Antibodies that interfere with the interaction between GAL3 and insulin receptors or integrins, and methods for using them.

Abstract

Disclosed herein are methods and compositions for disrupting the interaction between galectin-3 and insulin receptor or integrins. Also disclosed herein are methods and compositions for treating a disease or disorder in a subject, such as diabetes, inflammatory bowel syndrome, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority from U.S. Provisional Patent Application No. 62 / 944,833, filed on December 6, 2019.

[0002] Sequence listing reference This application is filed together with an electronic sequence listing. The sequence listing is presented as a file named "SeqListingIMMUT006WO.TXT" (size 405,344 bytes), created and last modified on December 2, 2020. The information in the electronic sequence listing is incorporated herein by reference in its entirety.

[0003] Aspects of this disclosure generally relate to antibodies or their conjugate fragments that block or interfere with the interaction between galectin-3 (Gal3) and insulin receptors (INSR) or integrins (ITG). This specification further discloses methods and compositions for the treatment of diseases or disorders, including but not limited to diabetes mellitus, inflammatory bowel syndrome, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, which may be associated with INSR and / or ITG dysfunction. [Background technology]

[0004] Galectin-3 (Gal3, GAL3) is a lectin, or carbohydrate-binding protein, that is specific to β-galactosides. In human cells, Gal3 is expressed and found in the nucleus, cytoplasm, cell surface, and extracellular space. Gal3 recognizes and interacts with β-galactose conjugates on various proteins. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2019 / 023247 [Patent Document 2] International Publication No. 2020 / 160156 [Patent Document 3] U.S. Patent No. 5,985,660 [Patent Document 4] European Patent No. 404,097 [Patent Document 5] International Publication No. 93 / 11161 [Patent Document 6] International Publication No. 00 / 24782 [Patent Document 7] U.S. Patent Application Publication No. 2003 / 0133939 [Patent Document 8] U.S. Patent No. 6,162,963 [Patent Document 9] U.S. Patent No. 6,150,584 [Patent Document 10] U.S. Patent No. 6,174,708 [Patent Document 11] U.S. Patent No. 5,624,659 [Patent Document 12] U.S. Patent No. 6,187,287 [Patent Document 13] European Patent No. 0,329,400 [Patent Document 14] U.S. Patent No. 5,270,202 [Patent Document 15] European Patent No. 699,755 [Patent Document 16] U.S. Patent No. 5,969,108 [Patent Document 17] U.S. Patent No. 5,695,937 [Patent Document 18] U.S. Patent No. 5,405,783 [Patent Document 19] U.S. Patent No. 5,412,087 [Patent Document 20] U.S. Patent No. 5,445,934 [Patent Document 21] U.S. Patent No. 5,208,020 [Patent Document 22] U.S. Patent No. 5,416,064 [Patent Document 23] U.S. Patent No. 7,276,497 [Patent Document 24] U.S. Patent No. 6,716,821 [Patent Document 25] U.S. Patent Application Publication No. 2013 / 29900 [Patent Document 26] U.S. Patent Application Publication No. 2013 / 323268 [Patent Document 27] U.S. Patent No. 6,884,869 [Patent Document 28] U.S. Patent No. 7,659,241 [Patent Document 29] U.S. Patent No. 7,498,298 [Patent Document 30] U.S. Patent No. 7,964,566 [Patent Document 31] U.S. Patent No. 7,750,116 [Patent Document 32] U.S. Patent No. 8,288,352 [Patent Document 33] U.S. Patent No. 8,703,714 [Patent Document 34] U.S. Patent No. 8,871,720 [Patent Document 35] U.S. Patent No. 8,404,678 [Patent Document 36] U.S. Patent No. 8,163,736 [Patent Document 37] U.S. Patent No. 8,426,402 [Patent Document 38] U.S. Patent No. 8,802,667 [Patent Document 39] U.S. Patent No. 8,809,320 [Patent Document 40] U.S. Patent No. 6,562,806 [Patent Document 41] U.S. Patent No. 6,608,192 [Patent Document 42] U.S. Patent No. 7,704,924 [Patent Document 43] U.S. Patent No. 7,067,511 [Patent Document 44] U.S. Patent No. 7,612,062 [Patent Document 45] U.S. Patent No. 7,244,724 [Patent Document 46] U.S. Patent No. 7,528,126 [Patent Document 47] U.S. Patent No. 7,049,311 [Patent Document 48] U.S. Patent No. 8,633,185 [Patent Document 49] U.S. Patent No. 8,501,934 [Patent Document 50] U.S. Patent No. 8,697,688 [Patent Document 51] U.S. Patent Application Publication No. 2014 / 0294868 [Patent Document 52] U.S. Patent No. 8,697,688 [Patent Document 53] U.S. Patent No. 9,242,013 [Patent Document 54] U.S. Patent Application Publication No. 2014 / 0286970 [Patent Document 55] U.S. Patent No. 8,936,910 [Patent Document 56] International Publication No. 2014 / 140317 [Patent Document 57] U.S. Patent Application Publication No. 2015 / 0105539 [Patent Document 58] U.S. Patent Application Publication No. 2015 / 0105540 [Patent Document 59] U.S. Patent No. 9,089,614 [License 60] International Publication No. 2015 / 038426 [License 61] U.S. Patent No. 6,821,783 [Non-licensed literature]

[0006] [Non-licensed Document 1] Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991 [Non-licensed Document 2] Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987 [Non-licensed Document 3] Lefranc et al., 2003, Dev Comp Immunol. 27:55-77 [Non-licensed Document 4] Kunik et al., 2012, Nucl Acids Res. W521-4 [Non-licensed Document 5] Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8 [Non-licensed Document 6] Chothia et al., 1986, J. Mol. Biol., 196: 901-17 [Non-licensed Document 7] Chothia et al., 1989, Nature, 342: 877-83 [Non-licensed Document 8] Martin et al., 1989, Proc Natl Acad Sci(USA), 86:9268-9272 [Non-licensed Document 9] "AbM.TM., A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK; Oxford Molecular, Ltd.

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[0007] Disclosed herein are methods for interfering with the interaction between galectin-3 (Gal3) and a) an insulin receptor (INSR) or b) an integrin, or both a) and b). In some embodiments, the method may involve contacting an anti-Gal3 antibody or a conjugated fragment thereof with the interaction between Gal3 and the insulin receptor or the integrin, or both, by selectively binding to Gal3 and interfering with the interaction between Gal3 and the insulin receptor or the integrin, or both.

[0008] Methods for treating diabetes in subjects requiring treatment are also disclosed herein. In some embodiments, the method includes treating diabetes in a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor or integrin or both.

[0009] Methods for treating inflammatory bowel syndrome in subjects of interest are also disclosed herein. In some embodiments, the methods include treating the inflammatory bowel syndrome of a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and integrins.

[0010] Methods for treating non-alcoholic fatty liver disease (NAFLD) in subjects requiring treatment are also disclosed herein. In some embodiments, the methods include treating the NAFLD of a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor.

[0011] Methods for treating non-alcoholic steatohepatitis (NASH) in subjects requiring treatment are also disclosed herein. In some embodiments, the method includes treating the NASH of a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor.

[0012] Also, (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -An anti-Gal3 antibody comprising a heavy chain variable region including CDR3, wherein V L-CDR1 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 100 to 128, and the V L -CDR2 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 129 to 144, and the V L -CDR3 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 145 to 168, and the V H -CDR1 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 27 to 47, and the V H -CDR2 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 48 to 69, and and the V H -CDR3 includes an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs: 70 to 99, and anti-Gal3 antibodies are also disclosed herein.

[0013] Pharmaceutical compositions comprising any one or more of the anti-Gal3 antibodies or binding fragments thereof disclosed herein are also disclosed herein. These pharmaceutical compositions can be used for the treatment of diabetes, inflammatory bowel disease, NAFLD, or NASH, or any combination thereof.

[0014] Antibodies that bind to human Gal3 and compete with any one of the anti-Gal3 antibodies or binding fragments disclosed herein for binding to human Gal3 are also disclosed herein. In some embodiments, the antibody that binds to human Gal3 may compete with an anti-Gal3 antibody or its binding fragment that binds to a specific peptide of Gal3. In some embodiments, the antibody that binds to human Gal3 may compete with an anti-Gal3 antibody or its binding fragment belonging to a specific bin. In some embodiments, the antibodies that bind to human Gal3 are 6H6.2D6, 20H5.A3, 20D11.2C6, 4G2.2G6, 13H12.2F8, 19B5.2E6, 15G7.2A7, 23H9.2E4, 19D9.2E5, 2D10.2B2, 4A11.2B5, 14H10.2C9, 3B11.2G2, 13A12.2E5, 7D8.2D8, and 15F10.2D6, 23B10.2B12, 6B3.2D3, F846C.1B2, F846C.1F5, F8 This may compete with 46C.1H12, F846C.1H5, F846C.2H3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1, F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, F847.14H4 (847.14H4), mIMT001, IMT001 (TB001), or IMT006 (TB006).

[0015] Also disclosed herein are methods for identifying antibodies that can interfere with the interaction between Gal3 and the insulin receptor or integrin. In some embodiments, the method includes (a) forming a Gal3-antibody complex by contacting the Gal3 protein with an antibody or a binding fragment thereof that selectively binds to Gal3; (b) contacting the Gal3 antibody complex with the insulin receptor or the integrin or both; (c) removing the unbound insulin receptor or integrin or both; and (d) detecting the insulin receptor or integrin or both bound to the Gal3 antibody complex. In some embodiments, if the insulin receptor or integrin or both are not detected in (d), the antibody or The binding fragment can interfere with the interaction between Gal3 and the insulin receptor or integrin, or both.

[0016] Methods for producing anti-Gal3 antibodies or their conjugate fragments are also disclosed herein. In some embodiments, the method includes expressing a nucleic acid encoding the anti-Gal3 antibody or its conjugate fragment in cells, and isolating the expressed anti-Gal3 antibody or its conjugate fragment from the cells. In some embodiments, the method may further include concentrating the anti-Gal3 antibody or its conjugate fragment to a desired concentration. In some embodiments, the cells are mammalian cells, insect cells, or bacterial cells. In some embodiments, the anti-Gal3 antibody or its conjugate fragment is one of the anti-Gal3 antibodies or its conjugate fragments disclosed herein. [Brief explanation of the drawing]

[0017] Various aspects of this disclosure are specifically described in the attached claims. A better understanding of the features and merits of this disclosure will be obtained by referring to the following detailed description illustrating exemplary embodiments in which the principles of this disclosure are utilized, accompanied by the following attached drawings. [Figure 1]Figure 1 shows the ability of galectin-3-targeted antibodies to block Gal3 and insulin receptor (INSR) binding, as measured by enzyme-linked immunosorbent assay (ELISA) at concentrations of 10 μg / mL, 3 μg / mL, and 1 μg / mL. The bars represent the mean ± standard deviation. [Figure 2] Figure 2 shows the titration of a limited series of galectin-3 targeted antibodies for blocking Gal3 and insulin receptor (INSR) binding, as measured by enzyme-linked immunosorbent assay (ELISA). The bars represent the mean ± standard deviation. [Figure 3A] Figure 3A summarizes the characteristics of an exemplary anti-Gal3 antibody. [Figure 3B] Figure 3B shows the identification of Gal3-conjugated antibody bins by antibody competition. The values ​​represent inhibition evaluated by biolayer interferometry. [Figure 4] Figure 4 shows the reduction in body weight gain in mice fed a normal diet or a 60% high-fat diet (HFD) for 8 weeks and administered IMT001-4 (TB001) targeting the isotype control antibody HuIgG4 or Gal3. The left panel shows the mean absolute value, and the right panel shows the mean percentage change ± standard error per animal. [Figure 5] Figure 5 shows glucose tolerance in mice treated as shown in Figure 4. The left panel shows the mean serum blood glucose levels after glucose bolus administration, and the right panel shows the mean area under the curve (AUC) from the data expressed as left panel ± standard error. [Figure 6] Figure 6 shows insulin resistance in mice treated as shown in Figure 4. The left panel shows the mean serum blood glucose levels after insulin bolus administration, and the right panel shows the mean area on the curve (AOC) from the data represented as left panel ± standard error. [Figure 7] Figure 7 shows hematoxylin-eosin staining of formalin-fixed, paraffin-embedded liver sections from mice treated as shown in Figure 4. Note the evidence of steatosis in HFD-fed mice administered with control IgG4 and the absence of fatty liver in mice administered with IMT001-4 (TB001). [Figure 8] Figure 8 shows serum liver enzyme ALT levels in mice treated as shown in Figure 4. The bars represent the mean ± standard error. [Figure 9] Figure 9 shows the evaluation of the relative binding affinity of integrin β-1 (ITGb1) to Gal3 as measured by ELISA. [Figure 10] Figure 10 shows the evaluation of the relative binding affinity of ITGb1 and Gal3 after blocking with an anti-Gal3 antibody, as measured by ELISA. [Figure 11] Figure 11 shows the evaluation of the relative binding affinity of integrin α-3 (ITGa3) to Gal3 as measured by ELISA. [Figure 12] Figure 12 shows the evaluation of the relative binding affinity of ITGa3 and Gal3 after blocking with an anti-Gal3 antibody, as measured by ELISA. [Figure 13] Figure 13 shows the evaluation of the relative binding affinity of integrin β-3 (ITGb3) to Gal3 as measured by ELISA. [Figure 14] Figure 14 shows the evaluation of the relative binding affinity of ITGb3 and Gal3 after blocking with an anti-Gal3 antibody, as measured by ELISA. [Figure 15] Figure 15 shows the evaluation of the relative binding affinity of integrin α-V (ITGaV) to Gal3 as measured by ELISA. [Figure 16] Figure 16 shows the evaluation of the relative binding affinity of ITGaV and Gal3 after blocking with an anti-Gal3 antibody, as measured by ELISA. [Figure 17] Figure 17 shows the evaluation of relative inhibition of Jurkat T cell adhesion after treatment with anti-Gal3 antibody or isotype control. [Figure 18] Figure 18 shows the blood Gal3 levels in Bks-Db or C57BL6 / J control mice. [Figure 19]Figure 19 shows Kaplan-Meier curves for healthy C57BL6 / J and Db / Db mice treated with anti-Gal3 antibody mTB001, a PBS-negative control, or a semaglutide-positive control. [Figure 20] Figure 20 shows the changes in fasting blood glucose levels in healthy C57BL6 / J mice or Db / Db mice administered either mTB001 or PBS. [Figure 21] Figure 21 shows the mean survival rate of NOD / ShiLtJ mice treated with mTB001 compared to an untreated control. [Figure 22A] Figure 22A shows the change in fasting blood glucose levels in NOD / ShiLtJ mice administered with mTB001 compared to an untreated control. [Figure 22B] Figure 22B shows the blood concentrations of C-peptide in NOD / ShiLtJ mice administered with mTB001 and in normal control mice, compared to an untreated control. [Figure 23] Figure 23 shows the primers used for RT-qPCR to quantify inflammatory cytokines in a mouse model of inflammatory bowel disease (IBD). [Figure 24] Figure 24 shows the colon length measured in DSS-induced IBD mice administered with mTB001 or PBS, compared to normal mice. [Figure 25] Figure 25 shows the quantification of serum IFN-γ in DSS-induced IBD mice administered with mTB001 (10 mg / kg and 1 mg / kg) or PBS, compared to normal mice. [Figure 26-1] Figure 26-1 shows the protein sequences of Gal3 and the insulin receptor (INSR). [Figure 26-2] Figure 26-2 shows the protein sequences of integrin β-1 (ITGb1) and integrin α-3 (ITGa3). [Figure 26-3] Figure 26-3 shows the protein sequences of integrin β-3 (ITGb3) and integrin α-V (ITGaV). [Figure 27]Figure 27 shows the peptide sequence of Gal3 used to generate and analyze antibodies. [Figure 28A] Figure 28A shows an exemplary variable heavy chain complementarity determining region (CDR) 1 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HCDR1s provided herein. [Figure 28B] Figure 28B shows an exemplary variable heavy chain CDR2 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HCDR2s provided herein. [Figure 28C] Figure 28C shows an exemplary variable heavy chain CDR3 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HCDR3s provided herein. [Figure 29A] Figure 29A shows an exemplary variable light chain CDR1 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LCDR1s provided herein. [Figure 29B] Figure 29B shows an exemplary variable light chain CDR2 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LCDR2s provided herein. [Figure 29C] Figure 29C shows an exemplary variable light chain CDR3 of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LCDR3s provided herein. [Figure 30-1] Figure 30-1 shows an exemplary heavy chain variable region (VH) sequence of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the VH sequences provided herein. [Figure 30-2]Figure 30-2 shows an exemplary heavy chain variable region (VH) sequence of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may include one or more of the VH sequences provided herein. [Figure 30-3] Figure 30-3 shows an exemplary heavy chain variable region (VH) sequence of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the VH sequences provided herein. [Figure 31-1] Figure 31-1 shows an exemplary light chain variable region (VL) sequence of an anti-Gal3 antibody disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the VL sequences provided herein. [Figure 31-2] Figure 31-2 shows exemplary light chain variable region (VL) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the VL sequences provided herein. [Figure 31-3] Figure 31-3 shows exemplary light chain variable region (VL) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the VL sequences provided herein. [Figure 32-1] Figure 32-1 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-2] Figure 32-2 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-3]Figure 32-3 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-4] Figure 32-4 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-5] Figure 32-5 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-6] Figure 32-6 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 32-7] Figure 32-7 shows exemplary heavy chain (HC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the HC sequences provided herein. [Figure 33-1] Figure 33-1 shows exemplary light chain (LC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LC sequences provided herein. [Figure 33-2] Figure 33-2 shows exemplary light chain (LC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LC sequences provided herein. [Figure 33-3]Figure 33-3 shows exemplary light chain (LC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the LC sequences provided herein. [Figure 33-4] Figure 33-4 shows exemplary light chain (LC) sequences of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may include one or more of the LC sequences provided herein. [Figure 34] Figure 34 shows exemplary combinations of variable heavy chains CDR1, CDR2, and CDR3 of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the heavy chain CDR combinations provided herein. [Figure 35] Figure 35 shows exemplary combinations of variable light chains CDR1, CDR2, and CDR3 of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the light chain CDR combinations provided herein. [Figure 36] Figure 36 shows exemplary combinations of heavy and light chain CDRs of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the heavy and light chain CDR combinations provided herein. [Figure 37] Figure 37 shows exemplary combinations of heavy chain and light chain variable regions of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the heavy chain and light chain variable region combinations provided herein. [Figure 38] Figure 38 shows exemplary combinations of heavy and light chains of anti-Gal3 antibodies disclosed herein. In some embodiments, any of the compositions or methods provided herein may comprise one or more of the heavy and light chain combinations provided herein. [Figure 39-1]Figure 39-1 shows alignments of several embodiments of the VH CDR region or VL CDR region of various embodiments of the anti-Gal3 antibody. In some embodiments, any of the methods or compositions provided herein may use any of the consensus CDRs 1, 2, 3, 4, 5, 6, or 7 provided herein. [Figure 39-2] Figure 39-2 shows alignments of several embodiments of the VH CDR region or VL CDR region of various embodiments of the anti-Gal3 antibody. In some embodiments, any of the methods or compositions provided herein may use any of the consensus CDRs 1, 2, 3, 4, 5, 6, or 7 provided herein. [Figure 39-3] Figure 39-3 shows alignments of several embodiments of the VH CDR region or VL CDR region of various embodiments of the anti-Gal3 antibody. In some embodiments, any of the methods or compositions provided herein may use any of the consensus CDRs 1, 2, 3, 4, 5, 6, or 7 provided herein. [Figure 39-4] Figure 39-4 shows alignments of several embodiments of the VH CDR region or VL CDR region of various embodiments of the anti-Gal3 antibody. In some embodiments, any of the methods or compositions provided herein may use any of the consensus CDRs 1, 2, 3, 4, 5, 6, or 7 provided herein. [Figure 40] Figure 40 shows peptides found to bind to exemplary anti-Gal3 antibodies disclosed herein (using the peptide nomenclature shown in Figure 27 as discussed herein) and binning of these exemplary antibodies. [Figure 41] Figure 41 shows the KD(M) values ​​of Gal3 binding for exemplary anti-Gal3 antibodies disclosed herein. [Modes for carrying out the invention]

[0018] Diabetes is a group of metabolic diseases characterized by persistently high blood sugar levels. There are three types of diabetes: type 1 diabetes, type 2 diabetes, and gestational diabetes. Type 1 diabetes is caused by the pancreas' inability to produce enough insulin due to a deficiency of insulin-producing beta cells. Type 2 diabetes is characterized by insulin resistance and can be caused by various lifestyle, dietary, and genetic factors, such as obesity, an unbalanced diet, and stress. Gestational diabetes occurs when a pregnant woman with no history of diabetes develops hyperglycemia.

[0019] Inflammatory bowel disease (IBD) is a general medical term encompassing inflammatory diseases of the small and colon. The two most widely recognized IBDs are Crohn's disease and ulcerative colitis, which have distinct symptoms and possible treatments. The exact cause of IBD is unknown, but it is thought to involve microbiome activity and diet. Symptoms are associated with abnormal immunological activity and inflammation of the gastrointestinal tract. Some treatments involve immunosuppressants (e.g., mesalazine, corticosteroids) or antibiotics that suppress specific bacteria in the microbiome, but sustained relief may only be possible through surgery. There is a long-term need for effective treatments for IBD.

[0020] Fatty liver disease, also known as fatty liver disease, is generally characterized by an abnormal retention of lipids within liver cells. Millions of people worldwide suffer from fatty liver disease. For example, the prevalence of fatty liver disease is estimated to range from 10% to 24% in various countries around the world. There are various causes of fatty liver disease. For example, non-alcoholic fatty liver disease (NAFLD) refers to a range of hepatic lipid disorders characterized by hepatic steatosis, usually without known secondary causes. NAFLD is divided into two subcategories: (a) non-alcoholic fatty liver (NAFL), defined as the presence of steatosis in the absence of histological evidence of hepatocyte damage, and (b) non-alcoholic steatohepatitis (NASH), which is fatty liver with hepatocyte damage and inflammation. NASH can occur with or without fibrosis, but can progress to fibrosis and cirrhosis. NAFLD is generally associated with obesity, dyslipidemia, diabetes, and other energy metabolism conditions such as metabolic syndrome. The prevalence of NAFLD is high. The prevalence of NAFLD in the general population is estimated at 20%, and the prevalence of NASH is estimated at 3-5%. The estimated prevalence of NAFLD among obese or diabetic patients is approximately 70%, and among patients with dyslipidemia, it is approximately 50%. However, there are currently no approved medications for the treatment of NAFLD / NASH.

[0021] Galectin-3 (Gal3) plays a crucial role in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. This activity is at least partially due to its immunomodulatory properties and binding affinity to other immunomodulatory proteins, signaling proteins, and other cell surface markers. Gal3 functions through distinct N-terminal and C-terminal domains. The N-terminal domain (isoform 1: amino acids 1-111) contains a tandem repeat domain (TRD, isoform 1: amino acids 36-109) and is largely involved in the oligomerization of Gal3. The C-terminal domain (isoform 1: amino acids 112-250) contains a carbohydrate recognition binding domain (CRD) that binds to β-galactosides.

[0022] Galectin-3 (Gal3) has been suggested herein to possess immunomodulatory activity. An example of this is the interaction between Gal3 and T-cell immunoglobulin-mucin domain-containing-3 (TIM-3), which induces suppression of immune responses such as T-cell activation, allowing cancer cells to evade immune clearance. Anti-Gal3 antibodies and methods of use have been discussed in Patent Documents 1 and 2, which are expressly incorporated herein by reference in their entirety.

[0023] Furthermore, Gal3 has been shown to be elevated in obese individuals, and is thought to cause insulin resistance and impaired glucose tolerance in these subjects. Gal3 is related to insulin receptor It has been shown to directly bind to the body and inhibit downstream signaling. Therefore, Gal3 may contribute to obesity-induced insulin resistance and chronic tissue inflammation.

[0024] In some embodiments, methods are disclosed for treating subjects who have, are suspected of having, or are at risk of developing diabetes mellitus, inflammatory bowel disease, non-alcoholic fatty liver disease, and / or non-alcoholic steatohepatitis with an anti-Gal3 antibody or a conjugated fragment thereof. In some embodiments, the anti-Gal3 antibody or a conjugated fragment thereof interferes with the interaction between Gal3 and the insulin receptor. In some embodiments, the anti-Gal3 antibody or a conjugated fragment thereof interferes with the interaction between Gal3 and the integrin. Compositions comprising an anti-Gal3 antibody or a conjugated fragment thereof that interferes with the interaction between Gal3 and the insulin receptor and / or between Gal3 and the integrin are further provided.

[0025] In some embodiments, various embodiments of anti-Gal3 antibodies or their conjugated fragments are provided herein. In some embodiments, various anti-Gal3 antibodies or their conjugated fragments may block the interaction between Gal3 and other molecules to which Gal3 binds. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of said anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3. Thus, although this disclosure also assumes an antigen-binding molecule whenever it refers to an antibody or its conjugated fragment, in short, this disclosure may simply refer to an antibody or its conjugated fragment.

[0026] In some embodiments, the anti-Gal3 antibodies or binding fragments disclosed herein interfere with the interaction between Gal3 and the insulin receptor (INSR). Some exemplary anti-Gal3 antibodies that strongly (e.g., at least 90%) interfere with the interaction between Gal3 and INSR include, but are not limited to, 6H6.2D6, 20H5.A3, 20D11.2C6, 4G2.2G6, 13H12.2F8, 19B5.2E6, 15G7.2A7, 23H9.2E4, 19D9.2E5, 2D10.2B2, 4A11.2B5, 14H10.2C9, 3B11.2G2, and 13A12.2E5. Some exemplary anti-Gal3 antibodies that moderately (e.g., at least 75%) interfere with the interaction between Gal3 and INSR include, but are not limited to, 7D8.2D8 and 15F10.2D6. Some exemplary anti-Gal3 antibodies that minimize (e.g., ≤30%) the interaction between Gal3 and INSR include, but are not limited to, 9H2.2H1, 12G5.D7, 13G4.2F8, and 24D12.2H9. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3. Note that the term “antigen-binding molecule” encompasses antibodies and their conjugated fragments and indicates a broader genus of choices.

[0027] In some embodiments, the anti-Gal3 antibodies or binding fragments disclosed herein interfere with the interaction between Gal3 and integrin β-1 (ITGb1). Some exemplary anti-Gal3 antibodies that strongly (e.g., at least 90%) interfere with the interaction between Gal3 and ITGb1 include, but are not limited to, TB001, TB006, and 846.1F5. Some exemplary anti-Gal3 antibodies that moderately (e.g., 40% to 60%) interfere with the interaction between Gal3 and ITGb1 include, but are not limited to, 3B11, 2D10, 7D8, 13A12, 14H10, 15F10, 20D11, 846.2H3, 846T.14A2, 847.10B9, 847.12F12, and 847.26F5. Some exemplary anti-Gal3 antibodies that do not interfere with the interaction between Gal3 and ITGb1 include, but are not limited to, 6B3.2D3 and 847.14H4. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0028] In some embodiments, the anti-Gal3 antibodies or binding fragments disclosed herein interfere with the interaction between Gal3 and integrin α-3 (ITGa3). Some exemplary anti-Gal3 antibodies that strongly interfere with the interaction between Gal3 and ITGa3 (e.g., at least 90%) include, but are not limited to, TB001, TB006, 2D10, 3B11, 7D8, 13A12, 14H10, 15F10, 19B5, 20D11.2C6, 20H5, 23H9, 846.1B2, 846.1F5, 846.1H5, 846.1H12, 846.2H3, 846T.14A2, 846T.14E4, 846T.16B5, 847.4B10, 847.10B9, 84712F12, and 847.26F5. Some exemplary anti-Gal3 antibodies that weakly (e.g., less than 35%) interfere with the interaction between Gal3 and ITGa3 include, but are not limited to, 6B3.2D3, 9H2.2H10, 12G5.D7, 13G4.2F8, 847.14H4, and 847.11B1. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0029] In some embodiments, the anti-Gal3 antibodies or binding fragments disclosed herein interfere with the interaction between Gal3 and integrin β-3 (ITGb3). Some exemplary anti-Gal3 antibodies that strongly interfere with the interaction between Gal3 and ITGb3 (e.g., at least 90%) include, but are not limited to, TB001, TB006, 2D10, 3B11.2G2, 13A12.2E5, 14H10.2C9, 19B5, 20D11.2C6, 20H5.A3, 23H9.2E4, 846.1B2, 846.1F5, 846.1H12, 846.2H3, 846T.14A2, 846T.14E4, 846T.16B5, 847.10B9, 847.12F12, and 847.26F5. Some exemplary anti-Gal3 antibodies that weakly (e.g., less than 10%) interfere with the interaction between Gal3 and ITGb3 include, but are not limited to, 6B3.2D3, 9H2.2H10, 12G5.D7, 13G4.2F8, 847.11B1, and 847.14H4. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0030] In some embodiments, the anti-Gal3 antibodies or binding fragments disclosed herein interfere with the interaction between Gal3 and integrin α-V (ITGaV). Some exemplary anti-Gal3 antibodies that strongly interfere with the interaction between Gal3 and ITGaV (e.g., at least 90%) include, but are not limited to, TB001, TB006, 2D10, 3B11.2G2, 14H10.2C9, 19B5, 20D11.2C6, 20H5.A3, 23H9.2E4, 846.1B2, 846.1F5, 846.2H3, 846T.14A2, 846T.16B5, 847.10B9, 847.12F12, 847.26F5, and 849.8D10. Some exemplary anti-Gal3 antibodies that weakly (e.g., less than 30%) interfere with the interaction between Gal3 and ITGaV include, but are not limited to, 6B3.2D3, 9H2.2H10, 12G5.D7, 13G4.2F8, 847.11B1, and 847.14H4. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0031] In some embodiments, administering any one of the anti-Gal3 antibodies or their conjugate fragments disclosed herein can reduce weight gain, insulin resistance, fatty liver, or liver dysfunction, or any combination thereof, in a subject.

[0032] In some embodiments, lymphocyte adhesion is reduced by interfering with the interaction between Gal3 and integrins. In some embodiments, inflammation in the target is reduced by administering either one of the anti-Gal3 antibodies or binding fragments disclosed herein.

[0033] In some embodiments, administration of any one of the anti-Gal3 antibodies or their conjugated fragments disclosed herein may reduce changes in fasting blood glucose levels, restore C-peptide levels, or both, and may be used as a treatment for type 1 and / or type 2 diabetes.

[0034] In some embodiments, administration of any one of the anti-Gal3 antibodies or their conjugate fragments disclosed herein can restore the reduction in pro-inflammatory colon length or reduce circulating inflammatory cytokines, or at least one of both.

[0035] definition The following detailed description refers to the accompanying drawings, which constitute part of it. In the drawings, unless otherwise indicated in the context, similar symbols usually identify similar components. The exemplary embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be used and other modifications may be made without departing from the spirit or scope of the subject matter presented herein. It will be readily apparent that the aspects of this disclosure outlined herein and shown in the drawings may be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly intended.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which the claimed invention pertains. It should be understood that the above overview and the following detailed description are illustrative and descriptive only and do not limit the claimed subject matter.

[0037] The section headings used herein are for constituent purposes only and should not be construed as limiting the gist of the invention described.

[0038] In this application, unless otherwise specified, the use of the singular includes the plural. Note that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context clearly indicates otherwise. In this application, unless otherwise specified, the use of “or” means “and / or.” Furthermore, the use of the term “including,” and other forms such as “include,” “includes,” and “included,” is not limited to this application.

[0039] "Approximately" means a quantity, level, value, number, frequency, percentage, dimension, size, volume, weight, or length that varies by up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to the reference quantity, level, value, number, frequency, percentage, dimension, size, volume, weight, or length.

[0040] Throughout this specification, unless otherwise required by context, the words “comprise,” “comprises,” and “comprising” are understood to mean that they include the described process or element or group of processes or elements, and do not exclude any other process or element or group of processes or elements. “Consisting of” means that it includes and is limited to what follows the phrase “consisting of.” Thus, the phrase “consisting of” indicates that the enumerated elements are necessary or essential, and other elements may not be present. “Essentially consisting of” means that it includes any elements enumerated after the phrase, limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure of the enumerated elements. Thus, the phrase “essentially consisting of” indicates that the enumerated elements are necessary or essential, but other elements are optional and may or may not be present depending on whether they have a significant effect on the activity or action of the enumerated elements.

[0041] As used herein, the terms “individual,” “subject,” and “patient” mean any mammal. In some embodiments, the mammal is human. In some embodiments, the mammal is non-human. None of the terms require, and are not limited to, a situation characterized by supervision (e.g., continuous or intermittent) of a healthcare professional (e.g., physician, registered nurse, nurse practitioner, physician's assistant, ward staff, or hospital staff).

[0042] The terms “polypeptide,” “peptide,” and “protein” are interchangeable herein and refer to polymers of amino acids of any length. Such polymers may be linear, cyclic, or branched, and may contain modified amino acids, and may be interrupted by non-amino acids. The term also includes amino acid polymers modified by any other operation, such as sulfation, glycosylation, lipidation, acetylation, phosphorylation, iodization, methylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, arginylation via transfer RNA, ubiquitination, or conjugation with a labeling component.

[0043] As used herein, the term “amino acid” refers to any natural and / or unnatural or synthetic amino acid, including glycine and both D- or L-optical isomers, as well as amino acid analogs and peptide mimetic compounds.

[0044] A polypeptide or amino acid sequence "derived" from a specified protein refers to the origin of the polypeptide. Preferably, the polypeptide has an amino acid sequence essentially identical to the polypeptide or a portion thereof encoded by its sequence, the portion consisting of at least 10-20 amino acids, or at least 20-30 amino acids, or at least 30-50 amino acids, or immunologically identifiable with the polypeptide encoded by the sequence. This term also includes polypeptides expressed from a specified nucleic acid sequence.

[0045] As used herein, the term “antibody” is intended to have the meaning attributed to those skilled in the art, and further to include a molecular structure comprising a polypeptide chain of a specific shape that fits to and recognizes an epitope, wherein the complex between the molecular structure and the epitope is stabilized by one or more non-covalent interactions. Antibodies may be polyclonal antibodies, but monoclonal antibodies are preferred because they can be replicated by cell culture or by recombination and can be modified to reduce their antigenicity.

[0046] In addition to whole immunoglobulins (or their recombinant counterparts), immunoglobulin fragments or "binding fragments" containing epitope binding sites (e.g., Fab', F(ab')2, single-chain variable fragments (scFv), diabodies, minibodies, nanobodies, single-domain antibodies (sdAb), or other fragments) are useful as antibody portions in the present invention. Such antibody fragments can be generated from whole immunoglobulins by cleavage with lysine, pepsin, papain, or other proteases. Minimal immunoglobulins are recombinant immunoglobulins. The technology may be utilized in the design. For example, “Fv” immunoglobulins for use in the present invention may be produced by linking a variable light chain region to a variable heavy chain region via a peptide linker (e.g., polyglycine or another sequence that does not form an alpha-helix or beta-sheet motif). Nanobody or single-domain antibodies may also be derived from alternative organisms such as dromedary camels, camels, llamas, alpacas, and sharks. In some embodiments, the antibody may be a conjugate, such as a pegylated antibody, drug, radioisotope, or toxin conjugate. Monoclonal antibodies against a specific epitope or combination of epitopes allow for the targeting and / or depletion of cell populations expressing the marker. Various methods may be used to screen cell populations expressing the marker using monoclonal antibodies. These include magnetic separation using antibody-coated magnetic beads, “panning” with antibodies attached to a solid matrix (i.e., a plate), and flow cytometry (e.g., Patent Document 3, the whole of which is expressly incorporated herein by reference).

[0047] As is well known in the art, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain. The “Fc region” may be a naturally occurring Fc region or a mutant Fc region. While the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is typically defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The numbering of residues in the Fc region is similar to the EU index numbering used in Kabat (Non-Patent Literature 1). The Fc region of an immunoglobulin generally contains two constant domains, CH2 and CH3. As is well known in the art, the Fc region may exist in dimeric or monomeric form.

[0048] As is well known in the art, the “constant region” of an antibody refers, either alone or in combination, to the constant region of the antibody light chain or the constant region of the antibody heavy chain.

[0049] The “variable region” of an antibody refers, either alone or in combination, to the variable region of the antibody light chain or the variable region of the antibody heavy chain. As is well known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions, and contribute to the formation of the antibody's antigen-binding site. When a variant of the target variable region is desired, particularly involving amino acid residue substitutions outside the CDR region (i.e., within the framework region), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the target variable region with the variable regions of other antibodies containing the same standard class CDR1 and CDR2 sequences as the target variable region (Non-Patent Literature 2).

[0050] In certain embodiments, a clear depiction of the CDR and identification of residues containing the antibody binding site are achieved by elucidating the structure of the antibody and / or the structure of the antibody-ligand complex. In certain embodiments, this can be achieved by any of the various techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, the CDR region can be identified or approximated using various analytical methods. Examples of such methods include, but are not limited to, Kabat's definition, Chothia's definition, the IMGT approach (Non-Patent Literature 3), computational programs such as Paratome (Non-Patent Literature 4), AbM's definition, and three-dimensional structure definitions.

[0051] Kabat's definition is a standard for numbering antibody residues and is typically used to identify CDR regions. See, for example, Non-Patent Document 5. Chothia's definition is similar to Kabat's, but takes into account the location of specific structural loop regions. See, for example, Non-Patent Documents 6 and 7. The AbM definition uses an integrated suite of computer programs created by the Oxford Molecular Group to model antibody structures. See, for example, Non-Patent Documents 8 and 9. The AbM definition models the tertiary structure of an antibody from its primary sequence using a combination of a knowledge database and ab initio methods, as described in Non-Patent Document 10. The contact definition is based on the analysis of available complex crystal structures. See, for example, Non-Patent Document 11. In another approach referred herein as the “stereotypic definition” of CDRs, the location of a CDR may be identified as a residue that makes an enthalpy contribution to antigen binding. See, for example, Non-Patent Document 12. Further other CDR boundary definitions may not strictly adhere to one of the above approaches but overlap with at least some of Kabat’s CDRs. However, a CDR may be shortened or extended in light of predictions or experimental findings that certain residues or groups of residues do not significantly affect antigen binding. As used herein, a CDR may refer to a CDR defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment including multiple CDRs, a CDR may be defined according to any of the following: Kabat's definition, Chothia's definition, the extended approach, IMGT, Paratome, AbM's definition, and / or the stereostructure definition, or any combination thereof.

[0052] As used herein with respect to antibodies, the term “competitive” means that the primary antibody or its antigen-binding moiety binds to the epitope in a manner sufficiently similar to the binding of the secondary antibody or its antigen-binding moiety, so that the binding of the primary antibody to its homologous epitope is detected to be reduced in the presence of the secondary antibody compared to the binding of the primary antibody in the absence of the secondary antibody. Alternatively, the binding of the secondary antibody to its epitope may also be detected to be reduced in the presence of the primary antibody, or it may not be. That is, the primary antibody may inhibit the secondary antibody from binding to its respective epitope without the secondary antibody inhibiting the primary antibody from binding to its respective epitope. However, if each antibody detectably inhibits the binding of other antibodies to their homologous epitopes or ligands, the antibodies are said to “cross-compete” with each other for binding to their respective epitopes to a similar or more or lesser extent. Both competitive antibodies and cross-competitive antibodies are encompassed in the present invention. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or part thereof), those skilled in the art will understand, based on the teachings provided herein, that such competing and / or cross-competing antibodies may be included and useful in the methods disclosed herein.

[0053] Antibodies that “preferentially bind” or “specifically bind” (as used interchangeably herein) to an epitope are well understood terms in the art, and methods for determining such specific or preferential binding are also well known in the art. A molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates with a particular cell or substance more frequently, and / or more quickly, and / or for a longer period of time, and / or with greater affinity to that particular cell or substance, compared to alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with higher affinity, and / or binding strength, and / or more easily, and / or for a longer period of time than it binds to other substances. For example, an antibody that specifically or preferentially binds to a CFD epitope is an antibody that binds to that epitope with higher affinity, and / or binding strength, and / or more easily, and / or for a longer period of time than it binds to other CFD epitopes or non-CFD epitopes. By interpreting this definition, it can be understood that, for example, an antibody (or partial or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Therefore, "specific binding" or "preferential binding" does not necessarily require exclusive binding (although it may include it). While not always the case, generally speaking, binding implies preferential binding.

[0054] As used herein, the term “antigen-binding molecule” refers to a molecule comprising an antigen-binding moiety that, optionally, binds to an antigen, to a scaffold or framework moiety that enables the antigen-binding moiety to assume a three-dimensional structure that facilitates the binding of the antigen-binding moiety or provides certain additional properties to the antigen-binding molecule. In some embodiments, the antigen is Gal3. In some embodiments, the antigen-binding moiety comprises at least one CDR from an antibody that binds to the antigen. In some embodiments, the antigen-binding moiety comprises all three CDRs from the heavy chain or light chain of the antibody that binds to the antigen. In some embodiments, the antigen-binding moiety comprises all six CDRs from the antibody that binds to the antigen (three from the heavy chain and three from the light chain). In some embodiments, the antigen-binding moiety is an antibody fragment.

[0055] Non-limiting examples of antigen-binding molecules include antibodies, antibody fragments (e.g., antigen-binding fragments of antibodies), antibody derivatives, and antibody analogs. More specific examples include, but are not limited to, single-chain variable fragments (scFv), nanobodies (e.g., the VH domain of camel heavy-chain antibodies (VHH fragment), see Non-Patent Literature 13), Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, Fd fragments, and complementarity-determining region (CDR) fragments. These molecules may originate from any mammalian source, such as humans, mice, rats, rabbits, pigs, dogs, cats, horses, donkeys, guinea pigs, goats, or camels. Antibody fragments may compete with intact antibodies for binding to target antigens, and such fragments may be generated by modification of intact antibodies (e.g., enzymatic or chemical cleavage) or newly synthesized using recombinant DNA technology or peptide synthesis. Antigen-binding molecules may include, for example, alternative protein scaffolds or artificial scaffolds having transplanted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds containing mutations introduced to stabilize the three-dimensional structure of antigen-binding molecules, and, for example, fully synthetic scaffolds containing biocompatible polymers. See, for example, Non-Patent Documents 14 and 15. Furthermore, peptide antibody mimes ("PAMs") and antibody mimeograph-based scaffolds utilizing fibronectin components as scaffolds may also be used.

[0056] Antigen-binding molecules may also include proteins containing one or more antibody fragments incorporated into a single polypeptide chain or multiple polypeptide chains. For example, antigen-binding molecules may include diabodies (see, for example, Patent Documents 4, 5, and Non-Patent Document 16), intrabodies, domain antibodies (a single VL or VH domain, or two or more VH domains linked by a peptide linker, see Non-Patent Document 17), maxibodies (two scFv fused to an Fc region, see Non-Patent Documents 18 and 19), triabodies, tetrabodies, minibodies (scFv fused to a CH3 domain, see Non-Patent Document 20), Examples include, but are not limited to, peptide bodies (one or more peptides bound to an Fc region, see Patent Document 6), linear antibodies (a pair of tandem Fd segments (VH-CH1-VH-CH1) that, together with a complementary light chain polypeptide, form a pair of antigen-binding regions, see Non-Patent Document 21), small modular immunopharmaceuticals (see Patent Document 7), and immunoglobulin fusion proteins (e.g., IgG-scFv, IgG-Fab, 2scFv-IgG, 4scFv-IgG, VH-IgG, IgG-VH, and Fab-scFv-Fc).

[0057] In certain embodiments, the antigen-binding molecule may have, for example, the structure of an immunoglobulin. An "immunoglobulin" is a tetrameric molecule, each tetramer containing two identical pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminus of each chain contains a variable region of approximately 100-110 or more amino acids, primarily responsible for antigen recognition. The carboxyl-terminus of each chain defines a constant region, primarily responsible for effector function.

[0058] The term "humanized" as applied to non-human (e.g., rodent or primate) antibodies refers to hybrid immunoglobulins, immunoglobulin chains, or fragments thereof that contain minimal sequences derived from non-human immunoglobulins.

[0059] As used herein, the terms “to treat” or “treatment” (and as well as well known in the art) mean an approach to obtain a beneficial or desired outcome in a condition of a subject, including clinical outcomes. Beneficial or desired outcomes include, but are not limited to, relief or improvement of one or more symptoms or conditions, whether partial or whole, detectable or undetectable; reduction of the severity of the disease; stabilization of the disease condition (i.e., prevention of exacerbation); prevention of transmission or spread of the disease; delay or slowing of disease progression; improvement or relief of the condition; reduction of disease recurrence; and remission. As used herein, “to treat” and “treatment” also include prophylactic treatment. A treatment method involves administering a therapeutically effective amount of an activator to a subject. The administration step may consist of a single dose or may include a series of doses. The composition is administered to the subject in an amount and duration sufficient to treat the subject. The length of the treatment period is determined by a variety of factors, including the severity of the condition, the age and genetic profile of the subject, the concentration of the activator, the activity of the composition used for treatment, or a combination thereof. It should be understood that the effective dose of a drug used for treatment or prevention may increase or decrease during the course of a particular treatment or prevention regime. Changes in dosage can be caused and revealed by standard diagnostic assays known in the art. In some cases, chronic administration may be necessary.

[0060] As used herein, the terms “effective amount” or “effective dose” have the obvious and ordinary meaning as understood in light of the specification and refer to the amount of the described composition or compound that produces an observable specified effect. The actual dose levels of the active ingredient in the active composition of the gist of the inventions of this disclosure may be modified to administer an amount of the active composition or compound that is effective in achieving a specified response for a particular subject and / or use. The selected dose level may vary based on a variety of factors, including but not limited to the activity of the composition, formulation, route of administration, combination with other drugs or treatments, severity of the condition being treated, and the physical condition and medical history of the subject being treated. In some embodiments, a minimum dose is administered, and if there is no dose-limiting toxicity, the dose is increased to a minimum effective amount. This specification is intended to evaluate the determination and adjustment of effective doses, as well as when and how such adjustments should be made.

[0061] The term "administer" includes oral administration, topical contact, administration as a suppository, intravenous, intraperitoneal, intramuscular, intrafocal, intrathecal, intranasal, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, and transdermal patches. "Concurrent administration" means that the first compound described herein is administered concurrently with the administration of the second compound described herein, either immediately before or immediately after.

[0062] As used herein, the term “therapeutic target” refers to a gene or gene product that, upon modulation of its activity (e.g., by modulation of expression, biological activity, etc.), can provide modulation of a disease phenotype. As used throughout, “modulation” means an increase or decrease of the phenomenon being described (e.g., modulation of biological activity means an increase or decrease of biological activity).

[0063] As used herein, the terms “treatment criteria,” “best practice,” and “standard treatment” refer to treatments accepted by physicians as appropriate, reasonable, effective, and / or widely used treatments for a particular disease. Treatment criteria for a particular disease depend on many different factors, including the biological effect of the treatment, the area or location in the body, the patient’s condition (e.g., age, weight, sex, genetic risk, other disorders, secondary conditions), toxicity, metabolism, bioaccumulation, treatment index, dosage, and other factors known in the art. Determining treatment criteria for a disease also involves establishing safety and efficacy in clinical trials, as standardized by regulatory authorities such as the U.S. Food and Drug Administration (FDA), the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Health Canada, the European Medicines Agency (EMA), the Australian Therapeutic Products Agency (TGA), the Central Pharmaceuticals Standards and Regulations Administration of India (CDSCO), the National Food and Drug Administration of China (NMPA), the Pharmaceuticals and Medical Devices Agency (PMDA), the Korea Food and Drug Safety Agency (MFDS), and the World Health Organization (WHO). Standard treatment for the disease may include, but is not limited to, surgery, radiotherapy, chemotherapy, targeted therapy, or immunotherapy.

[0064] The terms "%(w / w)" or "%(wt / wt)" (weight %) refer to the percentage expressed in relation to the weight of an ingredient or drug, multiplied by 100, of the total weight of the composition.

[0065] Unless otherwise specified, the complementary definition areas disclosed herein follow the IMGT definitions. In some embodiments, any of the CDRs disclosed herein may instead be interpreted by the definitions of Kabat, Chothia, or other definitions accepted by those skilled in the art.

[0066] It is understood that antibodies having the antibody names described herein may be referred to using a shortened version of the antibody name, unless there is conflict with another antibody described herein. For example, 2D10.2B2 may be referred to as 2D10, which may refer to a fragment of the antibody (e.g., having the same 1, 3, or 6 CDRs).

[0067] Gal3 Binder Anti-Gal3 antibodies or their conjugated fragments are disclosed herein and applicable to any of the methods or uses disclosed herein. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to the N-terminal domain of Gal3, the N-terminus of Gal3, or the tandem repeat domain (TRD) of Gal3. In some embodiments, the anti-Gal3 antibody or its conjugated fragment does not bind to the N-terminus of Gal3, the N-terminal domain of Gal3, or the TRD of Gal3. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to the C-terminus of Gal3, the C-terminal domain of Gal3, or the CRD of Gal3. In some embodiments, the anti-Gal3 antibody or its conjugated fragment does not bind to the C-terminus of Gal3, the C-terminal domain of Gal3, or the CRD of Gal3. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0068] In some embodiments, the anti-Gal3 antibody or its binding fragment binds to one or more peptides of SEQ ID NOs: 3-26. In some embodiments, the anti-Gal3 antibody or its binding fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof. In some embodiments, any of the anti-Gal3 antibodies or their binding fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or binding fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0069] In some embodiments, the anti-Gal3 antibody or its conjugate fragment binds to a Gal3 epitope containing a GxYPG motif, where x is the amino acid alanine (A), glycine (G), or valine (V). In some embodiments, the anti-Gal3 antibody described herein binds to a Gal3 epitope containing two GxYPG motifs separated by three amino acids, where x is A, G, or V. In some embodiments, any of the anti-Gal3 antibodies or their conjugate fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugate fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0070] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -Includes a heavy chain variable region including CDR3. In some embodiments, the V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 100-128. In some embodiments, the V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 129-144. In some embodiments, the V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 145-168. In some embodiments, the V H-CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 27-47. In some embodiments, the V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs.48-69. In some embodiments, the V H -CDR3 comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 70-99. In some embodiments, either the anti-Gal3 antibody or its conjugate fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugate fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0071] In some embodiments, the anti-GAL3 antibody or fragment thereof comprises at least one of the HCDRs provided herein, e.g., HCDR1, HCDR2, or HCDR3.

[0072] In some embodiments, Exemplary V H -The CDR1 sequence is shown in Figure 28A. In some embodiments, the exemplary V H -The CDR2 sequence is shown in Figure 28B. In some embodiments, Exemplary V H -The CDR3 sequence is shown in Figure 28C. In some embodiments, Exemplary V L -The CDR1 sequence is shown in Figure 29A. In some embodiments, the exemplary V L -The CDR2 sequence is shown in Figure 29B. In some embodiments, the exemplary V L -The CDR3 sequence is shown in Figure 29C.

[0073] In some embodiments, the heavy chain variable region of either the anti-Gal3 antibody or its conjugate fragment disclosed herein has at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with any sequence according to SEQ ID NOs. 169-206. Includes a sequence. In some embodiments, the heavy chain variable region of either the anti-Gal3 antibody or its binding fragment disclosed herein is selected from the group consisting of SEQ ID NOs: 169-206. In some embodiments, exemplary V H These are shown in Figures 30-1, 30-2, and 30-3. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0074] In some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein includes an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with any sequence represented by SEQ ID NOs. 207-245. In some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein is selected from the group consisting of SEQ ID NOs. 207-245. In some embodiments, exemplary V L This is shown in Figures 31-1 to 31-3.

[0075] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is

[0076] a) V in sequence number 169 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 207 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, VL -CDR2, V L -CDR3,

[0077] b) V in sequence number 170 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 208 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0078] c) V in sequence number 171 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 209 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0079] d) V in sequence number 172 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 210 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0080] e) V within SEQ ID NO: 173 H - CDR1, V H - CDR2, V H - the V that is CDR3 H - CDR1, V H - CDR2, V H - CDR3 and V within SEQ ID NO: 211 L - CDR1, V L - CDR2, V L - the V that is CDR3 L - CDR1, V L - CDR2, V L - CDR3

[0081] f) V within SEQ ID NO: 174 H - CDR1, V H - CDR2, V H - the V that is CDR3 H - CDR1, V H - CDR2, V H - CDR3 and V within SEQ ID NO: 212 L - CDR1, V L - CDR2, V L - the V that is CDR3 L - CDR1, V L - CDR2, V L - CDR3

[0082] g) V within SEQ ID NO: 175 H - CDR1, V H - CDR2, V H - the V that is CDR3 H - CDR1, V H - CDR2, V H - CDR3 and V within SEQ ID NO: 213 L - CDR1, V L - CDR2, V L - the V that is CDR3 L - CDR1, V L - CDR2, V L - CDR3

[0083] h) V within SEQ ID NO: 176 H - CDR1, V H - CDR2, V H - the V that is CDR3H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 214 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0084] i) V in sequence number 177 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 215 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0085] j) V in sequence number 178 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 216 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0086] k) V in sequence number 179 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 217L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0087] l) V in sequence number 180 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 218 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0088] m) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 219 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0089] n) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 220 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L-CDR1, V L -CDR2, V L -CDR3,

[0090] o) V in sequence number 182 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 221 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0091] p) V in sequence number 183 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 222 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0092] q) V in sequence number 184 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 223 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0093] r) V in sequence number 185 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 224 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0094] s) V in sequence number 186 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 225 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0095] t) V in sequence number 187 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 226 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0096] u) V in sequence number 188 H -CDR1, V H -CDR2, V H-CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 227 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0097] v) V in sequence number 189 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 228 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0098] w) V in sequence number 190 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 229 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0099] x) V in sequence number 191 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H-V in CDR3 and Sequence ID No. 230 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0100] y) V in sequence number 192 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 231 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0101] z) V in sequence number 193 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 232 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0102] aa) V in sequence number 194 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 233 L -CDR1, V L -CDR2, V L-CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0103] ab) V in sequence number 195 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 234 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0104] ac) V in sequence number 196 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 235 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0105] ad) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 236 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0106] ae) V in sequence number 198 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 237 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0107] af) V in sequence number 199 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 238 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0108] ag) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 239 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0109] ah) V in sequence number 200 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0110] ai) V in sequence number 201 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 241 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0111] aj) V in sequence number 202 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 242 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0112] ak) V in sequence number 203 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H-CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0113] al) V in sequence number 204 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 243 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0114] am) V in Sequence ID 205 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 244 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3, or

[0115] an) V in sequence number 206 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 245 L -CDR1, V L-CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L - Includes CDR3.

[0116] In some embodiments, exemplary heavy chain variable region CDR combinations are shown in Figure 34. In some embodiments, exemplary light chain variable region CDR combinations are shown in Figure 35. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0117] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is a) the heavy chain variable region of SEQ ID NO: 169 and the light chain variable region of SEQ ID NO: 207, b) the heavy chain variable region of SEQ ID NO: 170 and the light chain variable region of SEQ ID NO: 208, c) the heavy chain variable region of SEQ ID NO: 171 and the light chain variable region of SEQ ID NO: 209, d) the heavy chain variable region of SEQ ID NO: 172 and the light chain variable region of SEQ ID NO: 210, e) the heavy chain variable region of SEQ ID NO: 173 and the light chain variable region of SEQ ID NO: 211, f) the heavy chain variable region of SEQ ID NO: 174 and the light chain variable region of SEQ ID NO: 212 g) light chain variable region of SEQ ID NO: 175 and light chain variable region of SEQ ID NO: 213, h) heavy chain variable region of SEQ ID NO: 176 and light chain variable region of SEQ ID NO: 214, i) heavy chain variable region of SEQ ID NO: 177 and light chain variable region of SEQ ID NO: 215, j) heavy chain variable region of SEQ ID NO: 178 and light chain variable region of SEQ ID NO: 216, k) heavy chain variable region of SEQ ID NO: 179 and light chain variable region of SEQ ID NO: 217, l) heavy chain variable region of SEQ ID NO: 180 and light chain variable region of SEQ ID NO: 218, m) heavy chain variable region of SEQ ID NO: 181 and n) Light chain variable region of SEQ ID NO: 219, n) Heavy chain variable region of SEQ ID NO: 181 and light chain variable region of SEQ ID NO: 220, o) Heavy chain variable region of SEQ ID NO: 182 and light chain variable region of SEQ ID NO: 221, p) Heavy chain variable region of SEQ ID NO: 183 and light chain variable region of SEQ ID NO: 222, q) Heavy chain variable region of SEQ ID NO: 184 and light chain variable region of SEQ ID NO: 223, r) Heavy chain variable region of SEQ ID NO: 185 and light chain variable region of SEQ ID NO: 224, s) Heavy chain variable region of SEQ ID NO: 186 and light chain variable region of SEQ ID NO: 225, t) SEQ ID NO: 18 7) Heavy chain variable region and light chain variable region of SEQ ID NO: 226, u) Heavy chain variable region of SEQ ID NO: 188 and light chain variable region of SEQ ID NO: 227, v) Heavy chain variable region of SEQ ID NO: 189 and light chain variable region of SEQ ID NO: 228, w) Heavy chain variable region of SEQ ID NO: 190 and light chain variable region of SEQ ID NO: 229, x) Heavy chain variable region of SEQ ID NO: 191 and light chain variable region of SEQ ID NO: 230, y) Heavy chain variable region of SEQ ID NO: 192 and light chain variable region of SEQ ID NO: 231, z) Heavy chain variable region of SEQ ID NO: 193 and light chain variable region of SEQ ID NO: 232,

[0118] aa) Heavy chain variable region of SEQ ID NO: 194 and light chain variable region of SEQ ID NO: 233, ab) Heavy chain variable region of SEQ ID NO: 195 and light chain variable region of SEQ ID NO: 234, ac) Heavy chain variable region of SEQ ID NO: 196 and light chain variable region of SEQ ID NO: 235, ad) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 236, ae) Heavy chain variable region of SEQ ID NO: 198 and SEQ ID NO: Includes the light chain variable region of 237, af) the heavy chain variable region of SEQ ID NO: 199 and the light chain variable region of SEQ ID NO: 238, ag) the heavy chain variable region of SEQ ID NO: 197 and the light chain variable region of SEQ ID NO: 239, ah) the heavy chain variable region of SEQ ID NO: 200 and the light chain variable region of SEQ ID NO: 240, ai) the heavy chain variable region of SEQ ID NO: 201 and the light chain variable region of SEQ ID NO: 241, aj) the heavy chain variable region of SEQ ID NO: 202 and the light chain variable region of SEQ ID NO: 242, ak) the heavy chain variable region of SEQ ID NO: 203 and the light chain variable region of SEQ ID NO: 240, al) the heavy chain variable region of SEQ ID NO: 204 and the light chain variable region of SEQ ID NO: 243, am) the heavy chain variable region of SEQ ID NO: 205 and the light chain variable region of SEQ ID NO: 244, or an) the heavy chain variable region of SEQ ID NO: 206 and the light chain variable region of SEQ ID NO: 245. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0119] In some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the heavy chain (HC) sequences of SEQ ID NOs. 246-286. In some embodiments, exemplary HC sequences are shown in Figures 32-1 to 32-7. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0120] In some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the light chain (LC) sequences of SEQ ID NOs. 287-324. In some embodiments, exemplary HC sequences are shown in Figures 33-1 to 33-4. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0121] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2H1, 23B10.2B12, 6B3.2D3, F846C.1B2, F846C The antibodies are selected from the group consisting of .1F5, F846C.1H12, F846C.1H5, F846C.2H3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1, F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, F847.14H4 (847.14H4), mIMT001, IMT-001 (TB0001), and IMT-006 (TB006), or their conjugated fragments. In some embodiments, the heavy chain CDRs and light chain CDRs associated with each of the aforementioned antibodies are shown in Figure 36. In some embodiments, V associated with each antibody in the previous H and V L This is shown in Figure 37. In some embodiments, the HC and LC associated with each of the aforementioned antibodies are shown in Figure 38. In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0122] In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to a specific epitope within the Gal3 protein. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to a specific epitope within the Gal3 protein having the amino acid sequence provided by SEQ ID NO: 1 in Figure 26-1. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0123] In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 10, 15, or 20 amino acid residues in the peptide shown in Figure 27. In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 10, 15, or 20 amino acid residues within amino acid residues 1-20 of SEQ ID NO: 1. In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 10, 15, or 20 amino acid residues within amino acid residues 31-50 of SEQ ID NO: 1. In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 10, 15, or 20 amino acid residues within amino acid residues 51-70 of SEQ ID NO: 1. In some embodiments, the anti-Gal3 antibody or its conjugated fragment may be conjugated to at least 1, 2, 3, 4, 5, 6, 10, 15, or 20 amino acid residues within amino acid residues 61-80 of SEQ ID NO: 1. In some embodiments, any of the anti-Gal3 antibodies or their conjugated fragments provided herein, or any sequence of any of the anti-Gal3 antibodies or conjugated fragments, may be replaced with an antigen-binding molecule that binds to Gal3.

[0124] In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues in peptide 1 (SEQ ID NO: 3), peptide 2 (SEQ ID NO: 4), peptide 3 (SEQ ID NO: 5), peptide 4 (SEQ ID NO: 6), peptide 5 (SEQ ID NO: 7), peptide 6 (SEQ ID NO: 8), peptide 7 (SEQ ID NO: 9), peptide 8 (SEQ ID NO: 10), or peptide 17 (SEQ ID NO: 19), or any combination thereof. In some embodiments, the anti-Gal3 antibody or its conjugated fragment may bind to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid residues in peptide 6 (SEQ ID NO: 8). In some embodiments, either the anti-Gal3 antibody or its conjugated fragment provided herein, or any sequence of either said anti-Gal3 antibody or conjugated fragment, may be replaced with an antigen-binding molecule that binds to Gal3.

[0125] Some exemplary antibodies that bind to peptide 1 (SEQ ID NO: 3) are 6H6.2D6, 20H5.A3, 20D11.2C6, 19B5.2E6, 15G7.2A7, 23H9.2E4, F846C.1H5, F846TC.14A2, F846TC.7F10, F847C.10B9, F847C.12F12, F847C.26F5, and F847C.4B10.

[0126] Some exemplary antibodies that bind to peptide 2 (SEQ ID NO: 4) are 15F10.2D6, 7D8.2D8, F846TC.14E4, F849C.8D10, and F849C.8H3.

[0127] Some exemplary antibodies that bind to peptide 3 (SEQ ID NO: 5) are 15F10.2D6, 7D8.2D8, and F849C.8D10.

[0128] Some exemplary antibodies that bind to peptide 4 (sequence number 6) are 4G2.2G6, 3B11.2G2, 13A12.2E5, and 15F10.2D6.

[0129] Some exemplary antibodies that bind to peptide 5 (SEQ ID NO: 7) are IMT001 (TB001), F846C.1B2, and F846C.1H12.

[0130] Some exemplary antibodies that bind to peptide 6 (SEQ ID NO: 8) are IMT001 (TB001), IMT006 (TB006), 13H12.2F8, 19D9.2E5, 2D10.2B2, 4A11.2B5, 3B11.2D2, 13A12.2E5, and 14H10 These are .2C9, 23H9.2E4, F846C.1B2, F846C.1F5, F846C.1H12, F846C.1H12, F846C.2H3, and F846TC.16B5.

[0131] Some exemplary antibodies that bind to peptide 7 (SEQ ID NO: 9) are 6H6.2D6, 20H5.A3, 20D11.2C6, 13H12.2F8, 19B5.2E6, 23H9.2E4, 15G7.2A7, 19D9.2E5, 14H10.2C9, 7D8.2D8, 15F10.2D6, 14H10.2C9, F846C.1B2, F846TC.14A2, F847C.10B9, F847C.12F12, and F847C.26F5.

[0132] Some exemplary antibodies that bind to peptide 8 (SEQ ID NO: 10) are 23H9.2E4 and F846TC.14A2.

[0133] Some exemplary antibodies that bind to peptide 17 (SEQ ID NO: 19) are 7D8.2D8, F846C.1F5, F846C.1H12, F846TC.16B5, F847C.11B1, and F849C.8H3.

[0134] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is epitope binned. Exemplary binning processes are detailed in Examples 3 and 18. In some embodiments, antibody TB001 is classified into bin 1. In some embodiments, antibody 19D9.2E5 is classified into bin 2. In some embodiments, antibodies TB006, 4A11.2B5, 23B10.2B12, 19B5.2E6, 20H5.A3, 23H9.2E4, and 2D10.2B2 are classified into bin 3. In some embodiments, antibody 6H6.2D6 is classified into bin 4. In some embodiments, antibodies 15G7.2A7 and 20D11.2C6 are classified into bin 5. In some embodiments, antibody 4G2.2G6 is classified into bin 6. In some embodiments, antibodies 13A12.2E5 and 3B11.2G2 are classified into bin 7. In some embodiments, antibodies 14H10.2C9, 15F10.2D6, 7D8.2D8, F846TC.14E4, F846TC.7F10, and F849C.8D10 are classified into bottle 8. In some embodiments, antibody 6F7.C4 is classified into bottle 9. In some embodiments, antibody 12G5.D7 is classified into bottle 10. In some embodiments, antibody 6B3.2D3 is classified into bottle 11. In some embodiments, antibodies 9H2.2H10 and 13G4.2F8 are classified into bottle 12. In some embodiments, antibodies F846C.1B2, F846C.1F5, F846C.1H12, F846C.2H3, and F846TC.16B5 are classified into bottle 17. In some embodiments, antibodies F847C.10B9, F847C.12F12, and F847C.26F5 are classified into bottle 49.

[0135] In some embodiments, antibodies are disclosed herein that bind to human Gal3 and compete with anti-Gal3 antibodies or their binding fragments for binding to human Gal3. In some embodiments, the competing anti-Gal3 antibody or its binding fragment is any one of the anti-Gal3 antibodies disclosed herein. In some embodiments, the competing anti-Gal3 antibody or its binding fragment binds to peptide 1 (SEQ ID NO: 3), peptide 2 (SEQ ID NO: 4), peptide 3 (SEQ ID NO: 5), peptide 4 (SEQ ID NO: 6), peptide 5 (SEQ ID NO: 7), peptide 6 (SEQ ID NO: 8), peptide 7 (SEQ ID NO: 9), peptide 8 (SEQ ID NO: 10), peptide 17 (SEQ ID NO: 19), or any combination thereof. In some embodiments, the competing anti-Gal3 antibody or its binding fragment belongs to bin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 17, or 49. In some embodiments, the competing anti-Gal3 antibody or its conjugated fragment is 6H6.2D6, 20H5.A3, 20D11.2C6, 4G2.2G6, 13H12.2F8, 19B5.2E6, 15G7.2A7, 23H9.2E4, 19D9.2E5, 2D10.2B2, 4A11.2B5, 14H10.2C9, 3B11.2G2, 13A12.2E5, 7D8.2D8, and 15F10.2D6, 23B10.2B12, 6B3.2D3, F846C.1B2, F846C.1F5, F8 The following are selected from the group consisting of 46C.1H12, F846C.1H5, F846C.2H3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1, F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, 847.14H4, mIMT001, IMT001(TB001), and IMT006(TB006), or their binding fragments. In some embodiments, the antibody that binds to human Gal3 and competes with the anti-Gal3 antibody may be replaced with an antigen-binding molecule that binds to Gal3. In some embodiments, the competing anti-Gal3 antibody or its binding fragment may be replaced with an antigen-binding molecule that binds to Gal3.

[0136] In some cases, the anti-Gal3 antibody or its conjugated fragment includes a humanized antibody or its conjugated fragment. In other cases, the anti-Gal3 antibody or its conjugated fragment includes a chimeric antibody or its conjugated fragment. In some cases, the anti-Gal3 antibody includes a full-length antibody or its conjugated fragment. In some cases, the anti-Gal3 antibody or its conjugated fragment includes a bispecific antibody or its conjugated fragment. In some cases, the anti-Gal3 antibody or its conjugated fragment includes a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment.

[0137] In some cases, the anti-Gal3 antibody or its conjugate fragment is a bispecific antibody or its conjugate fragment. Exemplary bispecific antibody formats include Knobs-into-Holes (KiH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab® / Quadroma, Bispecific Monoclonal Antibodies (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), Azymetric®, Biclonics, Fab-scFv-Fc, and Two-in-one / Dual Action Fab. Examples include, but are not limited to, Fab(DAF), FinomAb, scFv-Fc-(Fab)-fusion, Dock-aNd-Lock(DNL), tandem diabody(TandAb), dual-affinity-ReTargeting(DART), nanobody, triplebody, tandem scFv(taFv), triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH. In some cases, the anti-Gal3 antibody or its conjugate fragment is a bispecific antibody or its conjugate fragment comprising the bispecific antibody format shown in Non-Patent Document 22.

[0138] In some embodiments, the anti-Gal3 antibody or its conjugate fragment may comprise an IgM, IgG (e.g., IgG1, IgG2, IgG3, or IgG4), IgA, or IgE framework. The IgG framework may comprise IgG1, IgG2, IgG3, or IgG4. In some cases, the anti-Gal3 antibody or its conjugate fragment comprises an IgG1 framework. In some cases, the anti-Gal3 antibody or its conjugate fragment comprises an IgG2 framework. In some cases, the anti-Gal3 antibody or its conjugate fragment comprises an IgG4 framework. The anti-Gal3 antibody or its conjugate fragment may further comprise an Fc mutation.

[0139] In some embodiments, the Fc region includes one or more mutations that modulate Fc receptor interactions to enhance effector functions, such as ADCC and / or CDC. In such cases, exemplary effector function modulating mutated residues include S239, K326, A330, I332, or E333, where the residue positions correspond to IgG1 and the residue numbering follows Kabat numbering (EU index in Non-Patent Literature 1). In some cases, the one or more mutations include S239D, K326W, A330L, I332E, E333A, E333S, or combinations thereof. In some cases, the one or more mutations include S239D, I332E, or combinations thereof. In some cases, the one or more mutations include S239D, A330L, I332E, or combinations thereof. In some cases, the one or more mutations include K326W, E333S, or a combination thereof. In some cases, the mutation includes E333A.

[0140] How to use In some embodiments, methods comprising an anti-Gal3 antibody or its binding fragment that binds to Gal3 and interferes with the interaction between Gal3 and another protein are disclosed herein. In some embodiments, this may be a direct interference with the interaction zone between Gal3 and the other protein, or an indirect modification such as binding that results in a conformational change of Gal3, as a result of Gal3 not binding to or becoming deactivated by the other protein. In some embodiments, this may also occur by binding to the first section of Gal3. In this case, the other part of the antibody or its binding fragment interferes with or modifies the interaction between Gal3 and the other protein. In some embodiments, the first section of Gal3 is the N-terminal domain of Gal3, the tandem repeat domain (TRD) of Gal3, or the C-terminal domain of Gal3. In some embodiments, the antibody or its binding fragment that binds to Gal3 does not bind to the C-terminal domain of Gal3. In some embodiments, any of the methods disclosed herein comprising an anti-Gal3 antibody or its binding fragment may be carried out using an antigen-binding molecule that binds to Gal3.

[0141] Methods for interfering with the interaction between Gal3 and the insulin receptor or integrin, or both, are disclosed herein. In some embodiments, the method comprises contacting an interaction site or surface on Gal3 (where Gal3 interacts with a) the insulin receptor or b) the integrin or c) both) with an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor or the integrin, or both. In some embodiments, Gal3 is expressed by one or more cells. In some embodiments, Gal3 is secreted from one or more cells. In some embodiments, the insulin receptor or integrin, or both, is expressed by one or more cells. In some cases, the method comprises contacting a plurality of cells expressing Gal3 and a plurality of cells expressing the insulin receptor or integrin, or both, with the antibody or a conjugated fragment thereof. In some cases, the method comprises contacting a plurality of cells expressing Gal3 secreted by a plurality of cells and a plurality of cells expressing the insulin receptor or integrin, or both, with the antibody or a conjugated fragment thereof. In some embodiments, the anti-Gal3 antibody or its binding fragment binds to the N-terminal domain of Gal3. In some embodiments, the interaction is reduced to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% in the absence of the anti-Gal3 antibody or its binding fragment. In some embodiments, the anti-Gal3 antibody or its binding fragment is any one of the anti-Gal3 antibodies or its binding fragments disclosed herein. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or its binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0142] Disclosed herein in several embodiments are methods for diagnosing a disease or disorder or its symptoms in a subject. In some embodiments, the disease or disorder is diabetes mellitus. In some embodiments, the disease or disorder is insulin-dependent diabetes mellitus. In some embodiments, the disease or disorder is insulin-independent diabetes mellitus. In some embodiments, the disease or disorder is type 1 diabetes mellitus. In some embodiments, the disease or disorder is type 2 diabetes mellitus. In some embodiments, the disease or disorder is inflammatory bowel disease. In some embodiments, the disease or disorder is non-alcoholic fatty liver disease. In some embodiments, the disease or disorder is non-alcoholic steatohepatitis. In some embodiments, the method includes contacting a subject or a part of a subject (e.g., tissue, blood / serum) with an anti-Gal3 antibody or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is conjugated to a detectable portion. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0143] In some embodiments of the methods disclosed herein, the insulin receptor comprises the sequence of SEQ ID NO: 2. In some embodiments, the Gal3-INSR interaction can be reduced to less than 80%, less than 75%, less than 70%, less than 60%, less than 59%, less than 50%, less than 40%, less than 34%, less than 30%, less than 20%, less than 14%, less than 10%, less than 7%, less than 5%, less than 4%, or less than 1%.

[0144] In some cases, the anti-Gal3 antibody binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 1 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 1.2 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 2 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 5 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 10 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 13.5 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 15 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 20 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 25 nM. In some cases, the anti-Gal3 antibody binds to Gal3 with a KD of less than 30 nM. Exemplary KD values ​​for Gal3 binding of anti-Gal3 antibodies are shown in Figure 41. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0145] In some embodiments of any method disclosed herein, the integrins are integrin α-1 (ITGa1), integrin α-2 (ITGa2), integrin α-3 (ITGa3), integrin α-4 (ITGa4), integrin α-5 (ITGa5), integrin α-6 (ITGa6), integrin α-7 (ITGa7), integrin α-8 (ITGa8), integrin α-9 (ITGa9), integrin α-10 (ITGa10), integrin α-11 (ITGa11), integrin α-D (ITGaD), integrin α- The integrins are selected from E (ITGaE), integrin α-L (ITGaL), integrin α-M (ITGaM), integrin α-V (ITGaV), integrin α-2B (ITGa2B), integrin α-2X (ITGa2X), integrin β-1 (ITGb1), integrin β-2 (ITGb2), integrin β-3 (ITGb3), integrin β-4 (ITGb4), integrin β-5 (ITGb5), integrin β-6 (ITGb6), integrin β-7 (ITGb7), integrin β-8 (ITGb8), or any combination thereof. In some embodiments, the integrins are selected from integrin β-1, integrin α-3, integrin β-3, or integrin α-V, or any combination thereof. In some embodiments, the integrins include the sequences of sequence numbers 339-342. In some embodiments, lymphocyte adhesion is reduced by interfering with the interaction between Gal3 and the integrin. In some embodiments, the lymphocyte adhesion is reduced by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages.

[0146] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to one or more peptides of SEQ ID NOs: 3-26. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0147] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to a Gal3 epitope containing a GxYPG motif, where x is the amino acid alanine (A), glycine (G), or valine (V). In some embodiments, the anti-Gal3 antibody described herein binds to a Gal3 epitope containing two GxYPG motifs separated by three amino acids, where x is A, G, or V. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0148] When applied to any of the uses disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -Includes a heavy chain variable region including CDR3. In some embodiments, the V L-CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 100-128. In some embodiments, the V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 129-144. In some embodiments, the V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 145-168. In some embodiments, the V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 27-47. In some embodiments, the V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs.48-69. In some embodiments, the V H -CDR3 comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs.70-99. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0149] When applied to any of the uses disclosed herein, in some embodiments, Exemplary V H -The CDR1 sequence is shown in Figure 28A. In some embodiments, the exemplary V H -The CDR2 sequence is shown in Figure 28B. In some embodiments, Exemplary V H-The CDR3 sequence is shown in Figure 28C. In some embodiments, Exemplary V L -The CDR1 sequence is shown in Figure 29A. In some embodiments, the exemplary V L -The CDR2 sequence is shown in Figure 29B. In some embodiments, the exemplary V L -The CDR3 sequence is shown in Figure 29C.

[0150] When applied to any of the uses disclosed herein, in some embodiments, the heavy chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein comprises an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity to any sequence by SEQ ID NOs. 169-206. In some embodiments, the heavy chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein is selected from the group consisting of SEQ ID NOs. 169-206. In some embodiments, exemplary V H These are shown in Figures 30-1, 30-2, and 30-3. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0151] When applied to any of the uses disclosed herein, in some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein contains an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity to any sequence by SEQ ID NOs. 207-245. In some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein is selected from the group consisting of SEQ ID NOs. 207-245. In some embodiments, exemplary V L These are shown in Figures 31-1 to 31-3. In some embodiments, any of the methods disclosed herein, including anti-Gal3 antibodies or binding fragments, may be carried out using an antigen-binding molecule that binds to Gal3.

[0152] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is

[0153] a) V in sequence number 169 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 207 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0154] b) V in sequence number 170 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 208 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0155] c) V in sequence number 171 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 209 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0156] d) V in sequence number 172 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 210 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0157] e) V in sequence number 173 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 211 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0158] f) V in sequence number 174 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 212 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0159] g) V in sequence number 175 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 213 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0160] h) V in sequence number 176 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 214 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0161] i) V in sequence number 177 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 215 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0162] j) V in sequence number 178 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H-CDR2, V H -V in CDR3 and Sequence ID No. 216 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0163] k) V in sequence number 179 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 217 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0164] l) V in sequence number 180 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 218 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0165] m) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 219 L -CDR1, V L -CDR2, VL -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0166] n) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 220 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0167] o) V in sequence number 182 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 221 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0168] p) V in sequence number 183 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 222 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, VL -CDR3,

[0169] q) V in sequence number 184 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 223 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0170] r) V in sequence number 185 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 224 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0171] s) V in sequence number 186 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 225 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0172] t) V in sequence number 187H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 226 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0173] u) V in sequence number 188 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 227 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0174] v) V in sequence number 189 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 228 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0175] w) V in sequence number 190 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H-CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 229 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0176] x) V in sequence number 191 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 230 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0177] y) V in sequence number 192 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 231 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0178] z) V in sequence number 193 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 232L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0179] aa) V in sequence number 194 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 233 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0180] ab) V in sequence number 195 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 234 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0181] ac) V in sequence number 196 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 235 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L-CDR1, V L -CDR2, V L -CDR3,

[0182] ad) The V within SEQ ID NO: 197 H -CDR1, V H -CDR2, V H The V which is -CDR3 H -CDR1, V H -CDR2, V H -CDR3 and the V within SEQ ID NO: 236 L -CDR​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ag) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 239 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0186] ah) V in sequence number 200 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0187] ai) V in sequence number 201 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 241 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0188] aj) V in sequence number 202 H -CDR1, V H-CDR2, V H The V that is -CDR3 H -CDR1, V H -CDR2, V H -CDR3 and the V within SEQ ID NO: 242 L -CDR1, V L -CDR2, V L The V that is -CDR3 L -CDR1, V L -CDR2, V L -CDR3

[0189] ak) The V within SEQ ID NO: 203 H -CDR1, V H -CDR2, V H The V that is -CDR3 H -CDR1, V H -CDR2, V H -CDR3 and the V within SEQ ID NO: 240 L -CDR1, V L -CDR2, V L The V that is -CDR3 L -CDR1, V L -CDR2, V L -CDR3

[0190] al) The V within SEQ ID NO: 204 H -CDR1, V H -CDR2, V H The V that is -CDR3 H -CDR1, V H -CDR2, V H -CDR3 and the V within SEQ ID NO: 243 L -CDR1, V L -CDR2, V L The V that is -CDR3 L -CDR¹, V L -CDR2, V L -CDR3

[0191] am) The V within SEQ ID NO: 205 H -CDR1, V H -CDR2, V H The V that is -CDR3 H -CDR1, V H -CDR2, VH -V in CDR3 and Sequence ID No. 244 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3, or

[0192] an) V in sequence number 206 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 245 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L - Includes CDR3.

[0193] In some embodiments, exemplary heavy chain variable region CDR combinations are shown in Figure 34. In some embodiments, exemplary light chain variable region CDR combinations are shown in Figure 35. In some embodiments, any of the methods disclosed herein, including anti-Gal3 antibodies or binding fragments, may be carried out using an antigen-binding molecule that binds to Gal3.

[0194] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is a) the heavy chain variable region of SEQ ID NO: 169 and the light chain variable region of SEQ ID NO: 207, b) the heavy chain variable region of SEQ ID NO: 170 and the light chain variable region of SEQ ID NO: 208, c) the heavy chain variable region of SEQ ID NO: 171 and the light chain variable region of SEQ ID NO: 209, d) the heavy chain variable region of SEQ ID NO: 172 and the light chain variable region of SEQ ID NO: 210, e) the heavy chain variable region of SEQ ID NO: 173 and the light chain variable region of SEQ ID NO: 211, f) g) Heavy chain variable region of sequence number 174 and light chain variable region of sequence number 212, h) Heavy chain variable region of sequence number 175 and light chain variable region of sequence number 213, i) Heavy chain variable region of sequence number 176 and light chain variable region of sequence number 214, j) Heavy chain variable region of sequence number 177 and light chain variable region of sequence number 215, k) Heavy chain variable region of sequence number 178 and light chain variable region of sequence number 216, l) Heavy chain variable region of sequence number 179 and light chain variable region of sequence number 217, m) Heavy chain variable region of sequence number 180 and light chain variable region of sequence number 218 n) Heavy chain variable region of SEQ ID NO: 181 and light chain variable region of SEQ ID NO: 219, n) Heavy chain variable region of SEQ ID NO: 181 and light chain variable region of SEQ ID NO: 220, o) Heavy chain variable region of SEQ ID NO: 182 and light chain variable region of SEQ ID NO: 221, p) Heavy chain variable region of SEQ ID NO: 183 and light chain variable region of SEQ ID NO: 222, q) Heavy chain variable region of SEQ ID NO: 184 and light chain variable region of SEQ ID NO: 223, r) Heavy chain variable region of SEQ ID NO: 185 and light chain variable region of SEQ ID NO: 224, s) Heavy chain variable region of SEQ ID NO: 186 and light chain variable region of SEQ ID NO: 225, t ) Heavy chain variable region of SEQ ID NO: 187 and light chain variable region of SEQ ID NO: 226, u) Heavy chain variable region of SEQ ID NO: 188 and light chain variable region of SEQ ID NO: 227, v) Heavy chain variable region of SEQ ID NO: 189 and light chain variable region of SEQ ID NO: 228, w) Heavy chain variable region of SEQ ID NO: 190 and light chain variable region of SEQ ID NO: 229, x) Heavy chain variable region of SEQ ID NO: 191 and light chain variable region of SEQ ID NO: 230, y) Heavy chain variable region of SEQ ID NO: 192 and light chain variable region of SEQ ID NO: 231, z) Heavy chain variable region of SEQ ID NO: 193 and light chain variable region of SEQ ID NO: 232,

[0195] aa) Heavy chain variable region of SEQ ID NO: 194 and light chain variable region of SEQ ID NO: 233, ab) Heavy chain variable region of SEQ ID NO: 195 and light chain variable region of SEQ ID NO: 234, ac) Heavy chain variable region of SEQ ID NO: 196 and light chain variable region of SEQ ID NO: 235, ad) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 236, ae) Heavy chain variable region of SEQ ID NO: 198 and light chain variable region of SEQ ID NO: 237, af) Heavy chain variable region of SEQ ID NO: 199 and light chain variable region of SEQ ID NO: 238, ag) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 239, ah ) The heavy chain variable region of SEQ ID NO: 200 and the light chain variable region of SEQ ID NO: 240, ai) The heavy chain variable region of SEQ ID NO: 201 and the light chain variable region of SEQ ID NO: 241, aj) The heavy chain variable region of SEQ ID NO: 202 and the light chain variable region of SEQ ID NO: 242, ak) The heavy chain variable region of SEQ ID NO: 203 and the light chain variable region of SEQ ID NO: 240, al) The heavy chain variable region of SEQ ID NO: 204 and the light chain variable region of SEQ ID NO: 243, am) The heavy chain variable region of SEQ ID NO: 205 and the light chain variable region of SEQ ID NO: 244, or an) The heavy chain variable region of SEQ ID NO: 206 and the light chain variable region of SEQ ID NO: 245. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0196] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the heavy chain (HC) sequences of SEQ ID NOs. 246 to 286. In some embodiments, exemplary HC sequences are shown in Figures 32-1 to 32-7. In some embodiments, any of the methods disclosed herein, comprising the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0197] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the light chain (LC) sequences of SEQ ID NOs. 287-324. In some embodiments, exemplary HC sequences are shown in Figures 33-1 to 33-4. In some embodiments, any of the methods disclosed herein, comprising the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0198] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2H1, 23B10.2B12, 6B 3.2D3, F846C.1B2, F846C.1F5, F846C.1H12, F846C.1H5, F846C.2H3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1, F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, 847.14H4, mIMT001, IMT-001(TB001), and IMT-006(TB006), or selected from the group consisting of these combined fragments. In some embodiments, the heavy chain CDR and light chain CDR associated with each of the aforementioned antibodies are shown in Figure 36. In some embodiments, the V associated with each of the aforementioned antibodies is shown. H and V L This is shown in Figure 37. In some embodiments, the HC and LC associated with each of the aforementioned antibodies are shown in Figure 38.

[0199] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises a payload. In some embodiments, the payload is conjugated to the anti-Gal3 antibody or its conjugated fragment. In some embodiments, the payload is a cytotoxic payload, a microtubule disruptor, a DNA modifier, an Akt inhibitor, a polymerase inhibitor, a detectable moiety, an immunomodulator, an immunomodulatory component, an immunotoxin, a nucleic acid polymer, an aptamer, a peptide, or any combination thereof. In some embodiments, the payload is a detectable moiety. In some embodiments, any of the methods disclosed herein comprising an anti-Gal3 antibody or conjugated fragment may be carried out using an antigen-binding molecule that binds to Gal3.

[0200] When applied to any of the methods of use disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a humanized antibody. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a full-length antibody or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a bispecific antibody or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises an IgG framework. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises an IgG1, IgG2, or IgG4 framework. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or its conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0201] In some cases, the anti-Gal3 antibody or its conjugated fragment described herein may be used to treat a disease or disorder or its symptoms. In some cases, the disease or disorder is diabetes mellitus. In some cases, the disease or disorder is insulin-dependent diabetes mellitus. In some cases, the disease or disorder is non-insulin-dependent diabetes mellitus. In some cases, the disease or disorder is type 1 diabetes mellitus. In some cases, the disease or disorder is type 2 diabetes mellitus. In some cases, the disease or disorder is inflammatory bowel disease. In some cases, the disease or disorder is non-alcoholic fatty liver disease (NAFLD). In some cases, the disease or disorder is non-alcoholic steatohepatitis (NASH). In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0202] In some cases, the method provides treatment for the disease or disorder in question. In some cases, the method includes administering an anti-Gal3 antibody or a conjugated fragment thereof to a subject having, suspected of having, or at risk of developing, a disease or disorder described herein. In some embodiments, the method includes administering an anti-Gal3 antibody or a conjugated fragment thereof to a subject having, suspected of having, or at risk of developing diabetes mellitus. In some embodiments, the method includes administering an anti-Gal3 antibody or a conjugated fragment thereof to a subject having, suspected of having, or at risk of developing IBD. In some embodiments, the method includes administering an anti-Gal3 antibody or a conjugated fragment thereof to a subject having, suspected of having, or at risk of developing NAFLD. In some embodiments, the method includes administering an anti-Gal3 antibody or a conjugated fragment thereof to a subject having, suspected of having, or at risk of developing NASH. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or a conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0203] In some embodiments, the method provides treatment for symptoms associated with diabetes in a subject. In some embodiments, the method provides reducing glucose tolerance in a subject of interest, comprising administering the anti-Gal3 antibody or a conjugated fragment thereof described herein to the subject. In some embodiments, administration of the anti-Gal3 antibody or a conjugated fragment thereof reduces the glucose tolerance of the subject by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages. In some embodiments, the method provides reducing insulin resistance in a subject of interest, comprising administering the anti-Gal3 antibody or a conjugated fragment thereof described herein to the subject. In some embodiments, administration of an anti-Gal3 antibody or its conjugate fragment reduces the insulin resistance of the subject by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages. In some embodiments, the method provides reducing weight gain in a subject of need, comprising administering the anti-Gal3 antibody or its conjugate fragment described herein to the subject. In some embodiments, administration of an anti-Gal3 antibody or its conjugate fragment reduces the weight gain of the subject by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages. In some embodiments, the method provides reducing fatty liver in a subject of need, comprising administering the anti-Gal3 antibody or its conjugate fragment described herein to the subject. In some embodiments, administration of an anti-Gal3 antibody or a conjugated fragment thereof reduces the fatty liver of the subject by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages.In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0204] Methods for treating diabetes in subjects requiring treatment are disclosed herein. In some embodiments, the method includes treating the diabetes of a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor or integrin or both. In some embodiments, the diabetes is insulin-dependent diabetes. In some embodiments, the diabetes is insulin-independent diabetes. In some embodiments, the diabetes is type 1 diabetes. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the treatment includes reducing glucose tolerance in the subject requiring treatment. In some embodiments, the treatment includes reducing insulin sensitivity in the subject requiring treatment. In some embodiments, the treatment includes reducing weight gain in the subject requiring treatment. In some embodiments, the treatment includes reducing fatty liver in the subject requiring treatment. In some embodiments, the method further includes selecting the subject as having diabetes or being at risk of developing diabetes prior to the administration step. In some embodiments, the method further includes detecting improvement in the symptoms associated with the target diabetes after the administration step. In some embodiments, the insulin receptor comprises the sequence of SEQ ID NO: 2. In some embodiments, the integrin is selected from ITGa1, ITGa2, ITGa3, ITGa4, ITGa5, ITGa6, ITGa7, ITGa8, ITGa9, ITGa10, ITGa11, ITGaD, ITGaE, ITGaL, ITGaM, ITGaV, ITGa2B, ITGa2X, ITGb1, ITGb2, ITGb3, ITGb4, ITGb5, ITGb6, ITGb7, ITGb8, or any combination thereof. In some embodiments, the integrin comprises a sequence selected from SEQ ID NOs: 339-342. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is administered together with one or more additional therapeutic compositions.

[0205] In some embodiments, the one or more additional therapeutic compositions include insulin, insulin derivatives or mimics thereof, insulin aspart, insulin glulisine, insulin lispro, insulin isophane, insulin degludec, insulin detemir, insulin zinc, insulin glargine (insulin glargine, vanadium, biguanide, metformin, phenformin, buformin, thiazolidinedione, rosiglitazone, pioglitazone, troglitazone, tolimidone, sulfonylurea, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide (gliclazide), glyclopyramide, gliquidone, meglitinide, repaglinide, nateglinide, α-glucosidase inhibitors, miglitol, acarbose, voglibose, incretin, glucagon-like peptide 1, glucagon-like peptide agonists, exenatide, liraglutide, taspoglutide, lixisenatide, semaglutide, dulaglutide, gastric suppressant peptide, dipeptidyl peptidase-4 inhibitors,This includes vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, gemigliptin, pramlintide, dapagliflozin, canagliflozin, empagliflozin, or remogliflozin, or combinations thereof. In some embodiments, any of the methods disclosed herein, including anti-Gal3 antibodies or binding fragments, may be carried out using antigen-binding molecules that bind to Gal3.

[0206] Methods for treating inflammatory bowel syndrome in subjects of interest are disclosed herein. In some embodiments, the method includes treating the inflammatory bowel syndrome of a subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and integrins. In some embodiments, the inflammatory bowel syndrome is ulcerative colitis, Crohn's disease, or both. In some embodiments, the method further includes selecting the subject as having or being at risk of developing inflammatory bowel syndrome prior to the administration step. In some embodiments, the method further includes detecting improvement in the symptoms of inflammatory bowel syndrome in the subject after the administration step. In some embodiments, interfering with the interaction between Gal3 and integrins reduces lymphocyte adhesion and / or activity in the subject. In some embodiments, the lymphocyte adhesion or activity, or both, is reduced by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages.

[0207] In some embodiments, the integrin is selected from ITGa1, ITGa2, ITGa3, ITGa4, ITGa5, ITGa6, ITGa7, ITGa8, ITGa9, ITGa10, ITGa11, ITGaD, ITGaE, ITGaL, ITGaM, ITGaV, ITGa2B, ITGa2X, ITGb1, ITGb2, ITGb3, ITGb4, ITGb5, ITGb6, ITGb7, ITGb8, or any combination thereof. In some embodiments, the integrin comprises a sequence selected from SEQ ID NOs: 339-342. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is administered together with one or more additional therapeutic compositions. In some embodiments, the one or more additional therapeutic compositions include mesalazine, an immunosuppressant, prednisone, a TNF inhibitor, azathioprine, methotrexate, 6-mercaptopurine, or rifaximin, or any combination thereof. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0208] Methods for treating non-alcoholic fatty liver disease in subjects of need are disclosed herein. In some embodiments, the method includes treating the subject's NAFLD by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0209] Methods for treating non-alcoholic steatohepatitis (NASH) in subjects of need are disclosed herein. In some embodiments, the method includes treating the NASH in the subject by administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0210] In some embodiments of any method disclosed herein, the interaction between Gal3 and the insulin receptor or integrin or both is described as the anti-Gal3 anti In the absence of the body or its binding fragment, the interaction decreases to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1%.

[0211] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to the N-terminal domain of Gal3. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM.

[0212] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to one or more peptides of SEQ ID NOs: 3-26. In some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0213] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment binds to a Gal3 epitope containing a GxYPG motif, where x is the amino acid alanine (A), glycine (G), or valine (V). In some embodiments, the anti-Gal3 antibody described herein binds to a Gal3 epitope containing two GxYPG motifs separated by three amino acids, where x is A, G, or V. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0214] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -Includes a heavy chain variable region including CDR3. In some embodiments, the V L-CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 100-128. In some embodiments, the V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 129-144. In some embodiments, the V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 145-168. In some embodiments, the V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 27-47. In some embodiments, the V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs.48-69. In some embodiments, the V H -CDR3 contains an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 70-99.

[0215] When applied to any of the therapeutic methods disclosed herein, in some embodiments, Exemplary V H -The CDR1 sequence is shown in Figure 28A. In some embodiments, the exemplary V H -The CDR2 sequence is shown in Figure 28B. In some embodiments, Exemplary V H -The CDR3 sequence is shown in Figure 28C. In some embodiments, Exemplary V L -The CDR1 sequence is shown in Figure 29A. In some embodiments, the exemplary VL -The CDR2 sequence is shown in Figure 29B. In some embodiments, the exemplary V L -The CDR3 sequence is shown in Figure 29C. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0216] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the heavy chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein comprises an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity to any sequence according to SEQ ID NOs. 169-206. In some embodiments, the heavy chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein is selected from the group consisting of SEQ ID NOs. 169-206. In some embodiments, exemplary V H These are shown in Figures 30-1, 30-2, and 30-3. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0217] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein comprises an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity to any sequence by SEQ ID NOs. 207-245. In some embodiments, the light chain variable region of any of the anti-Gal3 antibodies or their conjugate fragments disclosed herein is selected from the group consisting of SEQ ID NOs. 207-245. In some embodiments, exemplary V L These are shown in Figures 31-1 to 31-3. In some embodiments, any of the methods disclosed herein, including anti-Gal3 antibodies or binding fragments, may be carried out using an antigen-binding molecule that binds to Gal3.

[0218] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is

[0219] a) V in sequence number 169 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 207 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0220] b) V in sequence number 170 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 208 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0221] c) V in sequence number 171 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 209 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0222] d) V in sequence number 172 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 210 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0223] e) V in sequence number 173 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 211 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0224] f) V in sequence number 174 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 212 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0225] g) V in sequence number 175 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 213 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0226] h) V in sequence number 176 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 214 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0227] i) V in sequence number 177 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 215 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0228] j) V in sequence number 178 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H-CDR2, V H -V in CDR3 and Sequence ID No. 216 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0229] k) V in sequence number 179 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 217 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0230] l) V in sequence number 180 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 218 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0231] m) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 219 L -CDR1, V L -CDR2, VL -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0232] n) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 220 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0233] o) V in sequence number 182 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 221 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0234] p) V in sequence number 183 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 222 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, VL -CDR3,

[0235] q) V in sequence number 184 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 223 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0236] r) V in sequence number 185 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 224 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0237] s) V in sequence number 186 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 225 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0238] t) V in sequence number 187H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 226 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0239] u) V in sequence number 188 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 227 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0240] v) V in sequence number 189 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 228 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0241] w) V in sequence number 190 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H-CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 229 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0242] x) V in sequence number 191 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 230 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0243] y) V in sequence number 192 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 231 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0244] z) V in sequence number 193 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 232L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0245] aa) V in sequence number 194 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 233 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0246] ab) V in sequence number 195 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 234 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0247] ac) V in sequence number 196 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 235 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L-CDR1, V L -CDR2, V L -CDR3,

[0248] ad) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 236 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0249] ae) V in sequence number 198 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 237 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0250] af) V in sequence number 199 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 238 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0251] ag) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 239 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0252] ah) V in sequence number 200 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0253] ai) V in sequence number 201 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 241 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0254] aj) V in sequence number 202 H -CDR1, V H-CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 242 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0255] ak) V in sequence number 203 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0256] al) V in sequence number 204 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 243 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0257] am) V in Sequence ID 205 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, VH -V in CDR3 and Sequence ID No. 244 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3, or

[0258] an) V in sequence number 206 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 245 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L - Includes CDR3.

[0259] In some embodiments, exemplary heavy chain variable region CDR combinations are shown in Figure 34. In some embodiments, exemplary light chain variable region CDR combinations are shown in Figure 35. In some embodiments, any of the methods disclosed herein, including anti-Gal3 antibodies or binding fragments, may be carried out using an antigen-binding molecule that binds to Gal3.

[0260] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is a) the heavy chain variable region of SEQ ID NO: 169 and the light chain variable region of SEQ ID NO: 207, b) the heavy chain variable region of SEQ ID NO: 170 and the light chain variable region of SEQ ID NO: 208, c) the heavy chain variable region of SEQ ID NO: 171 and the light chain variable region of SEQ ID NO: 209, d) the heavy chain variable region of SEQ ID NO: 172 and the light chain variable region of SEQ ID NO: 210, e) the heavy chain variable region of SEQ ID NO: 173 and the light chain variable region of SEQ ID NO: 211, f) g) Heavy chain variable region of sequence number 174 and light chain variable region of sequence number 212, h) Heavy chain variable region of sequence number 175 and light chain variable region of sequence number 213, i) Heavy chain variable region of sequence number 176 and light chain variable region of sequence number 214, j) Heavy chain variable region of sequence number 177 and light chain variable region of sequence number 215, k) Heavy chain variable region of sequence number 178 and light chain variable region of sequence number 216, l) Heavy chain variable region of sequence number 179 and light chain variable region of sequence number 217, m) Heavy chain variable region of sequence number 180 and light chain variable region of sequence number 218 n) Heavy chain variable region of SEQ ID NO: 181 and light chain variable region of SEQ ID NO: 219, n) Heavy chain variable region of SEQ ID NO: 181 and light chain variable region of SEQ ID NO: 220, o) Heavy chain variable region of SEQ ID NO: 182 and light chain variable region of SEQ ID NO: 221, p) Heavy chain variable region of SEQ ID NO: 183 and light chain variable region of SEQ ID NO: 222, q) Heavy chain variable region of SEQ ID NO: 184 and light chain variable region of SEQ ID NO: 223, r) Heavy chain variable region of SEQ ID NO: 185 and light chain variable region of SEQ ID NO: 224, s) Heavy chain variable region of SEQ ID NO: 186 and light chain variable region of SEQ ID NO: 225, t ) Heavy chain variable region of SEQ ID NO: 187 and light chain variable region of SEQ ID NO: 226, u) Heavy chain variable region of SEQ ID NO: 188 and light chain variable region of SEQ ID NO: 227, v) Heavy chain variable region of SEQ ID NO: 189 and light chain variable region of SEQ ID NO: 228, w) Heavy chain variable region of SEQ ID NO: 190 and light chain variable region of SEQ ID NO: 229, x) Heavy chain variable region of SEQ ID NO: 191 and light chain variable region of SEQ ID NO: 230, y) Heavy chain variable region of SEQ ID NO: 192 and light chain variable region of SEQ ID NO: 231, z) Heavy chain variable region of SEQ ID NO: 193 and light chain variable region of SEQ ID NO: 232,

[0261] aa) Heavy chain variable region of SEQ ID NO: 194 and light chain variable region of SEQ ID NO: 233, ab) Heavy chain variable region of SEQ ID NO: 195 and light chain variable region of SEQ ID NO: 234, ac) Heavy chain variable region of SEQ ID NO: 196 and light chain variable region of SEQ ID NO: 235, ad) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 236, ae) Heavy chain variable region of SEQ ID NO: 198 and light chain variable region of SEQ ID NO: 237, af) Heavy chain variable region of SEQ ID NO: 199 and light chain variable region of SEQ ID NO: 238, ag) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 239, ah ) The heavy chain variable region of SEQ ID NO: 200 and the light chain variable region of SEQ ID NO: 240, ai) The heavy chain variable region of SEQ ID NO: 201 and the light chain variable region of SEQ ID NO: 241, aj) The heavy chain variable region of SEQ ID NO: 202 and the light chain variable region of SEQ ID NO: 242, ak) The heavy chain variable region of SEQ ID NO: 203 and the light chain variable region of SEQ ID NO: 240, al) The heavy chain variable region of SEQ ID NO: 204 and the light chain variable region of SEQ ID NO: 243, am) The heavy chain variable region of SEQ ID NO: 205 and the light chain variable region of SEQ ID NO: 244, or an) The heavy chain variable region of SEQ ID NO: 206 and the light chain variable region of SEQ ID NO: 245. In some embodiments, any of the methods disclosed herein, including an anti-Gal3 antibody or binding fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0262] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the heavy chain (HC) sequences of SEQ ID NOs. 246 to 286. In some embodiments, exemplary HC sequences are shown in Figures 32-1 to 32-7. In some embodiments, any of the methods disclosed herein, comprising the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0263] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises one of the light chain (LC) sequences of SEQ ID NOs. 287-324. In some embodiments, exemplary HC sequences are shown in Figures 33-1 to 33-4. In some embodiments, any of the methods disclosed herein, comprising the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0264] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2H1, 23B10.2B12, 6B 3.2D3, F846C.1B2, F846C.1F5, F846C.1H12, F846C.1H5, F846C.2H3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1, F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, 847.14H4, mIMT001, IMT-001(TB001), and IMT-006(TB006), or selected from the group consisting of these combined fragments. In some embodiments, the heavy chain CDR and light chain CDR associated with each of the aforementioned antibodies are shown in Figure 36. In some embodiments, the V associated with each of the aforementioned antibodies is shown. H and V L This is shown in Figure 37. In some embodiments, the HC and LC associated with each of the aforementioned antibodies are shown in Figure 38.

[0265] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is administered enterally, orally, intranasally, parenterally, intracranially, subcutaneously, intramuscularly, intradermally, or intravenously, or any combination thereof.

[0266] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment comprises a payload. In some embodiments, the payload is conjugated to the anti-Gal3 antibody or its conjugated fragment. In some embodiments, the payload is a cytotoxic payload, a microtubule disruptor, a DNA modifier, an Akt inhibitor, a polymerase inhibitor, a detectable moiety, an immunomodulator, an immunomodulatory component, an immunotoxin, a nucleic acid polymer, an aptamer, a peptide, or any combination thereof. In some embodiments, the payload is a detectable moiety.

[0267] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a humanized antibody. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a full-length antibody or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a bispecific antibody or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises an IgG framework. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is or comprises an IgG1, IgG2, or IgG4 framework. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or its conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0268] When applied to any of the therapeutic methods disclosed herein, in some embodiments, the anti-Gal3 antibody or its conjugated fragment is formulated for systemic administration. In some embodiments, the anti-Gal3 antibody or its conjugated fragment is formulated for parenteral administration. In some embodiments, two or more anti-Gal3 antibodies or conjugated fragments are administered. In some embodiments, when two or more anti-Gal3 antibodies or conjugated fragments are administered, two or more anti-Gal3 antibodies or their conjugated fragments may be selected from the anti-Gal3 antibodies or their conjugated fragments disclosed herein. In some embodiments, any of the methods disclosed herein, including the anti-Gal3 antibody or conjugated fragment, may be carried out using an antigen-binding molecule that binds to Gal3.

[0269] When applied to any of the methods of use or treatment disclosed herein, the subject is: The subject is a mammal. In some embodiments, the mammal is a human, cat, dog, mouse, rat, hamster, rodent, pig, cattle, horse, sheep, or goat. In some embodiments, the mammal is a human. In some embodiments, the subject has type 1 diabetes or type 2 diabetes.

[0270] Antibody production In some cases, anti-Gal3 antibodies or their conjugated fragments are produced by standard protocols by injecting the antigenic composition into the production animals. See, for example, Non-Patent Document 23. When the whole protein or a larger portion of the protein is used, antibodies can be produced by immunizing the production animals with the protein and a suitable adjuvant (e.g., Freund's adjuvant, an oil-in-water emulsion of Freund's complete adjuvant, etc.). When smaller peptides are used, it is advantageous to conjugate the peptide with a larger molecule to create an immunostimulatory conjugate. Commonly used conjugate proteins commercially available for such use include bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH). Peptides derived from the complete sequence may be used to produce antibodies against a specific epitope. Alternatively, a superior immune response can be induced when the polypeptide is conjugated to a carrier protein such as ovalbumin, BSA, or KLH to generate antibodies against a relatively short peptide portion of a protein target.

[0271] Polyclonal or monoclonal anti-Gal3 antibodies or their conjugate fragments can be produced from animals genetically modified to produce human immunoglobulins. Transgenic animals can be produced by first producing “knockout” animals that do not produce the animal’s native antibodies, and then stably transforming the animals at the human antibody locus (for example, by using human artificial chromosomes). In such cases, only human antibodies are produced by the animals. Techniques for producing such animals and inducing antibodies therefrom are described in Patent Documents 8 and 9, which are respectively fully incorporated herein by reference. Such antibodies are sometimes referred to as human heterologous antibodies.

[0272] Alternatively, an anti-Gal3 antibody or its conjugated fragment may be produced from a phage library containing a human variable region. See Patent Document 10, which is incorporated herein in its entirety by reference.

[0273] In some aspects of any embodiment disclosed herein, the anti-Gal3 antibody or its conjugated fragment is produced by a hybridoma.

[0274] In the case of monoclonal anti-Gal3 antibodies, hybridomas may be formed by isolating stimulated immune cells, such as those from the spleen of an inoculated animal. These cells can then be fused with immortalized cells, such as myeloma cells or transformed cells. These can replicate indefinitely in cell culture, thereby producing immortalized immunoglobulin-secreting cell lines. The immortalized cell lines used may be selected to be deficient in enzymes necessary for the utilization of specific nutrients. Many such cell lines (such as myeloma) are known to those skilled in the art and include, for example, thymidine kinase (TK) or hypoxanthine-guanine phosphoriboxyltransferase (HGPRT). These deficiencies allow for the selection of fusion cells, for example, based on their ability to grow on hypoxanthine aminopterin thymidine medium (HAT).

[0275] Furthermore, anti-Gal3 antibodies or their conjugated fragments can be generated by genetic engineering.

[0276] The anti-Gal3 antibodies or their conjugated fragments disclosed herein are, for example, used in anaphylaxis These may reduce the tendency to induce undesirable immune responses in humans, such as shock, and may also reduce the tendency to prime the immune response, thereby preventing repeated administration of antibody therapeutics or contrast agents (e.g., human anti-mouse antibody "HAMA" response). Such anti-Gal3 antibodies or their conjugates include, but are not limited to, humanized, chimeric, or heterologous human anti-Gal3 antibodies or their conjugates.

[0277] For the primary purpose of producing antibodies having human domains, chimeric anti-Gal3 antibodies or their conjugated fragments may be prepared by recombinant means, for example, by combining mouse variable light chain and heavy chain regions (VK and VH) obtained from mouse (or other animal-derived) hybridoma clones with human constant light chain and heavy chain regions. The production of such chimeric antibodies is well known in the art and can be achieved by standard means (for example, as described in Patent Document 11, which is fully incorporated herein by reference).

[0278] The term "humanized" applied to non-human (e.g., rodent or primate) antibodies refers to hybrid immunoglobulins, immunoglobulin chains, or fragments of non-human immunoglobulins that contain minimal sequences derived from them. In most cases, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues in the recipient's complementarity-determining region (CDR) are replaced with residues in the CDR of a non-human species (donor antibody) with desired specificity, affinity, and capability, such as mouse, rat, rabbit, or primate. In some cases, Fv framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, humanized antibodies may contain residues not found in either the recipient antibody or the transferred CDR or framework sequence. These modifications are made to further improve and optimize the antibody's performance and to minimize immunogenicity when introduced into the human body. In some cases, humanized antibodies contain substantially all of at least one, typically two, variable domains, with all or substantially all of the CDR region corresponding to a non-human immunoglobulin region, and all or substantially all of the FR region being a human immunoglobulin sequence. Humanized antibodies may also contain at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the human immunoglobulin.

[0279] Humanized antibodies can be modified to include human-like immunoglobulin domains and incorporate only the complementarity-determining regions of animal-derived antibodies. This can be achieved by carefully examining the sequences of the hypervariable loops in the variable regions of monoclonal antigen-binding units or monoclonal antibodies and adapting them to the structure of human antigen-binding units or human antibody chains. See, for example, Patent Document 12, which is fully incorporated herein by reference.

[0280] Methods for humanizing non-human antibodies are well known in the art. A “humanized” antibody is one in which at least part of its sequence has been modified from its original form to resemble a human immunoglobulin. In some versions, the heavy (H) constant (C) region and the light (L) constant (C) region are replaced with human sequences. This may be a fusion polypeptide containing a variable (V) region and a heterologous immunoglobulin C region. In some versions, the complementarity-determining region (CDR) contains a non-human antibody sequence, but the V framework region is also converted to a human sequence. See, for example, Patent Document 13. In some versions, the V region is humanized by designing consensus sequences for human and mouse V regions and converting different extra-CDR residues between the consensus sequences.

[0281] In principle, the framework sequence of a humanized antibody functions as a template for a CDR graft, but it has been demonstrated that direct CDR substitution into such a framework can lead to a significant loss of binding affinity to the antigen. Non-Patent Literature 24; Non-Patent Literature 25; and Non-Patent Literature 26. The higher the homology between the human antibody (HuAb) and the original mouse antibody (muAb), the more the human framework distorts the mouse CDR, reducing affinity. The likelihood of this occurring decreases. Based on sequence homology searches against antibody sequence databases, HuAb IC4 provides good framework homology to muM4TS.22, but other highly homologous HuAbs, particularly the κL chain of human subgroup I or the H chain of human subgroup III, are equally suitable. Non-Patent Document 27. Various computer programs, such as ENCAD (Non-Patent Document 28), can be used to predict the ideal sequence of the V region. Thus, this disclosure encompasses humanized antibodies (HuAbs) having different variable (V) regions. Determining appropriate V region sequences and optimizing these sequences is within the scope of the art. Methods for obtaining antibodies with reduced immunogenicity are also described in Patent Documents 14 and 15, which are respectively incorporated herein in their entirety by reference.

[0282] Humanized antibodies can be prepared by a process that analyzes the parent sequence and various conceptual humanized products using three-dimensional models of the parent sequence and the humanized sequence. Three-dimensional immunoglobulin models are well known to those skilled in the art. Computer programs are available that illustrate and display possible three-dimensional structures of selected candidate immunoglobulin sequences. Examination of these displays allows for the analysis of possible roles of residues in the function of the candidate immunoglobulin sequence, i.e., the analysis of residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, framework region (FR) residues can be selected and combined from consensus and import sequences so that desired antibody properties, such as increased affinity for the target antigen, can be achieved.

[0283] The process of humanizing the target antigen-binding unit may be as follows: The heavy chain and light chain variable regions of the optimal germline acceptor are selected based on the homology, standard structure, and physical properties of the human antibody germline for transplantation. Computer modeling of mVH / VL versus transplanted hVH / VL is performed to generate a prototype humanized antibody sequence. If the modeling indicates the need for reverse mutation of the framework, a second variant showing the FW modification is generated. DNA fragments encoding the selected germline framework and mouse CDR are synthesized. The synthesized DNA fragments are subcloned into an IgG expression vector, and the sequence is confirmed by DNA sequencing. The humanized antibody is expressed in cells such as 293F, and the protein is tested, for example, in MDM phagocytic assays and antigen-binding assays. The humanized antigen-binding unit is compared to the parent antigen-binding unit in terms of antigen-binding affinity, for example, by FACS on cells expressing the target antigen. If the affinity is more than twice as low as the parent antigen-binding unit, a second round of humanized variant generation and testing is possible as described above.

[0284] As described above, anti-Gal3 antibodies or their binding fragments can be either "monovalent" or "polyvalent." The former has one binding site per antigen-binding unit, while the latter contains multiple binding sites capable of binding to multiple antigens of the same or different types. Depending on the number of binding sites, the antigen-binding unit can be bivalent (having two antigen-binding sites), trivalent (having three antigen-binding sites), tetravalent (having four antigen-binding sites), etc.

[0285] Polyvalent anti-Gal3 antibodies or their conjugates can be further classified based on their binding specificity. A “monospecific” anti-Gal3 antibody or its conjugate is a molecule that can bind to one or more antigens of the same type. A “multispecific” anti-Gal3 antibody or its conjugate is a molecule that has binding specificity to at least two different antigens. Such molecules typically bind to only two different antigens (i.e., bispecific anti-Gal3 antibodies), but antibodies with additional specificity, such as triplicate antibodies, are included in this expression as used herein. This disclosure further provides multispecific anti-Gal3 antibodies. Multispecific anti-Gal3 antibodies or their conjugates are polyvalent molecules that can bind to at least two different antigens, for example, bispecific and triplicate molecules that exhibit binding specificity to two and three different antigens, respectively.

[0286] In some embodiments, the method further provides screening or identification of antibodies or binding fragments thereof that can interfere with the interaction between Gal3 and the insulin receptor or integrin, or both. A non-limiting example of such a method is described in Example 1. In some embodiments, the method comprises (a) contacting the Gal3 protein with an antibody or binding fragment thereof that selectively binds to Gal3 to form a Gal3-antibody complex; (b) contacting the Gal3 antibody complex with the insulin receptor or the integrin, or both; (c) removing the unbound insulin receptor or integrin, or both; and (d) detecting the insulin receptor or integrin, or both, bound to the Gal3 antibody complex, wherein if the insulin receptor or integrin, or both, are not detected in (d), the antibody or binding fragment thereof can interfere with the interaction between Gal3 and the insulin receptor or integrin, or both. In some cases, the method comprises an immunoassay. In some cases, the immunoassay is an enzyme-linked immunosorbent assay (ELISA).

[0287] Polynucleotides and vectors In some embodiments, the Disclosure provides isolated nucleic acids encoding either an anti-Gal3 antibody or a conjugate fragment thereof as disclosed herein. In other embodiments, the Disclosure provides a vector comprising a nucleic acid sequence encoding any anti-Gal3 antibody or a conjugate fragment thereof as disclosed herein. In some embodiments, the Disclosure provides isolated nucleic acids encoding the light chain CDR and heavy chain CDR of an anti-Gal3 antibody or a conjugate fragment thereof as disclosed herein.

[0288] In some embodiments, the nucleic acid encodes a heavy chain CDR1 peptide sequence selected from SEQ ID NOs: 27-47. In some embodiments, the nucleic acid encodes a heavy chain CDR2 peptide sequence selected from SEQ ID NOs: 48-69. In some embodiments, the nucleic acid encodes a heavy chain CDR3 peptide sequence selected from SEQ ID NOs: 70-99. In some embodiments, the nucleic acid encodes a light chain CDR1 peptide sequence selected from SEQ ID NOs: 100-128. In some embodiments, the nucleic acid encodes a light chain CDR2 peptide sequence selected from SEQ ID NOs: 129-144. In some embodiments, the nucleic acid encodes a light chain CDR3 peptide sequence selected from SEQ ID NOs: 145-168. In some embodiments, the nucleic acid encodes a heavy chain variable region peptide sequence selected from SEQ ID NOs: 169-206. In some embodiments, the nucleic acid encodes a light chain variable region peptide sequence selected from SEQ ID NOs: 207-245. In some embodiments, the nucleic acid encodes a heavy chain peptide sequence selected from SEQ ID NOs: 246-286. In some embodiments, the nucleic acid encodes a light chain peptide sequence selected from SEQ ID NOs: 287-324. In some embodiments, the nucleic acid encodes one of the peptide sequences shown in Figures 28A to 33-4.

[0289] Any one of the anti-Gal3 antibodies or their conjugate fragments described herein may be prepared by recombinant DNA techniques, synthetic chemical techniques, or a combination thereof. For example, sequences encoding desired components of an anti-Gal3 antibody, including light chain CDRs and heavy chain CDRs, are typically cloned and assembled into an expression vector using standard molecular techniques known in the art. These sequences can be assembled from other vectors encoding desired protein sequences, from PCR-generated fragments using their respective template nucleic acids, or by the association of synthetic oligonucleotides encoding the desired sequences. An expression system may be created by transfecting suitable cells with an expression vector containing the anti-Gal3 antibody or its conjugate fragment of interest.

[0290] Nucleotide sequences corresponding to various regions of the light or heavy chains of existing antibodies can be readily obtained and sequenced using conventional techniques including, but not limited to, hybridization, PCR, and DNA sequencing. Hybridoma cells that produce monoclonal antibodies serve as a preferred source of antibody nucleotide sequences. A vast number of hybridoma cells that produce a range of monoclonal antibodies are available from public or private repositories. The largest depositary is the American Type Culture Collection (ATCC®), which offers a diverse collection of well-characterized hybridoma cell lines. Alternatively, antibody nucleotides can be obtained from immunized or non-immunized rodents or humans and can form organs such as spleens and peripheral blood lymphocytes. Specific techniques applicable to the extraction and synthesis of antibody nucleotides are described in Non-Patent Documents 29, 30, 31, and 17.

[0291] The polynucleotide encoding the anti-Gal3 antibody or its binding fragment can also be modified, for example, by substituting the coding sequences of the human heavy chain constant region and light chain constant region for homologous non-human sequences. In this way, a chimeric antibody that retains the binding specificity of the original anti-Gal3 antibody or its binding fragment is prepared.

[0292] Methods for producing anti-Gal3 antibodies or their conjugate fragments are also disclosed herein. In some embodiments, the method includes expressing a nucleic acid encoding an anti-Gal3 antibody or its conjugate fragment in cells, and isolating the expressed anti-Gal3 antibody or its conjugate fragment from the cells. In some embodiments, the method further includes concentrating the anti-Gal3 antibody or its conjugate fragment to a desired concentration. In some embodiments, the cells are mammalian cells, insect cells, or bacterial cells. In some embodiments, the anti-Gal3 antibody or its conjugate fragment is one of the anti-Gal3 antibodies or conjugate fragments disclosed herein. Specific procedures for expressing antibodies in cells and isolating the expressed antibodies are conventionally known and can be carried out by those skilled in the art.

[0293] host cell In some embodiments, the Disclosure provides host cells expressing either one of the anti-Gal3 antibodies or their conjugated fragments disclosed herein. The host cells in question typically contain nucleic acids encoding either one of the anti-Gal3 antibodies or their conjugated fragments disclosed herein.

[0294] This disclosure provides host cells transfected with polynucleotides, vectors, or libraries of vectors. The vectors can be introduced into suitable prokaryotic or eukaryotic cells by any of several suitable means, including electroporation, microparticle guns, lipofection, infection (the vector binds to an infectious pathogen), and transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances. The choice of means for introducing the vector often depends on the characteristics of the host cell.

[0295] For most animal cells, any of the above methods is suitable for vector delivery. Preferred animal cells are vertebrate cells, preferably mammalian cells, that can express the exogenously introduced gene product in large quantities, e.g., at the milligram level. Non-limiting examples of preferred cells are NIH3T3 cells, COS cells, HeLa cells, and CHO cells.

[0296] Once introduced into suitable host cells, the expression of anti-Gal3 antibodies or their conjugated fragments can be determined using any nucleic acid or protein assay known in the art. For example, the presence of light chain CDR or heavy chain CDR transcription mRNA or anti-Gal3 antibodies or their conjugated fragments. It can be detected and / or quantified by conventional hybridization assays (e.g., Northern blot analysis), amplification procedures (e.g., RT-PCR), SAGE (Patent Document 17), and array-based techniques (e.g., Patent Documents 18, 19, and 20) using probes complementary to any region of the polynucleotide encoding the anti-Gal3 antibody or its binding fragment.

[0297] Vector expression can also be determined by examining the expressed anti-Gal3 antibody or its binding fragment. Various techniques for protein analysis are available in the art. These include, but are not limited to, radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassays, immunogeometry assays, in situ immunoassays (e.g., using gold colloid, enzyme, or radioisotope labeling), Western blotting, immunoprecipitation assays, immunofluorescence assays, and SDS-PAGE.

[0298] Payload (small molecule drug) In some embodiments, any anti-Gal3 antibody disclosed herein further comprises a payload. In some cases, the payload comprises a small molecule, its protein or functional fragment, a peptide, or a nucleic acid polymer.

[0299] In some cases, the number of payloads conjugated to an anti-Gal3 antibody (e.g., drug-to-antibody ratio or DAR) is approximately 1:1, with one payload per anti-Gal3 antibody. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 2:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 3:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 4:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 6:1. In some cases, the payload-to-anti-Gal3 antibody ratio is approximately 8:1. In some cases, the ratio of payload to anti-Gal3 antibody is approximately 12:1.

[0300] In some embodiments, the payload is a small molecule. In some cases, the small molecule is a cytotoxic payload. Exemplary cytotoxic payloads include, but are not limited to, microtubule disruptors, DNA modifiers, or Akt inhibitors.

[0301] In some embodiments, the payload includes a microtubule disruptor. Exemplary microtubule disruptors include, but are not limited to, 2-methoxyestradiol, auristatin, chalcone, colchicine, combretastatin, cryptophycin, dicthiostatin, discodermolide, dolastain, eleutherobin, epothilone, halichondrin, laurimalid, mytansine, noscapinoid, paclitaxel, perolside, fomopsin, podophyllotoxin, rhizoxin, spongistatin, taxane, tubulcin, vinca alkaloids, vinorelbine, or derivatives or analogues thereof.

[0302] In some embodiments, the mytansin is a mytansinoid. In some embodiments, the mytansinoid is DM1, DM4, or anthamitosin. In some embodiments, the mytansinoid is DM1. In some embodiments, the mytansinoid is DM4. In some embodiments, the mytansinoid is anthamitosin. In some embodiments, the mytansinoid is a mytansinoid derivative or analog as described in Patent Documents 21, 22, 23, and 24, or Patent Documents 25 and 26.

[0303] In some embodiments, the payload is drastatin or a derivative or analog thereof. In some embodiments, the drastatin is drastatin 10 or drastatin 15, or a derivative or analog thereof. In some embodiments, the drastatin 10 analog is auristatin, sobridotin, simprostatin 1, or simprostatin 3. In some embodiments, the drastatin 15 analog is semadin or tacidotin.

[0304] In some embodiments, the drastatin 10 analog is auristatin or an auristatin derivative. In some embodiments, the auristatin or auristatin derivative is auristatin E (AE), auristatin F (AF), auristatin E 5-benzoylvalerate (AEVB), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), or monomethyl auristatin D (MMAD), auristatin PE, or auristatin PYE. In some embodiments, the auristatin derivative is monomethyl auristatin E (MMAE). In some embodiments, the auristatin derivative is monomethyl auristatin F (MMAF). In some embodiments, the auristatin is an auristatin derivative or analog as described in Patent Documents 27, 28, 29, 30, 31, 32, 33, and 34.

[0305] In some embodiments, the payload includes a DNA modifier. In some embodiments, the DNA modifier includes a DNA cleaver, a DNA intercalator, a DNA transcription inhibitor, or a DNA crosslinker. In some cases, the DNA cleaver includes bleomycin A2, calicheamicin, or derivatives or analogs thereof. In some cases, the DNA intercalator includes doxorubicin, epirubicin, PNU-159682, duocalmycin, pyrrolobenzodiazepine, oligomycin C, daunorubicin, barbicin, topotecan, or derivatives or analogs thereof. In some cases, the DNA transcription inhibitor includes dactinomycin. In some cases, the DNA crosslinker includes mitomycin C.

[0306] In some embodiments, the DNA modifier includes amsacrin, anthracycline, camptothecin, doxorubicin, duocalmycin, enediyne, etoposide, indolinobenzodiazepine, netropsin, teniposide, or derivatives or analogs thereof.

[0307] In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, dactinomycin, mitramycin, nemorubicin, picanthrone, subarubicin, or barbicin.

[0308] In some embodiments, the camptothecin analog is topotecan, irinotecan, silatecan, cositecan, exatecan, rhoutecan, gimatecan, belothecan, rubitecan, or SN-38.

[0309] In some embodiments, the duocalmycin is duocalmycin A, duocalmycin B1, duocalmycin B2, duocalmycin C1, duocalmycin C2, duocalmycin D, duocalmycin SA, or CC-1065. In some embodiments, the engine is calicheamicin, esperamicin, or dynemicin A.

[0310] In some embodiments, the pyrrolobenzodiazepine is anthramycin, abeymycin, thikamycin, DC-81, mazetramycin, neotramycin A, neotramycin B, polotoramycin, protracalcin, sibanomicin (DC-102), cibilomycin, or tomaimycin. In some embodiments, the pyrrolobenzodiazepine is a tomaimycin derivative as described in Patent Documents 35 and 36. In some embodiments, the pyrrolobenzodiazepine is one of those described in Patent Documents 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, as well as Patent Document 51.

[0311] In some embodiments, the pyrrolobenzodiazepine is a pyrrolobenzodiazepine dimer. In some embodiments, the PBD dimer is a symmetric dimer. Examples of symmetric PBD dimers include, but are not limited to, SJG-136 (SG-2000), ZC-423 (SG2285), SJG-720, SJG-738, ZC-207 (SG2202), and DSB-120. In some embodiments, the PBD dimer is an asymmetric dimer. Examples of asymmetric PBD dimers include, but are not limited to, SJG-136 derivatives as described in Patent Documents 52, 53, and 54.

[0312] In some embodiments, the payload includes an Akt inhibitor. In some cases, the Akt inhibitor includes ipatasertib (GDC-0068) or a derivative thereof.

[0313] In some embodiments, the payload includes polymerase II inhibitors such as α-amanitin, and polymerase inhibitors including, but not limited to, poly(ADP-ribose) polymerase (PARP) inhibitors. Exemplary PARP inhibitors include, but are not limited to, iniparib (BSI 201), talazoparib (BMN-673), olaparib (AZD-2281), olaparib, rucaparib (AG014699, PF-01367338), veliparib (ABT-888), CEP 9722, MK 4827, BGB-290, or 3-aminobenzamides.

[0314] In some embodiments, the payload includes a detectable portion. As used herein, “detectable portion” may include atoms, molecules, or compounds useful for diagnosing, detecting, or visualizing the location and / or quantity of a target molecule, cell, tissue, organ, etc. Detectable portions that can be used according to embodiments herein include, but are not limited to, radioactive materials (e.g., radioisotopes, radionuclides, radiolabels, or radiotracers), dyes, contrast agents, fluorescent compounds or molecules, bioluminescent compounds or molecules, enzymes and enhancers (e.g., paramagnetic ions), or specific binding moieties such as streptavidin, avidin, or biotin. Furthermore, some nanoparticles, such as quantum dots or metallic nanoparticles, may be suitable for use as detectable portions.

[0315] Exemplary radioactive materials that may be used as detectable portions according to embodiments of this specification include: 18 F, 18 F-FAC, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 75 Sc, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99 mTC, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 PM, 153 Sm, 154-158 Gd, 161Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, and 225 Examples of paramagnetic ionic materials that can be used as detectable markers include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals with atomic numbers 6–9, 21–29, 42, 43, 44, or 57–71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0316] If the detectable marker is a radioactive metal or a paramagnetic ion, in some embodiments, the marker can be reacted with a reagent having a long tail to which one or more chelating groups are bound for binding to these ions. The long tail may be a polymer such as polylysine, a polysaccharide, or other derivatizable or derivatizable chain having a pendant group that can be bound to the chelating group for binding the ion. Examples of chelating groups that may be used according to embodiments herein include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), DOTA, NOTA, NOGADA, NETA, deferoxamine (DfO), porphyrin, polyamine, crown ether, bis-thiosemicarbazone, polyoxime, and similar groups. The chelate can be linked to an antigen-binding construct by a group that allows for the formation of a bond to a molecule with minimal loss of immunoreactivity and minimal aggregation and / or internal crosslinking. The same chelate, when complexed with a non-radioactive metal such as manganese, iron, or gadolinium, is useful for MRI when used with the antigen-binding constructs and carriers described herein. Macrocyclic chelates such as NOTA, NOGADA, DOTA, and TETA are used with a variety of metals and radioactive metals, respectively, including but not limited to gallium, yttrium, and copper radionuclides. Other cyclic chelates, such as macrocyclic polyethers, may be used to stably bind radionuclides, such as radium-223 for radioimmunotherapy (RAIT). In certain embodiments, the chelate moiety is used with aluminum- 18 PET contrast agents such as F-complexes can be attached to target molecules for use in PET analysis.

[0317] Exemplary contrast agents that may be used as a detectable portion according to embodiments of the present disclosure include, but are not limited to, barium, diatrizoates, iodinated poppy oil ethyl esters, gallium citrate, iocalmic acid, iocetamic acid, iodoamide, iodipamide, iodoxamic acid, iogulamide, iohexyl, iopamidol, iopanoic acid, ioprosemic acid, iocefamic acid, ioceric acid, iosramide meglumine, iosemetic acid, iotasul, iotetoluic acid, iotalamic acid, iotroxic acid, ioxaglucic acid, ioxotrizoic acid, iopodart, meglumine, metrizamide, metrizoates, propyliodone, thallium chloride, or combinations thereof.

[0318] Bioluminescent and fluorescent compounds or molecules and dyes that can be used as detectable portions according to embodiments of this disclosure include, but are not limited to, fluorescein, fluorescein thioisocyanate (FITC), OREGON GREEN®, rhodamine, Texas Red, tetrarhodamine isothiocyanate (TRITC), Cy3, Cy5 and similar, fluorescent markers (e.g., green fluorescent protein (GFP), phycoerythrin and similar), self-quenching fluorescent compounds activated by tumor-associated proteases, enzymes (e.g., luciferase, horseradish peroxidase, alkaline phosphatase and similar), nanoparticles, biotin, digoxigenin, or combinations thereof.

[0319] Enzymes that may be used as detectable portions according to embodiments of this disclosure include, but are not limited to, horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, β-galactosidase, β-glucuronidase, or β-lactamase. Such enzymes may be used in combination with chromogens, fluorescent compounds, or luminescent compounds to generate a detectable signal.

[0320] In some embodiments, the payload is nanoparticles. The term “nanoparticles” refers to microscopic particles whose size is measured in nanometers, e.g., particles with at least one dimension less than about 100 nm. Nanoparticles can be used as detectable substances because they are small enough to scatter rather than absorb visible light. For example, gold nanoparticles have remarkable visible light quenching properties and appear crimson to black in solution. As a result, compositions containing antigen-binding constructs conjugated to nanoparticles can be used for in vivo imaging of T cells in a subject. At the smallest end of the size range, nanoparticles are often referred to as clusters. Metallic, dielectric, and semiconductor nanoparticles, as well as hybrid structures (e.g., core-shell nanoparticles), are formed. Nanospheres, nanorods, and nanocups are just some of the grown shapes. Semiconductor quantum dots and nanocrystals are examples of additional types of nanoparticles. Such nanoscale particles can be used as payloads conjugated to any one of the anti-Gal3 antibodies disclosed herein.

[0321] In some embodiments, the payload includes an immunomodulator. Useful immunomodulators include antihormone agents that block hormonal effects on tumors, and immunosuppressants that suppress cytokine production, downregulate autoantigen expression, or mask MHC antigens. Representative antihormone agents include, for example, antiestrogens such as tamoxifen, raloxifene, aromatase that inhibits 4(5)-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY 117018, onapnstone, and toremifene, antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, and antiadrenal agents. Examples of immunosuppressants include, but are not limited to, 2-amino-6-aryl-5-substituted pyrimidines, azathioprine, cyclophosphamide, bromocriptine, danazol, dapsone, glutaraldehyde, anti-idiotype antibodies against MHC antigens and MHC fragments, cyclosporine A, steroids such as glucocorticoid steroids, streptokinase, or rapamycin.

[0322] In some embodiments, the payload includes immunomodulatory components. Exemplary immunomodulatory components include gancyclovier, etanercept, tacrolimus, sirolimus, voclosporine, cyclosporine, rapamycin, cyclophosphamide, azathioprine, and mycophenolate mofetil. Examples include, but are not limited to, mofetil, methotrexate, glucocorticoids and their analogues, xanthines, stem cell growth factors, lymphotoxins, hematopoietic factors, tumor necrosis factor (TNF) (e.g., TNFα), interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, and IL-21), colony-stimulating factors (e.g., granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)), interferons (e.g., interferon-α, interferon-β, interferon-γ), stem cell growth factors known as "S1 factors," erythropoietin, and thrombopoietin, or combinations thereof.

[0323] In some embodiments, the payload includes an immunotoxin. Examples of immunotoxins include, but are not limited to, fungal toxins such as lysine, radionuclides, Pokeweed antiviral proteins, Pseudomonas exotoxin A, diphtheria toxin, lysine A chain, strictosin, and phospholipase enzymes. See Non-Patent Documents 32 and 33 for general information.

[0324] In some cases, the payload includes nucleic acid polymers. In such cases, the nucleic acid polymer includes short-chain interfering nucleic acids (siNAs), short-chain interfering RNAs (siRNAs), double-stranded RNAs (dsRNAs), microRNAs (miRNAs), short hairpin RNAs (shRNAs), and antisense oligonucleotides. In other examples, the nucleic acid polymer includes, for example, mRNA encoding cytotoxic proteins or peptides or apoptosis-inducing proteins or peptides. Exemplary cytotoxic proteins or peptides include α-pore-forming toxins (e.g., cytolysin A from E. coli), β-pore-forming toxins (e.g., α-hemolysin, PVL (Pantone Vale-leucocidine), aerolidine, Clostridium epsilon toxin, Clostridium perfringens enterotoxin), and two-component toxins (anthrax toxin, edema toxin, Clostridium botulinum C2 toxin, Clostridium spirofome toxin, Clostridium perfringens iota toxin, Clostridium difficile (C. Examples of bacterial cytotoxins include difficile cytotoxic toxins (A and B), prions, parasporins, cholesterol-dependent cytolysins (e.g., pneumolysin), pore-forming toxins (e.g., gramicidin A), cyanotoxins (e.g., microcystin, nodularin), hematotoxins, neurotoxins (e.g., botulinum neurotoxin), cytotoxins, cholera toxin, diphtheria toxin, Pseudomonas exotoxin A, tetanus toxin, or immunotoxins (idarubicin, lysine A, CRM9, Pokeweed antiviral protein, DT). Exemplary apoptosis-inducing proteins or peptides include apoptosis protease activator-1 (Apaf-1), cytochrome c, initiator caspase proteins (CASP2, CASP8, CASP9, CASP10), apoptosis-inducing factor (AIF), p53, p73, p63, Bcl-2, Bax, granzyme B, poly-ADP-ribose polymerase (PARP), and P21-activated kinase 2 (PAK2). In additional examples, the nucleic acid polymer includes nucleic acid decoys. In some cases, the nucleic acid decoy is a mimic of a protein-binding nucleic acid, such as an RNA-based protein-binding mimic.Examples of nucleic acid decoys include transactivation region (TAR) decoys and Rev response element (RRE) decoys.

[0325] In some cases, the payload is an aptamer. The aptamer is a small oligonucleotide or peptide molecule that binds to a specific target molecule. Exemplary nucleic acid aptamers include DNA aptamers, RNA aptamers, or XNA aptamers, which are DNA aptamers containing RNA and / or one or more non-natural nucleotides. Exemplary nucleic acid aptamers include ARC19499 (Archemix), REG1 (Regado Biosciences), and ARC1905 (Ophthotech).

[0326] The nucleic acids according to the embodiments described herein may optionally include naturally occurring nucleic acids or one or more nucleotide analogs, or have structures different from those of naturally occurring nucleic acids. For example, 2'-modifications include halo groups, alkoxy groups, and allyloxy groups. In some embodiments, the 2'-OH group is substituted with a group selected from H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, where R is a C1-C6 alkyl, alkenyl, or alkynyl, and halo is F, Cl, Br, or I. Examples of modifying bonds include phosphorothioate bonds and 5'-N-phosphoramidite bonds.

[0327] Nucleic acids having various different nucleotide analogs, modified skeletons, or nucleoside bonds that do not exist in nature are used according to the embodiments described herein. In some cases, the nucleic acids include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine) or modified nucleosides. Examples of modified nucleotides include base-modified nucleosides (e.g., aracitidine, inosine, isoguanosine, nebularin, pseudouridine, 2,6-diaminopurine, 2-aminopurine, 2-thiothymidine, 3-deaza-5-azacitidine, 2'-deoxyuridine, 3-nitropyrrole, 4-methylindole, 4-thiouridine, 4-thiothymidine, 2-aminoadenosine, 2-thiothymidine, 2-thiouridine, 5-bromocytidine, 5-iodouridine, inosine, 6-azauridine, 6-chloropurine, 7-deazaadenosine, 7-deazaguanosine, 8-azadenosine, 8-azidoadenosine, benzimidazole, M1-methyladenosine, pyrrolo-pyrimidine, 2-amino-6-chloro These include purines, 3-methyladenosine, 5-propynylcytidine, 5-propynyluridine, 5-bromouridine, 5-fluorouridine, 5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine), chemically or biologically modified bases (e.g., methylated bases), modified sugars (e.g., 2'-fluororibose, 2'-aminoribose, 2'-azidribose, 2'-O-methylribose, L-enantiomerous nucleosides, arabinose, and hexoses), modified phosphate groups (e.g., phosphorothioates and 5'-N-phosphoramidite bonds), and combinations thereof. Natural and modified nucleotide monomers for the chemical synthesis of nucleic acids are readily available. In some cases, nucleic acids containing such modifications exhibit enhanced properties compared to nucleic acids consisting solely of naturally occurring nucleotides.In some embodiments, the nucleic acid modifications described herein are used to reduce and / or prevent digestion by nucleases (e.g., exonucleases, endonucleases, etc.). For example, the structure of the nucleic acid may be stabilized by including a nucleotide analog at the 3' end of one or both strands to reduce digestion.

[0328] Different nucleotide modifications and / or skeletal structures can be present at various positions in nucleic acids. Such modifications include morpholinos, peptide nucleic acids (PNAs), methylphosphonate nucleotides, thiolphosphonate nucleotides, 2'-fluoroN3-P5'-phosphoramidites, 1',5'-anhydrohexitol nucleic acids (HNAs), or combinations thereof.

[0329] Any of the anti-Gal3 antibodies disclosed herein may be conjugated to one or more payloads described herein (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more).

[0330] Conjugated Chemistry In some cases, the payload is conjugated to the anti-Gal3 antibody described herein by native ligation. In some cases, such conjugation is described in Non-Patent Documents 34, 35, 36, or 37. In some cases, such conjugation is described in Patent Document 55.

[0331] In some cases, the payload is conjugated to the anti-Gal3 antibody described herein by a site-specific method utilizing traceless coupling technology (Philochem). In some cases, the traceless coupling technology utilizes the N-terminal 1,2-aminothiol group of the binding site to conjugate to a polynucleic acid molecule containing an aldehyde group (see Non-Patent Document 38).

[0332] In some cases, the payload is conjugated to the anti-Gal3 antibody described herein by a site-specific method utilizing a non-natural amino acid incorporated into the binding site. In some cases, the non-natural amino acid includes p-acetylphenylalanine (pAcPhe). In some cases, the keto group of pAcPhe selectively binds to the conjugated site of the alkoxyamine derivative to form an oxime bond (see Non-Patent Document 39).

[0333] In some cases, the payload is conjugated to the anti-Gal3 antibody described herein by a site-specific method utilizing an enzyme-catalyzed process. In some cases, the site-specific mutagenesis method utilizes SMARTag® technology (Redwood). In some cases, SMARTag® technology includes the production of formylglycine (FGly) residues from cysteine ​​by formylglycine-producing enzyme (FGE) via an oxidation process in the presence of an aldehyde tag, followed by the conjugation of FGly to an alkylhydrazine-functionalized polynucleic acid molecule by hydrazino-Picte-Spengler (HIPS) ligation (see Non-Patent Documents 40 and 41).

[0334] In some cases, the enzyme-catalyzed process involves microbial transglutaminase (mTG). In some cases, the payload is conjugated to an anti-Gal3 antibody using the microbial transglutaminase-catalyzed process. In some cases, mTG catalyzes the formation of a covalent bond between the amide side chain of glutamine in the recognition sequence and the primary amine of the functionalized polynucleic acid molecule. In some cases, mTG is produced from Streptomyces mobarensis (see Non-Patent Document 42).

[0335] In some cases, the payload is conjugated to the anti-Gal3 antibody by a method utilizing a sequence-specific transpeptidase as described in Patent Document 56, in which the entire payload is explicitly incorporated by reference.

[0336] In some cases, the payload is conjugated to the anti-Gal3 antibody by the methods described in Patent Documents 57 and 58.

[0337] Linker In some cases, the linkers described herein include natural or synthetic polymers comprising long chains of branched or unbranched monomers and / or crosslinked networks of two-dimensional or three-dimensional monomers. In some cases, the linkers include polysaccharides, lignin, rubber, or polyalkylene oxides (e.g., polyethylene glycol).

[0338] In some cases, the linker may include, but is not limited to, α-,ω-dihydroxyl polyethylene glycol, biodegradable lactone-based polymers such as polyacrylic acid, polylactidic acid (PLA), poly(glycolic acid) (PGA), polypropylene, polystyrene, polyolefin, polyamide, polycyanoacrylate, polyimide, polyethylene terephthalate (PET, PETG), polyethylene terephthalate (PETE), polytetramethylene glycol (PTG), or polyurethane, and mixtures thereof. As used herein, mixtures refer to the use of different polymers within the same compound, as well as block copolymers. In some cases, a block copolymer is a polymer in which at least one section of the polymer is constructed from monomers of another polymer. In some cases, the linker may include polyalkylene oxide. In some cases, the linker may include PEG. In some cases, the linker may include polyethyleneimide (PEI) or hydroxyethyl starch (HES).

[0339] In some cases, polyalkylene oxides (e.g., PEG) are polydisperse or monodisperse compounds. In some cases, polydisperse materials have a dispersion distribution of different molecular weights of the material, characterized by average weight (weight-average) size and degree of dispersion. In some cases, monodisperse PEG consists of molecules of one size. In some embodiments, the linker is a polydisperse or monodisperse polyalkylene oxide (e.g., PEG), as shown. The molecular weight shown represents the average molecular weight of polyalkylene oxide (e.g., PEG) molecules.

[0340] In some embodiments, the linker comprises a polyalkylene oxide (e.g., PEG), the molecular weight of which is approximately 200 Da, 300 Da, 400 Da, 500 Da, 600 Da, 700 Da, 800 Da, 900 Da, 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1450 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, 2000 Da, 2100 Da, 2200 Da, 2300 Da, 2400 Da. These are 2500Da, 2600Da, 2700Da, 2800Da, 2900Da, 3000Da, 3250Da, 3350Da, 3500Da, 3750Da, 4000Da, 4250Da, 4500Da, 4600Da, 4750Da, 5000Da, 5500Da, 6000Da, 6500Da, 7000Da, 7500Da, 8000Da, 10,000Da, 12,000Da, 20,000Da, 35,000Da, 40,000Da, 50,000Da, 60,000Da, or 100,000Da.

[0341] In some embodiments, the polyalkylene oxide (e.g., PEG) is individual PEG, and individual PEG is a polymer PEG containing multiple repeating ethylene oxide units. In some cases, individual PEG (dPEG) contains 2 to 60, 2 to 50, or 2 to 48 repeating ethylene oxide units. In some cases, dPEG contains about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50, or more repeating ethylene oxide units. In some cases, dPEG contains about 2 or more repeating ethylene oxide units. In some cases, dPEG is synthesized stepwise from pure (e.g., about 95%, 98%, 99%, or 99.5%) starting materials as a single molecular weight compound. In some cases, dPEG has a specific molecular weight rather than an average molecular weight.

[0342] In some cases, the linker is a single PEG containing, optionally, 2 to 60, 2 to 50, or 2 to 48 repeating ethylene oxide units. In some cases, the linker contains a dPEG containing about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50, or more repeating ethylene oxide units.

[0343] In some embodiments, the linker is a polypeptide linker. In some cases, the polypeptide linker contains at least 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, or more amino acid residues. In some cases, the polypeptide linker contains at least 2, 3, 4, 5, 6, 7, 8, or more amino acid residues. In some cases, the polypeptide linker contains a maximum of 2, 3, 4, 5, 6, 7, 8, or fewer amino acid residues. In some cases, the polypeptide linker is a cleavable polypeptide linker (e.g., enzymatically or chemically). In some cases, the polypeptide linker is an incleavable polypeptide linker. In some cases, the polypeptide linker includes Val-Cit (valine-citrulline), Gly-Gly-Phe-Gly, Phe-Lys, Val-Lys, Gly-Phe-Lys, Phe-Phe-Lys, Ala-Lys, Val-Arg, Phe-Cit, Phe-Arg, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Leu-Ala-Leu, or Gly-Phe-Leu-Gly. In some cases, the polypeptide linker contains peptides such as Val-Cit (valine-citrulline), Gly-Gly-Phe-Gly, Phe-Lys, Val-Lys, Gly-Phe-Lys, Phe-Phe-Lys, Ala-Lys, Val-Arg, Phe-Cit, Phe-Arg, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Leu-Ala-Leu, or Gly-Phe-Leu-Gly. In some cases, the polypeptide linker contains L-amino acids, D-amino acids, or a mixture of both L-amino acids and D-amino acids.

[0344] In some cases, the linker includes a homobifunctional linker. Examples of homobifunctional linkers include Lomant's reagent "dithiobis(succinimidyl propionate) (DSP)", 3′3′-dithiobis(sulfosuccinimidyl propionate) (DTSSP), disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl)sverate (BS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfoDST), and ethyleneglyceride. Cobis(succinimidyl succinate) (EGS), disuccinimidyl glutarate (DSG), N,N'-disuccinimidyl carbonate (DSC), dimethyl adipimide (DMA), dimethyl pimelimide (DMP), dimethyl svelimide (DMS), dimethyl 3,3'-dithiobis(propionimidate) (DTBP), 1,4-di-3'-(2'-pyridyldithio)propionamide)butane (D Examples include, but are not limited to, PDPB, bismaleimide hexane (BMH), aryl halide-containing compounds (DFDNB), such as 1,5-difluoro-2,4-dinitrobenzene or 1,3-difluoro-4,6-dinitrobenzene, 4,4′-difluoro-3,3′-dinitrophenyl sulfone (DFDNPS), bis-[β-(4-azidosalicylamido)ethyl]disulfide (BASED), formaldehyde, glutaraldehyde, 1,4-butanediol diglycidyl ether, adipic acid dihydrazide, carbohydrazide, o-toluidine, 3,3′-dimethylbenzidine, benzidine, α,α′-p-diaminodiphenyl, diiodo-p-xylenesulfonic acid, N,N′-ethylene-bis(iodoacetamide), or N,N′-hexamethylene-bis(iodoacetamide).

[0345] In some embodiments, the linker includes a heterobifunctional linker. Exemplary heterobifunctional linkers include amine-reactive sulfhydryl crosslinking agents, such as N-succinimidyl 3-(2-pyridyldithio)propionic acid (sPDP), long-chain N-succinimidyl 3-(2-pyridyldithio)propionic acid (LC-sPDP), and water-soluble long-chain 3-(2-pyridyldithio)propionic acid N-succinimidyl (sulfo-LC-sPDP), succinimidyloxycarbonyl-α-methyl-α-(2-pyridyldithio)toluene (sMPT), sulfosuccinimidyl-6-[α-methyl-α-(2-pyridyldithio)toluamide]hexanoate (sulfo-LC-sMPT), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sMCC), sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC), m-maleimidobenzoyl-N-hydroxysuccinimid ester (MBs), m-maleimidobenzoyl N-N-hydroxysulfosuccinimide ester (sulfo-MBs), N-succinimidyl (4-iodoacetyl)aminobenzoate (sIAB), sulfosuccinimidyl (4-iodoacetyl)aminobenzoate (sulfo-sIAB), succinimidyl-4-(p-maleimidophenyl)butyrate (sMPB), sulfosuccinimidyl-4-(p-maleimidophenyl)butyrate (sulfo-sMPB), N-(γ-maleimidobutyryloxy)succinimide ester (GMBs), N-(γ-maleimidobutyryloxy)sulfosuccinimide ester (sulfo-GMBs), succinimidyl 6-((iodoacetyl)amino)hexanoate (sIAX), succinimidyl 6-[6-(((iodoacetyl)amino)hexanoyl)amino]hexanoate (sIAXX), succinimidyl 4-(((iodoacetyl)amino)methyl)cyclohexane-1-carboxylate (sIAC), succinimidyl 6-((((4-iodoacetyl)amino)methyl)cyclohexane-1-carbonyl)amino)hexanoate (sIACX), iodoacetic acid p-nitrophenyl (NPIA),

[0346] Carbonyl-reactive and sulfhydryl-reactive crosslinking agents, for example, 4-(4-N-maleimidophenyl)butyrate hydrazide (MPBH), 4-(N-maleimidomethyl)cyclohexane-1-carboxyl-hydrazide-8 (M2C2H), 3-(2-pyridyldithio)propionyl hydrazide (PDPH),

[0347] Amine-reactive and photoreactive crosslinking agents, for example, N-hydroxysuccinimidyl-4-azidosalicylic acid (NHs-AsA), N-hydroxysulfosuccinimidyl-4-azidosalicylic acid (sulfo-NHs-AsA), sulfosuccinimidyl-(4-azidosalicylamide)hexanoate (sulfo-NHs-LC-AsA), sulfosuccinimidyl-2-(ρ-azidosalicylamide)ethyl-1,3′-dithiopropionate (sAsD), N-hydroxysuccinimidyl-4-azidobenzoate (HsAB), N-hydroxysulfosuccinimidyl-4-azidobenzoate (sulfo-HsAB), N-succinimidyl-6-(4′- Azido-2'-nitrophenylamino)hexanoate (sANPAH), sulfosuccinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate (sulfo-sANPAH), N-5-azido-2-nitrobenzoyloxysuccinimide (ANB-NOs), sulfosuccinimidyl-2-(m-azido-o-nitrobenzamide)-ethyl-1,3'-dithiopropionate (sAND), N-succinimidyl-4(4-azidophenyl)1,3'-dithiopropionate (sADP), N-sulfosuccinimidyl(4-azidophenyl)-1,3'-dithiopropionate (sulfo-sADP), sulfosuccinimidyl 4-(ρ-azidophenyl)butyrate (sulfo-sAPB), sulfosuccinimidyl 2-(7-azido-4-methylcoumarin-3-acetamido)ethyl-1,3′-dithiopropionate (sAED), sulfosuccinimidyl 7-azido-4-methylcoumarin-3-acetate (sulfo-sAMCA), ρ-nitrophenyldiazopirubate (ρNPDP), ρ-nitrophenyl-2-diazo-3,3,3-trifluoropropionic acid (PNP-DTP),

[0348] Examples of sulfhydryl-reactive and photoreactive crosslinking agents include, but are not limited to, 1-(ρ-azidosalicylamide)-4-(iodoacetamide)butane (AsIB), N-[4-(ρ-azidosalicylamide)butyl]-3′-(2′-pyridyldithio)propionamide (APDP), benzophenone-4-iodoacetamide, and benzophenone-4-maleimide. Examples of carbonyl-reactive and photoreactive crosslinking agents include, but are not limited to, ρ-azidobenzoylhydrazide (ABH), carboxylate-reactive and photoreactive crosslinking agents include, for example, 4-(ρ-azidosalicylamide)butylamine (AsBA), and arginine-reactive and photoreactive crosslinking agents include, for example, ρ-azidophenylglyoxal (APG).

[0349] In some embodiments, the linker includes a benzoic acid group or a derivative thereof. In some cases, the benzoic acid group or a derivative thereof includes para-aminobenzoic acid (PABA). In some cases, the benzoic acid group or a derivative thereof includes gamma-aminobutyric acid (GABA).

[0350] In some embodiments, the linker comprises one or more of a maleimide group, a peptide moiety, and / or a benzoic acid group in any combination. In some embodiments, the linker comprises a combination of a maleimide group, a peptide moiety, and / or a benzoic acid group. In some cases, the maleimide group is maleimidocaproyl (MC). In some cases, the peptide group is Val-Cit. In some cases, the benzoic acid group is PABA. In some cases, the linker comprises an MC-Val-Cit group. In some cases, the linker comprises a Val-Cit-PABA group. In further cases, the linker comprises an MC-Val-Cit-PABA group.

[0351] In some embodiments, the linker is a self-sacrificing linker or a self-excluding linker. In some cases, the linker is a self-sacrificing linker. In other cases, the linker is a self-excluding linker (e.g., a cyclized self-excluding linker). In some cases, the linker includes the linkers described in Patent Document 59 or Patent Document 60.

[0352] In some embodiments, the linker is a dendritic linker. In some cases, the dendritic linker includes a branched, polyfunctional linker portion. In some cases, the dendritic linker includes a PAMAM dendrimer.

[0353] In some embodiments, the linker is a traceless linker or linker that, after cleavage, leaves no linker portion (e.g., atoms or linker groups) relative to the antibody or payload. Exemplary traceless linkers include, but are not limited to, germanium linkers, silicon linkers, sulfur linkers, selenium linkers, nitrogen linkers, phosphorus linkers, boron linkers, chromium linkers, or phenylhydrazide linkers. In some cases, the linker is a traceless aryl-triazene linker as described in Non-Patent Document 43. In some cases, the linker is a traceless linker as described in Non-Patent Document 44. In some cases, the linker is a traceless linker as described in Patent Document 61.

[0354] Pharmaceutical preparations Pharmaceutical formulations for treating the diseases described herein may include the above-mentioned anti-Gal3 antibody or its conjugated fragment. The anti-Gal3 antibody or its conjugated fragment may be formulated for systemic administration, or it may be formulated for parenteral administration.

[0355] In some embodiments, the anti-Gal3 antibody or its conjugated fragment is formulated as a pharmaceutical composition for administration to a subject via parenteral (e.g., intravenous, subcutaneous, intramuscular, intra-arterial, intradermal, intraperitoneal, intravitreous, intracerebral, or intraventricular), oral, intranasal, buccal, rectal, or transdermal administration routes. In some cases, the pharmaceutical compositions described herein are formulated for parenteral (e.g., intravenous, subcutaneous, intramuscular, intra-arterial, intradermal, intraperitoneal, intravitreous, intracerebral, or intraventricular) administration. In other examples, the pharmaceutical compositions described herein are formulated for systemic administration. In other examples, the pharmaceutical compositions described herein are formulated for oral administration. In yet another example, the pharmaceutical compositions described herein are formulated for intranasal administration.

[0356] In some cases, the pharmaceutical composition further comprises pH adjusters or buffers, which include acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0357] In some cases, the pharmaceutical composition contains one or more salts in amounts necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0358] In some cases, the pharmaceutical composition can provide a more stable environment, thus the compound The composition further includes diluents used to stabilize the salt. Salts dissolved in buffer solutions (which may also provide pH control or maintenance) are used as diluents in the art, including but not limited to phosphate-buffered saline. In certain examples, the diluent increases the bulk of the composition to facilitate tableting or to produce a sufficient bulk for a homogeneous formulation for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugars such as Di-Pac (Amstar), mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrose, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol, and bentonite.

[0359] In some embodiments, the pharmaceutical formulations include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, sustained-release formulations, rapidly dissolving formulations, tablets, capsules, pills, delayed-release formulations, sustained-release formulations, pulsatile-release formulations, multi-particle formulations (e.g., nanoparticle formulations), and mixed immediate-release and sustained-release formulations.

[0360] In some cases, the pharmaceutical formulation may further include additional therapeutic agents. Non-limiting examples of additional therapeutic agents include α-glucosidase inhibitors including acarbose (Precose) and miglitol (Glyset); metformin-alogliptin (Kazano®), metformin-canagliflozin (Invokamet®), metformin-dapagliflozin (Xigduo® XR), metformin-empagliflozin (Synjardy®), metformin-glipizide, metformin-glipidide (Glucovance®). Biguanides including metformin-linagliptin (Jentadueto®), metformin-pioglitazone (Actoplus), metformin-repaglinide (PrandiMet), metformin-rosiglitazone (Avandamet®), metformin-saxagliptin (Kombiglyze® XR), and metformin-sitagliptin (Janumet®); dopamine agonists including bromocriptine (Cycloset®);

[0361] Alogliptin (Nesina®), Alogliptin-Metformin (Kazano®), Alogliptin-Pioglitazone (Oseni), Linagliptin (Tradjenta), Linagliptin-Empagliflozin (Glyxambi®), Linagliptin-Metformin (Jentadueto®), Saxagliptin (Onglyza®), Saxagliptin-Metformin (Kombiglyze® XR), Sitagliptin (Januvia®), Sitagliptin-Metformin (Jan Dipeptidyl peptidase-4 (DPP-4) inhibitors including umet® and Janumet® XR, as well as sitagliptin and simvastatin (Juvisync); glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) including albiglutide (Tanzeum®), dulaglutide (Trulicity®), exenatide (Byetta®), sustained-release exenatide (Bydureon®), liraglutide (Victoza®), and semaglutide (Ozempic®);

[0362] Meglitinides including nateglinide (Starlix), repaglinide (Prandin), and repaglinide-metformin (Prandimet); sodium-glucose transporter (SGLT) 2 inhibitors including dapagliflozin (Farxiga), dapagliflozin-metformin (Xigduo® XR), canagliflozin (Invokana®), canagliflozin-metformin (Invokamet®), empagliflozin (Jardiance®), empagliflozin-linagliptin (Glyxambi®), empagliflozin-metformin (Synjardy®), and erzgliflozin (Steglatro); glimepiride (Am Sulfonylurea preparations including aryl (registered trademark), glimepiride-pioglitazone (Duetact), glimepiride-rosiglitazone (Avandaryl), gliclazide, glipizide (Glucotrol), glipizide-metformin (Metaglip), glybrid (DiaBeta (registered trademark), Glynase, Micronase), glybrid-metformin (Glucovance (registered trademark)), chlorpropamide (Diabinese), trazamide (Tolinase), and tolbutamide (Orinase (registered trademark), Tol-Tab); rosiglitazone (Avandia (registered trademark)), rosiglitazone-glimepiride (Avandaryl), rosiglitazone-metformin (Amaryl (registered trademark)) Examples include thiazolidinediones containing pioglitazone (Actos®), pioglitazone-alogliptin (Oseni), pioglitazone-glimepiride (Duetact), and pioglitazone-metformin (Actoplus Met, Actoplus Met XR).

[0363] Treatment regimen In some embodiments, the anti-Gal3 antibody or its conjugate fragment disclosed herein is administered for therapeutic purposes. In some embodiments, the anti-Gal3 antibody or its conjugate fragment is administered once daily, twice daily, three times daily, or more frequently. The anti-Gal3 antibody or its conjugate fragment is administered daily, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more frequently. The anti-Gal3 antibody is administered for at least one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, eighteen months, two years, three years, or longer.

[0364] If the patient's condition improves, the administration of anti-Gal3 antibody or its conjugate fragments may be continued at the physician's discretion. Alternatively, the dose of anti-Gal3 antibody or its conjugate fragments administered may be temporarily reduced or temporarily interrupted for a certain period (i.e., a “drug-free period”). In some cases, the length of the drug-free period may vary from 2 days to 1 year and may include, but are not limited to, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the drug-free period ranges from 10% to 100%, and these are just examples, but include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0365] After the patient's condition improves, a maintenance dose may be administered as needed. Subsequently, the dose, or the frequency of administration, or both, may be reduced as a function of symptoms to a level at which the treated disease, disorder, or condition is maintained.

[0366] In some embodiments, the amount of a given drug corresponding to such an amount will vary depending on factors such as the specific compound, the severity of the disease, the subject or host characteristics (e.g., body weight), for example, the specific drug administered, the route of administration, and the subject or host being treated. Depending on the specific circumstances of the case, such as the host, the dose is routinely determined using methods known in the art. In some cases, the desired dose is conveniently presented as a single dose, as divided doses administered simultaneously (or over a short period), or as sub-dose doses at appropriate intervals, for example, two, three, four, or more times per day.

[0367] Given the large number of variables in individual treatment plans and the frequent deviations from these recommendations, the aforementioned ranges are merely suggestive. Such dosages will be modified depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual patient, the severity of the disease or condition being treated, and the physician's judgment.

[0368] In some embodiments, the toxicity and therapeutic effect of such a therapeutic regimen are determined by, but are not limited to, standard pharmaceutical procedures in cell culture or experimental animals, including the determination of the LD50 (lethal dose for 50% of the population) and ED50 (dose that is therapeutically effective for 50% of the population). The dose-to-toxicity ratio is the therapeutic index and is expressed as the ratio of LD50 to ED50. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal experiments are used in formulating the range of doses for use in humans. Doses of such compounds are preferably within the range of blood concentrations containing the ED50 with the lowest toxicity. The dose varies within this range depending on the dosage form used and the route of administration utilized.

[0369] Kit / Manufactured product In certain embodiments, kits and articles for use with one or more of the compositions and methods described herein are disclosed herein. Such kits include a carrier, package, or container partitioned to accept one or more containers, such as vials, tubes, etc., each of which contains one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials, such as glass or plastic.

[0370] The products provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging materials suitable for the selected formulation and intended mode of administration and treatment.

[0371] For example, the container includes an anti-Gal3 antibody as disclosed herein, a host cell for producing one or more antibodies as described herein, and / or a vector containing a nucleic acid molecule encoding an antibody as described herein. Such a kit may optionally include an identifying description, label, or instructions relating to its use in the method described herein.

[0372] The kit typically includes a label listing the contents and instructions for use, as well as an accompanying document containing instructions for use. A set of instructions is usually also included.

[0373] In one embodiment, the label is on the surface of the container or associated with the container. In one embodiment, the label is on the surface of the container if the letters, numbers, or other characters forming the label are attached to, molded, or etched onto the container itself. The label is associated with the container if it is located within the receptacle or carrier that holds the container, for example, as an accompanying document. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic purpose. The label also indicates how to use the contents, such as the method described herein.

[0374] In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device containing one or more unit dosage forms comprising the compounds provided herein. For example, the pack may include metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a notice relating to a container of a form specified by the regulatory authority for the manufacture, use, or sale of the pharmaceutical. This notice reflects the authority's approval of the form of the drug for human or veterinary administration. Such notices may be, for example, labels or product inserts approved by the U.S. Food and Drug Administration (FDA) for prescription drugs. In one embodiment, compositions comprising the compounds provided herein, formulated on a suitable pharmaceutical carrier, are also prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0375] Some embodiments provided herein are described by the numbered arrangements provided below, and are also provided as possible combinations or overlapping embodiments.

[0376] 1. A method for interfering with the interaction between galectin-3 (Gal3) and the insulin receptor,

[0377] A method comprising contacting an antibody or a binding fragment thereof that selectively binds to and interferes with the interaction between Gal3 and the insulin receptor, in the interaction between Gal3 and the insulin receptor.

[0378] 2. The method according to arrangement 1, wherein Gal3 is expressed by cells.

[0379] 3. The method according to arrangement 1, wherein Gal3 is secreted by cells.

[0380] 4. The method according to any one of arrangements 1 to 3, wherein the insulin receptor is expressed by cells.

[0381] 5. The method according to any one of arrangements 1 to 4, wherein the antibody or its conjugated fragment is bound to the N-terminal domain of Gal3.

[0382] 6. The method according to any one of arrangements 1 to 5, wherein the antibody or its bound fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof.

[0383] 7. The method according to any one of arrangements 1 to 6, wherein the antibody or its conjugated fragment is bound to an epitope of Gal3 containing the amino acid sequence GxYPG, where x is alanine, glycine, or valine.

[0384] 8. The method according to any one of arrangements 1 to 7, wherein the interaction is reduced to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% in the absence of the antibody or its binding fragment.

[0385] 9. The method according to any one of arrangements 1 to 8, wherein the antibody or its binding fragment binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM.

[0386] 10. The antibody is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -Includes a heavy chain variable region containing CDR3,

[0387] The aforementioned V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 71-89.

[0388] The aforementioned V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 90-100.

[0389] The aforementioned V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 101-115.

[0390] The aforementioned V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 27-38.

[0391] The aforementioned V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 39-53, and

[0392] The aforementioned V H -CDR3 is a method according to any one of arrangements 1 to 9, comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to sequence numbers 54 to 70.

[0393] 11. The antibody is as shown in Table 9, V L -CDR1, V L -CDR2, V L -CDR3, V H -CDR1, V H -CDR2 and V H - The method according to any one of claims 1 to 10, including a combination of CDR3.

[0394] 12. The method according to any one of arrangements 1 to 11, wherein the antibody is selected from the group consisting of 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2H1, IMT-001 (TB001), and IMT-006 (TB006).

[0395] 13. The method according to any one of arrangements 1 to 12, wherein the antibody or its conjugated fragment comprises a humanized antibody.

[0396] 14. The method according to any one of arrangements 1 to 13, wherein the antibody or its conjugated fragment comprises a full-length antibody or its conjugated fragment.

[0397] 15. The method according to any one of arrangements 1 to 14, wherein the antibody or its conjugated fragment comprises a bispecific antibody or its conjugated fragment.

[0398] 16. The method according to any one of arrangements 1 to 15, wherein the antibody or its conjugated fragment comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment.

[0399] 17. The method according to any one of arrangements 1 to 16, wherein the antibody or its conjugated fragment comprises an IgG framework.

[0400] 18. The method according to any one of arrangements 1 to 17, wherein the antibody or its conjugated fragment comprises an IgG1, IgG2, or IgG4 framework.

[0401] 19. A method for treating diabetes in a subject in need, comprising administering to the subject an antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor, thereby treating the subject's diabetes.

[0402] 20. The method according to arrangement 19, wherein the diabetes is insulin-dependent diabetes.

[0403] 21. The method according to arrangement 19, wherein the diabetes is insulin-independent diabetes.

[0404] 22. The method according to arrangement 19, wherein the diabetes is type 1 diabetes.

[0405] 23. The method according to arrangement 19, wherein the diabetes is type II diabetes.

[0406] 24. The method according to any one of arrangements 19 to 23, wherein the treatment comprises reducing glucose tolerance in the subject requiring such treatment.

[0407] 25. The method according to any one of arrangements 19 to 24, wherein the treatment comprises reducing insulin sensitivity in the subject requiring such treatment.

[0408] 26. The method according to any one of the arrangements described in 19-25, wherein the treatment comprises reducing the weight gain of the subject requiring it.

[0409] 27. The method according to any one of arrangements 19 to 26, wherein the treatment comprises reducing fatty liver in the subject requiring the treatment.

[0410] 28. A method for treating non-alcoholic fatty liver disease (NAFLD) in a subject in need, comprising administering to the subject an antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor, thereby treating the subject's NAFLD.

[0411] 29. A method for treating non-alcoholic steatohepatitis (NASH) in a target population, wherein the agent selectively binds to Gal3 and enhances the interaction between Gal3 and the insulin receptor. A method comprising treating NASH in a subject by administering an interfering antibody or a conjugated fragment thereof to the subject.

[0412] 30. The method according to any one of arrangements 19 to 29, wherein the antibody or its conjugated fragment is bound to the N-terminal domain of Gal3.

[0413] 31. The method according to any one of arrangements 19 to 30, wherein the antibody or its bound fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof.

[0414] 32. The method according to any one of arrangements 19 to 31, wherein the antibody or its conjugated fragment is bound to a Gal3 epitope containing the amino acid sequence GxYPG, where x is alanine, glycine, or valine.

[0415] 33. The method according to any one of arrangements 19 to 32, wherein the interaction is reduced to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% in the absence of the antibody or its binding fragment.

[0416] 34. The method according to any one of arrangements 19 to 33, wherein the antibody or its binding fragment binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM.

[0417] 35. The antibody is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H-CDR2 and V H -Includes a heavy chain variable region containing CDR3,

[0418] The aforementioned V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 71-89.

[0419] The aforementioned V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 90-100.

[0420] The aforementioned V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 101-115.

[0421] The aforementioned V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 27-38.

[0422] The aforementioned V H -CDR2 is at least 60%, at least 70%, at least 80%, at least 90%, or 100% of any amino acid sequence according to SEQ ID NOs. 39-53. It includes an amino acid sequence having sequence identity, and

[0423] The aforementioned V H - The method according to any one of arrangements 19 to 34, wherein CDR3 comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 54 to 70.

[0424] 36. The antibody is as shown in Table 9, V L -CDR1, V L -CDR2, V L -CDR3, V H -CDR1, V H -CDR2 and V H - The method according to any one of claims 19 to 35, including a combination of CDR3.

[0425] 37. The method according to any one of arrangements 19 to 36, wherein the antibody is selected from the group consisting of 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2H1, IMT-001, and IMT-006.

[0426] 38. The method according to any one of arrangements 19 to 37, wherein the antibody or its conjugated fragment comprises a humanized antibody.

[0427] 39. The method according to any one of arrangements 19 to 38, wherein the antibody or its conjugated fragment comprises a full-length antibody or its conjugated fragment.

[0428] 40. The method according to any one of arrangements 19 to 39, wherein the antibody or its conjugated fragment comprises a bispecific antibody or its conjugated fragment.

[0429] 41. The method according to any one of arrangements 19 to 40, wherein the antibody or its conjugated fragment comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment.

[0430] 42. The method according to any one of arrangements 19 to 41, wherein the antibody or its conjugated fragment comprises an IgG framework.

[0431] 43. The method according to any one of arrangements 19 to 42, wherein the antibody or its conjugated fragment comprises an IgG1, IgG2, or IgG4 framework.

[0432] 44. The method according to any one of arrangements 19 to 43, wherein the subject has been diagnosed with type 1 diabetes or type 2 diabetes.

[0433] 45. The method according to any one of arrangements 19 to 44, wherein the antibody or its conjugated fragment is formulated for systemic administration.

[0434] 46. ​​The method according to any one of arrangements 19 to 45, wherein the antibody or its conjugated fragment is formulated for parenteral administration.

[0435] 47. The method according to any one of arrangements 19 to 46, wherein the subject is a mammal.

[0436] 48. The method according to arrangement 47, wherein the mammal is a human.

[0437] 49.(1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -An anti-Gal3 antibody containing a heavy chain variable region including CDR3,

[0438] The aforementioned V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 71-89.

[0439] The aforementioned V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 90-100.

[0440] The aforementioned V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 101-115.

[0441] The aforementioned V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 27-38.

[0442] The aforementioned V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 39-53, and

[0443] The aforementioned V H -CDR3 is an anti-Gal3 antibody containing an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity to any amino acid sequence according to SEQ ID NOs. 54-70.

[0444] 50. The anti-Gal3 antibody is as shown in Table 9, V L -CDR1, V L -CDR2, V L -CDR3, V H -CDR1, V H -CDR2 and V H -An anti-Gal3 antibody as described in arrangement 49, including the combination of CDR3.

[0445] 51. The anti-Gal3 antibody according to arrangement 49 or 50, wherein the anti-Gal3 antibody is selected from the group consisting of 6H6.2D6, 20H5.A3, 20D11.2C6, 4G2.2G6, 13H12.2F8, 19B5.2E6, 15G7.2A7, 23H9.2E4, 19D9.2E5, 2D10.2B2, 4A11.2B5, 14H10.2C9, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, IMT-001(TB001), and IMT-006(TB006).

[0446] 52. An antibody that binds to human Gal3 and competes with an anti-Gal3 antibody for binding to human Gal3, wherein the anti-Gal3 antibody is selected from the group consisting of 6H6.2D6, 20H5.A3, 20D11.2C6, 4G2.2G6, 13H12.2F8, 19B5.2E6, 15G7.2A7, 23H9.2E4, 19D9.2E5, 2D10.2B2, 4A11.2B5, 14H10.2C9, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, IMT001, and IMT006.

[0447] 53. Antibodies that can interfere with the interaction between Gal3 and the insulin receptor. A method for determining

[0448] (a) Forming a Gal3-antibody complex by contacting the Gal3 protein with an antibody that selectively binds to Gal3,

[0449] (b) Contacting the Gal3 antibody complex with the insulin receptor protein,

[0450] (c) Removal of unbound insulin receptor protein, and

[0451] (d) detecting the insulin receptor protein bound to the Gal3 antibody complex,

[0452] (d) A method wherein, if the insulin receptor protein is not detected, the antibody can interfere with the interaction between Gal3 and the insulin receptor.

[0453] 54. The method according to arrangement 53, wherein the method includes an immunoassay.

[0454] 55. The method according to arrangement 54, wherein the immunoassay is an enzyme-linked immunosorbent assay.

[0455] 56. A method for interfering with the interaction between galectin-3 (Gal3) and insulin receptors or integrins, or both,

[0456] A method comprising contacting an anti-Gal3 antibody or a binding fragment thereof with the anti-Gal3 antibody, which selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor or the integrin or both, in the interaction between Gal3 and the insulin receptor or the integrin or both.

[0457] 57. The method according to arrangement 56, wherein Gal3 is expressed by cells.

[0458] 58. The method described in arrangement 56, wherein Gal3 is secreted by cells.

[0459] 59. The method according to any one of arrangements 56 to 58, wherein the insulin receptor, the integrin, or both are expressed by cells.

[0460] 60. The method according to any one of arrangements 56 to 59, wherein the anti-Gal3 antibody or its conjugated fragment binds to the N-terminal domain of Gal3.

[0461] 61. The method according to any one of arrangements 56 to 60, wherein the anti-Gal3 antibody or its conjugated fragment is conjugated to one or more peptides of SEQ ID NOs. 3 to 26.

[0462] 62. The method according to any one of arrangements 56 to 61, wherein the anti-Gal3 antibody or its conjugated fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof.

[0463] 63. The anti-Gal3 antibody or its conjugated fragment binds to a Gal3 epitope containing the amino acid sequence GxYPG, where x is alanine, glycine, or valine, allene The method described in any one of the instructions in sections 56-62.

[0464] 64. The method according to any one of arrangements 56 to 63, wherein the interaction is reduced to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% in the absence of the anti-Gal3 antibody or its binding fragment.

[0465] 65. The method according to any one of arrangements 56 to 64, wherein the anti-Gal3 antibody or its binding fragment binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM.

[0466] 66. The anti-Gal3 antibody or its conjugated fragment is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H-Includes a heavy chain variable region containing CDR3,

[0467] The aforementioned V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 100-128.

[0468] The aforementioned V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 129-144.

[0469] The aforementioned V L -CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 145-168.

[0470] The aforementioned V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 27-47.

[0471] The aforementioned V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 48-69, and

[0472] The aforementioned V H - The method according to any one of arrangements 56 to 65, wherein CDR3 comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to sequence numbers 70 to 99.

[0473] 67. The method of arrangement 66, wherein the heavy chain variable region includes an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with any sequence according to SEQ ID NOs. 169 to 206.

[0474] 68. The method according to arrangement 66 or 67, wherein the heavy chain variable region is selected from the group consisting of sequence numbers 169 to 206.

[0475] 69. The light chain variable region is less than any sequence defined by sequence numbers 207-245. The method according to any one of arrangements 66 to 68, wherein each amino acid sequence has 75%, 80%, 85%, 90%, 95%, or 100% sequence identity.

[0476] 70. The method according to any one of arrangements 66 to 69, wherein the light chain variable region is selected from the group consisting of sequence numbers 207 to 245.

[0477] 71. The anti-Gal3 antibody or its conjugated fragment, as shown in Figure 36, V L -CDR1, V L -CDR2, V L -CDR3, V H -CDR1, V H -CDR2 and V H -A method according to any one of arrangements 56-70, including the combination of CDR3.

[0478] 72. The anti-Gal3 antibody or its conjugated fragment,

[0479] a) V in sequence number 169 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 207 L -CDR1, V L -CDR2, V L-CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0480] b) V in sequence number 170 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 208 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0481] c) V in sequence number 171 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 209 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0482] d) V in sequence number 172 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 210 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0483] e) V in sequence number 173 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 211 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0484] f) V in sequence number 174 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 212 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0485] g) V in sequence number 175 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 213 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0486] h) V in sequence number 176 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 214 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0487] i) V in sequence number 177 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 215 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0488] j) V in sequence number 178 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 216 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0489] k) V in sequence number 179 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, VH -CDR2, V H -V in CDR3 and Sequence ID No. 217 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0490] l) V in sequence number 180 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 218 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0491] m) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 219 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0492] n) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 220 L -CDR1, VL -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0493] o) V in sequence number 182 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 221 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0494] p) V in sequence number 183 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 222 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0495] q) V in sequence number 184 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 223 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L-CDR2, V L -CDR3,

[0496] r) V in sequence number 185 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 224 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0497] s) V in sequence number 186 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 225 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0498] t) V in sequence number 187 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 226 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0499] u) V in sequence number 188 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 227 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0500] v) V in sequence number 189 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 228 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0501] w) V in sequence number 190 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 229 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0502] x) V in sequence number 191 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned VH -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 230 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0503] y) V in sequence number 192 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 231 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0504] z) V in sequence number 193 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 232 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0505] aa) V in sequence number 194 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 233L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0506] ab) V in sequence number 195 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 234 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0507] ac) V in sequence number 196 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 235 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0508] ad) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 236 L -CDR1, V L -CDR2, V L-CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0509] ae) V in sequence number 198 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 237 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0510] af) V in sequence number 199 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 238 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0511] ag) V in sequence number 197 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 239 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0512] ah) V in sequence number 200 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0513] ai) V in sequence number 201 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 241 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0514] aj) V in sequence number 202 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 242 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0515] ak) V in sequence number 203 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 240 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0516] al) V in sequence number 204 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 243 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0517] am) V in Sequence ID 205 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 244 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3, or

[0518] an) V in sequence number 206 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H-CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 245 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L - The method described in any one of arrangements 56-71, including CDR3.

[0519] 73. The anti-Gal3 antibody or its conjugated fragment,

[0520] a) Heavy chain variable region of Sequence ID No. 169 and light chain variable region of Sequence ID No. 207,

[0521] b) Heavy chain variable region of Sequence ID No. 170 and light chain variable region of Sequence ID No. 208,

[0522] c) Heavy chain variable region of Sequence ID No. 171 and light chain variable region of Sequence ID No. 209,

[0523] d) Heavy chain variable region of Sequence ID No. 172 and light chain variable region of Sequence ID No. 210,

[0524] e) Heavy chain variable region of Sequence ID No. 173 and light chain variable region of Sequence ID No. 211,

[0525] f) Heavy chain variable region of sequence number 174 and light chain variable region of sequence number 212,

[0526] g) Heavy chain variable region of SEQ ID NO: 175 and light chain variable region of SEQ ID NO: 213,

[0527] h) Heavy chain variable region of sequence number 176 and light chain variable region of sequence number 214,

[0528] i) Heavy chain variable region of Sequence ID No. 177 and light chain variable region of Sequence ID No. 215,

[0529] j) Heavy chain variable region of Sequence ID No. 178 and light chain variable region of Sequence ID No. 216,

[0530] k) Heavy chain variable region of Sequence ID No. 179 and light chain variable region of Sequence ID No. 217,

[0531] l) Heavy chain variable region of sequence number 180 and light chain variable region of sequence number 218,

[0532] m) Heavy chain variable region of sequence number 181 and light chain variable region of sequence number 219,

[0533] n) Heavy chain variable region of sequence number 181 and light chain variable region of sequence number 220,

[0534] o) Heavy chain variable region of Sequence ID No. 182 and light chain variable region of Sequence ID No. 221,

[0535] p) Heavy chain variable region of Sequence ID No. 183 and light chain variable region of Sequence ID No. 222,

[0536] q) Heavy chain variable region of sequence number 184 and light chain variable region of sequence number 223,

[0537] r) Heavy chain variable region of sequence number 185 and light chain variable region of sequence number 224,

[0538] s) Heavy chain variable region of sequence number 186 and light chain variable region of sequence number 225,

[0539] t) Heavy chain variable region of Sequence ID No. 187 and light chain variable region of Sequence ID No. 226,

[0540] u) Heavy chain variable region of sequence number 188 and light chain variable region of sequence number 227,

[0541] v) Heavy chain variable region of sequence number 189 and light chain variable region of sequence number 228,

[0542] w) Heavy chain variable region of sequence number 190 and light chain variable region of sequence number 229,

[0543] x) Heavy chain variable region of sequence number 191 and light chain variable region of sequence number 230,

[0544] y) Heavy chain variable region of sequence number 192 and light chain variable region of sequence number 231,

[0545] z) Heavy chain variable region of sequence number 193 and light chain variable region of sequence number 232,

[0546] aa) Heavy chain variable region of sequence number 194 and light chain variable region of sequence number 233,

[0547] ab) Heavy chain variable region of sequence number 195 and light chain variable region of sequence number 234,

[0548] ac) Heavy chain variable region of sequence number 196 and light chain variable region of sequence number 235,

[0549] ad) Heavy chain variable region of Sequence ID No. 197 and light chain variable region of Sequence ID No. 236,

[0550] ae) Heavy chain variable region of sequence number 198 and light chain variable region of sequence number 237,

[0551] af) Heavy chain variable region of sequence number 199 and light chain variable region of sequence number 238,

[0552] ag) Heavy chain variable region of SEQ ID NO: 197 and light chain variable region of SEQ ID NO: 239,

[0553] ah) Heavy chain variable region of sequence number 200 and light chain variable region of sequence number 240,

[0554] ai) Heavy chain variable region of Sequence ID No. 201 and light chain variable region of Sequence ID No. 241,

[0555] aj) Heavy chain variable region of Sequence ID No. 202 and light chain variable region of Sequence ID No. 242,

[0556] ak) Heavy chain variable region of sequence number 203 and light chain variable region of sequence number 240,

[0557] al) Heavy chain variable region of SEQ ID NO: 204 and light chain variable region of SEQ ID NO: 243,

[0558] am) Heavy chain variable region of SEQ ID NO: 205 and light chain variable region of SEQ ID NO: 244, or

[0559] an) A method according to any one of arrangements 56 to 72, comprising the heavy chain variable region of sequence number 206 and the light chain variable region of sequence number 245.

[0560] 74. The anti-Gal3 antibody or its conjugated fragment is 13H12.2F8, 19D9.2E5, 14H10.2C9, 2D10.2B2, 4A11.2B5, 6H6.2D6, 20H5.A3, 19B5.2E6, 23H9.2E4, 20D11.2C6, 15G7.2A7, 4G2.2G6, 3B11.2G2, 13A12.2E5, 7D8.2D8, 15F10.2D6, 12G5.D7, 24D12.2H9, 13G4.2F8, 9H2.2 H1, 23B10.2B12, 6B3.2D3, F846C.1B2, F846C.1F5, F846C.1H12, F846C.1H5, F846C.2H 3, F846TC.14A2, F846TC.14E4, F846TC.16B5, F846TC.7F10, F847C.10B9, F847C.11B1 The method according to any one of arrangements 56 to 73, selected from the group consisting of F847C.12F12, F847C.26F5, F847C.4B10, F849C.8D10, F849C.8H3, 847.14H4, mIMT001, IMT-001(TB001), and IMT-006(TB006).

[0561] 75. The method according to any one of arrangements 56 to 74, wherein the anti-Gal3 antibody or its conjugated fragment comprises a humanized antibody.

[0562] 76. The method according to any one of arrangements 56 to 75, wherein the anti-Gal3 antibody or its conjugated fragment comprises a full-length antibody or its conjugated fragment.

[0563] 77. The method according to any one of arrangements 56 to 76, wherein the anti-Gal3 antibody or its conjugated fragment comprises a bispecific antibody or its conjugated fragment.

[0564] 78. The method according to any one of arrangements 56 to 77, wherein the anti-Gal3 antibody or its conjugated fragment comprises a monovalent Fab', a bivalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody, or its conjugated fragment.

[0565] 79. The method according to any one of arrangements 56 to 78, wherein the anti-Gal3 antibody or its conjugated fragment comprises an IgG framework.

[0566] 80. The method according to any one of arrangements 56 to 79, wherein the anti-Gal3 antibody or its conjugated fragment comprises an IgG1, IgG2, or IgG4 framework.

[0567] 81. The method according to any one of arrangements 56 to 80, wherein lymphocyte adhesion is reduced by interfering with the interaction between Gal3 and the integrin.

[0568] 82. The method of arrangement 81, wherein the lymphocyte adhesion is reduced by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or by any percentage within the range defined by any two of the aforementioned percentages.

[0569] 83. A method for treating diabetes in a subject in need, comprising administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor or integrin or both, thereby treating the subject's diabetes.

[0570] 84. The method according to arrangement 83, wherein the diabetes is insulin-dependent diabetes.

[0571] 85. The method according to arrangement 83, wherein the diabetes is insulin-independent diabetes.

[0572] 86. The method according to arrangement 83, wherein the diabetes is type 1 diabetes.

[0573] 87. The method according to arrangement 83, wherein the diabetes is type II diabetes.

[0574] 88. The method according to any one of arrangements 83 to 87, wherein the treatment comprises reducing glucose tolerance in the subject requiring such treatment.

[0575] 89. The method according to any one of the arrangements 83 to 88, wherein the treatment comprises reducing insulin sensitivity in the subject requiring such treatment.

[0576] 90. The method according to any one of the arrangements described in 83-89, wherein the treatment comprises reducing the weight gain of the subject requiring it.

[0577] 91. The method according to any one of arrangements 83 to 90, wherein the treatment comprises reducing fatty liver in the subject requiring the treatment.

[0578] 92. The method according to any one of arrangements 83 to 91, further comprising selecting the subject as having diabetes or being at risk of developing diabetes, prior to the administration step.

[0579] 93. The method according to any one of arrangements 83 to 92, further comprising detecting improvement in the symptoms related to the target diabetes after the administration step.

[0580] 94. The method according to any one of arrangements 83 to 93, wherein the insulin receptor comprises the sequence of SEQ ID NO: 2.

[0581] 95. A method of any one of arrangements 83 to 94, wherein the integrin is selected from ITGa1, ITGa2, ITGa3, ITGa4, ITGa5, ITGa6, ITGa7, ITGa8, ITGa9, ITGa10, ITGa11, ITGaD, ITGaE, ITGaL, ITGaM, ITGaV, ITGa2B, ITGa2X, ITGb1, ITGb2, ITGb3, ITGb4, ITGb5, ITGb6, ITGb7, ITGb8, or any combination thereof.

[0582] 96. The method according to any one of arrangements 83 to 95, wherein the integrin includes a sequence selected from sequence numbers 339 to 342.

[0583] 97. The method according to any one of arrangements 83 to 96, wherein the anti-Gal3 antibody or a conjugated fragment thereof is administered together with one or more additional therapeutic compositions.

[0584] 98. The one or more additional therapeutic compositions include insulin, insulin derivatives or mimics thereof, insulin aspart, insulin glulisine, insulin lispro, insulin isophane, insulin degludec, insulin detemir, insulin zinc, insulin glargine glargine, vanadium, biguanide, metformin, phenformin, buformin, thiazolidinedione, rosiglitazone, pioglitazone, troglitazone, tolimidone, sulfonylurea, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide (gliclazide), glyclopyramide, gliquidone, meglitinide, repaglinide, nateglinide, α-glucosidase inhibitors, miglitol, acarbose, voglibose, incretin, glucagon-like peptide 1, glucagon-like peptide agonists, exenatide, liraglutide, taspoglutide, lixisenatide, semaglutide, dulaglutide, gastric suppressant peptide, dipeptidyl peptidase-4 inhibitors,The method according to arrangement 97, comprising vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, gemigliptin, pramlintide, dapagliflozin, canagliflozin, empagliflozin, or remogliflozin, or a combination thereof.

[0585] 99. A method for treating inflammatory bowel syndrome in a subject in need, comprising administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and integrin, thereby treating the inflammatory bowel syndrome in the subject.

[0586] 100. The method according to arrangement 99, wherein the inflammatory bowel syndrome is ulcerative colitis, Crohn's disease, or both.

[0587] 101. The method according to arrangement 99 or 100, further comprising selecting the subject as having inflammatory bowel syndrome or being at risk of developing inflammatory bowel syndrome, prior to the administration step.

[0588] 102. The method according to any one of arrangements 99 to 101, further comprising detecting improvement in the symptoms associated with the target inflammatory bowel syndrome after the administration step.

[0589] 103. The method according to any one of arrangements 99 to 102, wherein lymphocyte adhesion in the subject is reduced by interfering with the interaction between Gal3 and the integrin.

[0590] 104. The method according to arrangement 103, wherein the lymphocyte adhesion is reduced by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or any percentage within the range defined by any two of the aforementioned percentages.

[0591] 105. The integrin is selected from ITGa1, ITGa2, ITGa3, ITGa4, ITGa5, ITGa6, ITGa7, ITGa8, ITGa9, ITGa10, ITGa11, ITGaD, ITGaE, ITGaL, ITGaM, ITGaV, ITGa2B, ITGa2X, ITGb1, ITGb2, ITGb3, ITGb4, ITGb5, ITGb6, ITGb7, ITGb8, or any combination thereof. The method described in any one of the instructions in Diment 99-104.

[0592] 106. The method according to any one of arrangements 99 to 105, wherein the integrin contains a sequence selected from sequence numbers 339 to 342.

[0593] 107. The method according to any one of arrangements 99 to 106, wherein the anti-Gal3 antibody or a conjugated fragment thereof is administered together with one or more additional therapeutic compositions.

[0594] 108. The method according to arrangement 107, wherein the one or more additional therapeutic compositions include mesalazine, an immunosuppressant, prednisone, a TNF inhibitor, azathioprine, methotrexate, 6-mercaptopurine, or rifaximin, or any combination thereof.

[0595] 109. A method for treating non-alcoholic fatty liver disease (NAFLD) in a subject in need, comprising administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor, thereby treating the subject's NAFLD.

[0596] 110. A method for treating non-alcoholic steatohepatitis (NASH) in a subject in need, comprising administering to the subject an anti-Gal3 antibody or a conjugated fragment thereof that selectively binds to Gal3 and interferes with the interaction between Gal3 and the insulin receptor, thereby treating the NASH in the subject.

[0597] 111. The method according to any one of arrangements 83 to 110, wherein the anti-Gal3 antibody or its conjugated fragment binds to the N-terminal domain of Gal3.

[0598] 112. The method according to any one of arrangements 83 to 111, wherein the anti-Gal3 antibody or a conjugated fragment thereof is conjugated to one or more peptides of SEQ ID NOs. 3 to 26.

[0599] 113. The method according to any one of arrangements 83 to 112, wherein the anti-Gal3 antibody or its conjugated fragment binds to an epitope located within the region of Gal3 defined by peptide 1 (ADNFSLHDALSGSGNPNPQG, SEQ ID NO: 3), peptide 4 (GAGGYPGASYPGAYPGQAPP, SEQ ID NO: 6), peptide 6 (GAYPGQAPPGAYPGAPGAYP, SEQ ID NO: 8), peptide 7 (AYPGAPGAYPGAPAPGVYPG, SEQ ID NO: 9), or a combination thereof.

[0600] 114. The method according to any one of arrangements 83 to 113, wherein the anti-Gal3 antibody or its conjugated fragment is bound to a Gal3 epitope containing the amino acid sequence GxYPG, where x is alanine, glycine, or valine.

[0601] 115. The method according to any one of arrangements 83 to 114, wherein the interaction is reduced to less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% in the absence of the anti-Gal3 antibody or its binding fragment.

[0602] 116. The anti-Gal3 antibody or its binding fragment binds to Gal3 with a dissociation constant (KD) of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM, in an adapted form. The method described in any one of the instructions in steps 83-115.

[0603] 117. The anti-Gal3 antibody or its conjugated fragment is (1)V L -CDR1, V L -CDR2 and V L -Light chain variable region including CDR3, and (2)V H -CDR1, V H -CDR2 and V H -Includes a heavy chain variable region containing CDR3,

[0604] The aforementioned V L -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 100-128.

[0605] The aforementioned V L -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 129-144.

[0606] The aforementioned V L-CDR3 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 145-168.

[0607] The aforementioned V H -CDR1 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 27-47.

[0608] The aforementioned V H -CDR2 contains an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 48-69, and

[0609] The aforementioned V H - The method according to any one of arrangements 83 to 116, wherein CDR3 comprises an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, or 100% sequence identity with any amino acid sequence according to SEQ ID NOs. 70 to 99.

[0610] 118. The method according to arrangement 117, wherein the heavy chain variable region includes an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with any sequence according to SEQ ID NOs. 169-206.

[0611] 119. The method according to arrangement 117 or 118, wherein the heavy chain variable region is selected from the group consisting of sequence numbers 169 to 206.

[0612] 120. The method according to any one of arrangements 117 to 119, wherein the light chain variable region includes an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, or 100% sequence identity with any sequence according to SEQ ID NOs. 207 to 245.

[0613] 121. The method according to any one of arrangements 117 to 120, wherein the light chain variable region is selected from the group consisting of sequence numbers 207 to 245.

[0614] 122. The anti-Gal3 antibody or its conjugated fragment, as shown in Figure 36, V L -CDR1, V L -CDR2, V L -CDR3, V H -CDR1, V H -CDR2 and V H -A method according to any one of arrangements 83-121, including the combination of CDR3.

[0615] 123. The anti-Gal3 antibody or its conjugated fragment,

[0616] a) V in sequence number 169 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 207 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0617] b) V in sequence number 170 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 208 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0618] c) V in sequence number 171 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 209 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0619] d) V in sequence number 172 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 210 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0620] e) V in sequence number 173 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 211 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0621] f) V in sequence number 174 H -CDR1, V H -CDR2, VH -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 212 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0622] g) V in sequence number 175 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 213 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0623] h) V in sequence number 176 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 214 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0624] i) V in sequence number 177 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H-V in CDR3 and Sequence ID No. 215 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0625] j) V in sequence number 178 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 216 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0626] k) V in sequence number 179 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 217 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0627] l) V in sequence number 180 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 218 L -CDR1, V L -CDR2, V L-CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0628] m) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 219 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0629] n) V in sequence number 181 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 220 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0630] o) V in sequence number 182 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 221 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0631] p) V in sequence number 183 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 222 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0632] q) V in sequence number 184 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 223 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0633] r) V in sequence number 185 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 224 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0634] s) V in sequence number 186 H -CDR1, VH -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID 225 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0635] t) V in sequence number 187 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 226 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0636] u) V in sequence number 188 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 227 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0637] v) V in sequence number 189 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H-CDR2, V H -V in CDR3 and Sequence ID No. 228 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0638] w) V in sequence number 190 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 229 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0639] x) V in sequence number 191 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ID No. 230 L -CDR1, V L -CDR2, V L -CDR3 is the aforementioned V L -CDR1, V L -CDR2, V L -CDR3,

[0640] y) V in sequence number 192 H -CDR1, V H -CDR2, V H -CDR3 is the aforementioned V H -CDR1, V H -CDR2, V H -V in CDR3 and Sequence ...

Claims

1. A composition comprising an anti-Gal3 antibody or a conjugated fragment thereof for interfering with the interaction between galectin-3 (Gal3) and the insulin receptor, The anti-Gal3 antibody or its conjugated fragment comprises (1) a light chain variable region (V L-CDR1, V L-CDR2, and V L-CDR3). Ｌ ) and (2) heavy chain variable region (V H-CDR1, V H-CDR2, and V H-CDR3) Ｈ ) including, The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 110, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 134, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 152, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 33, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

79. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 112, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 135, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 153, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 35, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 57, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

80. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 105, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 132, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 149, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 31, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 52, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 108, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 32, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 54, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 109, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 152, and the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO:

27. The VH-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 55, and the VH-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

78. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 100, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

70. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 104, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 131, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 148, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 107, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 29, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 53, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 102, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

72. The V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 103, the V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 130, the V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 146, the V H-CDR1 contains the amino acid sequence shown in SEQ ID NO: 30, the V H-CDR2 contains the amino acid sequence shown in SEQ ID NO: 51, and the V H-CDR3 contains the amino acid sequence shown in SEQ ID NO: 75, or A composition in which V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 101, V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 129, V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 145, V H-CDR1 contains the amino acid sequence shown in SEQ ID NO: 27, V H-CDR2 contains the amino acid sequence shown in SEQ ID NO: 48, and V H-CDR3 contains the amino acid sequence shown in SEQ ID NO:

71.

2. The composition according to claim 1, wherein the interaction is reduced to less than 70% of the interaction in the absence of the anti-Gal3 antibody or its binding fragment.

3. A pharmaceutical composition comprising an anti-Gal3 antibody or a conjugated fragment thereof for the treatment of type 1 diabetes or type 2 diabetes in a target population, The anti-Gal3 antibody or its conjugated fragment comprises (1) a light chain variable region (V L-CDR1, V L-CDR2, and V L-CDR3). Ｌ ) and (2) heavy chain variable region (V H-CDR1, V H-CDR2, and V H-CDR3) Ｈ ) including, The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 110, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 134, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 152, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 33, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

79. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 112, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 135, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 153, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 35, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 57, and the V H-CDR3 The amino acid sequence shown in SEQ ID NO: 80 is The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 105, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 132, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 149, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 31, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 52, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 108, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 32, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 54, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 109, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 152, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 55, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

78. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 100, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

70. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 104, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 131, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 148, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 107, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 29, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 53, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 102, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

72. The V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 103, the V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 130, the V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 146, the V H-CDR1 contains the amino acid sequence shown in SEQ ID NO: 30, the V H-CDR2 contains the amino acid sequence shown in SEQ ID NO: 51, and the V H-CDR3 contains the amino acid sequence shown in SEQ ID NO: 75, or The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 101, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

71. Pharmaceutical composition.

4. The pharmaceutical composition according to claim 3, wherein the treatment comprises reducing glucose tolerance in the subject requiring the treatment.

5. The pharmaceutical composition according to claim 3, wherein the treatment comprises reducing insulin sensitivity in the subject requiring it.

6. The pharmaceutical composition according to claim 3, wherein the treatment comprises reducing the weight gain of the subject requiring it.

7. The pharmaceutical composition according to claim 3, wherein the treatment comprises reducing fatty liver in the subject requiring it.

8. The pharmaceutical composition according to claim 3, which is administered together with one or more additional therapeutic compositions.

9. The one or more additional therapeutic compositions include insulin, insulin derivatives or imitations thereof, insulin aspart, insulin glulisine, insulin lispro, insulin isophene, insulin degludec, insulin detemir, insulin zinc, and insulin glargine. Glargine, vanadium, biguanide, metformin, phenformin, buformin, thiazolidinedione, rosiglitazone, pioglitazone, troglitazone AZONE, torimidone, sulfonylurea, tolbutamide, acetohexamide, tolazaamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide (gliclazide), glycopyramide, glycidone, meglitinide, repaglinide, nateglinide, α-glucosidase inhibitors, miglitol, acarbose, voglibose, increti (incretin), glucagon-like peptide 1, glucagon-like peptide agonist, exenatide, liraglutide, taspoglutide, lixisenatide, semaglutide, dulaglutide, gastric suppressant peptide, dipeptidyl peptidase-4 inhibitor,The pharmaceutical composition according to claim 8, comprising vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, gemigliptin, pramlintide, dapagliflozin, canagliflozin, empagliflozin, or remogliflozin, or a combination thereof.

10. The pharmaceutical composition according to claim 8, wherein the one or more additional therapeutic compositions include mesalazine, an immunosuppressant, prednisone, a TNF inhibitor, azathioprine, methotrexate, 6-mercaptopurine, or rifaximin, or any combination thereof.

11. The pharmaceutical composition according to claim 3, which is administered enterally, orally, intranasally, parenterally, intracranially, subcutaneously, intramuscularly, intradermally, or intravenously, or any combination thereof.

12. (1) V Ｌ - CDR1, V Ｌ - CDR2, and V Ｌ - CDR3-containing light chain variable region, and (2) V Ｈ - CDR1, V Ｈ - CDR2, and V Ｈ - CDR3-containing heavy chain variable region, an anti-Gal3 antibody comprising The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 110, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 134, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 152, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 33, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

79. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 112, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 135, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 153, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 35, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 57, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

80. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 105, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 132, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 149, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 31, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 52, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 108, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 32, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 54, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 109, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 152, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 55, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

78. The V L-CDR1 includes the amino acid sequence shown in SEQ ID NO: 100, the V L-CDR2 includes the amino acid sequence shown in SEQ ID NO: 129, the V L-CDR3 includes the amino acid sequence shown in SEQ ID NO: 145, the V H-CDR1 includes the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 includes the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 includes the amino acid sequence shown in SEQ ID NO:

70. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 104, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 131, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 148, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 27, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 48, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

76. The V L-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 107, the V L-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 133, the V L-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 151, the V H-CDR1 comprises the amino acid sequence shown in SEQ ID NO: 29, the V H-CDR2 comprises the amino acid sequence shown in SEQ ID NO: 53, and the V H-CDR3 comprises the amino acid sequence shown in SEQ ID NO:

77. The V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 102, the V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 129, and the V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 145 The amino acid sequence includes the amino acid sequence shown in SEQ ID NO: 27 for VH-CDR1, the amino acid sequence shown in SEQ ID NO: 48 for VH-CDR2, and the amino acid sequence shown in SEQ ID NO: 72 for VH-CDR3. The V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 103, the V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 130, the V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 146, the V H-CDR1 contains the amino acid sequence shown in SEQ ID NO: 30, the V H-CDR2 contains the amino acid sequence shown in SEQ ID NO: 51, and the V H-CDR3 contains the amino acid sequence shown in SEQ ID NO: 75, or An anti-Gal3 antibody wherein V L-CDR1 contains the amino acid sequence shown in SEQ ID NO: 101, V L-CDR2 contains the amino acid sequence shown in SEQ ID NO: 129, V L-CDR3 contains the amino acid sequence shown in SEQ ID NO: 145, V H-CDR1 contains the amino acid sequence shown in SEQ ID NO: 27, V H-CDR2 contains the amino acid sequence shown in SEQ ID NO: 48, and V H-CDR3 contains the amino acid sequence shown in SEQ ID NO:

71.

13. A pharmaceutical preparation comprising the anti-Gal3 antibody described in claim 12.

14. The pharmaceutical preparation according to claim 13 for use in the treatment of type 1 diabetes or type 2 diabetes.

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