Anti-siglec-7 antibodies and methods of use thereof

Abstract

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind on or more epitopes within a Siglec-7 protein, e.g., human Siglec-7 or a mammalian Siglec-7, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

1 .- 80 . (canceled) 
     
     
         81 . A method of preventing, reducing risk, or treating a disease,
 disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an anti-Siglec-7 antibody that decreases cell surface levels of Siglec-7, inhibits interaction between Siglec-7 and one or more Siglec-7 ligands, or both.   
     
     
         82 . The method of  claim 81 , wherein the disease, disorder, or injury is cancer, and wherein the anti-Siglec-7 antibody inhibits one or more Siglec-7 activities selected from the group consisting of:
 (a) promoting proliferation, maturation, migration, differentiation, and/or functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid derived suppressor cells, tumor-associated macrophages, tumor-associated suppressor neutrophils, tumor-associated suppressor NK cells, and regulatory T cells;   (b) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, immunosuppressor NK cells, myeloid derived suppressor cells, tumor-associated macrophages, tumor-associated suppressor neutrophils, tumor-associated suppressor NK cells, and regulatory T cells into tumors;   (c) increasing number of tumor-promoting myeloid/granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ;   (d) enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC);   (e) increasing expression of tumor-promoting cytokines in a tumor or in peripheral blood, optionally wherein the tumor-promoting cytokines are TGF-beta or IL-10;   (f) increasing tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes;   (g) decreasing activation of tumor-specific T lymphocytes with tumor killing potential;   (h) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential;   (i) decreasing infiltration of tumor-specific NK cells with tumor killing potential;   (j) decreasing the tumor killing potential of NK cells;   (k) decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response;   (l) increasing tumor volume;   (m) increasing tumor growth rate;   (n) increasing metastasis;   (o) increasing rate of tumor recurrence;   (p) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more target proteins selected from the group consisting of PD1/PDL1, CTLA4, CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GALS, TIM3, A2AR, LAG, DR-5, and any combination thereof, or one or more cancer vaccines;   (q) inhibition of PLCγ/PKC/calcium mobilization; and   (r) inhibition of PI3K/Akt, Ras/MAPK signaling.   
     
     
         83 . The method of  claim 82 , wherein the cancer expresses Siglec-7 or one or more Siglec-7 ligands. 
     
     
         84 . The method of  claim 82  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 cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and multiple myeloma. 
     
     
         85 . The method of  claim 81 , wherein the anti-Siglec-7 antibody exhibits one or more activities selected from the group consisting of:
 (a) increasing the number of tumor infiltrating CD3 +  T cells;   (b) inhibiting Siglec-7 binding to one or more Siglec-7 ligands;   (c) decreasing cell surface levels of Siglec-7 in peripheral immune cells   (d) reducing the number of non-tumorigenic CD14 +  myeloid cells, optionally wherein the non-tumorigenic CD14 +  myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +  myeloid cells are present in blood;   (e) reducing the number of non-tumorigenic CD14 +  myeloid cells, optionally wherein the non-tumorigenic CD14 +  myeloid cells are tumor infiltrating cells or optionally wherein the non-tumorigenic CD14 +  myeloid cells are present in the tumor;   (f) reducing PD-L1 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (g) reducing PD-L2 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (h) reducing CD11b levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (i) reducing B7-H3 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (j) reducing CD200R levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (k) reducing CD163 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (l) reducing CD206 levels in one or more cells, optionally wherein the one or more cells are non-tumorigenic myeloid-derived suppressor cells (MDSC);   (m) decreasing tumor growth rate of solid tumors;   (n) reducing tumor volume;   (o) increasing efficacy of one or more PD-1 inhibitors;   (p) increasing efficacy of one or more checkpoint inhibitor therapies and/or immune-modulating therapies, optionally wherein the one or more checkpoint inhibitor therapies and/or immune-modulating therapies target one or more of CTL4, the adenosine pathway, PD-L1, PD-L2, OX40, TIM3, LAGS, or any combination thereof;   (q) inhibiting differentiation, survival, and/or one or more functions of non-tumorigenic myeloid-derived suppressor cells (MDSC);   (r) inducing cell death of one or more myeloid-derived suppressor cells (MDSC);   (s) increasing proliferation of T cells in the presence of non-tumorigenic myeloid-derived suppressor cells (MDSC).   
     
     
         86 .- 117 . (canceled) 
     
     
         118 . The method of  claim 81 , wherein the anti-Siglec-7 antibody decreases cell surface levels of Siglec-7, decreases intracellular levels of Siglec-7, decreases total levels of Siglec-7, or any combination thereof. 
     
     
         119 . The method of  claim 81 , wherein the anti-Siglec-7 antibody induces Siglec-7 degradation, Siglec-7 cleavage, Siglec-7 internalization, Siglec-7 shedding, downregulation of Siglec-7 expression, or any combination thereof. 
     
     
         120 . The method of  claim 81 , wherein the antibody decreases cell surface levels of Siglec-7 in vivo. 
     
     
         121 . The method of  claim 81 , wherein the anti-Siglec-7 antibody inhibits cell surface clustering of Siglec-7. 
     
     
         122 . The method of  claim 81 , wherein the anti-Siglec-7 antibody inhibits one or more Siglec-7 activities. 
     
     
         123 . The method of  claim 81 , wherein the one or more Siglec-7 ligands are selected from the group consisting of Siglec-7 ligands expressed on red blood cells, Siglec-7 ligands expressed on bacterial cells, Siglec-7 ligands expressed on apoptotic cells, Siglec-7 ligands expressed on nerve cells, Siglec-7 ligands expressed on glial cells, Siglec-7 ligands expressed on microglia, Siglec-7 ligands expressed on astrocytes, Siglec-7 ligands expressed on tumor cells, Siglec-7 ligands expressed on viruses, Siglec-7 ligands expressed on dendritic cells, Siglec-7 ligands bound to beta amyloid plaques, Siglec-7 ligands bound to Tau tangles, Siglec-7 ligands on disease-causing proteins, Siglec-7 ligands on disease-causing peptides, Siglec-7 ligands expressed on macrophages, Siglec-7 ligands expressed on neutrophils, Siglec-7 ligands expressed on monocytes, Siglec-7 ligands expressed on natural killer cells, Siglec-7 ligands expressed on T cells, Siglec-7 ligands expressed on T helper cells, Siglec-7 ligands expressed on cytotoxic T cells, Siglec-7 ligands expressed on B cells, Siglec-7 ligands expressed on tumor-imbedded immunosuppressor dendritic cells, Siglec-7 ligands expressed on tumor-imbedded immunosuppressor macrophages, Siglec-7 ligands expressed on tumor-imbedded immunosuppressor neutrophils, Siglec-7 ligands expressed on tumor-imbedded immunosuppressor NK cells, Siglec-7 ligands expressed on myeloid-derived suppressor cells, Siglec-7 ligands expressed on regulatory T cells, secreted mucins, sialic acid, sialic acid-containing glycolipids, sialic acid-containing glycoproteins, alpha-2,8-disialyl containing glycolipids, branched alpha-2,6-linked sialic acid-containing glycoproteins, terminal alpha-2,6-linked sialic acid-containing glycolipids, terminal alpha-2,3-linked sialic acid-containing glycoproteins, and disialogangliosides. 
     
     
         124 . The method of  claim 81 , wherein the cell surface levels of Siglec-7 are measured on primary cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, and NK cells, or on cell lines, and wherein the cell surface levels of Siglec-7 are measured utilizing an in vitro cell assay. 
     
     
         125 . The method of  claim 81 , wherein the anti-Siglec-7 antibody does not reduce TREM2 expression. 
     
     
         126 . The method of  claim 81 , wherein the anti-Siglec-7 antibody binds to one or more amino acids within amino acid residues selected from the group consisting of:
 i. amino acid residues 60-69 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 60-69 of SEQ ID NO: 1;   ii. amino acid residues 60-69 and 117-127 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 60-69 and 117-127 of SEQ ID NO: 1;   iii. amino acid residues 111-122 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 111-122 of SEQ ID NO: 1;   iv. amino acid residues 111-122 and 282-291 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 111-122 and 282-291 of SEQ ID NO: 1;   v. amino acid residues 113-123 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 113-123 of SEQ ID NO: 1;   vi. amino acid residues 113-125 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 113-125 of SEQ ID NO: 1;   vii. amino acid residues 117-127 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 117-127 of SEQ ID NO: 1; and   viii. amino acid residues 282-291 of SEQ ID NO: 1, or amino acid residues on a mammalian Siglec-7 protein corresponding to amino acid residues 282-291 of SEQ ID NO: 1.   
     
     
         127 . The method of  claim 81 , wherein the anti-Siglec-7 antibody binds to one or more amino acid residues selected from the group consisting of 172, W74, N81, and R124 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian Siglec-7 protein corresponding to an amino acid residue selected from the group consisting of 172, W74, N81, and R124 of SEQ ID NO: 1. 
     
     
         128 . The method of  claim 81 , wherein the anti-Siglec-7 antibody competes with one or more antibodies selected from the group consisting of 1A12, 1E8, 2G4, 3E11, 4A1, 4E3, 4E3H1, 4E3H2, 7F12, and any combination thereof for binding to Siglec-7. 
     
     
         129 . The method of  claim 81 , wherein the anti-Siglec-7 antibody comprises a light chain variable domain comprising an HVR-L1, an HVR-L2, and an HVR-L3 and a heavy chain variable domain comprising an HVR-H1, an HVR-H2, and an HVR-H3, wherein:
 (a) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 7, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 20, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 33, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 46, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 59, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 72;   (b) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 8, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 21, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 34, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 47, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 60, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 73;   (c) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 10, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 23 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 23, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 36, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 49, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 62, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 75;   (d) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 11, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 24, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 37 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 37, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 50, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 63, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 76;   (e) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 12, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 25, the HVR-L3 somprises the amino acid sequence of SEQ ID NO: 38 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 38, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 51, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 64, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 77;   (f) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 14, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 27, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 40 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 40, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 53 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 53, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 66, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 79 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 79; or   (g) the HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 17, the HVR-L2 comprises the amino acid sequence of SEQ ID NO: 30 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 30, the HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 43, the HVR-H1 comprises the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 56, the HVR-H2 comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 69, and the HVR-H3 comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence with at least about 90% homology to SEQ ID NO: 82.   
     
     
         130 . The method of  claim 81 , wherein the anti-Siglec-7 antibody is of the IgG class, the IgM class, or the IgA class. 
     
     
         131 . The method of  claim 130 , wherein the anti-Siglec-7 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. 
     
     
         132 . The method of  claim 131 , wherein:
 (a) the anti-Siglec-7 antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, D265A, D270A, L234A, L235A, G237A, P238D, L328E, E233D, G237D, H268D, P271G, A330R, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, N297Q, P238S, P238A, A327Q, A327G, P329A, K322A, T394D, and any combination thereof, wherein the numbering of the residues is according to EU numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236;   (b) the anti-Siglec-7 antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 475), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU numbering;   (c) the anti-Siglec-7 antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof, wherein the numbering of the residues is according to EU numbering;   (d) the anti-Siglec-7 antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, E233P, F234V, L234A/F234A, S228P, S241P, L248E, T394D, N297A, N297Q, L235E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or   (e) the anti-Siglec-7 antibody has a hybrid IgG2/4 isotype, and optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU or, Kabat numbering.   
     
     
         133 . The method of  claim 81 , wherein Siglec-7 is a mammalian protein or a human protein. 
     
     
         134 . The method of  claim 81 , wherein the anti-Siglec-7 antibody binds Siglec-7 in a pH dependent manner. 
     
     
         135 . The method of  claim 81 , wherein the anti-Siglec-7 antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Siglec-7 or a mammalian Siglec-7 protein. 
     
     
         136 . The method of  claim 81 , wherein the anti-Siglec-7 antibody is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment. 
     
     
         137 . The method of  claim 81 , wherein the anti-Siglec-7 antibody is a murine antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. 
     
     
         138 . The method of  claim 81 , wherein the anti-Siglec-7 antibody has a dissociation constant (K D ) for human Siglec-7 that ranges from about 9.5 nM to about 17 pM, wherein the K D  is determined at a temperature of approximately 25° C. 
     
     
         139 . The method of  claim 81 , wherein the anti-Siglec-7 antibody binds to human dendritic cells with an EC 50  that ranges from 2 nM to 100 pM, wherein the EC 50  is determined at a temperature of approximately 4° C. 
     
     
         140 . The method of  claim 81 , wherein the anti-Siglec-7 antibody decreases cell surface levels of Siglec-7 with an EC 50  that ranges from 500 pM to 18 pM, wherein the EC 50  is determined at a temperature of approximately 37° C. 
     
     
         141 . The method of  claim 81 , wherein the anti-Siglec-7 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein:
 (a) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 7 or the amino acid sequence of SEQ ID NO: 7 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20 or the amino acid sequence of SEQ ID NO: 20 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 33 or the amino acid sequence of SEQ ID NO: 33 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 46 or the amino acid sequence of SEQ ID NO: 46 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59 or the amino acid sequence of SEQ ID NO: 59 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 72 or the amino acid sequence of SEQ ID NO: 72 having one conservative amino acid substitution;   (b) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 8 or the amino acid sequence of SEQ ID NO: 8 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 21 or the amino acid sequence of SEQ ID NO: 21 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34 or the amino acid sequence of SEQ ID NO: 34 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 47 or the amino acid sequence of SEQ ID NO: 47 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 60 or the amino acid sequence of SEQ ID NO: 60 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 73 or the amino acid sequence of SEQ ID NO: 73 having one conservative amino acid substitution;   (c) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10 or the amino acid sequence of SEQ ID NO: 10 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 23 or the amino acid sequence of SEQ ID NO: 23 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36 or the amino acid sequence of SEQ ID NO: 36 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49 or the amino acid sequence of SEQ ID NO: 49 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62 or the amino acid sequence of SEQ ID NO: 62 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75 or the amino acid sequence of SEQ ID NO: 75 having one conservative amino acid substitution;   (d) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11 or the amino acid sequence of SEQ ID NO: 11 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 24 or the amino acid sequence of SEQ ID NO: 24 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37 or the amino acid sequence of SEQ ID NO: 37 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 50 or the amino acid sequence of SEQ ID NO: 50 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63 or the amino acid sequence of SEQ ID NO: 63 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 76 or the amino acid sequence of SEQ ID NO: 76 having one conservative amino acid substitution;   (e) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12 or the amino acid sequence of SEQ ID NO: 12 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25 or the amino acid sequence of SEQ ID NO: 25 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 38 or the amino acid sequence of SEQ ID NO: 38 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 51 or the amino acid sequence of SEQ ID NO: 51 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 64 or the amino acid sequence of SEQ ID NO: 64 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 77 or the amino acid sequence of SEQ ID NO: 77 having one conservative amino acid substitution;   (f) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14 or the amino acid sequence of SEQ ID NO: 14 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27 or the amino acid sequence of SEQ ID NO: 27 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 40 or the amino acid sequence of SEQ ID NO: 40 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 53 or the amino acid sequence of SEQ ID NO: 53 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 66 or the amino acid sequence of SEQ ID NO: 66 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 79 or the amino acid sequence of SEQ ID NO: 79 having one conservative amino acid substitution; or   (g) the light chain variable domain comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 17 or the amino acid sequence of SEQ ID NO: 17 having one conservative amino acid substitution, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30 or the amino acid sequence of SEQ ID NO: 30 having one conservative amino acid substitution, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43 or the amino acid sequence of SEQ ID NO: 43 having one conservative amino acid substitution, and wherein the heavy chain variable domain comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 56 or the amino acid sequence of SEQ ID NO: 56 having one conservative amino acid substitution, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 69 or the amino acid sequence of SEQ ID NO: 69 having one conservative amino acid substitution, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 82 or the amino acid sequence of SEQ ID NO: 82 having one conservative amino acid substitution.   
     
     
         142 . The method of  claim 81 , wherein the anti-Siglec-7 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 189-208, 219-248, 259-268, 289-298, and 484-486. 
     
     
         143 . The method of  claim 81 , wherein the anti-Siglec-7 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 319-338, 349-378, 389-398, 419-428 and 490-492.