Anti-CD33 antibodies and methods of use thereof

1. A method of treating a disease 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, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to a CD33 protein, wherein the antibody comprises

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 60, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 62, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 63, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 64, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 67, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 68, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 69, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86;

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; or

a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 72, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.

2. The method of claim 1 , wherein the disease is Alzheimer's disease.

3. The method of claim 1 , wherein the method further comprises administering 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, 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, ataxia 10, atrial natriuretic factor, islet amyloid polypeptide (IAPP), insulin, apolipoprotein AL 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 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, LIGHT, BTLA, CD38, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR3, DR5, CD39, CD70, CD73, LAG3, TREM1, TREM2, Siglec-5, Siglec-7, Siglec-9, Siglec-11, SirpA, CD47, CSF1-receptor, phosphatidylserine, disease-causing nucleic acids, antisense GGCCCC (G2C4) repeat-expansion RNA, and any combination thereof.

4. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.

5. The method of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 65, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.

6. The method of claim 1 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

7. The method of claim 6 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

8. The method of claim 7 , wherein the antibody comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.

9. The method of claim 8 , wherein the antibody comprises a Fe region and

(a) the Fe region comprises an amino acid substitution at position E430G, wherein the numbering of the residue position is according to EU numbering;

(b) the Fe region comprises an amino acid substitution at positions L243A, L235A, and P33 IA, wherein the numbering of the residue position is according to EU numbering;

(c) the Fc region comprises an amino acid substitution at positions L243A, L235A, P33 IA, and E430G, wherein the numbering of the residue position is according to EU numbering;

(d) the Fc region comprises an amino acid substitution at positions K322A and E430G, wherein the numbering of the residue position is according to EU numbering;

(e) the Fe region comprises an amino acid substitution at positions P331S and E430G, wherein the numbering of the residue position is according to EU numbering;

(f) the Fe region comprises an amino acid substitution at positions A330S, P331S, and E430G, wherein the numbering of the residue position is according to EU numbering;

(g) the Fe region comprises an amino acid substitution at positions K322A, A330S, and P331S, wherein the numbering of the residue position is according to EU numbering;

(h) the Fe region comprises an amino acid substitution at positions K322A, P331S, and E430G, wherein the numbering of the residue position is according to EU numbering;

the Fe region comprises an amino acid substitution at position E430G, wherein the numbering of the residue position is according to EU numbering;

(i) the Fc region comprises an amino acid substitution at positions A330S, P331S, and E430G, wherein the numbering of the residue position is according to EU numbering;

(k) the Fe region comprises an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue position is according to EU numbering;

(l) the Fc region comprises an amino acid substitution at position C127S, wherein the numbering of the residue position is according to EU numbering; or

(m) the Fc region comprises an amino acid substitution at positions E345R, E430G and S440 Y, wherein the numbering of the residue position is according to EU numbering.

10. The method of claim 1 , wherein the antibody binds specifically to a human CD33 protein.

11. The method of claim 1 , wherein the antibody is a monoclonal antibody.

12. The method of claim 1 , wherein the antibody is of the IgG class and has an IgG2 isotype.

13. A method of treating a disease 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, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to a CD33 protein, wherein the antibody comprises

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 176 and a Tight chain comprising the amino acid sequence of SEQ ID NO: 185;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 176 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 177 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 177 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 178 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 178 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 179 and a light chain comprising the amino acid sequence of SEQ m NO: 185;

(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 179 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 180 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 180 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(in) a heavy chain comprising the amino acid sequence of SEQ ID NO: 182 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 182 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184 and a light chain comprising the amino acid sequence of SEQ ID NO: 185; or

(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185.

14. The method of claim 13 , wherein the antibody comprises

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 176 and a light chain comprising the amino acid sequence of SEQ m NO: 185;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 176 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 179 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 179 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 18:2 and a light chain comprising the amino acid sequence of SEQ ID NO: 185; or

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 182 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185.

15. The method of claim 13 , wherein the antibody comprises

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:177, and a light chain comprising the amino acid sequence of SEQ ID NO:185;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO:177 without the C-terminal lysine, and a light chain comprising the amino acid sequence of SEQ ID NO:185;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO:180, and a light chain comprising the amino acid sequence of SEQ ID NO:185;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 180 without the C-terminal lysine, and a light chain comprising the amino acid sequence of SEQ ID NO:185;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO:183, and a light chain comprising the amino acid sequence of SEQ NO:185; or

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 183 without the C-terminal lysine, and a light chain comprising the amino acid sequence of SEQ ID NO:185.

16. The method of claim 13 , wherein the antibody comprises

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 178 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 178 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 181 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184 and a light chain comprising the amino acid sequence of SEQ m NO: 185; or

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 184 without the C-terminal lysine and a light chain comprising the amino acid sequence of SEQ ID NO: 185.

17. The method of claim 13 , wherein the disease is Alzheimer's disease.

18. The method of claim 13 , wherein the method further comprises administering 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, 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, atrial natriuretic factor, islet amyloid polypeptide (IAPP), 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 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, LIGHT, BTLA, CD38, TIGIT, VISTA, KIR, GAL9, TIM1, TIM3, TIM4, A2AR3, DR5, CD39, CD70, CD73, LAG3, TREM1, TREM2, Siglec-5, Siglec-7, Siglec-9, Siglec-11, SirpA, CD47, CSF1-receptor, phosphatidylserine, disease-causing nucleic acids, antisense GGCCCC (G2C4) repeat-expansion RNA, and any combination thereof.

19. The method of claim 13 , wherein the antibody hinds specifically to a human CD33 protein.

20. The method of claim 13 , wherein the antibody is a monoclonal antibody.