ANTI-GD2 ANTIBODY FOR THE TREATMENT OF NEUROBLASTOMA
The invention relates to anti-ganglioside GD2 antibodies that comprise an antibody variable domain and antibody constant domains, wherein the variable domain comprises a heavy and light chain variable region comprising respectively at least the CDR3 of the heavy chain variable region of antibody ch14.18 and at least the CDR3 of the light chain variable region of antibody ch14.18; and an IgA hinge and C H 2 domain and to methods of treatment of subjects with a GD2 positive tumor, preferably neuroblastoma with these antibodies.
1 - 53 . (canceled)
54 . An engineered antibody that comprises:
(a) an antigen binding domain; and
(b) a constant domain that comprises an immunoglobulin A (IgA) heavy chain constant region that comprises a mutation in a tailpiece region, wherein said mutation is a substitution, or a deletion, wherein said mutation is not a deletion of amino acid residue C471, or Y472,
relative to a WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme, and
wherein the antigen binding domain is from an immunoglobulin G (IgG) antibody.
55 . The engineered antibody of claim 54 , wherein said IgA heavy chain constant region further comprises;
(i) an amino acid substitution at N337,
(ii) an amino acid substitution at 1338,
(iii) an amino acid substitution at T339,
(iv) an amino acid substitution at N166,
(v) an amino acid substitution at P221,
(vi) an amino acid substitution at C311, or
(vii) a combination thereof,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
56 . The engineered antibody of claim 54 , wherein the IgA heavy chain constant region further comprises;
(i) a N337T amino acid substitution,
(ii) a I338L amino acid substitution,
(iii) a T339S amino acid substitution,
(iv) a N166G amino acid substitution,
(v) a P221R amino acid substitution,
(vi) a C311S amino acid substitution, or
(vii) a combination thereof,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
57 . The engineered antibody of claim 54 , wherein the IgA heavy chain constant region further comprises;
(i) a N337T amino acid substitution,
(ii) a I338L amino acid substitution,
(iii) a T339S amino acid substitution, and
(iv) a N166G amino acid substitution,
relative to a WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
58 . The engineered antibody of claim 54 , wherein the IgA heavy chain constant region further comprises;
(i) a P221R amino acid substitution, and
(ii) a C311S amino acid substitution,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
59 . The engineered antibody of claim 54 , wherein the engineered antibody exhibits antibody-dependent cell mediated cytotoxicity (ADCC) as measured in a suitable in vitro ADCC assay.
60 . The engineered antibody of claim 54 , wherein the engineered antibody is monomeric or dimeric.
61 . A pharmaceutical composition comprising the engineered antibody of claim 54 .
62 . A method of treating a subject in need thereof comprising;
administering to the subject a therapeutically effective amount of the engineered antibody of claim 54 .
63 . An engineered antibody that comprises:
(a) an antigen binding domain; and
(b) a constant domain that comprises an immunoglobulin A (IgA) heavy chain constant region that comprises a mutation in a tailpiece region, wherein said mutation comprises a deletion of at least three amino acids, relative to a WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme, and wherein the antigen binding domain is from an immunoglobulin G (IgG) antibody.
64 . The engineered antibody of claim 63 , wherein the at least three amino acids comprise C471.
65 . The engineered antibody of claim 63 , wherein the at least three amino acids comprise Y472.
66 . The engineered antibody of claim 63 , wherein said IgA heavy chain constant region comprises;
(i) an amino acid substitution at N337,
(ii) an amino acid substitution at 1338,
(iii) an amino acid substitution at T339,
(iv) an amino acid substitution at N166,
(v) an amino acid substitution at P221,
(vi) an amino acid substitution at C311, or
(vii) a combination thereof,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
67 . The engineered antibody of claim 63 , wherein the IgA heavy chain constant region further comprises;
(i) a N337T amino acid substitution,
(ii) a I338L amino acid substitution,
(iii) a T339S amino acid substitution,
(iv) a N166G amino acid substitution,
(v) a P221R amino acid substitution,
(vi) a C311S amino acid substitution, or
(vii) a combination thereof,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
68 . The engineered antibody of claim 63 , wherein the IgA heavy chain constant region further comprises;
(i) a N337T amino acid substitution,
(ii) a I338L amino acid substitution,
(iii) a T339S amino acid substitution, and
(iv) a N166G amino acid substitution,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
69 . The engineered antibody of claim 63 , wherein the IgA heavy chain constant region further comprises;
(i) a P221R amino acid substitution, and
(ii) a C311S amino acid substitution,
relative to the WT IgA heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 11, numbering according to the myeloma IgA1 protein (Bur) scheme.
70 . The engineered antibody of claim 63 , wherein the engineered antibody exhibits antibody dependent cell mediated cytotoxicity (ADCC) as measured in a suitable in vitro ADCC assay.
71 . The engineered antibody of claim 63 , wherein the engineered antibody is monomeric or dimeric.
72 . A pharmaceutical composition comprising the engineered antibody of claim 63 .
73 . A method of treating a subject in need thereof comprising;
administering to the subject a therapeutically effective amount of the engineered antibody of claim 63 .