IL-1 Binding Proteins

Abstract

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 first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:
 VD1 is a first heavy chain variable domain;   VD2 is a second heavy chain variable domain;   C is a heavy chain constant domain;   X1 is a linker with the proviso that it is not CH1;   X2 is an Fc region; and   n is independently 0 or 1; and   wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n,   
       wherein:
 VD1 is a first light chain variable domain; 
 VD2 is a second light chain variable domain; 
 C is a light chain constant domain; 
 X1 is a linker with the proviso that it is not CH1; 
 X2 does not comprise an Fc region; and 
 n is independently 0 or 1; 
 wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 60-148, 196, 198, 200, 202, 204, 206, 208 and 210; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 213 and 227; 
 wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 149-189, 197, 199, 201, 203, 205, 207, 209 and 211; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 and 229; and 
 wherein the binding protein binds human IL-1β and human IL-1α. 
 
     
     
         2 . A binding protein comprising first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:
 VD1 is a first heavy chain variable domain;   VD2 is a second heavy chain variable domain;   C is a heavy chain constant domain;   X1 is a linker with the proviso that it is not CH1;   X2 is an Fc region; and   n is independently 0 or 1; and   wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n,   wherein:   VD1 is a first light chain variable domain;   VD2 is a second light chain variable domain;   C is a light chain constant domain;   X1 is a linker with the proviso that it is not CH1;   X2 does not comprise an Fc region; and   n is independently 0 or 1;   wherein, in said first polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 213 and 227; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 60-148, 196, 198, 200, 202, 204, 206, 208 and 210;   wherein, in said second polypeptide chain, VD1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 216 and 229; and VD2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 149-189, 197, 199, 201, 203, 205, 207, 209 and 211; and wherein the binding protein binds human IL-1β and human IL-1α.   
     
     
         3 - 30 . (canceled) 
     
     
         31 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide chain amino acid sequence of the binding protein of  claim 1 . 
     
     
         32 - 45 . (canceled) 
     
     
         46 . A method for reducing human IL-1 activity comprising contacting a human IL-1 protein with the binding protein of  claim 1  such that human IL-1 protein activity is reduced. 
     
     
         47 . A method for reducing human IL-1 activity in a human subject suffering from a disorder in which IL-1 activity is detrimental, comprising administering to the human subject the binding protein of  claim 1  or a crystal thereof, such that human IL-1 activity in the human subject is reduced. 
     
     
         48 . A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject the binding protein of  claim 1  or a crystal thereof such that treatment is achieved. 
     
     
         49 - 51 . (canceled) 
     
     
         52 . 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 S, 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: (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: (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 when CDR-H1 is S-Y-D-M-S(SEQ ID NO:17), then: 
 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). 
 
     
     
         53 - 101 . (canceled) 
     
     
         102 . An isolated nucleic acid encoding an amino acid sequence of the IL-1β binding protein of  claim 52 . 
     
     
         103 - 116 . (canceled) 
     
     
         117 . A method for reducing human IL-1 activity comprising contacting a human IL-1 protein with the binding protein of  claim 52 , such that human IL-1 protein activity is reduced. 
     
     
         118 . A method for reducing human IL-1 activity in a human subject suffering from a disorder in which IL-1 activity is detrimental, comprising administering to the human subject the binding protein of  claim 52  or a crystal thereof, such that human IL-1 activity in the human subject is reduced. 
     
     
         119 . A method for treating a subject for a disorder in which IL-1 activity is detrimental comprising administering to the subject the binding protein of  claim 52  or a crystal thereof, such that treatment is achieved. 
     
     
         120 - 122 . (canceled)