Dual-specific il-1a/ il-1b antibodies

Abstract

The invention provides an isolated, dual-specific antibody, or an antigen-binding portion thereof, which is specific for human IL-1α and human IL-1β. The dual specific antibodies of the invention also neutralize both human IL-1α and human IL-1β. The invention also provides domain antibodies (dAbs) specific for human IL-1α and human IL-1β.

1 . An isolated, dual-specific antibody, or an antigen-binding portion thereof, with the following characteristics:
 a) dissociates from human IL-1α with a K D  of 3×10 −7  M or less;   b) dissociates from human IL-1β with a K D  of 5×10 −5  M or less; and   c) does not bind mouse IL-1α or mouse IL-1β.   
     
     
         2 . The antibody, or antigen-binding portion, of  claim 1 , which has characteristics selected from the group consisting of:
 (a) neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less;   (b) neutralizes IL-1α in a standard in vitro assay with an ND 50  of 10 nM or less;   (c) neutralizes IL-1a in a standard in vitro assay with an ND 50  of 10 nM or less and neutralizes IL-1α in a standard MRC5 in vitro assay with an ND 50  of 10 nM or less;   (d) neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less or 200 nM or less;   (e) neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less or 200 nM or less; and
 neutralizes IL-1β in a standard in vitro MRC5 assay with an ND 50  of 200 nM or less; 
   (f) neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less or 200 nM or less; and
 neutralizes IL-1α in a standard in vitro assay with an ND 50  of 10 nM or less; 
   (g) neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less, and neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less;   (h) neutralizes human IL-1α in a standard in vitro MRC5 assay with an ND 50  of 900 nM or less, and/or neutralizes human IL-1β in a standard MRC5 in vitro assay with an ND 50  of 800 nM or less;   (i) dissociates from IL-1α with a K D  selected from the group consisting of 1×10 −8 M or less; 1×10 −9  M or less; 40-86 nM or less; 20-42 nM or less; 32-42 nM or less; 7-12 nM or less; 3.0×10 −7  M or less; 1.1×10 −7  M or less; 6.1×10 −8 M or less; 6×10 −8 M or less; 4.2×10 −8 M or less; 1.3×10 −8 M or less; and 1.1×10 −9  M or less;   (j) dissociates from IL-1β with a K D  selected from the group consisting of 5.4×10 −5  M or less; 2.8×10 −6 M or less; 1.3×10 −6 M or less; 9.3×10 −7  M or less; 2×10 −7  M or less; 1.1×10 −7  M or less; and 2.8×10 −8 M or less; and   (k) dissociates from IL-1β with a K D  selected from the group consisting of 5.4×10 −5  M or less; 2.8×10 −6 M or less; 1.3×10 −6 M or less; 9.3×10 −7  M or less; 2×10 −7  M or less; 1.1×10 −7  M or less; and 2.8×10 −8 M or less; and
 dissociates from IL-1α with a K D  selected from the group consisting of 1×10 −8 M or less; 1×10 −9  M or less; 40-86 nM or less; 20-42 nM or less; 32-42 nM or less; 7-12 nM or less; 3.0×10 −7  M or less; 1.1×10 −7  M or less; 6.1×10 −8 M or less; 6×10 −8 M or less; 4.2×10 −8 M or less; 1.3×10 −8 M or less; and 1.1×10 −9  M or less. 
   
     
     
         3 - 12 . (canceled) 
     
     
         13 . The antibody, or antigen-binding portion, of  claim 1 , comprising
 (a) a heavy chain variable region comprising complementary determining regions (CDRs) as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 16 (ABT1-96); SEQ ID NO: 52 (ABT2-108); SEQ ID NO: 44 (ABT2-65); SEQ ID NO: 16 (ABT1-96); SEQ ID NO: 32 (ABT2-13); SEQ ID NO: 20 (ABT1-98); SEQ ID NO: 4 (ABT1-6-23); and
 a light chain variable region comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 36 (ABT2-42); SEQ ID NO: 24 (ABT1-122); SEQ ID NO: 28 (ABT1-141); SEQ ID NO: 40 (ABT2-46); SEQ ID NO: 12 (ABT1-95); SEQ ID NO: 48 (ABT2-76); or 
   (b) at least two heavy chain variable regions each comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 16 (ABT1-96); SEQ ID NO: 32 (ABT2-13); SEQ ID NO: 4 (ABT1-6-23); SEQ ID NO: 40 (ABT2-46).   
     
     
         14 . (canceled) 
     
     
         15 . An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β comprising
 a variable light chain comprising complementary determining regions (CDRs) as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, and SEQ ID NO: 28, or 
 a variable heavy chain comprising CDRS as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 16, and SEQ ID NO: 20. 
 
     
     
         16 . The antibody, or antigen-binding portion thereof, of  claim 15  which has characteristics selected from the group consisting of:
 (a) dissociates from human IL-1β with a K D  selected from the group consisting of 5×10 −5  M or less; 5.4×10 −5 M or less; 2.8×10 −6  M or less; 1.3×10 −6  M or less; 9.3×10 −7  M or less; 2×10 −7  M or less; 1.1×10 −7  M or less; and 2.8×10 −8  M or less; 
 (b) neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less; 
 (c) neutralizes human IL-1β in a standard in vitro assay with an ND 50  of 800 nM or less; and 
 neutralizes human IL-1β in a standard in vitro MRC5 assay with an ND 50  of 800 nM or less; 
 (d) neutralizes IL-1β in a standard in vitro assay with an ND 50  of 200 nM or less; 
 (e) neutralizes IL-1β in a standard in vitro assay with an ND 50  of 200 nM or less; and
 neutralizes IL-1β in a standard in vitro MRC5 assay with an ND 50  of 200 nM or less; and 
 
 (f) dissociates from human IL-1β with a K D  of 5×10 −5  M or less and neutralizes human IL-1β in a standard in vitro MRC5 assay with an ND 50  of 800 nM or less. 
 
     
     
         17 - 21 . (canceled) 
     
     
         22 . The antibody, or an antigen-binding portion thereof, of  claim 15 , further comprising either
 a variable light chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 40, and SEQ ID NO: 48, or   a variable heavy chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 52.   
     
     
         23 . An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β comprising either
 a variable light chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 40, and SEQ ID NO: 48, or 
 a variable heavy chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 52. 
 
     
     
         24 . The antibody, or antigen-binding portion thereof, of  claim 23 , which has characteristics selected from the group consisting of:
 (a) dissociates from IL-1α with a K D  selected from the group consisting of 3.0×10 −7  M or less; 1.1×10 −7  M or less; 6×10 −8  M or less; 4.2×10 −8  M or less; 1×10 −8  M or less; 1×10 −9 M or less;   (b) dissociates from human IL-1α with a K D  of 1×10 −7  M or less and neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less;   (c) dissociates from human IL-1α with a K D  of 1×10 −7  M or less and neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less; and
 neutralizes human IL-1α in a standard in vitro MRC5 assay with an ND 50  of 900 nM or less; 
   (d) dissociates from human IL-1α with a K D  of 1×10 −7  M or less and neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less;
 neutralizes human IL-1α in a standard in vitro MRC5 assay with an ND 50  of 900 nM or less; and 
 neutralizes IL-1α in a standard in vitro assay with an ND 50  of 10 nM or less; 
   (e) dissociates from human IL-1α with a K D  of 1×10 −7  M or less and neutralizes human IL-1α in a standard in vitro assay with an ND 50  of 900 nM or less;
 neutralizes human IL-1α in a standard in vitro MRC5 assay with an ND 50  of 900 nM or less; 
 neutralizes IL-1α in a standard in vitro assay with an ND 50  of 10 nM or less; and 
 neutralizes IL-1α in a standard in vitro MRC5 assay with an ND 50  of 10 nM or less. 
   
     
     
         25 - 28 . (canceled) 
     
     
         29 . The isolated antibody, or an antigen-binding portion thereof, of  claim 23 , further comprising
 a variable light chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, and SEQ ID NO: 28, or   a variable heavy chain comprising CDRs as set forth in an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 16, and SEQ ID NO: 20.   
     
     
         30 . An isolated antibody, or an antigen-binding portion thereof, having dual-specificity for human IL-1α and human IL-1β, comprising
 an IL-1α antigen binding region having either a light chain variable sequence comprising a CDR3 selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 23, and SEQ ID NO: 27 or a heavy chain variable sequence comprising a CDR3 selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 15, SEQ ID NO: 19, and 
 an IL-1β antigen binding region having either a light chain variable sequence comprising a CDR3 selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 39, and SEQ ID NO: 47 or a heavy chain variable sequence comprising a CDR3 selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 43, and SEQ ID NO: 51. 
 
     
     
         31 . The antibody, or antigen-binding portion thereof, of  claim 30 , wherein
 (a) the light chain variable sequence of the IL-1α antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, and SEQ ID NO: 26;   (b) the heavy chain variable sequence of the IL-1α antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 18;   (c) the light chain variable sequence of the IL-1α antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, and SEQ ID NO: 26; and
 the light chain variable sequence of the IL-1α antigen binding region further comprises a CDR1 selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 21, and SEQ ID NO: 25; 
   (d) the heavy chain variable sequence of the IL-1α antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 18; and
 the heavy chain variable sequence of the IL-1α antigen binding region further comprises a CDR1 selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 17; or 
   (e) the light chain variable sequence of the IL-1β antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 38, and SEQ ID NO: 46;   (f) the heavy chain variable sequence of the IL-1β antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 43, and SEQ ID NO: 50;   (g) the light chain variable sequence of the IL-1β antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 38, and SEQ ID NO: 46; and
 the light chain variable sequence of the IL-1α antigen binding region further comprises a CDR1 selected from the group consisting of SEQ ID NO: 33, SEQ ID NO: 37, and SEQ ID NO: 45; or 
   (h) the heavy chain variable sequence of the IL-1β antigen binding region further comprises a CDR2 selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 43, and SEQ ID NO: 50; and
 the heavy chain variable sequence of the IL-1α antigen binding region further comprises a CDR1 selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 41, and SEQ ID NO: 49. 
   
     
     
         32 - 38 . (canceled) 
     
     
         39 . A dual-specific, isolated antibody, or antigen-binding portion thereof, comprising an IL-1α antigen binding region and an IL-1β antigen binding region, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region combination selected from the group consisting of
 a) a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 16 (ABT1-96) and a light chain variable region comprising CDRs as set forth in SEQ ID NO: 40 (ABT2-46); 
 b) light chain variable region comprising CDRs as set forth in SEQ ID NO: 24 (ABT1-122) and a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 52 (ABT2-108); 
 c) a light chain variable region comprising CDRs as set forth in SEQ ID NO: 28 (ABT1-141) and a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 52 (ABT2-108); 
 d) a light chain variable region comprising CDRs as set forth in SEQ ID NO: 28 (ABT1-141) and a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 44 (ABT2-65); 
 e) a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 16 (ABT1-96) and a light chain variable region comprising CDRs as set forth in SEQ ID NO: 36 (ABT2-42); 
 f) a light chain variable region comprising CDRs as set forth in SEQ ID NO: 12 (ABT1-95) and a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 32 (ABT2-13); 
 g) a light chain variable region comprising CDRs as set forth in SEQ ID NO: 24 (ABT1-122) and a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 44 (ABT2-65); and 
 h) a heavy chain variable region comprising CDRs as set forth in SEQ ID NO: 20 (ABT1-98) and a light chain variable region comprising CDRs as set forth in SEQ ID NO: 48 (ABT2-76). 
 
     
     
         40 . The antibody, or antigen-binding portion of  claim 1 , which has an IgG1 or an IgG4 heavy chain constant region. 
     
     
         41 . The antibody, or antigen-binding portion of  claim 1 , which is an antibody fragment selected from the group consisting of a Fab, a Fab′, a Fab 2 , a Fab′ 2 , an Fd, an Fd′, a single chain Fv (scFv), an scFv a , and a domain antibody (dAb). 
     
     
         42 . The antibody, or antigen-binding portion of  claim 1 , wherein the antibody, or antigen-binding portion thereof, is human. 
     
     
         43 . A pharmaceutical composition comprising the antibody, or antigen-binding portion thereof, of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         44 . The pharmaceutical composition of  claim 43 , which further comprises at least one additional therapeutic agent for treating a disorder in which IL-1α/IL-1β activity is detrimental. 
     
     
         45 . A method for inhibiting human IL-1α/IL-1β activity comprising contacting human IL-1α and IL-1β with the antibody, or antigen-binding portion thereof, of  claim 1  such that human IL-1α/IL-1β activity is inhibited. 
     
     
         46 . A method for inhibiting human IL-1α/IL-1β activity in a human subject suffering from a disorder in which IL-1α/IL-1β activity is detrimental, comprising administering to the human subject the antibody, or antigen-binding portion thereof, of  claim 1  such that human IL-1α/IL-1β activity in the human subject is inhibited. 
     
     
         47 . The method of  claim 46 , wherein the disorder in which IL-1α/IL-1β activity is detrimental is selected from the group consisting of an autoimmune disease, an intestinal disorder, a skin disorder, a neurological disorder, a metabolic disorder, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin dependent diabetes, mellitus, and psoriasis. 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 48 , wherein the antibody, or antigen binding portion thereof, is administered to the subject with an additional therapeutic agent. 
     
     
         50 . A single domain antibody (dAb) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, 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: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, and SEQ ID NO: 133. 
     
     
         51 . An isolated nucleic acid encoding a light chain CDR3 domain selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 23, and SEQ ID NO: 27. 
     
     
         52 . The isolated nucleic acid of  claim 51 , which encodes an antibody light chain variable region. 
     
     
         53 . The isolated nucleic acid of  claim 52 , which encodes a CDR2 domain selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, and SEQ ID NO: 26; and/or a CDR1 domain selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 21, and SEQ ID NO: 25. 
     
     
         54 . (canceled) 
     
     
         55 . An isolated nucleic acid encoding a heavy chain CDR3 domain selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 15, and SEQ ID NO: 19. 
     
     
         56 . The isolated nucleic acid of  claim 55 , which encodes an antibody heavy chain variable region. 
     
     
         57 . The isolated nucleic acid of  claim 56 , which encodes a CDR2 domain selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 18; and/or a CDR1 domain selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 17. 
     
     
         58 . (canceled) 
     
     
         59 . An isolated nucleic acid encoding a light chain CDR3 domain selected from the group consisting of SEQ ID NO: 35, SEQ ID NO: 39, and SEQ ID NO: 47. 
     
     
         60 . The isolated nucleic acid of  claim 59 , which encodes an antibody light chain variable region. 
     
     
         61 . The isolated nucleic acid of  claim 60 , which encodes a CDR2 domain selected from the group consisting of SEQ ID NO: 34, SEQ ID NO: 38, and SEQ ID NO: 46; and/or a CDR1 domain selected from the group consisting of SEQ ID NO: 33, SEQ ID NO: 37, and SEQ ID NO: 45. 
     
     
         62 . (canceled) 
     
     
         63 . An isolated nucleic acid encoding a heavy chain CDR3 domain selected from the group consisting of SEQ ID NO: 31, SEQ ID NO: 43, and SEQ ID NO: 51. 
     
     
         64 . The isolated nucleic acid of  claim 63 , which encodes an antibody heavy chain variable region. 
     
     
         65 . The isolated nucleic acid of  claim 64 , which encodes a CDR2 domain selected from the group consisting of SEQ ID NO: 30, SEQ ID NO: 42, and SEQ ID NO: 50; and/or a CDR1 domain selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 41, and SEQ ID NO: 49. 
     
     
         66 . (canceled) 
     
     
         67 . An isolated nucleic acid
 (a) encoding an antibody light chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 48, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, and SEQ ID NO: 133;   (b) encoding an antibody heavy chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO 8, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, 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: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, and SEQ ID NO: 92; or   (c) selected from the group consisting of SEQ ID NO: 134 to SEQ ID NO: 843.   
     
     
         68 - 69 . (canceled) 
     
     
         70 . A recombinant expression vector comprising a nucleic acid of  claim 67 . 
     
     
         71 . A polypeptide comprising an amino acid sequence encoded by the nucleic acid sequence of  claim 67 (c). 
     
     
         72 . An expression vector comprising:
 a) an episomal origin of replication;   b) an insertion site for inserting a nucleic acid sequence encoding a gene of interest;   c) a stuffer sequence at the insertion site; and   d) a nucleic acid encoding an antibody heavy or light chain constant region.   
     
     
         73 . The expression vector of  claim 72 , wherein the stuffer sequence comprises
 (i) a restriction enzyme site(s) selected from the group consisting of
 a) NruI, FspAI, or a combination thereof at the 5′ end of the stuffer sequence; 
 b) AfeI, SnaBI, BsiWI, HpaI, SalI, or a combination thereof at the 3′ end of the stuffer sequence; and 
 c) at least one restriction enzyme site from (a) and at least one restriction enzyme site from (b); and/or 
   (ii) a nucleic acid sequence having at least 80% identity to the sequence set forth at nucleotides 124 to 1100 of SEQ ID NO: 844.   
     
     
         74 . (canceled) 
     
     
         75 . The expression vector of  claim 72 , wherein the antibody heavy chain constant region is murine or human. 
     
     
         76 . The expression vector of  claim 72 , wherein the antibody constant region is selected from the group consisting of murine or human lambda, human kappa, human IgG3, IgA, IgE, IgM, murine IgG2b, murine IgG3, and an Fc domain. 
     
     
         77 . The expression vector of  claim 72 , wherein the gene of interest is an antibody heavy or light chain variable region. 
     
     
         78 . The expression vector of  claim 72 , comprising a sequence selected from the group consisting of SEQ ID NO: 844, SEQ ID NO: 845, SEQ ID NO: 846, SEQ ID NO: 847, SEQ ID NO: 848, SEQ ID NO: 849, SEQ ID NO: 850, SEQ ID NO: 851, SEQ ID NO: 852, SEQ ID NO: 853, SEQ ID NO: 854, and SEQ ID NO: 855. 
     
     
         79 . A host cell into which the recombinant expression vector of  claim 72  has been introduced. 
     
     
         80 . A method of synthesizing a human antibody that binds human IL-1α and IL-1β comprising culturing the host cell of  claim 78  in a culture medium until a human antibody that binds human IL-1α and IL-1β is synthesized by the cell.