Anti-galectin-9 antibodies and uses thereof

Abstract

Disclosed herein are anti-galectin-9 antibodies and methods of using the same to inhibit signal transduction pathways mediated by galectin-9 or eliminate pathological cells expressing galectin-9. Such anti-galectin-9 antibodies can also be used to diagnose and / or treat diseases associated with galectin-9, such as autoimmune diseases and solid tumors.

Description

Background Technology

[0001] In recent years, immune checkpoint blockade has shown unprecedented success as a cancer treatment. Antibodies are typically used to block immunosuppressive pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) pathways. While therapies targeting these two pathways have shown success in treating a variety of cancer types, response rates for anti-CTLA-4 and anti-PD-1 therapies in treated patients range from 10% to 60% depending on the cancer type, and the ability to exceed 60% response rates has not yet been demonstrated, even when used in combination (Kyvistborg et al., Enhancing responses to cancer immunotherapy; Science. 2018 Feb 2; 359(6375):516-517). Furthermore, a large number of cancer types are refractory to these therapies. As part of efforts to improve existing immunotherapies in clinical practice, the field has begun to focus on the role of abnormalities in interferon signaling and the upregulation of alternative checkpoints, which is a potential reason limiting current therapies. One potential alternative checkpoint is T-cell immunoglobulin mucin-3 (Tim-3) / galectin-9 (e.g., review in 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 composed of two carbohydrate recognition domains (CRDs), and was first discovered and described in patients with Hodgkin's lymphoma (HL) in 1997 (Tureci et al., J. Biol. Chem. 1997, 272, 6416–6422). Three isoforms exist, and it can be located intracellularly or extracellularly. Elevated levels of galectin-9 have been observed in a variety of cancers, including melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, pancreatic cancer, gastric cancer, colon cancer, and clear cell renal cell carcinoma (Wdowiak et al., Int. J. Mol. Sci. 2018, 19, 210). In renal cell carcinoma, patients with high galactagogue-9 expression exhibit more advanced disease progression, larger tumor size, and necrosis (Kawashima et al.; BJU Int. 2014; 113:320–332). In melanoma (considered one of the deadliest cancers due to its aggressive metastasis and resistance to treatment), galactagogue-9 is expressed in 57% of tumors and is significantly increased in plasma in patients with advanced melanoma compared to healthy controls (Enninga et al., Melanoma Res. 2016 Oct; 26(5):429–441). Multiple studies have demonstrated the utility of Gal-9 as a prognostic biomarker and, more recently, as a potential novel drug target (Enninga et al., 2016; Kawashima et al. BJUInt 2014; 113:320–332; Kageshita et al., Int J Cancer. 2002 Jun 20; 99(6):809-16, and references therein). Gal-9 has been described to play important roles in many cellular processes such as adhesion, cancer cell aggregation, apoptosis, and chemotaxis. Recent studies have shown that Gal-9 plays a role in supporting tumor-mediated immune regulation, for example, through negative regulation of Th1 responses, Th2 polarization, and macrophage polarization toward the M2 phenotype. This work also includes studies demonstrating that galactagogue-9 participates in the direct inactivation of T cells through interactions with T cell immunoglobulin and mucin 3 (TIM-3) receptors (Dardalhon et al., J Immunol., 2010, 185, 1383-1392; Sanchez-Fueyo et al., Nat Immunol., 2003, 4, 1093-1101). Galactagogue-9 has also been found to play a role in polarizing T cell differentiation into tumor suppressor phenotypes, as well as in promoting the programming of toxic macrophages and adaptive immunosuppression (Daley et al., Nat Med., 2017, 23, 556-567).In a mouse model of pancreatic ductal adenocarcinoma (PDA), it has been demonstrated that blocking the checkpoint interaction between galactagogue-9 and the receptor Dectin-1 on innate immune cells present in the tumor microenvironment (TME) enhances the antitumor immune response in the TME and slows tumor progression (Daley et al., Nat Med., 2017, 23, 556-567). It has also been found that galactagogue-9 binds to CD206, a surface marker of M2 macrophages, leading to reduced secretion of CVL22 (MDC), a macrophage-derived chemokine associated with longer survival and lower recurrence risk in lung cancer (Enninga et al., J Pathol. 2018 Aug; 245(4): 468-477).

[0003] Therefore, modulating the activity of galactagogue-9 and / or one or more of its receptors, alone or in combination with existing therapies, could provide novel cancer treatment options. This article describes novel human antibodies that bind to human galactagogue-9 and their therapeutic uses in cancer treatment. Summary of the Invention

[0004] This disclosure is based, at least in part, on the development of anti-galactoglobulin-9 antibodies that effectively inhibit signal transduction induced by galactoglobulin-9. Such antibodies can inhibit galactoglobulin-9 signal transduction and / or eliminate galactoglobulin-9 positive pathological cells, thereby benefiting the treatment of galactoglobulin-9 related diseases.

[0005] Therefore, one aspect of this disclosure provides an isolated anti-galactophage-9 antibody that binds to an epitope in the carbohydrate recognition domain (CRD) of a galactophage-9 polypeptide, such as a human galactophage-9 polypeptide. In some embodiments, the anti-galactophage-9 antibody described herein may bind to both a human galactophage-9 polypeptide and a non-human galactophage-9 polypeptide (e.g., mouse galactophage-9, rat galactophage-9, or primate galactophage-9). In some embodiments, the anti-galactophage-9 antibody binds to only one galactophage-9 CRD. In some embodiments, the anti-galactophage-9 antibody binds to two galactophage-9 CRDs, for example, with similar or different affinities. In some embodiments, the anti-galactophage-9 antibody disclosed herein binds to an epitope within the CRD1 region. In some embodiments, the anti-galactophage-9 antibody disclosed herein binds to an epitope within the CRD1 region, which may have the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-galactoglobulin-9 antibody disclosed herein binds to an epitope within the CRD1 region having the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-galactoglobulin-9 antibody binds to the same epitope as a reference 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. Antibodies 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, and / or competing with a reference antibody for binding to the CRD1 region. In some embodiments, the anti-galactoglobulin-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-galactoglobulin-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-galactoglobulin-9 antibody is a G9.1-8 antibody. In some embodiments, the antibody is a G9.1-8m13 antibody. In some instances, the anti-galactoglobulin-9 antibody may contain the same heavy chain complementarity-determining region (CDR) and the same light chain CDR as a reference antibody, such as any reference antibody provided herein. In one specific instance, the anti-galactoglobulin-9 antibody contains the same heavy chain variable region and the same light chain variable region as a reference antibody, such as any reference antibody provided above or elsewhere herein.

[0007] In some embodiments, the anti-galactogenin-9 antibody has a V comprising SEQ ID NO:21 or substantially consisting of SEQ ID NO:21 or consisting of SEQ ID NO:21. L Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising SEQ ID NO:86 or substantially consisting of SEQ ID NO:86 or consisting of SEQ ID NO:86. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a sequence comprising SEQ ID NO:21. L Sequence and V containing SEQ ID NO:86 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting essentially of SEQ ID NO:21. L The sequence and V, which is essentially composed of SEQ ID NO:86 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting of SEQ ID NO:21. L The sequence and the V consisting of SEQ ID NO:86 H sequence.

[0008] In some embodiments, the anti-galactogenin-9 antibody has a V comprising SEQ ID NO:22 or substantially consisting of SEQ ID NO:22 or consisting of SEQ ID NO:22. HSequence. In some embodiments, the anti-galactogenin-9 antibody has a sequence comprising SEQ ID NO:21. L Sequence and V containing SEQ ID NO:22 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting essentially of SEQ ID NO:21. L The sequence and V, which is essentially composed of SEQ ID NO:22 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting of SEQ ID NO:21. L The sequence and the V consisting of SEQ ID NO:22 H sequence.

[0009] In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO: 328, 329, and 337. L Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:361, 364, 374, 366, and 383. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:328, 329, and 337. L Sequences, and V containing one or more sequences shown in SEQ ID NO: 361, 364 and 374. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:328, 329, and 337. L Sequences, and V containing one or more sequences shown in SEQ ID NO:361, 366 and 383. H sequence.

[0010] In some embodiments, the anti-galactophage-9 antibody disclosed herein binds to an epitope within the CRD2 region of galactophage-9. In some embodiments, the anti-galactophage-9 antibody disclosed herein binds to an epitope within the CRD2 region of galactophage-9, wherein the CRD2 region may have the amino acid sequence of SEQ ID NO:4. In some embodiments, the anti-galactophage-9 antibody disclosed herein binds to an epitope within the CRD2 region having the amino acid sequence of SEQ ID NO:4. In some embodiments, the anti-galactophage-9 antibody binds to an epitope within the CRD2 region of galactophage-9, wherein the epitope comprises a tryptophan residue corresponding to residue W309 of SEQ ID NO:1. In some embodiments, the anti-galactophage-9 antibody binds to an epitope within the CRD2 region of galactophage-9, wherein the epitope does not contain one or more residues corresponding to R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO:1. In some embodiments, the anti-galactoglobulin-9 antibody may bind to an epitope within the CRD2 region of galactoglobulin-9, the epitope comprising a tryptophan residue corresponding to residue W309 of SEQ ID NO:1, and additionally excluding one or more residues corresponding to R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO:1. In some embodiments, the anti-galactoglobulin-9 antibody binds to the same epitope as a reference 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, G9.2-26, and G9.2-low affinity binding antibody, and / or competing with the reference antibody for binding to the CRD2 region. In some embodiments, the anti-galactoglobulin-9 antibody binds to the same epitope as antibody G9.2-17 or antibody G9.2-17mut6, and / or competes with antibody G9.2-17 or antibody G92-17mut6 for binding to the CRD2 region.In some embodiments, the anti-galactoglobulin-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-galactoglobulin-9 antibody is a G9.2-17 antibody or a G9.2-17mut6 antibody. In some embodiments, the anti-galactoglobulin-9 antibody has a V comprising SEQ ID NO:54 or consisting substantially of SEQ ID NO:54 or consisting of SEQ ID NO:54. L Sequence. In some embodiments, the anti-galactogenin-9 antibody has a sequence comprising SEQ ID NO:55 or substantially consisting of SEQ ID NO:55 or consisting of SEQ ID NO:55. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a sequence comprising SEQ ID NO:54. L Sequence and V containing SEQ ID NO:55 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting essentially of SEQ ID NO:54. L The sequence and V, which is essentially composed of SEQ ID NO:55 H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence consisting of SEQ ID NO:54. L The sequence and the V consisting of SEQ ID NO:55 H Sequence. In some embodiments, the antibody has a V sequence comprising SEQ ID NO:56. H Sequence. In some embodiments, the antibody has a V sequence consisting substantially of SEQ ID NO:56 or consisting of SEQ ID NO:56. H Sequence. In some embodiments, the isolated antibody has a V sequence comprising SEQ ID NO:54. L Sequence and V containing SEQ ID NO:56 H Sequence. In some embodiments, the isolated antibody has a V sequence consisting essentially of SEQ ID NO:54. L The sequence and V, which is essentially composed of SEQ ID NO:56 HSequence. In some embodiments, the isolated antibody has a V sequence consisting of SEQ ID NO:54. L The sequence and the V consisting of SEQ ID NO:56 H sequence.

[0011] In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO: 328, 329, and 352. L Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:361, 388, 406, and 407. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:328, 329, and 352. L Sequences, and V containing one or more sequences shown in SEQ ID NO: 361, 388 and 406. H Sequence. In some embodiments, the anti-galactogenin-9 antibody has a V sequence comprising one or more sequences shown in SEQ ID NO:328, 329, and 352. L Sequences, and V containing one or more sequences shown in SEQ ID NO:361, 388 and 407. H sequence.

[0012] In some instances, the anti-galactoglobulin-9 antibody may contain the same heavy chain complementarity-determining region (CDR) and the same light chain CDR as a reference antibody, such as any reference antibody provided herein. In one specific instance, the anti-galactoglobulin-9 antibody contains the same heavy chain variable region and the same light chain variable region as a reference antibody, such as any reference antibody provided herein. In some embodiments, the anti-galactoglobulin-9 antibody contains heavy chain complementarity-determining region 1 (CDR1), heavy chain complementarity-determining region 2 (CDR2), and heavy chain complementarity-determining region 3 (CDR3), which collectively have at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with the heavy chain CDR of the reference antibody, such as any reference antibody provided herein. In some embodiments, the anti-galactoglobulin-9 antibody comprises light chain CDR1, light chain CDR2, and light chain CDR3, which collectively share at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with a reference antibody, such as any reference antibody provided herein.

[0013] In some embodiments, the anti-galactoglobulin-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 collectively have at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with the heavy chain CDR of a reference antibody, such as any reference antibody provided herein; and light chain CDR1, light chain CDR2, and light chain CDR3, which collectively have at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with the light chain CDR of a reference antibody, such as any reference antibody provided herein. In some instances, the anti-galactoglobulin-9 antibody may comprise the same heavy chain CDR and the same light chain CDR as the reference antibody described above. In one specific instance, an anti-galactoglobulin-9 antibody may contain the same heavy chain variable region and the same light chain variable region as a reference antibody, such as any reference antibody provided herein. In some embodiments, exemplary isolated anti-galactogen 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-galactogen 9 antibodies binding 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 a G9.2-low affinity binder.

[0014] In some embodiments, the isolated anti-galactoglobulin 9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 is composed of an amino acid sequence selected from SEQ ID NO: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-galactoglobulin 9 antibody or its antigen-binding portion 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 NO: 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 is composed of an amino acid sequence selected from SEQ ID NO: 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-galactoglobulin 9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 NO: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-galactoglobulin 9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region consists of an amino acid sequence selected from SEQ ID NO: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 NO: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-galactoglobulin 9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the light chain variable region is composed of an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the isolated anti-galactoglobulin 9 antibody or its antigen-binding portion 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 NO: 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 NO: 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. Therefore, in some embodiments, this document provides isolated anti-galactoglobulin 9 antibody or its antigen-binding portion comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 NO: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 is composed of an amino acid sequence selected from SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27, and the heavy chain variable region is composed of an amino acid sequence selected from SEQ ID NO: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-galactoglobulin-9 antibody disclosed herein may contain V as described in the reference antibody disclosed herein. H Heavy chain variable structural domains (V) with at least 85% identity H Alternatively or additionally, anti-galactoglobulin-9 antibody may contain V of the reference antibody. L Light chain variable structural domains (V) with at least 85% identity L ).

[0018] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO: 55. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO: 55. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions comprising SEQ ID NO: 54 and 55, respectively. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises VL and VH regions comprising SEQ ID NO: 54 and 55, respectively. In some embodiments, the anti-galactoglobulin-9 antibody is clone 9.2-17. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO: 56. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions comprising SEQ ID NO:54 and 56, respectively. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises VL and VH regions comprising SEQ ID NO:54 and 56, respectively. In some embodiments, the anti-galactoglobulin-9 antibody is clone 9.2-17mut6.

[0019] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region comprising SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region consisting of SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region comprising SEQ ID NO:86. H In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region consisting of SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions comprising SEQ ID NO:21 and 86, respectively. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions comprising SEQ ID NO:21 and 86, respectively. In some embodiments, the anti-galactoglobulin-9 antibody is clone G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region comprising SEQ ID NO:22. HIn some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH region defined by SEQ ID NO:22. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions defined by SEQ ID NO:21 and 22, respectively. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions defined by SEQ ID NO:21 and 22, respectively. In some embodiments, the anti-galactoglobulin-9 antibody is clone G9.1-8.

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

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

[0022] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL region shown in SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VH region shown in SEQ ID NO: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) sequence identity with the VH region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region shown in SEQ ID NO: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 thereof) sequence identity with the VH region shown in SEQ ID NO: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) sequence identity with the VH region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VL region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH region shown in SEQ ID NO: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) of the VH region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VL region shown in SEQ ID NO:13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69 and 71, and ... The VH regions shown in NO: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 are VH regions with at least 80% (e.g. 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity.

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

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

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

[0027] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) the VL CDR1 amino acid sequence shown in SEQ ID NO:328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) the VL CDR3 amino acid sequence selected from SEQ ID NO:341-360; (d) the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 427, 428, 431, 435, 436, 437; (e) the VHCDR2 amino acid sequence selected from SEQ ID NO:362, 363, 387-389 and 446-466; and (f) the VH CDR3 amino acid sequence selected from SEQ ID NO:390-417. Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) the VL CDR1 amino acid sequence shown in SEQ ID NO:328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340; (d) the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 424-434; (e) the VH CDR2 amino acid sequence selected from SEQ ID NO:362-366 and 438-445; and (f) the VH CDR3 amino acid sequence selected from SEQ ID NO:367-386.

[0028] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion 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, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 comprises X1X2X3X4X5X6X7X8X9X... 10 KX11X 12 X 13GMDY (SEQ ID NO:468), where X1 = Y or S, X2 = T, S or not present, X3 = Y, S or not present, X4 = S or not present, X5 = W, S or not present, X6 = S or not present, X7 = G, S or not present, X8 = G, T, S or not present, X9 = I, Y, S or not present, 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-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 is composed of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 is composed of X1X2X3X4X5SX6X7X8SYADSVKG (SEQ ID NO:467), wherein X1 = Y or S, X2 = I or S, X3 = Y or S, X4 = P or S, X5 = Y or S, X6 = G or S, X7 = Y or S, and X8 = T or S. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 is composed of X1X2X3X4X5X6X7X8X9X 10 KX 11 X 12 X 13 The GMDY (SEQ ID NO:468) is composed of X1 = Y or S, X2 = T, S or not present, X3 = Y, S or not present, X4 = S or not present, X5 = W, S or not present, X6 = S or not present, X7 = G, S or not present, X8 = G, T, S or not present, X9 = I, Y, S or not present, 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-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 is composed of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 is composed of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 is composed of SEQ ID NO:337. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 comprises SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR2 comprises SEQ ID NO:366. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR3 comprises SEQ ID NO:383. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 is composed of SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR2 is composed of SEQ ID NO:366. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR3 is composed of SEQ ID NO:383.In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the anti-galactoglobulin-9 antibody comprises the same VH CDR as G9.1-8m13. In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 383, respectively. In one specific embodiment, the anti-galactoglobulin-9 antibody comprises the same VLCDR and VH CDR as G9.1-8m13.

[0030] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 comprises SEQ ID NO:352. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 is composed of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 is composed of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 is composed of SEQ ID NO:352. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the anti-galactoglobulin-9 antibody comprises the same VL CDR as G9.2-17. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the antibody contains the same VH CDR as G9.2-17. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion contains heavy chain variable regions and light chain variable regions, wherein the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 406, respectively.In one specific embodiment, the anti-galactoglobulin-9 antibody contains the same VL CDR and VH CDR as G9.2-17.

[0031] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1 amino acid sequence shown 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 thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340; and (d) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340; and (d) a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340. (e) VH CDR1 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR1 amino acid sequences shown in NO:361, 427, 428, 431, 435, 436, 437; (f) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR2 amino acid sequences selected from SEQ ID NO:362-366 and 438-445; and (c) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR3 amino acid sequences selected from SEQ ID NO:367-386.Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1 amino acid sequence shown 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 thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR3 amino acid sequence selected from SEQ ID NO:341-360; and (d) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR3 amino acid sequence selected from SEQ ID NO:341-360; and (d) a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1 amino acid sequence shown in SEQ ID NO:328. (e) VH CDR1 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR1 amino acid sequences shown in NO:361, 424-434; (f) VH CDR2 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR2 amino acid sequences selected from SEQ ID NO:362, 363, 387-389 and 446-466; and (f) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR3 amino acid sequences selected from SEQ ID NO:390-417.

[0032] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 328, 329, and 337. In some embodiments, the amino acid sequences of antibody VL CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of VL CDR1, CDR2, and CDR3 of G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 361, 366, and 383. In some embodiments, the amino acid sequences of antibody VH CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VHCDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13. In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 328, 329, and 337, respectively; and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 361, 366, and 383, respectively.In one specific embodiment, the amino acid sequences of antibodies VL CDR1, CDR2, and CDR3, and VH CDR1, CDR2, and CDR3, respectively, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with those of G9.1-8m13. In some embodiments, the anti-galactogenin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with those of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 328, 329, and 352. In some embodiments, the amino acid sequences of antibody VL CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of VL CDR1, CDR2, and CDR3 of G9.2-17, respectively. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the amino acid sequences of antibody VH CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of VH CDR1, CDR2, and CDR3 of G9.2-17, respectively.In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 328, 329, and 352, respectively, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 361, 388, and 406, respectively. In one specific embodiment, the amino acid sequences of antibodies VL CDR1, CDR2, and CDR3, as well as VH CDR1, CDR2, and CDR3, have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of VL CDR1, CDR2, and CDR3 and VH CDR1, CDR2, and CDR3 of G9.2-17.

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

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

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

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

[0042] In one embodiment, the anti-galactoglobulin-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 thereof) sequence identity with 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 thereof) sequence identity with SEQ ID NO:157. In another embodiment, the anti-galactoglobulin-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 thereof) sequence identity with 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 thereof) sequence identity with SEQ ID NO:210. In one embodiment, the anti-galactoglobulin-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 thereof) sequence identity with 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 thereof) sequence identity with SEQ ID NO:263. In another embodiment, the anti-galactoglobulin-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 thereof) sequence identity with 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 thereof) sequence identity with SEQ ID NO:316.

[0043] Any anti-galactoglobulin-9 antibody described herein may comprise a heavy chain variable region framework of VH 3-48; and / or a light chain variable region framework of Vκ1-39. In some embodiments, any VH and / or VL framework described herein is a germline VH and / or VL gene. In some embodiments, the anti-galactoglobulin-9 antibody described herein is a full-length antibody (e.g., an IgG molecule) or its antigen-binding fragment. In some instances, the antibody is a Fab or single-chain antibody. In any case, the antibody may be a human antibody or a humanized antibody.

[0044] On the other hand, this disclosure provides isolated nucleic acids or sets of nucleic acids that encode or co-encode any anti-galactoglobulin-9 antibody disclosed herein. In some cases, the heavy and light chains of the antibody are encoded by two separate nucleic acid molecules (nucleic acid sets). In other cases, the heavy and light chains of the antibody are encoded by a single nucleic acid molecule, which may be in a polycistronic form or under the control of different promoters. In some embodiments, the nucleic acid or set of nucleic acids resides on one or two vectors. In some instances, the one or two vectors may be one or two expression vectors. Furthermore, this disclosure provides host cells containing any isolated nucleic acid or set of nucleic acids encoding the anti-galactoglobulin-9 antibody described herein.

[0045] This article also provides a method for generating anti-galactagogue-9 antibodies, which includes culturing the host cells described herein under suitable conditions that allow antibody expression, and harvesting the resulting antibodies from the cell culture (e.g., from a culture medium).

[0046] In addition, this disclosure provides pharmaceutical compositions comprising any anti-galactoglobulin-9 antibody or nucleic acid encoding an anti-galactoglobulin-9 antibody, and a pharmaceutically acceptable carrier.

[0047] On the other hand, this disclosure is characterized by a method for inhibiting galactagogue-9-mediated cell signaling in a subject, the method comprising administering an effective amount of an anti-galactagogue-9 antibody or a pharmaceutical composition comprising an anti-galactagogue-9 antibody to a subject in need. In some embodiments, the anti-galactagogue-9 antibody is any anti-galactagogue-9 antibody disclosed herein or a pharmaceutical composition comprising such antibody. In some embodiments, the subject in need is a person who has, is suspected of having, or is at risk of having an autoimmune disease, solid tumor, microbial disease, hematologic malignancy, or allergic disease. Exemplary autoimmune diseases include, but are not limited to, rheumatoid diseases (e.g., rheumatoid arthritis), autoimmune respiratory diseases, autoimmune metabolic and / or endocrine disorders (e.g., type 1 diabetes) or fibrotic diseases. Exemplary solid tumors include, but are not limited to, pancreatic ductal adenocarcinoma (PDA), colorectal cancer (CRC), melanoma, cholangiocarcinoma, breast cancer, small cell and non-small cell lung cancer, upper and lower gastrointestinal malignancies, gastric cancer, squamous cell head and neck cancer, genitourinary cancer, hepatocellular carcinoma, ovarian cancer, sarcoma, mesothelioma, glioblastoma, esophageal cancer, bladder cancer, urothelial carcinoma, kidney cancer, cervical cancer, and endometrial cancer. Exemplary hematologic malignancies include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myedysplastic syndromes or myeloproliferative neoplasms, and other myeloproliferative and myelodyplastic disorders. In some instances, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galactagogue-9 and Dectin-1. In some embodiments, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galactagogue-9 and CD206. Alternatively or additionally, but not limited to, an effective amount of the pharmaceutical composition is sufficient to block the interaction between galactagogue-9 and Tim-3.

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

[0049] Any treatment method described herein may further include administering to the subject an inhibitor of a checkpoint molecule, an activator of a co-stimulatory receptor, or an inhibitor of a target of innate immune cells. 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 co-stimulatory receptors include, but are not limited to, OX40, GITR, CD137, CD40, CD27, and ICOS. Examples of targets of innate immune cells include, but are not limited to, KIR, NKG2A, CD96, TLR, and IDO.

[0050] This disclosure also provides pharmaceutical compositions for use in treating diseases associated with galactagogue-9 (e.g., those described herein), wherein said pharmaceutical compositions comprise an anti-galactagogue-9 antibody, such as any of the anti-galactagogue-9 antibodies described herein, or a nucleic acid encoding such an antibody, and a pharmaceutically acceptable carrier. Additionally, this disclosure provides the use of anti-galactagogue-9 antibodies or nucleic acids encoding nucleic acids in the preparation of medicaments for treating the target diseases described herein.

[0051] Details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will become apparent from the following drawings and detailed description of several embodiments, as well as from the appended claims. Attached Figure Description

[0052] The following figures form part of this specification and are included to further illustrate certain aspects of this disclosure. A better understanding of certain aspects of this disclosure can be achieved by referring to the figures and the detailed description of specific embodiments given herein.

[0053] Figure 1A-1B This includes a graph showing the binding characteristics of Fab to galactagogue-9CRD2 using phage ELISA. Figure 1A Binding to human and mouse galactagogue-9CRD2 was demonstrated by phage ELISA. Figure 1B Affinity of Fab clones to galactagogue-9CRD2 determined by competitive phage ELISA.

[0054] Figure 2A-2B This includes a graph showing the binding characteristics of Fab to galactagogue-9CRD1 using phage ELISA. Figure 2A The binding of the Fab clone to human and mouse galactagogue-9CRD1 was shown by phage ELISA. Figure 2B The affinity of Fab clones identified by competitive phage ELISA for galactagogue-9CRD1 was determined.

[0055] Figures 3A-3B Includes a graph showing epitope binning of G.9-2Fab clones (bound to CRD2) using a competitive phage ELISA. Figure 3A : The wells coated with mouse galactagogue-9CRD2 were pre-incubated with purified G9.2-1 or G9.2-3 Fab, and then phage-displayed galactagogue-9CRD2 binding Fab clones were added. Figure 3B The wells coated with human galactagogue-9CRD2 were pre-incubated with purified G9.2-15 or G9.2-17 Fab, and then phage-displayed galactagogue-9CRD2 binding Fab clones were added.

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

[0057] Figure 5 This includes a graph showing the affinity of purified G9.1 Fab with galactagogue-9CRD1, characterized using a bead-based binding assay. Figure 4 The experiments were conducted in the same manner. 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 This includes a graph showing surface plasmon resonance analysis of Fab G9.2-15 and Fab G9.2.17, illustrating the binding of human (top) and mouse (bottom) galactagogue-9 to CRD2. The binding and dissociation phases of the experiment are marked in the top inset. Left: Fab G9.2-15. Right: Fab G9.2-17.

[0059] Figure 7 The graph includes a SPR analysis of G9.2-17 human IgG4 showing its binding to CRD2 of human (top) and mouse (bottom) galactagogue-9. The gray line shows the sensor plot of the non-binding negative control G9.2-iso human IgG4.

[0060] Figure 8 Includes a graph showing galactagogue-9CRD2 staining of cell line samples using Fab. Histograms of flow cytometry data are also 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 This is a graph showing the inhibitory effects of G9.2-17 and G9.1-8 on the activation of galactagogue-9-mediated Dectin-1 signal transduction.

[0062] Figures 10A-10B This includes a diagram showing epitope mapping of G.9-2.17 on human galactagogue-9CRD2 via systematic mutagenesis. Figure 10A The graph shows the binding activity of G9.2-17 to the galactagogue-9CRD2 mutant as determined by phage ELISA. The decreased ELISA signal indicates a site on galactagogue-9CRD2 that is crucial for G9.2-17 binding. Figure 10B A diagram depicting the position of W309 mapped onto the crystal structure of human galactagogue-9CRD2 (PDB ID 3NV2), which is opposite to the binding site of the sugar ligand mapped onto the crystal structure (W309 corresponds to W277 in UniProt ID 000182-2; PDB ID 3NV2).

[0063] Figure 11 The graphs show 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 12This image contains a surface plasmon resonance analysis of Fab G9.2-17 (top) and Fab G9.2.17mut6 (bottom) showing the binding of human (left) and mouse (right) galactagogue-9 CRD2. Human or mouse galactagogue-9 CRD2 was immobilized on an Avicap chip pre-loaded with neutralizing avidin on a Pall ForteBio Pioneer instrument. The Fab sample was then flowed using the OneStep method. The binding and dissociation phases of the experiment are marked in the top inset.

[0065] Figure 13 This is a graph showing the binding characteristics of G9.2 Fab clones to wild-type galactagogue-9CRD2 or the W309K mutant using phage ELISA. The binding of Fab clones to human galactagogue-9CRD2 was determined using phage ELISA. Biotinylated wild-type human galactagogue-9CRD2, the W309K galactagogue-9CRD2 mutant, or galactagogue-9CRD2 pre-incubated with G9.2-17 IgG was immobilized in avidin-coated wells and incubated with a single phage-displayed Fab clone.

[0066] Figure 14 This is a Kaplan-Meier plot showing that blocking galactagogue-9 significantly prolonged survival in a pancreatic cancer animal model (KPC mice).

[0067] Figure 15 The image shows a mouse tumor, demonstrating that blocking galactagogue-9 and anti-PD1 produced an excellent response.

[0068] Figure 16 This is a bar graph showing the tumor quality in mice treated with G9.2-17mIgG1. Mice with orthotopically implanted KPC tumors (n=10 / group) were treated weekly for three weeks with either a commercially available isotype (200 μg) or commercially available αGal9 (200 μg) mAb or G9.2-IsomIgG1 (200 μg) or G9.2-17mIgG1 at two doses (200 μg or 400 μg). Tumors were removed and weighed, then processed and stained for flow cytometry.

[0069] Figure 17Bar graphs were plotted to show tumor weight in mice treated with G9.2-17mIgG2a alone or in combination with αPD1 mAb. Mice with orthotopically implanted KPC tumors (n = 10 / group) were treated weekly for three weeks with commercially available αPD-1 (200 μg) mAb or G9.2-17mIgG2a (200 μg) or a combination of G9.2-17 and αPD-1 or a matched allotype. Tumors were removed and weighed, 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] Figures 18A-18C A graph depicting the binding of purified G9.1-8m1-5mIgG1 to human galactagogue-9CRD1, characterized by a bead-based binding assay, is presented.

[0071] Figure 19A-19G A graph depicting the binding of purified G9.1-8m6-11Fab to human galactagogue-9CRD1, characterized by a bead-based binding assay, is presented.

[0072] Figures 20A-20C A graph depicting the affinity of purified G9.1-8m8, 9, and 11mIgG2a antibodies, characterized by a bead-based binding assay, for human galactagogue-9CRD1 is presented.

[0073] Figures 21A-21D A graph depicting the binding of purified G9.1-8m11-14Fab to human galactagogue-9CRD1, characterized by a bead-based binding assay, is presented.

[0074] Figures 22A-22D A graph depicting the binding of purified G9.1-8m12-14mIgG2a antibody to human galactagogue-9CRD1, characterized by a bead-based binding assay, is presented.

[0075] Figure 23 A graph depicting the results of the apoptosis assay shows that the Gal-9 antibody inhibits galactagogue-9-induced apoptosis in Jurkat cells. Jurkat cells were treated for 6 hours with or without galactagogue-9 (280 nM), G9.2-17 IgG (1 μM), and / or G9.1-8m13 IgG (1 μM). Figure 23Cells were then stained with annexin V and PI, followed by flow cytometry analysis. Annexin V-positive cells represent cells in early and late apoptosis. Bars represent the means of three replicates, and data points are represented individually. Statistical analysis was performed using an unpaired Student's t-test. (*p<0.05; **p<0.01; ***p<0.001; ****p<0.0001).

[0076] Figure 24 The graphs depicting the readings from the assay demonstrate that the anti-galactogenin-9 antibody disclosed herein disrupts the interaction between galactogenin-9 and CD206. Figure 24 A graph depicting an ELISA measuring the interaction between immobilized human galactagogue-9 and soluble CD206 in the absence and with the addition of G9.1-8m13 or G9.2-17 antibodies is shown. Wells coated with galactagogue-9 were incubated with CD206 with or without G9.1-8m13, G9.2-17, a combination of both antibodies, or the same antibody. (Experiments were 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 G9.1-8m13 and G9.2-17 antibodies inhibit the interaction between galactagogue-9 and CD206, and that their effects are additive.

[0077] Figure 25 A line graph was plotted showing the binding of purified G9.1-8m12-14 mIgG2a antibody to human galactagogue-9CRD2 compared to G9.1-8(WT), characterized by a bead-based binding assay.

[0078] Figure 26A and 26B A bar graph was plotted showing the difference in TNF-α levels in CD3+ T cells of patient-derived organoid tumor spheroids (PDOTS) from primary pancreatic adenocarcinoma tumor samples treated with G9.2-17IgG4 (100 nM) compared to an isotype control (100 nM). Figure 26A ) and IFNγ ( Figure 26B The expression of ).

[0079] Figures 27A-27C A bar graph was plotted showing the CD44 (CD3+ T cells) in patient-derived organoid tumor spheroids (PDOTS) of primary pancreatic adenocarcinoma tumor samples treated with G9.2-17IgG1 (100 nM) or G9.2-17IgG4 (100 nM) compared to IgG1 or IgG4 isotype controls (100 nM). Figure 27A), TNF-α Figure 27B ) and IFNγ ( Figure 27C The expression of ).

[0080] Figures 28A-28F A bar graph depicts the immunomodulatory profile of gallbladder cancer tumor samples (PDOTS) treated with G9.2-17IgG4 (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 ), TNF-α in CD8+ T cells ( Figure 28F ).

[0081] Figures 29A-29C A bar graph was plotted showing the CD44 (G9.2-17IgG1 (100 nM)) levels in CD3+ T cells of liver metastasis samples from colorectal cancer patients (PDOTS) treated with G9.2-17IgG1 (100 nM) or G9.2-17IgG4 (100 nM) compared to IgG1 (100 nM) or untreated controls (Utx). Figure 29A ), TNF-α Figure 29B ) and IFNγ ( Figure 29C )Express.

[0082] Figure 30 A line graph illustrating the role of G9.2-17 in the B16F10 subcutaneous syngeneic model was plotted. Tumors were implanted subcutaneously and the mice were treated with G9.2-17 IgG1 mouse mAb. Unless otherwise indicated in the legend, the drugs were administered intravenously (iv) on days 0 and 4.

[0083] Figure 31 A line graph depicting the role of G9.2-17 in the B16F10 subcutaneous syngeneic model is presented. Tumors were implanted subcutaneously and treated with G9.2-17 IgG2a mouse mAb. Animals were administered the drug on day 0, followed by administration every 4 days until the end of the experiment. Unless otherwise indicated in the legend, the mAb was administered intravenously.

[0084] Figure 32A graph depicting a cell-based binding assay was plotted, showing the CRL-2134 cell line incubated with biotinylated Fab and the binding of Fab detected using a neutralizing avidin conjugated with DyLight 650. Samples were then analyzed by flow cytometry. A strong signal was observed for the galactagogue-9 antibody G9.2-17, but not for the isotype control. Kk of both forms of Gal-9 antibody was also described. D The nM values ​​are as follows: G9.2-17hIgG1: 0.41±0.07; G9.2-17mIgG1: 2.91±0.66.

[0085] Figure 33A and 33B A graph depicting the thermostability assay of the anti-galactocyanin-9 antibody is presented. The first derivative of fluorescence emission is plotted as a function of temperature (-dF / dT). Melting temperature is expressed as the temperature at which the peak was observed. The thermal transition was determined by the binding change of the fluorophore SYPRO Orange (ThermoFisher) using a real-time PCR instrument at a heating rate of 1 °C per minute, essentially following the method described in: Vedadi et al., Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination; Proc Natl Acad Sci US A. 2006 Oct 24; 103(43):15835-40. Invention Details

[0086] This document provides antibodies capable of binding to galactagogue-9 (e.g., human, mouse, or both). In some embodiments, anti-galactagogue-9 antibodies bind to one or more epitopes in the CRD1 and / or CRD2 domains. Such anti-galactagogue-9 antibodies can inhibit galactagogue-9-mediated signal transduction (e.g., galactagogue-9 / Dectin-1 or galactagogue-9 / Tim-3 mediated signal transduction pathways) or eliminate pathological cells expressing galactagogue-9 by, for example, ADCC. Therefore, the anti-galactagogue-9 antibodies described herein can be used to inhibit any galactagogue-9 signal transduction and / or eliminate galactagogue-9-positive pathological cells, thereby benefiting the treatment of galactagogue-9-related diseases such as autoimmune diseases, solid tumors, allergic diseases, or hematologic disorders (e.g., hematologic malignancies).

[0087] Galactochonin-9 is a tandemly repeated lectin, a β-galactoside-binding protein, which has been shown to regulate cell-cell and cell-matrix interactions. It has been found to be strongly overexpressed in Hodgkin's disease tissues and other pathological conditions. It has also been found circulating in the tumor microenvironment (TME).

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

[0089] Furthermore, galactagogue-9 was found to interact with TIM-3, a type I cell surface glycoprotein expressed on the surface of leukemia stem cells in all acute myeloid leukemia species (except M3 (acute promyelocytic leukemia)) but not on normal human hematopoietic stem cells (HSCs). TIM-3 signaling linked by galactagogue-9 has been found to have pleiotropic effects on immune cells, inducing Th1 cell apoptosis (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, resulting in inflammation through innate immunity (Kuchroo et al., Nat Rev Immunol., 2008, 8:577-580). Furthermore, it was found that galactagogue-9 / TIM-3 signaling co-activates NF-κB and β-catenin signaling, which are two pathways promoting LSC self-renewal (Kikushige et al., Cell Stem Cell, 2015, 17(3):341-352). Anti-galactagogue-9 antibodies that interfere with galactagogue-9 / TIM-3 binding may have therapeutic effects, especially for leukemia and other hematologic malignancies. Therefore, in some embodiments, the anti-galactagogue-9 antibodies described herein disrupt the interaction between galactagogue-9 and TIM-3.

[0090] It was also found that galectin-9 interacts with CD206 (a mannose receptor highly expressed on M2-polarized macrophages), thereby promoting tumor survival (Enninga et al., CD206-positive myeloid cells bind galectin-9 and promote a tumor-supportive microenvironment. J Pathol. 2018 Aug; 245(4):468-477). Tumor-associated macrophages expressing CD206 are regulators of tumor immunosuppression, angiogenesis, metastasis, and recurrence (see, for example, Scodeller et al., Precision Targeting of Tumor Macrophages with a CD206 Binding Peptide. M1 and M2 had been described as the functional states of macrophages; Sci Rep. 2017 Nov7; 7(1):14655, and references therein). Specifically, M1 (also known as classically activated macrophages) are triggered by Th1-associated cytokines and bacterial products, express high levels of IL-12, and are tumor-killing. In contrast, M2 (so-called alternative activated macrophages) are activated by Th2-related factors, express high levels of anti-inflammatory cytokines (e.g., IL-10), and promote tumor progression (Biswas and Mantovani; Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm; Nat Immunol. 2010 Oct; 11(10):889-96). The pro-tumorigenic effects of M2 include promoting angiogenesis, promoting invasion and metastasis, and protecting tumor cells from chemotherapy-induced apoptosis (Hu et al., Functional significance of macrophages in pancreatic cancer biology; Tumour Biol. 2015 Dec; 36(12):9119–9126, and references therein). Tumor-associated macrophages are thought to have an M2-like phenotype and pro-tumorigenic effects.It has been shown that galectin-9 mediates the differentiation of bone marrow cells into the M2 phenotype (Enninga et al., Galectin-9 modulates immunity by promoting Th2 / M2 differentiation and impacts survival in patients with metastatic melanoma; Melanoma Res. 2016 Oct; 26(5):429-41). It is possible that galectin-9 binding to CD206 may lead to TAM reprogramming into the M2 phenotype, similar to what has been previously shown with dectin. Without being bound by theory, blocking the interaction between galectin-9 and CD206 could provide a mechanism by which anti-galectin-9 antibodies, such as those described in Tables 1 and 2 herein, such as antibody 9.1-8m13 and / or antibody 9.2-17, could have a therapeutic benefit. Therefore, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and CD206.

[0091] It also shows that galectin-9 interacts with protein disulfide isomerase (PDI) and 4-1BB (Bi S et al. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry; Proc Natl Acad Sci US A. 2011; 108(26):10650-5; Madiereddi et al. Galectin-9 control the therapeutic activity of 4-1BB-targeting antibodies. J Exp Med. 2014; 211(7):1433-48).

[0092] Anti-galactoglobulin-9 antibodies can be used as therapeutic agents for diseases associated with galactoglobulin-9 (e.g., diseases in which galactoglobulin-9 signal transduction plays a role). Beyond theoretical constraints, anti-galactoglobulin-9 antibodies can block galactoglobulin-9-mediated signal transduction pathways. For example, antibodies can interfere with the interaction between galactoglobulin-9 and its binding partners (e.g., Dectin-1, TIM-3, or CD206), thereby blocking signal transduction triggered by galactoglobulin-9 / ligand interactions. Alternatively or additionally, anti-galactoglobulin-9 antibodies can also exert their therapeutic effect by inducing blocking and / or cytotoxic effects against pathological cells expressing galactoglobulin-9, such as ADCC, CDC, or ADCP. Pathological cells are cells that directly or indirectly contribute to the occurrence and / or development of disease.

[0093] Therefore, this article describes anti-galactoglobulin-9 antibodies and their therapeutic use in treating diseases associated with galactoglobulin-9.

[0094] Antibodies that bind to galactagogue-9

[0095] This disclosure provides antibodies that bind to galactagogue-9 (e.g., human and / or mouse galactagogue-9).

[0096] In some cases, the anti-galactophage-9 antibody described herein binds to epitopes in the carbohydrate recognition domain (CRD) (e.g., CRD1 or CRD2) of galactophage-9. In some cases, the anti-galactophage-9 antibody may bind to both CRD1 and CRD2. Galactophage-9 is a protein well known in the art. For example, NCBI GenBank accessions BAB83625.1 and NP_034838.2 provide information on human and mouse galactophage-1, respectively. Exemplary human and mouse galactophage-9 peptides are provided herein; human galactophage-9 (isotype 1; aka “long”;) is provided as SEQ ID NO:1; human CRD1 and CRD2 are provided herein as SEQ ID NO:3 and SEQ ID NO:4, respectively; mouse galactophage-9 (isotype 1; aka “long”;) is provided as SEQ ID NO:2; mouse CRD1 and CRD2 are provided herein as SEQ ID NO:5 and SEQ ID NO:6, respectively.

[0097] The CRD1 domain (SEQ ID NO:3) of human galactagogue-9 comprises 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 (SEQ ID NO:5) of mouse galactagogue-9 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.

[0098] Galactochonin-9 peptides from other species are known in the art and can be obtained from publicly available gene databases (e.g., GenBank) using human or mouse sequences as queries. The CRD1 and CRD2 domains of the galactochonin-9 peptide can be identified by comparing the sequence of the galactochonin-9 peptide with the human or mouse galactochonin-9 sequence as described herein.

[0099] The antibodies described herein bind to galactagogue-9 or fragments thereof (e.g., CRD1 or CRD2). As used herein, the term "anti-galactagogue-9 antibody" refers to any antibody capable of binding to the galactagogue-9 polypeptide, which may have a suitable source, such as human or non-human mammals (e.g., mice, rats, rabbits, primates (e.g., monkeys, etc.)). In some embodiments, anti-galactagogue-9 antibodies can be used to therapeutically inhibit the biological activity of galactagogue-9. In some embodiments, anti-galactagogue-9 antibodies can be used in research or in diagnostic / prognostic methods, such as for detecting cells expressing galactagogue-9 in the assessment of therapeutic eligibility and / or efficacy. Alternatively or additionally, anti-galactagogue-9 antibodies can block the interaction between galactagogue-9 and its ligands (e.g., Dectin-1, TIM-3), thereby inhibiting signal transduction pathways, for example, triggered by galactagogue-9 / Dectin-1 or galactagogue-9 / TIM-3 interactions. Anti-galactoglobulin-9 antibodies can also cause cell death expressing galactoglobulin-9, for example, through antibody-dependent cell cytotoxicity (ADCC) mechanisms.

[0100] Antibodies (in various forms, which may be used interchangeably) are immunoglobulin molecules that specifically bind to a target, such as carbohydrates, polynucleotides, lipids, peptides, etc., through at least one antigen recognition site located in the variable region of an immunoglobulin molecule. As used herein, the term "antibody" (e.g., anti-galactoglobulin-9 antibody) encompasses not only complete (e.g., full-length) polyclonal or monoclonal antibodies, but also their antigen-binding fragments (e.g., Fab, Fab', F(ab')2, Fv), single chains (scFv), their mutants, fusion proteins containing antibody portions, humanized antibodies, chimeric antibodies, biantibodies, nanobodies, linear antibodies, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies), and any other modified conformation of an immunoglobulin molecule containing an antigen recognition site of desired specificity, including glycosylated variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. Antibodies (e.g., anti-galactoglobulin-9 antibody) include any class of antibodies, such as IgD, IgE, IgG, IgA, or IgM (or their subclasses), and the antibody need not be of any particular class. Immunoglobulins can be classified into different classes based on the amino acid sequence of their heavy chain constant domains. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Many of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are designated as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well-known.

[0101] Typical antibody molecules contain a heavy chain variable region (V) that is usually involved in antigen binding. H ) and light chain variable region (V L V H and V L The region can be further subdivided into highly variable regions, also known as “complementary determinant regions” (“CDRs”), interspersed with more conservative regions called “frame regions” (“FRs”). Each V H and V LIt typically consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methods known in the art, such as by Kabat definition, Chothia definition, AbM definition, and / or contact definition, all of which are well known in the art. See, for example, Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., 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; Allazikani 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).

[0102] The anti-galactoglobulin-9 antibody described herein may be a full-length antibody comprising two heavy chains and two light chains, each containing a variable domain and a constant domain. Alternatively, the anti-galactoglobulin-9 antibody may be an antigen-binding fragment of a full-length antibody. Examples of binding fragments covered in the term "antigen-binding fragment" of a full-length antibody include: (i) Fab fragments, consisting of V... L V H C L and C H (ii) A monovalent segment composed of a structural domain; (iii) A bivalent segment consisting of two Fab segments connected by a disulfide bridge in the hinge region; (iv) A segment composed of V H and C H (iv) The Fd fragment composed of a single-arm antibody; L and V H The Fv fragment composed of structural domains, the (v)dAb fragment (Ward et al., (1989) Nature 341:544-546), is composed of V H The structural domains consist of (vi) separate complementary determinant regions (CDRs) that preserve functionality. Furthermore, although the two structural domains V of the Fv segment... L and V HEncoded by different genes, but they can be linked together via synthetic adapters using recombination methods, thus forming a single protein chain, where V L and V H The regions pair to form monovalent molecules called single-chain Fv (scFv). See, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0103] The anti-galactoglobulin-9 antibodies described herein (as shown in Tables 1 and / or 2) can bind to and inhibit (e.g., reduce or eliminate) the activity of galactoglobulin-9. In some embodiments, the anti-galactoglobulin-9 antibodies described herein can bind to and inhibit the activity of galactoglobulin-9 by at least 30% (e.g., 31%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). The apparent inhibition constant (Ki) app or K i,app The measure of inhibitory efficacy provided is related to the concentration of inhibitor required to reduce enzyme activity, but not to the enzyme concentration. The inhibitory activity of the anti-galactoglobulin-9 antibody described herein can be determined using conventional methods known in the art.

[0104] antibody K i , app The apparent Ki value can be determined by measuring the inhibitory effect of different antibody concentrations on the degree of reaction (e.g., enzyme activity); the change in the pseudo-first-order rate constant (v) as a function of inhibitor concentration is fitted to the modified Morrison equation (Equation 1) to obtain an estimate of the apparent Ki value. For competitive inhibitors, Ki app Available from K i, app The y-intercept was obtained from the linear regression analysis of the substrate concentration plot.

[0105]

[0106] Where A equals v o / E, the initial rate (v) of the enzymatic reaction in the absence of inhibitor (I). o Divide by the total enzyme concentration (E). In some embodiments, the anti-galactoglobulin-9 antibody described herein is effective against the Ki of the target antigen or epitope. appValues ​​can be 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 smaller. In some embodiments, the anti-galactoglobulin-9 antibody may have a lower Ki value for the first target (e.g., galactoglobulin-9 CRD1) relative to the second target (e.g., galactoglobulin-9 CRD2). app Ki app The difference (e.g., for specificity or other comparisons) can be 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 instances, anti-galactoglobulin-9 antibodies inhibit the first antigen (e.g., the first protein in the first conformation or its mimicry) to a greater extent than the second antigen (e.g., the same first protein in the second conformation or its mimicry). In some embodiments, any anti-galactoglobulin-9 antibody may undergo further affinity maturation to reduce the Ki of the antibody against the target antigen or its epitope. app .

[0107] In some embodiments, anti-galactoglobulin-9 antibodies (e.g., in tumor-infiltrating immune cells, such as macrophages) inhibit Dectin-1 signaling. In some embodiments, the anti-galactoglobulin-9 antibody inhibits Dectin-1 signaling triggered by galactoglobulin-9 by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof). This inhibitory activity can be determined by conventional methods or by the assays described herein (e.g., Example 2). Alternatively or additionally, the anti-galactoglobulin-9 antibody may inhibit T-cell immunoglobulin mucin 3 (TIM-3) signaling initiated by galactoglobulin-9. In some embodiments, anti-galactoglobulin-9 antibodies (e.g., in tumor-infiltrating immune cells) inhibit T-cell immunoglobulin mucin 3 (TIM-3) signaling, for example, in some embodiments inhibiting at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). This inhibitory activity can be determined by conventional methods or by the assays described herein (e.g., Example 2).

[0108] In some embodiments, anti-galactoglobulin-9 antibodies (e.g., in tumor-infiltrating immune cells) inhibit CD206 signaling. In some embodiments, the anti-galactoglobulin-9 antibody results in at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof) inhibition of CD206 signaling triggered by galactoglobulin-9. This inhibitory activity can be determined by conventional methods or by the assays described herein (e.g., Example 13). In some embodiments, the anti-galactoglobulin-9 antibody blocks or prevents the binding of galactoglobulin-9 to CD206 by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof). This inhibitory activity can be determined by conventional methods or by the assays described herein (e.g., Example 13).

[0109] In some embodiments, any anti-galactotropic antibody described herein induces cytotoxicity, such as ADCC, in target cells expressing galactotropic 9, for example, where the target cells are cancer cells or immunosuppressive immune cells. In some embodiments, the anti-galactotropic antibody induces at least 30% apoptosis in immune cells (e.g., T cells) or cancer cells (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof). This inhibitory activity can be determined by conventional methods or by the assays described herein (e.g., Example 14). In some embodiments, any anti-galactotropic antibody described herein induces cytotoxicity against target cells expressing galactotropic 9, such as complement-dependent cytotoxicity (CDC).

[0110] Antibody-dependent cell-mediated phagocytosis (ADCP) is an important mechanism by which antibodies mediate some or all of their effects 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, with FcγRIIa (CD32a) on macrophages representing the major pathway.

[0111] In some embodiments, any anti-galactoglobulin-9 antibody described herein induces phagocytosis (ADCP) in target cells expressing galactoglobulin-9 (e.g., cancer cells or immunosuppressive immune cells). In some embodiments, the anti-galactoglobulin-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).

[0112] In some embodiments, any anti-galactotropic antibody described herein induces cytotoxicity against target cells (e.g., cancer cells or immunosuppressive immune cells), such as complement-dependent cytotoxicity (CDC). In some embodiments, the anti-galactotropic 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 increments thereof).

[0113] In some embodiments, any anti-galactoglobulin-9 antibody described herein induces T cell activation (e.g., in tumor-infiltrated T cells), i.e., directly or indirectly inhibits galactoglobulin-9-mediated inhibition of T cell activation. In some embodiments, the anti-galactoglobulin-9 antibody promotes T cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof). T cell activation can be determined by conventional methods or by assays described herein (e.g., Example 6 (e.g., measurements of CD44, OX40, IFNγ, PD-1)). In some embodiments, the anti-galactoglobulin-9 antibody promotes CD4+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments thereof). In one non-limiting example, the anti-galactoglobulin-9 antibody induces CD44 expression in CD4+ cells. In some embodiments, the anti-galactoglobulin-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 increments therein). In one non-limiting example, the anti-galactoglobulin-9 antibody induces IFNγ expression in CD4+ cells. In some embodiments, the anti-galactoglobulin-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 increments therein). In one non-limiting example, the anti-galactoglobulin-9 antibody induces TNFα expression in CD4+ cells. In some embodiments, the anti-galactoglobulin-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).

[0114] In some embodiments, the anti-galactoglobulin-9 antibody promotes CD8+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increments therein). In one non-limiting example, the anti-galactoglobulin-9 antibody induces CD44 expression in CD8+ cells. In some embodiments, the anti-galactoglobulin-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 increments therein). In one non-limiting example, the anti-galactoglobulin-9 antibody induces IFNγ expression in CD8+ cells. In some embodiments, the anti-galactoglobulin-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 increments therein). In a non-limiting example, the anti-galactoglobulin-9 antibody induces TNFα expression in CD8+ cells. In some embodiments, the anti-galactoglobulin-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 increments therein).

[0115] The antibodies described herein may be of mouse, rat, human, or any other origin (including chimeric or humanized antibodies). Such antibodies are not naturally occurring, meaning they will not be produced in animals without human intervention (e.g., immunizing such animals with a desired antigen or fragment thereof, or isolating them from an antibody library).

[0116] Any antibody described herein (e.g., anti-galactoglobulin-9 antibody) may be monoclonal or polyclonal. "Monoclonal antibody" refers to a homogeneous group of antibodies, and "polyclonal antibody" refers to a heterogeneous group of antibodies. These terms do not limit the source of the antibody or how it is prepared.

[0117] In some embodiments, the anti-galactoglobulin-9 antibody is a humanized antibody. In some embodiments, the anti-galactoglobulin-9 antibody is a humanized antibody having one or more elements or features described below or elsewhere herein. A humanized antibody refers to a form of non-human (e.g., mouse) antibody that is a specific chimeric immunoglobulin, immunoglobulin chain, or antigen-binding fragment thereof containing a minimal sequence derived from a non-human immunoglobulin. Typically, a humanized antibody is a human immunoglobulin (receptor antibody) in which the CDR residues of the receptor are replaced with CDR residues from a non-human species (donor antibody) such as mouse, rat, or rabbit, having the desired specificity, affinity, and capacity. In some cases, the Fv frame region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, humanized antibodies may contain residues that are not present in either the receptor antibody or the introduced CDR or frame sequence but are included to further refine and optimize antibody performance. In some cases, humanized antibodies may contain substantially all of at least one and typically two variable domains, wherein all or substantially all of the CDR regions correspond to those of non-human immunoglobulins and all or substantially all of the FR regions are those of human immunoglobulin common sequences. Humanized antibodies preferably also contain at least a portion of immunoglobulin constant regions or domains (Fc), typically of human immunoglobulins. The antibody may have an Fc region modified as described in WO 99 / 58572. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, or six) altered relative to the original antibody, also referred to as one or more CDRs “derived” from the original antibody. Humanized antibodies may also involve affinity maturation.

[0118] Methods for constructing humanized antibodies are also well known in the art. See, for example, Queen et al., Proc. Natl. Acad. Sci. USA, 86:10029-10033 (1989). In one instance, the V of a parental nonhuman antibody was prepared according to methods known in the art. H and V L Three-dimensional molecular modeling analysis was performed on the variable region. Next, the same molecular modeling analysis was used to identify the framework amino acid residues expected to be important for the formation of the correct CDR structure. In parallel, parental V... H and V L Using sequences as search queries, identify human V antibodies with amino acid sequences homologous to the parental non-human antibody from any antibody gene database. H and V L Chain. Then select person V. H and V L Receptor gene.

[0119] The selected CDR region within the human receptor gene can be replaced by a CDR region from a parental nonhuman antibody or a functional variant thereof. If necessary, the corresponding residues in the human receptor gene can be replaced with residues within the parental stroma framework region that are expected to play an important role in interacting with the CDR region.

[0120] In some embodiments, the anti-galactoglobulin-9 antibody is a chimeric antibody. In some embodiments, the anti-galactoglobulin-9 antibody is a chimeric antibody that may comprise a heavy constant region and a light constant region derived from a human antibody. A chimeric antibody is 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 the light and heavy chains mimic the variable regions derived from an antibody of one mammalian species (e.g., a non-human mammal, such as a mouse, rabbit, and rat), while the constant portions are sequence homologous to those of an antibody derived from another mammal (e.g., a human). In some embodiments, amino acid modifications may be made in the variable and / or constant regions.

[0121] In some embodiments, the anti-galactoglobulin-9 antibodies described herein specifically bind to a corresponding target antigen or its epitope, such as the galactoglobulin-9 antigen or epitope. "Specifically binding" an antibody to an antigen or epitope is a well-known term in the art. A molecule is said to exhibit "specific binding" if it reacts more frequently, more rapidly, for a longer duration, and / or with a greater affinity than with an alternative target. An antibody is said to "specifically bind" a target antigen or epitope if it binds to the target antigen or epitope with greater affinity, antibody affinity, easier binding, and / or for a longer duration than binding to other substances. For example, an antibody that specifically (or preferentially) binds to an antigen (galactoglobulin-9) or an antigenic epitope therein is an antibody that binds to the target antigen with greater affinity, antibody affinity, easier binding, and / or for a longer duration compared to binding to other antigens or other epitopes of the same antigen. It should also be understood for this definition that, for example, an antibody that specifically binds to a first target antigen may or may not specifically bind to or preferentially bind to a second target antigen. Thus, “specific binding” or “preferential binding” does not necessarily require (although it may include) exclusive binding. In some instances, antibodies that “specifically bind” to a target antigen or its epitope may not bind to other antigens or other epitopes of the same antigen (i.e., only baseline binding activity can be detected in conventional methods). In some embodiments, the anti-galactoglobulin-9 antibody described herein specifically binds to galactoglobulin-9. In some embodiments, the anti-galactoglobulin-9 antibody described herein specifically binds to CRD2 of galactoglobulin-9. In some embodiments, the anti-galactoglobulin-9 antibody described herein specifically binds to CRD1 of galactoglobulin-9. Alternatively or additionally, the anti-galactoglobulin-9 antibody described herein specifically binds to human galactoglobulin-9 or fragments thereof relative to the mouse counterpart, and vice versa (e.g., the binding affinity with one antigen is at least 10 times higher than the binding affinity with another antigen, as determined in the same assay under the same assay conditions).

[0122] In some embodiments, the anti-galactoglobulin-9 antibody binds only to CRD1 (and not to CRD2), for example, meaningless binding to CRD2 cannot be detected by conventional assay methods. In some embodiments, anti-galactoglobulin-9 or a 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 described herein or a fragment thereof may bind to both CRD1 and CRD2, but have a lower affinity for CRD2. In some embodiments, certain antibodies described herein or a fragment thereof may bind to both CRD1 and CRD2, but have a lower affinity for CRD1.

[0123] In some embodiments, the effects of the Gal-9 antibody binding CRD1 and the Gal-9 antibody binding CRD2 may be additive. In some embodiments, the effects of the Gal-9 antibody binding CRD1 and the Gal-9 antibody binding CRD2 may be synergistic. In some embodiments, a “cocktail” of two or more antibodies, i.e., a mixture, may be used in the composition. Such a composition may contain one or more antibodies described herein that bind to CRD1 and one or more antibodies described herein that bind to CRD2. In a non-limiting example, an antibody containing the variable region of clones 9.1-8m13 (e.g., SEQ ID NO:21 (light chain and SEQ ID NO:86)) may be combined with an antibody containing the variable region of clones 9.2-17 (SEQ ID NO:54 (light chain and SEQ ID NO:55) in the composition. The two antibodies may be mixed in equimolar amounts or in other proportions determined to be optimal for performance.

[0124] In some embodiments, the antibody may bind to both CRD1 and CRD2. In other cases, the anti-galactogenin-9 antibody described herein may cross-react with human and non-human galactogenin-9 (e.g., mouse), for example, with a binding affinity to human and non-human galactogenin-9 that differs by less than 5-fold, for example less than 2-fold, or substantially similar.

[0125] In some embodiments, the anti-galactoglobulin-9 antibody described herein has a suitable binding affinity for the target antigen (e.g., galactoglobulin-9) or its antigenic epitope. As used herein, “binding affinity” refers to the apparent association constant or K0. A K A It is the dissociation constant (K) D The reciprocal of ). The binding affinity (K) of the anti-galactogenin-9 antibody described in this article to the target antigen or antigenic epitope. D (at least 10) -5 10 -6 10 -7 10 -8 10 -9 10 -10 M or smaller. Increased binding affinity corresponds to K. D Decrease. The higher affinity of an antibody for the first antigen compared to the second antigen can be achieved by binding to the K+ receptor of the second antigen. A (or numerical value K) D Compared to the higher K binding to the first antigen A (or a smaller value K) DThis indicates that, in such cases, the antibody is specific to the first antigen (e.g., the first protein or its mimicry in the first conformation) relative to the second antigen (e.g., the same first protein in the second conformation; or the second protein). In some embodiments, the anti-galactogenin-9 antibody described herein has a higher binding affinity (higher Kc) to CRD1 of galactogenin-9 compared to its binding affinity to CRD2 of galactogenin-9. A or smaller K D In some embodiments, the anti-galactoglobulin-9 antibody described herein has a higher binding affinity for CRD2 of galactoglobulin-9 compared to its binding affinity for CRD1 (higher Kc). A or smaller K D Differences in affinity (e.g., for specificity or other comparisons) can be 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 anti-galactoglobulin-9 antibody may undergo further affinity maturation to enhance the binding affinity of the antibody to the target antigen or its epitope.

[0126] Binding affinity (or binding specificity) can be determined by a variety of methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopic methods (e.g., using fluorescence assays). 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).

[0127] These techniques can be used to measure the concentration of bound proteins as a function of the target protein concentration. Under certain conditions, the concentration fraction of bound proteins ([bound] / [total]) is typically correlated with the total target protein concentration ([target]) using the following formula:

[0128] [Combined] / [Total] = [Target] / (Kd+[Target])

[0129] However, it is not always necessary to determine K precisely. A Because sometimes obtaining a quantitative measurement of affinity is sufficient, for example, by using methods such as ELISA or FACS analysis, with K AThe affinity is proportional, and therefore can be used for comparison, such as determining whether a higher affinity is, for example, 2-fold higher, to obtain a qualitative measurement of affinity, or to obtain affinity inference, for example, through activity in a functional assay (e.g., in vitro assay). In some cases, in vitro binding assays indicate in vivo activity. In other cases, in vitro binding assays do not necessarily indicate in vivo activity. In some cases, tight binding is beneficial, but in other cases, tight binding may be less desirable in vivo, and antibodies with lower binding affinity may be more desirable. This article provides many exemplary anti-galactoglobulin-9 antibodies (specific to CRD1 or CRD2).

[0130] Exemplary antibody clones (reference antibodies) that bind to CRD1 in this disclosure 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) that bind to CRD2 in this disclosure 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.

[0131] Variable region

[0132] The exemplary anti-galactogen-9 antibodies that bind to CRD1 described herein are antibodies having the CDR and / or variable region sequences of the following antibodies, such as monoclonal, recombinant, and / or human 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, 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 exemplary anti-galactogen-9 antibodies that bind to CRD2 described herein are antibodies having the CDR and / or variable region sequences of the following antibodies, such as monoclonal, recombinant, and / or human 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, G9.2-9, 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, G9.2-10, G9.2-1 ... 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 method are shown in bold. Table 3 shows the CDRs of selected clones determined using the Kabat method. In this document, the terms “m” and “mut”, such as “9.1-8m” and “9.1-8mut”, are used interchangeably.For example, “G9.1-8m1”, “G9.1-8m2”, “G9.1-8m3”, “G9.1-8m4”, “G9.1-8m5”, “G9.1-8m6”, “G9.1-8m7”, “G9.1-8m8”, “G9.1-8m9”, “G9.1-8m10”, “G9.1-8m11”, “G9.1-8m12”, “G9.1-8m13”, and “G9.1-8m14” can be respectively associated with “G9.1-8mut1”. The following are interchangeable: “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”.

[0133] Table 1. Antibodies against CRD1

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] Table 2. Antibodies against CRD2

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] Table 3. Selected antibody CDR sequences

[0148]

[0149]

[0150]

[0151] As described herein, such anti-galactoglobulin-9 antibodies binding to CRD1 and CRD2 are isolated and structurally characterized. This disclosure also considers antibodies having at least 80% identity with their variable region or CDR sequence (e.g., at least 85%, at least 90%, at least 95%, or at least 99% identity). The VL amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2- are low-affinity binding agents in SEQ ID NO. NO:29, 13, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69 and 71 are shown. The VH amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26, and G9.2- are low-affinity binding agents in SEQ ID NO. NO: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. Therefore, this document provides isolated anti-galactoglobulin-9 antibodies or their antigen-binding moieties comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 NO: 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-galactoglobulin-9 antibody or its antigen-binding moiety, comprising 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 NO: 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 NO: 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. Therefore, this document provides isolated anti-galactoglobulin-9 antibody or its antigen-binding moiety, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 NO: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. Therefore, this article provides isolated anti-galactoglobulin-9 antibody or its antigen-binding moiety, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region consists of an amino acid sequence selected from SEQ ID NO: 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 NO: 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.

[0152] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having the sequence of SEQ ID NO:54. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having the sequence of SEQ ID NO:55. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having the sequence of SEQ ID NO:56. In some embodiments, the anti-galactoglobulin-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-galactoglobulin-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.

[0153] 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 respectively in SEQ ID NO. As shown in NO:7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27. The VH 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 respectively located in SEQ ID NO. As shown in SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87. Therefore, this document provides isolated anti-galactoglobulin-9 antibodies or their antigen-binding moieties comprising a heavy chain variable region 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-galactoglobulin-9 antibody or its antigen-binding moiety, comprising 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 NO: 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 is composed of an amino acid sequence selected from SEQ ID NO: 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.Therefore, this document provides isolated anti-galactoglobulin-9 antibody or its antigen-binding moiety, comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO: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 NO: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 is composed of an amino acid sequence selected from SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and 27, and the heavy chain variable region is composed of an amino acid sequence selected from SEQ ID NO: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.

[0154] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having the sequence of SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having the sequence of SEQ ID NO:22. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having the sequence of SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-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-galactoglobulin-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.

[0155] In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises any one of SEQ ID NO:7-87. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises one or more sequences selected from any sequence of SEQ ID NO:7-87, and any combination thereof.

[0156] In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises any one of SEQ ID NO:7-28 and 74-87. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises one or more sequences selected from any sequence of SEQ ID NO:7-28 and 74-87, and any combination thereof.

[0157] In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises any one of SEQ ID NO: 13, 29-73. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises one or more sequences selected from any sequence of SEQ ID NO: 13, 29-73, and any combination thereof. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises any one of SEQ ID NO: 54, 55, or 54 and 56. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises one or more sequences selected from any sequence of SEQ ID NO: 54, 55, or 54 and 56, and any combination thereof.

[0158] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region comprising SEQ ID NO: 54. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO: 55. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region consisting of SEQ ID NO: 54. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region consisting of SEQ ID NO: 55. In some embodiments, the anti-galactoglobulin-9 antibody comprises both VL and VH regions comprising SEQ ID NO: 54 and 55. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises both VL and VH regions consisting of SEQ ID NO: 54 and 55.

[0159] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region comprising SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region comprising SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region comprising SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises VL and VH regions comprising SEQ ID NO:21 and 86. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises VL and VH regions comprising SEQ ID NO:21 and 86.

[0160] In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL or VH region comprising any one of SEQ ID NO:21, 22, and 74-87. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL or VH region composed of SEQ ID NO:21, 22, and 74-87. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL and / or VH region comprising a sequence selected from SEQ ID NO:21, 22, and 74-87 and any combination thereof. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL and / or VH region composed of a sequence selected from SEQ ID NO:21, 22, and 74-87 and any combination thereof.

[0161] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:7 and SEQ ID NO:8. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:9 and SEQ ID NO:10. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:11 and SEQ ID NO:12. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:14. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:15 and SEQ ID NO:16. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:17 and SEQ ID NO:18. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:19 and SEQ ID NO:20. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:22. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:23 and SEQ ID NO:24. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:25 and SEQ ID NO:26. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:27 and SEQ ID NO:28. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:74. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:75. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:76. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:77. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:78.In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:79. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:80. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:81. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:82. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:83. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:84. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:108 and SEQ ID NO:85. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:21 and SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:29 and SEQ ID NO:30. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:31. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:32. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:33. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:34 and SEQ ID NO:35. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:36 and SEQ ID NO:37. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:38 and SEQ ID NO:39.In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:40 and SEQ ID NO:41. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:42 and SEQ ID NO:43. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:44 and SEQ ID NO:45. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:46 and SEQ ID NO:47. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:48 and SEQ ID NO:49. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:29 and SEQ ID NO:50. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:51. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:34 and SEQ ID NO:52. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:53. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:54 and SEQ ID NO:55. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:13 and SEQ ID NO:57. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:58 and SEQ ID NO:59. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:54 and SEQ ID NO:60. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:61 and SEQ ID NO:62. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:63 and SEQ ID NO:64.In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:65 and SEQ ID NO:66. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:54 and SEQ ID NO:56. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:67 and SEQ ID NO:68. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:69 and SEQ ID NO:70. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:71 and SEQ ID NO:72. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region comprising SEQ ID NO:54 and SEQ ID NO:73. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:7 and SEQ ID NO:8. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:9 and SEQ ID NO:10. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:11 and SEQ ID NO:12. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:14. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:15 and SEQ ID NO:16. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:17 and SEQ ID NO:18. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:19 and SEQ ID NO:20. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:22. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:23 and SEQ ID NO:24.In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:25 and SEQ ID NO:26. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:27 and SEQ ID NO:28. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:74. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:75. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:76. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:77. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:78. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:79. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:80. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:81. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:82. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:83. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:84. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:108 and SEQ ID NO:85. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:21 and SEQ ID NO:86.In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:29 and SEQ ID NO:30. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:31. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:32. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:33. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:34 and SEQ ID NO:35. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:36 and SEQ ID NO:37. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:38 and SEQ ID NO:39. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:40 and SEQ ID NO:41. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:42 and SEQ ID NO:43. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:44 and SEQ ID NO:45. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:46 and SEQ ID NO:47. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:48 and SEQ ID NO:49. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:29 and SEQ ID NO:50. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:51. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:34 and SEQ ID NO:52.In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:53. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:54 and SEQ ID NO:55. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:13 and SEQ ID NO:57. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:58 and SEQ ID NO:59. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:54 and SEQ ID NO:60. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:61 and SEQ ID NO:62. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:63 and SEQ ID NO:64. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:65 and SEQ ID NO:66. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:54 and SEQ ID NO:56. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:67 and SEQ ID NO:68. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:69 and SEQ ID NO:70. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region composed of SEQ ID NO:71 and SEQ ID NO:72. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region and a VH region consisting of SEQ ID NO:54 and SEQ ID NO:73.

[0162] In some embodiments, the anti-galactoglobulin-9 antibody comprises a sequence having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any anti-galactoglobulin-9 antibody described in the preceding paragraph. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region shown in SEQ ID NO:7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87) sequence identity with the VH region shown in SEQ ID NO: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) of the sequence identity. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region shown in SEQ ID NO: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 thereof) sequence identity with the VH region shown in SEQ ID NO: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) sequence identity with the VH region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL or VH region shown in SEQ ID NO:7-288 and 74-87. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL or VH region shown in SEQ ID NO:7-288 and 74-87 and any combination thereof.

[0163] In some embodiments, the anti-galactoglobulin-9 antibody comprises an antibody selected from 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, G9.1-9, 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 ... The VL regions of antibodies 9.1-8m6, 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 have VL regions with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity. In some embodiments, the anti-galactoglobulin-9 antibody comprises an antibody selected from 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, G9.1-9, 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 ... The VH regions of antibodies 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 have VH regions with at least 80% (e.g. 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity. In some embodiments, the anti-galactogenin-9 antibody comprises an antibody selected from 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, and G9.1. The VL or VH regions of antibodies 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 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity.

[0164] In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL or VH region shown in any one of SEQ ID NO:21, 22, and 74-87. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL or VH region shown in SEQ ID NO:21, 22, and 74-87 and any combination thereof.

[0165] In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region of G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH region of G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL or VH region of G9.1-8m13.

[0166] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region shown in SEQ ID NO:21. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH region shown in SEQ ID NO:86. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises VL and VH regions having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL and VH regions shown in SEQ ID NO:21 and 86.

[0167] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VL region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH region shown in SEQ ID NO: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) of the VH region shown in SEQ ID NO: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-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VL region shown in SEQ ID NO:13, 29, 34, 36, 38, 40, 42, 44, 46, 48, 29, 34, 54, 58, 61, 63, 65, 73, 67, 69 and 71, and ... The VH regions shown in SEQ ID NO: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 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL or VH regions shown in SEQ ID NO:29-75 and 77-85. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL or VH region shown in SEQ ID NO:13, 29-73, and any combination thereof. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL or VH region shown in any one of SEQ ID NO:54, 55, and 56.

[0168] In some embodiments, the anti-galactoglobulin-9 antibody comprises an antibody selected from 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- The VL regions of antibodies against 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 have VL regions with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity. In some embodiments, the anti-galactoglobulin-9 antibody comprises an antibody selected from 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- The VH regions of antibodies against 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 have VH regions with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity. In some embodiments, the anti-galactoglobulin-9 antibody comprises an antibody selected from G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, and G9.2-17m. The VL and VH regions of antibodies against G9.2-low affinity binders have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity.

[0169] In some embodiments, the anti-galactoglobulin-9 antibody comprises a heavy chain CDR having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with any one of the sequences selected from SEQ ID NO: 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) of sequence identity. Alternatively or additionally, the anti-galactoglobulin-9 antibody comprises a light chain CDR having at least 80% (e.g., 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with any one of the sequences selected from SEQ ID NO: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) of sequence identity.

[0170] In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL region of G9.2-17. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VH region of G9.2-17. In some specific embodiments, the anti-galactoglobulin-9 antibody comprises VL and VH regions having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with both the VL and VH regions of G9.2-17.

[0171] In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding fragment comprises a VL region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL region shown in SEQ ID NO: 54. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding fragment comprises a VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH region shown in SEQ ID NO: 55. In some specific embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding fragment comprises a VL and / or VH region having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL and / or VH regions shown in SEQ ID NO: 54 and 55.

[0172] Complementarity Determinant Region (CDR)

[0173] Anti-galactogen-9 antibodies (e.g., those binding to CRD1) may include G9.1-1, G9.1-2, G9.1-3, G9.1-4, G9.1-5, G9.1-6, G9.1-7, G9.1-8, G9.1-9, G9.1-10, G9.1-11, G9.1-8m1, G9.1-8m2, G9.1-8m3, and G9.1-8m4. Light chains CDR1, CDR2, and CDR3 and heavy chains CDR1, CDR2, and CDR3 of m4, G9.1-8m5, G9.1-8m6, G9.1-8m7, G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13, and G9.1-8m14 or combinations thereof. The amino acid sequences of VLCDR1 in 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 NO:328. The amino acid sequences of 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 SEQ ID NO:329. The amino acid sequences of 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 NO:330-340.The amino acid sequences of VH CDR1 in 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 NO. Shown in NO: 361, 427, 428, 431, 435, 436, 437. The amino acid sequences of 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 shown in SEQ ID NO:362-366 and 438-445. The amino acid sequences of VH CDR3 in 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 NO:367-386.

[0174] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR2 having the sequence of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR3 having a sequence selected from any one of SEQ ID NO:330-340. In some embodiments, the anti-galactoglobulin-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 one of SEQ ID NO:330-340. In some embodiments, the anti-galactoglobulin-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-galactoglobulin-9 antibody comprises a VH CDR1 having a sequence selected from any one of SEQ ID NO:361, 427, 428, 431, 435, 436, and 437. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR1 having the sequence of SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR2 having a sequence selected from any one of SEQ ID NO:362-366 and 438-445. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR2 having a sequence selected from SEQ ID NO:364 or 366. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR3 having a sequence selected from any one of SEQ ID NO:367-386. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR3 having a sequence selected from SEQ ID NO:374 or 383. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR1 having a sequence selected from any one of SEQ ID NO:361, 427, 428, 431, 435, 436, and 437, a VH CDR2 having a sequence selected from any one of SEQ ID NO:362-366 and 438-445, and a VH CDR3 having a sequence selected from any one of SEQ ID NO:367-386.In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:364, and VH CDR3 having the sequence of SEQ ID NO:374. In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:366, and VH CDR3 having the sequence of SEQ ID NO:383. In some embodiments, the anti-galactoglobulin-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, a VL CDR3 having a sequence selected from any one of SEQ ID NO:330-340, a VH CDR1 having a sequence selected from any one of SEQ ID NO:361, 427, 428, 431, 435, 436 and 437, a VH CDR2 having a sequence selected from any one of SEQ ID NO:362-366 and 438-445, and a VH CDR3 having a sequence selected from any one of SEQ ID NO:367-386. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO:328, VL CDR2 having the sequence of SEQ ID NO:329, VL CDR3 having the sequence of SEQ ID NO:337, VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:364, and VH CDR3 having the sequence of SEQ ID NO:374. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO:328, VLCDR2 having the sequence of SEQ ID NO:329, VL CDR3 having the sequence of SEQ ID NO:337, VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:366, and VH CDR3 having the sequence of SEQ ID NO:383. In any of these embodiments, the anti-galactoglobulin-9 antibody binds to CRD1.

[0175] In some embodiments, the anti-galactogen-9 antibody (e.g., bound to CRD2) comprises 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, and 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 or combinations thereof, light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3. The amino acid sequences of 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 binders are shown in SEQ ID NO:328. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26 and the VL CDR2 of the G9.2-low affinity binder are shown in SEQ ID NO:329.The amino acid sequences of 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 binders are shown in SEQ ID NO:341-360. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26 and G9.2-low affinity binders of VH CDR1 are shown in SEQ ID NO. Shown in NO:361, 424-434. The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26 and G9.2-low affinity binders of VH CDR2 are shown in SEQ ID NO. As shown in NO:362, 363, 387-389 and 446-466.The amino acid sequences of G9.2-1, G9.2-2, G9.2-3, G9.2-4, G9.2-5, G9.2-6, G9.2-7, G9.2-8, G9.2-9, G9.2-10, G9.2-11, G9.2-12, G9.2-13, G9.2-14, G9.2-15, G9.2-16, G9.2-17, G9.2-17mut6, G9.2-18, G9.2-19, G9.2-20, G9.2-21, G9.2-22, G9.2-23, G9.2-24, G9.2-25, G9.2-26 and the G9.2-low affinity binder VH CDR3 are shown in SEQ ID NO:390-417.

[0176] In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR1 having the sequence of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR2 having the sequence of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VL CDR3 having a sequence selected from any one of SEQ ID NO:341-360. In some embodiments, the anti-galactoglobulin-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 one of SEQ ID NO:341-360. In some embodiments, the anti-galactoglobulin-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-galactoglobulin-9 antibody comprises a VH CDR1 having a sequence selected from any one of SEQ ID NO:361 and 424-434. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR1 having the sequence of SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR2 having a sequence selected from any one of SEQ ID NO:362, 363, 387-389, and 446-466. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR2 having the sequence of SEQ ID NO:388. In some embodiments, the anti-galactoglobulin-9 antibody comprises a VH CDR3 having a sequence selected from any one of SEQ ID NO:390-417. In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR3 having the sequence of SEQ ID NO: 406 or 407. In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR1 having a sequence selected from any one of SEQ ID NO: 361 and 424-434, VH CDR2 having a sequence selected from any one of SEQ ID NO: 362, 363, 387-389 and 446-466, and VH CDR3 having a sequence selected from any one of SEQ ID NO: 390-417. In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO: 361, VH CDR2 having the sequence of SEQ ID NO: 388, and VH CDR3 having the sequence of SEQ ID NO: 406.In some embodiments, the anti-galactoglobulin-9 antibody comprises VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:388, and VH CDR3 having the sequence of SEQ ID NO:407. In some embodiments, the anti-galactoglobulin-9 antibody comprises VLCDR1 having the sequence of SEQ ID NO:328, VL CDR2 having the sequence of SEQ ID NO:329, VL CDR3 having a sequence selected from any one of SEQ ID NO:341-360, VH CDR1 having a sequence selected from any one of SEQ ID NO:361 and 424-434, VH CDR2 having a sequence selected from any one of SEQ ID NO:362, 363, 387-389, and 446-466, and VH CDR3 having a sequence selected from any one of 390-417. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO:328, VL CDR2 having the sequence of SEQ ID NO:329, VLCDR3 having the sequence of SEQ ID NO:352, VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:388, and VH CDR3 having the sequence of SEQ ID NO:406. In some embodiments, the anti-galactoglobulin-9 antibody comprises VL CDR1 having the sequence of SEQ ID NO:328, VL CDR2 having the sequence of SEQ ID NO:329, VL CDR3 having the sequence of SEQ ID NO:352, VH CDR1 having the sequence of SEQ ID NO:361, VH CDR2 having the sequence of SEQ ID NO:388, and VH CDR3 having the sequence of SEQ ID NO:407. In any of these embodiments, the anti-galactogenin-9 antibody binds to CRD1.

[0177] Because the binding specificity of galactagogue-9 is essentially determined by CDR1, 2, and 3 regions, the VH CDR1, 2, and 3 sequences and VL CDR1, 2, and 3 sequences disclosed above can be mixed and matched to generate new antibodies that bind galactagogue-9, provided that each resulting new antibody has both VL CDR1, 2, and 3 and VH CDR1, 2, and 3. Such antibodies generated from the new combinations of CDRs described herein can be tested using the binding assays described herein. In some embodiments, CDR1, CDR2, and / or CDR3 sequences from a specific VH or VL sequence are replaced with structurally similar CDR sequences. According to methods known in the art, new 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.

[0178] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) the VL CDR1 amino acid sequence shown in SEQ ID NO:328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) the VL CDR3 amino acid sequence selected from SEQ ID NO:330-340 and 341-360; (d) the VH CDR1 amino acid sequences shown in SEQ ID NO:361, 427, 428, 431, 435, 436, 437 and SEQ ID NO:361, 424-434; (e) the VH CDR2 amino acid sequence selected from SEQ ID NO:362-366 and 438-445, 362, 363 and 387-389 and 446-466; and (f) the VH CDR3 amino acid sequence selected from SEQ ID NO:367-386 and 390-417.

[0179] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR1 amino acid sequence shown in SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR2 amino acid sequence shown in SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR3 amino acid sequence selected from SEQ ID NO:330-340. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 427, 428, 431, 435, 436, and 437. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR2 amino acid sequence selected from SEQ ID NO:362-366 and 438-445. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR3 amino acid sequence selected from SEQ ID NO:367-386. Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) the VL CDR1 amino acid sequence shown in SEQ ID NO:328; (b) the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) the VL CDR3 amino acid sequence selected from SEQ ID NO:330-340; (d) the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 427, 428, 431, 435, 436, and 437; (e) the VH CDR2 amino acid sequence selected from SEQ ID NO:362-366 and 438-445; and (f) the VHCDR3 amino acid sequence selected from SEQ ID NO:367-386.

[0180] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR1 amino acid sequence shown in SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR2 amino acid sequence shown in SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VL CDR3 amino acid sequence selected from SEQ ID NO:341-360. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 424-434. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR2 amino acid sequence selected from SEQ ID NO:362, 363, 387-389, and 446-466. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises the VH CDR3 amino acid sequence selected from SEQ ID NO:390-417.

[0181] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) the VL CDR1 amino acid sequence shown in SEQ ID NO:328; and (b) the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) the VL CDR3 amino acid sequence selected from SEQ ID NO:341-360; (d) the VH CDR1 amino acid sequence shown in SEQ ID NO:361; (e) the VH CDR2 amino acid sequence selected from SEQ ID NO:362, 363, 387-389 and 446-466; and (f) the VH CDR3 amino acid sequence selected from SEQ ID NO:390-417.

[0182] 9.1 Antibody Cloning and Related CDRs

[0183] Cloning 9.1 - Light chain variable region of origin

[0184] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 330, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 330, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-1.

[0185] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 331, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 331, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-2.

[0186] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 332, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 332, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-3.

[0187] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-4.

[0188] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 334, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 334, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-5.

[0189] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 335, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 335, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-6.

[0190] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 336, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 336, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-7.

[0191] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-8.

[0192] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 338, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 338, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-9.

[0193] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 339, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 339, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-10.

[0194] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 340, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 340, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.1-11.

[0195] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion 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-galactoglobulin-9 antibody or its antigen-binding portion 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-galactoglobulin-9 antibody or its antigen-binding portion 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-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 is composed of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 is composed of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 is composed of SEQ ID NO:337. In some embodiments, the antibody comprises the same VL CDR as 9.1-8, 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 CDR as G9.1-8m13.

[0196] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 comprises SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy 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, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR3 comprises X1X2X3X4X5X6X7X8X9X... 10 KX 11 X 12 X 13GMDY (SEQ ID NO:468), where X1 = Y or S, X2 = T, S or not present, X3 = Y, S or not present, X4 = S or not present, X5 = W, S or not present, X6 = S or not present, X7 = G, S or not present, X8 = G, T, S or not present, X9 = I, Y, S or not present, X 10 =G, S or Y, X 11 =W or S, X 12 =V or S, and X 13 =W or S. In some instances, the anti-galactoglobulin-9 antibody contains G at X7, Y at X8, and / or T at X9 in the heavy chain CDR3 domain. Alternatively or additionally, the anti-galactoglobulin-9 antibody contains deletions at one or more of X4-X7 in the heavy chain CDR2 domain. In other instances, the anti-galactoglobulin-9 antibody contains S at one or more of X6-X8 in the heavy chain CDR2 domain. Alternatively or additionally, the anti-galactoglobulin-9 antibody contains deletions at one or more of X5-X7 in the heavy chain CDR3 domain. In yet another instance, the anti-galactoglobulin-9 antibody contains S at one or more of X6-X8 in the heavy chain CDR2 domain. Alternatively or additionally, the anti-galactoglobulin-9 antibody contains deletions at one or more of X3-X9 in the heavy chain CDR3 domain and / or X10 is Y.

[0197] Cloning 9.1 - Heavy chain variable region of origin

[0198] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 438, and 367, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 438, and 367, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-1.

[0199] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:435, 439, and 368, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:435, 439, and 368, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-2.

[0200] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:436, 363, and 369, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:436, 363, and 369, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-3.

[0201] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:437, 440, and 370, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:437, 440, and 370, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-4.

[0202] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:437, 441, and 371, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:437, 441, and 371, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-5.

[0203] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:427, 442, and 372, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:427, 442, and 372, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-6.

[0204] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 443, and 373, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 443, and 373, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-7.

[0205] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 374, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8.

[0206] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 363, and 384, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 363, and 384, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-9.

[0207] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 444, and 385, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:429, 444, and 385, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-10.

[0208] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 445, and 386, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:428, 445, and 386, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-11.

[0209] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 365, and 374, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 365, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m1.

[0210] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 374, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 374, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m2.

[0211] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 375, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 375, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m3.

[0212] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 376, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 376, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m4.

[0213] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 377, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 377, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m5.

[0214] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 378, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 378, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m6.

[0215] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 379, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 379, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m7.

[0216] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 380, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 380, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m8.

[0217] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 383, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 383, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m9.

[0218] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 381, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 381, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m10.

[0219] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 382, ​​respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 364, and 382, ​​respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m11.

[0220] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 380, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 380, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m12.

[0221] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 comprises SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR2 comprises SEQ ID NO:366. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR3 comprises SEQ ID NO:383. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR1 is composed of SEQ ID NO:361. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR2 is composed of SEQ ID NO:366. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region CDR3 is composed of SEQ ID NO:383. In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m13.

[0222] In some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 382, ​​respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 366, and 382, ​​respectively. In some embodiments, the antibody comprises the same VH CDR as G9.1-8m14.

[0223] Cloning 9.1-9.1 Heavy chain variable region and light chain variable region

[0224] In one specific embodiment, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 330, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 438, and 367, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 330 and SEQ ID NO:431, 438, and 367, respectively. In some embodiments, the antibody comprises the same VL CDR and VH CDR as G9.1-1.

[0225] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 331, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:435, 439, and 368, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 331 and SEQ ID NO:435, 439, and 368, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-2.

[0226] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 332, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:436, 363, and 369, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 332 and SEQ ID NO:436, 363, and 369, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-3.

[0227] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:437, 440, and 370, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:437, 440, and 370, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-4.

[0228] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 334, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:437, 441, and 371, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 334 and SEQ ID NO:437, 441, and 371, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-5.

[0229] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 335, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:427, 442, and 372, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 335 and SEQ ID NO:427, 442, and 372, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-6.

[0230] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 336, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 443, and 373, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 336 and SEQ ID NO:361, 443, and 373, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-7.

[0231] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 374, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 374, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-8.

[0232] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 338, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 363, and 384, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 338 and SEQ ID NO:361, 363, and 384, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-9.

[0233] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 339, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 444, and 385, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 339 and SEQ ID NO:429, 444, and 385, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-10.

[0234] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 340, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 445, and 386, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 340 and SEQ ID NO:428, 445, and 386, respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-11.

[0235] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 365, and 374, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 365, and 374, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m1.

[0236] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 374, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 366, and 374, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m2.

[0237] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 375, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 375, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m3.

[0238] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 376, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 376, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m4.

[0239] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 377, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 377, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m5.

[0240] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 378, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 378, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m6.

[0241] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 379, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 379, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m7.

[0242] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 380, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 380, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m8.

[0243] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 383, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 383, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m9.

[0244] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 381, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 381, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m10.

[0245] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 364, and 382, ​​respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 364, and 382, ​​respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m11.

[0246] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 380, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 366, and 380, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m12.

[0247] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 383, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 366, and 383, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.1-8m13.

[0248] In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein: the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 337, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 366, and 382, ​​respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 337 and SEQ ID NO:361, 366, and 382, ​​respectively. In one specific embodiment, the antibody comprises the same VLCDR and VH CDR as G9.1-8m14.

[0249] Sequence identity

[0250] In some embodiments, the anti-galactogenin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a corresponding V to the exemplary antibody described herein. L CDRs are light chain CDRs that, individually or collectively, possess at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity. Alternatively or additionally, anti-galactoglobulin-9 antibodies (e.g., specific for CRD1 or CRD2) may comprise the corresponding V of the exemplary antibodies described herein. H CDRs are compared with heavy chain CDRs that individually or collectively have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity.

[0251] In some embodiments, the anti-galactogenin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a corresponding V that binds to an antibody or antigenic portion selected from the group consisting of antibodies or antigenic portions thereof. LCDRs of light chains that individually or collectively share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity: 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-galactogenin-9 antibody (e.g., specific to CRD1 and / or CRD2) may comprise a corresponding V that binds to an antibody or its antigenic moiety selected from the following. H CDRs of heavy chains that share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity, either individually or collectively: 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, G9.1-8m 7. G9.1-8m8, G9.1-8m9, G9.1-8m10, G9.1-8m11, G9.1-8m12, G9.1-8m13 and G9.1-8m14.

[0252] In some embodiments, the anti-galactogenin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a corresponding V that binds to an antibody or antigenic portion selected from the group consisting of antibodies or antigenic portions thereof. L CDR and V HCDRs are light chain CDRs and heavy chain CDRs that individually or collectively share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity: 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.

[0253] In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VL CDR1 amino acid sequence shown in SEQ ID NO:374. In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329. In some embodiments, the anti-galactogenin-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 thereof) sequence identity with a VL CDR3 amino acid sequence selected from SEQ ID NO:330-340.

[0254] In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to CRD1 and / or CRD2) may comprise a VHCDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VH CDR1 amino acid sequence shown in SEQ ID NO:361, 427, 428, 431, 435, 436, 437. In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VH CDR2 amino acid sequence selected from SEQ ID NO:362-366 and 438-445. In some embodiments, the anti-galactoglobulin-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 thereof) sequence identity with the VH CDR3 amino acid sequence selected from SEQ ID NO:367-386.

[0255] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1 amino acid sequence shown 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 thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340; and (d) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340; and (d) a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:330-340. (e) VH CDR1 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR1 amino acid sequences shown in NO:361, 427, 428, 431, 435, 436, 437; (f) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR2 amino acid sequences selected from SEQ ID NO:362-366 and 438-445; and (c) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the VH CDR3 amino acid sequences selected from SEQ ID NO:367-386.

[0256] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:328, 329, and 337. In some embodiments, the amino acid sequences of the antibody VL CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the VL CDR1, CDR2, and CDR3 amino acid sequences of G9.1-8m13. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 361, 366, and 383. In some embodiments, the amino acid sequences of antibody VH CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of VH CDR1, CDR2, and CDR3 of G9.1-8m13. In one specific embodiment, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:328, 329, and 337, respectively, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:361, 366, and 383, respectively.In one specific embodiment, the amino acid sequences of antibodies VL CDR1, CDR2 and CDR3 and VH CDR1, CDR2 and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the amino acid sequences of VL CDR1, CDR2 and CDR3 and VH CDR1, CDR2 and CDR3 of G9.1-8m13, respectively.

[0257] 9.2 Antibody Cloning and Related CDRs

[0258] Cloning 9.2 - Light chain variable region of origin

[0259] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 341, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 341, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-1.

[0260] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-2.

[0261] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-3.

[0262] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 342, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 342, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-4.

[0263] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 343, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 343, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-5.

[0264] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 344, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 344, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-6.

[0265] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 345, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 345, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-7.

[0266] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 346, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 346, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-8.

[0267] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 347, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 347, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-9.

[0268] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 348, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 348, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-10.

[0269] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 349, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 349, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-11.

[0270] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 350, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 350, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-12.

[0271] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 341, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 341, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-13.

[0272] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-14.

[0273] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 343, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 343, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-15.

[0274] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-16.

[0275] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion 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-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 comprises SEQ ID NO:352. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR1 is composed of SEQ ID NO:328. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR2 is composed of SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region CDR3 is composed of SEQ ID NO:352. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-17.

[0276] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-17mut6.

[0277] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-18.

[0278] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 354, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 354, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-19.

[0279] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-20.

[0280] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 355, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 355, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-21.

[0281] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 356, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 356, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-22.

[0282] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 357, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 357, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-23.

[0283] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 358, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 358, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-24.

[0284] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 359, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 359, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-25.

[0285] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 360, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 360, respectively. In some embodiments, the antibody comprises the same VL CDR as G9.2-26.

[0286] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352, respectively. In some embodiments, the antibody comprises the same VL CDR as the G9.2-low affinity binder.

[0287] Cloning 9.2 - Heavy chain variable region of origin

[0288] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:424, 446, and 390, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:424, 446, and 390, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-1.

[0289] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 447, and 391, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 447, and 391, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-2.

[0290] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 448, and 392, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 448, and 392. In some embodiments, the antibody comprises the same VH CDR as G9.2-3.

[0291] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 449, and 393, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 449, and 393, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-4.

[0292] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 450, and 394, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 450, and 394, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-5.

[0293] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 451, and 395, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:431, 452, and 395, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-6.

[0294] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:425, 453, and 396, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:425, 453, and 396, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-7.

[0295] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:425, 453, and 397, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:425, 453, and 397, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-8.

[0296] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:426, 454, and 398, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:426, 454, and 398, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-9.

[0297] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:426, 387, and 399, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:426, 387, and 399, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-10.

[0298] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:432, 455, and 400, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:432, 455, and 400, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-11.

[0299] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:433, 456, and 401, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:433, 456, and 401, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-12.

[0300] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:434, 362, and 402, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:434, 362, and 402, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-13.

[0301] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 457, and 403, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 457, and 403, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-14.

[0302] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 458, and 404, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 458, and 404, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-15.

[0303] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 459, and 405, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 459, and 405, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-16.

[0304] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-17.

[0305] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 407, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 407, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-17mut6.

[0306] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:430, 363, and 408, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:430, 363, and 408, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-18.

[0307] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:430, 460, and 409, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:430, 460, and 409, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-19.

[0308] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 461, and 410, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:429, 461, and 410, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-20.

[0309] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 462, and 411, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:429, 462, and 411, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-21.

[0310] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 463, and 412, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:428, 463, and 412, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-22.

[0311] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 464, and 413, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:428, 464, and 413, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-23.

[0312] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 465, and 414, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:428, 465, and 414, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-24.

[0313] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:427, 466, and 415, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:427, 466, and 415, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-25.

[0314] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 389, and 416, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 389, and 416, respectively. In some embodiments, the antibody comprises the same VH CDR as G9.2-26.

[0315] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 417, respectively. In some embodiments, the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:361, 388, and 417, respectively. In some embodiments, the antibody comprises the same VH CDR as the G9.2-low affinity binder.

[0316] Cloning 9.2 - Heavy chain variable region and light chain variable region of origin

[0317] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 341, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:424, 446, and 390, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 341 and SEQ ID NO:424, 446, and 390, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-1.

[0318] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 447, and 391, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:431, 447, and 391, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-2.

[0319] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 448, and 392, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:431, 448, and 392, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-3.

[0320] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 342, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 449, and 393, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 342 and SEQ ID NO:431, 449, and 393, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-4.

[0321] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 343, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 450, and 394, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 343 and SEQ ID NO:431, 450, and 394, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-5.

[0322] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 344, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:431, 451, and 395, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 344 and SEQ ID NO:431, 451, and 395, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-6.

[0323] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 345, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:425, 452, and 396, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 345 and SEQ ID NO:425, 452, and 396, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-7.

[0324] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 346, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:245, 453, and 397, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 346 and SEQ ID NO:245, 453, and 397, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-8.

[0325] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 347, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:426, 454, and 398, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 347 and SEQ ID NO:426, 454, and 398, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-9.

[0326] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 348, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:426, 387, and 399, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 348 and SEQ ID NO:426, 387, and 399, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-10.

[0327] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 349, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:432, 455, and 400, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 349 and SEQ ID NO:432, 455, and 400, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-11.

[0328] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 350, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:433, 456, and 401, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 350 and SEQ ID NO:433, 456, and 401, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-12.

[0329] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 341, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:434, 362, and 402, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 341 and SEQ ID NO:434, 362, and 402, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-13.

[0330] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 457, and 403, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:361, 457, and 403, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-14.

[0331] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 343, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 458, and 404, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 343 and SEQ ID NO:361, 458, and 404, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-15.

[0332] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 459, and 405, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:361, 459, and 405, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-16.

[0333] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 406, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352 and SEQ ID NO:361, 388, and 406, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-17.

[0334] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 404, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352 and SEQ ID NO:361, 388, and 404, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as G9.2-17mut6.

[0335] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 333, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:430, 363, and 408, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 333 and SEQ ID NO:430, 363, and 408, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-18.

[0336] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 354, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:430, 460, and 409, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 354 and SEQ ID NO:430, 460, and 409, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-19.

[0337] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 461, and 410, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352 and SEQ ID NO:429, 461, and 410, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-20.

[0338] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 355, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:429, 462, and 411, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 355 and SEQ ID NO:429, 462, and 411, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-21.

[0339] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 356, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 463, and 412, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 356 and SEQ ID NO:428, 463, and 412, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-22.

[0340] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 357, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 464, and 413, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 357 and SEQ ID NO:428, 464, and 413, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-23.

[0341] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 358, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:428, 465, and 414, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 358 and SEQ ID NO:428, 465, and 414, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-24.

[0342] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 359, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:427, 466, and 415, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 359 and SEQ ID NO:427, 466, and 415, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-25.

[0343] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 360, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 389, and 416, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 360 and SEQ ID NO:361, 389, and 416, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VHCDR as G9.2-26.

[0344] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises heavy chain variable regions and light chain variable regions, wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:328, 329, and 352, respectively, and the heavy chain variable regions CDR1, CDR2, and CDR3 comprise SEQ ID NO:361, 388, and 417, respectively. In some embodiments, the light chain variable regions CDR1, CDR2, and CDR3 and the heavy chain variable regions CDR1, CDR2, and CDR3 are composed of SEQ ID NO:328, 329, and 352 and SEQ ID NO:361, 388, and 417, respectively. In one specific embodiment, the antibody comprises the same VL CDR and VH CDR as the G9.2-low affinity binder.

[0345] Sequence identity

[0346] In some embodiments, the anti-galactogenin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a corresponding V that binds to an antibody or antigenic portion selected from the group consisting of antibodies or antigenic portions thereof. LCDRs of light chains that individually or collectively share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity: 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, G9.2-1 1. 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-galactogenin-9 antibody (e.g., specific to CRD1 and / or CRD2) may comprise a corresponding V that binds to the antigenic portion of an antibody selected from the following. H CDRs of heavy chains that share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity, either individually or collectively: 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, G9.2-1 1. 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.

[0347] In some embodiments, the anti-galactogenin-9 antibody (e.g., specific for CRD1 and / or CRD2) may comprise a corresponding V that binds to an antibody or antigenic portion selected from the group consisting of antibodies or antigenic portions thereof. L CDR and V HCDRs are light chain CDRs and heavy chain CDRs that individually or collectively share at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increments thereof) sequence identity: 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. 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.

[0348] In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VL CDR1 amino acid sequence shown in SEQ ID NO:328. In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329. In some embodiments, the anti-galactoglobulin-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 thereof) sequence identity with a VL CDR3 amino acid sequence selected from SEQ ID NO:341-360.

[0349] In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VH CDR1 amino acid sequence shown in SEQ ID NO:361 and 424-434. In some embodiments, an anti-galactoglobulin-9 antibody (e.g., specific to 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 increments thereof) sequence identity with the VH CDR2 amino acid sequence selected from SEQ ID NO:362, 363, 387-389, and 446-466. In some embodiments, the anti-galactogenin-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 thereof) sequence identity with the VH CDR3 amino acid sequence selected from SEQ ID NO:390-417.

[0350] Therefore, in some embodiments, the anti-galactoglobulin-9 antibody or its antigen-binding portion comprises (a) a VL CDR1 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VL CDR1 amino acid sequence shown 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 thereof) sequence identity with the VL CDR2 amino acid sequence shown in SEQ ID NO:329; (c) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:341-360; and (d) a VL CDR3 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:341-360; and (d) a VL CDR2 amino acid sequence having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VLCDR3 amino acid sequence selected from SEQ ID NO:341-360. (e) VH CDR1 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR1 amino acid sequences shown in NO:361, 424-434; (f) VH CDR2 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR2 amino acid sequences selected from SEQ ID NO:362, 363, 387-389 and 446-466; and (f) VH CDR3 amino acid sequences having at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the VH CDR3 amino acid sequences selected from SEQ ID NO:390-417.

[0351] In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO: 328, 329, and 352. In some embodiments, the amino acid sequences of the antibody VL CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the VL CDR1, CDR2, and CDR3 of G9.2-17. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:361, 388, and 406. In some embodiments, the amino acid sequences of antibody VH CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increments thereof) sequence identity with the amino acid sequences of VH CDR1, CDR2, and CDR3 of G9.2-17. In some embodiments, the anti-galactoglobulin-9 antibody or its binding portion comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the light chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:328, 329, and 352, respectively, and the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99%, and any increment thereof) sequence identity with the amino acid sequences of the heavy chain variable regions CDR1, CDR2, and CDR3 shown in SEQ ID NO:361, 388, and 406, respectively.In one specific embodiment, the amino acid sequences of antibodies VL CDR1, CDR2 and CDR3 and VH CDR1, CDR2 and CDR3 have at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, 99% and any increment thereof) sequence identity with the amino acid sequences of VL CDR1, CDR2 and CDR3 and VH CDR1, CDR2 and CDR3 of G9.2-17.

[0352] Epitopes and constant regions

[0353] In some embodiments, the anti-galactophage-9 antibody described herein binds to the same epitope as any of the exemplary antibodies described herein (e.g., antibodies comprising any one of SEQ ID NO: 7-87 or its CDR) or competes with the exemplary antibody for binding to the galactophage-9 antigen. An epitope is a site on a target antigen that is recognized and bound by an antibody. This site may consist entirely of an amino acid component, entirely of a chemical modification of protein amino acids (e.g., a glycosyl moiety), or a combination thereof. Overlapping epitopes contain at least one common amino acid residue. Epitopes may be linear and typically 6-15 amino acids in length. Alternatively, epitopes may be conformational. Epitopes bound by antibodies can be determined using conventional techniques, such as epitope mapping (see, for example, the description below). Antibodies that bind to the same epitope as the exemplary antibodies described herein may bind to the exact same epitope or substantially overlapping epitopes (e.g., containing 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 a homologous antigen can be determined using competition assays well known in the art.

[0354] In some embodiments, the anti-galactophage-9 antibody may bind to at least one fragment of an epitope located in the CRD1 of the galactophage-9 protein (e.g., human galactophage-9 or mouse galactophage-9). In some embodiments, the antibody may bind to an epitope located entirely within the CRD1 of the galactophage-9 protein. In some embodiments, the antibody may bind to an epitope partially located within the CRD1 of the galactophage-9 protein. In some embodiments, the epitope bound by the anti-galactophage-9 antibody is a linear epitope. In some embodiments, the epitope bound by the anti-galactophage-9 antibody is a conformational epitope.

[0355] In some embodiments, the anti-galactophage-9 antibody may bind to at least one fragment of an epitope in the CRD2 of the galactophage-9 protein (e.g., human galactophage-9 or mouse galactophage-9). In some embodiments, the anti-galactophage-9 antibody may bind to an epitope entirely within the CRD2 of the galactophage-9 protein. In some specific embodiments in which the anti-galactophage-9 antibody binds to an epitope partially or entirely within the CRD2, the antibody binding comprises an epitope containing at least the residue W309. In some specific embodiments in which the anti-galactophage-9 antibody binds to an epitope partially or entirely within the CRD2, the epitope bound by the anti-galactophage-9 antibody does not contain one or more of R253, R271, Y330, R334, R341, and Y236 of SEQ ID NO:1. In some embodiments, the epitope bound by the anti-galactophage-9 antibody is a linear epitope comprising the residue W309. In some embodiments, the epitope to which the anti-galactogenein-9 antibody binds is a conformational epitope containing W309.

[0356] In some instances, anti-galactoglobulin-9 antibodies contain the same V as the exemplary antibodies described herein. H and / or V L CDR. Has the same V H and / or V L Two antibodies with a CDR mean that their CDRs are identical when determined by the same method (e.g., the Kabat method or the Chothia method known in the art). Such anti-galactogenin-9 antibodies may have the same V compared to the exemplary antibodies described herein. H The same V L Or both.

[0357] Two heavy chain variable regions (or two light chain variable regions) with the same CDR are defined as two heavy chain variable regions (or light chain variable regions) with the same CDR determined by the same numbering scheme. Exemplary numbering schemes used to determine antibody CDRs include the “Kabat” numbering scheme (Kabat et al. (1991), 5th edition. Public Health Service, National Institutes of Health, Bethesda, Md.), the “Chothia” numbering scheme (Al-Lazikani et al., (1997) JMB273, 927-948), the “Contact” numbering scheme (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)), the “IMGT” numbering scheme (Lefranc MP et al., Dev Comp Immunol, 2003 January; 27(1): 55-77), and the “AHo” numbering scheme (Honegger A and Pluckthun A, J Mol Biol, 2001 Jun. 8; 309(3): 657-70). As is known to those skilled in the art, the CDR regions of the exemplary anti-pKal and anti-FXII antibodies identified herein were determined using the “Chothia” numbering scheme used as an example.

[0358] Also within the scope of this disclosure are any functional variants of the exemplary anti-galactoglobulin-9 antibodies disclosed herein. Such functional variants are substantially similar to the exemplary antibodies in both structure and function. The functional variants contain a V that is substantially the same as that of the exemplary antibodies. H and V L CDR. For example, it may contain only a maximum of 5 (e.g., 4, 3, 2, or 1) amino acid residue variations throughout the entire CDR region of an antibody, and with substantially similar affinity (e.g., having the same order of magnitude of K). DThe same epitope of galactagogue-9 is bound to galactagogue-9. Alternatively or additionally, amino acid residue variations are conserved amino acid residue substitutions. As used herein, “conserved amino acid substitution” means an amino acid substitution that does not alter the relative charge or size characteristics of the protein to which the amino acid substitution is made. Variants can be prepared according to methods known to those skilled in the art for altering polypeptide sequences, methods which can be found, for example, in references compiling such methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook et al., 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, or Current Protocols in Molecular Biology, F.A. Mosurubel et al., John Wiley & Sons, Inc., New York. Conserved substitution of amino acids includes substitutions between amino acids within the following group: (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.

[0359] The "percentage of identity" between two amino acid sequences is determined using the following algorithms: Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified by Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such algorithms are incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul et al. J. Mol. Biol. 215:403-10, 1990. A BLAST protein search can be performed using the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the target protein molecule. In the case of a gap between two sequences, Gapped BLAST can be used as described by Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997. When using BLAST and Gapped BLAST procedures, the default parameters for each procedure (e.g., XBLAST and NBLAST) can be used. Anti-galactoglobulin-9 antibodies may contain a heavy chain variable region framework derived from a germline VH fragment subclass. 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), and the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, IGHV1-24, IGHV1-45, IGHV1-46, IGHV1-58, and IGHV1-69), the IGHV2 subfamily (e.g., IGHV2-5, IGHV2-26, and IGHV2-70), and the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, and IGHV2-69). The 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).

[0360] Alternatively or additionally, anti-galactoglobulin-9 antibodies may include a light chain variable region comprising a frame derived from a germline Vκ fragment. Examples include IGKV1 frames (e.g., IGKV1-05, IGKV1-12, IGKV1-27, IGKV1-33, or IGKV1-39), IGKV2 frames (e.g., IGKV2-28), IGKV3 frames (e.g., IGKV3-11, IGKV3-15, or IGKV3-20), and IGKV4 frames (e.g., IGKV4-1). In other cases, anti-galactoglobulin-9 antibodies may include a light chain variable region comprising a frame 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), and the IGλ3 framework (e.g., IGλV3-1, IGλV3-9, IGλV3-10, IGλV3-12, IGλV3-16, IGλV3-19, IGλV3-21, IGλV3- 25, IGλV3-27), IGλ4 frame (e.g., IGλV4-3, IGλV4-60, IGλV4-69), IGλ5 frame (e.g., IGλV5-39, IGλV5-45), IGλ6 frame (e.g., IGλV6-57), IGλ7 frame (e.g., IGλV7-43, IGλV7-46), IGλ8 frame (e.g., IGλV8-61), IGλ9 frame (e.g., IGλV9-49), or IGλ10 frame (e.g., IGλV10-54).

[0361] In some embodiments, the heavy chain of any anti-galactoglobulin-9 antibody described herein may further comprise a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or combinations thereof). The heavy chain constant region can be from any suitable source, such as human, mouse, rat, or rabbit. In one specific example, the heavy chain constant region is derived from human IgG (γ heavy chain) of any of the IgG subfamilies described herein.

[0362] In some embodiments, the heavy chain constant region of the antibody described herein may comprise a single domain (e.g., CH1, CH2, or CH3) of the constant region (e.g., SEQ ID NO: 419-423) or any combination of single domains. In some embodiments, the light chain constant region of the antibody described herein may comprise a single domain (e.g., CL) of the constant region (e.g., SEQ ID NO: 418). Exemplary light and heavy chain sequences are listed below. The hIgG1 LALA sequence contains two mutations, L234A and L235A, which inhibit FcgR binding; it also contains a P329G mutation to eliminate complement C1q binding, thereby eliminating all immune effector functions. These mutations are underlined and bolded in the sequences shown below. The hIgG4 Fab Arm Exchange mutant sequence contains a mutation (S228P) that inhibits Fab Arm Exchange, 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. Bold residues represent 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 and is cleaved during secretion, therefore it is not present in the mature antibody molecule. The mature protein (post-secretion) heavy chain begins with "EVQ," and the light chain begins with "DIQM."

[0363] Exemplary heavy and light chain sequences

[0364]

[0365]

[0366]

[0367] In some embodiments, the anti-galactoglobulin 9 antibody has a light chain comprising SEQ ID NO: 108, substantially composed of SEQ ID NO: 108, or composed of SEQ ID NO: 108. In some embodiments, the anti-galactoglobulin 9 antibody has a heavy chain comprising any one of the sequences selected from the group consisting of SEQ ID NO: 295, 242, 189, 157, 210, 263, 316, and 136, substantially composed of that sequence, or composed of that sequence. In some embodiments, the anti-galactoglobulin 9 antibody has a light chain comprising SEQ ID NO: 108, substantially composed of SEQ ID NO: 108, or composed of SEQ ID NO: 108, and a heavy chain comprising any one of the sequences selected from the group consisting of SEQ ID NO: 295, 242, 189, 157, 210, 263, 316, and 136, substantially composed of that sequence, or composed of that sequence. In some embodiments, the anti-galactoglobulin 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 NO: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galactoglobulin 9 antibody has a light chain substantially comprising SEQ ID NO: 108 and a heavy chain substantially comprising any one of the sequences selected from the group consisting of SEQ ID NO: 295, 242, 189, 157, 210, 263, 316, and 136. In some embodiments, the anti-galactoglobulin 9 antibody has a light chain comprising SEQ ID NO: 108 and a heavy chain compris...

Claims

1. An isolated nucleic acid molecule or a collection of nucleic acid molecules, comprising a nucleic acid sequence encoding a heavy chain variable (VH) region and a light chain variable (VL) region of an antibody that binds to human galectin-9, wherein the antibody comprises: (a) the heavy chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO:361, the heavy chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO:388, and the heavy chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO:406; and (b) the light chain complementary determining region 1 (CDR1) shown in SEQ ID NO:328, the light chain complementary determining region 2 (CDR2) shown in SEQ ID NO:329, and the light chain complementary determining region 3 (CDR3) shown in SEQ ID NO:

352.

2. The isolated nucleic acid molecule or nucleic acid molecule set according to claim 1, wherein the nucleic acid sequence encodes the VH shown in SEQ ID NO:55 and the VL shown in SEQ ID NO:

54.

3. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 1 or 2, wherein the nucleic acid sequence encodes the heavy chain (HC) and light chain (LC) of a full-length antibody, wherein the HC comprises the VH and the LC comprises the VL.

4. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 1 or 2, wherein the nucleic acid sequence encodes the VH region and VL region of a single-chain antibody.

5. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 1 or 2, wherein the nucleic acid sequence encodes the HC and LC of a human antibody.

6. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 1 or 2, wherein the nucleic acid sequence encodes the HC of an IgG molecule.

7. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 6, wherein the IgG molecule is an IgG1 molecule or an IgG4 molecule.

8. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 7, wherein the IgG molecule is an IgG4 molecule, and wherein the IgG4 has an S228P mutation relative to SEQ ID NO:

263.

9. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 1 or 2, wherein the nucleic acid sequence further encodes the HC constant region shown in SEQ ID NO:422 and the LC constant region shown in SEQ ID NO:

418.

10. The isolated nucleic acid molecule or set of nucleic acid molecules according to claim 9, wherein the nucleic acid sequence encodes the HC shown in SEQ ID NO: 316 and the LC shown in SEQ ID NO:

108.

11. One or two vectors, said one or two vectors comprising the isolated nucleic acid molecule or nucleic acid molecule set according to claim 1.

12. The one or two vectors according to claim 11, wherein the one or two vectors are one or two expression vectors.

13. One or two vectors according to claim 11 or 12, wherein the isolated nucleic acid molecule or set of nucleic acid molecules comprises a nucleic acid sequence encoding VH shown in SEQ ID NO:55 and VL shown in SEQ ID NO:

54.

14. One or two vectors according to claim 13, wherein the isolated nucleic acid molecule or set of nucleic acid molecules further comprises a nucleic acid sequence encoding the HC constant region shown in SEQ ID NO: 422 and the LC constant region shown in SEQ ID NO:

418.

15. One or two vectors according to claim 14, wherein the isolated nucleic acid molecule or set of nucleic acid molecules encodes the heavy chain as shown in SEQ ID NO:316 and the light chain as shown in SEQ ID NO:

108.

16. A host cell comprising one or two vectors according to claim 11.

17. The host cell according to claim 16, wherein the host cell is selected from the group consisting of Escherichia coli cells, simian COS cells, Chinese hamster ovary (CHO) cells and myeloma cells.

18. The host cell according to claim 16 or 17, wherein the one or two vectors encode the VH shown in SEQ ID NO:55 and the VL shown in SEQ ID NO:

54.

19. The host cell according to claim 18, wherein the one or two vectors further encode the HC constant region shown in SEQ ID NO: 422 and the LC constant region shown in SEQ ID NO:

418.

20. The host cell according to claim 19, wherein the one or two vectors encode the heavy chain as shown in SEQ ID NO:316 and the light chain as shown in SEQ ID NO:

108.

21. A method for producing an antibody that binds to human galectin-9, the method comprising: (i) culturing the host cell according to claim 16 or 17 under conditions that allow expression of the antibody; and (ii) harvesting the antibody thus produced from the cell culture.

22. The method of claim 21, wherein the antibody comprises the VH shown in SEQ ID NO:55 and the VL shown in SEQ ID NO:

54.

23. The method of claim 22, wherein the antibody further comprises a HC constant region shown in SEQ ID NO:422 and a LC constant region shown in SEQ ID NO:

418.

24. The method of claim 23, wherein the antibody comprises a heavy chain as shown in SEQ ID NO:316 and a light chain as shown in SEQ ID NO:

108.

25. Use of an antibody that binds to human galectin-9 in the preparation of a medicament for treating a hematological malignancy in a subject, wherein the antibody that binds to human galectin-9 comprises a heavy chain variable (VH) region and a light chain variable (VL) region of an antibody that binds to human galectin-9, wherein the antibody comprises: (a) the heavy chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO:361, the heavy chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO:388, and the heavy chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO:406; and (b) the light chain complementary determining region 1 (CDR1) set forth in SEQ ID NO:328, the light chain complementary determining region 2 (CDR2) set forth in SEQ ID NO:329, and the light chain complementary determining region 3 (CDR3) set forth in SEQ ID NO:352, The hematological malignancy is acute myeloid leukemia.

26. The use according to claim 25, wherein the antibody comprises the VH shown in SEQ ID NO:55 and the VL shown in SEQ ID NO:

54.

27. The use according to claim 25, wherein the antibody is an IgG1 molecule or an IgG4 molecule.

28. The use according to claim 27, wherein the antibody further comprises a HC constant region shown in SEQ ID NO: 422 and a LC constant region shown in SEQ ID NO:

418.

29. The use according to claim 28, wherein the antibody comprises a heavy chain shown in SEQ ID NO: 316 and a light chain shown in SEQ ID NO:

108.

30. The use according to any one of claims 25 to 29, wherein the antibody is used in combination with an inhibitor of a checkpoint molecule or a chemotherapeutic agent, wherein the checkpoint molecule is PD-1 or PD-L1, or wherein the chemotherapeutic agent is selected from the group consisting of vinblastine, vincristine, epothilone, teniposide, cytarabine and methotrexate.

31. The use according to claim 30, wherein the antibody is for co-use with the inhibitor of the checkpoint molecule, and wherein the inhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody.

32. Use of an antibody that binds to human galectin-9 in the preparation of a medicament for treating a solid tumor in a subject, wherein the antibody that binds to human galectin-9 comprises a heavy chain variable (VH) region and a light chain variable (VL) region of an antibody that binds to human galectin-9, wherein the antibody comprises: (a) the heavy chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO:361, the heavy chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO:388, and the heavy chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO:406; and (b) the light chain complementary determining region 1 (CDR1) set forth in SEQ ID NO:328, the light chain complementary determining region 2 (CDR2) set forth in SEQ ID NO:329, and the light chain complementary determining region 3 (CDR3) set forth in SEQ ID NO:352, The solid tumor is pancreatic cancer, colorectal cancer, melanoma, bile duct cancer or gallbladder cancer.

33. The use according to claim 32, wherein the antibody comprises the VH shown in SEQ ID NO:55 and the VL shown in SEQ ID NO:

54.

34. The use according to claim 32, wherein the antibody is an IgG1 molecule or an IgG4 molecule.

35. The use according to claim 33, wherein the antibody further comprises a HC constant region shown in SEQ ID NO: 422 and a LC constant region shown in SEQ ID NO:

418.

36. The use according to claim 35, wherein the antibody comprises the heavy chain shown in SEQ ID NO:316 and the light chain shown in SEQ ID NO:

108.

37. The use according to any one of claims 32 to 36, wherein the antibody is used in conjunction with an inhibitor of a checkpoint molecule or a chemotherapeutic agent; wherein the checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2 and CTLA-4, or wherein the chemotherapeutic agent is gemcitabine, paclitaxel or a combination thereof.

38. The use according to claim 37, wherein the antibody is used in combination with a PD-1 inhibitor, and the PD-1 inhibitor is an anti-PD1 antibody or an anti-PD-L1 antibody.

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