Anti-cd33 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 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.

1 - 79 . (canceled) 
     
     
         80 . A method of inducing or promoting the functionality or proliferation of one or more immune cells in an individual in need thereof, comprising administering to the individual an effective amount of an isolated antibody that binds to a CD33 protein, wherein the antibody decreases cell surface levels of CD33 to a greater extent than anti-CD33 antibody lintuzumab. 
     
     
         81 - 84 . (canceled) 
     
     
         85 . A method of decreasing the activity, functionality, or survival of tumor-imbedded immunosuppressor dendritic cells, tumor-imbedded immunosuppressor macrophages, or non-tumorigenic myeloid-derived suppressor cells in an individual in need thereof, comprising administering to the individual an effective amount of an isolated antibody that binds to a CD33 protein, wherein the antibody decreases cell surface levels of CD33 to a greater extent than anti-CD33 antibody lintuzumab. 
     
     
         86 - 87 . (canceled) 
     
     
         88 . A method of decreasing cell surface levels of CD33 on one or more cells in an individual in need thereof, comprising administering to the individual an effective amount of an isolated antibody that binds to a CD33 protein, wherein the antibody decreases cell surface levels of CD33 to a greater extent than anti-CD33 antibody lintuzumab. 
     
     
         89 . The method of  claim 88 , wherein the antibody decreases cell surface levels of CD33 in vivo. 
     
     
         90 . The method of  claim 88 , wherein the antibody decreases cell surface levels of CD33 with an EC 50  that is lower than that of anti-CD33 antibody lintuzumab. 
     
     
         91 . The method of  claim 88 , wherein the antibody decreases cell surface levels of CD33 to a greater extent than anti-CD33 antibody gemtuzumab. 
     
     
         92 . The method of  claim 91 , wherein the antibody decreases cell surface levels of CD33 with an EC 50  that is lower than that of anti-CD33 antibody gemtuzumab. 
     
     
         93 - 94 . (canceled) 
     
     
         95 . The method of  claim 88 , wherein the individual comprises a variant of CD33. 
     
     
         96 . The method of  claim 95 , 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.   
     
     
         97 - 115 . (canceled) 
     
     
         116 . The method of  claim 88 , wherein the antibody inhibits one or more CD33 activities, wherein the one or more CD33 activities are selected from the group consisting of:
 (a) CD33 binding to sialic acid-containing glycoproteins, or sialic acid-containing glycolipids, or both;   (b) 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;   (c) 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, granulocytes, neutrophils, microglia, M1 microglia, activated M1 microglia, and M2 microglia;   (d) 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, and disease-causing nucleic acids, wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, and 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   (e) binding to CD33 ligand on cells selected from the group consisting of neutrophils, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, and macrophages.   
     
     
         117 . The method of  claim 88 , wherein the 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. 
     
     
         118 . The method of  claim 88 , wherein the antibody binds to one or more amino acid residues selected from the group consisting of D18, P19, N20, F21, F44, P46, Y49, Y50, K52, and N53 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian CD33 protein corresponding to an amino acid residue selected from the group consisting of D18, P19, N20, F21, F44, P46, Y49, Y50, K52, and N53 of SEQ ID NO: 1. 
     
     
         119 . The method of  claim 88 , wherein the antibody competes with one or more antibodies for binding to CD33, or binds essentially the same CD33 epitope as one or more antibodies, wherein the one or more antibodies are selected from the group consisting of:
 (a) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 35, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 54;   (b) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an FR 1 of SEQ ID NO: 234, an HVR L1 of SEQ ID NO: 10, an FR 2 of SEQ ID NO: 83, an HVR L2 of SEQ ID NO: 13, an FR 3 of SEQ ID NO: 91, an HVR L3 of SEQ ID NO: 72, and an FR 4 of SEQ ID NO: 94, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 244;   (c) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 112, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 154;   (d) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 43, and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 20, an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 24, and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 28;   (e) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 134, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 168; and   (f) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 242, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 245.   
     
     
         120 . The method of  claim 88 , wherein the antibody is of the IgG class, the IgM class, or the IgA class. 
     
     
         121 . The method of  claim 120 , wherein the anti-CD33 antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. 
     
     
         122 . The method of  claim 121 , wherein the antibody binds an inhibitory Fc receptor. 
     
     
         123 . The method of  claim 122 , wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcTIIB). 
     
     
         124 . The method of  claim 88 , wherein the antibody:
 (a) 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, 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) has a human IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region and 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) 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) 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) has a hybrid IgG2/4 isotype, and 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.   
     
     
         125 . The method of  claim 88 , wherein the CD33 protein is a mammalian protein or a human protein. 
     
     
         126 . The method of  claim 125 , wherein the CD33 protein is a wild-type protein or a naturally occurring variant. 
     
     
         127 . The method of  claim 88 , 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 neutrophils, human granulocytes, and human microglia. 
     
     
         128 . The method of  claim 88 , wherein the individual is a human. 
     
     
         129 . The method of  claim 88 , wherein the antibody is an antibody fragment, and wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment. 
     
     
         130 . The method of  claim 88 , wherein the antibody is a murine antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. 
     
     
         131 . The method of  claim 88 , wherein the antibody is selected from the group consisting of:
 (a) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 10; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 13, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 13; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 16, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 16; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 19, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 19; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 23, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 23; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 27, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 27;   (b) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 10; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 13, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 13; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 72, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 72; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 231, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 231; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 23, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 23; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 27, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 27;   (c) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 10, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 10; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 69, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 69; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 72, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 72; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 19, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 19; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 23, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 23; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 27, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 27;   (d) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 11, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 11; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 14, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 14; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 17, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO:17; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 20, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 20; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 24, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 24; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 28, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 28;   (e) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 68, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 68; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 71, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 71; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 74, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 74; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 75, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 75; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 77, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 77; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 28, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 28; and   (f) an antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 228, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 228; an HVR-L2 comprising an amino acid sequence of SEQ ID NO: 229, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 229; an HVR-L3 comprising an amino acid sequence of SEQ ID NO: 230, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 230; and wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence of SEQ ID NO: 232, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 232; an HVR-H2 comprising an amino acid sequence of SEQ ID NO: 233, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 233; and an HVR-H3 comprising an amino acid sequence of SEQ ID NO: 29, or an amino acid sequence with at least about 90% homology to an amino acid sequence of SEQ ID NO: 29.   
     
     
         132 . The method of  claim 88 , wherein the antibody increases phagocytosis by microglia. 
     
     
         133 . The method of  claim 88 , wherein the antibody inhibits interaction between human CD33 and one or more CD33 ligands.