US2022281976A1PendingUtilityA1
Anti-cd33 antibodies and methods of use thereof
Est. expiryJun 12, 2035(~8.9 yrs left)· nominal 20-yr term from priority
C07K 16/2803A61K 2039/505C07K 2317/73A61P 35/00C12N 15/62C07K 2317/92C07K 16/2896C07K 2317/55C07K 2317/31C07K 2317/76C12N 15/85C07K 2317/24C07K 2317/21C07K 2317/34C07K 2317/70A61K 47/6801
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Claims
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 CD33 protein, e.g., human CD33 or a mammalian CD33, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody decreases cellular levels of CD33, or inhibits interaction between CD33 and one or more CD33 ligands, or both.
2 . The anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody decreases cell surface levels of CD33, decreases intracellular levels of CD33, decreases 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 - 3 , wherein the anti-CD33 antibody decreases 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 - 3 , wherein the anti-CD33 antibody decreases 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 - 5 , wherein the antibody decreases 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 decreasing cellular levels of CD33.
8 . The anti-CD33 antibody of any one of claims 1 - 7 , wherein the anti-CD33 antibody inhibits cell surface clustering of CD33.
9 . The anti-CD33 antibody of any one of claims 1 - 8 , wherein the anti-CD33 antibody inhibits one or more CD33 activities.
10 . The anti-CD33 antibody of claim 9 , wherein the one or more CD33 activities selected from the group consisting of:
(a) CD33 binding to sialic acid-containing glycoproteins, or sialic acid-containing glycolipids, or both; (b) modulate expression of one or more anti-inflammatory cytokines, optionally wherein the one or more anti-inflammatory cytokines are selected from a group consisting of IL-4, IL-10, IL-13, IL-35, IL-16, TGF-beta, IL-1Ra, G-CSF, and soluble receptors for TNF, IFN-beta1a, IFN-beta1b, or IL-6; (c) modulate 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) modulate expression of one or more pro-inflammatory cytokines, optionally wherein the one or more pro-inflammatory cytokines are selected from the group consisting of IFN-a4, 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) modulate 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; (f) modulate expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2, CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, and PYCARD; (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) decreasing 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) inhibition of phagocytosis of one or more of apoptotic neurons, nerve tissue debris, dysfunctional synapses, non-nerve tissue debris, bacteria, other foreign bodies, disease-causing proteins, disease-causing peptides, disease-causing nucleic acids, or tumor cells; optionally wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and the tumor cells are from a cancer selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, or thyroid cancer; (k) binding to CD33 ligand on tumor cells; (l) binding to CD33 ligand on cells selected from the group consisting of neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, T cells, and macrophages; (m) inhibition of 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 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 functionality of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, immunosuppressor neutrophils, and regulatory T cells; (p) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, myeloid derived suppressor cells, tumor-associated macrophages, immunosuppressor neutrophils, and regulatory T cells into tumors; (q) increasing number of tumor-promoting myeloid/granulocytic immune-suppressive cells in a tumor, in peripheral blood, or other lymphoid organ; (r) enhancing tumor-promoting activity of myeloid-derived suppressor cells; (s) enhancing tumor-promoting activity of myeloid-derived suppressor cells (MDSC); (t) decreasing activation of tumor-specific T lymphocytes with tumor killing potential; (u) decreasing infiltration of tumor-specific NK cells with tumor killing potential; (v) decreasing infiltration of tumor-specific B lymphocytes with potential to enhance immune response; (w) decreasing infiltration of tumor-specific T lymphocytes with tumor killing potential; (x) increasing tumor volume; (y) increasing tumor growth rate; and (z) decreasing efficacy of one or more immune-therapies that modulate anti-tumor T cell responses, optionally wherein the one or more immune-therapies are immune-therapies that target one or more proteins selected from the group consisting of CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, DR-5, TREM1, TREM2, CSF-1 receptor, and any combination thereof, or of one or more cancer vaccines.
11 . The anti-CD33 antibody of any one of claims 1 - 10 , 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 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.
12 . The anti-CD33 antibody of claim 11 , wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 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 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.
13 . The anti-CD33 antibody of any one of claims 1 - 10 , wherein the anti-CD33 antibody binds a discontinuous CD33 epitope.
14 . The anti-CD33 antibody of any one 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 peptide, eight or more peptides, nine or more peptides, or 10 or more peptides.
15 . The anti-CD33 antibody of claim 14 , wherein each of the peptides comprise five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues of the amino acid sequence of SEQ ID NO: 1; or five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more amino acid residues on a mammalian CD33 protein corresponding to the amino acid sequence of SEQ ID NO: 1.
16 . The anti-CD33 antibody of any one of claims 1 - 10 , wherein the anti-CD33 antibody binds to a conformational epitope of CD33.
17 . The anti-CD33 antibody of any one of claims 1 - 16 , wherein the anti-CD33 antibody competes with one or more antibodies 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-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 for binding to CD33.
18 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody does not significantly decrease cell surface levels of CD33.
19 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody does not significantly decrease cell surface levels of CD33, and does not inhibit interaction between CD33 and one or more CD33 ligands.
20 . The anti-CD33 antibody of claim 18 or claim 19 , wherein the antibody decreases cellular levels of CD33 by less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% as compared to cellular levels of CD33 in the absence of the anti-CD33 antibody.
21 . The anti-CD33 antibody of any one of claims 18 - 20 , wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 241-247 of SEQ ID NO: 1; or within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO: 1.
22 . The anti-CD33 antibody of any one of claims 18 - 21 , wherein the anti-CD33 antibody competes 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 for binding to CD33.
23 . The anti-CD33 antibody of any one of claims 1 - 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 cell lines, and wherein the cellular levels of CD33 are measured utilizing an in vitro cell assay.
24 . The anti-CD33 antibody of any one of claims 1 - 23 , wherein the one or more CD33 ligands are selected from the group consisting of CD33 ligands expressed on red blood cells, CD33 ligands expressed on bacterial cells, CD33 ligands expressed on apoptotic cells, CD33 ligands expressed on tumor cells, CD33 ligands expressed on viruses, CD33 ligands expressed on dendritic cells, CD33 ligands expressed on nerve cells, CD33 ligands expressed on gala cells, CD33 ligands expressed on microglia, CD33 ligands expressed on astrocytes, CD33 ligands on beta amyloid plaques, CD33 ligands on Tau tangles, CD33 ligands on disease-causing proteins, CD33 ligands on disease-causing peptides, CD33 ligands expressed on macrophages, CD33 ligands expressed on natural killer cells, CD33 ligands expressed on T cells, CD33 ligands expressed on T helper cells, CD33 ligands expressed on cytotoxic T cells, CD33 ligands expressed on B cells, CD33 ligands expressed on tumor-imbedded immunosuppressor dendritic cells, CD33 ligands expressed on tumor-imbedded immunosuppressor macrophages, CD33 ligands expressed on myeloid-derived suppressor cells, CD33 ligands expressed on regulatory T cells, secreted mucins, 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 of any one of claims 1 - 24 , wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain, or the heavy chain variable domain, or both comprise at least one, two, three, four, five, or six HVRs selected from HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3 of an antibody 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-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.
26 . The anti-CD33 antibody of claim 25 , wherein:
(a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23; (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115; (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: 161-230.
27 . The anti-CD33 antibody of any one of claims 1 - 24 , wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115; and
wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and
(c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230.
28 . The anti-CD33 antibody of any one of claims 1 - 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: 285-362; and/or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 363-432.
29 . 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 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 of claim of claim 29 , wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 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 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.
31 . 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 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 of claim of claim 31 , wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 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.
33 . 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 within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 241-247 of SEQ ID NO: 1.
34 . An isolated human 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 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-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, C-109, and any combination thereof.
35 . An isolated human 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 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-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.
36 . An isolated human 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 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-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 . The anti-CD33 antibody of any one of claims 34 - 36 , wherein:
(a) the HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23; (b) the HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; (c) the HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115; (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: 161-230.
38 . The anti-CD33 antibody of any one of claims 34 - 36 , wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115; and
wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and
(c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230 or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230.
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 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody competes with one or more antibodies 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-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 for binding to CD33.
41 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody competes with one or more antibodies 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-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 for binding to CD33.
42 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody competes 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 for binding to CD33.
43 . An isolated human anti-CD33 antibody which binds essentially the same CD33 epitope as an antibody 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-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 . An isolated human anti-CD33 antibody which binds essentially the same CD33 epitope as an antibody 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-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 which binds 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 . An isolated human anti-CD33 antibody, wherein the anti-CD33 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-38; and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-115; or
wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 116-136, or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-160; and
(c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230 or an amino acid sequence with at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-230.
47 . The anti-CD33 antibody of any one of claims 1 - 46 , wherein the antibody is of the IgG class the IgM class, or the IgA class.
48 . The anti-CD33 antibody of claim 47 , wherein the anti-CD33 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.
49 . The anti-CD33 antibody of claim 48 , wherein the antibody binds an inhibitory Fc receptor.
50 . The anti-CD33 antibody of claim 49 , wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB).
51 . The anti-CD33 antibody of claim 50 , wherein:
(a) the anti-CD33 antibody has a human 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, A330L, 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-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 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-CD33 antibody has a human 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-CD33 antibody has a hybrid IgG2/4 isotype, and optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU numbering.
52 . The anti-CD33 antibody of claim 48 , wherein:
(a) the anti-CD33 antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, 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 a residue position selected from the group consisting of: P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU 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 a residue position selected from the group consisting of: E233P, F234V, L234A/F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering.
53 . The anti-CD33 antibody of claim 52 , wherein:
(a) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU numbering; (b) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or (c) the Fc region further comprises a S228P amino acid substitution according to EU numbering.
54 . The anti-CD33 antibody of any one of claims 1 - 53 , wherein the CD33 protein is a mammalian protein or a human protein.
55 . The anti-CD33 antibody of any one of claims 1 - 54 , wherein the CD33 protein is a wild-type protein.
56 . The anti-CD33 antibody of any one of claims 1 - 54 , wherein the CD33 protein is a naturally occurring variant.
57 . The anti-CD33 antibody of any one of claims 1 - 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 cell, human cytotoxic T cells, human granulocytes, and human microglia.
58 . The anti-CD33 antibody of any one of claims 1 - 57 , wherein the anti-CD33 antibody binds specifically to a mammalian CD33 protein, or a human CD33 protein, or both.
59 . The anti-CD33 antibody of any one of claims 1 - 57 , wherein the anti-CD33 antibody binds specifically to human CD33, or mouse CD33, or both.
60 . The anti-CD33 antibody of any one of claims 1 - 59 , wherein the anti-CD33 antibody binds CD33 in a pH dependent manner.
61 . The anti-CD33 antibody of claim 60 , wherein the anti-CD33 antibody binds CD33 at a pH that ranges from 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 - 62 , wherein 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.
64 . The anti-CD33 antibody of any one of claims 1 - 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, a naturally occurring variant of human CD33, and a disease variant of human CD33.
65 . The anti-CD33 antibody of claim 63 or claim 64 , wherein the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human CD33, a naturally occurring variant of human CD33, and a disease variant of human CD33.
66 . The anti-CD33 antibody of any one of claims 63 - 65 , wherein the fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment.
67 . The anti-CD33 antibody of any one of claims 1 - 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 - 66 , wherein the anti-CD33 antibody is a bispecific antibody recognizing a first antigen and a second antigen.
69 . The anti-CD33 antibody of claim 68 , wherein the first antigen is CD33 and the second antigen is:
(a) an antigen facilitating transport across the blood-brain-barrier; (b) an antigen facilitating transport across the blood-brain-barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopep peptide, and ANG1005; (c) a disease-causing agent selected from the group consisting of disease-causing peptides or proteins and disease-causing nucleic acids, wherein the disease-causing peptides or proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA; and (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or 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, DR5, and phosphatidylserine; and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells.
70 . The anti-CD33 antibody of any one of claims 1 - 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 of claim 71 , wherein the anti-CD33 antibody is conjugated to a toxin selected from the group consisting of ricin, ricin A-chain, doxorubicin, daunorubicin, a maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin, mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin, calicheamicin, Saponaria officinalis inhibitor, glucocorticoid, auristatin, auromycin, yttrium, bismuth, combrestatin, duocarmycins, dolastatin, cc1065, and a cisplatin.
73 . The anti-CD33 antibody of any one of claims 1 - 72 , wherein the anti-CD33 antibody is used in combination with one or more antibodies that specifically bind a disease-causing agent selected from the group consisting of disease-causing peptides, disease-causing proteins, amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and any combination thereof; or with one or more antibodies that bind an immunomodulatory protein selected from the group consisting of: 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, disease-causing nucleic acids, antisense GGCCCC (G2C4) repeat-expansion RNA, and any combination thereof.
74 . The anti-CD33 antibody of any one of the preceding claims, wherein the anti-CD33 antibody has dissociation constant (K D ) for human CD33 and mouse CD33 that ranges from less than about 100 nM to less than about 0.304 nM.
75 . The anti-CD33 antibody of any one of the preceding claims, wherein the anti-CD33 antibody has dissociation constant (K D ) for human CD33 that ranges from less than about 100 nM to less than about 0.304 nM.
76 . The anti-CD33 antibody of any one of the preceding claims, wherein the anti-CD33 antibody has dissociation constant (K D ) for mouse CD33 that ranges from less than about 25.8 nM to less than about 0.445 nM.
77 . An isolated nucleic acid comprising a nucleic acid sequence encoding the anti-CD33 antibody of 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 . A method of producing an anti-CD33 antibody, comprising culturing the host cell of claim 79 so that the anti-CD33 antibody is produced.
81 . The method of claim 80 , further comprising recovering the anti-CD33 antibody produced by the host cell.
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 - 76 , and a pharmaceutically acceptable carrier.
84 . A method of preventing, reducing risk, or treating a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, taupathy disease, infections, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an agent that decreases cellular levels of CD33, or inhibits interaction between CD33 and one or more CD33 ligands, or both.
85 . The method of claim 84 , wherein the disease, disorder, or injury is cancer.
86 . The method of claim 84 or claim 85 , wherein the cancer expresses CD33.
87 . The method of any one of claims 84 - 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 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.
88 . The method of any one of claims 84 - 87 , wherein the disease, disorder, or injury is cancer, and wherein the agent inhibits one or more CD33 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, myeloid derived suppressor cells, tumor-associated macrophages and regulatory T cells; (b) enhancing infiltration of one or more of immunosuppressor dendritic cells, immunosuppressor macrophages, immunosuppressor neutrophils, myeloid derived suppressor cells, tumor-associated macrophages, 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; (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 the 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 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, Ras/MAPK signaling.
89 . A method of inducing or promoting the survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that decreases cellular levels of CD33, or inhibits interaction between CD33 and one or more CD33 ligands, or both.
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 . The method of any one of claims 84 - 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 - 90 , wherein the agent is an isolated human anti-CD33 antibody.
93 . The method of claim 92 , wherein the anti-CD33 antibody is the anti-CD33 antibody of any one of claims 1 - 76 .
94 . A method of decreasing the activity, functionality, or survival of regulatory T cells, tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia (CML) cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an agent that binds or interacts with CD33.
95 . The method of claim 94 , wherein the agent is an isolated human anti-CD33 antibody or anti-CD33 antibody conjugate.
96 . The method of claim 95 , wherein the anti-CD33 antibody is the anti-CD33 antibody of any one of claims 1 - 76 .
97 . A method of decreasing cellular levels of CD33, or inhibiting 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 the individual a therapeutically effective amount of an human isolated anti-CD33 antibody.
98 . The method of claim 96 , wherein the anti-CD33 antibody decreases cellular levels of CD33 in vivo.
99 . The method of claim 97 or claim 98 , wherein the anti-CD33 antibody is the anti-CD33 antibody of any one of claims 1 - 17 and 23 - 76 .
100 . The method of any one of claims 84 - 99 , wherein the individual comprises a variant of CD33.
101 . The method of claim 100 , wherein the variant comprises one or more polymorphisms selected from the group consisting of:
(a) SNP rs3865444 AC ; (b) SNP rs3865444 CC ; (c) SNP rs35112940 GG, AA, AG ; (d) SNP rs12459419 CC, CT or TT ; and any combinations thereof.
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 . 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 . 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 anti-HVEM antibody, an anti-B- and T-lymphocyte attenuator (BTLA) antibody, an anti-Killer inhibitory receptor (KIR) antibody, an anti-GALS antibody, an anti-TIM3 antibody, an anti-AZAR 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 . The method of claim 102 , wherein the one or more standard or investigational anti-cancer therapies are selected from the group consisting of radiotherapy, cytotoxic chemotherapy, targeted therapy, imatinib therapy, trastuzumab therapy, etanercept therapy, adoptive cell transfer (ACT) therapy, chimeric antigen receptor T cell transfer (CAR-T) therapy, vaccine therapy, and cytokine therapy.
106 . The method of any one of claims 84 - 105 , further comprising administering to the individual at least one antibody that specifically binds to an inhibitory cytokine.
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 . 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 . The method of any one of claims 84 - 108 , further comprising administering to the individual at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein.
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 . 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 agonist anti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOS antibody, an agonist anti-CD28 antibody, an agonistic anti-TREM1 antibody, an agonistic anti-TREM2 antibody, an agonist anti-CD137/4-1BB antibody, an agonist anti-CD27 antibody, an agonist anti-glucocorticoid-induced TNFR-related protein GITR antibody, and any combination thereof.
112 . The method of any one of claims 84 - 111 , further comprising administering to the individual at least one stimulatory cytokine.
113 . The method of claim 112 , wherein the at least one stimulatory cytokine is administered in combination with the anti-CD33 antibody.
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-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, IL-23, CXCL10, IL-33, CRP, IL-33, MCP-1, MIP-1-beta, and any combination thereof.Join the waitlist — get patent alerts
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