Anti-CD33 antibodies and methods of use thereof

1. An isolated human anti-CD33 antibody that binds to a human CD33 protein, wherein the anti-CD33 antibody comprises 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 with at least about 90% homology to the amino acid sequence of SEQ ID NO: 16, an HVR-L2 comprising an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 33, and an HVR-L3 comprising an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 95, and

wherein the heavy chain variable domain comprises an HVR-H1 comprising an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 120, an HVR-H2 comprising an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 141, and an HVR-H3 comprising an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 209.

2. The human anti-CD33 antibody of claim 1 , wherein the antibody decreases cell surface levels of CD33.

3. The human anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody binds to one or more amino acids within amino acid residues 19-259 or 19-135 of SEQ ID NO: 1; or within amino acid residues on a mammalian CD33 protein corresponding to amino acid residues 19-259 or 19-135 of SEQ ID NO: 1.

4. The human anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody competes with one or more antibodies 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: 305, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 381;

(b) 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: 319, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 393;

(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: 342, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 411;

(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: 327, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 400; and

(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: 312, and wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 377,

and any combination thereof for binding to CD33.

5. The human anti-CD33 antibody of claim 1 , wherein the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

6. The human anti-CD33 antibody of claim 5 , 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.

7. The human anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody is an antibody fragment.

8. The human anti-CD33 antibody of claim 7 , wherein the anti-CD33 antibody is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment.

9. The human anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody is a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.

10. The human anti-CD33 antibody of claim 1 , wherein the anti-CD33 antibody has a dissociation constant (K D ) for human CD33 that ranges from less than about 100 nM to less than about 0.304 nM.

11. The human anti-CD33 antibody of claim 1 , wherein the antibody inhibits interaction between human CD33 and one or more CD33 ligands.

12. An isolated nucleic acid comprising a nucleic acid sequence encoding the anti-CD33 antibody of claim 1 .

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

14. A host cell comprising the vector of claim 13 .

15. A method of producing an anti-CD33 antibody, comprising culturing the host cell of claim 14 so that the anti-CD33 antibody is produced.

16. A method of treating a disease, disorder, or injury selected from the group consisting of Alzheimer's disease, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and multiple myeloma, wherein the method comprises administering to an individual in need thereof a therapeutically effective amount of the human anti-CD33 antibody of claim 1 .