Interleukin-13 binding proteins
View Patent ↗The present invention encompasses IL-13 binding proteins. Specifically, the invention relates to antibodies that are chimeric, CDR grafted and humanized antibodies. Preferred antibodies have high affinity for hIL-13 and neutralize hIL-13 activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Method of making and method of using the antibodies of the invention are also provided. The antibodies, or antibody portions, of the invention are useful for detecting hIL-13 and for inhibiting hIL-13 activity, e.g., in a human subject suffering from a disorder in which hIL-13 activity is detrimental.
1. A binding protein comprising an antigen binding domain, said binding protein capable of binding IL-13, said antigen binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein:
CDR-H1 is selected from the group consisting of:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 (SEQ ID NO: 64), wherein;
X 1 is T, D, G, or S;
X 2 is S;
X 3 is D;
X 4 is M, S, Y, L, or H;
X 5 is G, W, Y, A, S, or N;
X 6 is V, I, or M; and
X 7 is D, H, S, Y, N, or G;
residues 31-35 of SEQ ID NO:32;
residues 31-35 of SEQ ID NO:34;
residues 31-35 of SEQ ID NO:36;
residues 31-35 of SEQ ID NO:38;
residues 31-35 of SEQ ID NO:39;
residues 31-35 of SEQ ID NO:41;
residues 31-35 of SEQ ID NO:42;
residues 31-35 of SEQ ID NO:44;
residues 31-35 of SEQ ID NO:52;
residues 31-35 of SEQ ID NO:54;
residues 31-35 of SEQ ID NO:56;
residues 31-35 of SEQ ID NO:58;
residues 31-35 of SEQ ID NO:60; and
residues 31-35 of SEQ ID NO:62;
CDR-H2 is selected from the group consisting of:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (SEQ ID NO: 65), wherein;
X 1 is M, E, H, R, S, G, or L;
X 2 is I or not present;
X 3 is H, Y, A, D, S, or W;
X 4 is P, S, W, or G;
X 5 is S, G, E, or D;
X 6 is D, G, S, E, or N;
X 7 is S, Y or G;
X 8 is E, N, Y, V, or R;
X 9 is T, I, or K;
X 10 is R, Y, I, D, or A;
X 11 is L, Y, D, or F;
X 12 is N, P, S, or D;
X 13 is Q, E, D, P, or S;
X 14 is K, M, S, T, A, or V;
X 15 is F, L, V, or M;
X 16 is K, R, or Q; and
X 17 is D, G, or S;
residues 50-65 of SEQ ID NO:44;
residues 52-67 of SEQ ID NO:46;
residues 52-67 of SEQ ID NO:48;
residues 52-67 of SEQ ID NO:50;
residues 50-65 of SEQ ID NO:54;
residues 50-65 of SEQ ID NO:56;
residues 50-65 of SEQ ID NO:58;
residues 50-65 of SEQ ID NO:60; and
residues 50-65 of SEQ ID NO:62;
CDR-H3 is selected from the group consisting of:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 (SEQ ID NO: 66), wherein;
X 1 is W, T, G, Y, D, or I;
X 2 is R, A, S, G, or V;
X 3 is T, F, Y, or S;
X 4 is S, T, or Y;
X 5 is Y, F, or G;
X 6 is F, or Y;
X 7 is S, Y, I, or F;
X 8 is D, L, Y, or P;
X 9 is Y;
X 10 is G;
X 11 is Y, A, P, or E;
X 12 is F, M, S, L, or I;
X 13 is D, V, N, or K; and
X 14 is Y, or F;
residues 99-105 of SEQ ID NO:32;
residues 99-105 of SEQ ID NO:34;
residues 99-109 of SEQ ID NO:36;
residues 99-109 of SEQ ID NO:38;
residues 99-100 of SEQ ID NO:42;
residues 98-106 of SEQ ID NO:44;
residues 100-112 of SEQ ID NO:46;
residues 100-112 of SEQ ID NO:48;
residues 100-112 of SEQ ID NO:50;
residues 99-107 of SEQ ID NO:52;
residues 98-107 of SEQ ID NO:54;
residues 98-107 of SEQ ID NO:56;
residues 98-107 of SEQ ID NO:58;
residues 98-107 of SEQ ID NO:60; and
residues 98-107 of SEQ ID NO:62;
CDR-L1 is selected from the group consisting of:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 (SEQ ID NO: 67), wherein;
X 1 is K, or R;
X 2 is S, or A;
X 3 is S or T;
X 4 is Q, K, or I;
X 5 is N, S, T, G, or E;
X 6 is L, T, or S;
X 7 is L, Q, or V;
X 8 is Y, N, H, D, or T;
X 9 is S, I, or T;
X 10 is S, D, N, H, or Y;
X 11 is N, or G;
X 12 is Q;
X 13 is K, F, N, E, or S;
X 14 is N, T, or S;
X 15 is Y, or F;
X 16 is L, A, or M; and
X 17 is A, D, E, H, or N;
residues 24-39 of SEQ ID NO:33;
residues 24-39 of SEQ ID NO:35;
residues 24-39 of SEQ ID NO:37;
residues 24-39 of SEQ ID NO:40;
residues 24-39 of SEQ ID NO:43;
residues 24-34 of SEQ ID NO:47;
residues 24-34 of SEQ ID NO:49;
residues 24-34 of SEQ ID NO:51;
residues 23-36 of SEQ ID NO:53;
residues 24-38 of SEQ ID NO:55;
residues 24-38 of SEQ ID NO:57;
residues 24-38 of SEQ ID NO:59;
residues 24-38 of SEQ ID NO:61; and
residues 24-38 of SEQ ID NO:63;
CDR-L2 is X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 (SEQ ID NO: 68), wherein;
X 1 is L, S, K, T, W, or Y;
X 2 is V, T, or A;
X 3 is S, or N;
X 4 is N, K, T, M, or R;
X 5 is R, K, or L;
X 6 is F, D, E, H, P, or A; and
X 7 is S, R, or P;
and
CDR-L3 is selected from the group consisting of:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 (SEQ ID NO: 69), wherein;
X 1 is F, W, Q or A;
X 2 is Q or L;
X 3 is H, G, Y, W, or N;
X 4 is N, S, T, L, or Y;
X 5 is Y, T, S, E, or H;
X 6 is L, V, F, Y, N, G, P, or D;
X 7 is P, or, H;
X 8 is L, F, Y, W, or R; and
X 9 is T, or V; and
residues 94-102 of SEQ ID NO:40.
2. The binding protein according to claim 1 , wherein at least one of the CDR comprises an amino acid sequence selected from the group consisting of:
residues 31-35 of SEQ ID NO.:32
residues 24-34 of SEQ ID NO.:47
(CDR-H1);
(CDR-L1);
residues 50-66 of SEQ ID NO.:32
residues 50-56 of SEQ ID NO.:47
(CDR-H2);
(CDR-L2);
residues 99-105 of SEQ ID NO.:32
residues 89-97 of SEQ ID NO.:47
(CDR-H3);
(CDR-L3);
residues 24-39 of SEQ ID NO.:33
residues 31-37 of SEQ ID NO.:48
(CDR-L1);
(CDR-H1);
residues 55-61 of SEQ ID NO.:33
residues 52-67 of SEQ ID NO.:48
(CDR-L2);
(CDR-H2);
residues 94-102 of SEQ ID NO.:33
residues 100-112 of SEQ ID NO.:48
(CDR-L3);
(CDR-H3);
residues 31-35 of SEQ ID NO.:34
residues 24-34 of SEQ ID NO.:49
(CDR-H1);
(CDR-L1);
residues 50-66 of SEQ ID NO.:34
residues 50-56 of SEQ ID NO.:49
(CDR-H2);
(CDR-L2);
residues 99-105 of SEQ ID NO.:34
residues 89-97 of SEQ ID NO.:49
(CDR-H3);
(CDR-L3);
residues 24-39 of SEQ ID NO.:35
residues 31-37 of SEQ ID NO.:50
(CDR-L1);
(CDR-H1);
residues 55-61 of SEQ ID NO.:35
residues 52-67 of SEQ ID NO.:50
(CDR-L2);
(CDR-H2);
residues 94-102 of SEQ ID NO.:35
residues 100-112 of SEQ ID NO.:50
(CDR-L3);
(CDR-H3);
residues 31-35 of SEQ ID NO.:36
residues 24-34 of SEQ ID NO.:51
(CDR-H1);
(CDR-L1);
residues 50-66 of SEQ ID NO.:36
residues 60-66 of SEQ ID NO.:51
(CDR-H2);
(CDR-L2);
residues 99-109 of SEQ ID NO.:36
residues 89-97 of SEQ ID NO.:51
(CDR-H3);
(CDR-L3);
residues 24-39 of SEQ ID NO.:37
residues 31-35 of SEQ ID NO.:52
(CDR-L1);
(CDR-H1);
residues 55-61 of SEQ ID NO.:37
residues 50-66 of SEQ ID NO.:52
(CDR-L2);
(CDR-H2);
residues 94-102 of SEQ ID NO.:37
residues 99-107 of SEQ ID NO.:52
(CDR-L3);
(CDR-H3);
residues 31-35 of SEQ ID NO.:38
residues 23-36 of SEQ ID NO.:53
(CDR-H1);
(CDR-L1);
residues 50-66 of SEQ ID NO.:38
residues 52-58 of SEQ ID NO.:53
(CDR-H2);
(CDR-L2);
residues 99-109 of SEQ ID NO.:38
residues 91-99 of SEQ ID NO.:53
(CDR-H3);
(CDR-L3);
residues 31-35 of SEQ ID NO.:39
residues 31-35 of SEQ ID NO.:54
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO.:39
residues 50-65 of SEQ ID NO.:54
(CDR-H2);
(CDR-H2);
residues 99-112 of SEQ ID NO.:39
residues 98-107 of SEQ ID NO.:54
(CDR-H3);
(CDR-H3);
residues 24-39 of SEQ ID NO.:40
residues 24-38 of SEQ ID NO.:55
(CDR-L1);
(CDR-L1);
residues 55-61 of SEQ ID NO.:40
residues 54-60 of SEQ ID NO.:55;
(CDR-L2);
(CDR-L2);
residues 94-102 of SEQ ID NO.:40
residues 93-101 of SEQ ID NO.:55
(CDR-L3);
(CDR-L3);
residues 31-35 of SEQ ID NO.:41
residues 31-35 of SEQ ID NO.:56
(CDR-H1);
(CDR-H1);
residues 50-66 of SEQ ID NO.:41
residues 50-65 of SEQ ID NO.:56
(CDR-H2);
(CDR-H2);
residues 99-112 of SEQ ID NO.:41
residues 98-107 of SEQ ID NO.:56
(CDR-H3);
(CDR-H3);
residues 31-35 of SEQ ID NO.:42
residues 24-38 of SEQ ID NO.:57
(CDR-H1);
(CDR-L1);
residues 50-66 of SEQ ID NO.:42
residues 54-60 of SEQ ID NO.:57
(CDR-H2);
(CDR-L2);
residues 99-100 of SEQ ID NO.:42
residues 93-101 of SEQ ID NO.:57
(CDR-H3);
(CDR-L3);
residues 24-39 of SEQ ID NO.:43
residues 31-35 of SEQ ID NO.:58
(CDR-L1);
(CDR-H1);
residues 55-61 of SEQ ID NO.:43
residues 50-65 of SEQ ID NO.:58
(CDR-L2);
(CDR-H2);
residues 94-102 of SEQ ID NO.:43
residues 98-107 of SEQ ID NO.:58
(CDR-L3);
(CDR-H3);
residues 31-35 of SEQ ID NO.:44
residues 24-38 of SEQ ID NO.:59
(CDR-H1);
(CDR-L1);
residues 50-65 of SEQ ID NO.:44
residues 54-60 of SEQ ID NO.:59
(CDR-H2);
(CDR-L2);
residues 98-106 of SEQ ID NO.:44
residues 93-101 of SEQ ID NO.:59
(CDR-H3);
(CDR-L3);
residues 24-40 of SEQ ID NO.:45
residues 31-35 of SEQ ID NO.:60
(CDR-L1);
(CDR-H1);
residues 56-62 of SEQ ID NO.:45
residues 50-65 of SEQ ID NO.:60
(CDR-L2);
(CDR-H2);
residues 95-103 of SEQ ID NO.:45
residues 98-107 of SEQ ID NO.:60
(CDR-L3);
(CDR-H3);
residues 31-37 of SEQ ID NO.:46
residues 24-38 of SEQ ID NO.:61
(CDR-H1);
(CDR-L1);
residues 52-67 of SEQ ID NO.:46;
residues 54-60 of SEQ ID NO.:61
(CDR-H2);
(CDR-L2);
residues 100-112 of SEQ ID NO.:46
residues 93-101 of SEQ ID NO.:61
(CDR-H3);
(CDR-L3);
residues 31-35 of SEQ ID NO.:62
(CDR-H1);
residues 50-65 of SEQ ID NO.:62
(CDR-H2);
residues 98-107 of SEQ ID NO.:62
(CDR-H3);
residues 24-38 of SEQ ID NO.:63
(CDR-L1);
residues 54-60 of SEQ ID NO.:63
(CDR-L2); and
residues 93-101 of SEQ ID NO.:63
(CDR-L3).
3. The binding protein according to claim 1 , wherein at least 3 CDRs are selected from a variable domain CDR set selected from the group consisting of:
VH 25C8 CDR Set
VH 25C8 CDR-H1
Residues 31-35 of SEQ ID NO.: 32
VH 25C8 CDR-H2
Residues 50-66 of SEQ ID NO.: 32
VH 25C8 CDR-H3
Residues 99-105 of SEQ ID NO.: 32
VL 25C8 CDR Set
VL 25C8 CDR-L1
Residues 24-39 of SEQ ID NO.: 33
VL 25C8 CDR-L2
Residues 55-61 of SEQ ID NO.: 33
VL 25C8 CDR-L3
Residues 94-102 of SEQ ID NO.: 33
VH 9C11 CDR Set
VH 9C11 CDR-H1
Residues 31-35 of SEQ ID NO.: 34
VH 9C11 CDR-H2
Residues 50-66 of SEQ ID NO.: 34
VH 9C11 CDR-H3
Residues 99-105 of SEQ ID NO.: 34
VL 9C11 CDR Set
VL 9C11 CDR-L1
Residues 24-39 of SEQ ID NO.: 35
VL 9C11 CDR-L2
Residues 55-61 of SEQ ID NO.: 35
VL 9C11 CDR-L3
Residues 94-102 of SEQ ID NO.: 35
VH 21D9 CDR Set
VH 21D9 CDR-H1
Residues 31-35 of SEQ ID NO.: 36
VH 21D9 CDR-H2
Residues 50-66 of SEQ ID NO.: 36
VH 21D9 CDR-H3
Residues 99-109 of SEQ ID NO.: 36
VL 21D9 CDR Set
VL 21D9 CDR-L1
Residues 24-39 of SEQ ID NO.: 37
VL 21D9 CDR-L2
Residues 55-61 of SEQ ID NO.: 37
VL 21D9 CDR-L3
Residues 94-102 of SEQ ID NO.: 37
VH 22D10 CDR Set
VH 22D10 CDR-H1
Residues 31-35 of SEQ ID NO.: 38
VH 22D10 CDR-H2
Residues 50-66 of SEQ ID NO.: 38
VH 22D10 CDR-H3
Residues 99-109 of SEQ ID NO.: 38
VL 22D10 CDR Set
VL 22D10 CDR-L1
Residues 24-39 of SEQ ID NO.: 37
VL 22D10 CDR-L2
Residues 55-61 of SEQ ID NO.: 37
VL 22D10 CDR-L3
Residues 94-102 of SEQ ID NO.: 37
VH 5F1 CDR Set
VH 5F1 CDR-H1
Residues 31-35 of SEQ ID NO.: 39
VH 5F1 CDR-H2
Residues 50-66 of SEQ ID NO.: 39
VH 5F1 CDR-H3
Residues 99-112 of SEQ ID NO.: 39
VL 5F1 CDR Set
VL 5F1 CDR-L1
Residues 24-39 of SEQ ID NO.: 40
VL 5F1 CDR-L2
Residues 55-61 of SEQ ID NO.: 40
VL 5F1 CDR-L3
Residues 94-102 of SEQ ID NO.: 40
VH 5G1 CDR Set
VH 5G1 CDR-H1
Residues 31-35 of SEQ ID NO.: 41
VH 5G1 CDR-H2
Residues 50-66 of SEQ ID NO.: 41
VH 5G1 CDR-H3
Residues 99-112 of SEQ ID NO.: 41
VL 5G1 CDR Set
VL 5G1 CDR-L1
Residues 24-39 of SEQ ID NO.: 40
VL 5G1 CDR-L2
Residues 55-61 of SEQ ID NO.: 40
VL 5G1 CDR-L3
Residues 94-102 of SEQ ID NO.: 40
VH 3H7 CDR Set
VH 3H7 CDR-H1
Residues 31-35 of SEQ ID NO.: 42
VH 3H7 CDR-H2
Residues 50-66 of SEQ ID NO.: 42
VH 3H7 CDR-H3
Residues 99-100 of SEQ ID NO.: 42
VL 3H7 CDR Set
VL 3H7 CDR-L1
Residues 24-39 of SEQ ID NO.: 43
VL 3H7 CDR-L2
Residues 55-61 of SEQ ID NO.: 43
VL 3H7 CDR-L3
Residues 94-102 of SEQ ID NO.: 43
VH 14B2 CDR Set
VH 14B2 CDR-H1
Residues 31-35 of SEQ ID NO.: 44
VH 14B2 CDR-H2
Residues 50-65 of SEQ ID NO.: 44
VH 14B2 CDR-H3
Residues 98-106 of SEQ ID NO.: 44
VL 14B2 CDR Set
VL 14B2 CDR-L1
Residues 24-40 of SEQ ID NO.: 45
VL 14B2 CDR-L2
Residues 56-62 of SEQ ID NO.: 45
VL 14B2 CDR-L3
Residues 95-103 of SEQ ID NO.: 45
VH 13C5 CDR Set
VH 13C5 CDR-H1
Residues 31-37 of SEQ ID NO.: 46
VH 13C5 CDR-H2
Residues 52-67 of SEQ ID NO.: 46
VH 13C5 CDR-H3
Residues 100-112 of SEQ ID NO.: 46
VL 13C5 CDR Set
VL 13C5 CDR-L1
Residues 24-34 of SEQ ID NO.: 47
VL 13C5 CDR-L2
Residues 50-56 of SEQ ID NO.: 47
VL 13C5 CDR-L3
Residues 89-97 of SEQ ID NO.: 47
VH 29G5 CDR Set
VH 29G5 CDR-H1
Residues 31-37 of SEQ ID NO.: 48
VH 29G5 CDR-H2
Residues 52-67 of SEQ ID NO.: 48
VH 29G5 CDR-H3
Residues 100-112 of SEQ ID NO.: 48
VL 29G5 CDR Set
VL 29G5 CDR-L1
Residues 24-34 of SEQ ID NO.: 49
VL 29G5 CDR-L2
Residues 50-56 of SEQ ID NO.: 49
VL 29G5 CDR-L3
Residues 89-97 of SEQ ID NO.: 49
VH 33C3 CDR Set
VH 33C3 CDR-H1
Residues 31-37 of SEQ ID NO.: 50
VH 33C3 CDR-H2
Residues 52-67 of SEQ ID NO.: 50
VH 33C3 CDR-H3
Residues 100-112 of SEQ ID NO.: 50
VL 33C3 CDR Set
VL 33C3 CDR-L1
Residues 24-34 of SEQ ID NO.: 51
VL 33C3 CDR-L2
Residues 60-66 of SEQ ID NO.: 51
VL 33C3 CDR-L3
Residues 89-97 of SEQ ID NO.: 51
VH 4A8 CDR Set
VH 4A8 CDR-H1
Residues 31-35 of SEQ ID NO.: 52
VH 4A8 CDR-H2
Residues 50-66 of SEQ ID NO.: 52
VH 4A8 CDR-H3
Residues 99-107 of SEQ ID NO.: 52
VL 4A8 CDR Set
VL 4A8 CDR-L1
Residues 23-36 of SEQ ID NO.: 53
VL 4A8 CDR-L2
Residues 52-58 of SEQ ID NO.: 53
VL 4A8 CDR-L3
Residues 91-99 of SEQ ID NO.: 53
VH 1B6 CDR Set
VH 1B6 CDR-H1
Residues 31-35 of SEQ ID NO.: 54
VH 1B6 CDR-H2
Residues 50-65 of SEQ ID NO.: 54
VH 1B6 CDR-H3
Residues 98-107 of SEQ ID NO.: 54
VL 1B6 CDR Set
VL 1B6 CDR-L1
Residues 24-38 of SEQ ID NO.: 55
VL 1B6 CDR-L2
Residues 54-60 of SEQ ID NO.: 55
VL 1B6 CDR-L3
Residues 93-101 of SEQ ID NO.: 55
VH 3E5 CDR Set
VH 3E5 CDR-H1
Residues 31-35 of SEQ ID NO.: 56
VH 3E5 CDR-H2
Residues 50-65 of SEQ ID NO.: 56
VH 3E5 CDR-H3
Residues 98-107 of SEQ ID NO.: 56
VL 3E5 CDR Set
VL 3E5 CDR-L1
Residues 24-38 of SEQ ID NO.: 57
VL 3E5 CDR-L2
Residues 54-60 of SEQ ID NO.: 57
VL 3E5 CDR-L3
Residues 93-101 of SEQ ID NO.: 57
VH 6C8 CDR Set
VH 6C8 CDR-H1
Residues 31-35 of SEQ ID NO.: 58
VH 6C8 CDR-H2
Residues 50-65 of SEQ ID NO.: 58
VH 6C8 CDR-H3
Residues 98-107 of SEQ ID NO.: 58
VL 6C8 CDR Set
VL 6C8 CDR-L1
Residues 24-38 of SEQ ID NO.: 59
VL 6C8 CDR-L2
Residues 54-60 of SEQ ID NO.: 59
VL 6C8 CDR-L3
Residues 93-101 of SEQ ID NO.: 59
VH 5D3 CDR Set
VH 5D3 CDR-H1
Residues 31-35 of SEQ ID NO.: 60
VH 5D3 CDR-H2
Residues 50-65 of SEQ ID NO.: 60
VH 5D3 CDR-H3
Residues 98-107 of SEQ ID NO.: 60
VL 5D3 CDR Set
VL 5D3 CDR-L1
Residues 24-38 of SEQ ID NO.: 61
VL 5D3 CDR-L2
Residues 54-60 of SEQ ID NO.: 61
VL 5D3 CDR-L3
Residues 93-101 of SEQ ID NO.: 61
VH 8E6 CDR Set
VH 8B6 CDR-H1
Residues 31-35 of SEQ ID NO.: 62
VH 8B6 CDR-H2
Residues 50-65 of SEQ ID NO.: 62
VH 8B6 CDR-H3
Residues 98-107 of SEQ ID NO.: 62
VL 8B6 CDR Set
VL 8B6 CDR-L1
Residues 24-38 of SEQ ID NO.: 63
VL 8B6 CDR-L2
Residues 54-60 of SEQ ID NO.: 63
VL 8B6 CDR-L3
Residues 93-101 of SEQ ID NO.: 63.
4. The binding protein according to claim 3 , comprising at least two variable domain CDR sets.
5. The binding protein according to claim 4 , wherein said at least two variable domain CDR sets are selected from a group consisting of:
VH 25C8 CDR Set & VL 25C8 CDR Set;
VH 9C11 CDR Set & VL 9C11 CDR Set;
VH 21D9 CDR Set & VL 21D9 CDR Set;
VH 22D10 CDR Set & VL 22D10 CDR Set;
VH 5F1 CDR Set & VL 5F1 CDR Set;
VH 5G1 CDR Set & VL 5G1 CDR Set;
VH 3H7 CDR Set & VL 3H7 CDR Set;
VH 14B2 CDR Set & VL 14B2 CDR Set;
VH 13C5 CDR Set & VL 13C5 CDR Set;
VH 29G5 CDR Set & VL 29G5 CDR Set;
VH 33C3 CDR Set & VL 33C3 CDR Set;
VH 4A8 CDR Set & VL 4A8 CDR Set;
VH 1B6 CDR Set & VL 1B6 CDR Set;
VH 3E5CDR Set & VL 3E5 CDR Set;
VH 6C8 CDR Set & VL 6C8 CDR Set;
VH 5D3 CDR Set & VL 5D3 CDR Set; and
VH 8B6 CDR Set & VL 8B6 CDR Set.
6. The binding protein according to claim 5 , further comprising a human acceptor framework.
7. The binding protein according to claim 6 , wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO.: 6
SEQ ID NO.: 7
SEQ ID NO.: 8
SEQ ID NO.: 9
SEQ ID NO.: 10
SEQ ID NO.: 11
SEQ ID NO.: 12
SEQ ID NO.: 13
SEQ ID NO.: 14
SEQ ID NO.: 15
SEQ ID NO.: 16
SEQ ID NO.: 17
SEQ ID NO.: 18
SEQ ID NO.: 19
SEQ ID NO.: 20
SEQ ID NO.: 21
SEQ ID NO.: 22
SEQ ID NO.: 23
SEQ ID NO.: 24
SEQ ID NO.: 25
SEQ ID NO.: 26
SEQ ID NO.: 27
SEQ ID NO.: 28
SEQ ID NO.: 29
SEQ ID NO.: 30
AND
SEQ ID NO.: 31.
8. The binding protein according to claim 6 , wherein said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.
9. The binding protein according to claim 7 , wherein said human acceptor framework comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of:
a residue adjacent to a CDR;
a glycosylation site residue;
a rare residue;
a residue capable of interacting with human IL-13;
a residue capable of interacting with a CDR;
a canonical residue;
a contact residue between heavy chain variable region and light chain variable region;
a residue within a Vernier zone; and
a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.
10. The binding protein according to claim 9 , wherein the key residue is selected from the group consisting of 2L, 15L, 22L, 41L, 42L, 44L, 49L, 50L, 51L, 62L, 71L, 73L, 10H, 44H, 46H, 48H, 67H, 68H, 70H, 72H, 74H, 76H, 83H, 84H, 86H, 87H, and 97H.
11. The binding protein according to claim 10 , wherein the binding protein is a consensus human variable domain.
12. The binding protein according to claim 1 , wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:
SEQ ID NO.: 70
SEQ ID NO.: 71
SEQ ID NO.: 72
SEQ ID NO.: 73
SEQ ID NO.: 74
SEQ ID NO.: 75
SEQ ID NO.: 76
SEQ ID NO.: 77
SEQ ID NO.: 78
SEQ ID NO.: 79
SEQ ID NO.: 80
SEQ ID NO.: 81
SEQ ID NO.: 82
SEQ ID NO.: 83
SEQ ID NO.: 84
SEQ ID NO.: 85
SEQ ID NO.: 92
SEQ ID NO.: 93
and
SEQ ID NO.: 94.
13. The binding protein according to claim 12 wherein said binding protein comprises two variable domains, wherein said two variable domains have amino acid sequences selected from the group consisting of:
SEQ ID NO.: 70
SEQ ID NO.: 71
SEQ ID NO.: 72
SEQ ID NO.: 73
SEQ ID NO.: 74
SEQ ID NO.: 75
SEQ ID NO.: 76
SEQ ID NO.: 77
SEQ ID NO.: 78
SEQ ID NO.: 79
SEQ ID NO.: 80
SEQ ID NO.: 81
SEQ ID NO.: 82
SEQ ID NO.: 83
SEQ ID NO.: 84
SEQ ID NO.: 85
SEQ ID NO.: 92
SEQ ID NO.: 93
and
SEQ ID NO.: 94.
14. The binding protein according to claim 10 , wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of:
SEQ ID NO.:70 SEQ ID NO.:78 SEQ ID NO.:92
SEQ ID NO.:71 SEQ ID NO.:79 SEQ ID NO.:93
SEQ ID NO.:72 SEQ ID NO.:80 and
SEQ ID NO.:73 SEQ ID NO.:81 SEQ ID NO.:94.
SEQ ID NO.:74 SEQ ID NO.:82
SEQ ID NO.:75 SEQ ID NO.:83
SEQ ID NO.:76 SEQ ID NO.:84
SEQ ID NO.:77 SEQ ID NO.:85.
15. The binding protein according to claim 1 or 13 , wherein the binding protein is capable of modulating a biological function of IL-13.
16. The binding protein according to claim 1 or 13 , wherein the binding protein is capable of neutralizing IL-13.
17. The binding protein according to claim 1 or 13 , wherein said binding protein has an on rate constant (K on ) to said target selected from the group consisting of: at least about 10 2 M −1 s −1 ; at least about 10 3 M −1 s −1 ; at least about 10 4 M −1 s −1 ; at least about 10 5 M −1 s −1 ; and at least about 10 6 M −1 s −1 ; as measured by surface plasmon resonance.
18. The binding protein according to claim 1 or 13 , wherein said binding protein has an off rate constant (K off ) to said target selected from the group consisting of: at most about 10 −3 s −1 ; at most about 10 −4 s −1 ; at most about 10 −5 s −1 ; and at most about 10 −6 s −1 , as measured by surface plasmon resonance.
19. The binding protein according to claim 1 or 13 , wherein said binding protein has a dissociation constant (K D ) to said target selected from the group consisting of: at most about 10 −7 M; at most about 10 −8 M; at most about 10 −9 M; at most about 10 −10 M; at most about 10 −11 M; at most about 10 −12 M; and at most 10 −13 M.
20. An antibody construct comprising a binding protein described in claim 1 , said antibody construct further comprising a linker polypeptide or an immunoglobulin constant domain.
21. The antibody construct according to claim 20 , wherein the antibody construct is selected from the group consisting of:
an immunoglobulin molecule, a disulfide linked Fv,
a monoclonal antibody, a scFv,
a chimeric antibody, a single domain antibody,
a CDR-grafted antibody, a diabody,
a humanized antibody, a multispecific antibody,
a Fab, a dual specific antibody, and
a Fab′, a bispecific antibody.
a F(ab′)2,
a Fv.
22. The antibody construct according to claim 20 , wherein the antibody construct comprises a heavy chain immunoglobulin constant domain selected from the group consisting of:
a human IgM constant domain, a human IgG4 constant domain,
a human IgG1 constant domain, a human IgE constant domain,
a human IgG2 constant domain, and
a human IgG3 constant domain, a human IgA constant domain.
23. The antibody construct according to claim 20 , wherein the antibody construct comprises an immunoglobulin constant domain having an amino acid sequence selected from the group consisting of:
SEQ ID NO.:2
SEQ ID NO.:3
SEQ ID NO.:4
and
SEQ ID NO.:5.
24. An antibody conjugate comprising an antibody construct of claim 21 , said antibody conjugate further comprising an agent selected from the group consisting of: an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.
25. The antibody conjugate according to claim 24 , wherein said agent is an imaging agent selected from the group consisting of a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin.
26. The antibody conjugate according to claim 24 , wherein said imaging agent is a radiolabel selected from the group consisting of: 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
27. The antibody conjugate according to claim 24 , wherein said agent is a therapeutic or cytotoxic agent selected from the group consisting of; an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, and an apoptotic agent.
28. The antibody construct according to claim 21 , wherein the antibody construct possesses a human glycosylation pattern.
29. The binding protein according to claim 1 , wherein said binding protein is a crystallized binding protein.
30. The antibody construct according to claim 20 , wherein said antibody construct is a crystallized antibody construct.
31. The antibody construct according to claim 30 , wherein said crystallized antibody construct is a carrier-free pharmaceutical controlled release crystallized antibody construct.
32. The antibody construct according to claim 31 , wherein said antibody construct has a greater half life in vivo than the soluble counterpart of said antibody construct.
33. The antibody construct according to claim 31 , wherein said antibody construct retains biological activity.
34. A composition for the release of an antibody construct said composition comprising:
(a) a formulation, wherein said formulation comprises a crystallized antibody construct according to claim 30 , and an ingredient; and
(b) at least one polymeric carrier.
35. The composition according to claim 34 , wherein said polymeric carrier is a polymer selected from one or more of the group consisting of: poly (acrylic acid), poly (cyanoacrylates), poly (amino acids), poly (anhydrides), poly (depsipeptide), poly (esters), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutryate), poly (caprolactone), poly (dioxanone); poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo) phosphazene], poly (ortho esters), poly (vinyl alcohol), poly (vinylpyrrolidone), maleic anhydride-alkyl vinyl ether copolymers, pluronic polyols, albumin, alginate, cellulose and cellulose derivatives, collagen, fibrin, gelatin, hyaluronic acid, oligosaccharides, glycaminoglycans, sulfated polysaccharides, blends and copolymers thereof.
36. The composition according to claim 34 , wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
37. A pharmaceutical composition comprising the binding protein of claim 1 , and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 , wherein said pharmaceutically acceptable carrier functions as adjuvant useful to increase the absorption, or dispersion of said binding protein.
39. The pharmaceutical composition of claim 38 , wherein said adjuvant is hyaluronidase.
40. The pharmaceutical composition of claim 37 , further comprising at least one additional therapeutic agent for treating a disorder in which IL-13 activity is detrimental.
41. The pharmaceutical composition of claim 37 comprising an additional agent, wherein said additional agent is selected from the group consisting of: a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor, a kinase inhibitor, a co-stimulation molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or functional fragment thereof; methotrexate, a cyclosporin, a rapamycin, an FK506, a detectable label or reporter, a TNF antagonist, an anti-rheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteroid, an anabolic steroid, an erythropoietin, an immunization, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an oral steroid, an epinephrine or analog, a cytokine, and a cytokine antagonist.