ANTI-SIGLEC-9 ANTIBODIES AND METHODS OF USE THEREOF

Description

FIELD OF THE INVENTION

[0001] This present disclosure relates to anti-Siglec-9 antibodies and therapeutic uses of such antibodies.BACKGROUND OF THE INVENTION

[0002] Sialic acid-binding Ig-like lectin-9 (Siglec-9), is a type 1, immunoglobulin-like, transmembrane protein expressed on immune and hematopoietic cells, including immature and mature myeloid cells, such as monocytes, macrophages, dendritic cells, neutrophils, and microglial cells, as well as lymphoid cells, such as natural killer cells, and subsets of T cells (Crocker et al. (2007) Nat Rev Immunol. 7:255-266; O'Reilly and Paulson (2009) Trends in Pharm. Sci. 30:5:240-248; and Macauley et al. (2014) Nat. Rev. Imm. 14: 653-666). Siglec-9 is a member of the Siglec family of lectins that bind sialic acid residues of glycoproteins and glycolipids. One potential binding target for Siglec proteins is gangliosides; that is, glycolipids that consist of a ceramide linked to a sialylated glycan. Most gangliosides share a common lacto-ceramide core and one or more sialic acid residues. Diversity in the Siglec ligands is generated by the addition of other neutral sugars and sialic acid in different linkages, either branched or terminal, and modification of sialic acid itself.

[0003] Fourteen Siglec proteins have been identified in humans and nine in mice that are comprised of 2-17 extracellular Ig domains including an amino-terminal V-set domain that contains the sialic acid-binding site. The sialic acid-binding region is located on the V-set Ig-like domain, which contains a two aromatic residues and one arginine motif highly conserved in all Siglecs (Crocker et al. (2007) Nat Rev Immunol. 7:255-266; McMillan and Crocker (2008) Carbohydr Res. 343:2050-2056; Von Gunten and Bochner (2008) Ann NY Acad Sci. 1143:61-82; May et al. (1998) Mol Cell. 1:719-728; Crocker et al. (1999) Biochem J. 341:355-361; and Crocker and Varki (2001) Trends Immunol. 2:337-342). The binding sites to sialylated ligands have been mapped by crystal structures with and without ligand bound (Attrill et al., (2006) J. Biol. Chem.281 32774-32783; Alphey et al. (2003) J. Biol. Chem. 278:5 3372-3377; Varki et al., Glycobiology, 16 pp. 1R-27R; and May et al. (1998) Mol. Cell 1:5:719-728). Since cell membranes are rich in sialic acids, ligand binding by Siglecs can occur in cis and in trans, both affecting their functional properties. Each Siglec has a distinct preference for binding the diverse types of sialylated glycans that are found on the surface of mammalian cells (Crocker et al. (2007) Nat Rev Immunol. 7:255-266; and Crocker et al. (2007) Nat Rev Immunol. 7:255-266). Most Siglec proteins, including Siglec-9, contain one or more immunoreceptor tyrosine-based inhibitory motif (ITIM) sequences in their cytoplasmic tails, which enable them as inhibitory receptors and negative regulators of immune functions through recruitment of the tyrosine phosphatases SHP1 and SHP2 (Crocker et al. (2007) Nat Rev Immunol. 7:255-266; McMillan and Crocker (2008) Carbohydr Res. 343:2050-2056; and Von Gunten and Bochner (2008) Ann NY Acad Sci. 1143:61-82). Certain Siglecs contain immunoreceptor tyrosine-based activating motif (ITAM) sequences in their cytoplasmic tails, which enable them to act as activating receptors and positive regulators of immune function through predicted recruitment of spleen tyrosine kinase (Syk) (Macauley SM. et al., (2014) Nature Reviews Immunology 14, 653-666). The Siglec protein family is associated with multiple human diseases including, autoimmunity, susceptibility to infection, multiple types of cancer including lymphoma, leukemia and acute myeloid leukemia, systemic lupus erythematosus, rheumatoid arthritis, neurodegenerative disorders, asthma, allergy, sepsis, chronic obstructive pulmonary disease, graft-versus-host disease, eosinophilia, and osteoporosis (Macauley SM. et al., (2014) Nature Reviews Immunology 14, 653-666).

[0004] Siglec-9 was cloned in 2000 from peripheral blood mononuclear cells (Angata and Varki (2000) J. Biol. Chem. 275:29: 22127-22135) and selective expression was detected on granulocytes and monocytes. An independent group isolated Siglec-9 from HL-60 (human promyelocytic leukemia) cells and demonstrated expression on monocytes, neutrophils, NK cells and a small subset of T cells (Zhang et al. (2000) J. Biol. Chem. 275:29 22121-22126).

[0005] Siglec-9 contains an extracellular N-terminal Ig-like (immunoglobulin-like) V-type domain, two Ig-like C2-set domains as well as two consensus ITIM motifs in its cytoplasmic domain. Expression of Siglec-9 in COS cells demonstrated sialic acid-dependent binding of red blood cells, which is mediated by terminal α2-3 or α2-6 sialic acid linkages (Angata and Varki (2000) J. Biol. Chem. 275: 22127-22135, Zhang et al. (2000) J. Biol. Chem. 275:29 22121-22126). It was further confirmed that Siglec-9 is masked by endogenous cellular sialic acids and binds to exogenous terminal α2-3 or α2-6 sialic acid probes only upon sialidase treatment of the cells (Yamaji (2002) J. Biol. Chem. 277:8 6324-6332). Ligand specificity within the N-terminal V-set Ig-like domain of Siglec-9 was mapped to a small region, Asn 70< -Lys 75< , by swapping Siglec-7 with Siglec-9 regions and vice versa. Acquisition of the respective Siglec ligand specificity within these amino acid residues supports the notion that ligand specificity is dictated by interactions in the variable C-C' loop (Yamaji (2002) J. Biol. Chem. 277:8 6324-6332). Pathogens have apparently subverted the sialic acid as "self" system as it has been reported that group B Streptococcus can bind Siglec-9 on human neutrophils thereby reducing the immune response to the bacteria, which can either be pathogenic or commensal (Carlin et al (2009) Blood 113: 3333-3336). Other sources of in vivo Siglec-9 sialic acid ligands are tumor-secreted mucins, such as MUC1, MUC2, MUC16; Siglec-9 was shown to bind mucins from the sera of cancer patients (Ohta et al. (2010) Biochem. and Biophys. Res. Comm. 402: 663-669; Belisle et al. (2010) Mol. Cancer 9:118).

[0006] Siglec-9 undergoes phosphorylation of Tyr-433, and Tyr-456 by tyrosine kinases, likely c-Src or Lck, and functions as an inhibitory receptor (Avril et al., (2004) J. Imm. 173: 6841-6849). Following phosphorylation on the proximal Tyr-433 in the ITIM domain, Siglec-9 binds SHP-2 / PTPN11 and SHP-1 / PTPN6. The membrane distal ITIM motif does not appear to contribute significantly as mutation did not preclude tyrosine phosphorylation or inhibitory function of Siglec-9. Siglec-9 was shown to inhibit FcεRI-mediated activities in rat basophilic leukemia cells, which have been previously used to characterize an inhibitory receptor class expressed on NK cells called KIRs (Killer Ig-like receptors) (Avril et al., (2004) J. Imm. 173: 6841-6849). Phosphatase activity is additionally associated with decreased intracellular calcium mobilization, and decreased tyrosine phosphorylation on multiple proteins (Ulyanova, T., et al., (1999) Eur J Immunol 29, 3440-3449; Paul, S.P., et al., (2000). Blood 96, 483-490) as well as with blockade of signal transduction and immune response, in part, through dephosphorylation of signaling molecules on adjacent activating receptors, including those that contain ITAM motifs, pattern recognition receptors, Toll-like receptors and damage-associated molecular pattern (DAMP) receptors. It has been proposed that the association between ITIM-containing Siglec receptors and activating receptors may be mediated by extracellular ligands that bind and bridge these receptors (Macauley SM. et al., (2014) Nature Reviews Immunology 14, 653-666).

[0007] Some, but not all, Siglec ligands induce receptor downregulation (Macauley SM. et al., (2014) Nature Reviews Immunology 14, 653-666). Ligand-induced receptor degradation has been reported for tyrosine kinase receptors (Monsonego-Oran et al., (2002) Febs letters 528, 83-89; and Fasen et al., (2008) Cell & Molecular Biology 9. 251-266), as well as for steroid receptors (Callige et al., (2005) Mol. Cell. Biol. 25. 4349-4358; and Pollenz et al., (2006) Chemico-Biological Interactions. 164. 49-59). Siglec-9 is thought to be to constitutively recycled in acute myeloid leukemia (AML) cells and has been shown to mediate rapid endocytosis of an anti-Siglec-9 monoclonal antibody on these cells (Biedermann et al. (2007) Leuk. Res. 31:2:211-220). However, no decrease in cellular levels of Siglec-9 has been reported in either AML or normal primary immune cells. Likewise, no receptor recycling or antibody-dependent receptor down regulation has been reported in any type of primary cells. Expression of Siglec-9 on the cell surface is dependent in part on the membrane proximal ITIM motif, but not the distal motif, according to mutational analysis performed in an overexpression system (Biedermann et al. (2007) Leuk. Res. 31:2:211-220).

[0008] Siglec-9 has been described as having immunomodulatory effects on cytokine production. Overexpression of Siglec-9 in a macrophage cell line and concomitant TLR stimulation has been shown to be associated with a decrease in production of proinflammatory cytokines TNF-alpha and IL-6, as well as upregulation of IL-10 (Ando et al. (2008) Biochem. And Biophys. Res. Comm. 369:878-883). It has also been shown that tumor-produced mucins bind to Siglec-9, as well as immature DCs (Ohta et al. (2010) Biochem. and Biophys. Res. Comm. 402: 663-669). In the presence of LPS and mucins, immature DCs produced less IL-12, but IL-10 production was maintained. This suggests that Siglec-9 skews cytokine production from pro-inflammatory to anti-inflammatory, thereby maintaining an immunological state of tolerance as opposed to clearance of offending pathogens, cancer, or other pathologies.

[0009] The inhibitory role of Siglec-9 has been further characterized in the function of natural killer cells and regulation of lymphoid cells, such as T cells and neutrophils (Crocker et al., (2012) Ann. N Y Acad. Sci. 1253, 102-111; Pillai et al., (2012) Annu. Rev. Immunol. 30, 357-392; von Gunten and Bochner (2008) Ann. N Y Acad. Sci. 1143, 61-82; Jandus et al. (2014) J. Clin. Invest. 124(4) 1810-1820; Ikehara et al. (2004) J. Biol. Chem. 279:41 43117-43125; and von Gunten et al. (2005) Blood 106(4) 1423-1431). Functional studies in natural killer cells have demonstrated that tumor cells expressing Siglec-9 binding sialic acid ligands inhibit NK cell activation and tumor cell killing. Many human tumors robustly upregulate sialic acid ligands that bind Siglec-9, which enables immune evasion and cancer progression (Jandus et al. (2014) J. Clinic. Invest. 124:4: 1810-1820). It is thought that sialic acid upregulation on tumors facilitates a state of "super self" that strongly inhibits natural killer cell immunosurveillance (Macauley and Paulson (2014) Nat. Chem. Biol. 10:1:7-8). In lymphoid lineage cells, Siglec-9 has been shown to negatively regulate T cell receptor signaling via ITIM tyrosine phosphorylation and SHP-1 binding. Downstream TCR signaling molecules ZAP-70 showed reduced phosphorylation on Tyr 319< and decreased NFAT transcriptional activity. The inhibitory effects of Siglec-9 on TCR signaling were reduced upon mutation of a conserved Arg residue in the sialic acid ligand-binding domain (Ikehara et al. (2004) J. Biol. Chem. 279:41 43117-43125). In neutrophils, Siglec-9 engagement mediates cell death via apoptotic and non-apoptotic mechanisms. Neutrophils derived from non-diseased or rheumatoid arthritis and acute septic shock patients underwent Siglec-9 dependent death, demonstrated by antibody crosslinking. Septic or RA-patient-derived neutrophils demonstrated significantly more cell death upon Siglec-9 ligation; this increase could be mimicked by short term pre-incubation with pro-inflammatory cytokines, suggesting that inflammation leads to priming of the Siglec-9 death pathway (Belisle et al. (2010) Mol. Cancer 9:118).

[0010] The murine homolog of Siglec-9 is Siglec-E, which is 53% similar. Siglec-E was shown to bind human red blood cells in a sialic acid dependent manner, and functionally like Siglec-9, recruits SHP-1 and SHP-2 via ITIMs to mediate inhibitory signaling in immune cells (Yu et al Biochem. J. (2001) 353, 483-492). In mice, genetic inactivation of Siglec-E does not lead to obvious developmental, histological, or behavioral abnormalities; and Siglec-E-deficient mice breed normally, indicating that Siglec-E is not an essential gene and that its function may be limited to innate immunity (McMillan et al. (2013) Blood 121:11: 2084-2094). Upon challenge of Siglec-E deficient mice with aerosol LPS, increased neutrophil recruitment in the lung was demonstrated, which could be reversed by blockade of the β2-integrin CD11b. The Siglec-E deficient neutrophils were shown to have increased phosphorylation of Syk and p38 MAPK in a CD11b-dependent manner. This suggests that Siglec-E functions to suppress neutrophil recruitment in a model of acute lung inflammation (McMillan et al. (2013) Blood 121:11: 2084-2094). In a syngeneic cancer model, neutrophils from Siglec-E deficient mice enhanced tumor cell killing ex vivo and demonstrated increased ROS production and apoptosis inducing ligands such as TRAIL and FasL (Laubli et al (2014) PNAS 111 (39) 14211-14216).

[0011] In oncology, Siglec-9 has been suggested as a therapeutic target for acute myeloid leukemia as it is expressed on primary AML cells, yet absent from progenitors on numerous patient bone marrow samples (Biedermann et al. (2007) Leuk. Res. 31:2:211-220). In solid cancers, epithelial tumor cells produce heavily glycosylated mucins that bind Siglec-9, suggesting that blocking the increased ligand interactions would be therapeutically beneficial (Ohta et al. (2010) Biochem. and Biophys. Res. Comm. 402: 663-669; Belisle et al. (2010) Mol. Cancer 9:118). Furthermore, robust expression of Siglec-9 ligands and tumor infiltrating Siglec-9 +< immune cells were found in histological sections of colorectal, breast, ovarian, non-small lung cell, and prostate cancer (Laubli et al (2014) PNAS 111 (39) 14211-14216). A naturally occurring Siglec-9 K131Q (A391C) polymorphism (rs16988910) that reduces sialyl ligand binding was found to significantly improve early survival (<2 years) in non-small-cell lung cancer patients, though the effect was lost after 2 years (Laubli et al (2014) PNAS 111 (39) 14211-14216).

[0012] It has recently been proposed that sialylglycoproteins expressed on cancer cells transduce 'activation' signals into tumor cells via Siglec-9 binding, resulting in degradation of Focal adhesion kinase (FAK) and increased cell motility and invasion (Sabit et al. (2013) J. Biol. Chem. 288(49): 35417-35427). These results suggest that Siglec-9-sialyl ligand interactions not only contribute to inhibitory effects on numerous cell types of the immune system, but could also enhance tumor metastasis via direct effects on cancer cells.

[0013] Nguyen et al. (2006) Experimental Hematology 34(6): 728-735 describes expression of multiple CD33-related Siglecs on normal and malignant myelomonocytic cells and using individual anti-Siglec antibodies along with a saporin toxin-conjugated secondary antibody to target myelomonocytic leukemia cells for cell killing.

[0014] Antibodies to Siglec-9 have been described in, for example, WO2007049044, US8394382, EP1954318, and US20130302317. However, no antibodies that decrease the cellular levels of Siglec-9 or that disrupt the interactions between Siglec-9 and one or more of its ligands have been reported.

[0015] Accordingly, there is a need for therapeutic antibodies that specifically bind Siglec-9 and reduce Siglec-9 expression on the cell surface, reduce interactions between Siglec-9 and one or more Siglec-9 ligands, and / or reduce one or more Siglec-9 activities in order to treat one or more diseases, disorders, and conditions associated with undesired Siglec-9 activity.

[0016] The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).SUMMARY OF THE CLAIMED INVENTION

[0017] The claimed invention relates to an isolated anti-Siglec-9 antibody; wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, and the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 26.

[0018] The claimed invention also relates to an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-Siglec-9 antibody; a vector comprising the nucleic acid; an isolated host cell comprising the vector; a method of producing an anti-Siglec-9 antibody, comprising culturing the host cell so that the anti-Siglec-9 antibody is produced; and a pharmaceutical composition comprising the anti-Siglec-9 antibody, and a pharmaceutically acceptable carrier.

[0019] The claimed invention also relates to the anti-Siglec-9 antibody for use in a method of preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer; use of the anti-Siglec-9 antibody in an in vitro method of detecting a Siglec-9 protein in a tissue sample derived from an individual; and the anti-Siglec-9 antibody for use in a method of diagnosis comprising detecting a Siglec-9 protein in an individual.SUMMARY OF ASPECTS OF THE PRESENT DISCLOSURE

[0020] This section provides a summary of certain aspects of the present disclosure. The invention is as defined in the claims.

[0021] The present disclosure is generally directed to Siglec-9 agents, such as anti-Siglec-9 antibodies, and methods of using such Siglec-9 agents. The methods provided herein find use in preventing, reducing risk, or treating an individual having dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, sarcoidosis, diseases of aging, seizures, spinal cord injury, traumatic brain injury, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget's disease of bone, solid and blood cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, tumors that express Siglec-9 and / or Siglec-9 ligands, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, type I HIV, and Haemophilus influenza. The methods provided herein also find use in inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof. The methods provided herein find further use in decreasing the activity, functionality, or survival of regulatory T cells, tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, neutrophils, natural killer (NK) cells, myeloid-derived suppressor cells, tumor-associated macrophages, neutrophils, NK cells, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia (CML) cell in an individual in need thereof. The methods provided herein also find use in decreasing cellular levels of Siglec-9.

[0022] Certain aspects of the present disclosure are based, at least in part, on the identification of anti-Siglec-9 antibodies that are capable of decreasing cell surface levels of Siglec-9 on human primary immune cells and Siglec-9-expressing cell lines and / or that are capable of inhibiting the binding of Siglec-9 ligands to Siglec-9 (see, e.g., Examples 3-5).

[0023] Accordingly, certain aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody decreases cellular levels of Siglec-9. In some embodiments, the anti-Siglec-9 antibody decreases cellular levels of Siglec-9 without inhibiting interaction between Siglec-9 and one or more Siglec-9 ligands. In some embodiments, the antibody further inhibits interaction between Siglec-9 and one or more Siglec-9 ligands. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody decreases cellular levels of Siglec-9 and inhibits interaction between Siglec-9 and one or more Siglec-9 ligands.

[0024] In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody decreases cell surface levels of Siglec-9, decreases intracellular levels of Siglec-9, decreases total levels of Siglec-9, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody induces Siglec-9 degradation, Siglec-9 cleavage, Siglec-9 internalization, Siglec-9 shedding, downregulation of Siglec-9 expression, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibody decreases cellular levels of Siglec-9 in vivo. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody inhibits cell surface clustering of Siglec-9. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody inhibits one or more Siglec-9 activities. In some embodiments that may be combined with any of the preceding embodiments, the one or more Siglec-9 activities selected from the group consisting of: (a) Siglec-9 binding to one or more Siglec-9 ligands, optionally wherein the one or more Siglec-9 ligands are selected from the group consisting of sialic acid-containing glycoproteins, sialic acid-containing glycolipids, and any combination thereof; (b) Siglec-9 binding to SHP1 or SHP2; (c) phosphorylation of Tyr-433, Tyr-456, or both, induced by one or more SRC family tyrosine kinases, optionally, wherein the one or more SRC family tyrosine kinases are selected from the group consisting of Syk, LCK, FYM, and ZAP-70; (d) modulated expression of one or more pro-inflammatory cytokines, optionally wherein the one or more pro-inflammatory cytokines are selected from a group consisting FN-α4, IFN-beta, IL-1β, IL-1alpha, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-γ, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-33, MCP-1, and MIP-1-beta; (e) modulated expression of one or more pro-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; (f) modulated expression of one or more anti-inflammatory cytokines, optionally wherein the one or more anti-inflammatory cytokines are selected from the group consisting of IL-4, IL-10, IL-13, IL-35, IL-16, TGF-beta, IL-1Ra, G-CSF, and soluble receptors for TNF, IFN-beta1a, IFN-beta1b, or IL-6; (g) modulated expression of one or more anti-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; (h) modulate expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and PYCARD; (i) inhibition of extracellular signal-regulated kinase (ERK) phosphorylation; (j) decreasing tyrosine phosphorylation on one or more cellular proteins, optionally, wherein the one or more cellular proteins comprise ZAP-70 and the tyrosine phosphorylation occurs on Tyr-319 of ZAP-70; (k) modulated expression of C-C chemokine receptor 7 (CCR7); (l) inhibition of microglial cell chemotaxis toward CCL19-expressing and CCL21-expressing cells; (m) decreasing T cell proliferation induced by one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, and M2 NK cells; (n) inhibition of osteoclast production, decreased rate of osteoclastogenesis, or both; (o) decreasing survival of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (p) decreasing proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (q) inhibiting migration of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (r) inhibiting one or more functions of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (s) inhibiting maturation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (t) inhibition of one or more types of clearance selected from the group consisting of apoptotic neuron clearance, nerve tissue debris clearance, dysfunctional synapse clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, and tumor cell clearance; optionally wherein the disease-causing protein is selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides and the tumor cell is from a cancer selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer; (u) inhibition of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, dysfunctional synapses, non-nerve tissue debris, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, or tumor cells; optionally wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and the tumor cells are from a cancer selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer; (v) binding to Siglec-9 ligand on tumor cells; (w) binding to Siglec-9 ligand on cells selected from the group consisting of neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, and NK cells; (x) inhibition of tumor cell killing by one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (y) inhibiting anti-tumor cell proliferation activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (z) inhibition of anti-tumor cell metastasis activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (aa) inhibition of one or more ITAM motif containing receptors, optionally wherein the one or more ITAM motif containing receptors are selected from the group consisting of TREM1, TREM2, Sirp beta, FcgR, DAP10, and DAP12; (bb) inhibition of signaling by one or more pattern recognition receptors (PRRs), optionally wherein the one or more PRRs are selected from the group consisting of receptors that identify pathogen-associated molecular patterns (PAMPs), receptors that identify damage-associated molecular patterns (DAMPs), and any combination thereof; (cc) inhibition of one or more receptors comprising the motif D / Ex 0-2 YxxL / IX 6-8 YxxL / I (SEQ ID NO: 252); (dd) inhibition of signaling by one or more Toll-like receptors; (ee) inhibition of the JAK-STAT signaling pathway; (ff) inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB); (gg) de-phosphorylation of an ITAM motif containing receptor; (hh) modulated expression of one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells, optionally wherein the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells comprise CD86, C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and / or PYCARD, and the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells are expressed on one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (ii) increasing expression of one or more Siglec-9-dependent genes; (jj) normalization of disrupted Siglec-9-dependent gene expression; (kk) decreasing expression of one or more ITAM-dependent genes, optionally wherein the one more ITAM-dependent genes are activated by nuclear factor of activated T cells (NFAT) transcription factors; (ll) promoting differentiation of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells; (mm) promoting or rescuing functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells; (nn) increasing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells into tumors; (oo) increasing the number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; (pp) enhancing tumor-promoting activity of myeloid-derived suppressor cells; (qq) increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10; (rr) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (ss) enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC); (tt) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (uu) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (vv) decreasing the tumor killing potential of NK cells; (ww) decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; (xx) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; (yy) increasing tumor volume; (zz) increasing tumor growth rate; (aaa) increasing metastasis; (bbb) increasing rate of tumor recurrence; (ccc) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from the group consisting of PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, DR-5, TREM1, TREM2, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines; (ddd) inhibition of PLCy / PKC / calcium mobilization; and (eee) inhibition of PI3K / Akt, Ras / MAPK signaling. In some embodiments that may be combined with any of the preceding embodiments, the one or more Siglec-9 activities are selected from the group consisting of: (a) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, myeloid derived suppressor cells, tumor-associated macrophages, immunosuppressor neutrophils, non-tumorigenic CD45 +< CD14 +< myeloid cells, and regulatory T cells into tumors; (b) increasing number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; (r) enhancing tumor-promoting activity of non-tumorigenic myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (c) enhancing survival of non-tumorigenic myeloid-derived suppressor cells (MDSC) and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (d) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (e) decreasing activation of CD45 +< CD3 +< T lymphocytes with tumor killing potential; (f) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (g) decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; (h) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; and (i) decreasing infiltration of CD45 +< CD3 +< T lymphocytes. In some embodiments that may be combined with any of the preceding embodiments, the one or more Siglec-9 activities selected from the group consisting of: (a) Siglec-9 binding to one or more Siglec-9 ligands, optionally wherein the one or more Siglec-9 ligands are selected from the group consisting of sialic acid-containing glycoproteins, sialic acid-containing glycolipids, and any combination thereof; (b) decreasing proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (c) inhibiting migration of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (d) inhibiting one or more functions of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (e) inhibition of one or more types of clearance selected from the group consisting of apoptotic neuron clearance, nerve tissue debris clearance, dysfunctional synapse clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, and tumor cell clearance; optionally wherein the disease-causing protein is selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides and the tumor cell is from a cancer selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer; (f) inhibition of tumor cell killing by one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (g) inhibiting anti-tumor cell proliferation activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (h) modulating expression of one or more inflammatory receptors, optionally wherein the one or more inflammatory receptors comprise CD86 and the one or more inflammatory receptors are expressed on one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (i) promoting or rescuing functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells; (j) increasing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, non-tumorigenic CD45 +< CD14 +< myeloid cells, and regulatory T cells into tumors; (k) increasing the number of tumor-promoting myeloid / granulocytic immune-suppressive cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells in a tumor, in peripheral blood, or other lymphoid organ; (l) enhancing tumor-promoting activity of myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (m) enhancing survival of non-tumorigenic myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (n) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (o) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (p) increasing tumor volume; (q) increasing tumor growth rate; and (r) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from the group consisting of PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, TREM1, TREM2, CD39, CD73, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody exhibits one or more activities selected from the group consisting of consisting of: (a) increasing the number of tumor infiltrating CD3 +< T cells; (b) decreasing cellular levels of CD33 in non-tumorigenic CD14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (c) reducing the number of non-tumorigenic CD14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (d) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (e) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (f) reducing B7-H2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (g) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (h) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (i) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (j) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (k) decreasing tumor growth rate of solid tumors; (l) reducing tumor volume; (m) increasing efficacy of one or more PD-1 inhibitors; (n) increasing efficacy of one or more checkpoint inhibitor therapies and / or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and / or immune-modulating therapies target one or more of CTLA4, the adenosine pathway, PD-L1, PD-L2, OX40, TIM3, LAG3, or any combination thereof; (o) increasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof; (p) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC); (q) inhibiting differentiation, survival, and / or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (r) killing CD33-expressing immunosuppressor non-tumorigenic myeloid cells and / or non-tumorigenic CD14-expressing cells in solid tumors and associated blood vessels when conjugated to a chemical or radioactive toxin. In some embodiments that may be combined with any of the preceding embodiments, the one or more Siglec-9 ligands are selected from the group consisting of Siglec-9 ligands expressed on red blood cells, Siglec-9 ligands expressed on bacterial cells, Siglec-9 ligands expressed on apoptotic cells, Siglec-9 ligands expressed on nerve cells, Siglec-9 ligands expressed on glia cells, Siglec-9 ligands expressed on microglia, Siglec-9 ligands expressed on astrocytes, Siglec-9 ligands expressed on tumor cells, Siglec-9 ligands expressed on viruses, Siglec-9 ligands expressed on dendritic cells, Siglec-9 ligands bound to beta amyloid plaques, Siglec-9 ligands bound to Tau tangles, Siglec-9 ligands on disease-causing proteins, Siglec-9 ligands on disease-causing peptides, Siglec-9 ligands expressed on macrophages, Siglec-9 ligands expressed on neutrophils, Siglec-9 ligands expressed on natural killer cells, Siglec-9 ligands expressed on monocytes, Siglec-9 ligands expressed on T cells, Siglec-9 ligands expressed on T helper cells, Siglec-9 ligands expressed on cytotoxic T cells, Siglec-9 ligands expressed on B cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor dendritic cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor macrophages, Siglec-9 ligands expressed on myeloid-derived suppressor cells, Siglec-9 ligands expressed on regulatory T cells, secreted mucins, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,8-disialyl containing glycolipids, branched alpha-2,6-linked sialic acid-containing glycoproteins, terminal alpha-2,6-linked sialic acid-containing glycolipids, terminal alpha-2,3-linked sialic acid-containing glycoproteins, and disialogangliosides. In some embodiments that may be combined with any of the preceding embodiments, the cellular levels of Siglec-9 are measured on primary cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, and NK cells, or on cell lines, and wherein the cellular levels of Siglec-9 are measured utilizing an in vitro cell assay. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody does not reduce TREM2 expression. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody exhibits one or more activities selected from the group consisting of consisting of: (a) increasing the number of tumor infiltrating CD3 +< T cells; (b) decreasing cellular levels of Siglec-9 in non-tumorigenic CD14+ myeloid cells, optionally wherein the non-tumorigenic CD14+ myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14+ myeloid cells are present in blood; (c) reducing the number of non-tumorigenic CD14+ myeloid cells, optionally wherein the non-tumorigenic CD14+ myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14+ myeloid cells are present in blood; (d) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (e) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (f) reducing B7-H2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (g) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (h) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (i) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (j) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (k) decreasing tumor growth rate of solid tumors; (l) reducing tumor volume; (m) increasing efficacy of one or more PD-1 inhibitors; (n) increasing efficacy of one or more checkpoint inhibitor therapies and / or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and / or immune-modulating therapies target one or more of CTLA4, the adenosine pathway, PD-L1, PD-L2, PD-L1, PD-L2, OX40, TIM3, LAG3, or any combination thereof; (o) increasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof; (p) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC); (q) inhibiting differentiation, survival, and / or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (r) killing Siglec-9-expressing immunosuppressor non-tumorigenic myeloid cells and / or non-tumorigenic CD14-expressing cells in solid tumors and associated blood vessels when conjugated to a chemical or radioactive toxin.

[0025] In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds a discontinuous Siglec-9 epitope. In some embodiments that may be combined with any of the preceding embodiments, the discontinuous Siglec-9 epitope comprises two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or 10 or more peptides. In some embodiments that may be combined with any of the preceding embodiments, each of the peptides comprise five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues of the amino acid sequence of SEQ ID NO: 1; or five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues on a mammalian Siglec-9 protein corresponding to the amino acid sequence of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to a conformational epitope of Siglec-9. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 20-347, 20-140, 141-347, 146-347, 146-229, 236-336, or 146-347 of SEQ ID NO: 1; or within amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 20-347, 20-140, 141-347, 146-347, 146-229, 236-336, or 146-347 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues selected from the group consisting of: i. amino acid residues 62-76 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 of SEQ ID NO: 1; ii. amino acid residues 62-76 and 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 and 86-92 of SEQ ID NO: 1; iii. amino acid residues 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-92 of SEQ ID NO: 1; iv. amino acid residues 86-96 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 of SEQ ID NO: 1; v. amino acid residues 86-96 and 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 and 105-116 of SEQ ID NO: 1; vi. amino acid residues 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 105-116 of SEQ ID NO: 1; vii. amino acid residues 107-115 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 107-115 of SEQ ID NO: 1; and viii. amino acid residues 185-194 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 185-194 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 and 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 and 86-92 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-92 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 and 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 and 105-116 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 105-116 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 107-115 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 107-115 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 185-194 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 185-194 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds to one or more amino acid residues selected from the group consisting of L22, H48, W50, I51, Y52, K123, I126, D189, P190, R194 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian Siglec-7 protein corresponding to an amino acid residue selected from the group consisting of L22, H48, W50, I51, Y52, K123, I126, D189, P190, R194 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody competes with one or more antibodies selected from the group consisting of 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, 17C2, and any combination thereof for binding to Siglec-9.

[0026] In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain, the heavy chain variable domain, or both comprise at least one, two, three, four, five, or six HVRs selected from HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3 of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2. In some embodiments that may be combined with any of the preceding embodiments: (a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173; or (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175; or (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177; or (d) the HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179; or (e) the HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181; or (f) the HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183. In some embodiments that may be combined with any of the preceding embodiments: (a) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 6, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 10, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 14, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 19, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 22, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 26; or (b) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 7, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 11, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 15, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 20, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 23, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 27; or (c) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 8, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 12, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 16, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 24, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 28; or (d) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 13, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 17, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 25, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 29; or (e) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 8, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 12, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 18, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 24, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 28; or (f) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 172, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 174, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 176, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 178, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 180, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 182; or (g) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 173, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 175, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 177, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 179, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 181, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 183. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 17, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 18, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 174, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 176, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 178, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 180, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 173, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 175, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177, and wherein the heavy chain variable region comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 179, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 181, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177; and wherein the heavy chain variable domain comprises: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-115 and 197-204; and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-170 and 205-212. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein: (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 61; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 116; or (b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 72; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 127; or (c) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 83; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 138; or (d) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 94; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 149; or (e) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 105; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 160; or (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 197; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 205; or (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 201; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 210. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2; and / or a heavy chain variable domain of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2.

[0027] Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 20-347, 20-140, 141-347, 146-347, 146-229, 236-336, or 146-347 of SEQ ID NO: 1; or within amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 20-347, 20-140, 141-347, 146-347, 146-229, 236-336, or 146-347 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues selected from the group consisting of: i. amino acid residues 62-76 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 of SEQ ID NO: 1; ii. amino acid residues 62-76 and 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 and 86-92 of SEQ ID NO: 1; iii. amino acid residues 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-92 of SEQ ID NO: 1; iv. amino acid residues 86-96 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 of SEQ ID NO: 1; v. amino acid residues 86-96 and 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 and 105-116 of SEQ ID NO: 1; vi. amino acid residues 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 105-116 of SEQ ID NO: 1; vii. amino acid residues 107-115 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 107-115 of SEQ ID NO: 1; and viii. amino acid residues 185-194 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 185-194 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 and 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 and 86-92 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-92 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 and 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 and 105-116 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 105-116 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 107-115 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 107-115 of SEQ ID NO: 1. In some embodiments, the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 185-194 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 185-194 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acid residues selected from the group consisting of L22, H48, W50, I51, Y52, K123, I126, D189, P190, R194 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian Siglec-7 protein corresponding to an amino acid residue selected from the group consisting of L22, H48, W50, I51, Y52, K123, I126, D189, P190, R194 of SEQ ID NO: 1.

[0028] Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 62-76 and 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 62-76 and 86-92 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-92 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-92 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 86-96 and 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 86-96 and 105-116 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 105-116 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 105-116 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 107-115 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 107-115 of SEQ ID NO: 1. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody binds to one or more amino acids within amino acid residues 185-194 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-9 protein corresponding to amino acid residues 185-194 of SEQ ID NO: 1.

[0029] Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain, the heavy chain variable domain, or both comprise at least one, two, three, four, five, or six HVRs selected from HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3 of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2. In some embodiments: (a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173; or (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175; or (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177; or (d) the HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179; or (e) the HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181; or (f) the HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183. In some embodiments: (a) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 6, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 10, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 14, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 19, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 22, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 26; or (b) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 7, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 11, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 15, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 20, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 23, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 27; or (c) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 8, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 12, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 16, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 24, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 28; or (d) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 13, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 17, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 25, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 29; or (e) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 8, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 12, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 18, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 21, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 24, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 28; or (f) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 172, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 174, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 176, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 178, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 180, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 182; or (g) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 173, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 175, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 177, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 179, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 181, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 183. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 17, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 18, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 174, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 176, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 178, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 180, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182. In some embodiments, the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 173, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 175, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 179, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 181, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183. In some embodiments, the light chain variable domain comprises: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177; and wherein the heavy chain variable domain comprises: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183.

[0030] Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 26. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 27. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 13, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 17, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 25, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 29. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 18, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 174, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 176, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 178, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 180, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 182. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 173, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 175, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 179, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 181, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 61-115 and 197-204 and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-170 and 205-212. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, and wherein: (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 61; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 116; or (b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 72; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 127; or (c) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 83; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 138; or (d) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 94; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 149; or (e) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 105; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 160; or (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 197; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 205; or (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 201; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 210. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2; and / or a heavy chain variable domain of a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody competes with one or more antibodies selected from the group consisting of 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, 17C2, and any combination thereof for binding to Siglec-9. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody which binds essentially the same Siglec-9 epitope as a monoclonal antibody selected from the group consisting of: 2D4, 2D5, 5B1, 6B2, 6D8, 7H12, 5C6, 12B12, and 17C2. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-Siglec-9 antibody, wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6-9, 172, and 173; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-13, 174, and 175; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 14-18, 176, and 177; and wherein the heavy chain variable domain comprises: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 178, and 179; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-25, 180, and 181; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-29, 182, and 183.

[0031] In some embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class the IgM class, or the IgA class. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds an inhibitory Fc receptor. In some embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments that may be combined with any of the preceding embodiments: (a) the anti-Siglec-9 antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, T394D, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236; (b) the anti-Siglec-9 antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 171), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and / or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU numbering; (c) the anti-Siglec-9 antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; (d) the anti-Siglec-9 antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, E233P, F234V, L234A / F234A, S228P, S241P, L248E, T394D, N297A, N297Q, L235E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or (e) the anti-Siglec-9 antibody has a hybrid IgG2 / 4 isotype, and optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU or, Kabat numbering. In some embodiments that may be combined with any of the preceding embodiments: (a) the anti-Siglec-9 antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, D270A, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; (b) the anti-Siglec-9 antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: P238S , V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or (c) the anti-Siglec-9 antibody has an IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: E233P, F234V, L234A / F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering. In some embodiments that may be combined with any of the preceding embodiments: (a) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; (b) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T,T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or (c) the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype. n some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody comprises an S228P amino acid substitution at residue position 228, an F234A amino acid substitution at residue position 234, and an L235A amino acid substitution at residue position 235, wherein the numbering of the residue position is according to EU or Kabat numbering. In some embodiments that may be combined with any of the preceding embodiments, the Siglec-9 protein is a mammalian protein or a human protein. In some embodiments that may be combined with any of the preceding embodiments, the Siglec-9 protein is a wild-type protein. In some embodiments that may be combined with any of the preceding embodiments, the Siglec-9 protein is a naturally occurring variant. In some embodiments that may be combined with any of the preceding embodiments, the Siglec-9 protein is expressed on one or more cells selected from the group consisting of human dendritic cells, human macrophages, human neutrophils, human NK cells, human monocytes, human osteoclasts, human T cells, human T helper cell, human cytotoxic T cells, human granulocytes, and human microglia. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds specifically to a mammalian Siglec-9 protein, human Siglec-9 protein, or both. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds Siglec-9 in a pH dependent manner. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody binds Siglec-9 at a pH that ranges from 5.5 to 8.0. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody dissociates from Siglec-9 at a pH of less than 5.0. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Siglec-9 or a mammalian Siglec-9 protein. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human Siglec-9, a naturally occurring variant of human Siglec-9, and a disease variant of human Siglec-9. In some embodiments that may be combined with any of the preceding embodiments, the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human Siglec-9, a naturally occurring variant of human Siglec-9, and a disease variant of human Siglec-9. In some embodiments that may be combined with any of the preceding embodiments, the fragment is an Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is a murine antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is a bispecific antibody recognizing a first antigen and a second antigen. In some embodiments that may be combined with any of the preceding embodiments, the first antigen is Siglec-9 and the second antigen is: (a) an antigen facilitating transport across the blood-brain-barrier; (b) an antigen facilitating transport across the blood-brain-barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopep peptide, and ANG1005; (c) a disease-causing agent selected from the group consisting of disease-causing peptides or proteins or, disease-causing nucleic acids, wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides; (d) ligands and / or proteins expressed on immune cells, wherein the ligands and / or proteins selected from the group consisting of PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, CD39, CD73, and phosphatidylserine; and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is a conjugated antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is conjugated to a detectable marker, a toxin, or a therapeutic agent. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is conjugated to a toxin selected from the group consisting of ricin, ricin A-chain, doxorubicin, daunorubicin, a maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Saponaria officinalis inhibitor, glucocorticoid, auristatin, auromycin, yttrium, bismuth, combrestatin, duocarmycins, dolastatin, cc1065, and a cisplatin. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is used in combination with one or more antibodies that specifically bind a disease-causing protein selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and any combination thereof; or with one or more antibodies that bind an immunomodulatory protein selected from the group consisting of: PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, CD39, CD73, TREM1, TREM2, CD33, Siglec-5, Siglec-7, Siglec-11, phosphatidylserine, disease-causing nucleic acids, antisense GGCCCC (G2C4) repeat-expansion RNA, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody has dissociation constant (K D ) for human Siglec-9 and mammalian Siglec-9 that ranges from about 10 nM to about 10 pM, or less than 10 pM, wherein the K D is determined at a temperature of approximately 25°C. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody has dissociation constant (K D ) for human Siglec-9 that ranges from about 9 nM to about 300 pM, or less than 300 pM, wherein the K D is determined at a temperature of approximately 25°C. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody has dissociation constant (K D ) for human Siglec-9 that ranges from about 9 nM to about 230 pM, or less than 230 pM, wherein the K D is determined at a temperature of approximately 25°C.

[0032] Other aspects of the present disclosure relate to an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-Siglec-9 antibody of any of the preceding embodiments. Other aspects of the present disclosure relate to a vector comprising the nucleic acid of any of the preceding embodiments. Other aspects of the present disclosure relate to an isolated host cell comprising the vector of any of the preceding embodiments. Other aspects of the present disclosure relate to a method of producing an anti-Siglec-9 antibody, comprising culturing the host cell of any of the preceding embodiments so that the anti-Siglec-9 antibody is produced. In some embodiments, the method further comprises recovering the anti-Siglec-9 antibody produced by the host cell. Other aspects of the present disclosure relate to an isolated anti-Siglec-9 antibody produced by the method of any of the preceding embodiments. Other aspects of the present disclosure relate to a pharmaceutical composition comprising the anti-Siglec-9 antibody of any of the preceding embodiments, and a pharmaceutically acceptable carrier.

[0033] Other aspects of the present disclosure relate to a method of preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, sarcoidosis, diseases of aging, seizures, spinal cord injury, traumatic brain injury, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget's disease of bone, and cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, tumors that express Siglec-9, tumors that express one or more Siglec-9 ligands, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, type I HIV, and Haemophilus influenza, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both. Other aspects of the present disclosure relate to an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both for use in preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, sarcoidosis, diseases of aging, seizures, spinal cord injury, traumatic brain injury, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget's disease of bone, and cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, tumors that express Siglec-9, tumors that express one or more Siglec-9 ligands, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, type I HIV, and Haemophilus influenza. Other aspects of the present disclosure relate to use of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both in the manufacture of a medicament for preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, acute disseminated encephalomyelitis, granulomartous disorders, sarcoidosis, diseases of aging, seizures, spinal cord injury, traumatic brain injury, age related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget's disease of bone, and cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, tumors that express Siglec-9, tumors that express one or more Siglec-9 ligands, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, type I HIV, and Haemophilus influenza. Other aspects of the present disclosure relate to a method of preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both. Other aspects of the present disclosure relate to an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both for use in preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer. Other aspects of the present disclosure relate to use of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both in the manufacture of a medicament for preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer. In some embodiments the disease, disorder, or injury is cancer, and wherein the agent inhibits one or more Siglec-9 activities selected from the group consisting of: (a) promoting proliferation, maturation, migration, differentiation, and / or functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid derived suppressor cells, tumor-associated macrophages, tumor-associated suppressor neutrophils, tumor-associated suppressor NK cells, and regulatory T cells; (b) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid derived suppressor cells, tumor-associated macrophages, tumor-associated suppressor neutrophils, tumor-associated suppressor NK cells, and regulatory T cells into tumors; (c) increasing number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; (d) enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC); (e) increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10; (f) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (g) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (h) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; (i) increasing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, non-tumorigenic CD45 +< CD14 +< myeloid cells, and regulatory T cells into tumors; (j) increasing the number of tumor-promoting myeloid / granulocytic immune-suppressive cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells in a tumor, in peripheral blood, or other lymphoid organ; (k) enhancing tumor-promoting activity of myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (l) enhancing survival of non-tumorigenic myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; (m) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (n) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (o) increasing tumor volume; (p) increasing tumor growth rate; (q) increasing metastasis; (r) increasing rate of tumor recurrence; (s) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from the group consisting of PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, CD39, CD73, and any combination thereof, or one or more cancer vaccines; (t) inhibition of PLCy / PKC / calcium mobilization; and (u) inhibition of PI3K / Akt, Ras / MAPK signaling. In some embodiments, the cancer expresses Siglec-9 or one or more Siglec-9 ligands. In some embodiments that may be combined with any of the preceding embodiments, the disease, disorder, or injury is cancer, and the agent inhibits one or more Siglec-9 activities selected from the group consisting of: (a) promoting proliferation, maturation, migration, differentiation, and / or functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, non-tumorigenic myeloid derived suppressor cells, tumor-associated macrophages, , non-tumorigenic CD14 +< myeloid cells, and regulatory T cells; (b) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, non-tumorigenic myeloid derived suppressor cells, tumor-associated macrophages, and regulatory T cells into tumors; (c) increasing number of tumor-promoting myeloid / granulocytic immune-suppressive cells and / or non-tumorigenic CD14 +< myeloid cells in a tumor, in peripheral blood, or other lymphoid organ; (d) enhancing tumor-promoting activity of non-tumorigenic myeloid-derived suppressor cells and / or non-tumorigenic CD14 +< myeloid cells; (e) increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10; (f) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (g) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (h) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; (i) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (j) decreasing tumor killing potential of NK cells; (k) decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; (l) increasing tumor volume; (m) increasing tumor growth rate; (n) increasing metastasis; (o) increasing rate of tumor recurrence; (p) increasing expression of one or more PD-1 ligands; (q) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more proteins selected from the group consisting of CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, DR-5, TREM1, TREM2, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines; (r) inhibition of PLCy / PKC / calcium mobilization; (s) inhibition of PI3K / Akt, Ras / MAPK signaling; and (t) decreasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the disease, disorder, or injury is cancer, and the agent exhibits one or more activities selected from the group consisting of consisting of: (a) increasing the number of tumor infiltrating CD3 +< T cells; (b) decreasing cellular levels of Siglec-9 in non-tumorigenic CD 14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (c) reducing the number of non-tumorigenic CD14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (d) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (e) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (f) reducing B7-H2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (g) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (h) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (i) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (j) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (k) decreasing tumor growth rate of solid tumors; (l) reducing tumor volume; (m) increasing efficacy of one or more PD-1 inhibitors; (n) increasing efficacy of one or more checkpoint inhibitor therapies and / or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and / or immune-modulating therapies target one or more of CTLA4, the adenosine pathway, PD-L1, PD-L2, OX40, TIM3, LAG3, or any combination thereof; (o) increasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof; (p) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (q) inhibiting differentiation, survival, and / or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (r) killing Siglec-9-expressing immunosuppressor myeloid cells and / or CD 14-expressing cells in solid tumors and associated blood vessels when conjugated to a chemical or radioactive toxin. In some embodiments that may be combined with any of the preceding embodiments, the agent exhibits one or more activities selected from the group consisting of consisting of: (a) increasing the number of tumor infiltrating CD3 +< T cells; (b) decreasing cellular levels of CD33 in non-tumorigenic CD14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (c) reducing the number of non-tumorigenic CD14 +< myeloid cells, optionally wherein the non-tumorigenic CD14 +< myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +< myeloid cells are present in blood; (d) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (e) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (f) reducing B7-H2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (g) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (h) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (i) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (j) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (k) decreasing tumor growth rate of solid tumors; (l) reducing tumor volume; (m) increasing efficacy of one or more PD-1 inhibitors; (n) increasing efficacy of one or more checkpoint inhibitor therapies and / or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and / or immune-modulating therapies target one or more of CTLA4, the adenosine pathway, PD-L1, PD-L2, OX40, TIM3, LAG3, or any combination thereof; (o) increasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof; (p) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (q) inhibiting differentiation, survival, and / or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (r) killing CD33-expressing immunosuppressor myeloid cells and / or CD14-expressing cells in solid tumors and associated blood vessels when conjugated to a chemical or radioactive toxin. In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and multiple myeloma. In some embodiments, the agent is selected from the group consisting of an antibody, a soluble Siglec-9 receptor, a Siglec-9-Fc fusion protein, a Siglec-9 immunoadhesin, an antisense molecule, an siRNA, a small molecule inhibitor, a protein, and a peptide. In some embodiments, the agent is an isolated anti-Siglec-9 antibody. In some embodiments, the anti-Siglec-9 antibody is the anti-Siglec-9 antibody of any of the preceding embodiments. In some embodiments, the one or more immune cells are selected from the group consisting of dendritic cells, macrophages, neutrophils, NK cells, microglia, T cells, T helper cells, cytotoxic T cells, and any combination thereof.

[0034] Other aspects of the present disclosure relate to a method of inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both. Other aspects of the present disclosure relate to an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both for use in inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof. Other aspects of the present disclosure relate to use of an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both in the manufacture of a medicament for inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof. In some embodiments the one or more immune cells are selected from the group consisting of dendritic cells, macrophages, neutrophils, NK cells, microglia, T cells, T helper cells, cytotoxic T cells, and any combination thereof. In some embodiments, the agent is selected from the group consisting of an antibody, a soluble Siglec-9 receptor, a Siglec-9-Fc fusion protein, a Siglec-9 immunoadhesin, an antisense molecule, an siRNA, a small molecule inhibitor, a protein, and a peptide. In some embodiments, the agent is an isolated anti-Siglec-9 antibody. In some embodiments, the anti-Siglec-9 antibody is the anti-Siglec-9 antibody of any of the preceding embodiments. In some embodiments, the one or more immune cells are selected from the group consisting of dendritic cells, macrophages, neutrophils, NK cells, microglia, T cells, T helper cells, cytotoxic T cells, and any combination thereof.

[0035] Other aspects of the present disclosure relate a method of decreasing the activity, functionality, or survival of regulatory T cells, tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia (CML) cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that binds or interacts with Siglec-9. Other aspects of the present disclosure relate to use of an agent that binds or interacts with Siglec-9 for use in decreasing the activity, functionality, or survival of regulatory T cells, tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia (CML) cells in an individual in need thereof. Other aspects of the present disclosure relate to use of an agent that binds or interacts with Siglec-9 in the manufacture of a medicament for decreasing the activity, functionality, or survival of regulatory T cells, tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia (CML) cells in an individual in need thereof. In some embodiments, the agent is an isolated anti-Siglec-9 antibody or anti-Siglec-9 antibody conjugate. In some embodiments, the anti-Siglec-9 antibody is the anti-Siglec-9 antibody of any of the preceding embodiments.

[0036] Other aspects of the present disclosure relate a method of decreasing cellular levels of Siglec-9 on one or more cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated anti-Siglec-9 antibody. Other aspects of the present disclosure relate to use of an isolated anti-Siglec-9 antibody for use in decreasing cellular levels of Siglec-9 on one or more cells in an individual in need thereof. Other aspects of the present disclosure relate to use of an isolated anti-Siglec-9 antibody in the manufacture of a medicament for decreasing cellular levels of Siglec-9 on one or more cells in an individual in need thereof. In some embodiments, the anti-Siglec-9 antibody decreases cellular levels of Siglec-9 in vivo. In some embodiments, the anti-Siglec-9 antibody is the anti-Siglec-9 antibody of any of the preceding embodiments.

[0037] In some embodiments that may be combined with any of the preceding embodiments, the method further comprising administering to the individual at least one antibody that specifically binds to an inhibitory checkpoint molecule, and / or one or more standard or investigational anti-cancer therapies. In some embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with the anti-Siglec-9 antibody. In some embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory checkpoint molecule is selected from the group consisting of an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, and anti-HVEM antibody, an anti- B- and T-lymphocyte attenuator (BTLA) antibody, an anti-Killer inhibitory receptor (KIR) antibody, an anti-GAL9 antibody, an anti-TIM-1 antibody, an anti-TIM3 antibody, an anti-TIM-4 antibody, an anti-A2AR antibody, an anti-CD39 antibody, an anti-CD73 antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, an anti-CD30 antibody, an anti-TNFa antibody, an anti-CD33 antibody, an anti-Siglec-5 antibody, an anti-Siglec-7 antibody, an anti-Siglec-11 antibody, an antagonistic anti-TREM1 antibody, an antagonistic anti-TREM2 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, an anti-CD2 antibody, an anti-CD5 antibody, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the one or more standard or investigational anti-cancer therapies are selected from the group consisting of radiotherapy, cytotoxic chemotherapy, targeted therapy, imatinib therapy, trastuzumab therapy, etanercept therapy, adoptive cell transfer (ACT) therapy, chimeric antigen receptor T cell transfer (CAR-T) therapy, vaccine therapy, and cytokine therapy. In some embodiments that may be combined with any of the preceding embodiments, the method further comprising administering to the individual at least one antibody that specifically binds to an inhibitory cytokine. In some embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with the anti-Siglec-9 antibody. In some embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory cytokine is selected from the group consisting of an anti-CCL2 antibody, an anti-CSF-1 antibody, an anti-IL-2 antibody, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the method further comprising administering to the individual at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein. In some embodiments that may be combined with any of the preceding embodiments, the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with the anti-Siglec-9 antibody. In some embodiments that may be combined with any of the preceding embodiments, the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is selected from the group consisting of an agonist anti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOS antibody, an agonist anti-CD28 antibody, an agonistic anti-TREM1 antibody, an agonistic anti-TREM2 antibody, an agonist anti-CD137 / 4-1BB antibody, an agonist anti-CD27 antibody, an agonist anti-glucocorticoid-induced TNFR-related protein GITR antibody, an agonist anti-CD30 antibody, an agonist anti-BTLA antibody, an agonist anti-HVEM antibody, an agonist anti-CD2 antibody, an agonist anti-CD5 antibody, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the method further comprising administering to the individual at least one stimulatory cytokine. In some embodiments that may be combined with any of the preceding embodiments, the at least one stimulatory cytokine is administered in combination with the anti-Siglec-9 antibody. In some embodiments that may be combined with any of the preceding embodiments, the at least one stimulatory cytokine is selected from the group consisting of IFN-α4, IFN-β, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-γ, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, IL-33, MCP-1, MIP-1-beta, and any combination thereof.

[0038] Other aspects of the present disclosure relate to a method of assessing responsiveness of a subject in need thereof to an agent that binds or interacts with Siglec-9, the method comprising: a. measuring the expression levels of CD45 +< and CD14 +< on non-tumorigenic myeloid cells in a blood sample obtained from the subject prior to administering to the subject an anti-Siglec-9 antibody; b. administering to the subject a therapeutically effective amount of the agent; and c. measuring the expression levels of CD45 +< and CD14 +< on non-tumorigenic myeloid cells in a blood sample obtained from the subject after administration of the anti-Siglec-9 antibody, wherein a reduction in the levels of CD45 +< CD14 +< on non-tumorigenic myeloid cells after administration of the anti-Siglec-9 antibody indicates the subject is responsive to the agent. In some embodiments, the method of assessing responsiveness further comprises administering one or more additional therapeutically effective amounts of the agent. In some embodiments that may be combined with any of the preceding embodiments, the agent is selected from the group consisting of an antibody, a soluble Siglec-9 receptor, a Siglec-9-Fc fusion protein, a Siglec-9 immunoadhesin, a soluble Siglec receptor, a Siglec-Fc fusion protein, a Siglec immunoadhesin, an antisense molecule, an siRNA, a small molecule inhibitor, a protein, and a peptide. In some embodiments that may be combined with any of the preceding embodiments, the agent is an isolated anti-Siglec-9 antibody or anti-Siglec-9 antibody conjugate. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is the anti-Siglec-9 antibody of any of the preceding embodiments.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1A depicts an amino acid sequence alignment between human Siglec-9 (SEQ ID NO: 1), chimpanzee Siglec-9 (SEQ ID NO: 2), green monkey Siglec-9 (SEQ ID NO: 3), rhesus macaque Siglec-9 (SEQ ID NO: 4), and mouse Siglec-9 (SEQ ID NO: 5). An asterisk ("*") indicates positions which have a single, fully conserved residue; A colon (":") indicates conservation between groups of strongly similar properties - scoring > 0.5 in the Gonnet PAM 250 matrix; and a period (".") indicates conservation between groups of weakly similar properties - scoring =< 0.5 in the Gonnet PAM 250 matrix. FIG. 1B depicts binding reactivity in percentage to wild-type Siglec-9 (% WT) of antibodies of the present disclosure to the indicated Siglec-9 mutants. FIG. 1C depicts a Phyre2-derived model of Siglec-9 (based on the crystal structure of Siglec-5; PDB ID 2ZG2) indicating amino acid residues involved in binding of anti-Siglec-9 antibody 2D4. Critical residues for binding are indicated with red spheres. FIG. 1D depicts a Phyre2-derived model of Siglec-9 (based on the crystal structure of Siglec-5; PDB ID 2ZG2) indicating amino acid residues involved in binding of anti-Siglec-9 antibody 5C6. Critical residues for binding are indicated with red spheres. FIG. 1E depicts a Phyre2-derived model of Siglec-9 (based on the crystal structure of Siglec-5; PDB ID 2ZG2) indicating amino acid residues involved in binding of anti-Siglec-9 antibody 12B12. Critical residues for binding are indicated with red spheres. FIG. 2 shows glycan-binding specificities of human Siglec proteins, such as Siglec-9. This figure shows a summary of the most commonly reported specificities for the most commonly studied sialylated glycans. Relative binding within studies of each Siglec is indicated as ++, strong binding; +, detectable binding; and -, very weak or undetectable binding. Not shown is the recently reported strong-binding preference of hSiglec-8 and mSiglec-F for 6'-sulfated-sialyl-Lewis x (sLex) and of hSiglec-9 for 6-sulfated-sLex. With a few exceptions (CD22 and MAG), results of binding specificity studies of human Siglecs by different investigators using different assays have varied significantly. In addition to assay formats and glycan linker issues, the density and arrangement of the ligands studied could be responsible for this variation (Varki et al., (2006) Glycobiol. 16:1R-27R). FIG. 3 shows the structure and metabolism of disialogangliosides in mammalian brain. The nomenclature of disialogangliosides in the figure follows the system of Svennerholm (1964) J. Lipid Res. 5:145-155 (Ariga T et al. (2008) J. Lipid Res. 49:1157-1175). FIG. 4 depicts results of FACS analysis demonstrating Siglec-9 expression in human primary immune cells. FIG. 5 depicts FACS analysis of Siglec-9 antibodies binding to human primary dendritic cells compared to isotype controls. FIG. 6A depicts Biacore sensorgrams showing binding affinity of Siglec-9 antibodies of the present disclosure to purified Siglec-9-his tagged protein. FIG. 6B depicts ForteBio sensorgrams showing binding affinity of Siglec-9 antibodies of the present disclosure to purified Siglec-9-his tagged protein. FIG. 6C depicts shows a schematic for combining antibody light chain variable region (VL) sequences of humanized versions of anti-Siglec-9 antibody 5C6 (AbM S9-5C6.3). Additional variations are listed below each sequence. The figure includes sequences for versions of humanized antibody 5C6. In the figure, IGKV230*01 (SEQ ID NO: 213); Joining region (SEQ ID NO: 214); 5C6.3 (SEQ ID NO: 215); 2-30*01 (SEQ ID NO: 216); h5C6.3-L1 (SEQ ID NO: 217); h5C6.3-L2 (SEQ ID NO: 218); h5C6.3-L3 (SEQ ID NO: 219). FIG. 6D shows a schematic for combining antibody heavy chain variable region (VH) sequences of humanized versions of anti-Siglec-9 antibody 5C6 (AbM S9-5C6.3). Additional variations are listed below each sequence. The figure includes sequences for versions of humanized antibody 5C6. In the figure, IGHV1-18*01 (SEQ ID NO: 220); Joining region (SEQ ID NO: 221); 5C6.3 (SEQ ID NO: 222); 1-18*01 (SEQ ID NO: 223); h5C6.3-H1 (SEQ ID NO: 224); h5C6.3-H2 (SEQ ID NO: 225); h5C6.3-H3 (SEQ ID NO: 226) ; h5C6.3-H4 (SEQ ID NO: 227). FIG. 6E shows a schematic for combining antibody light chain variable region (VL) sequences of humanized versions of anti-Siglec-9 antibody 12B12 (AbM S9-12B12.2). Additional variations are listed below each sequence. The figure includes sequences for versions of humanized antibody 12B12. In the figure, IGKV1-39*01 (SEQ ID NO: 228); Joining region (SEQ ID NO: 229); 12B12.2 (SEQ ID NO: 230); 1-39*01 (SEQ ID NO: 231); h12B12.2-L1 (SEQ ID NO: 232); h12B12.2-L2 (SEQ ID NO: 233); h12B12.2-L3 (SEQ ID NO: 234). FIG. 6F shows a schematic for combining antibody heavy chain variable region (VH) sequences of humanized versions of anti-Siglec-9 antibody 12B12 (AbM S9-12B12.2). Additional variations are listed below each sequence. The figure includes sequences for versions of humanized antibody 12B12. In the figure, IGHV3-23*04 (SEQ ID NO: 235); Joining region (SEQ ID NO: 236); 12B12.2 (SEQ ID NO: 237); 3-23*04 (SEQ ID NO: 238); h12B12.2-H1 (SEQ ID NO: 239); h12B12.2-H2 (SEQ ID NO: 240). For FIG. 6C-6F, CDR sequences are depicted in bold; residue numbering shown as sequential (seq) or according to Chothia; "b" refers to buried sidechain; "p" refers to partially buried; "i" refers to sidechain at interface between VH and VL domains; sequence differences between human and murine germlines are noted by an asterisk (*); potential additional mutations in frameworks are noted below the sequence; potential changes in CDR sequences are noted below each CDR sequence (such changes may prevent asparagine (N) deamidation, tryptophan (W) oxidation, or isoaspartate (DG) formation). FIG. 7A-7H depict Siglec-9 antibody-dependent downregulation of cell surface Siglec-9 receptor on various human cell types. FIG. 7A depicts THP-1 acute monocytic lymphoma cells. FIG. 7B depicts human primary monocytes. FIG. 7C depicts human primary microglia. FIG. 7D depicts human primary macrophages. FIG. 7E depicts human primary dendritic cells. FIG. 7F depicts antibody titration with human primary dendritic cells. FIG. 7G shows in vivo reduction in cell surface levels of Siglec-9 following antibody treatment in vivo. FIG. 7H shows expression of unrelated receptor CD33. CD33 was used as a control. Cell surface levels of CD33 were not significantly reduced following antibody treatment in vivo. FIG. 7I depicts an antibody concentration titration curve for reducing cell surface expression of Siglec-9 on human primary macrophages with Siglec-9 antibodies 5C6 (S9-5C6), 12B12 (S9-12B12), 17C2 (S9-17C2), and isotype control (mIgG2a). FIG. 7J depicts an antibody concentration titration curve for reducing cell surface expression of control receptor CD11b on human primary macrophages with Siglec-9 antibodies 5C6 (S9-5C6), 12B12 (S9-12B12), 17C2 (S9-17C2), and isotype control (mIgG2a). FIG. 7K depicts Siglec-9 and CD33 expression in peripheral myeloid cells from humanized NSG mice 21 days after treatment with anti-Siglec-9 antibody 2D4 or isotype control antibody (MOPC-21). FIG. 7L shows in vivo reduction in cell surface levels of Siglec-9 following antibody treatment in vivo. FIG. 7M shows expression of unrelated receptor CD33. CD33 was used as a control. Cell surface levels of CD33 were not significantly reduced following antibody treatment in vivo. FIG. 7N shows FACS gating strategy for blood samples from humanized NSG mice 21 days after treatment with anti-Siglec-9 antibody 2D4 or isotype control antibody (MOPC21). FIG. 7O depicts levels of Siglec-9 surface expression and TREM2 surface expression on human dendritic cells after treatment with an anti-Siglec-9 antibody 2D4 or an isotype control antibody, as compared to a no antibody control. FIG. 7P depicts levels of CD11c surface expression, Siglec-9 surface expression, and TREM2 surface expression on human dendritic cells after treatment with an anti-Siglec-9 antibody 2D4. FIG. 7Q depicts ability of Siglec-9 antibodies of the present disclosure to block binding of Siglec-9 (Siglec-9-FC) to sialic acid ligands endogenously expressed on U937 cancer cells. FIG. 8 depicts FACS analysis showing that sialic acid ligands on dendritic cells restrict T cell proliferation during mixed lymphocyte reaction with human primary cells. FIG. 9 depicts results showing that sialic acid Siglec-9 ligands on dendritic cells restrict T cell proliferation during mixed lymphocyte reaction. FIG. 10A-10H depict results showing Siglec-9 receptor and increased Siglec-9 ligand expression on human myeloid cells induced by various stimuli. FIG. 10A and 10B depict results showing Siglec-9 receptor and increased Siglec-9 ligand expression on human primary dendritic cells after treatment with tumor supernatant. FIG. 10C and 10D depict results showing increased Siglec-9 ligand expression on human primary dendritic cells after treatment with tumor supernatant. FIG. 10E and 10F depict results showing Siglec-9 receptor expression on human dendritic cells during LPS-induced inflammation. FIG. 10G and 10H depict results showing an increase in sialic acid expression on human myeloid cells during LPS-induced inflammation. These finding indicate that tumors can evade immune surveillance by upregulating the level of inhibitory ligands to Siglec-9 on the tumor cells and on immune cells. FIG. 11 depicts results showing that sialidase treatment to remove Siglec-9 ligands from E. coli increases phagocytosis by human primary dendritic cells. FIG. 12 depicts Siglec-9 ligand expression in brain sections from an Alzheimer's disease brain (AD) and a healthy brain (non-AD). FIG. 12 shows immunohistochemistry staining of Siglec-9-Fc in AD and non-AD brain samples from two donors (Donor 1 and Donor 2). FIG. 13 depicts results showing that expression of inhibitory Siglec-9 ligands is increased in lung tumor cells, melanoma cells, and colon cancer cells. The results indicate that inhibitory Siglec-9 ligands contribute to cancer pathology in these tumor types. FIG. 14 depicts expression of Siglec-9 in cells of NOG mice injected with human peripheral blood cells. 12 weeks after engraftment with human fetal liver CD34 +< cells, humanized mice were transplanted with patient-derived melanoma. Peripheral blood, spleen, and tumor tissues were dissociated and analyzed for immune cell markers and Siglec-9 expression. For FACS analysis, human hematopoietic cells were identified by CD45 expression, then gated CD14+, CD3+ populations. The results indicate that inhibitory Siglec-9 ligands contribute to cancer pathology in this tumor type. FIG. 15A depicts a PD-1 / Siglec-9 combination antibody treatment protocol for a mouse model of patient-derived cancer in immunologically humanized mice. FIG. 15B depicts in vivo reduction in cell surface levels of Siglec-9 on CD14+ myeloid cells from blood samples of mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15C depicts in vivo cell surface levels of control receptor CD33 on CD14+ myeloid cells from blood samples of mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15D depicts in vivo reduction in peripheral blood CD14 +< myeloid cells from mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15E depicts in vivo increase in peripheral blood CD3 +< T cells in blood samples from mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15F depicts in vivo reduction in tumor infiltrating CD14 +< myeloid cells from mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15G depicts in vivo increase in tumor infiltrating CD3 +< T cells from mice treated with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4. FIG. 15H depicts mean tumor volume after treatment with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4 in mice that were engrafted with human immune stem cells from human donor 984480112. FIG. 15I depicts mean tumor volume after treatment with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody 2D4 in mice that were engrafted with human immune stem cells from human donor 17509112. FIG. 15J depicts mean tumor volume after treatment with Keytruda ®< (pembrolizumab) anti-PD-1 antibody alone or in combination with anti-Siglec-9 antibody2D4 in mice that were engrafted with human immune stem cells from human donor 165547112. DETAILED DESCRIPTION OF THE PRESENT DISCLOSUREGeneral techniques

[0040] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).Definitions

[0041] As used herein, the term "preventing" includes providing prophylaxis with respect to occurrence or recurrence of a particular disease, disorder, or condition in an individual. An individual may be predisposed to, susceptible to a particular disease, disorder, or condition, or at risk of developing such a disease, disorder, or condition, but has not yet been diagnosed with the disease, disorder, or condition.

[0042] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or symptoms of disease, and may or may not have displayed detectable disease or symptoms of disease prior to the treatment methods described herein. "At risk" denotes that an individual has one or more risk factors, which are measurable parameters that correlate with development of a particular disease, disorder, or condition, as known in the art. An individual having one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition than an individual without one or more of these risk factors.

[0043] As used herein, the term "treatment" refers to clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of progression, ameliorating or palliating the pathological state, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully "treated", for example, if one or more symptoms associated with a particular disease, disorder, or condition are mitigated or eliminated.

[0044] An "effective amount" refers to at least an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the treatment to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. An effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved..

[0045] A "therapeutically effective amount" is at least the minimum concentration required to effect a measurable improvement of a particular disease, disorder, or condition. A therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the Siglec-9 protein antagonist to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the Siglec-9 protein antagonist are outweighed by the therapeutically beneficial effects.

[0046] As used herein, administration "in conjunction" with another compound or composition includes simultaneous administration and / or administration at different times. Administration in conjunction also encompasses administration as a co-formulation or administration as separate compositions, including at different dosing frequencies or intervals, and using the same route of administration or different routes of administration.

[0047] An "individual" for purposes of treatment, prevention, or reduction of risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. Preferably, the individual is human.

[0048] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0049] The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. The pairing of a V H and V L together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0050] The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ") and mu ("µ"), respectively. The γ and α classes are further divided into subclasses (isotypes) on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (W.B. Saunders Co., 2000).

[0051] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V H ) followed by a number of constant domains. Each light chain has a variable domain at one end (V L ) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains.

[0052] An "isolated" antibody, such as an anti-Siglec-9 antibody of the present disclosure, is one that has been identified, separated and / or recovered from a component of its production environment (e.g., naturally or recombinantly). Preferably, the isolated polypeptide is free of association with all other contaminant components from its production environment. Contaminant components from its production environment, such as those resulting from recombinant transfected cells, are materials that would typically interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified: (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under nonreducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant T cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step.

[0053] The "variable region" or "variable domain" of an antibody, such as an anti-Siglec-9 antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as "V H " and "V L ", respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.

[0054] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies, such as anti-Siglec-9 antibodies of the present disclosure,. The V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent-cellular toxicity.

[0055] The term "monoclonal antibody" as used herein refers to an antibody, such as an anti-Siglec-9 antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against one or more antigenic sites. In some embodiments, a monoclonal antibody of the present disclosure can be a bispecific antibody. In contrast to polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the one or more antigenic sites. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by a variety of techniques, including, for example, phage-display technologies (see, e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Nat'l Acad. Sci. USA 101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004), the hybridoma method (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3):253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2d ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995).

[0056] The terms "full-length antibody," "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody, such as an anti-Siglec-9 antibody of the present disclosure, in its substantially intact form, as opposed to an antibody fragment. Specifically whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, the intact antibody may have one or more effector functions.

[0057] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding and / or the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab') 2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

[0058] Papain digestion of antibodies, such as anti-Siglec-9 antibodies of the present disclosure, produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (V H ), and the first constant domain of one heavy chain (C H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab') 2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the C H 1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab') 2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0059] The Fc fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.

[0060] "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0061] "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding. For a review of the sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0062] "Functional fragments" of antibodies, such as anti-Siglec-9 antibodies of the present disclosure, comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the F region of an antibody which retains or has modified FcR binding capability. Examples of antibody fragments include linear antibody, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

[0063] The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the V H and V L domains such that inter-chain but not intra-chain pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the V H and V L domains of the two antibodies are present on different polypeptide chains. Diabodies are described in greater detail in, for example, EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0064] As used herein, a "chimeric antibody" refers to an antibody (immunoglobulin), such as an anti-Siglec-9 antibody of the present disclosure, in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies of interest herein include PRIMATIZED ®< antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest. As used herein, "humanized antibody" is used a subset of "chimeric antibodies."

[0065] "Humanized" forms of non-human (e.g., murine) antibodies, such as anti-Siglec-9 antibodies of the present disclosure, are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, and the like. The number of these amino acid substitutions in the FR is typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0066] A "human antibody" is one that possesses an amino-acid sequence corresponding to that of an antibody, such as an anti-Siglec-9 antibody of the present disclosure, produced by a human and / or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE ™< technology). See also, for example, Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.

[0067] The term "hypervariable region," "HVR," or "HV," when used herein refers to the regions of an antibody-variable domain, such as that of an anti-Siglec-9 antibody of the present disclosure, that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003)). Indeed, naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0068] A number of HVR delineations are in use and are encompassed herein. The HVRs that are EU or Kabat complementarity-determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between the EU or Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody-modeling software. The "contact" HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below. LoopKabatAbMChothiaContactL1L24-L34L24-L34L26-L32L30-L36L2L50-L56L50-L56L50-L52L46-L55L3L89-L97L89-L97L91-L96L89-L96H1H31-H35BH26-H35BH26-H32H30-H35B (Kabat numbering)H1H31-H35H26-H35H26-H32H30-H35 (Chothia numbering)H2H50-H65H50-H58H53-H55H47-H58H3H95-H102H95-H102H96-H101H93-H101

[0069] HVRs may comprise "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65 or 49-65 (a preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) in the VH. The variable-domain residues are numbered according to EU or Kabat et al., supra, for each of these extended-HVR definitions.

[0070] "Framework" or "FR" residues are those variable-domain residues other than the HVR residues as herein defined.

[0071] The phrase "variable-domain residue-numbering as in EU or Kabat" or "amino-acid-position numbering as in EU or Kabat," and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in EU or Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The EU or Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard" Kabat numbered sequence.

[0072] The EU or Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU or Kabat numbering system" or "EU index" is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless stated otherwise herein, references to residue numbers in the variable domain of antibodies means residue numbering by the Kabat numbering system. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU or Kabat numbering system (e.g., see United States Patent Publication No. 2010-280227).

[0073] An "acceptor human framework" as used herein is a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. Where pre-existing amino acid changes are present in a VH, preferable those changes occur at only three, two, or one of positions 71H, 73H and 78H; for instance, the amino acid residues at those positions may by 71A, 73T and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0074] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for the VL, the subgroup may be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al., supra. Additionally, for the VH, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0075] An "amino-acid modification" at a specified position, e.g., of an anti-Siglec-9 antibody of the present disclosure, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent the specified residue. Insertion "adjacent" to a specified residue means insertion within one to two residues thereof. The insertion may be N-terminal or C-terminal to the specified residue. The preferred amino acid modification herein is a substitution.

[0076] An "affinity-matured" antibody, such as an anti-Siglec-9 antibody of the present disclosure, is one with one or more alterations in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody that does not possess those alteration(s). In one embodiment, an affinity-matured antibody has nanomolar or even picomolar affinities for the target antigen. Affinity-matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH- and VL-domain shuffling. Random mutagenesis of HVR and / or framework residues is described by, for example: Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896 (1992).

[0077] As use herein, the term "specifically recognizes" or "specifically binds" refers to measurable and reproducible interactions such as attraction or binding between a target and an antibody, such as an anti-Siglec-9 antibody of the present disclosure, that is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody, such as an anti-Siglec-9 antibody of the present disclosure, that specifically or preferentially binds to a target or an epitope is an antibody that binds this target or epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other targets or other epitopes of the target. It is also understood by reading this definition that, for example, an antibody (or a moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds to a target may have an association constant of at least about 10 3< M -1< or 10 4< M -1< , sometimes about 10 5< M -1< or 10 6< M -1< , in other instances about 10 6< M -1< or 10 7< M -1< , about 10 8< M -1< to 10 9< M -1< , or about 10 10< M -1< to 10 11< M -1< or higher. A variety of immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0078] As used herein, an "interaction" between a Siglec-9 protein and a second protein encompasses, without limitation, protein-protein interaction, a physical interaction, a chemical interaction, binding, covalent binding, and ionic binding. As used herein, an antibody "inhibits interaction" between two proteins when the antibody disrupts, reduces, or completely eliminates an interaction between the two proteins. An antibody of the present disclosure, or fragment thereof, "inhibits interaction" between two proteins when the antibody or fragment thereof binds to one of the two proteins.

[0079] An "agonist" antibody or an "activating" antibody is an antibody, such as an agonist anti-Siglec-9 antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of the antigen after the antibody binds the antigen.

[0080] A "blocking" antibody, an "antagonist" antibody, or an "inhibitory" antibody is an antibody, such as an anti-Siglec-9 antibody of the present disclosure, that inhibits or reduces (e.g., decreases) antigen binding to one or more ligand after the antibody binds the antigen, and / or that inhibits or reduces (e.g., decreases) one or more activities or functions of the antigen after the antibody binds the antigen. In some embodiments, blocking antibodies, antagonist antibodies, or inhibitory antibodies substantially or completely inhibit antigen binding to one or more ligand and / or one or more activities or functions of the antigen.

[0081] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.

[0082] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU or Kabat numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3 and IgG4.

[0083] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.

[0084] A "variant Fc region" comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g. from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.

[0085] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. (see, e.g., M. Daëron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0086] Binding to FcRn in vivo and serum half-life of human FcRn high-affinity binding polypeptides can be assayed, e.g., in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which the polypeptides having a variant Fc region are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcRs. See also, e.g., Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0087] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN ™< (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full length of the sequences being compared.

[0088] An "isolated" cell is a molecule or a cell that is identified and separated from at least one contaminant cell with which it is ordinarily associated in the environment in which it was produced. In some embodiments, the isolated cell is free of association with all components associated with the production environment. The isolated cell is in a form other than in the form or setting in which it is found in nature. Isolated cells are distinguished from cells existing naturally in tissues, organs, or individuals. In some embodiments, the isolated cell is a host cell of the present disclosure.

[0089] An "isolated" nucleic acid molecule encoding an antibody, such as an anti-Siglec-9 antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. Preferably, the isolated nucleic acid is free of association with all components associated with the production environment. The isolated nucleic acid molecules encoding the polypeptides and antibodies herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from nucleic acid encoding the polypeptides and antibodies herein existing naturally in cells.

[0090] The term "vector," as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double stranded DNA into which additional DNA segments may be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors," or simply, "expression vectors." In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably as the plasmid is the most commonly used form of vector.

[0091] "Polynucleotide," or "nucleic acid," as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may comprise modification(s) made after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps," substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotides(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), in which each R or R' is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

[0092] A "host cell" includes an individual cell or cell culture that can be or has been a recipient for vector(s) for incorporation of polynucleotide inserts. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the present disclosure.

[0093] "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN ™< , polyethylene glycol (PEG), and PLURONICS ™< .

[0094] As used herein, the term "apoptosis" refers to gene-directed process of intracellular cell destruction. Apoptosis is distinct from necrosis; it includes cytoskeletal disruption, cytoplasmic shrinkage and condensation, expression of phosphatidylserine on the outer surface of the cell membrane and blebbing, resulting in the formation of cell membrane bound vesicles or apoptotic bodies. The process is also referred to as "programmed cell death." During apoptosis, characteristic phenomena such as curved cell surfaces, condensation of nuclear chromatin, fragmentation of chromosomal DNA, and loss of mitochondrial function are observed. Various known technologies may be used to detect apoptosis, such as staining cells with Annexin V, propidium iodide, DNA fragmentation assay and YO-PRO-1 (Invitrogen). In some embodiments, staining with Annexin V and propidium iodide may be used, and the combined percentages of the Annexin V+ / PI+, Annexin V+ / PI- and Annexin V- / PI+ populations are considered as dead cells.

[0095] As used herein, the term "agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both" refers to a molecule that reduces (including significantly), decreases, blocks, inhibits, or interferes with a Siglec-9 (mammalian, such as a human Siglec-9) biological activity in vitro, in situ, and / or in vivo. The term "agent" implies no specific mechanism of biological action whatsoever, and expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with a Siglec-9 whether direct or indirect, and whether interacting with a Siglec-9, one or more of its ligands, or through another mechanism, and its consequences which can be achieved by a variety of different, and chemically divergent, compositions. Exemplary agents include, without limitation, an anti-Siglec-9 antibody that specifically binds to a Siglec-9, a soluble Siglec-9 receptor protein, a soluble Siglec-9-Fc fusion protein (e.g., Siglec-9 immunoadhesin), a soluble Siglec receptor that binds to a Siglec-9 ligand, a Siglec-Fc fusion protein (e.g., Siglec immunoadheisn) that binds to a Siglec-9 ligand, an anti-sense molecule directed to a nucleic acid encoding a Siglec-9, a short interfering RNA ("siRNA") molecule directed to a nucleic acid encoding a Siglec-9, a Siglec-9 inhibitory compound, an RNA or DNA aptamer that binds to a Siglec-9, and a Siglec-9 structural analog. In some embodiments, a Siglec-9 inhibitor (e.g., an antibody) binds (physically interacts with) an agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both, binds to a Siglec-9 ligand, and / or inhibits (reduces) Siglec-9 synthesis or production. In other embodiments, an agent of the present disclosure inhibitor binds a Siglec-9 and prevents its binding to one or more of its ligands. In still other embodiments, an agent of the present disclosure reduces or eliminates expression (i.e., transcription or translation) of a Siglec-9. Examples of types of agent that decreases cellular levels of Siglec-9, inhibits interaction between Siglec-9 and one or more Siglec-9 ligands, or both are provided herein.

[0096] As used herein, the term "agent that binds or interacts with Siglec-9" refers to a molecule that either directly or indirectly interacts with a Siglec-9 protein. The term "agent" implies no specific mechanism of biological action whatsoever, and expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with a Siglec-9 whether direct or indirect, and whether interacting with a Siglec-9or through another mechanism, and its consequences which can be achieved by a variety of different, and chemically divergent, compositions. Exemplary agents include, without limitation, an anti-Siglec-9 antibody that specifically binds to a Siglec-9.

[0097] As used herein, the term "RNA interference" or "RNAi" refers generally to a process in which a double-stranded RNA molecule or a short hairpin RNA molecule reducing or inhibiting the expression of a nucleic acid sequence with which the double-stranded or short hairpin RNA molecule shares substantial or total homology. The term "short interfering RNA" or "siRNA" or "RNAi agent" refers to an RNA sequence that elicits RNA interference. See Kreutzer et al., WO 00 / 44895; Zernicka-Goetz et al., WO 01 / 36646; Fire, WO 99 / 32619; Mello and Fire, WO 01 / 29058. As used herein, siRNA molecules include RNA molecules encompassing chemically modified nucleotides and non-nucleotides. The term "ddRNAi agent" refers to a DNA-directed RNAi agent that is transcribed from an exogenous vector. The terms "short hairpin RNA" or "shRNA" refer to an RNA structure having a duplex region and a loop region. In certain embodiments, ddRNAi agents are expressed initially as shRNAs.

[0098] As used herein, the term "aptamer" refers to a heterologous oligonucleotide capable of binding tightly and specifically to a desired molecular target, such as, for example, common metabolic cofactors (e.g., Coenzyme A, S-adenosyl methionine, and the like), proteins (e.g., complement protein C5, antibodies, and the like), or conserved structural elements in nucleic acid molecules (e.g., structures important for binding of transcription factors and the like). Aptamers typically comprise DNA or RNA nucleotide sequences ranging from about 10 to about 100 nucleotides in length, from about 10 to about 75 nucleotides in length, from about 10 to about 50 nucleotides in length, from about 10 to about 35 nucleotides in length, and from about 10 to about 25 nucleotides in length. Synthetic DNA or RNA oligonucleotides can be made using standard solid phase phosphoramidite methods and equipment, such as by using a 3900 High Throughput DNA Synthesizer ™< , available from Applied Biosystems (Foster City, CA). Aptamers frequently incorporate derivatives or analogs of the commonly occurring nucleotides found in DNA and RNA (e.g., A, G, C, and T / U), including backbone or linkage modifications (e.g., peptide nucleic acid (PNA) or phosphothioate linkages) to increase resistance to nucleases, binding avidity, or to otherwise alter their pharmacokinetic properties. Exemplary modifications are set forth in U.S. Patent Nos. 6,455,308; 4,469,863; 5,536,821; 5,541,306; 5,637,683; 5,637,684; 5,700,922; 5,717,083; 5,719,262; 5,739,308; 5,773,601; 5,886,165; 5,929,226; 5,977,296; 6,140,482; and in WIPO publications WO 00 / 56746 and WO 01 / 14398. Methods for synthesizing oligonucleotides comprising such analogs or derivatives are disclosed, for example, in the patent publications cited above, and in U.S. Patent Nos. 6,455,308; 5,614,622; 5,739,314; 5,955,599; 5,962,674; 6,117,992; and in WO 00 / 75372.

[0099] The term "about" as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0100] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly indicates otherwise. For example, reference to an "antibody" is a reference to from one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0101] It is understood that aspect and embodiments of the present disclosure described herein include "comprising," "consisting," and "consisting essentially of" aspects and embodiments.Overview

[0102] The present disclosure relates to agents (e.g., anti-Siglec-9 antibodies) that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind Siglec-9 without decreasing cellular levels of Siglec-9 and / or without inhibiting interaction between Siglec-9 and one or more Siglec-9 ligands; methods of making and using such agents (e.g., anti-Siglec-9 antibodies); pharmaceutical compositions containing such agents (e.g., anti-Siglec-9 antibodies); nucleic acids encoding such agents (e.g., anti-Siglec-9 antibodies); and host cells containing nucleic acids encoding such agents (e.g., anti-Siglec-9 antibodies).

[0103] In some embodiments, anti-Siglec-9 antibodies of the present disclosure have one or more antagonistic activities that are due, at least in part, to the ability of the antibodies inhibit the interaction between Siglec-9 and one or more natural glycan ligands. In some embodiments, the anti-Siglec-9 antibodies of the present disclosure may have one or more antagonistic activities that are due, at least in part, to the ability of the antibodies to reduce cellular expression (e.g., cell surface expression) of Siglec-9 by inducing degradation, down regulation, cleavage, receptor desensitization, and / or lysosomal targeting of Siglec-9.

[0104] In some embodiments, antibody-induced Siglec-9 activity can be determined or tested in vitro by any of the techniques disclosed herein (see, e.g., Examples 1-5), including, without limitation, testing plate-binding of full-length anti-Siglec-9 antibodies to increase the density of antibodies exposed to Siglec-9, cross-linking anti-Siglec-9 antibodies with a secondary antibody, cross-linking anti-Siglec-9 antibodies with cells that express one or more Fcg receptors (e.g., FcgRIIB), using Siglec-9 antibodies in solution, and using Fab fragments of Siglec-9 antibodies.

[0105] Certain aspects of the present disclosure are based, at least in part, on the identification of agents, such as anti-Siglec-9 antibodies, that exhibit the ability to compete with one or more Siglec-9 ligands for binding to Siglec-9 and / or the ability to decrease cell surface levels of Siglec-9 on cells, resulting in the reduction, neutralization, prevention, or curbing of one or more Siglec-9 activities. Exemplary Siglec-9 activities include, without limitation, phosphorylation of Tyr-433 and Tyr-456 by a Src family tyrosine kinase, such as Syk, LCK, FYM, and / or ZAP70; recruitment of and binding to the tyrosine-specific protein phosphatases SHP1 and SHP2; recruitment of and binding to PLC-gamma1, which acts as a guanine nucleotide exchange factor for Dynamini-1; recruitment of and binding to SH2-domain containing protein (e.g., Crkl); recruitment of and binding to the spleen tyrosine kinase Syk; recruitment of and binding to SH3-SH2-SH3 growth factor receptor-bound protein 2 (Grb2); recruitment of and binding to multiple SH2-containing proteins; modulated expression of one or more pro-inflammatory cytokines, such as FN-α4, IFN-beta, IL-1β, IL-1alpha, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-y, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, CRP, MCP-1, and MIP-1-beta; modulated expression of one or more pro-inflammatory cytokines in one or more cells selected from macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; increased expression of one or more anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, IL-35, IL-16, TGF-beta, IL-1Ra, G-CSF, and soluble receptors for TNF, IFN-betala, IFN-betalb, or IL-6; modulated expression of one or more anti-inflammatory cytokines in one or more cells selected from macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; modulate expression of one or more proteins selected from C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and PYCARD; inhibition of extracellular signal-regulated kinase (ERK) phosphorylation; decreasing tyrosine phosphorylation on one or more cellular proteins, optionally, wherein the one or more cellular proteins comprise ZAP-70 and the tyrosine phosphorylation occurs on Tyr-319 of ZAP-70; modulated expression of C-C chemokine receptor 7 (CCR7); inhibition of microglial cell chemotaxis toward CCL19-expressing and CCL21-expressing cells; decreasing T cell proliferation induced by one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, and M2 NK cells; inhibition of osteoclast production, decreased rate of osteoclastogenesis, or both; decreasing survival of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; decreasing proliferation of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting migration of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting one or more functions of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting maturation of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibition of one or more types of clearance selected from apoptotic neuron clearance, nerve tissue debris clearance, dysfunctional synapse clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, and tumor cell clearance; optionally wherein the disease-causing protein is selected from amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides and the tumor cell is from a cancer selected from bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer; inhibition of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, dysfunctional synapses, non-nerve tissue debris, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, or tumor cells; optionally wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and the tumor cells are from a cancer selected from bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer; binding to Siglec-9 ligand on tumor cells; binding to Siglec-9 ligand on cells selected from neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, and NK cells; inhibition of tumor cell killing by one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibiting anti-tumor cell proliferation activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibition of anti-tumor cell metastasis activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibition of one or more ITAM motif containing receptors, optionally wherein the one or more ITAM motif containing receptors are selected from TREM1, TREM2, Sirp beta, FcgR, DAP10, and DAP12; inhibition of signaling by one or more pattern recognition receptors (PRRs), optionally wherein the one or more PRRs are selected from receptors that identify pathogen-associated molecular patterns (PAMPs), receptors that identify damage-associated molecular patterns (DAMPs), and any combination thereof; inhibition of one or more receptors comprising the motif D / Ex 0-2 YxxL / IX 6-8 YxxL / I (SEQ ID NO: 252); inhibition of signaling by one or more Toll-like receptors; inhibition of the JAK-STAT signaling pathway; inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB); de-phosphorylation of an ITAM motif containing receptor; modulated expression of one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells, optionally wherein the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells comprise CD86, C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and / or PYCARD, and the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells are expressed on one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; increasing expression of one or more Siglec-9-dependent genes; normalization of disrupted Siglec-9-dependent gene expression; decreasing expression of one or more ITAM-dependent genes, optionally wherein the one more ITAM-dependent genes are activated by nuclear factor of activated T cells (NFAT) transcription factors; promoting or rescuing functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells; increasing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells into tumors; increasing the number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; enhancing tumor-promoting activity of myeloid-derived suppressor cells; increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10; increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC); decreasing activation of tumor-specific T lymphocytes with tumor killing potential; decreasing infiltration of tumor-specific NK cells with tumor killing potential; decreasing the tumor killing potential of NK cells; decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; increasing tumor volume; increasing tumor growth rate; increasing metastasis; increasing rate of tumor recurrence; decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, TREM1, TREM2, CD39, CD73, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines; inhibition of PLCy / PKC / calcium mobilization; and inhibition of PI3K / Akt, Ras / MAPK signaling.

[0106] In some embodiments, treatment of cancer with agents, such as Siglec-9 blocking antibodies: (i) directly or indirectly decrease the survival, proliferation, maturation, differentiation, and / or functionality of tumor-promoting myeloid / granulocytic immune-suppressive cells that accumulate in the tumor, in peripheral blood, and in lymphoid organs of cancer patients; (ii) decrease the number of tumor-promoting myeloid / granulocytic immune-suppressive cells in the tumor, in the peripheral blood, and in other lymphoid organs of a cancer patient; (iii) block tumor-promoting activity of myeloid-derived suppressor cells (MDSC); (iv) decrease expression of tumor-promoting cytokines, such as TGF-beta and IL-10, in the tumor and in the peripheral blood of a cancer patient; (v) decrease tumor-promoting FoxP3+ regulatory T lymphocyte infiltration in the tumor; (vi) increase infiltration and activation of T lymphocytes with tumor killing potential; (vii) increase infiltration of tumor-specific NK cells with tumor killing potential; (viii) increase the tumor killing potential of NK cells; (ix) increase infiltration of tumor-specific B lymphocytes with potential to enhance immune response; (x) decrease tumor volume; (xi) reduce tumor growth rate; (xii) reduce and / or inhibit metastasis; (xiii) reduce rate of tumor recurrence; (xiv) increase efficacy of immune-therapy that modulates anti-tumor T cell responses, such as PD1 / PDL1, CTLA4, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, KIR, GAL9, CD2, CD5, CD39, CD73, CD30, TIGIT, VISTA, TIM1, TIM3, TIM4, and cancer vaccines, (xv) induce, activate, or otherwise increase PLCy / PKC / calcium mobilization; and (xvi) induce, activate, or otherwise increase PI3K / Akt, Ras / MAPK signaling.

[0107] Immunosuppressor cells are sometimes also referred to as myeloid-derived suppressor cells (MDSC). In humans, MDSCs can be defined by one of the following combination of markers: (1) CD14 +< HLA-DR low / -< , (2) CD14 +< IL4Rα +< , (3) CD14 +< HLA-DR -< IL4Rα +< , (4) CD34 +< CD14 +< CD11b +< Siglec-9 +< , (5) CD11b +< CD14 +< Siglec-9 +< , (6) Siglec-9 +< HLA-DR -< , (7) Lin -< HLA-DR -< , (8) Lin -< HLA-DR -< Siglec-9 +< , (9) Lin -< HLA-DR -< Siglec-9 +< CD11b +< , (10) Lin -< Siglec-9 +< CD11b +< CD15 +< , (11) Lin -< HLA-DR -< Siglec-9 +< CD11b +< CD14 +< CD15 +< , (12) CD11b +< CD14 +< Siglec-9 +< , (13) CD11b +< CD14 -< HLA-DR -< Siglec-9 +< CD15 +< , (14) Siglec-9 +< HLA-DR -< CD15 +< , (15) CD15 +< IL4Rα +< , (16) CD11b +< CD15 +< CD66b +< , (17) CD15 +< FSC low< SSC high< , (18) CD15 high< Siglec-9 +< , (19) CD11b +< CD14 -< CD15 +< , (20) CD66b +< SSC high< , and (21) CD11b +< CD15 +< (see also Solito S et al. Annals of the NY Academy of Sciences, 2014). In mice, MDSCs can be defined by the expression of the surface markers CD45 +< , CD11b +< , Gr1 +< , and / or Il4Ra +< . Additional exemplary immunosuppressive monocytic lineages are CD45 +< , CD11b +< , Gr1 low< ; and CD45 +< , CD11c +< .

[0108] The present disclosure further relates to agents that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies. In certain embodiments, the anti-Siglec-9 antibodies do not significantly decrease cell surface levels of Siglec-9, and / or do not inhibit interaction between Siglec-9 and one or more Siglec-9 ligands.Siglec-9 proteins

[0109] In one aspect, the present disclosure provides agents, such as isolated (e.g., monoclonal) antibodies, that interact with or otherwise bind to regions, such as epitopes, within a Siglec-9 protein of the present disclosure. In some embodiments, agents of the present disclosure, such as anti-Siglec-9 antibodies of the present disclosure, bind to a Siglec-9 protein and modulate one or more Siglec-9 activities after binding to the Siglec-9 protein, for example, an activity associated with Siglec-9 expression in a cell. Siglec-9 proteins of the present disclosure include, without limitation, a mammalian Siglec-9 protein, human Siglec-9 protein, mouse Siglec-9 protein, and rat Siglec-9 protein.

[0110] Siglec-9 is variously referred to as a Siglec-9 molecule, Sialic acid-binding Ig-like lectin 9, CD329 antigen, CD329; CDw329, FOAP-9, and OBBP-LIKE.

[0111] Siglec-9 is an immunoglobulin-like receptor primarily expressed on myeloid lineage cells, including without limitation, macrophages, neutrophils, NK cells, dendritic cells, osteoclasts, monocytes, and microglia. In some embodiments, Siglec-9 forms a receptor-signaling complex with CD64. In some embodiments, Siglec-9 signaling results in the downstream inhibition of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signals are important for the inhibition of Siglec-9 activities, e.g., in the context of an infection response. TLRs also play a key role in the pathological inflammatory response, e.g., TLRs expressed in macrophages, neutrophils, NK cells and dendritic cells.

[0112] Various Siglec-9 homologs are known, including without limitation, human Siglec-9, chimpanzee Siglec-9, green monkey Siglec-9, rhesus macaque Siglec-9, and mouse Siglec-9. The amino acid sequence of human Siglec-9 is set forth below as SEQ ID NO: 1:

[0113] In some embodiments, the Siglec-9 is a preprotein that includes a signal sequence. In some embodiments, the Siglec-9 is a mature protein. In some embodiments, the mature Siglec-9 protein does not include a signal sequence. In some embodiments, the mature Siglec-9 protein is expressed on a cell. In some embodiments, the mature Siglec-9 protein is expressed on a cell, such as the surface of a cell, including, without limitation, human dendritic cells, human macrophages, human monocytes, human osteoclasts, human neutrophils, human T cells, human helper T cell, human cytotoxic T cells, human granulocytes, and human microglia. Agents of the present disclosure, such as anti-Siglec-9 antibodies of the present disclosure, may bind any of the Siglec-9 proteins of the present disclosure expressed on any cell disclosed herein.

[0114] Siglec-9 proteins of the present disclosure, such as human Siglec-9, contain several domains, including without limitation, a signal sequence located at amino acid residues 1-17 SEQ ID NO: 1, an extracellular immunoglobulin-like variable-type (IgV) domain located at amino acid residues 20-140 of SEQ ID NO: 1, two Ig-like C2-type domains located at amino acid residues 146-229 and 236-336 of SEQ ID NO: 1, a transmembrane domain located at amino acid residues 348-370 of SEQ ID NO: 1, an ITIM motif located at amino acid residues 431-436 of SEQ ID NO: 1, and SLAM-like motif located at amino acid residues 454-459 of SEQ ID NO: 1. As one of skill in the art will appreciate, the beginning and ending residues of the domains of the present disclosure may vary depending upon the computer modeling program used or the method used for determining the domain.

[0115] Certain aspects of the present disclosure provide anti-Siglec-9 antibodies that bind to a human Siglec-9, or a homolog thereof, including without limitation a mammalian Siglec-9 protein and Siglec-9 orthologs from other species. Exemplary Siglec-9 homologs and orthologs are listed in Table A. Table A: Siglec-9 homologs and orthologs Organism Siglec-9 Accession Number Chimpanzee (Pan troglodytes)NCBI Accession No. XP_003316614Green monkey (Chlorocebus sabaeus)NCBI Accession No. XP_007995940.1Rhesus macaque (Macaca mulatta)NCBI Accession No. XP_001114560.2Mouse (Mus musculus)NCBI Accession No. NP_112458.2

[0116] Accordingly, as used herein a "Siglec-9" protein of the present disclosure includes, without limitation, a mammalian Siglec-9 protein, human Siglec-9 protein, and primate Siglec-9 protein. Additionally, anti-Siglec-9 antibodies of the present disclosure may bind an epitope within one or more of a mammalian Siglec-9 protein, human Siglec-9 protein, and primate Siglec-9. In some embodiments, anti-Siglec-9 antibodies of the present disclosure may bind specifically to a mammalian Siglec-9 protein, human Siglec-9 protein, or both. In certain embodiments, anti-Siglec-9 antibodies of the present disclosure may bind specifically to human Siglec-9, primate Siglec-9, or both.

[0117] In some embodiments, agents of the present disclosure that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies of the present disclosure, may bind Siglec-9 in a pH dependent manner. In some embodiments, agents of the present disclosure, such as anti-Siglec-9 antibodies, can bind to Siglec-9 at a neutral pH and be internalized without dissociating from the Siglec-9 protein. Alternatively, at an acidic pH agents of the present disclosure, such as anti-Siglec-9 antibodies, may dissociate from Siglec-9 once they are internalized and are then degraded by endosome / lysosome pathway. In certain embodiments, an anti-Siglec-9 antibody binds Siglec-9 at a pH that ranges from 5.5 to 8.0, from 5.5 to 7.5, from 5.5 to 7.0, from 5.5 to 6.5, from 5.5 to 6.0, from 6.0 to 8.0, from 6.5 to 8.0, from 7.0 to 8.0, from 7.5 to 8.0, from 6.0 to 7.5, from 6.0 to 7.0, from 6.5 to 7.5. In certain embodiments, an anti-Siglec-9 antibody dissociates from Siglec-9 at a pH of less than 6.0, less than 5.5, less than 5.0, less than 4.5, less than 4.0, less than 3.5, less than 3.0, less than 2.5, or less than 2.0.

[0118] In some embodiments, agents of the present disclosure that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies of the present disclosure, bind to a wild-type Siglec-9 protein of the present disclosure, naturally occurring variants thereof, and / or disease variants thereof.

[0119] In some embodiments, agents of the present disclosure that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies of the present disclosure, bind a variant of human Siglec-9.

[0120] In some embodiments, agents of the present disclosure that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies of the present disclosure, bind to a Siglec-9 protein expressed on the surface of a cell including, without limitation, human dendritic cells, human macrophages, human NK cells, human monocytes, human osteoclasts, human neutrophils, human T cells, human T helper cell, human cytotoxic T cells, human granulocytes, and human microglia. In some embodiments, agents of the present disclosure that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands, or that bind or interact with Siglec-9, such as anti-Siglec-9 antibodies of the present disclosure, bind to a Siglec-9 protein expressed on the surface of a cell and modulate (e.g., induce or inhibit) at least one Siglec-9 activity of the present disclosure after binding to the surface expressed Siglec-9 protein. In some embodiments of the present disclosure, the anti-Siglec-9 antibody binds specifically to a Siglec-9 protein. In some embodiments of the present disclosure, the anti-Siglec-9 antibody further binds to at least one additional Siglec protein. In some embodiments, the anti-Siglec-9 antibody modulates one or more activities of the at least one additional Siglec protein or of a cell expressing the at least one additional Siglec protein.Siglec-9 ligands

[0121] Siglec-9 proteins of the present disclosure can interact with (e.g., bind to) one or more Siglec-9 ligands.

[0122] Exemplary Siglec-9 ligands include, without limitation, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,8-disialyl containing glycolipids, branched alpha-2,6-linked sialic acid-containing glycoproteins, terminal alpha-2,6-linked sialic acid-containing glycolipids, terminal alpha-2,3-linked sialic acid-containing glycoproteins, disialogangliosides (e.g., gangliosides or glycolipids containing a ceramide linked to a sialylated glycan), secreted mucins, Siglec-9 ligands expressed on red blood cells, Siglec-9 ligands expressed on bacterial cells, Siglec-9 ligands expressed on apoptotic cells, Siglec-9 ligands expressed on nerve cells, Siglec-9 ligands expressed on glia cells, Siglec-9 ligands expressed on microglia, Siglec-9 ligands expressed on astrocytes, Siglec-9 ligands expressed on tumor cells, Siglec-9 ligands expressed on viruses, Siglec-9 ligands expressed on dendritic cells, Siglec-9 ligands bound to beta amyloid plaques, Siglec-9 ligands bound to Tau tangles, Siglec-9 ligands on disease-causing proteins, Siglec-9 ligands on disease-causing peptides, Siglec-9 ligands expressed on macrophages, Siglec-9 ligands expressed on neutrophils, Siglec-9 ligands expressed on natural killer cells, Siglec-9 ligands expressed on monocytes, Siglec-9 ligands expressed on T cells, Siglec-9 ligands expressed on T helper cells, Siglec-9 ligands expressed on cytotoxic T cells, Siglec-9 ligands expressed on B cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor dendritic cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor macrophages, Siglec-9 ligands expressed on myeloid-derived suppressor cells, Siglec-9 ligands expressed on regulatory T cells. In some embodiments, Siglec-9 ligands of the present disclosure are ganglioside (e.g., disialogangliosides). Disialogangliosides generally share a common lacto-ceramide core and one or more sialic acid residues.

[0123] Further examples of suitable Siglec-9 ligands are depicted in FIG. 2.

[0124] Further examples of suitable ganglioside (e.g., disialogangliosides) ligands are depicted in FIG. 3 and listed in Table B. Generally, a ganglioside (e.g., disialogangliosides) is a molecule composed of a glycosphingolipid with one or more sialic acids (e.g., n-acetyl-neuraminic acid, NANA) linked on the sugar chain. Table B: Structures of exemplary ganglioside Siglec-9 ligands GM2-1 = aNeu5Ac(2-3)bDGalp(1-?)bDGalNAc(1-?)bDGalNAc(1-?)bDGlcp(1-1)CerGM3 = aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)CerGM2,GM2a(?) = bDGalpNAc(1-4)[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGM2b(?) = aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlep(1-1)CerGM1,GM1a = bDGalp(1-3)bDGalNAc[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)Cerasialo-GM1,GA1 = bDGalp(1-3)bDGalpNAc(1-4)bDGalp(1-4)bDGlcp(1-1)Cerasialo-GM2,GA2 = bDGalpNAc(1-4)bDGalp(1-4)bDGlcp(1-1)CerGM1b = aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)bDGalp(1-4)bDGlcp(1-1)CerGD3 = aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)CerGD2 = bDGalpNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGD1a = aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-3)]bDGalp(1-4)bDGlep(1-1)CerGD1alpha = aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-6)]bDGalp(1-4)bDGlcp(1-1)CerGD1b = bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGT1a = aNeu5Ac(2-8)aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGT1,GT1b = aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerOAc-GT1b = aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)aXNeu5Ac9Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGT1c = bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlcp(1-1)CerGT3 = aNeu5Ac(2-8)aNeu5Ac(2-8)aNeu5Ac(2-3)bDGal(1-4)bDGlc(1-1)CerGQ1b = aNeuSAc(2-8)aNeu5Ac(2-3)bDGalp(1-3)bDGalNAc(1-4)[aNeu5Ac(2-8)aNeu5Ac(2-3)]bDGalp(1-4)bDGlep(1-1)CerGGal = aNeu5Ac(2-3)bDGalp(1-1)Cerwhere:aNeu5Ac = 5-acetyl-alpha-neuraminic acidaNeu5Ac9Ac = 5,9-diacetyl-alpha-neuraminic acidbDGalp = beta-D-galactopyranosebDGalpNAc = N-acetyl-beta-D-galactopyranosebDGlep = beta-D-glucopyranoseCer = ceramide (general N-acylated sphingoid) Siglec-9 agents

[0125] Certain aspects of the present disclosure relate to agents (e.g., Siglec-9 agents) that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands. Other aspects of the present disclosure relate to agents (e.g., Siglec-9 agents) that bind Siglec-9 without decreasing cellular levels of Siglec-9 and / or without inhibiting interaction between Siglec-9 and one or more Siglec-9 ligands. Further aspects of the present disclosure relate to agents (e.g., Siglec-9 agents) that bind or interact with Siglec-9. In some embodiments, agents of the present disclosure block, inhibit, reduce, or interfere with one or more activities of a Siglec-9 protein in vitro, in situ, and / or in vivo. In some embodiments, agents of the present disclosure do not block, inhibit, reduce, or interfere with one or more activities of a Siglec-9 protein in vitro, in situ, and / or in vivo. In some embodiments, agents of the present disclosure, increase, activate or induce one or more activities of a Siglec-9 protein in vitro, in situ, and / or in vivo.

[0126] In certain embodiments, agents of the present disclosure are agents (e.g., Siglec-9 agents) that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligand. An agent of the present disclosure that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is a molecule having one or more of the following characteristics: (1) inhibits or reduces one or more Siglec-9 activities; (2) the ability to inhibit or reduce binding of a Siglec-9 to one or more of its ligands; (3) the ability to reduce Siglec-9 expression (such as at the mRNA level and / or at protein level) in Siglec-9-expressing cells; (4) the ability to interact, bind, or recognize a Siglec-9 protein; (5) the ability to specifically interact with or bind to a Siglec-9 protein; and (6) the ability to treat, ameliorate, or prevent any aspect of a disease or disorder described or contemplated herein.

[0127] Exemplary agents that inhibit the production of Siglec-9 include, without limitation, compounds that specifically inhibit Siglec-9 synthesis and / or release, antisense molecules directed to a Siglec-9, or a short interfering RNA (siRNA) molecule directed to a nucleic acid encoding a Siglec-9. Additional exemplary agents that inhibit one or more Siglec-9 activities include, without limitation, anti-Siglec-9 antibodies that specifically bind to a Siglec-9 protein, compounds that specifically inhibit one or more Siglec-9 activities such as small molecule inhibitors and / or peptide inhibitors, compounds that specifically inhibit Siglec-9 binding to one or more ligands, a Siglec-9 structural analog, or an RNA or DNA aptamer that binds a Siglec-9. In some embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is an allosteric inhibitor. In some embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is an orthosteric inhibitor.

[0128] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is a small molecule inhibitor, including, without limitation, small peptides or peptide-like molecules, soluble peptides, and synthetic non-peptidyl organic or inorganic compounds. A small molecule inhibitor may have a molecular weight of any of about 100 to about 20,000 daltons (Da), about 500 to about 15,000 Da, about 1000 to about 10,000 Da. Methods for making and testing the inhibitory effect a small molecule has on one or more Siglec-9 activities are well known in the art and such methods can be used to assess the effect of the small molecule inhibitor on Siglec-9 activity. For example, any of the methods and assays disclosed herein may be used to screen for small molecule inhibitors that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligand.

[0129] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is an anti-Siglec-9 antibody that binds or physically interacts with a Siglec-9. The antibody may have nanomolar or even picomolar affinities for the target antigen (e.g., Siglec-9). In certain embodiments, the Kd of the antibody is about 0.05 to about 100 nM. For example, Kd of the antibody is any of about 100 nM, about 50 nM, about 10 nM, about 1 nM, about 900 pM, about 800 pM, about 790 pM, about 780 pM, about 770 pM, about 760 pM, about 750 pM, about 740 pM, about 730 pM, about 720 pM, about 710 pM, about 700 pM, about 650 pM, about 600 pM, about 590 pM, about 580 pM, about 570 pM, about 560 pM, about 550 pM, about 540 pM, about 530 pM, about 520 pM, about 510 pM, about 500 pM, about 450 pM, about 400 pM, about 350 pM about 300 pM, about 290 pM, about 280 pM, about 270 pM, about 260 pM, about 250 pM, about 240 pM, about 230 pM, about 220 pM, about 210 pM, about 200 pM, about 150 pM, about 100 pM, or about 50 pM to any of about 2 pM, about 5 pM, about 10 pM, about 15 pM, about 20 pM, or about 40 pM. Methods for the preparation and selection of antibodies that interact and / or bind with specificity to a Siglec-9 are described herein.

[0130] In certain embodiments, an agent that decreases cellular levels of Siglec-9and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands comprises at least one antisense molecule capable of blocking or decreasing the expression of a functional Siglec-9 by targeting nucleic acids encoding a Siglec-9. Nucleic acid sequences of Siglec-9 are known in the art. For example, a human Siglec-9 can have a nucleic acid sequence as shown in NCBI Accession number NM_001198558.1 and a chimpanzee Siglec-9 can have a nucleic acid sequence as shown in NCBI Accession No. XM_003316566.3 and a mouse SIGLEC-E can have a nucleic acid sequence as shown in NCBI Accession No. NM_031181.2. Methods are known for the preparation of antisense oligonucleotide molecules and such methods can be used to prepare antisense oligonucleotides that will specifically bind one or more of a Siglec-9 mRNA without cross-reacting with other polynucleotides. Exemplary sites of targeting include, but are not limited to, the initiation codon, the 5' regulatory regions, the coding sequence, including any conserved consensus regions, and the 3' untranslated region. In certain embodiments, the antisense oligonucleotides are about 10 to about 100 nucleotides in length, about 15 to about 50 nucleotides in length, about 18 to about 25 nucleotides in length, or more. In certain embodiments, the oligonucleotides further comprise chemical modifications to increase nuclease resistance and the like, such as, for example, phosphorothioate linkages and 2'-O-sugar modifications known to those of ordinary skill in the art.

[0131] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands comprises at least one siRNA molecule capable of blocking or decreasing the expression of a functional Siglec-9 by targeting nucleic acids encoding a Siglec-9. Methods for preparation of siRNA molecules are well known in the art and such methods can be used to prepare siRNA molecules that will specifically target a Siglec-9 mRNA without cross-reacting with other polynucleotides. siRNA molecules may be generated by methods such as by typical solid phase oligonucleotide synthesis, and often will incorporate chemical modifications to increase half-life and / or efficacy of the siRNA agent, and / or to allow for a more robust delivery formulation. Alternatively, siRNA molecules are delivered using a vector encoding an expression cassette for intracellular transcription of siRNA.

[0132] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands is an RNA or DNA aptamer that binds or physically interacts with a Siglec-9, and blocks interactions between a Siglec-9 and one or more of its ligands. In certain embodiments, the aptamer comprises at least one RNA or DNA aptamer that binds to a mature form of Siglec-9.

[0133] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands comprises at least one Siglec-9 structural analog. The term Siglec-9 structural analog refers to compounds that have a similar three dimensional structure as part of that of a Siglec-9 and which bind to one or more CD3 ligands under physiological conditions in vitro or in vivo, wherein the binding at least partially inhibits a Siglec-9 biological activity. Suitable Siglec-9 structural analogs can be designed and synthesized through molecular modeling of Siglec-9 binding to a ligand, such as a Siglec-9 ligand of the present disclosure. The Siglec-9 structural analogs can be monomers, dimers, or higher order multimers in any desired combination of the same or different structures to obtain improved affinities and biological effects. In some embodiments, the agent binds to or interacts with an amino acid sequence of a Siglec-9.

[0134] In certain embodiments, an agent that decreases cellular levels of Siglec-9 and / or inhibits interaction between Siglec-9 and one or more Siglec-9 ligands comprises a soluble Siglec-9 receptor protein, a soluble Siglec-9-Fc fusion protein (e.g., Siglec-9 immunoadhesin), a soluble Siglec receptor that binds to a Siglec-9 ligand, a Siglec-Fc fusion protein (e.g., Siglec immunoadhesin) that binds to a Siglec-9 ligand. In certain embodiments, such agents bind one or more Siglec-9 ligands and thereby prevent the interaction between a given Siglec-9 ligand and a functional Siglec-9 receptor.

[0135] In certain embodiments, agents of the present disclosure are agents (e.g., Siglec-9 agents) that bind or interact with Siglec-9. Exemplary agents that bind or interact with Siglec-9 include, without limitation, inert anti-Siglec-9 antibodies, agonist anti-Siglec-9 antibodies, Siglec-9 ligands, Siglec-9 ligand agonist fragments, Siglec-9 immunoadhesins, Siglec-9 soluble receptors, Siglec-Fc fusion proteins (e.g., Siglec immunoadhesins), soluble Siglec receptors, Siglec-9 ligand mimetics, and small molecule compounds. A small molecule compound may have a molecular weight of any of about 100 to about 20,000 daltons (Da), about 500 to about 15,000 Da, about 1000 to about 10,000 Da. Methods for making and testing the effect an agent has on one or more Siglec-9 activities are well known in the art and such methods can be used to assess the effect of the small molecule inhibitor on Siglec-9 activity. For example, any of the methods and assays disclosed herein may be used to screen for small molecule inhibitors that bind or interact with Siglec-9.Assays

[0136] Agents that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands may be identified and / or characterized using methods well known in the art, such as, for example, radiolabeled inhibitor assays, optical assays, protein binding assays, biochemical screening assays, immunoassays, mass shift measurement assays, fluorescence assays, and / or fluorogenic peptide cleavage assays.Binding assays and other assays

[0137] In certain embodiments, agents that decrease cellular levels of Siglec-9 and / or inhibit interaction between Siglec-9 and one or more Siglec-9 ligands can be identified by techniques well known in the art for detecting the presence of a Siglec-9 agent candidate's interaction and / or binding affinity to a Siglec-9.

[0138] In certain embodiments, agents that interact with a Siglec-9 can be identified using a radiolabeled inhibitor assay. For example, a known amount of a radiolabeled agent candidate may be incubated with a known amount of immobilized Siglec-9 and a buffer. Subsequently, the immobilized Siglec-9 may be washed with a buffer and the immobilized Siglec-9 may be measured for the remaining presence of the radiolabeled Siglec-9 agent candidate using techniques known in the art, such as, for example, a gamma counter. A measurement indicating the presence of a radiolabeled substance may indicate the radiolabeled agent candidate is capable of interacting with and / or binding to Siglec-9.

[0139] In certain embodiments, an agent that interacts with a Siglec-9 may be identified using an optical technique. An exemplary optical technique to detect a Siglec-9 agent may include, e.g., attaching Siglec-9 to a colorimetric resonant grafting surface, thereby shifting the wavelength of reflected light due to changes in the optical path the light must take, and subsequently measuring additional changes in the wavelength of reflected light when a candidate agent is allowed to interact with Siglec-9. For example, no change in the measured wavelength of reflected light when an agent is incubated with Siglec-9 may indicate that the agent candidate is unable to interact with Siglec-9. Changes in the measured wavelength of reflected light when an agent candidate is incubated with Siglec-9 may indicate that the agent candidate is capable of binding and / or interacting with Siglec-9.

[0140] In certain embodiments, an agent that interacts with a Siglec-9 may be identified using a protein-binding assay. An exemplary protein-binding assay to detect a Siglec-9 agent may include, e.g., co-immunoprecipitation of a Siglec-9 in the presence of the agent candidate. For example, a Siglec-9 may be incubated with the agent candidate in buffer, and subsequently an immobilized molecule specific to capture a Siglec-9, such as, for example, an anti-Siglec-9 antibody, may be used to capture Siglec-9 in the presence of the agent candidate and bind the Siglec-9, potentially with an interacting agent candidate, during wash procedures known in the art. Subsequently, Siglec-9, potentially with an interacting agent candidate, can be released and the presence of an agent candidate may be detected, based on the agent candidate characteristics, by techniques, such as, for example, mass spectrometry and / or Western blot.

[0141] In certain embodiments, an agent that interacts with a Siglec-9 may be identified using a biochemical and / or an immunoassay assay well known in the art. An exemplary technique may include, e.g., an assay to quantitatively measure changes in Siglec-9 concentration and / or protein half-life using techniques, such as, for example, Western blot, immunostaining, and co-immunoprecipitation. For example, an agent candidate may be incubated with a sample containing a Siglec-9, such as a cell expressing Siglec-9, and subsequently Siglec-9 protein quantity and / or cellular levels may be measured at points during a time course study. Changes in protein quantity, cellular levels, and / or protein half-life in comparison to a control treatment may indicate that the Siglec-9 agent candidate may be capable of altering Siglec-9 half-life and / or activity.

[0142] In certain embodiments, a mass shift measurement assay may be used to identify an agent that interacts with a Siglec-9. An exemplary mass shift measurement assay may include, e.g., detecting the presence of a strongly and / or covalently bound Siglec-9 agent by measuring a change in Siglec-9 mass when the agent candidate is interacting with Siglec-9 by using instruments, such as, but not limited to, a mass spectrometer. For example, a mass shift assay may be performed on a whole protein and / or a peptide-based analysis, depending on the nature of the agent candidate interaction. Detection of a mass shift correlating with the addition of said agent candidate to Siglec-9 may indicate that the agent candidate may be capable of interacting with or otherwise inhibiting a Siglec-9. Additionally, an exemplary mass shift measurement assay may include, e.g., detecting the addition of mass to Siglec-9 correlating with the respective agent candidate mass when the agent candidate is interacting with Siglec-9 using techniques, such as, for example, surface plasmon resonance. For example, the change in the refractive index of light may be measured and correlated with a change in mass of Siglec-9 attached to a sensor surface.

[0143] In certain embodiments, a chemical cross-linking assay may be used to identify a Siglec-9 agent that interacts with a Siglec-9. For example, an agent candidate may be incubated with a Siglec-9, in vivo or in vitro, with a molecule cross-linker capable of covalently linking an agent candidate interacting with Siglec-9 to said Siglec-9 molecule. Subsequently, techniques, such as, but not limited to, mass spectrometry and / or Western blot, may be used to identify an agent candidate that may be capable of interacting with or otherwise inhibiting Siglec-9. For example, detection of Siglec-9covalently cross-linked with the agent candidate may indicate that the agent candidate may be capable of interacting with or otherwise inhibiting Siglec-9.

[0144] In certain embodiments, agents that interact with a Siglec-9 may be identified using a fluorescence assay. For example, a known amount of a fluorescent agent candidate may be incubated with a known amount of immobilized Siglec-9 and a buffer. Subsequently, the immobilized Siglec-9 may be washed with a buffer and the immobilized Siglec-9 may be measured for the remaining presence of a fluorescent Siglec-9 agent candidate using techniques known in the art, such as, but not limited to, fluorescence detection. A measurement indicating the presence of a fluorescent substance may indicate the fluorescent agent candidate is capable of interacting with and / or binding to Siglec-9.Activity assays

[0145] Assays known in the art and described herein (e.g., Examples 1-10) can be used for identifying and testing biological activities of Siglec-9 agents of the present disclosure. In some embodiments, assays for testing the ability of Siglec-9 agents for modulating one or more Siglec-9 activities are provided.Anti-Siglec-9 antibodies

[0146] Certain aspects of the present disclosure relate to anti-Siglec-9 antibodies that decrease cellular levels of Siglec-9 and / or inhibit interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands. In some embodiments, the anti-Siglec-9 antibody decreases cellular levels of Siglec-9 without inhibiting the interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands. In some embodiments, the anti-Siglec-9 antibody inhibits the interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands. In some embodiments, the anti-Siglec-9 antibody decreases cellular levels of Siglec-9 and inhibits the interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands. Other aspects of the present disclosure relate to anti-Siglec-9 antibodies that bind Siglec-9 without decreasing cellular levels of Siglec-9 and / or without inhibiting interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands.

[0147] As disclosed herein, Siglec-9 may be constitutively recycled on cells, and as such may recycle into the cell (e.g., endocytose) any agents (e.g., antibodies) that bind Siglec-9 on the cell surface. However, such endocytosis may not lead to a decrease in cellular levels (e.g., cell surface levels) of Siglec-9. While it has been shown that acute myeloid leukemia (AML) cells may mediate endocytosis of anti-Siglec-9 antibodies bound to surface-expressed Siglec-9, no decrease in cellular levels of Siglec-9 was demonstrated. Accordingly, certain aspects of the present disclosure relate to anti-Siglec-9 antibodies that not only bind to cell surface-expressed Siglec-9, but also decrease cellular levels of Siglec-9. In some embodiments, anti-Siglec-9 antibodies of the present disclosure bind cell surface-expressed Siglec-9 and are further endocytosed into the cell. In some embodiments, anti-Siglec-9 antibodies of the present disclosure bind cell surface-expressed Siglec-9 without being endocytosed into the cell.

[0148] Cellular levels of Siglec-9 may refer to, without limitation, cell surface levels of Siglec-9, intracellular levels of Siglec-9, and total levels of Siglec-9. In some embodiments, a decrease in cellular levels of Siglec-9 comprises decrease in cell surface levels of Siglec-9. As used herein, an anti-Siglec-9 antibody decreases cell surface levels of Siglec-9 if it induces a decrease of 21% or more in cell surface levels of Siglec-9 as measured by any in vitro cell-based assays or suitable in vivo model described herein or known in the art, for example utilizing flow cytometry, such as fluorescence-activated cell sorting (FACS), to measure cell surface levels of Siglec-9. In some embodiments, a decrease in cellular levels of Siglec-9 comprises a decrease in intracellular levels of Siglec-9. As used herein, an anti-Siglec-9 antibody decreases intracellular levels of Siglec-9 if it induces a decrease of 21% or more in intracellular levels of Siglec-9 as measured by any in vitro cell-based assays or suitable in vivo model described herein or known in the art, for example immunostaining, Western blot analysis, co-immunoprecipitation, and cell cytometry. In some embodiments, a decrease in cellular levels of Siglec-9 comprises a decrease in total levels of Siglec-9. As used herein, an anti-Siglec-9 antibody decreases total levels of Siglec-9 if it induces a decrease of 21% or more in total levels of Siglec-9 as measured by any in vitro cell-based assays or suitable in vivo model described herein or known in the art, for example immunostaining, Western blot analysis, co-immunoprecipitation, and cell cytometry. In some embodiments, the anti-Siglec-9 antibodies induce Siglec-9 degradation, Siglec-9 cleavage, Siglec-9 internalization, Siglec-9 shedding, and / or downregulation of Siglec-9 expression. In some embodiments, cellular levels of Siglec-9 are measured on primary cells (e.g., dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, and macrophages) or on cell lines utilizing an in vitro cell assay.

[0149] In some embodiments, anti-Siglec-9 antibodies of the present disclosure decrease cellular levels of Siglec-9 by at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more as compared to cellular levels of Siglec-9 in the absence of the anti-Siglec-9 antibody.

[0150] Any in vitro cell-based assays or suitable in vivo model described herein or known in the art may be used to measure inhibition of interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands. In some embodiments, anti-Siglec-9 antibodies of the present disclosure inhibit interaction (e.g., binding) between Siglec-9 and one or more Siglec-9 ligands by at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more at saturating antibody concentrations (e.g., 67 nM) utilizing any in vitro assay or cell-based culture assay described herein or known in the art.

[0151] In some embodiments, anti-Siglec-9 antibodies of the present disclosure inhibit cell surface clustering of Siglec-9. In some embodiments, anti-Siglec-9 antibodies of the present disclosure inhibit one or more activities of a Siglec-9 protein, including, without limitation, phosphorylation of Tyr-433 and Tyr-456 by a Src family tyrosine kinase, such as Syk, LCK, FYM, and / orZAP70; recruitment of and binding to the tyrosine-specific protein phosphatases SHP1 and SHP2; recruitment of and binding to PLC-gamma1, which acts as a guanine nucleotide exchange factor for Dynamini-1; recruitment of and binding to SH2-domain containing protein (e.g., Crkl); recruitment of and binding to the spleen tyrosine kinase Syk; recruitment of and binding to SH3-SH2-SH3 growth factor receptor-bound protein 2 (Grb2); recruitment of and binding to multiple SH2-containing proteins; modulated expression of one or more pro-inflammatory cytokines, optionally wherein the one or more anti-inflammatory cytokines are selected from a group consisting FN-α4, IFN-beta, IL-1β, IL-1alpha, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-y, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-33, MCP-1, and MIP-1-beta; modulated expression of one or more pro-inflammatory cytokines in one or more cells selected from macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; modulated expression of one or more anti-inflammatory cytokines, optionally wherein the one or more anti-inflammatory cytokines are selected from IL-4, IL-10, IL-13, IL-35, IL-16, TGF-beta, IL-1Ra, G-CSF, and soluble receptors for TNF, IFN-beta1a, IFN-betalb, or IL-6; modulated expression of one or more anti-inflammatory cytokines in one or more cells selected from macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, and microglial cells; modulate expression of one or more proteins selected from C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and PYCARD; inhibition of extracellular signal-regulated kinase (ERK) phosphorylation; decreasing tyrosine phosphorylation on one or more cellular proteins, optionally, wherein the one or more cellular proteins comprise ZAP-70 and the tyrosine phosphorylation occurs on Tyr-319 of ZAP-70; modulated expression of C-C chemokine receptor 7 (CCR7); inhibition of microglial cell chemotaxis toward CCL19-expressing and CCL21-expressing cells; decreasing T cell proliferation induced by one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, and M2 NK cells; inhibition of osteoclast production, decreased rate of osteoclastogenesis, or both; decreasing survival of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; decreasing proliferation of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting migration of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting one or more functions of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibiting maturation of one or more cells selected from dendritic cells, bone marrow-derived dendritic cells, macrophages, neutrophils, NK cells, M1 macrophages, M1 neutrophils, M1 NK cells, activated M1 macrophages, activated M1 neutrophils, activated M1 NK cells, M2 macrophages, M2 neutrophils, M2 NK cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; inhibition of one or more types of clearance selected from apoptotic neuron clearance, nerve tissue debris clearance, dysfunctional synapse clearance, non-nerve tissue debris clearance, bacteria clearance, other foreign body clearance, disease-causing protein clearance, disease-causing peptide clearance, and tumor cell clearance; optionally wherein the disease-causing protein is selected from amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides and the tumor cell is from a cancer selected from bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer; inhibition of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, dysfunctional synapses, non-nerve tissue debris, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, or tumor cells; optionally wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and the tumor cells are from a cancer selected from bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer; binding to Siglec-9 ligand on tumor cells; binding to Siglec-9 ligand on cells selected from neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, and NK cells; inhibition of tumor cell killing by one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibiting anti-tumor cell proliferation activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibition of anti-tumor cell metastasis activity of one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; modulated expression of one or more inflammatory receptors, optionally wherein the one or more inflammatory receptors comprise CD86 and the one or more inflammatory receptors are expressed on one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; inhibition of one or more ITAM motif containing receptors, optionally wherein the one or more ITAM motif containing receptors are selected from TREM1, TREM2, Sirp beta, FcgR, DAP10, and DAP12; inhibition of signaling by one or more pattern recognition receptors (PRRs), optionally wherein the one or more PRRs are selected from receptors that identify pathogen-associated molecular patterns (PAMPs), receptors that identify damage-associated molecular patterns (DAMPs), and any combination thereof; inhibition of one or more receptors comprising the motif D / Ex 0-2 YxxL / IX 6-8 YxxL / I (SEQ ID NO: 252); inhibition of signaling by one or more Toll-like receptors; inhibition of the JAK-STAT signaling pathway; inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB); de-phosphorylation of an ITAM motif containing receptor; modulated expression of one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells, optionally wherein the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells comprise CD86, C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and / or PYCARD, and the one or more inflammatory receptors, proteins of the complement cascade, and / or receptors that are expressed on immune cells are expressed on one or more of microglia, macrophages, neutrophils, NK cells, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; increasing expression of one or more Siglec-9-dependent genes; normalization of disrupted Siglec-9-dependent gene expression; decreasing expression of one or more ITAM-dependent genes, optionally wherein the one more ITAM-dependent genes are activated by nuclear factor of activated T cells (NFAT) transcription factors; promoting or rescuing functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells; increasing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated neutrophils, tumor-associated NK cells, and regulatory T cells into tumors; increasing the number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; enhancing tumor-promoting activity of myeloid-derived suppressor cells; increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10; increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC); decreasing activation of tumor-specific T lymphocytes with tumor killing potential; decreasing infiltration of tumor-specific NK cells with tumor killing potential; decreasing the tumor killing potential of NK cells; decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; increasing tumor volume; increasing tumor growth rate; increasing metastasis; increasing rate of tumor recurrence; decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from PD1 / PDL1, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, LIGHT, BTLA, CD30, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR, LAG3, DR-5, CD2, CD5, TREM1, TREM2, CD39, CD73, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines; inhibition of PLCy / PKC / calcium mobilization; inhibition of PI3K / Akt, Ras / MAPK signaling; enhancement of infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, myeloid derived suppressor cells, tumor-associated macrophages, immunosuppressor neutrophils, non-tumorigenic CD45 +< CD14 +< myeloid cells, and regulatory T cells into tumors; increase in the number of tumor-promoting myeloid / granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; (r) enhancing tumor-promoting activity of non-tumorigenic myeloid-derived suppressor cells and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; enhancement of survival of non-tumorigenic myeloid-derived suppressor cells (MDSC) and / or non-tumorigenic CD45 +< CD14 +< myeloid cells; decrease in activation of tumor-specific T lymphocytes with tumor killing potential; (e) decreasing activation of CD45 +< CD3 +< T lymphocytes with tumor killing potential; decrease in infiltration of tumor-specific NK cells with tumor killing potential; decrease in infiltration of tumor-specific B lymphocytes with potential to enhance immune response; decrease in infiltration of tumor-specific T lymphocytes with tumor killing potential; and decrease in infiltration of CD45 +< CD3 +< T lymphocytes.

[0152] In some embodiments, the anti-Siglec-9 antibodies inhibit interaction (e.g., binding) between a Siglec-9 protein of the present disclosure and one or more Siglec-9 ligands including, without limitation, Siglec-9 ligands expressed on red blood cells, Siglec-9 ligands expressed on bacterial cells, Siglec-9 ligands expressed on apoptotic cells, Siglec-9 ligands expressed on nerve cells, Siglec-9 ligands expressed on glia cells, Siglec-9 ligands expressed on microglia, Siglec-9 ligands expressed on astrocytes, Siglec-9 ligands expressed on tumor cells, Siglec-9 ligands expressed on viruses, Siglec-9 ligands expressed on dendritic cells, Siglec-9 ligands bound to beta amyloid plaques, Siglec-9 ligands bound to Tau tangles, Siglec-9 ligands on disease-causing proteins, Siglec-9 ligands on disease-causing peptides, Siglec-9 ligands expressed on macrophages, Siglec-9 ligands expressed on neutrophils, Siglec-9 ligands expressed on natural killer cells, Siglec-9 ligands expressed on monocytes, Siglec-9 ligands expressed on T cells, Siglec-9 ligands expressed on T helper cells, Siglec-9 ligands expressed on cytotoxic T cells, Siglec-9 ligands expressed on B cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor dendritic cells, Siglec-9 ligands expressed on tumor-imbedded immunosuppressor macrophages, Siglec-9 ligands expressed on myeloid-derived suppressor cells, Siglec-9 ligands expressed on regulatory T cells, secreted mucins, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,8-disialyl containing glycolipids, branched alpha-2,6-linked sialic acid-containing glycoproteins, terminal alpha-2,6-linked sialic acid-containing glycolipids, terminal alpha-2,3-linked sialic acid-containing glycoproteins, and gangliosides (e.g., disialogangliosides).

[0153] In some embodiments, anti-Siglec-9 antibodies of the present disclosure bind to a Siglec-9 protein of the present disclosure expressed on the surface of cell and the naked antibodies inhibit interaction (e.g., binding) between the Siglec-9 protein and one or more Siglec-9 ligands. In some embodiments, anti-Siglec-9 antibodies of the present disclosure that bind to a Siglec-9 protein of the present disclosure inhibit interaction (e.g., binding) between the Siglec-9 protein and one or more Siglec-9 ligands by reducing the effective levels of Siglec-9 that is available to interact with these proteins either on the cell surface or inside the cell. In some embodiments, anti-Siglec-9 antibodies of the present disclosure that bind to a Siglec-9 protein of the present disclosure inhibit interaction (e.g., binding) between the Siglec-9 protein and one or more Siglec-9 ligands by inducing degradation of Siglec-9.

[0154] In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody exhibits one or more activities selected from the group consisting of consisting of: (a) increasing the number of tumor infiltrating CD3 +< T cells; (b) decreasing cellular levels of Siglec-9 in non-tumorigenic CD14+ myeloid cells, optionally wherein the non-tumorigenic CD14+ myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14+ myeloid cells are present in blood; (c) reducing the number of non-tumorigenic CD14+ myeloid cells, optionally wherein the non-tumorigenic CD14+ myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14+ myeloid cells are present in blood; (d) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (e) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (f) reducing B7-H2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (g) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (h) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (i) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (j) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC); (k) decreasing tumor growth rate of solid tumors; (l) reducing tumor volume; (m) increasing efficacy of one or more PD-1 inhibitors; (n) increasing efficacy of one or more checkpoint inhibitor therapies and / or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and / or immune-modulating therapies target one or more of CTLA4, the adenosine pathway, PD-L1, PD-L2, PD-L1, PD-L2, OX40, TIM3, LAG3, or any combination thereof; (o) increasing efficacy of one or more chemotherapy agents, optionally wherein the one or more of the chemotherapy agents are gemcitabine, capecitabine, anthracyclines, doxorubicin (Adriamycin ®< ), epirubicin (Ellence ®< ), taxanes, paclitaxel (Taxol ®< ), docetaxel (Taxotere ®< ), 5-fluorouracil (5-FU), cyclophosphamide (Cytoxan ®< ), carboplatin (Paraplatin ®< ), and any combination thereof; (p) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC); (q) inhibiting differentiation, survival, and / or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC); and (r) killing Siglec-9-expressing immunosuppressor non-tumorigenic myeloid cells and / or non-tumorigenic CD 14-expressing cells in solid tumors and associated blood vessels when conjugated to a chemical or radioactive toxin. In some embodiments that may be combined with any of the preceding embodiments, the anti-Siglec-9 antibody is not conjugated to an agent, optionally wherein the agent is drug, toxi...

Claims

1. An isolated anti-Siglec-9 antibody; wherein the anti-Siglec-9 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, and the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 26.

2. The anti-Siglec-9 antibody of claim 1, wherein the antibody is of the IgG class, the IgM class, or the IgA class.

3. The anti-Siglec-9 antibody of claim 2, wherein the anti-Siglec-9 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

4. The anti-Siglec-9 antibody of claim 3, wherein the anti-Siglec-9 antibody has a murine IgG1 isotype.

5. The anti-Siglec-9 antibody of claim 3, wherein: (a) the anti-Siglec-9 antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, T394D, and any combination thereof, wherein the numbering of the residues is according to EU numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236; (b) the anti-Siglec-9 antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 171), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and / or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU numbering; (c) the anti-Siglec-9 antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof, wherein the numbering of the residues is according to EU numbering; (d) the anti-Siglec-9 antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, E233P, F234V, L234A / F234A, S228P, S241P, L248E, T394D, N297A, N297Q, L235E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or (e) the anti-Siglec-9 antibody has a hybrid IgG2 / 4 isotype, and optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU numbering.

6. The anti-Siglec-9 antibody of claim 1, wherein the anti-Siglec-9 antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Siglec-9 or a mammalian Siglec-9 protein, optionally wherein the fragment is an Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

7. The anti-Siglec-9 antibody of any one of claims 1 to 6, wherein the anti-Siglec-9 antibody is a murine antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

8. The anti-Siglec-9 antibody of claim 7, wherein the antibody is a murine antibody.

9. The anti-Siglec-9 antibody of any one of the preceding claims, wherein the anti-Siglec-9 antibody has dissociation constant (KD) for human Siglec-9 and mammalian Siglec-9 that ranges from about 10 nM to about 10 pM, or less than 10 pM, wherein the KD is determined by bio-layer interferometry at a temperature of 25°C.

10. The anti-Siglec-9 antibody of any one of the preceding claims, wherein the anti-Siglec-9 antibody has dissociation constant (KD) for human Siglec-9 that ranges from about 9 nM to about 230 pM, or less than 230 pM, wherein the KD is determined by bio-layer interferometry at a temperature of 25°C.

11. An isolated nucleic acid comprising a nucleic acid sequence encoding the anti-Siglec-9 antibody of any one of the preceding claims.

12. A vector comprising the nucleic acid of claim 11.

13. An isolated host cell comprising the vector of claim 12.

14. A method of producing an anti-Siglec-9 antibody, comprising culturing the host cell of claim 13 so that the anti-Siglec-9 antibody is produced.

15. A pharmaceutical composition comprising the anti-Siglec-9 antibody of any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

16. The anti-Siglec-9 antibody according to any one of claims 1 to 10, for use in a method of preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer.

17. Use of the anti-Siglec-9 antibody according to any one of claims 1 to 10 in an in vitro method of detecting a Siglec-9 protein in a tissue sample derived from an individual.

18. The anti-Siglec-9 antibody according to any one of claims 1 to 10 for use in a method of diagnosis comprising detecting a Siglec-9 protein in an individual.