IL-1 binding proteins
View Patent ↗Proteins that bind IL-1α and IL-1β are described along with their use in compositions and methods for treating, preventing, and diagnosing IL-1-related disorders and for detecting IL-1α and IL-1β in cells, tissues, samples, and compositions.
1. A binding protein comprising an antigen binding domain, said binding protein capable of binding human IL-1β, said antigen binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:
CDR-H1: X 1 -Y-D-M-S (SEQ ID NO:190), wherein;
X 1 is K or R;
CDR-H2: Y-X 2 -S-X 4 -G-G-X 7 -G-T-Y-Y-P-D-X 14 -X 15 -K-G (SEQ ID NO: 191), wherein;
X 2 is I or V;
X 4 is S or H;
X 7 is G or A;
X 14 is T or S; and
X 15 is V or A;
CDR-H3: G-G-V-X 4 -K-G-X 7 -F-D-X 10 (SEQ ID NO: 192), wherein;
X 4 is T or Y;
X 7 is Y or C; and
X 10 is V, E, L, M, Q, or Y;
CDR-L1: R-A-S-G-N-I-X 7 -X 8 -X 9 -L-X 11 (SEQ ID NO:193), wherein;
X 7 is H, Y, or W;
X 8 is N, G, T, Q, E, H, D, or K;
X 9 is Y or W; and
X 11 is T, A, or N;
CDR-L2: X 1 -A-K-X 4 -L-X 6 -X 7 (SEQ ID NO:194), wherein;
X 1 is N, Q, or D;
X 4 is T, N, I, E, or S;
X 6 is A, M, or E; and
X 7 is D, E, S, or A;
and
CDR-L3: Q-X 2 -F-W-X 5 -X 6 -P-X 8 -X 9 (SEQ ID NO:195) wherein;
X 2 is H or Q;
X 5 is S, N, T, K, R, or M;
X 6 is I or L;
X 8 is Y or A; and
X 9 is T, I, and N
except that:
CDR-H2 cannot be Y-I-S-S-G-G-G-G-T-Y-Y-P-D-T-V-K-G (SEQ ID NO: 18);
CDR-H3 cannot be G-G-V-T-K-G-Y-F-D-V (SEQ ID NO: 19);
CDR-L1 cannot be R-A-S-G-N-I-H-N-Y-L-T (SEQ ID NO:20);
CDR-L2 cannot be N-A-K-T-L-A-D (SEQ ID NO: 21); and
CDR-L3 cannot be Q-H-F-W-S-I-P-Y-T (SEQ ID NO: 22).
2. The binding protein according to claim 1 , comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3
wherein the CDR-H1 is an amino acid selected from the group consisting of
residues 31-35 of SEQ ID NO:60;
residues 31-35 of SEQ ID NO:61;
residues 31-35 of SEQ ID NO:114; and
residues 31-35 of SEQ ID NO:117;
wherein the CDR-H2 is an amino acid selected from the group consisting of
residues 50-66 of SEQ ID NO:60;
residues 50-66 of SEQ ID NO:71;
residues 50-66 of SEQ ID NO:105;
residues 50-66 of SEQ ID NO:113;
residues 50-66 of SEQ ID NO:123;
residues 50-66 of SEQ ID NO:131; and
residues 50-66 of SEQ ID NO:133;
wherein the CDR-H3 is an amino acid selected from the group consisting of
residues 99-108 of SEQ ID NO:60 (CDR-H3);
residues 99-108 of SEQ ID NO:61 (CDR-H3);
residues 99-108 of SEQ ID NO:64 (CDR-H3);
residues 99-108 of SEQ ID NO:78 (CDR-H3);
residues 99-108 of SEQ ID NO:87 (CDR-H3);
residues 99-108 of SEQ ID NO:92 (CDR-H3);
residues 99-108 of SEQ ID NO:104 (CDR-H3); and
residues 99-108 of SEQ ID NO:140 (CDR-H3);
wherein the CDR-L1 is an amino acid selected from the group consisting of
residues 24-34 of SEQ ID NO:59 (CDR-L1);
residues 24-34 of SEQ ID NO:149 (CDR-L1);
residues 24-34 of SEQ ID NO:150 (CDR-L1);
residues 24-34 of SEQ ID NO:151 (CDR-L1);
residues 24-34 of SEQ ID NO:153 (CDR-L1);
residues 24-34 of SEQ ID NO:156 (CDR-L1);
residues 24-34 of SEQ ID NO:159 (CDR-L1);
residues 24-34 of SEQ ID NO:164 (CDR-L1);
residues 24-34 of SEQ ID NO:167 (CDR-L1);
residues 24-34 of SEQ ID NO:174 (CDR-L1);
residues 24-34 of SEQ ID NO:179 (CDR-L1); and
residues 24-34 of SEQ ID NO:188 (CDR-L1);
wherein the CDR-L2 is an amino acid selected from the group consisting of
residues 50-56 of SEQ ID NO:59 (CDR-L2);
residues 50-56 of SEQ ID NO:149 (CDR-L2);
residues 50-56 of SEQ ID NO:151(CDR-L2);
residues 50-56 of SEQ ID NO:156 (CDR-L2);
residues 50-56 of SEQ ID NO:167 (CDR-L2);
residues 50-56 of SEQ ID NO:169 (CDR-L2);
residues 50-56 of SEQ ID NO:171 (CDR-L2);
residues 50-56 of SEQ ID NO:175 (CDR-L2);
residues 50-56 of SEQ ID NO:176 (CDR-L2);
residues 50-56 of SEQ ID NO:178 (CDR-L2);
residues 50-56 of SEQ ID NO:180 (CDR-L2);
residues 50-56 of SEQ ID NO:181 (CDR-L2);
residues 50-56 of SEQ ID NO:185 (CDR-L2); and
residues 50-56 of SEQ ID NO:187 (CDR-L2); or
wherein the CDR-L3 is an amino acid selected from the group consisting of
residues 89-97 of SEQ ID NO:59 (CDR-L3);
residues 89-97 of SEQ ID NO:149 (CDR-L3);
residues 89-97 of SEQ ID NO:150 (CDR-L3);
residues 89-97 of SEQ ID NO:151 (CDR-L3);
residues 89-97 of SEQ ID NO:155 (CDR-L3);
residues 89-97 of SEQ ID NO:160 (CDR-L3);
residues 89-97 of SEQ ID NO:167 (CDR-L3);
residues 89-97 of SEQ ID NO:176 (CDR-L3);
residues 89-97 of SEQ ID NO:181 (CDR-L3);
residues 89-97 of SEQ ID NO:182 (CDR-L3);
residues 89-97 of SEQ ID NO:183 (CDR-L3); and
residues 89-97 of SEQ ID NO:188 (CDR-L3).
3. The binding protein according to claim 1 , wherein at least three CDRs are from a set of CDRs selected from the group of CDR sets consisting of:
CDR
Set
SEQ ID NO.
1
residues 31-35 of SEQ ID NO: 60
(CDR-H1);
residues 50-66 of SEQ ID NO: 60
(CDR-H2);
residues 99-108 of SEQ ID NO: 60
(CDR-H3);
2
residues 31-35 of SEQ ID NO: 61
(CDR-H1);
residues 50-66 of SEQ ID NO: 61
(CDR-H2);
residues 99-108 of SEQ ID NO: 61
(CDR-H3);
3
residues 31-35 of SEQ ID NO: 63
(CDR-H1);
residues 50-66 of SEQ ID NO: 63
(CDR-H2);
residues 99-108 of SEQ ID NO: 63
(CDR-H3);
4
residues 31-35 of SEQ ID NO: 64
(CDR-H1);
residues 50-66 of SEQ ID NO: 64
(CDR-H2);
residues 99-108 of SEQ ID NO: 64
(CDR-H3);
5
residues 31-35 of SEQ ID NO: 65
(CDR-H1);
residues 50-66 of SEQ ID NO: 65
(CDR-H2);
residues 99-108 of SEQ ID NO: 65
(CDR-H3);
6
residues 31-35 of SEQ ID NO: 71
(CDR-H1);
residues 50-66 of SEQ ID NO: 71
(CDR-H2);
residues 99-108 of SEQ ID NO: 71
(CDR-H3);
7
residues 31-35 of SEQ ID NO: 73
(CDR-H1);
residues 50-66 of SEQ ID NO: 73
(CDR-H2);
residues 99-108 of SEQ ID NO: 73
(CDR-H3);
8
residues 31-35 of SEQ ID NO: 78
(CDR-H1);
residues 50-66 of SEQ ID NO: 78
(CDR-H2);
residues 99-108 of SEQ ID NO: 78
(CDR-H3);
9
residues 31-35 of SEQ ID NO: 81
(CDR-H1);
residues 50-66 of SEQ ID NO: 81
(CDR-H2);
residues 99-108 of SEQ ID NO: 81
(CDR-H3);
10
residues 31-35 of SEQ ID NO: 87
(CDR-H1);
residues 50-66 of SEQ ID NO: 87
(CDR-H2);
residues 99-108 of SEQ ID NO: 87
(CDR-H3);
11
residues 31-35 of SEQ ID NO: 92
(CDR-H1);
residues 50-66 of SEQ ID NO: 92
(CDR-H2);
residues 99-108 of SEQ ID NO: 92
(CDR-H3);
12
residues 31-35 of SEQ ID NO: 93
(CDR-H1);
residues 50-66 of SEQ ID NO: 93
(CDR-H2);
residues 99-108 of SEQ ID NO: 93
(CDR-H3);
13
residues 31-35 of SEQ ID NO: 95
(CDR-H1);
residues 50-66 of SEQ ID NO: 95
(CDR-H2);
residues 99-108 of SEQ ID NO: 95
(CDR-H3);
14
residues 31-35 of SEQ ID NO: 104
(CDR-H1);
residues 50-66 of SEQ ID NO: 104
(CDR-H2);
residues 99-108 of SEQ ID NO: 104
(CDR-H3);
15
residues 31-35 of SEQ ID NO: 105
(CDR-H1);
residues 50-66 of SEQ ID NO: 105
(CDR-H2);
residues 99-108 of SEQ ID NO: 105
(CDR-H3);
16
residues 31-35 of SEQ ID NO: 113
(CDR-H1);
residues 50-66 of SEQ ID NO: 113
(CDR-H2);
residues 99-108 of SEQ ID NO: 113
(CDR-H3);
17
residues 31-35 of SEQ ID NO: 114
(CDR-H1);
residues 50-66 of SEQ ID NO: 114
(CDR-H2);
residues 99-108 of SEQ ID NO: 114
(CDR-H3);
18
residues 31-35 of SEQ ID NO: 115
(CDR-H1);
residues 50-66 of SEQ ID NO: 115
(CDR-H2);
residues 99-108 of SEQ ID NO: 115
(CDR-H3);
19
residues 31-35 of SEQ ID NO: 117
(CDR-H1);
residues 50-66 of SEQ ID NO: 117
(CDR-H2);
residues 99-108 of SEQ ID NO: 117
(CDR-H3);
20
residues 31-35 of SEQ ID NO: 121
(CDR-H1);
residues 50-66 of SEQ ID NO: 121
(CDR-H2);
residues 99-108 of SEQ ID NO: 121
(CDR-H3);
21
residues 31 35 of SEQ ID NO: 123
(CDR H1);
residues 50 66 of SEQ ID NO: 123
(CDR H2);
residues 99 108 of SEQ ID NO: 123
(CDR H3);
21
residues 31-35 of SEQ ID NO: 131
(CDR-H1);
residues 50-66 of SEQ ID NO: 131
(CDR-H2);
residues 99-108 of SEQ ID NO: 131
(CDR-H3);
22
residues 31-35 of SEQ ID NO: 133
(CDR-H1);
residues 50-66 of SEQ ID NO: 133
(CDR-H2);
residues 99-108 of SEQ ID NO: 133
(CDR-H3);
23
residues 31-35 of SEQ ID NO: 140
(CDR-H1);
residues 50-66 of SEQ ID NO: 140
(CDR-H2);
residues 99-108 of SEQ ID NO: 140
(CDR-H3);
24
residues 24-34 of SEQ ID NO: 149
(CDR-L1);
residues 50-56 of SEQ ID NO: 149
(CDR-L2);
residues 89-97 of SEQ ID NO: 149
(CDR-L3);
25
residues 24-34 of SEQ ID NO: 150
(CDR-L1);
residues 50-56 of SEQ ID NO: 150
(CDR-L2);
residues 89-97 of SEQ ID NO: 150
(CDR-L3);
26
residues 24-34 of SEQ ID NO: 151
(CDR-L1);
residues 50-56 of SEQ ID NO: 151
(CDR-L2);
residues 89-97 of SEQ ID NO: 151
(CDR-L3);
27
residues 24-34 of SEQ ID NO: 153
(CDR-L1);
residues 50-56 of SEQ ID NO: 153
(CDR-L2);
residues 89-97 of SEQ ID NO: 153
(CDR-L3);
28
residues 24-34 of SEQ ID NO: 155
(CDR-L1);
residues 50-56 of SEQ ID NO: 155
(CDR-L2);
residues 89-97 of SEQ ID NO: 155
(CDR-L3);
29
residues 24-34 of SEQ ID NO: 156
(CDR-L1);
residues 50-56 of SEQ ID NO: 156
(CDR-L2);
residues 89-97 of SEQ ID NO: 156
(CDR-L3);
30
residues 24-34 of SEQ ID NO: 157
(CDR-L1);
residues 50-56 of SEQ ID NO: 157
(CDR-L2);
residues 89-97 of SEQ ID NO: 157
(CDR-L3);
31
residues 24-34 of SEQ ID NO: 159
(CDR-L1);
residues 50-56 of SEQ ID NO: 159
(CDR-L2);
residues 89-97 of SEQ ID NO: 159
(CDR-L3);
32
residues 24-34 of SEQ ID NO: 160
(CDR-L1);
residues 50-56 of SEQ ID NO: 160
(CDR-L2);
residues 89-97 of SEQ ID NO: 160
(CDR-L3);
33
residues 24-34 of SEQ ID NO: 162
(CDR-L1);
residues 50-56 of SEQ ID NO: 162
(CDR-L2);
residues 89-97 of SEQ ID NO: 162
(CDR-L3);
34
residues 24-34 of SEQ ID NO: 164
(CDR-L1);
residues 50-56 of SEQ ID NO: 164
(CDR-L2);
residues 89-97 of SEQ ID NO: 164
(CDR-L3);
35
residues 24-34 of SEQ ID NO: 165
(CDR-L1);
residues 50-56 of SEQ ID NO: 165
(CDR-L2);
residues 89-97 of SEQ ID NO: 165
(CDR-L3);
36
residues 24-34 of SEQ ID NO: 166
(CDR-L1);
residues 50-56 of SEQ ID NO: 166
(CDR-L2);
residues 89-97 of SEQ ID NO: 166
(CDR-L3);
37
residues 24-34 of SEQ ID NO: 167
(CDR-L1);
residues 50-56 of SEQ ID NO: 167
(CDR-L2);
residues 89-97 of SEQ ID NO: 167
(CDR-L3);
38
residues 24-34 of SEQ ID NO: 169
(CDR-L1);
residues 50-56 of SEQ ID NO: 169
(CDR-L2);
residues 89-97 of SEQ ID NO: 169
(CDR-L3);
39
residues 24-34 of SEQ ID NO: 171
(CDR-L1);
residues 50-56 of SEQ ID NO: 171
(CDR-L2);
residues 89-97 of SEQ ID NO: 171
(CDR-L3);
40
residues 24-34 of SEQ ID NO: 172
(CDR-L1);
residues 50-56 of SEQ ID NO: 172
(CDR-L2);
residues 89-97 of SEQ ID NO: 172
(CDR-L3);
41
residues 24-34 of SEQ ID NO: 174
(CDR-L1);
residues 50-56 of SEQ ID NO: 174
(CDR-L2);
residues 89-97 of SEQ ID NO: 174
(CDR-L3);
42
residues 24-34 of SEQ ID NO: 175
(CDR-L1);
residues 50-56 of SEQ ID NO: 175
(CDR-L2);
residues 89-97 of SEQ ID NO: 175
(CDR-L3);
43
residues 24-34 of SEQ ID NO: 176
(CDR-L1);
residues 50-56 of SEQ ID NO: 176
(CDR-L2);
residues 89-97 of SEQ ID NO: 176
(CDR-L3);
44
residues 24-34 of SEQ ID NO: 177
(CDR-L1);
residues 50-56 of SEQ ID NO: 177
(CDR-L2);
residues 89-97 of SEQ ID NO: 177
(CDR-L3);
45
residues 24-34 of SEQ ID NO: 178
(CDR-L1);
residues 50-56 of SEQ ID NO: 178
(CDR-L2);
residues 89-97 of SEQ ID NO: 178
(CDR-L3);
46
residues 24-34 of SEQ ID NO: 179
(CDR-L1);
residues 50-56 of SEQ ID NO: 179
(CDR-L2);
residues 89-97 of SEQ ID NO: 179
(CDR-L3);
47
residues 24-34 of SEQ ID NO: 180
(CDR-L1);
residues 50-56 of SEQ ID NO: 180
(CDR-L2);
residues 89-97 of SEQ ID NO: 180
(CDR-L3);
48
residues 24-34 of SEQ ID NO: 181
(CDR-L1);
residues 50-56 of SEQ ID NO: 181
(CDR-L2);
residues 89-97 of SEQ ID NO: 181
(CDR-L3);
49
residues 24-34 of SEQ ID NO: 182
(CDR-L1);
residues 50-56 of SEQ ID NO: 182
(CDR-L2);
residues 89-97 of SEQ ID NO: 182
(CDR-L3);
50
residues 24-34 of SEQ ID NO: 183
(CDR-L1);
residues 50-56 of SEQ ID NO: 183
(CDR-L2);
residues 89-97 of SEQ ID NO: 183
(CDR-L3);
51
residues 24-34 of SEQ ID NO: 184
(CDR-L1);
residues 50-56 of SEQ ID NO: 184
(CDR-L2);
residues 89-97 of SEQ ID NO: 184
(CDR-L3);
52
residues 24-34 of SEQ ID NO: 185
(CDR-L1);
residues 50-56 of SEQ ID NO: 185
(CDR-L2);
residues 89-97 of SEQ ID NO: 185
(CDR-L3);
53
residues 24-34 of SEQ ID NO: 187
(CDR-L1);
residues 50-56 of SEQ ID NO: 187
(CDR-L2);
residues 89-97 of SEQ ID NO: 187
(CDR-L3);
54
residues 24-34 of SEQ ID NO: 188
(CDR-L1);
residues 50-56 of SEQ ID NO: 188
(CDR-L2);
residues 89-97 of SEQ ID NO: 188
(CDR-L3);
55
residues 24-34 of SEQ ID NO: 189
(CDR-L1);
residues 50-56 of SEQ ID NO: 189
(CDR-L2);
residues 89-97 of SEQ ID NO: 189
(CDR-L3).
56
residues 24-34 of SEQ ID NO: 59
(CDR-L1);
residues 50-56 of SEQ ID NO: 59
(CDR-L2);
residues 89-97 of SEQ ID NO: 59
(CDR-L3).
4. The binding protein according to claim 3 , comprising CDRs from two CDR sets, wherein said two CDR sets comprise a VH CDR Set selected from the group consisting of CDR Sets 1-23, and a VL CDR Set selected from the group consisting of CDR Sets 24-56.
5. The binding protein according to any one of claims 1 , 2 , and 4 , further comprising a human acceptor framework.
6. The binding protein according to claim 5 , wherein said human acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 7-10, 13-16, 25, 240-316, and 317-381.
7. The binding protein according to claim 5 , 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.
8. The binding protein according to claim 5 , 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-1β; 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.
9. The binding protein according to claim 8 , wherein the key residue by Kabat numbering is selected from the group consisting of: 2H, 4H, 24H, 26H, 27H, 29H, 34H, 35H, 37H, 39H, 44H, 45H, 47H, 48H, 49H, 50H, 51H, 58H, 59H, 60H, 63H, 67H, 69H, 71H, 73H, 76H, 78H, 91H, 93H, 94H, 2L, 4L, 25L, 29L, 27bL, 33L, 34L, 36L, 38L, 43L, 44L, 46L, 47L, 48L, 49L, 55L, 58L, 62L, 64L, 71L, 87L, 89L, 90L, 91L, 94L, and 95L.
10. The binding protein according to claim 5 , wherein the binding protein comprises a consensus human variable domain.
11. The binding protein according to claim 4 , wherein said binding protein comprises at least one variable domain having an amino acid sequence selected from the group consisting of SEQ ID NOs 59-122 and 124-211.
12. The binding protein according to claim 11 , wherein said binding protein comprises two variable domains.
13. The binding protein according to claim 12 , wherein said two variable domains comprise amino acid sequences selected from the group consisting of:
SEQ ID NO: 60 and SEQ ID NO: 149
SEQ ID NO: 198 and SEQ ID
NO: 199
SEQ ID NO: 60 and SEQ ID NO: 173
SEQ ID NO: 202 and SEQ ID
NO: 203
SEQ ID NO: 67 and SEQ ID NO: 151
SEQ ID NO: 206 and SEQ ID
NO: 207
SEQ ID NO: 88 and SEQ ID NO: 159
SEQ ID NO: 210 and SEQ ID
NO: 211
SEQ ID NO: 96 and SEQ ID NO: 155
SEQ ID NO: 103 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 182
SEQ ID NO: 104 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 167
SEQ ID NO: 105 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 164
SEQ ID NO: 106 and SEQ ID
NO: 59
SEQ ID NO: 73 and SEQ ID NO: 174
SEQ ID NO: 107 and SEQ ID
NO: 59
SEQ ID NO: 86 and SEQ ID NO: 159
SEQ ID NO: 108 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 169
SEQ ID NO: 109 and SEQ ID
NO: 59
SEQ ID NO: 91 and SEQ ID NO: 165
SEQ ID NO: 110 and SEQ ID
NO: 59
SEQ ID NO: 76 and SEQ ID NO: 175
SEQ ID NO: 111 and SEQ ID
NO: 59
SEQ ID NO: 99 and SEQ ID NO: 189
SEQ ID NO: 112 and SEQ ID
NO: 59
SEQ ID NO: 100 and SEQ ID NO: 168
SEQ ID NO: 113 and SEQ ID
NO: 59
SEQ ID NO: 71 and SEQ ID NO: 170
SEQ ID NO: 114 and SEQ ID
NO: 59
SEQ ID NO: 84 and SEQ ID NO: 188
SEQ ID NO: 115 and SEQ ID
NO: 59
SEQ ID NO: 78 and SEQ ID NO: 179
SEQ ID NO: 116 and SEQ ID
NO: 59
SEQ ID NO: 93 and SEQ ID NO: 176
SEQ ID NO: 117 and SEQ ID
NO: 59
SEQ ID NO: 87 and SEQ ID NO: 154
SEQ ID NO: 118 and SEQ ID
NO: 59
SEQ ID NO: 85 and SEQ ID NO: 162
SEQ ID NO: 119 and SEQ ID
NO: 59
SEQ ID NO: 89 and SEQ ID NO: 170
SEQ ID NO: 120 and SEQ ID
NO: 59
SEQ ID NO: 75 and SEQ ID NO: 181
SEQ ID NO: 121 and SEQ ID
NO: 59
SEQ ID NO: 92 and SEQ ID NO: 184
SEQ ID NO: 122 and SEQ ID
NO: 59
SEQ ID NO: 200 and SEQ ID NO: 201
SEQ ID NO: 124 and SEQ ID
NO: 59
SEQ ID NO: 204 and SEQ ID NO: 205
SEQ ID NO: 125 and SEQ ID
NO: 59
SEQ ID NO: 208 and SEQ ID NO: 209
SEQ ID NO: 126 and SEQ ID
NO: 59
SEQ ID NO: 63 and SEQ ID NO: 150
SEQ ID NO: 127 and SEQ ID
NO: 59
SEQ ID NO: 97 and SEQ ID NO: 187
SEQ ID NO: 128 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 156
SEQ ID NO: 129 and SEQ ID
NO: 59
SEQ ID NO: 92 and SEQ ID NO: 153
SEQ ID NO: 130 and SEQ ID
NO: 59
SEQ ID NO: 94 and SEQ ID NO: 166
SEQ ID NO: 131 and SEQ ID
NO: 59
SEQ ID NO: 82 and SEQ ID NO: 159
SEQ ID NO: 132 and SEQ ID
NO: 59
SEQ ID NO: 101 and SEQ ID NO: 158
SEQ ID NO: 133 and SEQ ID
NO: 59
SEQ ID NO: 96 and SEQ ID NO: 157
SEQ ID NO: 134 and SEQ ID
NO: 59
SEQ ID NO: 70 and SEQ ID NO: 161
SEQ ID NO: 135 and SEQ ID
NO: 59
SEQ ID NO: 83 and SEQ ID NO: 158
SEQ ID NO: 136 and SEQ ID
NO: 59
SEQ ID NO: 102 and SEQ ID NO: 185
SEQ ID NO: 137 and SEQ ID
NO: 59
SEQ ID NO: 98 and SEQ ID NO: 160
SEQ ID NO: 138 and SEQ ID
NO: 59
SEQ ID NO: 74 and SEQ ID NO: 186
SEQ ID NO: 139 and SEQ ID
NO: 59
SEQ ID NO: 95 and SEQ ID NO: 157
SEQ ID NO: 140 and SEQ ID
NO: 59
SEQ ID NO: 72 and SEQ ID NO: 178
SEQ ID NO: 141 and SEQ ID
NO: 59
SEQ ID NO: 96 and SEQ ID NO: 163
SEQ ID NO: 142 and SEQ ID
NO: 59
SEQ ID NO: 77 and SEQ ID NO: 183
SEQ ID NO: 143 and SEQ ID
NO: 59
SEQ ID NO: 90 and SEQ ID NO: 171
SEQ ID NO: 144 and SEQ ID
NO: 59
SEQ ID NO: 79 and SEQ ID NO: 180
SEQ ID NO: 145 and SEQ ID
NO: 59
SEQ ID NO: 381 and SEQ ID NO: 151
SEQ ID NO: 146 and SEQ ID
NO: 59
SEQ ID NO: 81 and SEQ ID NO: 177
SEQ ID NO: 147 and SEQ ID
NO: 59
SEQ ID NO: 80 and SEQ ID NO: 172
SEQ ID NO: 148 and SEQ ID
NO: 59
SEQ ID NO: 196 and SEQ ID NO: 197
14. The binding protein according to any one of claims 1 , 2 , and 4 , wherein the binding protein is capable of modulating a biological function of IL-1.
15. The binding protein according to any one of claims 1 , 2 , and 4 , wherein the binding protein is capable of neutralizing IL-1.
16. The binding protein according to any one of claims 1 , 2 , and 4 , wherein the binding protein has an on rate constant (K on ) to IL-1β 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.
17. The binding protein according to any one of claims 1 , 2 , and 4 , wherein the binding protein has an off rate constant (K off ) to IL-1β 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.
18. The binding protein according to any one of claims 1 , 2 , and 4 , wherein the binding protein has a dissociation constant (K D ) to IL-1β 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.
19. An IL-1β binding protein construct comprising a binding protein as described in claim 1 , said IL-1β binding protein construct further comprising a linker or an immunoglobulin constant domain.
20. The IL-1β binding protein construct according to claim 19 , wherein said IL-1β binding protein is selected from the group consisting of: an immunoglobulin molecule, a disulfide linked Fv, a monoclonal antibody, an scFv, a chimeric antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, an Fab, a dual specific antibody, a Fab′, a bispecific antibody, and a F(ab′) 2 , a dual variable domain immunoglobulin (DVD-Ig), and an Fv.
21. The IL-1β binding protein construct according to claim 19 , wherein said binding protein 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, and a human IgA constant domain.
22. The IL-1β binding protein construct according to claim 19 , wherein said binding protein construct comprises an immunoglobulin constant domain having an amino acid sequence selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
23. An IL-1β binding protein conjugate comprising an IL-1β binding protein construct as described in claim 19 , said IL-1β binding protein conjugate further comprising an agent selected from the group consisting of an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent.
24. The IL-1β binding protein conjugate according to claim 23 , 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.
25. The IL-1β binding protein conjugate according to claim 24 , wherein said radiolabel is 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.
26. The IL-1β binding protein conjugate according to claim 23 , 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.
27. The IL-1β binding protein construct according to claim 19 , wherein said binding protein possesses a human glycosylation pattern.
28. The IL-1β binding protein according to claim 1 , wherein said binding protein is a crystallized binding protein.
29. The IL-1β binding protein construct according to claim 19 , wherein said IL-1β binding protein construct is a crystallized IL-1β binding protein construct.
30. The IL-1β binding protein conjugate according to claim 23 , wherein said IL-1β binding protein conjugate is a crystallized binding protein.
31. The crystallized IL-1β binding protein according to claim 28 , wherein said crystallized IL-1β binding protein is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein.
32. The crystallized IL-1β binding protein construct according to claim 29 , wherein said crystallized IL-1β binding protein construct is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein construct.
33. The crystallized IL-1β binding protein conjugate according to claim 30 , wherein said crystallized IL-1β binding protein conjugate is a carrier-free pharmaceutical controlled release crystallized IL-1β binding protein conjugate.
34. The crystallized IL-1β binding protein according to claim 28 , wherein said crystallize IL-1β binding protein has a greater half life in vivo than the soluble counterpart.
35. The IL-1β binding protein construct according to claim 29 , wherein said crystallized IL-1β binding protein construct has a greater half life in vivo than the soluble counterpart.
36. The crystallized IL-1β binding protein conjugate according to claim 30 , wherein said crystallized IL-1β binding protein conjugate has a greater half life in vivo than the soluble counterpart.
37. The crystallized IL-1β binding protein according to claim 28 , wherein said crystallized IL-1β binding protein retains biological activity.
38. The crystallized IL-1β binding protein construct according to claim 29 , wherein said crystallized IL-1β binding protein construct retains biological activity.
39. The crystallized IL-1β binding protein construct according to claim 30 , wherein said crystallized IL-1β binding protein conjugate retains biological activity.
40. A composition for the release of a crystallized IL-1β binding protein according to claim 28 , a crystallized IL-1β binding protein construct according to claim 29 , or a crystallized IL-1β binding protein conjugate according to claim 30 , said composition comprising:
(a) a formulation, wherein said formulation comprises a crystallized IL-1β binding protein according to claim 28 , a crystallized IL-1β binding protein construct according to claim 29 , or a crystallized IL-1β binding protein conjugate according to claim 30 , and an ingredient; and
(b) at least one polymeric carrier.
41. The composition according to claim 40 , 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.
42. The composition according to claim 40 , wherein said ingredient is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.
43. A pharmaceutical composition comprising a binding protein as described in claim 1 , and a pharmaceutically acceptable carrier.
44. The pharmaceutical composition according to claim 43 further comprising at least one additional agent.
45. The pharmaceutical composition according to claim 44 , 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 blockers; an anti-cytokine antibody or functional fragment thereof; methotrexate; cyclosporin; rapamycin; FK506; a detectable label or reporter; a TNF antagonist; an antirheumatic; 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 epinephrine or analog thereof; a cytokine; and a cytokine antagonist.
46. A pharmaceutical composition comprising an IL-1β binding protein conjugate as described in claim 23 and a pharmaceutically acceptable carrier.
47. The pharmaceutical composition according to claim 46 , wherein the IL-1β binding protein conjugate comprises 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.
48. The pharmaceutical composition according to claim 47 , 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.
49. The pharmaceutical composition according to claim 46 , wherein said IL-1β binding protein conjugate comprises 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, a toxin, and an apoptotic agent.
50. The binding protein according to claim 4 , wherein said two CDR sets comprise CDR Set 1 and CDR Set 24.
51. The binding protein according to claim 4 , wherein said two CDR sets comprise CDR Set 4 and CDR Set 56.
52. The binding protein according to claim 4 , wherein said two CDR sets comprise CDR Set 2 and CDR Set 56.
53. The binding protein according to claim 4 , wherein said two CDR sets comprise CDR Set 5 and CDR Set 56.
54. The binding protein according to claim 4 , wherein said two CDR sets comprise CDR Set 3 and CDR Set 25.
55. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:196 and SEQ ID NO:197.
56. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:198 and SEQ ID NO:199.
57. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:200 and SEQ ID NO:201.
58. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:202 and SEQ ID NO:203.
59. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:204 and SEQ ID NO:205.
60. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:206 and SEQ ID NO:207.
61. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:208 and SEQ ID NO:209.
62. The binding protein according to claim 11 , wherein said at least one variable domain comprises the amino acid sequences of SEQ ID NO:210 and SEQ ID NO:211.
63. A pharmaceutical composition comprising the binding protein of any of claims 50 - 62 and a pharmaceutically acceptable carrier.