Anti-CD33 antibodies and methods of use thereof

Abstract

To provide anti-CD33 antibodies, pharmaceutical compositions, and methods for treating dementia and other diseases.SOLUTION: The present disclosure generally relates to compositions comprising antibodies, such as monoclonal, chimeric, or humanized antibodies, or antibody fragments, that specifically bind to one or more epitopes within a CD33 protein, for example, human or mammalian CD33, and to the use of such compositions for preventing, reducing the risk of, or treating a subject in need thereof.SELECTED DRAWING: Figure 12B

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 175,180, filed June 12, 2015, and U.S. Provisional Patent Application No. 62 / 245,790, filed October 23, 2015, each of which is incorporated by reference herein in its entirety.

[0002] Submission of sequence listing as an ASCII text file The contents of the following submission, an ASCII text file, are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (File Name: 735022000140SEQLISTING.TXT, Date Recorded: June 11, 2016, Size: 247KB).

[0003] The present disclosure relates to anti-CD33 antibodies and therapeutic uses of such antibodies. [Background technology]

[0004] The myeloid cell surface antigen CD33 precursor (CD33), also known as Siglec-3, is a type 1 immunoglobulin-like transmembrane protein expressed on immune and hematopoietic cells, including immature and mature myeloid cells, dendritic cells, and microglial cells (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; Handgretinger et al. (1993) Immunol Lett. 37:223-228; and Hernandez-Caselles et al. (2006) J Leukoc Biol. 79:46-58). CD33 expression is downregulated to low levels on peripheral granulocytes and resident macrophages, and this protein is reported to be absent on astrocytes, oligodendrocytes, endothelial cells, and resting T cells (Griffin JD et al., (1984) Leukemia Research Vol. S, No. 4, pp. 521-534). CD33 is a member of the Siglec family of lectins that bind to sialic acid residues on glycoproteins and glycolipids. One possible binding target of Siglec proteins is gangliosides, glycolipids consisting of ceramide linked to sialylated glycans. Most gangliosides share a common lacto-ceramide core and one or more sialic acid residues. The diversity of Siglec ligands is generated by the addition of other neutral sugars and sialic acids via different linkages, as well as by modification of the sialic acid itself.

[0005] Fourteen Siglec proteins have been identified in humans and nine in mice, which consist of 2–17 extracellular Ig domains including an amino-terminal V-set domain containing a sialic acid binding site. The sialic acid-binding region is located on a V-set Ig-like domain, which contains two aromatic residues and an arginine motif that are 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). Binding sites for sialylated ligands have been mapped by co-crystal structures (Attrill et al., (2006) J. Biol. Chem. 281:32774-32783, and Varki et al., Glycobiology, 16 pp. 1R-27R). Because cell membranes are rich in sialic acid, ligand binding by Siglecs can occur in cis and trans, both of which affect their functional properties. Each Siglec has different binding preferences for the various types of sialylated glycans 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 CD33-related Siglecs, including Siglec-3, contain one or more immunoreceptor tyrosine-based inhibitory motif (ITIM) sequences in their cytoplasmic tails, which can act as inhibitory receptors and negative regulators of immune function by recruiting 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 activation motif (ITAM) sequences in their cytoplasmic tails, which can function as activating receptors and positive regulators of immune function through the 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 cancer types including lymphoma, leukemia, and acute myeloid leukemia, systemic lupus erythematosus, rheumatoid arthritis, neurodegenerative disorders, asthma, allergies, sepsis, chronic obstructive pulmonary disease, graft-versus-host disease, eosinophilia, and osteoporosis (Macauley SM. et al., (2014) Nature Reviews Immunology 14, 653-666).

[0006] Siglec-3 (CD33) was cloned in 1988 (Peiper et al. (1988) Blood. 72:314-321; Simmons and Seed (1988) J Immunol. 141:2797-2800), and selective expression was detected on blast cells, promyelocytes, and myelocytes in the bone marrow, as well as on monocytes in peripheral blood (Griffit JD et al. (1984) Leukemia Research Vol. S, No. 4, pp. 521-534). Expression on a subset of mitogen- or alloantigen-activated human T cells and natural killer (NK) cells has also been reported (Hernandez-Caselles T. et al. (2006) Journal of Leukocyte Biology. 79, 46-58). In addition, CD33 is expressed in 85-90% of adult and pediatric cases of acute myeloid leukemia (Griffin, JD, et al., (1984). Leuk Res 8, 521-534).

[0007] CD33 contains an Ig-like C2-type (immunoglobulin-like) and an Ig-like V-type (immunoglobulin-like) extracellular domain, as well as two ITIM-like motifs in its cytoplasmic domain. Three alternatively spliced ​​forms (isoforms) of CD33 have been identified, including a high-molecular-weight variant designated CD33M, an Ig-like V-type domain (ligand-binding site), and a smaller isoform called CD33m, which lacks the disulfide bond connecting the V and C domains. In addition, tissue-specific post-translational modifications of CD33 have been reported (Hernandez-Caselles T. et al., (2006) Journal of Leukocyte Biology. 79, 46-58; and Perez-Oliva et al., (2011) Glycobiol. 21, 757-770). CD33 undergoes ligand-induced phosphorylation at serine 307 (Ser-307) and serine 342 (Ser-342) by protein kinase C (Grobe, K et al., (2002) Blood 99, 3188-3196) and at Tyr-340 and Tyr-358 by Src family tyrosine kinases such as LCK (Paul, SP, et al., (2000) Blood 96, 483-490).

[0008] After phosphorylation of its ITIM domain, primarily at Tyr-340 and further at Tyr-358, CD33 associates with SHP-2 / PTPN11 and SHP-1 / PTPN6. The association of these phosphatases with CD33 is enhanced after co-ligation of CD33 with CD64 (Taylor, VC et al., (1999), J. Biol. Chem. 274, 11505-11512). Phosphatase activity is associated with decreased intracellular calcium mobilization and decreased tyrosine phosphorylation of several proteins (Ulyanova, T., et al., (1999) Eur J Immunol 29, 3440-3449; Paul, SP, et al., (2000) Blood 96, 483-490), and is also associated with blockade of signal transduction and immune responses, in part by dephosphorylation of signaling molecules on adjacent activating receptors, including those containing ITAM motifs, pattern recognition receptors, Toll-like receptors, and damage-associated molecular pattern (DAMP) receptors. CD33 activation also results in the tyrosine phosphorylation of and association with the proto-oncogenes c-Cbl, Vav, and Syk (Balaian, L. et al., (2001) Leuk Res 25, 1115-1125). c-Cbl is an E3 ubiquitin ligase that induces CBL-dependent ubiquitination and proteosomal degradation of retinoic acid-inducible genes, including CD33, upon activation (Taylor et al. (1999) J Biol Chem. 274:11505-11512, Ulyanova et al. (1999) Eur J Immunol. 29:3440-3449, Paul et al. (2000) Blood. 96:483-490, and Lajaunias et al. (2005) Eur J Immunol. 35:243-251). Some, but not all, Siglec ligands induce receptor downregulation (Macauley SM et al. (2014) Nature Reviews Immunology 14, 653-666).Similar mechanisms of ligand-induced receptor degradation have 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).

[0009] Activation of CD33 signaling has also been shown to be associated with decreased production of the proinflammatory cytokines IL-1 beta, IL-8, and TNF-alpha from innate immune cells. These activities of CD33 are thought to be mediated by activation of phosphoinositide 3-kinase (PI3K) (Lajaunias F. et al. (2005). Eur. J. Immunol. 2005. 35:243-251). It has been proposed that the association between ITIM-containing Siglec receptors and activated receptors may be mediated by extracellular ligands that bind and crosslink these receptors (Macauley SM. et al. (2014) Nature Reviews Immunology 14, 653-666).

[0010] Several studies have demonstrated the inhibitory role of CD33 in regulating innate immunity and mediating cell-cell interactions that inhibit or limit immune responses (Crocker et al., (2012) Ann. NY Acad. Sci. 1253, 102-111; Pillai et al., (2012) Annu. Rev. Immunol. 30, 357-392; von Gunten and Bochner (2008) Ann. NY Acad. Sci. 1143, 61-82; Griciuc et al., (2013) Neuron 78, 1-13; Ferlazzo et al. (2000) Eur J Immunol. 30:827-833; Vitale et al. (2001) Proc Natl Acad Sci USA. 98:5764-5769; and Hernandez-Caselles T. et al. (Brinkman-Van der Linden et al., (2003) Mol. Cell. Biol. 23, 4199-4206). CD33 inactivation in mice does not result in obvious developmental, histological, or behavioral abnormalities, and CD33-deficient mice reproduce normally, indicating that CD33 is not an essential gene and its function may be limited to innate immunity (Brinkman-Van der Linden et al., (2003) Mol. Cell. Biol. 23, 4199-4206).

[0011] Genome-wide association studies (GWAS) conducted in expanded cohorts (e.g., thousands of individuals) have identified a single nucleotide polymorphism (SNP) in CD33, rs3865444 CC (also known as AKArs3826656) and rs3865444 AA We identified rs3865444 as a genetic regulator of risk for late-onset Alzheimer's disease. AAThe SNP is associated with reduced full-length CD33 protein levels and increased expression of a CD33 isoform lacking the Ig-V ligand-binding domain (Raj T. et al. (2014) Human Molecular Genetics), and has been suggested to confer protection against Alzheimer's disease (AD). In contrast, homozygous rs3865444 CC The heterozygous rs3865444 allele has been suggested to constitute a risk allele for AD and is associated with an approximately seven-fold increase in cell surface expression of full-length CD33 in peripheral blood monocytes of young and elderly individuals. AC showed a 3-4 fold increase in CD33 cell surface expression and is therefore also considered a risk factor for AD. CD33 is expressed during all three stages of activation in microglia and macrophages, but age does not affect CD33 surface expression. The polymorphic allele rs3865444 CC and rs3865444 AC It is also associated with a decreased ability of monocytes to phagocytose amyloid beta 42 (A-beta42) peptide in vitro and an increase in neuritic amyloid pathology and fibrillar amyloid in vivo.

[0012] An increased number of activated human microglia, which may be less functional and unable to clear amyloid beta plaques, has also been reported for the risk allele, rs3865444 C This indicates that the allele is dominant for functional traits and may be involved in amyloid accumulation in the prodromal stage of Alzheimer's disease (AD). Cis associated with increased neuritic amyloid plaque burden, but not with the amount of neurofibrillary tangles (Bradshaw et al., (2013) Nat. Neurosci. 16, 848-850.). This SNP is located upstream of the 5'UTR of the CD33 gene, but may exhibit linkage disequilibrium with functional variant(s) located in the coding region (Bertram, et al. (2008). Am. J. Hum. Genet. 83, 623-632, Hollingworth, et al. (2011) Nat. Genet. 43, 429-435, and Naj, et al. (2011) Nat. Genet. 43, 436-441), which may result in alternative splicing and removal of the ligand-binding domain encoded by exon 2 (Malik et al., (2013) J. Neuros, 33: 13320-13325, and Raj et al., (2014), Human Molecular Genetics, 23, 2729). CD33 mRNA and protein levels, as well as the number of CD33-positive microglia, have been shown to be increased in AD brains compared with age-matched controls. However, rs3865444 AA AD brain microglia from carriers of the rs3865444 allele C Compared to AD brains from carriers of the non-protective allele, it remained associated with lower levels of CD33 expression and reduced levels of insoluble A-beta42 peptide.

[0013] Increased numbers of CD33-immunoreactive microglia have been shown to correlate with elevated levels of insoluble A-beta42 and elevated amyloid plaque burden in Alzheimer's disease (AD) cases. Using semiquantitative histological measures of plaque and neurofibrillary tangle lesions, Walker et al. found that SNP rs3865444 CC (also known as rs3826656) allele and rs3865444 AAThere was no significant difference in pathology between alleles (Walker et al., (2015) Neurobiology of Aging 36 571-582). However, increased expression of CD33 mRNA was associated with increased AD pathology in temporal cortex brain samples (Walker et al., (2015) Neurobiology of Aging 36 571-582).

[0014] Gain- and loss-of-function studies have shown that CD33 is both necessary and sufficient to inhibit microglial uptake of A-beta42. Furthermore, analysis of a CD33m variant lacking the sialic acid-binding V-type immunoglobulin-like (V-Ig) domain demonstrates that sialic acid binding is required for CD33 to mediate inhibition of A-beta42 phagocytosis and clearance by microglia (Perez-Oliva et al., (2011) Glycobiol. 21, 757-770). Furthermore, the APP / PS1 transgenic mouse model of Alzheimer's disease, in which the CD33 gene is ablated, exhibits a significant reduction in insoluble A-beta42 levels and A-beta plaque burden (Griciuc et al., (2013) Neuron 78, 1-13, and Bradshaw et al., (2013) Nat. Neurosci. 16, 848-850).

[0015] In oncology, CD33 variants resulting in reduced expression of CD33 have been shown to be associated with improved survival in childhood acute myeloid leukemia (AML). 3-year overall survival from remission was significantly higher for variant rs35112940. GG The rate was 84% ​​+ / - 8% in patients with rs3865444, which is associated with reduced full-length CD33 expression. AAThe non-protective allele is in strong linkage disequilibrium with the rs12459419 variant. The remission rate for the non-protective allele is 68% + / - 15%. Carriers of the protective allele also have a lower risk of relapse and superior disease-free survival. Similarly, patients homozygous for the less variant allele (TT) of rs12459419, which is associated with a greater than 46% reduction in full-length CD33 expression, are more likely to have a favorable disease outcome than carriers of the CC and CT variants (52% vs. 31%) and are more likely to have significantly lower diagnostic blast CD33 expression than other genotypes. This is also the case in patients treated with anti-CD33 antibodies and toxic calicheamicin-gamma derivatives (Mortland et al., (2013) Clin Cancer Res, 1-8). 2459419 TT Carriers of the allele plus rs12459419 CT Carriers of the allele show a greater than 25% reduction in full-length CD33 expression and also a reduced risk of Alzheimer's disease (Malik M. et al. (2015) Human Molecular Genetics, 1-14). This suggests that reducing CD33 expression or functionality may be beneficial in Alzheimer's disease and cancer. However, no data have been reported regarding the ability of anti-CD33 antibodies to downregulate CD33 or block CD33 ligand / receptor interactions in physiologically relevant primary immune cells.

[0016] Antibodies against CD33 are described, for example, in US7,342,110, US7,557,189, US8119787, US8,337,855, US8,124,069, US5,730,982, US7,695,71, WO2012074097, WO2004043344, WO1993020848, WO2012045752, WO2007014743, WO2003093298, WO2011036183, WO1991009058, WO2008058021, WO2011038301, Hoyer et al. al., (2008) Am.J.Clin. Pathol.129,316-323, Rollins-Raval and Roth, (2012) Histopathology 60,933-942), Perez-Oliva et al., (2011) Glycobiol.21,757-770), Ferlazzo et al. (2000) Eur J Immunol.30:827-833, Vitale et al.,(2001)Proc Natl Acad Sci USA.98:5764-5769,Jandus et al.,(2011)Biochem.Pharmacol.82,323-332,O'Reilly and Paulson,(2009)Trends Pharmacol.Sci.30,240-248, Jurcic,(2012) Curr Hematol Malig Rep 7,65-73, and Ricart,(2011) Clin.Cancer Res.17,6417-6427. However, these antibodies are mainly used to either detect CD33 on cells or target toxins, such as calicheamicin-gamma derivatives, to kill leukemia cells that express CD33. Furthermore, no data has been reported showing the ability of anti-CD33 antibodies to treat solid tumor cells that do not express CD33 by enhancing anti-tumor immune responses.

[0017] Thus, there is a need for therapeutic antibodies to treat one or more diseases, disorders, and conditions associated with unwanted CD33 activity.

[0018] All references cited herein, including patents, patent applications, and patent publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0019] The present disclosure is generally directed to CD33 agents, such as human anti-CD33 antibodies, and methods of using such CD33 agents. The methods provided herein include methods for treating dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy, 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, and pulmonary tuberculosis. Ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration Sexual assault, respiratory tract infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, solid and blood cancers, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL) The methods provided herein find use in preventing, reducing the risk of, or treating individuals with: acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow-derived tumors, tumors expressing CD33, thyroid cancer, infectious diseases, CNS herpes, parasitic infections, trypanosomiasis infections, Cruzi infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, group B streptococcus infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type 1, and Haemophilus influenzae. 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 reducing the activity, functionality, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof.

[0020] Certain aspects of the present disclosure are based, at least in part, on the identification of human anti-CD33 antibodies that can reduce cell surface levels of CD33 on human primary immune cells and CD33-expressing cell lines, and / or that can inhibit binding of CD33 to the CD33 ligand on erythrocytes (see, e.g., Examples 3-5).

[0021] One class of antibodies has been shown to be able to reduce the cell surface levels of CD33 without inhibiting the binding of CD33 ligand to CD33, a second class of antibodies has been shown to be able to inhibit the binding of CD33 ligand to CD33 without reducing the cell surface levels of CD33, and a third class of antibodies has been shown to be able to both reduce the cell surface levels of CD33 and inhibit the binding of CD33 ligand to CD33.

[0022] Surprisingly, a further class of antibodies has been shown to bind to CD33 without reducing cell surface levels of CD33 and without inhibiting binding of CD33 ligand to CD33 (see, e.g., Example 5).

[0023] Accordingly, certain embodiments of the present disclosure relate to isolated human anti-CD33 antibodies (e.g., monoclonal anti-CD33 antibodies) that reduce cellular levels of CD33, or inhibit the interaction between CD33 and one or more CD33 ligands, or both. Other embodiments of the present disclosure relate to isolated human anti-CD33 antibodies, which bind to CD33 in a pH-dependent manner.

[0024] Other aspects of the present disclosure relate to agents that reduce cellular levels of CD33 or inhibit the interaction between CD33 and one or more CD33 ligands, or both. In some embodiments, the agent is selected from the group consisting of an antibody, a soluble CD33 receptor, a CD33-Fc fusion protein, a CD33 immunoadhesin, a soluble Siglec receptor that binds one or more CD33 ligands, 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, the agent is an isolated (e.g., monoclonal) anti-CD33 antibody.

[0025] In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody reduces cell surface levels of CD33, reduces intracellular levels of CD33, reduces total levels of CD33, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody induces CD33 degradation, CD33 cleavage, CD33 internalization, CD33 shedding, downregulation of CD33 expression, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody reduces cellular levels of CD33 without inhibiting the interaction between CD33 and one or more CD33 ligands. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody reduces cellular levels of CD33 and inhibits the interaction between CD33 and one or more CD33 ligands. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces cellular levels of CD33 in vivo. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody inhibits the interaction between CD33 and one or more CD33 ligands without reducing cellular levels of CD33. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody inhibits cell surface clustering of CD33. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody inhibits one or more CD33 activities. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities are (a) CD33 binding to sialic acid-containing glycoproteins, or sialic acid-containing glycolipids, or both; (b) CD33 binding to SHP1 or SHP2; (c) phosphorylation of Tyr-340, or Tyr-358, 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, and FYM; (d) phosphorylation of Ser-307, or Ser-342, or both, optionally induced by protein kinase C; (e) modulation of 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-beta 1a, IFN-beta 1b, or IL-6; (f) modulation of expression of macrophages, dendritic cells, bone marrow, or the like. (g) modulating the expression of one or more anti-inflammatory cytokines in one or more cells selected from the group consisting of bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (g) modulating the expression of one or more pro-inflammatory cytokines, optionally the one or more pro-inflammatory cytokines being IFN-α4, IFN-b, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11 (h) modulation of the expression of one or more pro-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (i) C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA,(j) inhibiting extracellular signal-regulated kinase (ERK) phosphorylation; (k) reducing tyrosine phosphorylation on multiple cellular proteins; (l) modulating the expression of CC chemokine receptor 7 (CCR7); (m) inhibiting microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; (n) inhibiting the expression of dendritic cells, bone marrow-derived dendritic cells, monocytes, and microglial cells; (o) inhibiting osteoclast production or decreasing the rate of osteoclast formation, or both; (p) inhibiting T cell proliferation induced by one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, eosinophils, and eosinophils; (q) reducing the survival of one or more cells selected from the group consisting of neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (q) reducing the proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (r) dendritic cells. inhibiting the migration of one or more cells selected from the group consisting of: (s) dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia;(t) decreasing one or more functions of one or more cells selected from the group consisting of neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (t) inhibiting the maturation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia. (u) inhibition of clearance of one or more selected from the group consisting of apoptotic neuron clearance, neural tissue debris clearance, dysfunctional synapse clearance, non-neural tissue debris clearance, bacterial clearance, other foreign body clearance, pathogenic protein clearance, pathogenic peptide clearance, and tumor cell clearance, wherein optionally the pathogenic protein is amyloid beta, oligomeric amyloid beta, amyloid beta plaque, amyloid precursor protein or a fragment 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 bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, the tumor cell is selected from the group consisting of gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin, and proline-arginine (PR) repeat peptide; and the tumor cell is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer,(v) inhibiting phagocytosis of one or more of apoptotic neurons, neural tissue debris, dysfunctional synapses, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells, wherein optionally the pathogenic nucleic acid is an antisense GGCCCC(G2C4) repeat expanded RNA, and the pathogenic protein is amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid peptides, or tumor cells; Id 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 bodies, 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 (w) binding to a CD33 ligand on tumor cells; (x) binding to a CD33 ligand on cells selected from the group consisting of neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages; (y) binding to a CD33 ligand on cells selected from the group consisting of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, and T helper cells;or cytotoxic T cells; (z) inhibiting the anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (aa) inhibiting the anti-tumor cell metastasis activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (bb) inhibiting 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, FcgR, DAP10, and DAP12; (cc) inhibiting 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 recognize pathogen-associated molecular patterns (PAMPs), receptors that recognize damage-associated molecular patterns (DAMPs), and any combination thereof; (dd) motif D / Ex; 0~2 YxxL / IX 6~8(ee) inhibition of signal transduction by one or more Toll-like receptors; (ff) inhibition of the JAK-STAT signaling pathway; (gg) inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB); (hh) dephosphorylation of ITAM motif-containing receptors; (ii) modulation of expression of one or more inflammatory receptors, optionally wherein the one or more inflammatory receptors comprise CD86, and wherein the one or more inflammatory receptors are expressed on one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (jj) increasing expression of one or more CD33-dependent genes. (kk) normalizing disruption of CD33-dependent gene expression; (ll) reducing expression of one or more ITAM-dependent genes, optionally wherein the one or more ITAM-dependent genes are activated by the nuclear factor of activated T cells (NFAT) transcription factor; (mm) promoting differentiation of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells; (nn) promoting functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells; (oo) promoting differentiation of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells. (pp) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs; (qq) enhancing the tumor-promoting activity of myeloid-derived suppressor cells; (rr) increasing the expression of tumor-promoting cytokines in tumors or peripheral blood, where the tumor-promoting cytokines are TGF-beta or IL-10; (ss) increasing the tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (tt) enhancing the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs); (uu) decreasing the activation of tumor-killing tumor-specific T lymphocytes; (vv) decreasing the infiltration of tumor-killing tumor-specific NK cells; (ww) decreasing the tumor-killing activity of NK cells; (xx) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs ... (yy) increasing tumor volume; (zz) increasing tumor growth rate; (aaa) increasing metastasis; (bbb) increasing tumor recurrence rate; (ccc) decreasing the effectiveness of one or more immunotherapies that modulate anti-tumor T cell responses, optionally wherein the one or more immunotherapies are CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, P D-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, DR-5, TREM1, TREM2, CSF-1 receptor, and any combination thereof, or one or more cancer vaccines; (ddd) inhibition of PLCγ / 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 CD33 activities are (a) CD33 binding to sialic acid-containing glycoproteins, or sialic acid-containing glycolipids, or both; (b) modulation of 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-beta 1a, IFN-beta 1b, or IL-6. (c) modulating the expression of one or more anti-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (d) modulating the expression of one or more pro-inflammatory cytokines, optionally the one or more pro-inflammatory cytokines being IFN-α4, IFN-b, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-α-gamma ... (e) modulation of expression of one or more proinflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (f) modulation of expression of one or more proinflammatory cytokines in one or more cells selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1qD, C1qE, C1qF, C1qH, C1qI ... (g) modulation of the expression of one or more proteins selected from the group consisting of R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, CD14, CD16, HLA-DR, and CCR2; (g) modulation of the expression of one or more proteins selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, M2 microglia, macrophages, M1 macrophages, and activated M1 macrophages;and M2 macrophages; (h) reducing the proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (i) reducing the proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M (j) decreasing one or more functions of one or more cells selected from the group consisting of M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (j) inhibiting phagocytosis of one or more of apoptotic neurons, neural tissue debris, dysfunctional synapses, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells. Optionally, the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat expanded RNA, and the pathogenic protein is amyloid beta, oligomeric amyloid beta, amyloid beta plaque, amyloid precursor protein or a fragment 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, or ataxin 2. , ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta2 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,(k) binding to CD33 ligand on tumor cells; (l) binding to neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, and macrophages; (l) binding to CD33 ligand on tumor cells ... (m) inhibiting tumor cell killing by one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (n) inhibiting the anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (o) inhibiting the anti-tumor cell proliferation activity of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, or immunosuppressive macrophages. (p) enhancing the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells into tumors; (q) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs; (r) enhancing the tumor-promoting activity of myeloid-derived suppressor cells; (s) enhancing the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs). (t) reducing the activation of tumor-specific T lymphocytes with tumor-killing ability; (u) reducing the infiltration of tumor-specific NK cells with tumor-killing ability; (v) reducing the infiltration of tumor-specific B lymphocytes with the ability to enhance immune responses; (w) reducing the infiltration of tumor-specific T lymphocytes with tumor-killing ability; (x) increasing tumor volume; (y) increasing tumor growth rate; and (z) reducing the effectiveness of one or more immunotherapies that modulate anti-tumor T cell responses, optionally wherein the one or more immunotherapies are selected from the group consisting of CD40,or one or more cancer vaccines. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include CD33 binding to sialic acid-containing glycoproteins, sialic acid-containing glycolipids, or both. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include CD33 binding to SHP1 or SHP2. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include phosphorylation of Tyr-340 or Tyr-358, 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, and FYM. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include phosphorylation of Ser-307 or Ser-342, or both, optionally wherein the phosphorylation is induced by protein kinase C. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulating 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-beta 1a, IFN-beta 1b, or IL-6. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulating expression of one or more anti-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulation of expression of one or more proinflammatory cytokines, optionally wherein the one or more proinflammatory cytokines are selected from the group consisting of IFN-α4, IFN-β, IL-1β, TNF-α, IL-6, IL-8, CRP, an IL-20 family member, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP, IL-33, MIP-1-beta, and MCP-1. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulation of expression of one or more proinflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulating the 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. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting extracellular signal-regulated kinase (ERK) phosphorylation. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing tyrosine phosphorylation on multiple cellular proteins. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulating the expression of CC chemokine receptor 7 (CCR7). In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing 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, M1 macrophages, activated M1 macrophages, and M2 macrophages. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting osteoclast production or reducing the rate of osteoclast formation, or both. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing survival of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting migration of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities comprise decreasing one or more functions in one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities comprise inhibiting maturation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities comprise inhibition of clearance of one or more selected from the group consisting of apoptotic neuron clearance, neural tissue debris clearance, dysfunctional synapse clearance, non-neural tissue debris clearance, bacterial clearance, other foreign body clearance, pathogenic protein clearance, pathogenic peptide clearance, and tumor cell clearance, and optionally the pathogenic 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 bodies, 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 The tumor cell is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting phagocytosis of one or more of apoptotic neurons, neural tissue debris, dysfunctional synapses, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells; and optionally, the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat expanded RNA; and the pathogenic protein is 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 9, amyloid precursor protein ... Taxin 10, Lewy bodies, 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 and the tumor cell is a cell of a cancer selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include binding to a CD33 ligand on the tumor cell.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include binding to a CD33 ligand on cells selected from the group consisting of neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting tumor cell killing by one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibiting anti-tumor cell metastasis activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include 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, FcgR, DAP10, and DAP12. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include 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 recognize pathogen-associated molecular patterns (PAMPs), receptors that recognize damage-associated molecular patterns (DAMPs), and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include: In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities are mediated by the motif D / Ex. 0~2 YxxL / IX 6~8In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of one or more receptors comprising YxxL / I (SEQ ID NO: 451). In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of signaling by one or more Toll-like receptors. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of the JAK-STAT signaling pathway. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include dephosphorylation of an ITAM motif-containing receptor. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include modulating expression of one or more inflammatory receptors, optionally wherein the one or more inflammatory receptors include CD86, and wherein the one or more inflammatory receptors are expressed on one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing expression of one or more CD33-dependent genes. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include normalizing disruption of CD33-dependent gene expression. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include decreasing expression of one or more ITAM-dependent genes, optionally wherein the one or more ITAM-dependent genes are activated by the nuclear factor of activated T cells (NFAT) transcription factor. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include promoting differentiation of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include promoting the functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include enhancing the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells into tumors. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include enhancing the tumor-promoting activity of myeloid-derived suppressor cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing expression of a tumor-promoting cytokine in the tumor or in peripheral blood, where optionally the tumor-promoting cytokine is TGF-beta or IL-10. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include enhancing the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs). In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing activation of tumor-specific T lymphocytes with tumor-killing potential. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing infiltration of tumor-specific NK cells with tumor-killing potential. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities comprises reducing the tumor-killing ability of NK cells.In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing the infiltration of tumor-specific B lymphocytes capable of enhancing an immune response. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing tumor volume. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing tumor growth rate. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing metastasis. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include increasing tumor recurrence rate. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include reducing the effectiveness of one or more immunotherapies that modulate anti-tumor T-cell responses, optionally wherein the one or more immunotherapies modulate 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. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of PLCγ / PKC / calcium mobilization. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 activities include inhibition of PI3K / Akt, Ras / MAPK signaling. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is not conjugated to the agent, and optionally the agent is a drug, toxin, chemotherapeutic agent, or radioisotope.

[0026] In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is selected from the group consisting of: i. amino acid residues 39-51 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51 of SEQ ID NO:1; ii. amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO:1; iii. amino acid residues 42-56 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 42-56 of SEQ ID NO:1; iv. amino acid residues 44-52 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO:1; amino acid residues 44 to 52 and 114 to 122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52 and 114 to 122 of SEQ ID NO: 1; vi. amino acid residues 44 to 52 and 241 to 248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52 and 241 to 248 of SEQ ID NO: 1; vii. amino acid residues 44 to 52, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1; viii. amino acid residues 44 to 53 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 53 of SEQ ID NO: 1; ix.amino acid residues 44 to 53, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 53, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1; x. amino acid residues 45 to 52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 52 of SEQ ID NO: 1; xi. amino acid residues 45 to 55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 55 of SEQ ID NO: 1 xii. amino acid residues 45 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1; xiii. amino acid residues 45 to 55, 64 to 71, 76 to 86, 118 to 128, and 241 to 249 of SEQ ID NO: 1, or amino acids on a mammalian CD33 protein corresponding to amino acid residues 45 to 55, 64 to 71, 76 to 86, 118 to 128, and 241 to 249 of SEQ ID NO: 1. residues, xiv. amino acid residues 49 to 55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49 to 55 of SEQ ID NO: 1; xv. amino acid residues 49 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1; xvi. amino acid residues 64 to 71 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 64 to 71 of SEQ ID NO: 1. xvii. amino acid residues 76 to 86 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 76 to 86 of SEQ ID NO: 1; xviii. amino acid residues 84 to 98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84 to 98 of SEQ ID NO: 1; xix. amino acid residues 84 to 98 and 111 to 122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84 to 98 and 111 to 122 of SEQ ID NO: 1; xx.amino acid residues 88 to 98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 88 to 98 of SEQ ID NO: 1; xxi. amino acid residues 93 to 103 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 93 to 103 of SEQ ID NO: 1; xxii. amino acid residues 109 to 118 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109 to 118 of SEQ ID NO: 1; xxiii. amino acid residues 110 to 120 of SEQ ID NO: 1, or a sequence xxiv. amino acid residues 110 to 121 of SEQ ID NO: 1 or amino acid residues 110 to 121 of SEQ ID NO: 1 on a mammalian CD33 protein; xxv. amino acid residues 111 to 122 of SEQ ID NO: 1 or amino acid residues 111 to 122 of SEQ ID NO: 1 on a mammalian CD33 protein; xxvi. amino acid residues 112 to 122 of SEQ ID NO: 1 or amino acid residues 112 to 122 of SEQ ID NO: 1 on a mammalian CD33 protein. xxvii. amino acid residues 114 to 122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 114 to 122 of SEQ ID NO: 1; xxviii. amino acid residues 117 to 130 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 117 to 130 of SEQ ID NO: 1; xxix. amino acid residues 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 118 to 128 of SEQ ID NO: 1. xxx. amino acid residues 137 to 147 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137 to 147 of SEQ ID NO: 1; xxxi. amino acid residues 183 to 197 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183 to 197 of SEQ ID NO: 1; and xxxii. amino acid residues 241 to 245 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 245 of SEQ ID NO: 1; xxxiii.The antibody binds to one or more amino acids within an amino acid residue selected from the group consisting of amino acid residues 241 to 247 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 247 of SEQ ID NO: 1, xxxiv. amino acid residues 241 to 248 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 248 of SEQ ID NO: 1, and xxxv. amino acid residues 241 to 249 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 249 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 44-53 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 44-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-52 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-52 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55, 76-86, 64-71, 118-128, and 241-249 of SEQ ID NO:1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55, 76-86, 64-71, 118-128, and 241-249 of SEQ ID NO:1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 47-53 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 47-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-53 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-55 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 50-55 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 50-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 64-71 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 64-71 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 76-86 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 76-86 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 84-98 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 84-98 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 84-98 and 111-122 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 84-98 and 111-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 88-98 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 88-98 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 93-103 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 93-103 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 109-118 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 109-118 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 110-120 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 110-120 of SEQ ID NO:1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 110-121 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 110-121 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 111-122 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 111-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 112-122 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 112-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 114-122 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 114-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 117-130 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 117-130 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 118-128 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 118-128 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 137-147 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 137-147 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 183-197 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 183-197 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-245 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-245 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-247 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-247 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-248 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-248 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-249 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-249 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to a discontinuous CD33 epitope.In some embodiments that may be combined with any of the preceding embodiments, the discontinuous CD33 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 ten or more peptides. In some embodiments that may be combined with any of the preceding embodiments, each of the peptides comprises five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or twenty or more amino acid residues in 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, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or twenty or more amino acid residues on a mammalian CD33 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-CD33 antibody binds to a conformational epitope of CD33. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to a conformational epitope of CD33. competes with one or more antibodies selected from the group consisting of C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, C-109, and any combination thereof.

[0027] Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-CD33 antibodies, where the anti-CD33 antibodies do not significantly reduce cell surface levels of CD33. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-CD33 antibodies, where the anti-CD33 antibodies do not significantly reduce cell surface levels of CD33 and do not inhibit the interaction between CD33 and one or more CD33 ligands. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces the cellular level of CD33 by less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% when compared to the cellular level of CD33 in the absence of the anti-CD33 antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-247 of SEQ ID NO:1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO:1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody competes for binding to CD33 with one or more antibodies selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof.

[0028] In some embodiments that may be combined with any of the preceding embodiments, the cellular level of CD33 is measured on primary cells or on a cell line selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages, and the cellular level of CD33 is measured using an in vitro cell assay. In some embodiments that may be combined with any of the preceding embodiments, the one or more CD33 ligands are a CD33 ligand expressed on red blood cells, a CD33 ligand expressed on bacterial cells, a CD33 ligand expressed on apoptotic cells, a CD33 ligand expressed on tumor cells, a CD33 ligand expressed on viruses, a CD33 ligand expressed on dendritic cells, a CD33 ligand expressed on neurons, a CD33 ligand expressed on gala cells, a CD33 ligand expressed on microglia, a CD33 ligand expressed on astrocytes, a CD33 ligand on beta-amyloid plaques, a CD33 ligand on tau tangles, a CD33 ligand on a pathogenic protein, a CD33 ligand on a pathogenic peptide, a CD33 ligand expressed on macrophages, a CD33 ligand expressed on natural killer cells, The CD33 ligand is selected from the group consisting of CD33 ligand, CD33 ligand expressed on T cells, CD33 ligand expressed on T helper cells, CD33 ligand expressed on cytotoxic T cells, CD33 ligand expressed on B cells, CD33 ligand expressed on tumor-buried immunosuppressive dendritic cells, CD33 ligand expressed on tumor-buried immunosuppressive macrophages, CD33 ligand expressed on myeloid-derived suppressor cells, CD33 ligand expressed on regulatory T cells, secreted mucin, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,6-linked sialic acid-containing glycolipids, alpha-2,6-linked sialic acid-containing glycoproteins, alpha-2,3-linked sialic acid-containing glycolipids, alpha-2,3-linked sialic acid-containing glycoproteins, alpha-1-acid glycoprotein (AGP), CD24 protein, and gangliosides.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain, or the heavy chain variable domain, or both, are selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-50, C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-6 5, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-8 and C-7, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, and C-109. In some embodiments that may be combined with any of the preceding embodiments, (a) HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, (b) HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38, (c) HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, (d) HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, (e) HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, or (f) HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; and (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115. and HVR-L3 comprising an amino acid sequence having homology to the amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136, and the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230. In some embodiments that may be combined with any of the preceding embodiments, (1) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 39, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 161; (2) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 162; (3) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 41, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 163; (4) HVR-L (1) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 42, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 164; (5) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, and HVR- (6) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 44, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 166, (7) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29,HVR-L3 comprises the amino acid sequence of SEQ ID NO: 45, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 167; (8) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 46, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 119, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 168. (9) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 47, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 169; (10) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 48, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 11 (11) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 30, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 49, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 163; (12) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, and HVR HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 50, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 121, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 170; (13) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 51, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 171, (14) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 52, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 123, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 172, (15) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 53 (16) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 54, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 174. (17) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 174. HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 56, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 175; (18) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 56, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 175; (19) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 57, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 177; (20) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 58, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 178; (21) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 59; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 127, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 148, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 179; (22) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 60; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 127, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 149, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 180; (23) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 61; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (24) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 23 (25) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 35, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 63, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 129, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 183; (26) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 64, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181, (27) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 65, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 184, (28) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 66 (29) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 36, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 67, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 185. (30) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 185. HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 68, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 125, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 186, (31) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 69, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises (31) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 187; (32) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 70; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 188; (33) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 71, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 189; (34) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 37, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 72, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, and HVR-H2 comprises SEQ ID NO: 14; (35) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 73, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 191; (36) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 192; (37) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 75, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 193. (38) HVR HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 76, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 194, (39) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 77, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR -H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 195; (40) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 78, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 152, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 196; (41) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 79, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 197; (42) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 36, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 80, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 185. (43) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 81, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 198; (44) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 82, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 11 (44) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 153, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 199; (45) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 83; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 154, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 200; (46) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, and HVR- HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 84, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 155, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 201; (47) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 37, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 85, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 202, (48) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 86, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 203, (49) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33 (50) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 38, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 88, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150; HVR-H3 comprises the amino acid sequence of SEQ ID NO: 205, (51) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 89, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181, (52) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27. (53) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 91, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 161; (54) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 21, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 92, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 131, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 157, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 206; (55) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 93, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 132, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 207. (56) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 94, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (57) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 22, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 74, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 12 HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 208; (58) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 95; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 209; (59) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, and HVR- HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 96, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 125, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 146, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 210; (60) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 97, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 211, (61) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 98, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 133, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 212, (62) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 99, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 213, (63) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises SEQ ID NO: 1 00, wherein HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 214; (64) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 101, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 158, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 215; (65) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 102, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 216; (66) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 103, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 217; (67) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 104, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 134, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 218; (68) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 105, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 135; (69) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 106, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 220; (70) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 2 (71) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 108, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 221. (72) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 109, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 223; (73) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 110, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 224; (74) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 71, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 225; (75) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17;HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 111, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 226; (76) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 112, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 130. (77) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 113, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 228. (78) HVR-L1 comprises the amino acid sequence of SEQ ID NO: HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 114, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 229; (79) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 101, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 102; (80) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 115, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 226. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 285-362;and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 363 to 432.

[0029] Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-CD33 antibodies that bind to one or more amino acids within amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:1. In some embodiments, the anti-CD33 antibody is selected from the group consisting of: i. amino acid residues 39-51 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51 of SEQ ID NO: 1; ii. amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1; iii. amino acid residues 42-56 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 42-56 of SEQ ID NO: 1; iv. amino acid residues 44-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO: 1; v. amino acid residues 44-52 and 114-122 of SEQ ID NO: 1, or amino acid residues 44-52 and 114-122 of SEQ ID NO: 1 amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52 and 241 to 248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52 and 241 to 248 of SEQ ID NO: 1; vii. amino acid residues 44 to 52, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 52, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1 3 protein; viii. amino acid residues 44 to 53 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 53 of SEQ ID NO: 1; ix. amino acid residues 44 to 53, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44 to 53, 76 to 86, 64 to 71, and 118 to 128 of SEQ ID NO: 1; x.amino acid residues 45 to 52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 52 of SEQ ID NO: 1; xi. amino acid residues 45 to 55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 55 of SEQ ID NO: 1; xii. amino acid residues 45 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1; xii i. amino acid residues 45 to 55, 64 to 71, 76 to 86, 118 to 128, and 241 to 249 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45 to 55, 64 to 71, 76 to 86, 118 to 128, and 241 to 249 of SEQ ID NO: 1; xiv. amino acid residues 49 to 55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49 to 55 of SEQ ID NO: 1; xv. amino acid residues 49 to 55, 64 to 71, 76 to 86, and 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49 to 55 of SEQ ID NO: 1 xvi. amino acid residues 64 to 71 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 64 to 71 of SEQ ID NO: 1; xvii. amino acid residues 76 to 86 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 76 to 86 of SEQ ID NO: 1; xviii. amino acid residues 84 to 98 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84 to 98 of SEQ ID NO: 1. xix. amino acid residues 84 to 98 and 111 to 122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84 to 98 and 111 to 122 of SEQ ID NO: 1; xx. amino acid residues 88 to 98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 88 to 98 of SEQ ID NO: 1; xxi. amino acid residues 93 to 103 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 93 to 103 of SEQ ID NO: 1; xxii.amino acid residues 109 to 118 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109 to 118 of SEQ ID NO: 1; xxiii. amino acid residues 110 to 120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110 to 120 of SEQ ID NO: 1; xxiv. amino acid residues 110 to 121 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110 to 121 of SEQ ID NO: 1; xxv. amino acid residues 111 to 122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 111 to 122 of SEQ ID NO: 1; xxvi. amino acid residues 112 to 122 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 112 to 122 of SEQ ID NO: 1; xxvii. amino acid residues 114 to 122 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 114 to 122 of SEQ ID NO: 1; xxviii. amino acid residues 117 to 130 of SEQ ID NO: 1 or amino acid residues 117 to 130 of SEQ ID NO: 1 30 of a mammalian CD33 protein; xxix. amino acid residues 118 to 128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 118 to 128 of SEQ ID NO: 1; xxx. amino acid residues 137 to 147 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137 to 147 of SEQ ID NO: 1; xxxi. amino acid residues 183 to 197 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183 to 197 of SEQ ID NO: 1. amino acid residues, and xxxii. amino acid residues 241 to 245 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 245 of SEQ ID NO: 1; xxxiii. amino acid residues 241 to 247 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 247 of SEQ ID NO: 1; xxxiv. amino acid residues 241 to 248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 248 of SEQ ID NO: 1; and xxxv.The antibody binds to one or more amino acids within amino acid residues 241-249 of SEQ ID NO: 1 or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-249 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 44-53 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 44-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-52 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-52 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 45-55, 76-86, 64-71, 118-128, and 241-249 of SEQ ID NO:1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 45-55, 76-86, 64-71, 118-128, and 241-249 of SEQ ID NO:1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 47-53 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 47-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-53 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-53 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-55 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 50-55 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 50-55 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 64-71 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 64-71 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 76-86 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 76-86 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 84-98 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 84-98 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 84-98 and 111-122 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 84-98 and 111-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 88-98 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 88-98 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 93-103 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 93-103 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 109-118 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 109-118 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 110-120 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 110-120 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 110-121 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 110-121 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 111-122 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 111-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 112-122 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 112-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 114-122 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 114-122 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 117-130 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 117-130 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 118-128 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 118-128 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 137-147 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 137-147 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 183-197 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 183-197 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-245 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-245 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-247 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-247 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-248 of SEQ ID NO: 1 or one or more amino acids within the amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-248 of SEQ ID NO: 1.In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-249 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-249 of SEQ ID NO:1.

[0030] Another aspect of the present disclosure relates to isolated (e.g., monoclonal) anti-CD33 antibodies that bind to one or more amino acids within amino acid residues 19-135 or 145-228 of SEQ ID NO:1, or one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 19-135 or 145-228 of SEQ ID NO:1. In some embodiments, the anti-CD33 antibody binds to one or more amino acids selected from the group consisting of: i. amino acid residues 44-52 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO:1; ii. amino acid residues 109-118 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109-118 of SEQ ID NO:1; iii. amino acid residues 112-122 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 112-122 of SEQ ID NO:1; iv. amino acid residues 137-147 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137-147 of SEQ ID NO:1; and v. amino acid residues 183-197 of SEQ ID NO:1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183-197 of SEQ ID NO:1. Another aspect of the present disclosure relates to isolated (e.g., monoclonal) anti-CD33 antibodies that bind to one or more amino acids within amino acid residues 241-247 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein that correspond to amino acid residues 241-247 of SEQ ID NO:1.

[0031] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, or the light chain variable domain, or both, are selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C- C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-50, C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66 , C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C and 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 an antibody selected from the group consisting of C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-109, and any combination thereof.Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, or the light chain variable domain, or both, are C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39 , C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, C-109, and any combination thereof. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, or the light 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 an antibody selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof.In some embodiments that may be combined with any of the preceding embodiments, (a) HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, (b) HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38, (c) HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, (d) HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, (e) HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, or (f) HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230. In some embodiments that may be combined with any of the preceding 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: 9-23, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; and (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115. and HVR-L3 comprising: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230. In some embodiments that may be combined with any of the preceding embodiments, (1) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 39, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 161; (2) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 162; (3) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 41, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 163; (4) HVR-L (1) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 42, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 164; (5) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, and HVR- (6) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 44, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 166, (7) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29,HVR-L3 comprises the amino acid sequence of SEQ ID NO: 45, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 167; (8) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 46, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 119, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 168. (9) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 47, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 169; (10) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 48, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 11 (11) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 30, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 49, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 117, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 163; (12) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, and HVR HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 50, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 121, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 170; (13) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 51, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 171, (14) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 52, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 123, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 172, (15) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 31, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 53 (16) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 54, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 174. (17) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 174. HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 56, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 175; (18) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 56, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 175; (19) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 57, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 177; (20) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 58, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 178; (21) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 59; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 127, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 148, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 179; (22) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 60; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 127, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 149, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 180; (23) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 61; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (24) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 23 (25) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 35, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 63, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 129, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 183; (26) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 64, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181, (27) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 65, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 184, (28) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 66 (29) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 36, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 67, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 185. (30) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 185. HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 68, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 125, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 186, (31) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 69, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises (31) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 187; (32) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 70; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 188; (33) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 71, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 189; (34) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 37, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 72, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, and HVR-H2 comprises SEQ ID NO: 14; (35) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 73, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 191; (36) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 192; (37) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 75, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 193. (38) HVR HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 76, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 194, (39) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 77, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR -H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 195; (40) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 78, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 152, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 196; (41) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 79, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 197; (42) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 36, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 80, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 185. (43) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 81, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 198; (44) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 82, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 11 (44) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 153, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 199; (45) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 83; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 154, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 200; (46) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, and HVR- HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 84, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 155, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 201; (47) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 37, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 85, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 202, (48) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 86, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 151, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 203, (49) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 87, H VR-H1 comprises the amino acid sequence of SEQ ID NO: 130, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 156, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 204; (50) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 38, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 88, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 205; (51) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17; HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 89, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (52) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 90, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (53) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 91, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137; HVR-H3 comprises the amino acid sequence of SEQ ID NO: 161, (54) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 21, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 92, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 131, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 157, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 206; (55) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 93, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 132, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 139, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 207. (56) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 94, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 128, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 150, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 181; (57) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 22, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 74, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 12 HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 208; (58) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 95; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 209; (59) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, and HVR- HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 96, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 125, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 146, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 210; (60) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 97, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142;HVR-H3 comprises the amino acid sequence of SEQ ID NO: 211, (61) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 98, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 133, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 212, (62) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 99, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 213, (63) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises SEQ ID NO: 1 00, wherein HVR-H1 comprises the amino acid sequence of SEQ ID NO: 124, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 144, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 214; (64) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 101, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 158, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 215; (65) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 102, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 138, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 216; (66) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 103, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 217; (67) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 104, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 134, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 218; (68) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 105, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 135; (69) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 106, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 118, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 140, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 220; (70) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 250; 29, wherein HVR-L3 comprises the amino acid sequence of SEQ ID NO: 107, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 136, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 143, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 221, (71) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 108, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 126, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 221. (72) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 109, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 223, (73) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 110, and HVR-H HVR-L1 comprises the amino acid sequence of SEQ ID NO: 120, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 141, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 224; (74) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 34, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 71, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 145, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 225; (75) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17;HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 111, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 226; (76) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 112, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 130. (77) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 113, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 228. (78) HVR-L1 comprises the amino acid sequence of SEQ ID NO: HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 114, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 229; (79) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 101, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 102; HVR-L1 comprises the amino acid sequence of SEQ ID NO: 116, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 137, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 230, or (80) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 115, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 122, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 142, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 226.

[0032] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 285-432. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-CD33 antibodies, wherein the anti-CD33 antibodies are selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97 C-41, C-42, C-43, C-44, C-45, C-47, C-50, C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-109, and any combination thereof. Other aspects of the present disclosure relate to isolated (e.g., monoclonal) anti-CD33 antibodies, wherein the anti-CD33 antibodies are selected from the group consisting of C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-10, C-11, C-12, , C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, C-109, and any combination thereof.Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, which competes for binding to CD33 with one or more antibodies selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof. Other aspects of the present disclosure include C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-50, C and C-109.Other aspects of the present disclosure include C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, The present invention relates to an isolated (e.g., monoclonal) anti-CD33 antibody that binds to essentially the same CD33 epitope as an antibody selected from the group consisting of C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, and C-109. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody that binds to essentially the same CD33 epitope as an antibody selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, and C-95.

[0033] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) anti-CD33 antibody, the anti-CD33 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; and (c) an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115. or the heavy chain variable domain comprises (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136, or an amino acid sequence at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160, or an amino acid sequence at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137 to 160; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230, or an amino acid sequence at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230.

[0034] In some embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, IgM class, or IgA class. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 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 to 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-CD33 antibody has a human IgG1 isotype and is 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, A327 and (b) an anti-CD33 antibody having a human IgG1 isotype and comprising an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, and optionally the IgG2 isotype CH1 and hinge region is selected from the group consisting of: Q, A327G, P329A, K322A, T394D, A330L, and any combination thereof, wherein residue numbering is according to EUt numbering, or an amino acid deletion in the Fc region at a position corresponding to glycine 236; LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 437), optionally wherein the antibody Fc region comprises a S267E amino acid substitution, or a L328F amino acid substitution, or both, and / or a N297A or N297Q amino acid substitution, wherein residue numbering is according to EU numbering; and (c) an anti-CD33 antibody comprising:(d) an anti-CD33 antibody having a human IgG2 isotype and comprising one or more amino acid substitutions in the Fc region at residue positions 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 residue numbering is according to EU numbering; and (d) an anti-CD33 antibody having a human murine IgG4 isotype and comprising one or more amino acid substitutions in the Fc region at residue positions 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 residue numbering is according to EU numbering; or (e) the anti-CD33 antibody has a hybrid IgG2 / 4 isotype, optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, and wherein the residues are numbered according to EU numbering. In some embodiments that may be combined with any of the preceding embodiments, (a) the anti-CD33 antibody has a human IgG1 isotype and is selected from the group consisting of N297A, N297Q, D265A, D270A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, (b) the anti-CD33 antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, T256E, and any combination thereof, wherein residue numbering is according to EU numbering;and any combination thereof, wherein residue numbering is according to EU numbering; or (c) the anti-CD33 antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions 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 residue numbering is according to EU 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, where the residue numbering is according to EU 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, where the residue numbering is according to EU numbering; or (c) the Fc region further comprises a S228P amino acid substitution according to EU numbering. In some embodiments that may be combined with any of the preceding embodiments, the CD33 protein is a mammalian or human protein. In some embodiments that may be combined with any of the preceding embodiments, the CD33 protein is a wild-type protein. In some embodiments that may be combined with any of the preceding embodiments, the CD33 protein is a naturally occurring variant. In some embodiments that may be combined with any of the preceding embodiments, the CD33 protein is expressed on one or more cells selected from the group consisting of human dendritic cells, human macrophages, human monocytes, human osteoclasts, human neutrophils, human T cells, human T helper cells, human cytotoxic T cells, human granulocytes, and human microglia. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is a mammalian CD33 protein, or a human CD33 protein,In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody specifically binds to human CD33, mouse CD33, or both. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to CD33 in a pH-dependent manner. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody binds to CD33 at a pH ranging from 5.5 to 8.0. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody dissociates from CD33 at a pH below 5.0. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human CD33 or a mammalian CD33 protein. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human CD33, naturally occurring variants of human CD33, and disease variants of human CD33. In some embodiments that may be combined with any of the preceding embodiments, the antibody fragment is crosslinked to a second antibody fragment that binds one or more human proteins selected from the group consisting of human CD33, naturally occurring variants of human CD33, and disease variants of human CD33. In some embodiments that may be combined with any of the preceding embodiments, the fragment is a 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-CD33 antibody is a human antibody, 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-CD33 antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In some embodiments that may be combined with any of the preceding embodiments, the first antigen is CD33 and the second antigen is (a) an antigen that facilitates transport across the blood-brain barrier, (b) an antigen 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, llama single domain antibody, TMEM 30(A), a protein transduction domain, an antigen that facilitates transport across the blood-brain barrier selected from the group consisting of TAT, Syn-B, penetratin, a polyarginine peptide, angiopep peptide, and ANG1005; (c) a pathogen selected from the group consisting of a pathogenic peptide or protein and a pathogenic nucleic acid, wherein the pathogenic peptide or protein is amyloid beta, oligomeric amyloid beta, amyloid beta plaque, amyloid precursor protein or a fragment 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 fibrillation ... (d) a ligand and / or protein expressed on an immune cell, the ligand and / or protein being selected from the group consisting of: thorium diuretic 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 product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin, and proline-arginine (PR) repeat peptide; the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat expanded RNA; and (e) a ligand and / or protein expressed on an immune cell, the ligand and / or protein being selected from the group consisting of CD40, OX40, ICOS, CD28,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-CD33 antibody is a conjugated antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 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-CD33 antibody is selected from the group consisting of ricin, ricin A chain, doxorubicin, daunorubicin, maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogenin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, saponaria officinalis inhibitor, glucocorticoid, auristatin, auromycin, yttrium, bismuth, combrestatin, duocarmycin, dolastatin, cc1065, and cisplatin. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is conjugated to a toxin selected from the group consisting of a pathogenic peptide, a pathogenic protein, 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 bodies, 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 in combination with one or more antibodies that bind to an immunomodulatory protein 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, TREM1, TREM2, Siglec-5, Siglec-7, Siglec-9, Siglec-11, phosphatidylserine, pathogenic nucleic acid, antisense GGCCCC (G2C4) repeat expanded RNA, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody has a dissociation constant (K, for human CD33 and mouse CD33) ranging from less than about 100 nM to less than about 0.304 nM. D In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody has a dissociation constant (K) for human CD33 that ranges from less than about 100 nM to less than about 0.304 nM. D In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody has a dissociation constant (K) for murine CD33 that ranges from less than about 25.8 nM to less than about 0.445 nM. D )

[0035] Other aspects of the present disclosure relate to an isolated nucleic acid comprising a nucleic acid sequence encoding the anti-CD33 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 a 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-CD33 antibody, the method comprising culturing the host cell of any of the preceding embodiments to produce the anti-CD33 antibody. In some embodiments, the method further comprises recovering the anti-CD33 antibody produced by the host cell. Other aspects of the present disclosure relate to an isolated human anti-CD33 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-CD33 antibody of any of the preceding embodiments and a pharmaceutically acceptable carrier. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is not conjugated to an agent, and optionally the agent is a drug, toxin, chemotherapeutic agent, or radioisotope.

[0036] Other aspects of the present disclosure include the use of a therapeutic agent for the treatment 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, and the like. Colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration Respiratory tract infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, as well as cancers including bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, 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), and thyroid cancer. The present invention relates to a method of preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow derived tumors, tumors expressing CD33, thyroid cancer, infectious diseases, CNS herpes, parasitic infections, trypanosomiasis infections, Cruzi infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, group B streptococcal infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type 1, and Haemophilus influenzae, the method comprising administering to an individual in need thereof a therapeutically effective amount of an agent that reduces cellular levels of CD33 or inhibits the interaction between CD33 and one or more CD33 ligands, or both. Other aspects of the present disclosure include the use of therapeutic agents for the treatment of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, taupathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, and ulcers. Colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal Membrane degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute The present invention relates to an agent that decreases cellular levels of CD33 or inhibits the interaction between CD33 and one or more CD33 ligands, or both, for use in preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow-derived tumors, tumors expressing CD33, thyroid cancer, infectious diseases, CNS herpes, parasitic infections, trypanosomiasis infections, Cruzi infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, group B streptococcal infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type 1, and Haemophilus influenzae. Other aspects of the present disclosure include the treatment of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,Amyotrophic lateral sclerosis, Huntington's disease, taupathy, 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, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, 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, bone formation, osteopetrosis, Paget's disease of bone, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, 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 myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow-derived tumors, tumors expressing CD33, thyroid cancer, infections, CNS herpes, parasitic infections, trypanosomiasis infections, Cruzi infections, Pseudomonas The present invention relates to the use of an agent that reduces cellular levels of CD33 or inhibits the interaction between CD33 and one or more CD33 ligands, or both, in the manufacture of a medicament for preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of: Streptococcus aeruginosa infection, Leishmania donovani infection, Group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type 1, and Haemophilus influenzae. In some embodiments, the agent is an antibody, a soluble CD33 receptor, a CD33-Fc fusion protein, a CD33 immunoadhesin, a soluble Siglec receptor that binds one or more CD33 ligands, a Siglec-Fc fusion protein, a Siglec immunoadhesin, an antisense molecule,In some embodiments, the agent is selected from the group consisting of an siRNA, a small molecule inhibitor, a protein, and a peptide. In some embodiments, the agent is an isolated human anti-CD33 antibody. In some embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments. In some embodiments, the disease, disorder, or injury is cancer, and the agent is selected from the group consisting of: (a) promoting the proliferation, maturation, migration, differentiation, and / or functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells; (b) enhancing tumor infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells; (c) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in the tumor, in the peripheral blood, or in other lymphoid organs; (d) enhancing the tumor-promoting activity of myeloid-derived suppressor cells; (e) increasing expression of tumor-promoting cytokines in the tumor or in the peripheral blood, where optionally the tumor-promoting cytokine is TGF-beta or IL-10; (f) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (i) reducing the infiltration of tumor-specific NK cells with tumor-killing ability; (j) reducing the tumor-killing ability of NK cells; (k) reducing the infiltration of tumor-specific B lymphocytes with the ability to enhance immune responses; (l) increasing tumor volume; (m) increasing tumor growth rate; (n) increasing metastasis; (o) increasing the rate of tumor recurrence. (p) decreasing the effectiveness of one or more immunotherapies that modulate an anti-tumor T cell response, optionally wherein the one or more immunotherapies are a cancer vaccine or CTLA4, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, 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, (q) inhibiting one or more CD33 activities selected from the group consisting of: (i) targeting one or more proteins selected from the group consisting of: (i) inhibiting PLCγ / PKC / calcium mobilization; and (ii) inhibiting PI3K / Akt, Ras / MAPK signaling. 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 CD33 receptor, a CD33-Fc fusion protein, a CD33 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 human anti-CD33 antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments.

[0037] Another aspect of the present disclosure relates to a method of preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy, infectious disease, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both. Another aspect of the present disclosure relates to an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both, for use in preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy, infectious disease, and cancer. Another aspect of the present disclosure relates to the use of an agent that reduces cellular levels of CD33 or inhibits the interaction between CD33 and one or more CD33 ligands, or both, in the manufacture of a medicament for preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy, infectious disease, and cancer. In some embodiments, the agent is selected from the group consisting of an antibody, a soluble CD33 receptor, a CD33-Fc fusion protein, a CD33 immunoadhesin, a soluble Siglec receptor that binds one or more CD33 ligands, 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, the agent is an isolated human anti-CD33 antibody. In some embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments. In some embodiments that may be combined with any of the preceding embodiments,Or the lesion is cancer. In some embodiments that may be combined with any of the preceding embodiments, the cancer expresses CD33. In some embodiments that may be combined with any of the preceding 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 carcinoma, 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 that may be combined with any of the preceding embodiments, the agent (a) promotes the proliferation, maturation, migration, differentiation, and / or functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells; (b) enhances the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells into tumors; (c) increases the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs; (d) enhances the tumor-promoting activity of myeloid-derived suppressor cells; (e) increases the expression of tumor-promoting cytokines in tumors or in peripheral blood, and optionally (f) increasing the tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (g) decreasing the activation of tumor-specific T lymphocytes with tumor-killing ability; (h) decreasing the infiltration of tumor-specific T lymphocytes with tumor-killing ability; (i) decreasing the infiltration of tumor-specific NK cells with tumor-killing ability; (j) decreasing the tumor-killing ability of NK cells; (k) decreasing the infiltration of tumor-specific B lymphocytes with the ability to enhance immune responses; (l) increasing tumor volume; (m) increasing tumor growth rate; (n) increasing metastasis; (o) increasing tumor recurrence rate; (p) decreasing the effectiveness of one or more immunotherapies that modulate anti-tumor T cell responses, optionally wherein the one or more immunotherapies are selected from the group consisting of CD40, OX40,an immunotherapy or one or more cancer vaccines targeting one or more proteins selected from the group consisting of 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; (q) inhibiting one or more CD33 activities selected from the group consisting of: inhibition of PLCγ / PKC / calcium mobilization; and (r) inhibiting PI3K / Akt, Ras / MAPK signaling. In some embodiments that may be combined with any of the preceding embodiments, the disease, disorder, or injury is an infectious disease. In some embodiments that may be combined with any of the preceding embodiments, the infection is selected from the group consisting of CNS herpes, a parasitic infection, a trypanosomiasis infection, a Cruzi infection, a Pseudomonas aeruginosa infection, a Leishmania donovani infection, a group B streptococcus infection, a Campylobacter jejuni infection, a Neisseria meningiditis infection, HIV type 1, and Haemophilus influenzae.

[0038] Other aspects of the present disclosure relate to methods of preventing cancer, reducing the risk of cancer, or treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both. Other aspects of the present disclosure relate to agents that reduce cellular levels of CD33, or inhibit the interaction between CD33 and one or more CD33 ligands, or both, for use in preventing, reducing the risk of, or treating cancer in an individual in need thereof. Other aspects of the present disclosure relate to the use of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both, in the manufacture of a medicament for preventing, reducing the risk of, or treating cancer in an individual in need thereof. In some embodiments, the agent is selected from the group consisting of an antibody, a soluble CD33 receptor, a CD33-Fc fusion protein, a CD33 immunoadhesin, a soluble Siglec receptor that binds one or more CD33 ligands, 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, the agent is an isolated human anti-CD33 antibody. In some embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments. 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 carcinoma, 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 cancer is a CD33-expressing cancer. In some embodiments, the cancer comprises a tumor that expresses CD33. In some embodiments that may be combined with any of the preceding embodiments, the agent is selected from the group consisting of (a) immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells,(b) promoting the proliferation, maturation, migration, differentiation, and / or functionality of one or more of tumor-associated macrophages and regulatory T cells; (b) enhancing the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells into tumors; (c) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in tumors, peripheral blood, or other lymphoid organs; and (d) enhancing the tumor-promoting activity of myeloid-derived suppressor cells. (e) increasing the expression of tumor-promoting cytokines in tumors or in peripheral blood, where the tumor-promoting cytokines are optionally TGF-beta or IL-10; (f) increasing the tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (g) decreasing the activation of tumor-specific T lymphocytes with tumor-killing ability; (h) decreasing the infiltration of tumor-specific T lymphocytes with tumor-killing ability; (i) decreasing the infiltration of tumor-specific NK cells with tumor-killing ability; (j) decreasing the activation of NK cells with tumor-killing ability; (k) reducing tumor killing capacity; (l) reducing the infiltration of tumor-specific B lymphocytes capable of enhancing immune responses; (l) increasing tumor volume; (m) increasing tumor growth rate; (n) increasing metastasis; (o) increasing tumor recurrence rate; (p) reducing the effectiveness of one or more immunotherapies that modulate anti-tumor T cell responses, optionally the one or more immunotherapies being CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, P an immunotherapy or one or more cancer vaccines targeting one or more proteins selected from the group consisting of D-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; (q) inhibiting one or more CD33 activities selected from the group consisting of inhibition of PLCγ / PKC / calcium mobilization, and (r) inhibiting PI3K / Akt, Ras / MAPK signaling;

[0039] Other aspects of the present disclosure relate to methods of inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both. Other aspects of the present disclosure relate to agents that reduce cellular levels of CD33, or inhibit the interaction between CD33 and one or more CD33 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 the use of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 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, microglia, neutrophils, T cells, T helper cells, cytotoxic T cells, and any combination thereof. 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 CD33 receptor, a CD33-Fc fusion protein, a CD33 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 human anti-CD33 antibody. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments.

[0040] Another aspect of the present disclosure relates to a method of reducing the activity, functionality, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an agent that binds to or interacts with CD33. Another aspect of the present disclosure relates to an agent that binds to or interacts with CD33 for use in reducing the activity, functionality, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof. Another aspect of the present disclosure relates to the use of an agent that binds to or interacts with CD33 in the manufacture of a medicament for reducing the activity, functionality, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof. In some embodiments, the agent is selected from the group consisting of an antibody, an antagonist antibody, an inactive antibody, an agonist antibody, a CD33 ligand, a CD33 ligand agonist fragment, a CD33 immunoadhesin, a CD33 ligand mimetic, a soluble CD33 receptor, a CD33-Fc fusion protein, a soluble Siglec receptor that binds one or more CD33 ligands, a Siglec-Fc fusion protein that binds one or more CD33 ligands, and a small molecule compound. In some embodiments, the agent is an isolated human anti-CD33 antibody or an anti-CD33 antibody conjugate. In some embodiments, the anti-CD33 antibody conjugate comprises an anti-CD33 antibody conjugated to a detectable marker, a toxin, or a therapeutic agent.In some embodiments, the anti-CD33 antibody conjugate is selected from the group consisting of ricin, ricin A chain, doxorubicin, daunorubicin, maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogenin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, saponaria officinalis inhibitor, glucocorticoid, auristatin, auromycin, yttrium, bismuth, combrestatin, duocarmycin, dolastatin, cc1065, and cisplatin. In some embodiments that may be combined with any of the preceding embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments that does not significantly reduce cell surface levels of CD33 and / or does not inhibit the interaction between CD33 and one or more CD33 ligands.

[0041] Another aspect of the present disclosure relates to a method of reducing the cellular level of CD33 on one or more cells in an individual in need thereof, or inhibiting the interaction between CD33 and one or more CD33 ligands, or both, comprising administering to the individual a therapeutically effective amount of an isolated human anti-CD33 antibody. Another aspect of the present disclosure relates to an isolated human anti-CD33 antibody for use in reducing the cellular level of CD33 on one or more cells in an individual in need thereof, or inhibiting the interaction between CD33 and one or more CD33 ligands, or both. Another aspect of the present disclosure relates to the use of an isolated human anti-CD33 antibody in the manufacture of a medicament for reducing the cellular level of CD33 on one or more cells in an individual in need thereof, or inhibiting the interaction between CD33 and one or more CD33 ligands, or both. In some embodiments, the one or more cells are selected from dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages, and / or cell lines. In some embodiments, the anti-CD33 antibody reduces the cellular level of CD33 in vivo. In some embodiments, the anti-CD33 antibody is selected from the group consisting of an antagonist anti-CD33 antibody, an inactive anti-CD33 antibody, and an agonist anti-CD33 antibody, hi some embodiments, the anti-CD33 antibody is the anti-CD33 antibody of any of the preceding embodiments.

[0042] In some embodiments that may be combined with any of the preceding embodiments, the individual comprises a variant of CD33. In some embodiments that may be combined with any of the preceding embodiments, the variant is a) SNP rs3865444 AC , (b) SNP rs3865444 CC , (c) SNP rs35112940 GG、AA、AG , (d) SNP rs12459419 CC、CTまたはTTand any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the method further comprises 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 an anti-CD33 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 an 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-TIM3 antibody, an anti-A2AR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, an anti-TNFα antibody, an anti-Siglec-5 antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec-11 antibody, an antagonistic anti-TREM1 antibody, an antagonistic anti-TREM2 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 anticancer therapies are selected from the group consisting of radiation therapy, 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 comprises 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 an anti-CD33 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 comprises administering to the individual at least one agonist 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 agonist antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with an anti-CD33 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 agonistic anti-CD40 antibody, an agonistic anti-OX40 antibody, an agonistic anti-ICOS antibody, an agonistic anti-CD28 antibody, an agonistic anti-TREM1 antibody, an agonistic anti-TREM2 antibody, an agonistic anti-CD137 / 4-1BB antibody, an agonistic anti-CD27 antibody, an agonistic anti-glucocorticoid-inducible TNFR-related protein GITR antibody, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the method further comprises 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 an anti-CD33 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-b, IL-1β, TNF-α, IL-6, IL-8, CRP, an IL-20 family member, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, IL-33, CRP, IL-33, MCP-1, MIP-1-beta, and any combination thereof. [Brief explanation of the drawings]

[0043] [Figure 1] The CD33 structure and domain structure are shown, along with a scheme depicting individual amino acids identified as phosphorylation or ubiquitination events or as relatively frequent nonsynonymous single nucleotide polymorphisms (SNPs). Abbreviations: CBL: casitas B-lineage lymphoma E3 ubiquitin ligase; C2: C2-set Ig-like domain; ECS: elongin B / C-cullin-5 SPRY domain ubiquitin ligase; P: phospho-, PKC: protein kinase C; SFK: Src family kinase; SHP-1 / 2: Src homology region 2 domain-containing phosphatase-1 and -2; SOCS3: suppressor of cytokine signaling 3; Ub: ubiquitin; V: V-set Ig-like domain (Cowan et al., (2013) Frontiers in Bioscience 18:1311-1334). [Figure 2-1] 1 shows an amino acid sequence alignment between human CD33 (SEQ ID NO: 1) and mouse CD33 (SEQ ID NO: 2), rat CD33 (SEQ ID NO: 3), chimpanzee CD33 (SEQ ID NO: 4), rhesus monkey CD33 (SEQ ID NO: 5), dog CD33 (SEQ ID NO: 6), bovine CD33 (SEQ ID NO: 7), and zebrafish CD33 (SEQ ID NO: 8). An asterisk ("*") indicates a position with a single, completely conserved residue, a colon (":") indicates conservation between groups with strongly similar properties, i.e., groups scoring >0.5 in the Gonnet PAM250 matrix, and a period (".") indicates conservation between groups with weakly similar properties, i.e., groups scoring <0.5 in the Gonnet PAM250 matrix. [Figure 2-2]1 shows an amino acid sequence alignment between human CD33 (SEQ ID NO: 1) and mouse CD33 (SEQ ID NO: 2), rat CD33 (SEQ ID NO: 3), chimpanzee CD33 (SEQ ID NO: 4), rhesus monkey CD33 (SEQ ID NO: 5), dog CD33 (SEQ ID NO: 6), bovine CD33 (SEQ ID NO: 7), and zebrafish CD33 (SEQ ID NO: 8). An asterisk ("*") indicates a position with a single, completely conserved residue, a colon (":") indicates conservation between groups with strongly similar properties, i.e., groups scoring >0.5 in the Gonnet PAM250 matrix, and a period (".") indicates conservation between groups with weakly similar properties, i.e., groups scoring <0.5 in the Gonnet PAM250 matrix. [Figure 3] Glycan-binding specificity of human Siglec proteins, including CD33. This figure provides an overview of the most commonly reported specificities for the most commonly tested sialylated glycans. Relative binding within each Siglec assay is indicated as ++ (strong binding), + (detectable binding), and - (very weak or undetectable binding). The recently reported strong binding preference of hSiglec-8 and mSiglec-F for 6'-sulfated sialyl Lewis x (sLex) and hSiglec-9 for 6-sulfated sLex is not shown. With a few exceptions (CD22 and MAG), results of human Siglec binding specificity assays varied significantly between different researchers using different assays. In addition to assay format and glycan linker issues, the density and arrangement of the tested ligands could be responsible for this variability (Varki et al., (2006) Glycobiol. 16:1R-27R). [Figure 4] Figure 1 shows the structure and metabolism of gangliosides in the mammalian brain. The nomenclature of gangliosides 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). [Figure 5] 1 shows the results of FACS analysis demonstrating CD33 expression on human primary immune cells. [Figure 6A] 1 shows the results of a FACS analysis demonstrating anti-CD33 antibody binding to human primary dendritic cells utilizing anti-CD33 antibodies of the present disclosure. [Figure 6B] 1 shows the results of a FACS analysis demonstrating anti-CD33 antibody binding to human primary dendritic cells utilizing anti-CD33 antibodies of the present disclosure. [Figure 7] 1 shows the results of a FACS analysis utilizing anti-CD33 antibodies of the present disclosure showing anti-CD33 antibody binding to recombinant CHO cells expressing human CD33. [Figure 8] 1 shows Biacore analysis of anti-CD33 antibodies of the disclosure binding to recombinant CD33 receptor at pH 5.0, 6.0, and 7.3. A subset of CD33 antibodies binds to CD33 in a pH-dependent manner. [Figure 9A]

[0023] Figure 1 shows a diagram of the human CD33 protein and the binding site of an anti-CD33 antibody. Using an anti-CD33 antibody of the present disclosure, the linear epitope binding site of the anti-CD33 antibody is shown. The CD33 backbone is depicted in transparent gray representation. The linear binding region identified for the antibody is listed in the figure. [Figure 9B]

[0023] Figure 1 shows a diagram of the binding site of the human CD33 protein and anti-CD33 antibodies. A schematic diagram of the discontinuous epitope binding site for antibody C-64 is shown. The discontinuous binding regions 84EETQGRFRLLGDPSR98 (residues 84-98 of SEQ ID NO: 1) and 111RDNGSYFFRMER122 (residues 111-122 of SEQ ID NO: 1) are listed in the diagram. [Figure 9C]

[0023] Figure 1 shows a diagram of the binding site of the human CD33 protein and anti-CD33 antibodies. A schematic diagram of the discontinuous epitope binding site for antibody C-39 is shown. The discontinuous binding regions 39VPCTFFHPIPYYD51 (residues 39-51 of SEQ ID NO: 1), 88GRFRLLGDPSR98 (residues 88-98 of SEQ ID NO: 1), and 110RRDNGSYFFRM120 (residues 110-120 of SEQ ID NO: 1) are listed in the diagram. [Figure 10A]10A and 10B show results demonstrating that anti-CD33 antibodies and anti-CD33 antibody Fab fragments of the present disclosure inhibit ligand binding to CD33 using anti-CD33 antibodies of the present disclosure. [Figure 10B] Figures 10A and 10B show results demonstrating that anti-CD33 antibodies and anti-CD33 antibody Fab fragments of the present disclosure can inhibit ligand binding to CD33 using anti-CD33 antibodies of the present disclosure. Results using anti-CD33 antibody Fab fragments are shown. Antibodies C-44, C-67, and C-19, as well as Fab fragments of antibodies C-37, C-39, C-61, and C-65, were able to block the binding of sialic acid ligands on red blood cells to plate-bound CD33. [Figure 11A] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on cells. 1 shows the results of anti-CD33 antibody-induced reduction of CD33 cell surface levels on the U937 histiocytic lymphoma cell line. [Figure 11B] 1 shows results demonstrating that anti-CD33 antibodies of the disclosure reduce cell surface levels of CD33 on cells. 1 shows the results of anti-CD33 antibody-induced reduction of CD33 cell surface levels on human primary monocytes. [Figure 11C] 1 shows results demonstrating that anti-CD33 antibodies of the disclosure reduce cell surface levels of CD33 on cells. 1 shows the results of anti-CD33 antibody-induced reduction of CD33 cell surface levels on human primary dendritic cells. [Figure 11D] 1 shows results demonstrating that anti-CD33 antibodies of the disclosure reduce cell surface levels of CD33 on cells. 1 shows the results of anti-CD33 antibody-induced reduction of CD33 cell surface levels on human primary macrophages. [Figure 11E-F]Figure 11E shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on cells. Figure 11F shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on cells. Figure 11F shows the expression of the unrelated receptor, Siglec-9. Siglec-9 was used as a control. Siglec-9 cell surface levels were unchanged after antibody treatment in vivo. [Figure 12A]

[0023] Figure 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. FACS analysis of antibody-mediated CD33 downregulation is shown. Surface levels of the control receptor, CD11c, remain unaffected. [Figure 12B] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. 1 shows a four-point titration analysis of CD33 antibody downregulation of cell surface receptors on human primary dendritic cells. [Figure 12C] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. 2 shows an analysis of CD33 antibody downregulation of cell surface receptors on human primary microglial cells. [Figure 12D] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. 2 shows an analysis of CD33 antibody dose-dependent downregulation of cell surface receptors on primary human microglial cells. [Figure 12E] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. 1 shows an analysis of CD33 antibody dose-dependent downregulation of cell surface receptors on human primary dendritic cells. [Figure 12F] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on human primary dendritic cells. 2 shows an analysis of CD33 antibody dose-dependent downregulation of cell surface receptors on human primary monocytes. [Figure 13] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure reduce cell surface levels of CD33 on recombinant CHO cells expressing human CD33. [Figure 14] 1 shows results demonstrating that anti-CD33 antibody-induced reduction in cell surface levels of CD33 is maintained over time in human primary monocytes after antibody withdrawal. [Figure 15] 1 shows FACS analysis demonstrating that sialic acid CD3 ligands on dendritic cells limit T cell proliferation during a mixed lymphocyte reaction with human primary cells. [Figure 16] 1 shows results demonstrating that sialic acid CD33 ligands on dendritic cells limit T cell proliferation during a mixed lymphocyte reaction. [Figure 17A] 1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased CD33 expression on human primary dendritic cells after treatment with tumor supernatant. [Figure 17B] 1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased CD33 expression on human primary dendritic cells after treatment with tumor supernatant. [Figure 17C] 1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased CD33 expression on human dendritic cells during LPS-induced inflammation. [Figure 17D] 1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased CD33 expression on human dendritic cells during LPS-induced inflammation. [Figure 17E] 1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased expression of sialic acid on human bone marrow cells during LPS-induced inflammation. [Figure 17F]1 shows results showing increased expression of CD33 and CD33 ligand on human bone marrow cells induced by various stimuli. 2 shows results showing increased expression of sialic acid on human bone marrow cells during LPS-induced inflammation. [Figure 18] 1 shows results demonstrating that sialidase treatment, which removes CD33 ligand from E. coli, increases phagocytosis by human primary dendritic cells. [Figure 19] 1 shows results demonstrating that anti-CD33 antibodies of the present disclosure result in increased phagocytosis of E. coli by primary human macrophages. [Figure 20A] Figure 1 shows CD33 ligand expression in brain sections from Alzheimer's disease brains (AD) and healthy brains (non-AD). Figure 2 shows immunohistochemical staining of CD33-Fc in AD and non-AD brains. Control IgG1-Fc does not bind to these cells. [Figure 20B] Figure 1 shows CD33 ligand expression in brain sections from Alzheimer's disease (AD) and healthy (non-AD) brains. One-way ANOVA statistical analysis of CD33-Fc and control receptor staining from five AD and five non-AD brain samples is shown, indicating that inhibitory CD33 ligand contributes to AD pathology. [Figure 21A] 1 shows CD33 receptor expression in brain sections from Alzheimer's disease brains (AD) and healthy brains (non-AD). Immunohistochemical staining of CD33 antibody compared to isotype control in AD and non-AD brain sections. [Figure 21B] Figure 1 shows CD33 receptor expression in brain sections from Alzheimer's disease brains (AD) and healthy brains (non-AD). One-way ANOVA statistical analysis results of CD33 antibody and isotype control staining from five AD and five non-AD brain samples are shown. [Figure 22A] 1 shows results demonstrating the expression of CD33 and its ligands in tumors. 2 shows results demonstrating that expression of inhibitory CD33 ligands is increased in lung tumor cells, melanoma cells, and colon cancer cells. 3 shows results demonstrating that inhibitory CD33 ligands contribute to cancer pathology. [Figure 22B]1 shows results showing the expression of CD33 and its ligand in tumors. 2 shows results showing CD33 expression in human immune cells from peripheral blood, spleen, and cells infiltrating patient-derived melanoma in an immunodeficient mouse model lacking mature mouse T cells, B cells, and NK cells, which was transplanted with human CD45+ immune cells and patient-derived melanoma. [Figure 22C] 1 shows results demonstrating the expression of CD33 and its ligands in tumors. 1 shows CD33 expression in CD3+ T cells, CD11b+ cells, and Gr1+Cd11b+ immune cells from the spleen and in cells infiltrating the breast cancer tumor EMT-6 in a mouse tumor model. [Figure 22D] (a) and (b) show results demonstrating the expression of CD33 and its ligands in tumors. (b) show CD33 expression in CD45- T cells, Gr1+ cells, and Gr1-CD11b- immune cells from the spleen and in cells infiltrating the breast cancer tumor EMT-6 in a mouse tumor model. (c) The results indicate that CD33 and its immunoinhibitory ligands are involved in immune responses to multiple solid tumor types. [Figure 23A] 1 shows results demonstrating inhibition of colon carcinoma tumor growth in mice in which CD33 was genetically nullified. Control mice with normal CD33 expression (WT mice) are shown. [Figure 23B] 1 shows results demonstrating inhibition of colon carcinoma tumor growth in mice in which CD33 has been genetically nullified. 2 shows mice in which CD33 has been genetically inactivated (CD33KO mice). [Figure 23C] 23A and 23B show results demonstrating inhibition of colon carcinoma tumor growth in mice in which CD33 was genetically nullified. Results are summarized in Figures 23A and 23B, showing median tumor volumes. [Figure 23D] Results showing inhibition of colon carcinoma tumor growth in mice in which CD33 was genetically nullified. Kaplan-Meier survival plots demonstrating that CD33KO mice bearing colon carcinoma survive longer than corresponding WT mice bearing colon carcinoma. [Figure 23E]Figure 1 shows results demonstrating inhibition of colon carcinoma tumor growth in mice in which CD33 was genetically nullified. Figure 2 shows FACS analysis of murine CD33 expression. Detailed cell population analysis was performed on spleens and tumors from WT and CD33KO mice, as well as naive spleens. The results indicate that blocking CD33 function (either genetically or pharmacologically) leads to beneficial outcomes in cancer. [Figure 24A] 1 shows the expression levels of CD33 in wild-type and CD33 knockout THP-1 cells. [Figure 24B] 1 shows the expression levels of CD14 in wild-type and CD33 knockout THP-1 cells. [Figure 24C] Cytokine levels in wild-type and CD33 knockout THP-1 cells treated with different concentrations of LPS or with IL-6, IL-8, and GM-CSF are shown. [Figure 24D] 1 shows the levels of activation markers in wild-type and CD33 knockout THP-1 cells treated with different concentrations of LPS or with IL-6, IL-8, and GM-CSF. DETAILED DESCRIPTION OF THE INVENTION

[0044] general technology The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and may be based on conventional methods, e.g., those described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, Current Protocols in Molecular Biology (F.M. Amusable, 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 (JECellis, ed., 1998) Academic Press, Animal Cell Culture (RIFreshney), ed., 1987), Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JBGriffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons, Handbook of Experimental Immunology (DMWeir and CC Blackwell, eds.), Gene Transfer Vectors for Mammalian Cells (J.M. Miller and MP Calos, eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994), Current Protocols in Immunology (JEColigan et al., eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Immunobiology (CA 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 These are commonly used using widely available methods such as those described in 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).

[0045] definition As used herein, the term "preventing" includes providing prophylaxis against the onset or recurrence of a particular disease, disorder, or condition in an individual who may be predisposed to, susceptible to, or at risk of developing a particular disease, disorder, or condition, but who has not yet been diagnosed with the disease, disorder, or condition.

[0046] As used herein, an individual who is "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms before the treatment methods described herein, and may or may not show detectable disease or disease symptoms. "At risk" refers to an individual who has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition, as known in the art. Individuals who have one or more of these risk factors have a higher probability of developing a particular disease, disorder, or condition than individuals who do not have one or more of these risk factors.

[0047] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of clinical pathology in an individual being treated. Desirable effects of treatment include reducing the rate of progression, improving or alleviating 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 alleviated or eliminated.

[0048] 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 may be provided in one or more administrations. The effective amount herein may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the treatment to elicit a desired response in the individual. An effective amount is also an amount in which any toxic or adverse 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, reducing the severity, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during disease development. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, such as by targeting, delaying disease progression, and / or prolonging survival. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to perform prophylactic or therapeutic treatment, either directly or indirectly.As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be obtained in combination with another drug, compound, or pharmaceutical composition.Therefore, an "effective amount" may be considered to be related to administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if it can or does achieve a desired result in combination with one or more other agents.

[0049] A "therapeutically effective amount" is at least the minimum concentration required to produce a measurable improvement in a particular disease, disorder, or condition. The therapeutically effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the CD33 protein antagonist to induce a desired response in an individual. A therapeutically effective amount is also an amount in which any toxic or adverse effects of the CD33 protein antagonist are outweighed by the therapeutically beneficial effects.

[0050] As used herein, administration "in combination with" another compound or composition includes simultaneous administration and / or administration at different times. Combined administration also encompasses administration as a co-formulation or as separate compositions, administration at different dosing frequencies or intervals, and administration using the same or different routes of administration.

[0051] An "individual" for purposes of treatment, prevention, or risk reduction refers to any animal classified as a mammal, including humans, domestic and livestock animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. Preferably, the individual is a human.

[0052] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody." The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as the antibody exhibits the desired biological activity.

[0053] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. H and V LThe pairing of these two amino acids together forms a single antigen-binding site. For the structure and properties of different antibody classes, 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.

[0054] Light chains 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 sequence of their constant domains. Depending on the amino acid sequence of their heavy chain constant domains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function; for example, 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; see, e.g., Abbas et al., Cellular and Molecular Immunology, 4 th ed. (WB Saunders Co., 2000).

[0055] "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 contains a variable domain (V H) at one end followed by multiple constant domains. Each light chain has a variable domain (V L ) at its other end and a constant domain, with the light-chain constant domain aligned with the first constant domain of the heavy chain and the light-chain variable domain aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.

[0056] An "isolated" antibody, such as an anti-CD33 antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, an isolated polypeptide is free from association with all other contaminating components from its production environment. Contaminating components from its production environment, such as those arising from recombinantly transfected cells, are materials that would typically interfere with research, diagnostic, or therapeutic uses of 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, and in some embodiments, greater than 99% by weight, of the antibody, as determined, for example, by the Lowry method; (2) to an extent 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 non-reducing or reducing conditions using Coomassie blue, or preferably silver staining. 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, isolated polypeptide or antibody will be prepared by at least one purification step.

[0057] A "variable region" or "variable domain" of an antibody, such as an anti-CD33 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 and light chains are referred to as "V H " and "V LThese domains are generally the most variable parts of an antibody (compared to other antibodies of the same class) and contain the antigen-binding sites.

[0058] The term "variable" refers to the fact that certain segments of the variable domains vary considerably in sequence among antibodies, such as the anti-CD33 antibodies of the present disclosure. The V domains mediate antigen binding and define the specificity of a particular antibody for its particular antigen. However, variability is not uniformly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light- and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Naturally occurring heavy- and light-chain variable domains each contain four FR regions, which are primarily arranged in a beta-sheet configuration, joined by three HVRs that form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held in close proximity by the FR regions and, together with the HVRs of 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 Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0059] The term "monoclonal antibody," as used herein, refers to an antibody, such as an anti-CD33 antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., each individual antibody within the population is identical and excludes possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against one or more antigenic sites. In some embodiments, antibodies (e.g., monoclonal antibodies) of the present disclosure may be bispecific. 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 one or more antigenic sites. The modifier "monoclonal" indicates the character of the antibody as obtained from a population of substantially homogeneous antibodies, and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be generated by a variety of techniques, such as phage display technology (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), hybridoma methods (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, 2nd ed. 1988), Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), and techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (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 See, for example, Huszar, Intern. Rev. Immunol. 13:65-93 (1995).

[0060] The terms "full length antibody," "intact antibody," or "whole antibody" are used interchangeably and refer to an antibody in its substantially intact form, as opposed to an antibody fragment, such as an anti-CD33 antibody of the present disclosure. In particular, whole antibodies include those having 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, an intact antibody may have one or more effector functions.

[0061] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding region 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. Pat. No. 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.

[0062] Papain digestion of an antibody, such as the anti-CD33 antibody of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments, and a residual "Fc" fragment, the name of which reflects its ability to readily crystallize. The Fab fragment contains the variable region domains of the heavy chains (V H ), and the first constant domain of one heavy chain (C H 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 with different antigen-binding activities and is still capable of cross-linking antigen. The Fab' fragment contains one or more cysteines from the antibody hinge region, C HF(ab')2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) in the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0063] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of the antibody are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0064] An "Fv" is the minimum antibody fragment containing a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. The folding of these two domains generates six hypervariable loops (three loops each from the H and L chains), which provide 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 containing only three antigen-specific HVRs) has the ability to recognize and bind antigen, although with lower affinity than the entire binding site.

[0065] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising VH and VL antibody domains linked into a single polypeptide chain. Preferably, the sFv polypeptide contains a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. H Domains and V L For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0066] A "functional fragment" of an antibody, such as an anti-CD33 antibody of the present disclosure, comprises a portion of an intact antibody, generally comprising the antigen-binding or variable region of the intact antibody or the F region of the antibody that retains FcR binding ability or has altered FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0067] The term "diabody" refers to V domains that undergo inter-chain but not intra-chain pairing, thereby resulting in bivalent fragments, i.e., fragments with two antigen-binding sites. H Domains and V L These refer to small antibody fragments prepared by constructing sFv fragments (see previous paragraph) with a short linker (approximately 5-10 residues) between the domains. Bispecific diabodies are heterodimers of two "crossover" sFv fragments, combining the V domains of two antibodies. H and V L The domains are present on different polypeptide chains. Diabodies are described in further detail in, for example, EP 404,097, WO 93 / 11161, and Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0068] As used herein, "chimeric antibody" refers to an antibody (immunoglobulin) in which a portion of the heavy and / or light chain is identical to or homologous to the corresponding sequence of an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to the corresponding sequence of an antibody derived from another species or belonging to another antibody class or subclass, such as the anti-CD33 antibody of the present disclosure, as well as to fragments of such antibodies, so long as these fragments 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, in which the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing macaque monkeys with an antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0069] "Humanized" forms of non-human (e.g., murine) antibodies, such as the anti-CD33 antibodies of the present disclosure, are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, humanized antibodies are human immunoglobulins (recipient antibodies) 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 cases, 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 improve antibody performance, such as binding affinity. Generally, 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 which improve antibody performance, e.g., binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FRs typically will be no more than six in the H chain and no more than three in the L chain. The humanized antibody also optionally will 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.

[0070] A "human antibody" is an antibody produced by a human, e.g., an antibody having an amino acid sequence corresponding to that of an anti-CD33 antibody of the present disclosure, and / or an antibody produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. See Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for preparing human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); and 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 antigen to transgenic animals, e.g., immunized xenomouse (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology), which have been engineered to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been inactivated. See also, e.g., Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated by human B cell hybridoma technology.

[0071] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops, such as those regions of the anti-CD33 antibodies of the present disclosure. Antibodies generally contain six HVRs: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In natural antibodies, H3 and L3 exhibit the greatest diversity of the six HVRs, and H3 in particular is thought 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). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable even in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0072] Numerous HVR delineations are in use and are encompassed herein. The EU or Kabat complementarity-determining regions (CDRs) HVRs are based on sequence variability and are most commonly used (Kabat et al., supra). Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent a compromise between EU or Kabat CDRs and Chothia structural loops and are used in Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on analysis of available complex crystal structures. Each residue in these HVRs is described below. TIFF2025160190000002.tif43170

[0073] HVRs may include "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 (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.

[0074] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0075] The phrases "variable domain residue numbering as in EU or Kabat" or "amino acid position numbering as in EU or Kabat," and variations thereof, refer to the numbering system used for the heavy 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, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) as well as inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc., according to Kabat). The EU or Kabat numbering of residues may be determined for a given antibody by alignment of homologous regions of the antibody sequence with the "standard" Kabat numbering sequence.

[0076] The EU or Kabat numbering system is generally used when referring to residues 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 residues 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 numbering of residues in a human IgG1 EU antibody. Unless otherwise specified herein, references to residue numbers in the variable domain of an antibody refer to the numbering of residues according to the Kabat numbering system. Unless otherwise specified herein, references to residue numbers in the constant domain of an antibody refer to the numbering of residues according to the EU or Kabat numbering system (see, e.g., U.S. Patent Publication No. 2010-280227).

[0077] 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 or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 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. When pre-existing amino acid changes are present in the VH, preferably these changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is a sequence identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0078] 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 VL, the subgroup may be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al., supra. Furthermore, for VH, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0079] An "amino acid modification" at a particular position, for example, of an anti-CD33 antibody of the present disclosure, refers to the substitution or deletion of the particular residue, or the insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue means an insertion within one to two residues of the particular residue. The insertion may be N-terminal or C-terminal to the particular residue. A preferred amino acid modification herein is a substitution.

[0080] An "affinity matured" antibody, such as an anti-CD33 antibody of the present disclosure, is an antibody that contains one or more changes in one or more of its HVRs that improve the affinity of the antibody for an antigen, compared to a parent antibody that does not possess those change(s). In one embodiment, the affinity matured antibody has nanomolar or picomolar affinity 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, for example, in 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).

[0081] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction, such as attraction or binding, between a target and an antibody, such as an anti-CD33 antibody of the present disclosure, and determine the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody, such as an anti-CD33 antibody of the present disclosure, that specifically or selectively binds to a target or epitope is an antibody that binds to this target or epitope with higher affinity, avidity, more readily, and / or for a longer duration than it binds to other targets or other epitopes of targets. For example, it is further understood from reading this definition that an antibody (or moiety) that specifically or selectively binds to a first target may or may not specifically or selectively bind to a second target. Thus, "specific binding" or "selective binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds to a target has 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 cases, about 10 6 M -1 Or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 , or about 10 10 M -1 ~10 11 M -1The binding constant may be greater than or equal to 100 kJ / min. 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.

[0082] As used herein, an "interaction" between a CD33 protein and a second protein includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. As used herein, an antibody "inhibits the interaction" between two proteins if the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody, or fragment thereof, of the present disclosure "inhibits the interaction" between two proteins if the antibody or fragment thereof binds to one of the two proteins.

[0083] An "agonist" or "activating" antibody is an antibody, such as an agonist anti-CD33 antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0084] A "blocking," "antagonist," or "inhibitory" antibody is an antibody, such as an anti-CD33 antibody of the present disclosure, that inhibits or reduces (e.g., decreases) antigen binding to one or more ligands and / or inhibits or reduces (e.g., decreases) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, a blocking, antagonist, or inhibitory antibody substantially or completely inhibits antigen binding to one or more ligands and / or one or more activities or functions of the antigen.

[0085] 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.

[0086] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain and includes 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 the amino acid residue at position Cys226, or from position Pro230, to the carboxyl-terminus thereof. The C-terminal lysine of the Fc region (residue 447 according to the EU or Kabat numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population from which all K447 residues have been removed, an antibody population from which none of the K447 residues have been removed, and an antibody population 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.

[0087] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A and A allotypes), native-sequence human IgG2 Fc regions, native-sequence human IgG3 Fc regions, and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0088] A "variant Fc region" comprises an amino acid sequence that 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 the native-sequence Fc region or to the Fc region of a parent polypeptide, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or in the Fc region of the parent polypeptide. A variant Fc region herein will preferably have at least about 80% homology to the native-sequence Fc region and / or to the Fc region of the parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto.

[0089] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is a receptor that binds IgG antibodies (gamma receptors), including 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 their cytoplasmic domains. 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. Daeron, 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 identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0090] The in vivo FcRn binding and serum half-life of human FcRn high-affinity binding polypeptides can be assayed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates administered with polypeptides having variant Fc regions. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished FcR binding. See also, e.g., Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0091] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence refer to the percentage of amino acid residues in a candidate sequence that are identical to those in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, 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, necessary to achieve maximum alignment over the entire length of the sequences being compared.

[0092] An "isolated" nucleic acid molecule encoding an antibody, such as the anti-CD33 antibody of the present disclosure, is a nucleic acid molecule that has been identified and separated from at least one contaminant nucleic acid molecule normally associated with the environment in which it is produced. Preferably, an isolated nucleic acid is free from association with all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are in a form other than the form or setting in which they are found in nature. Thus, isolated nucleic acid molecules are distinguished from nucleic acids naturally occurring in cells that encode the polypeptides and antibodies of the present disclosure.

[0093] 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, a "plasmid," 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, into which 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. As used herein, "plasmid" and "vector" may be used interchangeably, as the plasmid is the most commonly used form of vector.

[0094] "Polynucleotide," or "nucleic acid," when used interchangeably herein, refers to a polymer of nucleotides of any length, and includes 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 include modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications 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 include modification(s) performed after synthesis, such as conjugation with a label. Other types of modifications include, for example, "caps," substitutions of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications, such as uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), modifications containing pendant moieties, such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), intercalator modifications (e.g., acridine, psoralens, etc.), chelator-containing modifications (e.g., metals, radioactive metals, boron, metal oxides, etc.), alkylator-containing modifications, modified linkage modifications (e.g., alpha anomeric nucleic acids, etc.), as well as unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present on the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or conjugated to solid or semi-solid supports. The 5'- and 3'-terminal OH groups may be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also contain analogous forms of ribose or deoxyribose sugars commonly 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, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and base nucleoside analogs such as methyl riboside, etc. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which the 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"), where each R or R' is independently H, or a substituted or unsubstituted alkyl (1-20 C), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl, optionally containing an ether (-O-) linkage. Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0095] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporating a polynucleotide insert. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or 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.

[0096] "Carrier," as used herein, includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals 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) polypeptides, 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 non-ionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0097] As used herein, the term "apoptosis" refers to a gene-directed process of intracellular cell destruction. Unlike necrosis, apoptosis involves cytoskeletal disruption, cytoplasmic shrinkage and condensation, the expression of phosphatidylserine on the outer surface of the cell membrane, and blebbing, resulting in the formation of membrane-bound vesicles or apoptotic bodies. This process is also referred to as "programmed cell death." During apoptosis, characteristic phenomena are observed, such as a curved cell surface, condensation of nuclear chromatin, fragmentation of chromosomal DNA, and loss of mitochondrial function. Various known techniques, such as staining cells with annexin V, propidium iodide, DNA fragmentation assays, and YO-PRO-1 (Invitrogen), may be used to detect apoptosis. In some embodiments, staining with annexin V and propidium iodide may be used, and a mixed percentage of annexin V / PI, annexin V / PI, and annexin V / PI populations is considered dead cells.

[0098] As used herein, the term "agent that reduces cellular levels of CD33, inhibits the interaction between CD33 and one or more CD33 ligands, or both" refers to a molecule that reduces (including significantly), decreases, blocks, inhibits, or interferes with CD33 (such as mammalian, e.g., human CD33) biological activity in vitro, in situ, and / or in vivo. The term "agent" does not imply any particular biological mechanism of action, but rather expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with CD33, whether direct or indirect, interacting with CD33, one or more of its ligands, or by another mechanism, and the results that can be achieved by a variety of different, chemically distinct compositions. Exemplary agents include, but are not limited to, anti-CD33 antibodies that specifically bind to CD33, soluble CD33 receptor proteins, soluble CD33-Fc fusion proteins (e.g., CD33 immunoadhesins), soluble Siglec receptors that bind to CD33 ligands, Siglec-Fc fusion proteins (e.g., Siglec immunoadhesins) that bind to CD33 ligands, antisense molecules directed to nucleic acids encoding CD33, short interfering RNA ("siRNA") molecules directed to nucleic acids encoding CD33, CD33 inhibitory compounds, RNA or DNA aptamers that bind to CD33, and CD33 structural analogs. In some embodiments, a CD33 inhibitor (e.g., an antibody) binds to (physically interacts with), binds to a CD33 ligand, and / or inhibits (reduces) CD33 synthesis or production, which reduces cellular levels of CD33, inhibits the interaction between CD33 and one or more CD33 ligands, or both. In other embodiments, inhibitory agents of the present disclosure bind to CD33 and prevent its binding to one or more of its ligands. In yet other embodiments, agents of the present disclosure reduce or eliminate the expression (i.e., transcription or translation) of CD33.Examples of the types of agents that decrease cellular levels of CD33, inhibit the interaction between CD33 and one or more CD33 ligands, or both, are provided herein.

[0099] As used herein, the term "agent that binds to or interacts with CD33" refers to a molecule that interacts either directly or indirectly with the CD33 protein. The term "agent" does not imply any particular biological mechanism of action, but rather expressly includes and encompasses all possible pharmacological, physiological, and biochemical interactions with CD33, whether direct or indirect, with CD33 or through another mechanism, and the results that may be achieved by a variety of different, chemically distinct compositions. Exemplary agents include, but are not limited to, anti-CD33 antibodies that specifically bind to CD33.

[0100] As used herein, the term "RNA interference" or "RNAi" generally refers to the process by which double-stranded or short hairpin RNA molecules reduce or inhibit the expression of a nucleic acid sequence with which the double-stranded or short hairpin RNA molecule shares substantial or complete homology. The term "short interfering RNA" or "siRNA" or "RNAi agent" refers to an RNA sequence that induces RNA interference. See WO 00 / 44895 to Kreutzer et al., WO 01 / 36646 to Zernicka-Goetz et al., WO 99 / 32619 to Fire, and WO 01 / 29058 to Mello and Fire. As used herein, siRNA molecules include RNA molecules that contain chemically modified nucleotides and non-nucleotides. The term "ddRNAi agent" refers to a DNA-directed RNAi agent transcribed from an exogenous vector. The term "short hairpin RNA" or "shRNA" refers to an RNA structure having a double-stranded region and a loop region. In certain embodiments, a ddRNAi agent is initially expressed as an shRNA.

[0101] As used herein, the term "aptamer" refers to a heterologous oligonucleotide capable of binding strongly and specifically to a desired molecular target, such as a common metabolic cofactor (e.g., coenzyme A, S-adenosylmethionine, etc.), a protein (e.g., complement protein C5, antibodies, etc.), or a conserved structural element in a nucleic acid molecule (e.g., a structure important for transcription factor binding). Aptamers typically comprise DNA or RNA nucleotide sequences ranging from about 10 to about 100 nucleotides in length, about 10 to about 75 nucleotides in length, about 10 to about 50 nucleotides in length, about 10 to about 35 nucleotides in length, and about 10 to about 25 nucleotides in length. Synthetic DNA or RNA oligonucleotides can be generated using standard solid-phase phosphoramidite methods and equipment, such as by using the 3900 High Throughput DNA Synthesizer™ available from Applied Biosystems (Foster City, CA). Aptamers often incorporate derivatives or analogs of commonly occurring nucleotides found in DNA and RNA (e.g., A, G, C, and T / U), and they contain backbone or linkage modifications (e.g., peptide nucleic acid (PNA) or phosphothioate linkages) to increase resistance to nucleases, binding avidity, or otherwise alter their pharmacokinetic properties. Exemplary modifications are described 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 WO00 / 56746 and WO01 / 14398.Methods for synthesizing oligonucleotides containing such analogs or derivatives are disclosed, for example, in the patent publications cited above, and in U.S. Pat. Nos. 6,455,308, 5,614,622, 5,739,314, 5,955,599, 5,962,674, 6,117,992, and WO 00 / 75372.

[0102] The term "about," as used herein, refers to a normal range of error for each value that would be readily apparent to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter per se.

[0103] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, a reference to an "antibody" is a reference to one to many antibodies, including, for example, molar amounts, etc., including equivalents thereof known to those skilled in the art, etc.

[0104] Aspects and embodiments of the present disclosure described herein are understood to include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0105] overview The present disclosure relates to agents (e.g., human anti-CD33 antibodies) that reduce cellular levels of CD33 and / or inhibit the interaction between CD33 and one or more CD33 ligands, methods of making and using such agents (e.g., human anti-CD33 antibodies), pharmaceutical compositions containing such agents (e.g., human anti-CD33 antibodies), nucleic acids encoding such agents (e.g., human anti-CD33 antibodies), and host cells containing nucleic acids encoding such agents (e.g., human anti-CD33 antibodies).

[0106] In some embodiments, human anti-CD33 antibodies of the disclosure have one or more antagonistic activities that result, at least in part, from the ability of the antibody to inhibit the interaction between CD33 and one or more natural glycan ligands. In some embodiments, anti-CD33 antibodies of the disclosure may have one or more antagonistic activities that result, at least in part, from the ability of the antibody to reduce cellular expression (e.g., cell surface expression) of CD33 by inducing degradation, downregulation, cleavage, receptor desensitization, and / or lysosomal targeting of CD33.

[0107] In some embodiments, antibody-induced CD33 activity can be determined or tested in vitro by any of the techniques disclosed herein (see, e.g., Examples 1-5), including, but not limited to, testing plate binding of full-length anti-CD33 antibodies to increase the density of antibody exposed to CD33, crosslinking anti-CD33 antibodies with a secondary antibody, crosslinking anti-CD33 antibodies with cells expressing one or more Fcg receptors (e.g., FcgRIIB), using CD33 antibodies in solution, and using Fab fragments of CD33 antibodies.

[0108] Certain aspects of the present disclosure are based, at least in part, on the identification of agents, such as human anti-CD33 antibodies, that exhibit the ability to compete with one or more CD33 ligands for binding to CD33 and / or reduce cell surface levels of CD33 on cells, resulting in the reduction, neutralization, prevention, or inhibition of one or more CD33 activities, such as phosphorylation of one or more of Tyr-340 and Tyr-358 by Src family tyrosine kinases, such as LCK and FYN, or inhibition of tyrosine-specific protein phosphatase SH. Recruitment and binding of P1 and SHP2, recruitment and binding of PLC-gamma 1, which functions as a guanine nucleotide exchange factor for Dynamini-1, recruitment and binding of SH2 domain-containing proteins (e.g., Crkl), recruitment and binding of the spleen tyrosine kinase Syk, recruitment and binding of SH3-SH2-SH3 growth factor receptor-bound protein 2 (Grb2), recruitment and binding of multiple SH2-containing proteins, phosphorylation of Ser-307 and Ser-342 by protein kinase C, monocytes, modulation of the expression of soluble receptors for one or more anti-inflammatory cytokines, i.e., IL-4, IL-10, IL-13, IL-35, IL-16, TGF-beta, IL-1Ra, G-CSF, and TNF, IFN-beta 1a, IFN-beta 1b, or IL-6, in macrophages, T cells, dendritic cells, neutrophils, and / or microglia; reducing intracellular calcium mobilization; and modulation of the expression of soluble receptors for one or more pro-inflammatory cytokines, i.e., IFN-beta 1a, IFN-beta 1b, or IL-6, in monocytes, macrophages, T cells, dendritic cells, neutrophils, and / or microglia. N-b, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP, IL-33, MIP-1-beta, and MC Regulation of P-1 expression, C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4,modulation of expression of one or more proteins selected from ITGAX and PYCARD; inhibition of extracellular signal-regulated kinase (ERK) phosphorylation; reducing tyrosine phosphorylation on multiple cellular proteins; modulation of CC chemokine receptor 7 (CCR7) expression; inhibition of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; activation of phosphoinositide 3-kinase; reducing cell growth of monocytes, macrophages, T cells, dendritic cells, and / or microglia; dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, M1 microglia, and macrophages. reducing T cell proliferation induced by activated M1 microglia, M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, and / or M2 macrophages; inhibiting osteoclast production, reducing the rate of osteoclast formation, or both; neutrophils, dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, microglia, M1 microglia, activated M1 microglia, and / or M2 microglia; Reducing the survival of macroglia, reducing the proliferation of neutrophils, dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, microglia, M1 microglia, activated M1 microglia, and / or M2 microglia, reducing the proliferation of neutrophils, dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells inhibiting the migration of neutrophils, granulocytes, microglia, M1 microglia, activated M1 microglia, and / or M2 microglia; decreasing one or more functions of neutrophils, dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, microglia, M1 microglia, activated M1 microglia, and / or M2 microglia;Inhibiting the maturation of activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, microglia, M1 microglia, activated M1 microglia, and / or M2 microglia; Increasing cell death and apoptosis of monocytes, macrophages, T cells, dendritic cells, neutrophils, and / or microglia; Reducing the phagocytic activity of monocytes, macrophages, T cells, dendritic cells, neutrophils, and / or microglia; reducing glial proliferation; reducing the overall functionality of monocytes, macrophages, T cells, dendritic cells, neutrophils, and / or microglia; reducing the phosphorylation of ITAM-containing receptors; reducing the phosphorylation of signaling molecules that mediate ITAM signaling; reducing the activation of pattern recognition receptors; reducing the activation of Toll-like receptors; reducing the activation of damage-associated clearance of cellular and protein debris; the interaction between CD33 and one or more of its ligands; the interaction between CD33 and co-receptors such as CD64; and reducing the activation of apoptotic cells. reducing clearance of one or more selected from neuron clearance, neural tissue debris clearance, dysfunctional synapse clearance, non-neuronal tissue debris clearance, bacterial or other foreign body clearance, pathogenic protein clearance, and tumor cell clearance; inhibiting phagocytosis of one or more of apoptotic neurons, neural tissue debris, dysfunctional synapses, non-neuronal tissue debris, bacteria, other foreign body, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, pathogenic lipids, or tumor cells; inhibiting clearance of pathogenic nucleic acids, and optionally The pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat expansion RNA, amyloid beta, amyloid beta plaque, amyloid precursor protein or a fragment 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 b...

Claims

1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both.

2. The anti-CD33 antibody of claim 1, wherein the anti-CD33 antibody reduces cell surface levels of CD33, reduces intracellular levels of CD33, reduces total levels of CD33, or any combination thereof.

3. The anti-CD33 antibody of claim 1 or claim 2, wherein the anti-CD33 antibody induces CD33 degradation, CD33 cleavage, CD33 internalization, CD33 shedding, downregulation of CD33 expression, or any combination thereof.

4. The anti-CD33 antibody of any one of claims 1 to 3, wherein the anti-CD33 antibody reduces cellular levels of CD33 without inhibiting the interaction between CD33 and one or more CD33 ligands.

5. The anti-CD33 antibody of any one of claims 1 to 3, wherein the anti-CD33 antibody reduces cellular levels of CD33 and inhibits the interaction between CD33 and one or more CD33 ligands.

6. The anti-CD33 antibody of any one of claims 1 to 5, wherein the antibody reduces cellular levels of CD33 in vivo.

7. The anti-CD33 antibody of claim 1, wherein the anti-CD33 antibody inhibits the interaction between CD33 and one or more CD33 ligands without reducing cellular levels of CD33.

8. The anti-CD33 antibody of any one of claims 1 to 7, wherein the anti-CD33 antibody inhibits cell surface clustering of CD33.

9. The anti-CD33 antibody of any one of claims 1 to 8, wherein the anti-CD33 antibody inhibits one or more CD33 activities.

10. the one or more CD33 activities (a) CD33 binding to sialic acid-containing glycoproteins, or sialic acid-containing glycolipids, or both; (b) modulating the 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-beta 1a, IFN-beta 1b, or IL-6; (c) modulating the expression of one or more anti-inflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (d) modulating the expression of one or more inflammatory cytokines, optionally wherein the one or more inflammatory cytokines are selected from the group consisting of IFN-α4, IFN-b, IL-1β, TNF-α, IL-6, IL-8, CRP, IL-20 family members, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP, IL-33, MIP-1-beta, and MCP-1; (e) modulating the expression of one or more inflammatory cytokines in one or more cells selected from the group consisting of macrophages, dendritic cells, bone marrow-derived dendritic cells, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, and microglial cells; (f) modulation of the 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; (g) reducing 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, M1 macrophages, activated M1 macrophages, and M2 macrophages; (h) reducing the proliferation of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (i) decreasing one or more functions of one or more cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, T cells, T helper cells, cytotoxic T cells, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia; (j) inhibiting the phagocytosis of one or more of apoptotic neurons, neural tissue debris, dysfunctional synapses, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells, wherein optionally the pathogenic nucleic acid is an antisense GGCCCCC (G2C4) repeat expanded RNA, and the pathogenic protein is 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 bodies, 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 the tumor cells are selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer; (k) binding to CD33 ligand on tumor cells; (l) binding to a CD33 ligand on a cell selected from the group consisting of a neutrophil, a dendritic cell, a bone marrow-derived dendritic cell, a monocyte, a microglia, a T cell, and a macrophage; (m) inhibiting tumor cell killing by one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (n) inhibiting the anti-tumor cell proliferation activity of one or more of microglia, macrophages, dendritic cells, bone marrow-derived dendritic cells, neutrophils, T cells, T helper cells, or cytotoxic T cells; (o) promoting the functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells; (p) enhancing the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressive neutrophils, and regulatory T cells into tumors; (q) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in the peripheral blood or other lymphoid organs in tumors; (r) enhancing the tumor-promoting activity of myeloid-derived suppressor cells; (s) enhancing the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs); (t) reducing the activation of tumor-specific T lymphocytes with tumor-killing ability; (u) reducing the infiltration of tumor-specific NK cells with tumor-killing ability; (v) reducing the infiltration of tumor-specific B lymphocytes, which have the ability to enhance immune responses; (w) reducing the infiltration of tumor-specific T lymphocytes with tumor-killing ability; (x) increasing tumor volume; (y) increasing tumor growth rate, and (z) reducing the effectiveness of one or more immunotherapies that modulate anti-tumor T-cell responses, optionally wherein the one or more immunotherapies are immunotherapies targeting 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 one or more cancer vaccines.

10. The anti-CD33 antibody of claim 9, selected from the group consisting of:

11. 11. The anti-CD33 antibody of any one of claims 1 to 10, wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 19 to 259, 19 to 135, 145 to 228, or 229 to 259 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 19 to 259, 19 to 135, 145 to 228, or 229 to 259 of SEQ ID NO:

1.

12. the anti-CD33 antibody i. amino acid residues 39-51 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51 of SEQ ID NO: 1; ii. amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1; iii. amino acid residues 42-56 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 42-56 of SEQ ID NO: 1; iv. amino acid residues 44-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO: 1; v. amino acid residues 44-52 and 114-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 and 114-122 of SEQ ID NO: 1; vi. amino acid residues 44-52 and 241-248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 and 241-248 of SEQ ID NO: 1; vii. amino acid residues 44-52, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52, 76-86, 64-71, and 118-128 of SEQ ID NO: 1; viii. amino acid residues 44-53 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-53 of SEQ ID NO: 1; ix. amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1; x. amino acid residues 45-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-52 of SEQ ID NO: 1; xi. amino acid residues 45-55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55 of SEQ ID NO: 1; xii. amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1; xiii. amino acid residues 45-55, 64-71, 76-86, 118-128, and 241-249 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55, 64-71, 76-86, 118-128, and 241-249 of SEQ ID NO: 1; xiv. amino acid residues 49-55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49-55 of SEQ ID NO: 1; xv. amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1; xvi. amino acid residues 64-71 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 64-71 of SEQ ID NO: 1; xvii. amino acid residues 76-86 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 76-86 of SEQ ID NO: 1; xviii. amino acid residues 84-98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84-98 of SEQ ID NO: 1; xix. amino acid residues 84-98 and 111-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84-98 and 111-122 of SEQ ID NO: 1; xx. amino acid residues 88-98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 88-98 of SEQ ID NO: 1; xxi. amino acid residues 93-103 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 93-103 of SEQ ID NO: 1; xxii. amino acid residues 109-118 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109-118 of SEQ ID NO: 1; xxiii. amino acid residues 110-120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110-120 of SEQ ID NO: 1; xxiv. amino acid residues 110-121 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110-121 of SEQ ID NO: 1; xxv. amino acid residues 111-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 111-122 of SEQ ID NO: 1; xxvi. amino acid residues 112-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 112-122 of SEQ ID NO: 1; xxvii. amino acid residues 114-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 114-122 of SEQ ID NO: 1; xxviii. amino acid residues 117-130 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 117-130 of SEQ ID NO: 1; xxix. amino acid residues 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 118-128 of SEQ ID NO: 1; xxx. amino acid residues 137-147 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137-147 of SEQ ID NO: 1; xxxi. Amino acid residues 183-197 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183-197 of SEQ ID NO: 1, and xxxii. amino acid residues 241-245 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-245 of SEQ ID NO: 1; xxxiii. Amino acid residues 241-247 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO: 1; xxxiv. amino acid residues 241-248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-248 of SEQ ID NO: 1, and xxxv. Amino acid residues 241-249 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-249 of SEQ ID NO: 1 The anti-CD33 antibody of claim 11, which binds to one or more amino acids within the amino acid residues selected from the group consisting of:

13. The anti-CD33 antibody of any one of claims 1 to 10, wherein the anti-CD33 antibody binds to a discontinuous CD33 epitope.

14. 14. The anti-CD33 antibody of claim 13, wherein the discontinuous CD33 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 ten or more peptides.

15. 15. The anti-CD33 antibody of claim 14, wherein each of the peptides comprises 5 or more, 6 or more, 7 or more, 8 or more, 9 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 in the amino acid sequence of SEQ ID NO: 1, or 5 or more, 6 or more, 7 or more, 8 or more, 9 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 CD33 protein corresponding to the amino acid sequence of SEQ ID NO:

1.

16. The anti-CD33 antibody according to any one of claims 1 to 10, which binds to a conformational epitope of CD33.

17. The anti-CD33 antibody is selected from the group consisting of C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C-100, C-101, C-102, C-103, C-104, C-105, C , C-43, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, C-109, and any combination thereof.

18. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody does not significantly reduce cell surface levels of CD33.

19. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody does not significantly reduce cell surface levels of CD33 and does not inhibit the interaction between CD33 and one or more CD33 ligands.

20. 20. The anti-CD33 antibody of claim 18 or claim 19, wherein the antibody reduces the cellular level of CD33 by less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% when compared to the cellular level of CD33 in the absence of the anti-CD33 antibody.

21. 21. The anti-CD33 antibody of any one of claims 18 to 20, wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241 to 247 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241 to 247 of SEQ ID NO:

1.

22. 22. The anti-CD33 antibody of any one of claims 18 to 21, wherein the anti-CD33 antibody competes for binding to CD33 with one or more antibodies selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof.

23. 23. The anti-CD33 antibody of any one of claims 1 to 22, wherein the cellular levels of CD33 are measured on primary cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages, or on a cell line, and the cellular levels of CD33 are measured using an in vitro cell assay.

24. The one or more CD33 ligands are selected from the group consisting of a CD33 ligand expressed on red blood cells, a CD33 ligand expressed on bacterial cells, a CD33 ligand expressed on apoptotic cells, a CD33 ligand expressed on tumor cells, a CD33 ligand expressed on viruses, a CD33 ligand expressed on dendritic cells, a CD33 ligand expressed on neuronal cells, a CD33 ligand expressed on galactocellular carcinoma (GALA) cells, a CD33 ligand expressed on microglia, a CD33 ligand expressed on astrocytes, a CD33 ligand on beta-amyloid plaques, a CD33 ligand on tau tangles, a CD33 ligand on a pathogenic protein, a CD33 ligand on a pathogenic peptide, a CD33 ligand expressed on macrophages, a CD33 ligand expressed on natural killer cells, a CD33 ligand expressed on T cells, and a CD33 ligand expressed on T cells. The anti-CD33 antibody of any one of claims 1 to 23, wherein the CD33 ligand is selected from the group consisting of a CD33 ligand expressed on macrophage cells, a CD33 ligand expressed on cytotoxic T cells, a CD33 ligand expressed on B cells, a CD33 ligand expressed on tumor-buried immunosuppressive dendritic cells, a CD33 ligand expressed on tumor-buried immunosuppressive macrophages, a CD33 ligand expressed on myeloid-derived suppressor cells, a CD33 ligand expressed on regulatory T cells, secreted mucin, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,6-linked sialic acid-containing glycolipids, alpha-2,6-linked sialic acid-containing glycoproteins, alpha-2,3-linked sialic acid-containing glycolipids, alpha-2,3-linked sialic acid-containing glycoproteins, alpha-1-acid glycoprotein (AGP), CD24 protein, and gangliosides.

25. The anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain, the heavy chain variable domain, or both are selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C- -18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33 , C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-50, C- 51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C-89, C-90, C-91, C-92, The anti-CD33 antibody of any one of claims 1 to 24, comprising 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 an antibody selected from the group consisting of C-93, C-94, C-95, and C-109.

26. (a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115; (d) the HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136; (e) the HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; or (f) the HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230; 26. The anti-CD33 antibody of claim 25.

27. The anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, and the light chain variable domain comprises: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115. Including, the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230. The anti-CD33 antibody of any one of claims 1 to 24, comprising:

28. The anti-CD33 antibody of any one of claims 1 to 24, wherein the anti-CD33 antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 285 to 362, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 363 to 432.

29. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 19-259, 19-135, 145-228, or 229-259 of SEQ ID NO:

1.

30. the anti-CD33 antibody i. amino acid residues 39-51 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51 of SEQ ID NO: 1; ii. amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 39-51, 88-98, and 110-120 of SEQ ID NO: 1; iii. amino acid residues 42-56 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 42-56 of SEQ ID NO: 1; iv. amino acid residues 44-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO: 1; v. amino acid residues 44-52 and 114-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 and 114-122 of SEQ ID NO: 1; vi. amino acid residues 44-52 and 241-248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 and 241-248 of SEQ ID NO: 1; vii. amino acid residues 44-52, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52, 76-86, 64-71, and 118-128 of SEQ ID NO: 1; viii. amino acid residues 44-53 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-53 of SEQ ID NO: 1; ix. amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-53, 76-86, 64-71, and 118-128 of SEQ ID NO: 1; x. amino acid residues 45-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-52 of SEQ ID NO: 1; xi. amino acid residues 45-55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55 of SEQ ID NO: 1; xii. amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1; xiii. amino acid residues 45-55, 64-71, 76-86, 118-128, and 241-249 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 45-55, 64-71, 76-86, 118-128, and 241-249 of SEQ ID NO: 1; xiv. amino acid residues 49-55 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49-55 of SEQ ID NO: 1; xv. amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 49-55, 64-71, 76-86, and 118-128 of SEQ ID NO: 1; xvi. amino acid residues 64-71 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 64-71 of SEQ ID NO: 1; xvii. amino acid residues 76-86 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 76-86 of SEQ ID NO: 1; xviii. amino acid residues 84-98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84-98 of SEQ ID NO: 1; xix. amino acid residues 84-98 and 111-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 84-98 and 111-122 of SEQ ID NO: 1; xx. amino acid residues 88-98 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 88-98 of SEQ ID NO: 1; xxi. amino acid residues 93-103 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 93-103 of SEQ ID NO: 1; xxii. amino acid residues 109-118 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109-118 of SEQ ID NO: 1; xxiii. amino acid residues 110-120 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110-120 of SEQ ID NO: 1; xxiv. amino acid residues 110-121 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 110-121 of SEQ ID NO: 1; xxv. amino acid residues 111-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 111-122 of SEQ ID NO: 1; xxvi. amino acid residues 112-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 112-122 of SEQ ID NO: 1; xxvii. amino acid residues 114-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 114-122 of SEQ ID NO: 1; xxviii. amino acid residues 117-130 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 117-130 of SEQ ID NO: 1; xxix. amino acid residues 118-128 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 118-128 of SEQ ID NO: 1; xxx. amino acid residues 137-147 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137-147 of SEQ ID NO: 1; xxxi. Amino acid residues 183-197 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183-197 of SEQ ID NO: 1, and xxxii. amino acid residues 241-245 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-245 of SEQ ID NO: 1; xxxiii. Amino acid residues 241-247 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO: 1; xxxiv. amino acid residues 241-248 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-248 of SEQ ID NO: 1, and xxxv. Amino acid residues 241-249 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-249 of SEQ ID NO: 1 30. The anti-CD33 antibody of claim 29, which binds to one or more amino acids within the amino acid residues selected from the group consisting of:

31. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 19-135 or 145-228 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 19-135 or 145-228 of SEQ ID NO:

1.

32. the anti-CD33 antibody i. amino acid residues 44-52 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 44-52 of SEQ ID NO: 1; ii. amino acid residues 109-118 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 109-118 of SEQ ID NO: 1; iii. amino acid residues 112-122 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 112-122 of SEQ ID NO: 1; iv. amino acid residues 137-147 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 137-147 of SEQ ID NO: 1, and v. Amino acid residues 183-197 of SEQ ID NO: 1, or amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 183-197 of SEQ ID NO: 1 The anti-CD33 antibody of claim 31, which binds to one or more amino acids within the amino acid residues selected from the group consisting of:

33. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-247 of SEQ ID NO:1, or to one or more amino acids within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO:

1.

34. 1. An isolated human anti-CD33 antibody, the anti-CD33 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, the light chain variable domain, or both are selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, 5, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-3 1, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-4 7, C-50, C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-6 9, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C-89, C-90, C-91, The isolated human anti-CD33 antibody comprises 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 an antibody selected from the group consisting of C-92, C-93, C-94, C-95, C-109, and any combination thereof.

35. 1. An isolated human anti-CD33 antibody, the anti-CD33 antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, or the light chain variable domain, or both, is selected from the group consisting of C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C- and any combination thereof.

36. 1. An isolated human anti-CD33 antibody, comprising a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain, the light 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 an antibody selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof.

37. (a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115; (d) the HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136; (e) the HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; or (f) the HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230; The anti-CD33 antibody according to any one of claims 34 to 36.

38. the light chain variable domain (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115. Including, the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230 or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230. The anti-CD33 antibody of any one of claims 34 to 36, comprising:

39. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 285-432.

40. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody is selected from the group consisting of C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-48, C-49, C-50, C-51, C-52, C-53, C-54, C-55, C-56, C-57, C-58, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-71, C-72, C-73, C-74, C-75, C-76, C-77, C-78, C-79, C-80, C-81, C-82, C-83, C-84, C-85, C-86, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-96, C-97, C-98, C-99, C- C-44, C-45, C-47, C-50, C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, C-109, and any combination thereof.

41. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody is selected from the group consisting of C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, the isolated human anti-CD33 antibody competes with one or more antibodies selected from the group consisting of C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, C-109, and any combination thereof.

42. 1. An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody competes for binding to CD33 with one or more antibodies selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, C-95, and any combination thereof.

43. C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19, C-20, C-22, C-23, C-24, C-25 , C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-47, C-50 , C-51, C-56, C-57, C-59, C-60, C-61, C-62, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-75, C-76, C77, C-78, C-79, C83, C-84, C-87, C-88, C-89, C-90, C-91, C-92, C-93, C-94, C-95, and C-109.

44. C-3, C-5, C-7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17, C-19, C-20, C-22, C-23, C-24, C-25 , C-26, C-27, C-28, C-29, C-30, C-31, C-32, C-33, C-34, C-35, C-36, C-37, C-38, C-39, C-40, C-41, C-42, C-4 1. An isolated human anti-CD33 antibody that binds to essentially the same CD33 epitope as an antibody selected from the group consisting of C-3, C-44, C-45, C-47, C-56, C-57, C-59, C-60, C-61, C-63, C-64, C-65, C-66, C-67, C-68, C-69, C-70, C-72, C-73, C-78, C-87, C-88, C-89, C-90, C-91, and C-109.

45. An isolated human anti-CD33 antibody that binds to essentially the same CD33 epitope as an antibody selected from the group consisting of C-1, C-2, C-4, C-6, C-18, C-50, C-51, C-62, C-75, C-76, C77, C-79, C83, C-84, C-92, C-93, C-94, and C-95.

46. 1. An isolated human anti-CD33 antibody, the anti-CD33 antibody comprising a light chain variable domain and a heavy chain variable domain, the light chain variable domain comprising: (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23; (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 38; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39 to 115. contains, or the heavy chain variable domain (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 116 to 136; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160, or an amino acid sequence having at least about 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230 or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161 to 230. The isolated human anti-CD33 antibody comprising:

47. The anti-CD33 antibody of any one of claims 1 to 46, wherein the antibody is of the IgG class, IgM class, or IgA class.

48. 48. The anti-CD33 antibody of claim 47, wherein the anti-CD33 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

49. 49. The anti-CD33 antibody of claim 48, wherein the antibody binds to an inhibitory Fc receptor.

50. 50. The anti-CD33 antibody of claim 49, wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB).

51. (a) the anti-CD33 antibody has a human IgG1 isotype and is 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, S one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of 254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, T394D, A330L, and any combination thereof, wherein said residue numbering is according to EU numbering; or an amino acid deletion in the Fc region at a position corresponding to glycine 236; (b) the anti-CD33 antibody has a human 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: 437), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, or 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-CD33 antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions 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 said residues is according to EU numbering; (d) the anti-CD33 antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions 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 said residues is according to EU numbering; or (e) the anti-CD33 antibody has a hybrid IgG2 / 4 isotype, optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, wherein the numbering of the residues is according to EU numbering; 51. The anti-CD33 antibody of claim 50.

52. (a) the anti-CD33 antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, D270A, 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-CD33 antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions 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 said residues is according to EU numbering; or (c) the anti-CD33 antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions 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 numbering.

49. The anti-CD33 antibody of claim 48.

53. (a) the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, wherein the numbering of said residues is according to EU numbering; (b) the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of said residues is according to EU numbering; or (c) the Fc region further comprises a S228P amino acid substitution according to EU numbering.

53. The anti-CD33 antibody of claim 52.

54. 54. The anti-CD33 antibody of any one of claims 1 to 53, wherein the CD33 protein is a mammalian or human protein.

55. The anti-CD33 antibody of any one of claims 1 to 54, wherein the CD33 protein is a wild-type protein.

56. The anti-CD33 antibody of any one of claims 1 to 54, wherein the CD33 protein is a naturally occurring variant.

57. 57. The anti-CD33 antibody of any one of claims 1 to 56, wherein the CD33 protein is expressed on one or more cells selected from the group consisting of human dendritic cells, human macrophages, human monocytes, human osteoclasts, human neutrophils, human T cells, human T helper cells, human cytotoxic T cells, human granulocytes, and human microglia.

58. The anti-CD33 antibody of any one of claims 1 to 57, wherein the anti-CD33 antibody specifically binds to a mammalian CD33 protein, or a human CD33 protein, or both.

59. The anti-CD33 antibody of any one of claims 1 to 57, wherein the anti-CD33 antibody specifically binds to human CD33, mouse CD33, or both.

60. The anti-CD33 antibody of any one of claims 1 to 59, wherein the CD33 antibody binds to CD33 in a pH-dependent manner.

61. The anti-CD33 antibody of claim 60, wherein the anti-CD33 antibody binds to CD33 at a pH in the range of 5.5 to 8.

0.

62. The anti-CD33 antibody of claim 60, wherein the anti-CD33 antibody dissociates from CD33 at a pH of less than 5.

0.

63. The anti-CD33 antibody of any one of claims 1 to 62, wherein the anti-CD33 antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human CD33 or mammalian CD33 protein.

64. The anti-CD33 antibody of any one of claims 1 to 62, wherein the anti-CD33 antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human CD33, naturally occurring variants of human CD33, and disease variants of human CD33.

65. 65. The anti-CD33 antibody of claim 63 or claim 64, wherein the antibody fragment is crosslinked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human CD33, naturally occurring variants of human CD33, and disease variants of human CD33.

66. The anti-CD33 antibody of any one of claims 63 to 65, wherein the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

67. The anti-CD33 antibody of any one of claims 1 to 66, wherein the anti-CD33 antibody is a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

68. The anti-CD33 antibody of any one of claims 1 to 66, which is a bispecific antibody that recognizes a first antigen and a second antigen.

69. The first antigen is CD33, and the second antigen is (a) an antigen that facilitates transport across the blood-brain barrier; (b) an antigen that facilitates 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, llama single domain antibody, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopep peptide, and ANG1005; (c) A pathogen selected from the group consisting of a pathogenic peptide or protein and a pathogenic nucleic acid, wherein the pathogenic peptide or protein is selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or a fragment 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 bodies, atrial natriuretic factor, pancreatic islet amyloid polypeptide, peptide, 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 product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin, and proline-arginine (PR) repeat peptide, and the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat-expanded RNA; and (d) a ligand and / or protein expressed on an immune cell, wherein the ligand and / or protein is 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, DR5, and phosphatidylserine; and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells 69. The anti-CD33 antibody of claim 68,

70. The anti-CD33 antibody of any one of claims 1 to 69, wherein the anti-CD33 antibody is a conjugated antibody.

71. The anti-CD33 antibody of claim 70, wherein the anti-CD33 antibody is conjugated to a detectable marker, a toxin, or a therapeutic agent.

72. The anti-CD33 antibody is selected from the group consisting of ricin, ricin A chain, doxorubicin, daunorubicin, maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxyanthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogelin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Saponaria 72. The anti-CD33 antibody of claim 71, conjugated to a toxin selected from the group consisting of a C. officinalis inhibitor, a glucocorticoid, an auristatin, an auromycin, yttrium, bismuth, a combrestatin, a duocarmycin, a dolastatin, CC1065, and cisplatin.

73. The anti-CD33 antibody is capable of inhibiting a pathogenic peptide, a pathogenic protein, amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or a fragment 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, or ataxin 3. , ataxin 7, ataxin 8, ataxin 10, Lewy bodies, 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 in combination with one or more antibodies that specifically bind to a pathogen selected from the group consisting of CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin, and proline-arginine (PR) repeat peptide, and any combination thereof 3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, TREM1, TREM2, Siglec-5, Siglec-7, Siglec-9, Siglec-11, phosphatidylserine, pathogenic nucleic acid, antisense GGCCCC (G2C4) repeat expanded RNA, and any combination thereof.

74. The anti-CD33 antibody has a dissociation constant (K) of human CD33 and mouse CD33 in the range of less than about 100 nM to less than about 0.304 nM. Ｄ 10. The anti-CD33 antibody of any one of the preceding claims, having the following structure:

75. The anti-CD33 antibody has a dissociation constant (K) of human CD33 in the range of less than about 100 nM to less than about 0.304 nM. Ｄ 10. The anti-CD33 antibody of any one of the preceding claims, having the following structure:

76. The anti-CD33 antibody has a dissociation constant (K) of murine CD33 in the range of less than about 25.8 nM to less than about 0.445 nM. Ｄ 10. The anti-CD33 antibody of any one of the preceding claims, having the following structure:

77. 10. An isolated nucleic acid comprising a nucleic acid sequence encoding an anti-CD33 antibody according to any one of the preceding claims.

78. A vector comprising the nucleic acid of claim 77.

79. A host cell comprising the vector of claim 78.

80. 80. A method for producing an anti-CD33 antibody, comprising culturing the host cell of claim 79 so that the anti-CD33 antibody is produced.

81. 81. The method of claim 80, further comprising recovering the anti-CD33 antibody produced by the host cell.

82. 82. An isolated human anti-CD33 antibody produced by the method of claim 80 or claim 81.

83. A pharmaceutical composition comprising the anti-CD33 antibody of any one of claims 1 to 76 and a pharmaceutically acceptable carrier.

84. A method for preventing, reducing the risk of, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy, infectious disease, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both.

85. 85. The method of claim 84, wherein the disease, disorder, or injury is cancer.

86. 86. The method of claim 84 or claim 85, wherein the cancer expresses CD33.

87. 87. The method of any one of claims 84 to 86, wherein 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 carcinoma, 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 myelogenous leukemia (CML), and multiple myeloma.

88. the disease, disorder, or injury is cancer and the agent is (a) promoting the proliferation, maturation, migration, differentiation, and / or functionality of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells; (b) enhancing the infiltration of one or more of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells into tumors; (c) increasing the number of tumor-promoting myeloid / granulocytic immunosuppressive cells in the peripheral blood or other lymphoid organs in tumors; (d) enhancing the tumor-promoting activity of myeloid-derived suppressor cells; (e) increasing expression of a tumor-promoting cytokine in the tumor or in peripheral blood, optionally wherein the tumor-promoting cytokine is TGF-beta or IL-10; (f) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (g) reducing the activation of tumor-specific T lymphocytes with tumor-killing ability; (h) reducing the infiltration of tumor-specific T lymphocytes with tumor-killing ability; (i) reducing the infiltration of tumor-specific NK cells with tumor-killing ability; (j) reducing the tumor-killing ability of NK cells; (k) reducing the infiltration of tumor-specific B lymphocytes, which have the ability to enhance immune responses; (l) increasing tumor volume; (m) increasing tumor growth rate; (n) increasing metastasis; (o) increasing the rate of tumor recurrence; (p) reducing the effectiveness of one or more immunotherapies that modulate anti-tumor T-cell responses, optionally wherein the one or more immunotherapies are cancer vaccines or target one or more proteins selected from the group consisting of CTLA4, CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, 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; (q) inhibition of PLCγ / PKC / calcium mobilization, and (r) Inhibition of PI3K / Akt and Ras / MAPK signaling 88. The method of any one of claims 84 to 87, wherein the method inhibits one or more CD33 activities selected from the group consisting of:

89. A method for 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 said individual a therapeutically effective amount of an agent that reduces cellular levels of CD33, or inhibits the interaction between CD33 and one or more CD33 ligands, or both.

90. 90. The method of claim 89, wherein the one or more immune cells are selected from the group consisting of dendritic cells, macrophages, microglia, neutrophils, T cells, T helper cells, cytotoxic T cells, and any combination thereof.

91. 91. The method of any one of claims 84 to 90, wherein the agent is selected from the group consisting of an antibody, a soluble CD33 receptor, a CD33-Fc fusion protein, a CD33 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.

92. The method of any one of claims 84 to 90, wherein the agent is an isolated human anti-CD33 antibody.

93. The method of claim 92, wherein the anti-CD33 antibody is an anti-CD33 antibody according to any one of claims 1 to 76.

94. 1. A method for reducing the activity, functionality, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an agent that binds to or interacts with CD33.

95. 95. The method of claim 94, wherein the agent is an isolated human anti-CD33 antibody or an anti-CD33 antibody conjugate.

96. The method of claim 95, wherein the anti-CD33 antibody is an anti-CD33 antibody according to any one of claims 1 to 76.

97. A method for reducing cellular levels of CD33, or inhibiting the interaction between CD33 and one or more CD33 ligands, or both, on one or more cells in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a human isolated anti-CD33 antibody.

98. 97. The method of claim 96, wherein the anti-CD33 antibody reduces cellular levels of CD33 in vivo.

99. The method of claim 97 or claim 98, wherein the anti-CD33 antibody is an anti-CD33 antibody described in any one of claims 1 to 17 and 23 to 76.

100. The method of any one of claims 84 to 99, wherein the individual comprises a variant of CD33.

101. wherein the variant is (a)SNP rs3865444 ＡＣ 、 (b)SNP rs3865444 ＣＣ 、 (c)SNP rs35112940 ＧＧ、ＡＡ、ＡＧ 、 (d) SNP rs12459419 ＣＣ、ＣＴまたはＴＴ , and any combination thereof 101. The method of claim 100, comprising one or more polymorphisms selected from the group consisting of:

102. 102. The method of any one of claims 84-101, 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.

103. 103. The method of claim 102, wherein the at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with the anti-CD33 antibody.

104. 104. The method of claim 102 or claim 103, wherein 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 an 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-TIM3 antibody, an anti-A2AR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, an anti-TNFa antibody, an anti-Siglec-5 antibody, an anti-Siglec-7 antibody, an anti-Siglec-9 antibody, an anti-Siglec-11 antibody, an antagonistic anti-TREM1 antibody, an antagonistic anti-TREM2 antibody, and any combination thereof.

105. 103. The method of claim 102, wherein the one or more standard or investigational anti-cancer therapies are selected from the group consisting of radiation therapy, 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.

106. 106. The method of any one of claims 84 to 105, further comprising administering to the individual at least one antibody that specifically binds to the inhibitory cytokine.

107. 107. The method of claim 106, wherein the at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with the anti-CD33 antibody.

108. 108. The method of claim 106 or claim 107, wherein 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.

109. 109. The method of any one of claims 84 to 108, further comprising administering to said individual at least one agonist antibody that specifically binds to a stimulatory checkpoint protein.

110. 110. The method of claim 109, wherein the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with the anti-CD33 antibody.

111. 111. The method of claim 109 or claim 110, wherein the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is selected from the group consisting of an agonistic anti-CD40 antibody, an agonistic anti-OX40 antibody, an agonistic anti-ICOS antibody, an agonistic anti-CD28 antibody, an agonistic anti-TREM1 antibody, an agonistic anti-TREM2 antibody, an agonistic anti-CD137 / 4-1BB antibody, an agonistic anti-CD27 antibody, an agonistic anti-glucocorticoid-inducible TNFR-related protein GITR antibody, and any combination thereof.

112. 112. The method of any one of claims 84 to 111, further comprising administering to the individual at least one stimulatory cytokine.

113. 113. The method of claim 112, wherein the at least one stimulatory cytokine is administered in combination with the anti-CD33 antibody.

114. 114. The method of claim 112 or claim 113, wherein the at least one stimulatory cytokine is selected from the group consisting of IFN-a4, IFN-b, IL-1 beta, TNF-alpha, IL-6, IL-8, CRP, an IL-20 family member, LIF, IFN-gamma, OSM, CNTF, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10, IL-33, CRP, IL-33, MCP-1, MIP-1-beta, and any combination thereof.

Images