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m3.

[0226] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 376. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 376. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m4.

[0227] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 377. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 377. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m5.

[0228] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 378. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 378. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m6.

[0229] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 379. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 379. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m7.

[0230] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 380. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 380. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m8.

[0231] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 383. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 383. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m9.

[0232] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 381. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 381. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m10.

[0233] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 364, and 382. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 364, and 382. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m11.

[0234] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 380. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 366, and 380. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m12.

[0235] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 383. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 366, and 383. In one specific embodiment, the antibody comprises the same VL and VH CDRs as G9.1-8m13.

[0236] In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 328, 329, and 337, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 361, 366, and 382. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 337, and SEQ ID NOs: 361, 366, and 382. In one specific 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 for CRD1 and / or CRD2) may be a corresponding V antibody of the exemplary antibodies described herein. L Alternatively, or in addition, an anti-galectin-9 antibody (e.g., specific for CRD1 or CRD2) may comprise a light chain CDR that has at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with the CDR. Alternatively, or in addition, an anti-galectin-9 antibody (e.g., specific for CRD1 or CRD2) may comprise a light chain CDR that has at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with the V of the exemplary antibodies described herein. H The heavy chain CDRs may have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with the CDRs, individually or collectively.

[0238] In some embodiments, the anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) 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, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1 G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, or a corresponding V L The CDRs may comprise light chain CDRs that, individually or collectively, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the CDRs. In some embodiments, the anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) 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, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-12, G9.1-13, G9.1-14, G9.1-15, G9.1-16, G9.1-17, G9.1-18, G9.1-19, G9.1-20, G9.1-21, G9.1-22, G9.1-23, G9.1-24, G9.1-25, G9.1-26, G9.1-27, G9.1-28, G9.1-29, G9.1-30, G9.1-31, G9.1-32, G9.1-33, G9.1-34, G9.1-35, G9.1-36, G9.1-37, G9.1-38, G9.1-39, G9.1-40, G9.1-41, G9.1-42, G9.1-43, G9.1-44, G9.1-45, G9.1-46, G9.1-47, G9.1-48, G9.1-49, G9.1-50 G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, or a corresponding V H The heavy chain CDRs may have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with the CDRs, individually or collectively.

[0239] In some embodiments, the anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) 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, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1 G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14, or a corresponding V L CDR and V H The CDRs may comprise light chain CDRs and heavy chain CDRs that, individually or collectively, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with each other.

[0240] In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL CDR1 amino acid sequence set forth in SEQ ID NO: 374. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL CDR2 amino acid sequence set forth in SEQ ID NO: 329. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity 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 for CRD1 and / or CRD2) may comprise a VH CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH CDR1 amino acid sequences set forth in SEQ ID NOs: 361, 427, 428, 431, 435, 436, and 437. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VH CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity 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 for CRD1 and / or CRD2) may comprise a VH CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to a VH CDR3 amino acid sequence selected from SEQ ID NOs: 367-386.

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

[0243] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light 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 therein) sequence identity to the light chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth 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 therein) 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 binding portion thereof comprises heavy and light chain variable regions, wherein 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 therein) sequence identity to the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth 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 therein) sequence identity to the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13.In one specific embodiment, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light 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 therein) sequence identity to the light chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 328, 329, and 337, respectively, and 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 therein) sequence identity to the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth 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 therein) sequence identity to 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 from clone 9.2 In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 341, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 341, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-1.

[0245] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-2.

[0246] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-3.

[0247] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 342, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 342, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-4.

[0248] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 343, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 343, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-5.

[0249] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 344, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 344, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-6.

[0250] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 345, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 345, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-7.

[0251] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 346, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 346. In some embodiments, the antibody comprises the same VL CDRs as G9.2-8.

[0252] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 347, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 347, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-9.

[0253] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 348, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 348, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-10.

[0254] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 349, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 349, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-11.

[0255] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 350, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 350, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-12.

[0256] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 341, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 341. In some embodiments, the antibody comprises the same VL CDRs as G9.2-13.

[0257] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-14.

[0258] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 343, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 343, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-15.

[0259] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333. In some embodiments, the antibody comprises the same VL CDRs as G9.2-16.

[0260] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR1 comprises SEQ ID NO: 328. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR2 comprises SEQ ID NO: 329. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, and the light chain variable region CDR3 comprises SEQ ID NO: 352. In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, and the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-17.

[0261] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-17mut6.

[0262] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-18.

[0263] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 354, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 354, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-19.

[0264] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-20.

[0265] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 355, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 355, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-21.

[0266] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 356, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 356, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-22.

[0267] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 357, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 357, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-23.

[0268] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 358, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 358, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-24.

[0269] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 359, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 359, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-25.

[0270] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 360, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 360, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-26.

[0271] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the light chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDRs as G9.2-low affinity binder.

[0272] Heavy chain variable region from clone 9.2 In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 424, 446, and 390, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 424, 446, and 390, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-1.

[0273] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 447, and 391, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 431, 447, and 391, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-2.

[0274] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 448, and 392, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 431, 448, and 392, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-3.

[0275] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 449, and 393, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 431, 449, and 393, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-4.

[0276] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 450, and 394, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 431, 450, and 394, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-5.

[0277] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 451, and 395, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 431, 452, and 395. In some embodiments, the antibody comprises the same VH CDRs as G9.2-6.

[0278] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 425, 453, and 396, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 425, 453, and 396, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-7.

[0279] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 425, 453, and 397, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 425, 453, and 397, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-8.

[0280] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 426, 454, and 398, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 426, 454, and 398, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-9.

[0281] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 426, 387, and 399, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 426, 387, and 399, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-10.

[0282] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 432, 455, and 400, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 432, 455, and 400, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-11.

[0283] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 433, 456, and 401, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 433, 456, and 401, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-12.

[0284] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 434, 362, and 402, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 434, 362, and 402, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-13.

[0285] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 457, and 403, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 457, and 403, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-14.

[0286] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 458, and 404, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 458, and 404, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-15.

[0287] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 459, and 405, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 459, and 405, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-16.

[0288] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 406, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 388, and 406. In some embodiments, the antibody comprises the same VH CDRs as G9.2-17.

[0289] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 407, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 388, and 407, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-17mut6.

[0290] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 430, 363, and 408, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 430, 363, and 408, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-18.

[0291] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 430, 460, and 409, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 430, 460, and 409, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-19.

[0292] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 429, 461, and 410, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 429, 461, and 410, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-20.

[0293] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 429, 462, and 411, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 429, 462, and 411, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-21.

[0294] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 463, and 412, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 428, 463, and 412, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-22.

[0295] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 464, and 413, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 428, 464, and 413, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-23.

[0296] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 465, and 414, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 428, 465, and 414, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-24.

[0297] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 427, 466, and 415, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 427, 466, and 415. In some embodiments, the antibody comprises the same VH CDRs as G9.2-25.

[0298] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 389, and 416, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 389, and 416, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-26.

[0299] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 417, respectively. In some embodiments, the heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 361, 388, and 417, respectively. In some embodiments, the antibody comprises the same VH CDRs as G9.2-low affinity binder.

[0300] Heavy and light chain variable regions from clone 9.2 In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 341, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 424, 446, and 390, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 G9.2-1.

[0301] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 447, and 391, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 G9.2-2.

[0302] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 448, and 392, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 333, and SEQ ID NOs: 431, 448, and 392. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-3.

[0303] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 342, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 449, and 393, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 343, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 450, and 394, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 344, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 431, 451, and 395, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 345, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 425, 452, and 396, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 346, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 245, 453, and 397, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 347, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 426, 454, and 398, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 347, and SEQ ID NOs: 426, 454, and 398. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-9.

[0309] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 348, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 426, 387, and 399, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 349, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 432, 455, and 400, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 350, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 433, 456, and 401, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 341, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 434, 362, and 402, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 457, and 403, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 343, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 458, and 404, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 459, and 405, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 406, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 404, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 333, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 430, 363, and 408, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 354, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 430, 460, and 409, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of SEQ ID NOs: 328, 329, and 354, and SEQ ID NOs: 430, 460, and 409. In one particular embodiment, the antibody comprises the same VL and VH CDRs as G9.2-19.

[0320] In some embodiments, the anti-galectin-9 antibody, or binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 429, 461, and 410, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 355, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 429, 462, and 411, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 356, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 463, and 412, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 357, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 464, and 413, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 358, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 428, 465, and 414, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 359, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 427, 466, and 415, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof, comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 360, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 389, and 416, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 binding portion thereof comprises heavy and light chain variable regions, wherein the light chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 328, 329, and 352, respectively, and the heavy chain variable region CDR1, CDR2, and CDR3 regions comprise SEQ ID NOs: 361, 388, and 417, respectively. In some embodiments, the light and heavy chain variable region CDR1, CDR2, and CDR3 regions consist of 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 for CRD1 and / or CRD2) 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 binders. L The CDRs may comprise light chain CDRs that, individually or collectively, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the CDRs. In some embodiments, the anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) 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, G9.2-27, G9.2-28, G9.2-29, G9.2-30, G9.2-31, G9.2-32, G9.2-33, G9.2-34, G9.2-35, G9.2-36, G9.2-37, G9.2-38, G9.2-39, G9.2-40, G9.2-41, G9.2-42, G9.2-43, G9.2-44, G9.2-45, G9.2-46, G9.2-47, G9.2-48, G9.2-49, G9.2-5 , 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 binders. H The heavy chain CDRs may have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with the CDRs, individually or collectively.

[0329] In some embodiments, the anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) 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 binders. L CDR and V H The CDRs may comprise light chain CDRs and heavy chain CDRs that, individually or collectively, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity with each other.

[0330] In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL CDR1 amino acid sequence set forth in SEQ ID NO: 328. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VL CDR2 amino acid sequence set forth in SEQ ID NO: 329. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity 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 for CRD1 and / or CRD2) may comprise a VH CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH CDR1 amino acid sequence set forth in SEQ ID NOs: 361, 424 to 434. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VH CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to a VH CDR2 amino acid sequence selected from SEQ ID NOs: 362, 363, 387 to 389, and 446 to 466. In some embodiments, an anti-galectin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a VH CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to a VH CDR3 amino acid sequence selected from SEQ ID NOs: 390-417.

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

[0333] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light 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 therein) sequence identity to the light chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth 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 therein) 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 binding portion thereof comprises heavy and light chain variable regions, wherein 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 therein) sequence identity to the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth 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% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to the VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises heavy and light chain variable regions, wherein the light 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 therein) sequence identity to the light chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 328, 329, and 352, respectively, and 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 therein) sequence identity to the heavy chain variable region CDR1, CDR2, and CDR3 amino acid sequences set forth in SEQ ID NOs: 361, 388, and 406, respectively. 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 therein) sequence identity to the VL CDR1, CDR2, and CDR3 and VH CDR1, CDR2, and CDR3 amino acid sequences of G9.2-17.

[0334] Epitopes and constant regions 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., antibodies comprising any of SEQ ID NOS: 7-87 or their CDRs) or compete for binding to the galectin-9 antigen with the exemplary antibodies. "Epitope" refers to the site on a target antigen recognized and bound by an antibody. The site may consist entirely of amino acid components, entirely of chemical modifications of amino acids in proteins (e.g., glycosyl moieties), or a combination thereof. Overlapping epitopes contain at least one common amino acid residue. Epitopes may be linear, typically 6-15 amino acids in length. Alternatively, epitopes may be conformational. The epitope to which an antibody binds can be determined by routine techniques, such as epitope mapping (see, e.g., below). An antibody that binds to the same epitope as the exemplary antibodies described herein may bind to the exact same epitope as the exemplary antibody or to a substantially overlapping epitope (e.g., comprising 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 two antibodies compete with each other for binding to their cognate antigen can be determined by competition assays well known in the art.

[0335] In some embodiments, the anti-galectin-9 antibody can bind to an epitope, at least a segment of which is within the CRD1 of a galectin-9 protein (e.g., human galectin-9 or mouse galectin-9). In some embodiments, the antibody can bind to an epitope that is entirely within the CRD1 of a galectin-9 protein. In some embodiments, the antibody can bind to an epitope that is partially within the CRD1 of a 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 conformational epitope.

[0336] In some embodiments, the anti-galectin-9 antibody can bind to an epitope, at least a segment of which is located within CRD2 of a galectin-9 protein (e.g., human galectin-9 or mouse galectin-9). In some embodiments, the anti-galectin-9 antibody can bind to an epitope located entirely within CRD2 of a galectin-9 protein. In certain embodiments, where the anti-galectin-9 antibody binds to an epitope partially or completely within CDR2, the antibody binds to an epitope comprising at least residue W309. In certain embodiments, where the anti-galectin-9 antibody binds to an epitope partially or completely within CDR2, the epitope to which the anti-galectin-9 antibody binds does not include 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 encompassing residue W309. In some embodiments, the epitope to which the anti-galectin antibody binds is a conformational epitope that includes W309.

[0337] In some instances, the anti-galectin-9 antibody has the same V H and / or V L Includes CDR. H and / or V L Two antibodies with CDRs are identical if their CDRs are determined by the same approach (e.g., the Kabat or Chothia methods known in the art). Such anti-galectin-9 antibodies have the same V compared to the exemplary antibodies described herein. H , the same V L , or both.

[0338] Two heavy chain variable regions (or two light chain variable regions) having the same CDRs means that the CDRs in the 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 June 8; 309(3):657-70). As known to those of skill in the art, the CDR regions of the exemplary anti-pKal and anti-FXII antibodies identified herein are determined by the "Chothia" numbering scheme, which is used as an example.

[0339] Also within the scope of the present disclosure are functional variants of any of the exemplary anti-galectin-9 antibodies disclosed herein. Such functional variants are substantially similar to the exemplary antibodies, both structurally and functionally. Functional variants have substantially the same V H and V L For example, it may involve mutation of as few as five (e.g., four, three, two, or one) amino acid residues in the entire CDR region of an antibody and still have substantially similar affinity (e.g., the same order of K DThe amino acid sequence of the galectin-9 mutant binds to the same epitope of galectin-9 (having a specific binding site). Alternatively, or in addition, the amino acid residue mutation is a conservative amino acid residue substitution. As used herein, a "conservative amino acid substitution" refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for modifying polypeptide sequences known to those skilled in the art, for example, as found in 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, F.M. Ausubel, et al., eds., John Wiley & Sons, Inc., New York). Conservative substitutions of amino acids include substitutions made between amino acids within 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 "percent identity" of two amino acid sequences is determined using the algorithm of Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified in Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (Altschul, et al. J. Mol. Biol. 215:403-10, 1990). BLAST protein searches can be performed with the XBLAST program (score=50, wordlength=3) to obtain amino acid sequences homologous to a protein molecule of interest. If gaps exist between the two sequences, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997. When using BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. An anti-galectin-9 antibody may comprise a heavy chain variable region framework derived from a subclass of germline VH fragment. Such germline VH regions are well known in the art. See, for example, the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php.Examples include 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), the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, 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, the anti-galectin-9 antibody may comprise a light chain variable region comprising a framework derived from a germline Vκ fragment. Examples include an IGKV1 framework (e.g., IGKV1-05, IGKV1-12, IGKV1-27, IGKV1-33, or IGKV1-39), an IGKV2 framework (e.g., IGKV2-28), an IGKV3 framework (e.g., IGKV3-11, IGKV3-15, or IGKV3-20), and an IGKV4 framework (e.g., IGKV4-1). In another example, the anti-galectin-9 antibody may comprise a light chain variable region comprising a framework derived from a germline Vλ fragment. Examples include 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), and the I Examples include a Gλ4 framework (e.g., IGλV4-3, IGλV4-60, IGλV4-69), an IGλ5 framework (e.g., IGλV5-39, IGλV5-45), an IGλ6 framework (e.g., IGλV6-57), an IGλ7 framework (e.g., IGλV7-43, IGλV7-46), an IGλ8 framework (e.g., IGλV8-61), an IGλ9 framework (e.g., IGλV9-49), or an 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 comprise 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 of the IgG subfamilies described herein.

[0343] In some embodiments, the heavy chain constant region of an antibody described herein may comprise a single constant region domain (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 an antibody described herein may comprise a single constant region domain (e.g., CL) (e.g., SEQ ID NO: 418). Exemplary light and heavy chain sequences are provided below. The hIgG1 LALA sequence contains two mutations (L234A and L235A) that abrogate FcgR binding and the P329G mutation abolishes complement C1q binding, thereby abolishing all immune effector function. These mutations are underlined and bolded in the sequences provided below. The hIgG4 Fab Arm exchange mutant sequence contains a mutation to abrogate Fab Arm exchange (S228P), which is underlined and bolded. The light chain sequence of G9.2-17 is 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 bolded residues 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 the expression vector where it is cleaved during secretion and is therefore not present in the mature antibody molecule. The mature proteins (after secretion) begin with "EVQ" for the heavy chain and "DIM" for the light chain.

[0344] Exemplary Heavy and Light Chain Sequences TIFF0007800872000018.tif102169TIFF0007800872000019.tif229169TIFF0007800872000020.tif207169

[0345] In some embodiments, the anti-galectin-9 antibody has a light chain comprising, consisting essentially of, or consisting of SEQ ID NO: 108. In some embodiments, the anti-galectin-9 antibody has a heavy chain comprising, consisting essentially of, or consisting of any 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 comprising, consisting essentially of, or consisting of SEQ ID NO: 108 and a heavy chain comprising, consisting essentially of, or consisting of any 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 comprising SEQ ID NO: 108 and a heavy chain comprising any 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 any 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 any 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 comprises a heavy chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) to SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 423. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) to SEQ ID NO: 421. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 421. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 421.

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

[0348] In some embodiments, the anti-galectin-9 antibody comprises an altered constant region. In some embodiments, the anti-galectin-9 antibody comprises an altered constant region that is immunologically inert, e.g., does not trigger complement-mediated lysis or stimulate antibody-dependent cellular cytotoxicity (ADCC). ADCC activity can be assessed using the methods disclosed in U.S. Pat. No. 5,500,362. In other embodiments, the constant region is altered 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 comprises a heavy chain IgG4 constant region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 422. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 422. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 422. In some embodiments, the constant region of the anti-galectin-9 antibody comprises a light chain IgG4 constant region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a light chain IgG4 constant region comprising SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a light chain IgG4 constant region consisting of SEQ ID NO: 418. In some embodiments, the IgG is a variant with 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 comprises a heavy chain IgG1 constant region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region comprising SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region consisting of SEQ ID NO: 420. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a light chain IgG1 constant region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) sequence identity to SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a light chain IgG1 constant region comprising SEQ ID NO: 418. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a light chain IgG4 constant region consisting of SEQ ID NO:418.

[0349] In some embodiments, the anti-galectin-9 antibody has, for the light chain, a chain corresponding to SEQ ID NOs: 88-98 (anti-galectin-9 antibody that binds to CRD1) and SEQ ID NOs: 99-115 (anti-galectin-9 antibody that binds to CRD2); for the heavy chain, exemplary heavy chain amino acid sequences correspond to SEQ ID NOs: 116-140 (hIgG1); 169-193 (hIgG1 LALA); 222-246 (hIgG4); 275-299 (hIgG4 exchange mutant) (anti-galectin-9 antibody that binds to CRD1), and SEQ ID NOs: 141-168 (hIgG1); 194-221 (hIgG1 LALA); 247-274 (hIgG4); 300-327 (hIgG4 exchange mutant) (anti-galectin-9 antibody that binds to CRD2). The IgG LALA, IgG4 exchange mutant 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 set forth in SEQ ID NOs: 88-98 and 99-115.

[0350] Light chain 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 therein) sequence identity to any of the light chains (or variable regions thereof) shown herein (e.g., the light chain sequences shown in SEQ ID NOs: 88-98). In some embodiments, the light 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 therein) sequence identity to any of the light chains shown herein (e.g., the light chain sequences shown in SEQ ID NOs: 88-98). In some embodiments, the light chain of the anti-galectin-9 antibody comprises the amino acid sequence shown in SEQ ID NOs: 88-98. In some embodiments, the light chain of the anti-galectin-9 antibody consists of the amino acid sequence shown in SEQ ID NOs: 88-98.

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

[0352] 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 therein) sequence identity to the light chain sequence set forth in SEQ ID NO: 95 (or the variable region thereof). In some embodiments, the light 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 therein) sequence identity to the light chain sequence set forth in SEQ ID NO: 95. In some embodiments, the light chain of the anti-galectin-9 antibody comprises the amino acid sequence set forth in SEQ ID NO: 95 (or the variable region thereof). In some embodiments, the light chain of the anti-galectin-9 antibody consists of the amino acid sequence set forth in SEQ ID NO: 95.

[0353] Heavy chain from clone 9.1 In some embodiments, the amino acid sequence of the heavy chain of exemplary anti-galectin antibodies corresponds to the sequence set forth in SEQ ID NOs: 116-140 (hIgG1); 169-193 (hIgG1 LALA); 222-246 (hIgG4); 275-299 (hIgG4 exchange mutant) (anti-galectin-9 antibodies that bind to CRD1). In some embodiments, the heavy chain of the anti-galectin-9 antibody comprises an amino acid sequence having at least 80% sequence identity (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment therein) to any of the heavy chains (or variable regions thereof) set forth herein, e.g., the sequences set forth in SEQ ID NOs: 116-140; 169-193; 222-246; 275-299 (anti-galectin-9 antibodies that bind 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 therein) sequence identity to any of the sequences set forth in the heavy chains shown herein, e.g., 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 comprises the heavy chain amino acid sequence set forth 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 set forth 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 antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 116. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 117. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 118. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 119. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 120. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 121. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 122. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 123. In some embodiments, the anti-galectin-9 antibody, or antigen-binding portion thereof, comprises the heavy chain sequence of SEQ ID NO: 124. In some embodiments, the anti-galectin-9 antibody, or antige...

Claims

1. 1. A pharmaceutical composition for reprogramming an immune response to target tumor cells in a subject, the pharmaceutical composition comprising an antibody that binds to human galectin-9; A pharmaceutical composition, wherein the antibody comprises a heavy chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO: 361, a heavy chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO: 388, and a heavy chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO: 406, and the antibody comprises a light chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO: 328, a light chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO: 329, and a light chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO:

352.

2. The pharmaceutical composition of claim 1 , wherein the antibody is an IgG molecule.

3. The pharmaceutical composition of claim 2 , wherein the antibody is an IgG1 or IgG4 antibody.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 55 and a VL comprising the amino acid sequence of SEQ ID NO:

54.

5. 2. The pharmaceutical composition of claim 1, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO:

108.

6. 10. The pharmaceutical composition of claim 1, wherein the subject is a human patient with a solid tumor or a hematological malignancy.

7. the solid tumor is selected from the group consisting of glioblastoma, brainstem glioma, melanoma, squamous cell carcinoma, sarcoma, upper and lower gastrointestinal malignancies, gastrointestinal carcinoid tumors, breast cancer, lung cancer, squamous cell head and neck cancer, and genitourinary cancer; or the hematological malignancy is selected from the group consisting of leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myeloproliferative neoplasm; The pharmaceutical composition according to claim 6.

8. A pharmaceutical composition for inhibiting the activity of galectin-9 in a subject, comprising an antibody that binds to human galectin-9, A pharmaceutical composition, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO:

108.

9. A pharmaceutical composition for treating a solid tumor in a human subject, comprising an antibody that binds to human galectin-9, A pharmaceutical composition, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 316 and a light chain comprising the amino acid sequence of SEQ ID NO:

108.

10. The pharmaceutical composition of any one of claims 1 to 9 for use in combination with a checkpoint inhibitor or a chemotherapeutic agent.

11. The pharmaceutical composition of claim 10 for use in combination with a checkpoint inhibitor that is an anti-PD-1 antibody.

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