Humanized anti-beta-amyloid antibodies
Antigen binding proteins that bind β-amyloid peptide, in particular human β-amyloid peptide; methods of treating diseases or disorders characterized by elevated β-amyloid levels or β-amyloid deposits, particularly Alzheimer's disease and diseases or disorders affecting the eye or optic nerve characterized by elevated β-amyloid levels or β-amyloid deposits, including age related macular degeneration and glaucoma type diseases and β-amyloid dependent cataract formation, with the antigen binding proteins; pharmaceutical compositions comprising the antigen binding proteins; and methods of manufacture.
1. A therapeutic humanized antibody which is an antibody or antigen binding fragment thereof which binds an epitope of β-amyloid peptide that is within the region of residues 28-35 of β-amyloid and which comprises the following CDRs:
CDRH1: VYYVH (SEQ ID No:1)
CDRH2: RIDPENGETIYTPKFQD (SEQ ID No:2)
CDRH3: SGY (SEQ ID No:3)
CDRL1: RSSKSLLHRNGITYLY (SEQ ID No:4)
CDRL2: QMSNLAS (SEQ ID No:5)
CDRL3: AQNLELWT (SEQ ID No:6).
2. A therapeutic antibody according to claim 1 in which the human acceptor heavy chain framework is derived from IGHV1-24 and the JH4 minigene and the human acceptor light chain framework is derived from IGKV2-28 and JK-1 minigene optionally containing one or more substitutions of amino acid residues based on the corresponding residues found in the donor V H domain having the sequence: SEQ ID No:19 and V L domain having the sequence: SEQ ID No:21 that maintain all or substantially all of the binding affinity of the donor antibody for β-amyloid peptide.
3. A therapeutic antibody according to claim 2 in which the human acceptor heavy chain framework has one or more amino acid residue substitutions selected from the following residues (or conservative substitutions thereof):
Kabat Numbering of
Human Framework
Corresponding residue
residue
Residue (donor IGHV1-24)
in murine 6F6
1
Q
E
5
V
Q
13
K
E
24
V
G
27
Y
F
28
T
N
29
L
I
30
T
K
37
V
L
40
A
L
41
P
T
48
M
I
66
R
K
67
V
A
69
M
L
71
E
V
75
T
S
76
D
N
93
A
V
94
T
S
4. A therapeutic antibody according to claim 3 in which the human acceptor heavy chain framework comprises the following residues (or a conservative substitute thereof):
Kabat Numbering of
Human Framework
residue
Residue (donor IGHV1-24)
Residue substitution
13
K
E
24
V
G
27
Y
F
28
T
N
29
L
I
30
T
K
37
V
L
40
A
L
48
M
I
66
R
K
67
V
A
69
M
L
71
E
V
93
A
V
94
T
S
5. A therapeutic antibody according to any of claims 2 to 4 in which the human acceptor light chain framework has one or more amino acid residue substitutions selected from the following residues (or conservative substitutions thereof):
Kabat Numbering of
Human Framework
residue
Residue (donor IGHV1-24)
Residue substitution
8
P
A
11
L
N
43
S
P
63
S
T
64
G
S
100
Q (JK-1)
G
104
V (JK-1)
L
6. A therapeutic antibody according to claim 5 in which the human acceptor light chain framework comprises the following residues (or a conservative substitute thereof):
Kabat Numbering of
Human Framework
residue
Residue (donor IGHV1-24)
Residue substitution
11
L
N
64
G
S
7. A therapeutic antibody which binds to β-amyloid peptide comprising a V H domain having the sequence set forth in SEQ ID No:65 and a V L domain having the sequence set forth in SEQ ID No:71.