CD33 ANTIBODIES AND USE OF SAME TO TREAT CANCER
The invention provides murine, chimeric, and humanized antibodies that specifically hind to CD33. The antibodies are useful for treatment and diagnoses of various cancers as well as detecting CD33.
1 - 17 . (canceled)
18 . A method of treating a patient having or at risk of having a cancer that expresses CD33, comprising administering to the patient an effective regime of an antibody-drug conjugate comprising an antibody that specifically binds to a human CD33 protein, wherein the antibody comprises a mature heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) comprising SEQ ID NOS:19-21 respectively, and a mature light chain variable region comprising three light chain CDRs comprising SEQ ID NOS:22-24 respectively.
19 . The method of claim 18 , wherein the cancer is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute promyelocytic leukemia (APL), chronic myelogenous leukemia (CIVIL), chronic myelomonocytic leukemia (CMML), a chronic myeloproliferative disorders, precursor B-cell acute lymphoblastic leukemia (preB-ALL), precursor T-cell acute lymphoblastic leukemia (preT-ALL), multiple myeloma (MM), mast cell disease, or myeloid Sarcoma.
20 - 44 . (canceled)
45 . A method of treating a patient having acute myeloid leukemia (AML), comprising administering to the patient an effective regime of an antibody that specifically binds to a human CD33 protein, wherein the antibody comprises a mature heavy chain variable region comprising three heavy chain complementarity determining regions (CDRs) comprising SEQ ID NOS:19-21 respectively, and a mature light chain variable region comprising three light chain CDRs comprising SEQ ID NOS:22-24 respectively.
46 . The method of claim 45 , wherein the antibody is conjugated to a cytotoxic or cytostatic agent.
47 . The method of claim 46 , wherein the antibody is conjugated to a cytotoxic agent.
48 . The method of claim 47 , wherein the cytotoxic agent is conjugated to the antibody via an enzyme cleavable linker.
49 . The method of claim 47 , wherein the cytotoxic agent is a DNA minor groove binder.
50 . The method of claim 47 , wherein the cytotoxic agent has the formula
51 . The method of claim 50 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:18 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:8.
52 . The method of claim 50 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:27 or SEQ ID NO:29 and the light chain constant region has an amino acid sequence comprising SEQ ID NO:25.
53 . The method of claim 18 , wherein the patient has the cancer.
54 . The method of claim 53 , wherein the antibody-drug conjugate is of formula I:
L −(LU− D ) p (I)
wherein L is an antibody, LU is a Linker unit and D is a therapeutic agent and p is the average number of drug molecules per antibody and ranges from 2 to 8.
55 . The method of claim 54 , wherein p is 4.
56 . The method of claim 54 , wherein LU is conjugated to the antibody via a thiol group of a cysteine residue of the antibody.
57 . The method of claim 54 , wherein the therapeutic agent is a cytotoxic agent.
58 . The method of claim 54 , wherein the linker is an enzyme cleavable linker.
59 . The method of claim 58 , wherein the linker is a peptidyl linker.
60 . The method of claim 54 , wherein the linker is a non-cleavable linker.
61 . The method of claim 57 , wherein the cytotoxic agent is a DNA minor groove binder.
62 . The method of claim 61 , wherein the DNA minor groove binder is a pyrrolo[1,4]benzodiazepine.
63 . The method of claim 62 , wherein the pyrrolo[1,4]benzodiazepine has the formula
64 . The method of claim 54 , wherein the cytotoxic agent is an auristatin.
65 . The method of claim 64 , wherein the auristatin is monomethyl auristatin E or F.
66 . The method 54 , wherein the antibody drug conjugate has a formula of any of
67 . The method of claim 18 , wherein the antibody is a humanized antibody.
68 . The method of claim 67 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:18 provided that position H48 is occupied by I, position H66 is occupied by K, position H67 is occupied by A, position H69 is occupied by L, position H71 is occupied by A, and position H94 is occupied by S and a mature light chain variable region at least 90% identical to SEQ ID NO:8 provided position L22 is occupied by N, position L46 is occupied by T, position L69 is occupied by Q, and position L71 by Y, as determined by the Kabat numbering system.
69 . The method of claim 68 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:18 and a mature light chain variable region at least 95% identical to SEQ ID NO:8.
70 . The method of claim 67 , wherein the antibody the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.
71 . The method of claim 70 , wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region.
72 . The method of claim 70 , wherein the heavy chain constant region is of IgG1 isotype.
73 . The method of claim 70 , wherein the heavy chain constant region has an amino acid sequence comprising SEQ ID NO:27 or SEQ ID NO:29 and the light chain constant region has an amino acid sequence comprising SEQ ID NO:25.
74 . The method of claim 73 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:18 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:8.
75 . The method of claim 73 , wherein the antibody is conjugated to a pyrrolo[1,4]benzodiazepine.
76 . The method of claim 51 , further comprising detecting expression of CD33 on the cancer.