IL-I binding proteins

[0001] This application is a divisional of U.S. application Ser. No. 13/107,439, filed May 13, 2011, which claims the benefit of priority of U.S. Provisional Application No. 61/334,917, filed May 14, 2010, and of U.S. Provisional Application No. 61/425,701, filed Dec. 21, 2010, the contents of which are incorporated herein in their entireties by reference.

[0002] The present invention relates to IL-1 binding proteins, and specifically to their uses in the prevention and/or treatment of acute and chronic immunological diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, multiple sclerosis, and other autoimmune diseases.

[0003] Cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), are molecules produced by a variety of cells, such as monocytes and macrophages, that are mediators of inflammatory processes. Interleukin-1 is a cytokine with a wide range of biological and physiological effects, including fever, prostaglandin synthesis (in, e.g., fibroblasts, muscle cells and endothelial cells), T-lymphocyte activation, and interleukin-2 production.

[0004] The original members of the IL-1 superfamily are IL-1α, IL-1β, and the IL-1 Receptor antagonist (IL-1Ra, IL-1RA, IL-1ra, IL-1Rα). IL-1α and IL-1β are pro-inflammatory cytokines involved in immune defense against infection. The IL-1Rα is a molecule that competes for receptor binding with IL-1α and IL-1β, blocking their role in immune activation. Recent years have seen the addition of other molecules to the IL-1 superfamily including IL-18 (see Dinarello et al., FASEB J., 8(15):1314-3225 (1994); Huising et al., Dev. Comp. Immunol., 28(5):395-413 (2004)) and six more genes with structural homology to IL-1α, IL-1β, or IL-1RA. These latter six members are named IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, and IL1F10. In accordance, IL-1α, IL-1β, and 1L-1RA have been renamed IL-1F1, IL-1F2, and IL-1F3, respectively (see Sims et al., Trends Immunol., 22(10): 536-537 (2001); Dunn et al., Trends Immunol., 22(10): 533-536 (2001)). A further putative member of the IL-1 family has been described called IL-33 or IL-1F11, although this name is not officially accepted in the HGNC gene family nomenclature database.

[0005] Both IL-1α and IL-1β are produced by macrophages, monocytes and dendritic cells. They form an important part of the inflammatory response of the body against infection. These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration of leukocytes, the cells that fight pathogens, to sites of infection and re-set the hypothalamus thermoregulatory center, leading to an increased body temperature which expresses itself as fever. IL-1 is therefore called an endogenous pyrogen. The increased body temperature helps the body's immune system to fight infection. IL-1 is also important in the regulation of hematopoiesis. IL-1β production in peripheral tissue has also been associated with hyperalgesia (increased sensitivity to pain) associated with fever (Morgan et al., Brain Res., 1022(1-2): 96-100 (2004)). For the most part, these two forms of IL-1 bind to the same cellular receptor. This receptor is composed of two related, but non-identical, subunits that transmit intracellular signals via a pathway that is mostly shared with certain other receptors. These include the Toll family of innate immune receptors and the receptor for IL-18. IL-1α and IL-1β also possess similar biological properties, including induction of fever, slow wave sleep, and neutrophilia, T- and B-lymphocyte activation, fibroblast proliferation, cytotoxicity for certain cells, induction of collagenases, synthesis of hepatic acute phase proteins, and increased production of colony stimulating factors and collagen.

[0006] cDNAs encoding the two distinct forms of IL-1 have been isolated and expressed; these cDNAs represent two different gene products, termed IL-1β (Auron et al., Proc. Natl. Acad. Sci. USA, 81: 7907-7911 (1984)) and IL-1α (Lomedico et al., Nature, 312: 458-462 (1984)). IL-1β is the predominant form produced by human monocytes both at the mRNA and protein levels. The two forms of human IL-1 share only 26% amino acid homology. Despite their distinct polypeptide sequences, the two forms of IL-1 have structural similarities (Auron et al., J. Mol. Cell. Immunol., 2: 169-177 (1985)), in that the amino acid homology is confined to discrete regions of the IL-1 molecule.

[0007] IL-1α and IL-1β are produced as precursor peptides. In other words they are made as a long protein that is then processed to release a shorter, active molecule, which is called the mature protein. Mature IL-1β, for example, is released from Pro-IL-1β following cleavage by a certain member of the caspase family of proteins, called caspase-1 or the interleukin-1 converting enzyme (ICE). The 3-dimensional structure of the mature forms of each member of the human IL-1 superfamily is composed of 12-14 β-strands producing a barrel-shaped protein.

[0008] Although a variety of antibodies to IL-1 have been described in the nearly two decades of work since the discovery of this critical proinflammatory cytokine, there remains a need for improved antibodies that can effectively mediate or neutralize the activity of IL-1 in the inflammatory response and autoimmune disorders and for use in detecting IL-1β in samples and tissues.

[0009] This invention pertains to proteins that bind human IL-1α and IL-1β. Binding proteins of the invention include but are not limited to antibodies, antigen binding portions thereof, and multivalent, multispecific binding proteins such as DVD-Ig™ binding proteins that can bind human IL-1α and IL-1β. The invention also provides methods of making and using the IL-1α and IL-1β binding proteins described herein as well as various compositions that may be used in methods of detecting IL-1α and IL-1β in a sample or in methods of treating or preventing a disorder in an individual that is associated with or suspected to be associated with IL-1 activity.

[0010] In an embodiment, the invention provides 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:

• • [0011] VD1 is a first heavy chain variable domain;
  • [0012] VD2 is a second heavy chain variable domain;
  • [0013] C is a heavy chain constant domain;
  • [0014] X1 is a linker with the proviso that it is not CH1;
  • [0015] X2 is an Fc region; and
  • [0016] n is independently 0 or 1; and
  • [0017] wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein:
  • [0018] VD1 is a first light chain variable domain;
  • [0019] VD2 is a second light chain variable domain;
  • [0020] C is a light chain constant domain;
  • [0021] X1 is a linker with the proviso that it is not CH1;
  • [0022] X2 does not comprise an Fc region; and
  • [0023] n is independently 0 or 1;

[0024] 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;

[0025] 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

[0026] wherein the binding protein binds human IL-1β and human IL-1α.

[0027] In an embodiment, a binding protein described above comprises a first polypeptide chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 212, 217, 226, 230, 232, 234, and 236.

[0028] In another embodiment, a binding protein described above comprises a second polypeptide chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 218, 228, 231, 233, 235, and 237.

[0029] In another aspect of the invention, a binding protein comprises first and second polypeptide chains, wherein said first polypeptide chain comprises a first VD1-(X1)n-VD2-C-(X2)n, wherein:

• • [0030] VD1 is a first heavy chain variable domain;
  • [0031] VD2 is a second heavy chain variable domain;
  • [0032] C is a heavy chain constant domain;
  • [0033] X1 is a linker with the proviso that it is not CH1;
  • [0034] X2 is an Fc region; and
  • [0035] n is independently 0 or 1; and
  • [0036] wherein said second polypeptide chain comprises a second VD1-(X1)n-VD2-C-(X2)n, wherein:
  • [0037] VD1 is a first light chain variable domain;
  • [0038] VD2 is a second light chain variable domain;
  • [0039] C is a light chain constant domain;
  • [0040] X1 is a linker with the proviso that it is not CH1;
  • [0041] X2 does not comprise an Fc region; and
  • [0042] n is independently 0 or 1;

[0043] 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;

[0044] 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.

[0045] In another embodiment, a binding protein described above comprises a first polypeptide chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 219 and 221.

[0046] In another embodiment, a binding protein described above comprises a second polypeptide chain that comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 220 and 222.

[0047] In another aspect, the invention provides a binding protein described above, wherein:

• • [0048] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:212, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 215, 228, 231, 233 and 235;
  • [0049] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:217, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 218 and 237;
  • [0050] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:219, then said second polypeptide chain comprises the amino acid sequence of SEQ ID NO:220;
  • [0051] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:221, then said second polypeptide chain comprises SEQ ID NO:222;
  • [0052] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:226, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 228, 215, 231, 233, and 235;
  • [0053] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:230, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 231, 215, 228, 233, and 235;
  • [0054] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:232, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 233, 215, 228, 231, and 235;
  • [0055] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:234, then said second polypeptide chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 235, 215, 228, 231, and 233; and
  • [0056] when said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:236, then said second polypeptide chain comprises SEQ ID NO:237.
  • [0057] In another aspect, the invention provides a protein described above, wherein:
  • [0058] said first polypeptide chain comprises SEQ ID NO:212, and said second polypeptide chain comprises SEQ ID NO:215; or
  • [0059] said first polypeptide chain comprises SEQ ID NO:217, and said second polypeptide chain comprises SEQ ID NO:218; or
  • [0060] said first polypeptide chain comprises SEQ ID NO:219, and said second polypeptide chain comprises SEQ ID NO:220; or
  • [0061] said first polypeptide chain comprises SEQ ID NO:221, and said second polypeptide chain comprises SEQ ID NO:222; or
  • [0062] said first polypeptide chain comprises SEQ ID NO:226, and said second polypeptide chain comprises SEQ ID NO:228; or
  • [0063] said first polypeptide chain comprises SEQ ID NO:230, and said second polypeptide chain comprises SEQ ID NO:231; or
  • [0064] said first polypeptide chain comprises SEQ ID NO:232, and said second polypeptide chain comprises SEQ ID NO:233; or
  • [0065] said first polypeptide chain comprises SEQ ID NO:234, and said second polypeptide chain comprises SEQ ID NO:235; or
  • [0066] said first polypeptide chain comprises SEQ ID NO:236, and said second polypeptide chain comprises SEQ ID NO:237.

[0067] In an embodiment, a binding protein of the invention described above comprises two first polypeptide chains and two second polypeptide chains.

[0068] In another aspect, in a binding protein described above X1 or X2 is an amino acid sequence selected from the group consisting of SEQ ID NOs:26-57, 233, 224, and 225.

[0069] In another embodiment, the invention provides a binding protein described above wherein the Fc region is selected from the group consisting of a native sequence Fc region and a variant sequence Fc region. In another embodiment, the Fc region is selected from the group consisting of an Fc region from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD.

[0070] In another embodiment, the invention provides a binding protein conjugate that comprises a binding protein described above and further comprises an agent. Such agents include, but are not limited to, an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent. Preferred imaging agents include, but are not limited to, a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin. Preferred radiolabels include, but are not limited to, ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm. A preferred therapeutic or cytotoxic agent includes, but is not limited to, 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.

[0071] The invention also provides a binding protein comprising an antigen binding domain, wherein the binding protein is capable of binding human IL-1β and the antigen-binding domain comprises six CDRs, i.e., CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, as defined below:

• • [0072] CDR-H1: X₁-Y-D-M-S (SEQ ID NO:190), wherein;
    • [0073] X₁ is S, K or R;
  • [0074] CDR-H2: Y-X₂-S-X₄-G-G-X₇-G-T-Y-Y-P-D-X₁₄-X₁₅-K-G (SEQ ID NO: 191),
    • [0075] wherein;
    • [0076] X₂ is I or V;
    • [0077] X₄ is S or H;
    • [0078] X₇ is G or A;
    • [0079] X₁₄ is T or S; and
    • [0080] X₁₅ is V or A;
  • [0081] CDR-H3: G-G-V-X₄-K-G-X₇-F-D-X₁₀ (SEQ ID NO:192), wherein;
    • [0082] X₄ is T or Y;
    • [0083] X₇ is Y or C; and
    • [0084] X₁₀ is V, E, L, M, Q, or Y;
  • [0085] CDR-L1: R-A-S-G-N-I-X₇-X₈-X₉-L-X₁₁ (SEQ ID NO:193), wherein;
    • [0086] X₇ is H, Y, or W;
    • [0087] X₈ is N, G, T, Q, E, H, D, or K;
    • [0088] X₉ is Y or W; and
    • [0089] X₁₁ is T, A, or N;
  • [0090] CDR-L2: X₁-A-K-X₄-L-X₆-X₇ (SEQ ID NO:194), wherein;
    • [0091] X₁ is N, Q, or D;
    • [0092] X₄ is T, N, I, E, or S;
    • [0093] X₆ is A, M, or E; and
    • [0094] X₇ is D, E, S, or A;

[0095] and

• • [0096] CDR-L3: Q-X₂-F-W-X_5-X6-P-X₈-X₉ (SEQ ID NO:195), wherein;
    • [0097] X₂ is H or Q;
    • [0098] X₅ is S, N, T, K, R, or M;
    • [0099] X₆ is I or L;
    • [0100] X₈ is Y or A; and
    • [0101] X₉ is T, I, and N;
  • [0102] except that when CDR-H1 is S-Y-D-M-S (SEQ ID NO:17), then:
  • [0103] 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);
  • [0104] CDR-H3 cannot be G-G-V-T-K-G-Y-F-D-V (SEQ ID NO: 19);
  • [0105] CDR-L1 cannot be R-A-S-G-N-I-H-N-Y-L-T (SEQ ID NO:20);
  • [0106] CDR-L2 cannot be N-A-K-T-L-A-D (SEQ ID NO:21); and
  • [0107] CDR-L3 cannot be Q-H-F-W-S-I-P-Y-T (SEQ ID NO:22).

[0108] In an embodiment, an isolated binding protein described above comprises at least one CDR that comprises an amino acid sequence selected from the group of CDR sequences consisting of:

[0109]

residues 31-35 of SEQ ID NO: 60	residues 31-35 of SEQ ID NO: 63
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 60	residues 50-66 of SEQ ID NO: 63
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 60	residues 99-108 of SEQ ID NO: 63
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 149	residues 24-34 of SEQ ID NO: 150
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 149	residues 50-56 of SEQ ID NO: 150
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 149	residues 89-97 of SEQ ID NO: 150
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 69	residues 31-35 of SEQ ID NO: 97
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 69	residues 50-66 of SEQ ID NO: 97
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 69	residues 99-108 of SEQ ID NO: 97
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 173	residues 24-34 of SEQ ID NO: 187
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 173	residues 50-56 of SEQ ID NO: 187
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 173	residues 89-97 of SEQ ID NO: 187
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 67	residues 31-35 of SEQ ID NO: 90
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 67	residues 50-66 of SEQ ID NO: 90
(CDR-H2)	(CDR-H2)
residues 99-108 of SEQ ID NO: 67	residues 99-108 of SEQ ID NO: 90
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 151	residues 24-34 of SEQ ID NO: 156
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 151	residues 50-56 of SEQ ID NO: 156
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 151	residues 89-97 of SEQ ID NO: 156
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 88	residues 31-35 of SEQ ID NO: 92
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 88	residues 50-66 of SEQ ID NO: 92
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 88	residues 99-108 of SEQ ID NO: 92
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 159	residues 24-34 of SEQ ID NO: 153
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 159	residues 50-56 of SEQ ID NO: 153
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 159	residues 89-97 of SEQ ID NO: 153
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 96	residues 31-35 of SEQ ID NO: 94
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 96	residues 50-66 of SEQ ID NO: 94
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 96	residues 99-108 of SEQ ID NO: 94
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 155	residues 24-34 of SEQ ID NO: 166
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 155	residues 50-56 of SEQ ID NO: 166
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 155	residues 89-97 of SEQ ID NO: 166
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 90	residues 31-35 of SEQ ID NO: 82
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 90	residues 50-66 of SEQ ID NO: 82
(CDR-H2)	(CDR-H2)
residues 99-108 of SEQ ID NO: 90	residues 99-108 of SEQ ID NO: 82
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 182	residues 24-34 of SEQ ID NO: 159
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 182	residues 50-56 of SEQ ID NO: 159
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 182	residues 89-97 of SEQ ID NO: 159
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 90	residues 31-35 of SEQ ID NO: 101
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 90	residues 50-66 of SEQ ID NO: 101
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 90	residues 99-108 of SEQ ID NO: 101
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 167	residues 24-34 of SEQ ID NO: 158
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 167	residues 50-56 of SEQ ID NO: 158
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 167	residues 89-97 of SEQ ID NO: 158
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 90	residues 31-35 of SEQ ID NO: 96
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 90	residues 50-66 of SEQ ID NO: 96
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 90	residues 99-108 of SEQ ID NO: 96
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 164	residues 24-34 of SEQ ID NO: 157
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 164	residues 50-56 of SEQ ID NO: 157
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 164	residues 89-97 of SEQ ID NO: 157
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 73	residues 31-35 of SEQ ID NO: 70
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 73	residues 50-66 of SEQ ID NO: 70
(CDR-H2);	(CDR-H2)
residues 99-108 of SEQ ID NO: 73	residues 99-108 of SEQ ID NO: 70
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 174	residues 24-34 of SEQ ID NO: 161
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 174	residues 50-56 of SEQ ID NO: 161
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 174	residues 89-97 of SEQ ID NO: 161
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 86	residues 31-35 of SEQ ID NO: 83
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 86	residues 50-66 of SEQ ID NO: 83
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 86	residues 99-108 of SEQ ID NO: 83
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 159	residues 24-34 of SEQ ID NO: 158
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 159	residues 50-56 of SEQ ID NO: 158
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 159	residues 89-97 of SEQ ID NO: 158
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 90	residues 31-35 of SEQ ID NO: 102
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 90	residues 50-66 of SEQ ID NO: 102
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 90	residues 99-108 of SEQ ID NO: 102
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 169	residues 24-34 of SEQ ID NO: 185
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 169	residues 50-56 of SEQ ID NO: 185
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 169	residues 89-97 of SEQ ID NO: 185
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 91	residues 31-35 of SEQ ID NO: 98
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 91	residues 50-66 of SEQ ID NO: 98
(CDR-H2)	(CDR-H2);
residues 99-108 of SEQ ID NO: 91	residues 99-108 of SEQ ID NO: 98
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 165	residues 24-34 of SEQ ID NO: 160
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 165	residues 50-56 of SEQ ID NO: 160
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 165	residues 89-97 of SEQ ID NO: 160
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 76	residues 31-35 of SEQ ID NO: 74
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 76	residues 50-66 of SEQ ID NO: 74
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 76	residues 99-108 of SEQ ID NO: 74
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 175	residues 24-34 of SEQ ID NO: 186
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 175	residues 50-56 of SEQ ID NO: 186
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 175	residues 89-97 of SEQ ID NO: 186
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 99	residues 31-35 of SEQ ID NO: 95
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 99	residues 50-66 of SEQ ID NO: 95
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 99	residues 99-108 of SEQ ID NO: 95
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 189	residues 24-34 of SEQ ID NO: 157
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 189	residues 50-56 of SEQ ID NO: 157
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 189	residues 89-97 of SEQ ID NO: 157
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 100	residues 31-35 of SEQ ID NO: 72
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 100	residues 50-66 of SEQ ID NO: 72
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 100	residues 99-108 of SEQ ID NO: 72
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 168	residues 24-34 of SEQ ID NO: 178
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 168	residues 50-56 of SEQ ID NO: 178
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 168	residues 89-97 of SEQ ID NO: 178
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 71	residues 31-35 of SEQ ID NO: 96
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 71	residues 50-66 of SEQ ID NO: 96
(CDR-H2)	(CDR-H2);
residues 99-108 of SEQ ID NO: 71	residues 99-108 of SEQ ID NO: 96
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 170	residues 24-34 of SEQ ID NO: 163
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 170	residues 50-56 of SEQ ID NO: 163
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 170	residues 89-97 of SEQ ID NO: 163
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 84	residues 31-35 of SEQ ID NO: 77
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 84	residues 50-66 of SEQ ID NO: 77
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 84	residues 99-108 of SEQ ID NO: 77
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 188	residues 24-34 of SEQ ID NO: 183
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 188	residues 50-56 of SEQ ID NO: 183
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 188	residues 89-97 of SEQ ID NO: 183
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 78	residues 31-35 of SEQ ID NO: 90
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 78	residues 50-66 of SEQ ID NO: 90
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 78	residues 99-108 of SEQ ID NO: 90
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 179	residues 24-34 of SEQ ID NO: 171
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 179	residues 50-56 of SEQ ID NO: 171
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 179	residues 89-97 of SEQ ID NO: 171
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 93	residues 31-35 of SEQ ID NO: 79
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 93	residues 50-66 of SEQ ID NO: 79
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 93	residues 99-108 of SEQ ID NO: 79
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 176	residues 24-34 of SEQ ID NO: 180
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 176	residues 50-56 of SEQ ID NO: 180
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 176	residues 89-97 of SEQ ID NO: 180
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 87	residues 31-35 of SEQ ID NO: 381
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 87	residues 50-66 of SEQ ID NO: 381
(CDR-H2)	(CDR-H2);
residues 99-108 of SEQ ID NO: 87	residues 99-108 of SEQ ID NO: 381
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 154	residues 24-34 of SEQ ID NO: 152
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 154	residues 50-56 of SEQ ID NO: 152
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 154	residues 89-97 of SEQ ID NO: 152
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 85	residues 31-35 of SEQ ID NO: 81
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 85	residues 50-66 of SEQ ID NO: 81
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 85	residues 99-108 of SEQ ID NO: 81
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 162	residues 24-34 of SEQ ID NO: 177
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 162	residues 50-56 of SEQ ID NO: 177
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 162	residues 89-97 of SEQ ID NO: 177
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 89	residues 31-35 of SEQ ID NO: 80
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 89	residues 50-66 of SEQ ID NO: 80
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 89	residues 99-108 of SEQ ID NO: 80
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 170	residues 24-34 of SEQ ID NO: 172
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 170	residues 50-56 of SEQ ID NO: 172
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 170	residues 89-97 of SEQ ID NO: 172
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 75	residues 31-35 of SEQ ID NO: 196
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 75	residues 50-66 of SEQ ID NO: 196
(CDR-H2)	(CDR-H2);
residues 99-108 of SEQ ID NO: 75	residues 99-108 of SEQ ID NO: 196
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 181	residues 24-34 of SEQ ID NO: 197
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 181	residues 50-56 of SEQ ID NO: 197
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 181	residues 89-97 of SEQ ID NO: 197
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 92	residues 31-35 of SEQ ID NO: 198
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 92	residues 50-66 of SEQ ID NO: 198
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 92	residues 99-108 of SEQ ID NO: 198
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 184	residues 24-34 of SEQ ID NO: 199
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 184	residues 50-56 of SEQ ID NO: 199
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 184	residues 89-97 of SEQ ID NO: 199
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 200	residues 31-35 of SEQ ID NO: 202
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 200	residues 50-66 of SEQ ID NO: 202
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 200	residues 99-108 of SEQ ID NO: 202
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 201	residues 24-34 of SEQ ID NO: 203
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 201	residues 50-56 of SEQ ID NO: 203
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 201	residues 89-97 of SEQ ID NO: 203
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 204	residues 31-35 of SEQ ID NO: 206
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 204	residues 50-66 of SEQ ID NO: 206
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 204	residues 99-108 of SEQ ID NO: 206
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 205	residues 24-34 of SEQ ID NO: 207
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 205	residues 50-56 of SEQ ID NO: 207
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 205	residues 89-97 of SEQ ID NO: 207
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 208	residues 31-35 of SEQ ID NO: 210
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 208	residues 50-66 of SEQ ID NO: 210
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 208	residues 99-108 of SEQ ID NO: 210
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 209	residues 24-34 of SEQ ID NO: 211
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 209	residues 50-56 of SEQ ID NO: 211
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 209	residues 89-97 of SEQ ID NO: 211
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 103	residues 31-35 of SEQ ID NO: 126
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 103	residues 50-66 of SEQ ID NO: 126
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 103	residues 99-108 of SEQ ID NO: 126
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 104	residues 31-35 of SEQ ID NO: 127
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 104	residues 50-66 of SEQ ID NO: 127
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 104	residues 99-108 of SEQ ID NO: 127
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 105	residues 31-35 of SEQ ID NO: 128
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 105	residues 50-66 of SEQ ID NO: 128
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 105	residues 99-108 of SEQ ID NO: 128
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 106	residues 31-35 of SEQ ID NO: 129
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 106	residues 50-66 of SEQ ID NO: 129
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 106	residues 99-108 of SEQ ID NO: 129
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 107	residues 31-35 of SEQ ID NO: 130
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 107	residues 50-66 of SEQ ID NO: 130
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 107	residues 99-108 of SEQ ID NO: 130
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 108	residues 31-35 of SEQ ID NO: 131
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 108	residues 50-66 of SEQ ID NO: 131
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 108	residues 99-108 of SEQ ID NO: 131
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 109	residues 31-35 of SEQ ID NO: 132
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 109	residues 50-66 of SEQ ID NO: 132
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 109	residues 99-108 of SEQ ID NO: 132
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 110	residues 31-35 of SEQ ID NO: 133
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 110	residues 50-66 of SEQ ID NO: 133
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 110	residues 99-108 of SEQ ID NO: 133
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 111	residues 31-35 of SEQ ID NO: 134
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 111	residues 50-66 of SEQ ID NO: 134
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 111	residues 99-108 of SEQ ID NO: 134
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 112	residues 31-35 of SEQ ID NO: 135
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 112	residues 50-66 of SEQ ID NO: 135
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 112	residues 99-108 of SEQ ID NO: 135
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 113	residues 31-35 of SEQ ID NO: 136
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 113	residues 50-66 of SEQ ID NO: 136
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 113	residues 99-108 of SEQ ID NO: 136
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 114	residues 31-35 of SEQ ID NO: 137
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 114	residues 50-66 of SEQ ID NO: 137
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 114	residues 99-108 of SEQ ID NO: 137
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 115	residues 31-35 of SEQ ID NO: 138
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 115	residues 50-66 of SEQ ID NO: 138
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 115	residues 99-108 of SEQ ID NO: 138
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 116	residues 31-35 of SEQ ID NO: 139
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 116	residues 50-66 of SEQ ID NO: 139
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 116	residues 99-108 of SEQ ID NO: 139
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 117	residues 31-35 of SEQ ID NO: 140
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 117	residues 50-66 of SEQ ID NO: 140
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 117	residues 99-108 of SEQ ID NO: 140
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 118	residues 31-35 of SEQ ID NO: 141
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 118	residues 50-66 of SEQ ID NO: 141
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 118	residues 99-108 of SEQ ID NO: 141
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 119	residues 31-35 of SEQ ID NO: 142
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 119	residues 50-66 of SEQ ID NO: 142
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 119	residues 99-108 of SEQ ID NO: 142
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 120	residues 31-35 of SEQ ID NO: 143
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 120	residues 50-66 of SEQ ID NO: 143
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 120	residues 99-108 of SEQ ID NO: 143
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 121	residues 31-35 of SEQ ID NO: 144
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 121	residues 50-66 of SEQ ID NO: 144
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 121	residues 99-108 of SEQ ID NO: 144
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 122	residues 31-35 of SEQ ID NO: 145
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 122	residues 50-66 of SEQ ID NO: 145
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 122	residues 99-108 of SEQ ID NO: 145
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 123	residues 31-35 of SEQ ID NO: 146
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 123	residues 50-66 of SEQ ID NO: 146
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 123	residues 99-108 of SEQ ID NO: 146
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 124	residues 31-35 of SEQ ID NO: 147
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 124	residues 50-66 of SEQ ID NO: 147
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 124	residues 99-108 of SEQ ID NO: 147
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-L1);	(CDR-L1);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3);
residues 31-35 of SEQ ID NO: 125	residues 31-35 of SEQ ID NO: 148
(CDR-H1);	(CDR-H1);
residues 50-66 of SEQ ID NO: 125	residues 50-66 of SEQ ID NO: 148
(CDR-H2);	(CDR-H2);
residues 99-108 of SEQ ID NO: 125	residues 99-108 of SEQ ID NO: 148
(CDR-H3);	(CDR-H3);
residues 24-34 of SEQ ID NO: 59	residues 24-34 of SEQ ID NO: 59
(CDR-LI);	(CDR-LI);
residues 50-56 of SEQ ID NO: 59	residues 50-56 of SEQ ID NO: 59
(CDR-L2);	(CDR-L2);
residues 89-97 of SEQ ID NO: 59	residues 89-97 of SEQ ID NO: 59
(CDR-L3);	(CDR-L3).

[0110] In another embodiment, a binding protein described above comprises at least three CDRs, wherein the three CDRs are from a CDR set selected from the group of CDR sets consisting of:

[0111]

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 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);
3	residues 31-35 of SEQ ID NO: 69
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 69
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 69
	(CDR-H3);
4	residues 24-34 of SEQ ID NO: 173
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 173
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 173
	(CDR-L3);
5	residues 31-35 of SEQ ID NO: 67
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 67
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 67
	(CDR-H3);
6	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);
7	residues 31-35 of SEQ ID NO: 88
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 88
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 88
	(CDR-H3);
8	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);
9	residues 31-35 of SEQ ID NO: 96
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 96
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 96
	(CDR-H3);
10	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);
11	residues 31-35 of SEQ ID NO: 90
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 90
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 90
	(CDR-H3);
12	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);
13	residues 31-35 of SEQ ID NO: 90
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 90
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 90
	(CDR-H3);
14	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);
15	residues 31-35 of SEQ ID NO: 90
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 90
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 90
	(CDR-H3);
16	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);
17	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);
18	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);
19	residues 31-35 of SEQ ID NO: 86
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 86
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 86
	(CDR-H3);
20	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);
21	residues 31-35 of SEQ ID NO: 90
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 90
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 90
	(CDR-H3);
22	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);
23	residues 31-35 of SEQ ID NO: 91
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 91
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 91
	(CDR-H3);
24	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);
25	residues 31-35 of SEQ ID NO: 76
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 76
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 76
	(CDR-H3);
26	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);
27	residues 31-35 of SEQ ID NO: 99
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 99
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 99
	(CDR-H3);
28	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);
29	residues 31-35 of SEQ ID NO: 100
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 100
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 100
	(CDR-H3);
30	residues 24-34 of SEQ ID NO: 168
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 168
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 168
	(CDR-L3);
31	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);
32	residues 24-34 of SEQ ID NO: 170
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 170
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 170
	(CDR-L3);
33	residues 31-35 of SEQ ID NO: 84
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 84
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 84
	(CDR-H3);
34	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);
35	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);
36	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);
37	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);
38	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);
39	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);
40	residues 24-34 of SEQ ID NO: 154
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 154
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 154
	(CDR-L3);
41	residues 31-35 of SEQ ID NO: 85
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 85
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 85
	(CDR-H3);
42	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);
43	residues 31-35 of SEQ ID NO: 89
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 89
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 89
	(CDR-H3);
44	residues 24-34 of SEQ ID NO: 170
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 170
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 170
	(CDR-L3);
45	residues 31-35 of SEQ ID NO: 75
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 75
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 75
	(CDR-H3);
46	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);
47	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);
48	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);
49	residues 31-35 of SEQ ID NO: 200
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 200
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 200
	(CDR-H3);
50	residues 24-34 of SEQ ID NO: 201
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 201
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 201
	(CDR-L3);
51	residues 31-35 of SEQ ID NO: 204
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 204
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 204
	(CDR-H3);
52	residues 24-34 of SEQ ID NO: 205
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 205
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 205
	(CDR-L3);
53	residues 31-35 of SEQ ID NO: 208
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 208
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 208
	(CDR-H3);
54	residues 24-34 of SEQ ID NO: 209
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 209
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 209
	(CDR-L3);
55	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);
56	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);
57	residues 31-35 of SEQ ID NO: 97
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 97
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 97
	(CDR-H3);
58	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);
59	residues 31-35 of SEQ ID NO: 90
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 90
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 90
	(CDR-H3);
60	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);
61	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);
62	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);
63	residues 31-35 of SEQ ID NO: 94
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 94
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 94
	(CDR-H3);
64	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);
65	residues 31-35 of SEQ ID NO: 82
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 82
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 82
	(CDR-H3);
66	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);
67	residues 31-35 of SEQ ID NO: 101
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 101
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 101
	(CDR-H3);
68	residues 24-34 of SEQ ID NO: 158
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 158
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 158
	(CDR-L3);
69	residues 31-35 of SEQ ID NO: 96
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 96
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 96
	(CDR-H3);
70	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);
71	residues 31-35 of SEQ ID NO: 70
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 70
	(CDR-H2)
	residues 99-108 of SEQ ID NO: 70
	(CDR-H3);
72	residues 24-34 of SEQ ID NO: 161
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 161
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 161
	(CDR-L3);
73	residues 31-35 of SEQ ID NO: 83
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 83
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 83
	(CDR-H3);
74	residues 24-34 of SEQ ID NO: 158
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 158
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 158
	(CDR-L3);
75	residues 31-35 of SEQ ID NO: 102
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 102
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 102
	(CDR-H3);
76	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);
77	residues 31-35 of SEQ ID NO: 98
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 98
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 98
	(CDR-H3);
78	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);
79	residues 31-35 of SEQ ID NO: 74
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 74
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 74
	(CDR-H3);
80	residues 24-34 of SEQ ID NO: 186
	(CDR-L1);
	residues 50-56 of SEQ ID NO: 186
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 186
	(CDR-L3);
81	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);
82	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);
83	residues 31-35 of SEQ ID NO: 72
	(CDR-H1);
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	residues 50-56 of SEQ ID NO: 59
	(CDR-L2);
	residues 89-97 of SEQ ID NO: 59
	(CDR-L3);
191	residues 31-35 of SEQ ID NO: 144
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 144
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 144
	(CDR-H3);
192	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);
193	residues 31-35 of SEQ ID NO: 145
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 145
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 145
	(CDR-H3);
194	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);
195	residues 31-35 of SEQ ID NO: 146
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 146
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 146
	(CDR-H3);
196	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);
197	residues 31-35 of SEQ ID NO: 147
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 147
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 147
	(CDR-H3);
198	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);
199	residues 31-35 of SEQ ID NO: 148
	(CDR-H1);
	residues 50-66 of SEQ ID NO: 148
	(CDR-H2);
	residues 99-108 of SEQ ID NO: 148
	(CDR-H3);
200	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).

[0112] In an embodiment, a binding protein described above comprises CDRs from two CDR sets selected from the above group of CDR sets.

[0113] In another embodiment, the invention provides a binding protein comprising CDRs from two CDR sets from the group above, wherein the two CDR sets are selected from the group consisting of:

[0114]

	CDR Set 1 and CDR Set 2
	CDR Set 3 and CDR Set 4
	CDR Set 5 and CDR Set 6
	CDR Set 7 and CDR Set 8
	CDR Set 9 and CDR Set 10
	CDR Set 11 and CDR Set 12
	CDR Set 13 and CDR Set 14
	CDR Set 15 and CDR Set 16
	CDR Set 17 and CDR Set 18
	CDR Set 19 and CDR Set 20
	CDR Set 21 and CDR Set 22
	CDR Set 23 and CDR Set 24
	CDR Set 25 and CDR Set 26
	CDR Set 27 and CDR Set 28
	CDR Set 29 and CDR Set 30
	CDR Set 31 and CDR Set 32
	CDR Set 33 and CDR Set 34
	CDR Set 35 and CDR Set 36
	CDR Set 37 and CDR Set 38
	CDR Set 39 and CDR Set 40
	CDR Set 41 and CDR Set 42
	CDR Set 43 and CDR Set 44
	CDR Set 45 and CDR Set 46
	CDR Set 47 and CDR Set 48
	CDR Set 49 and CDR Set 50
	CDR Set 51 and CDR Set 52
	CDR Set 53 and CDR Set 54
	CDR Set 55 and CDR Set 56
	CDR Set 57 and CDR Set 58
	CDR Set 59 and CDR Set 60
	CDR Set 61 and CDR Set 62
	CDR Set 63 and CDR Set 64
	CDR Set 65 and CDR Set 66
	CDR Set 67 and CDR Set 68
	CDR Set 69 and CDR Set 70
	CDR Set 71 and CDR Set 72
	CDR Set 73 and CDR Set 74
	CDR Set 75 and CDR Set 76
	CDR Set 77 and CDR Set 78
	CDR Set 79 and CDR Set 80
	CDR Set 81 and CDR Set 82
	CDR Set 83 and CDR Set 84
	CDR Set 85 and CDR Set 86
	CDR Set 87 and CDR Set 88
	CDR Set 89 and CDR Set 90
	CDR Set 91 and CDR Set 92
	CDR Set 93 and CDR Set 94
	CDR Set 95 and CDR Set 96
	CDR Set 97 and CDR Set 98
	CDR Set 99 and CDR Set 100
	CDR Set 101 and CDR Set 102
	CDR Set 103 and CDR Set 104
	CDR Set 105 and CDR Set 106
	CDR Set 107 and CDR Set 108
	CDR Set 109 and CDR Set 110
	CDR Set 111 and CDR Set 112
	CDR Set 113 and CDR Set 114
	CDR Set 115 and CDR Set 116
	CDR Set 117 and CDR Set 118
	CDR Set 119 and CDR Set 120
	CDR Set 121 and CDR Set 122
	CDR Set 123 and CDR Set 124
	CDR Set 125 and CDR Set 126
	CDR Set 127 and CDR Set 128
	CDR Set 129 and CDR Set 130
	CDR Set 131 and CDR Set 132
	CDR Set 133 and CDR Set 134
	CDR Set 135 and CDR Set 136
	CDR Set 137 and CDR Set 138
	CDR Set 139 and CDR Set 140
	CDR Set 141 and CDR Set 142
	CDR Set 143 and CDR Set 144
	CDR Set 145 and CDR Set 146
	CDR Set 147 and CDR Set 148
	CDR Set 149 and CDR Set 150
	CDR Set 151 and CDR Set 152
	CDR Set 153 and CDR Set 154
	CDR Set 155 and CDR Set 156
	CDR Set 157 and CDR Set 158
	CDR Set 159 and CDR Set 160
	CDR Set 161 and CDR Set 162
	CDR Set 163 and CDR Set 164
	CDR Set 165 and CDR Set 166
	CDR Set 167 and CDR Set 168
	CDR Set 169 and CDR Set 170
	CDR Set 171 and CDR Set 172
	CDR Set 173 and CDR Set 174
	CDR Set 175 and CDR Set 176
	CDR Set 177 and CDR Set 178
	CDR Set 179 and CDR Set 180
	CDR Set 181 and CDR Set 182
	CDR Set 183 and CDR Set 184
	CDR Set 185 and CDR Set 186
	CDR Set 187 and CDR Set 188
	CDR Set 189 and CDR Set 190
	CDR Set 191 and CDR Set 192
	CDR Set 193 and CDR Set 194
	CDR Set 195 and CDR Set 196
	CDR Set 197 and CDR Set 198
	CDR Set 199 and CDR Set 200

[0115] In another embodiment, a binding protein described above further comprises a human acceptor framework. Preferably, the human framework comprises an amino acid sequence selected group consisting SEQ ID NOs: 7-10, 13-16, 25, 240-316, and 317-381. In an embodiment, a binding protein of the invention comprises a human framework sequence selected from the group consisting of SEQ ID NOS:7-10 and 13-16.

[0116] Binding proteins of the invention include those that comprise a human acceptor framework comprising 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.

[0117] In another embodiment, a binding protein of the invention comprises a human acceptor framework, wherein said 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. In an exemplary embodiment, a binding protein of the invention comprises a key residue, wherein said key residue 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, 95L (all Kabat numbering). An exemplary subset of these residues for the humanization of a binding protein of the invention consists of 27H, 48H, 67H, 69H, 93H, 36L, 43L, 46L, 47L, 49L, 58L, 71L, and 87L.

[0118] In another embodiment, a binding protein of the invention comprises a consensus human variable domain.

[0119] In an embodiment, an IL-1β binding protein of the invention comprises at least one variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:60-189.

[0120] In another embodiment, a binding protein of the invention comprises at least one variable heavy chain (VH) region (or domain) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 60-148, 196, 198, 200, 202, 204, 206, 208, and 210.

[0121] In another embodiment, a binding protein according to the invention comprises at least one variable light chain (VL) region (or domain) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:149-189.

[0122] In still another embodiment, a binding protein according to the invention comprises at least one VH region comprising 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 at least one VL region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:149-189, 197, 199, 201, 203, 205, 207, 209, and 211.

[0123] In an embodiment, a binding protein according to the invention comprises two variable domains, wherein the two variable domains comprise amino acid sequences selected from the group consisting of:

[0124]

SEQ ID NO: 60 and SEQ ID NO: 149	SEQ ID NO: 198 and SEQ ID
	NO: 199
SEQ ID NO: 69 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: 123 and SEQ ID
	NO: 59
SEQ ID NO: 204 and SEQ ID NO: 205	SEQ ID NO: 124 and SEQ ID
	NO: 59
SEQ ID NO: 208 and SEQ ID NO: 209	SEQ ID NO: 125 and SEQ ID
	NO: 59
SEQ ID NO: 63 and SEQ ID NO: 150	SEQ ID NO: 126 and SEQ ID
	NO: 59
SEQ ID NO: 97 and SEQ ID NO: 187	SEQ ID NO: 127 and SEQ ID
	NO: 59
SEQ ID NO: 90 and SEQ ID NO: 156	SEQ ID NO: 128 and SEQ ID
	NO: 59
SEQ ID NO: 92 and SEQ ID NO: 153	SEQ ID NO: 129 and SEQ ID
	NO: 59
SEQ ID NO: 94 and SEQ ID NO: 166	SEQ ID NO: 130 and SEQ ID
	NO: 59
SEQ ID NO: 82 and SEQ ID NO: 159	SEQ ID NO: 131 and SEQ ID
	NO: 59
SEQ ID NO: 101 and SEQ ID NO: 158	SEQ ID NO: 132 and SEQ ID
	NO: 59
SEQ ID NO: 96 and SEQ ID NO: 157	SEQ ID NO: 133 and SEQ ID
	NO: 59
SEQ ID NO: 70 and SEQ ID NO: 161	SEQ ID NO: 134 and SEQ ID
	NO: 59
SEQ ID NO: 83 and SEQ ID NO: 158	SEQ ID NO: 135 and SEQ ID
	NO: 59
SEQ ID NO: 102 and SEQ ID NO: 185	SEQ ID NO: 136 and SEQ ID
	NO: 59
SEQ ID NO: 98 and SEQ ID NO: 160	SEQ ID NO: 137 and SEQ ID
	NO: 59
SEQ ID NO: 74 and SEQ ID NO: 186	SEQ ID NO: 138 and SEQ ID
	NO: 59
SEQ ID NO: 95 and SEQ ID NO: 157	SEQ ID NO: 139 and SEQ ID
	NO: 59
SEQ ID NO: 72 and SEQ ID NO: 178	SEQ ID NO: 140 and SEQ ID
	NO: 59
SEQ ID NO: 96 and SEQ ID NO: 163	SEQ ID NO: 141 and SEQ ID
	NO: 59
SEQ ID NO: 77 and SEQ ID NO: 183	SEQ ID NO: 142 and SEQ ID
	NO: 59
SEQ ID NO: 90 and SEQ ID NO: 171	SEQ ID NO: 143 and SEQ ID
	NO: 59
SEQ ID NO: 79 and SEQ ID NO: 180	SEQ ID NO: 144 and SEQ ID
	NO: 59
SEQ ID NO: 381 and SEQ ID NO: 152	SEQ ID NO: 145 and SEQ ID
	NO: 59
SEQ ID NO: 81 and SEQ ID NO: 177	SEQ ID NO: 146 and SEQ ID
	NO: 59
SEQ ID NO: 80 and SEQ ID NO: 172	SEQ ID NO: 147 and SEQ ID
	NO: 59
SEQ ID NO: 196 and SEQ ID NO: 197	SEQ ID NO: 148 and SEQ ID
	NO: 59

[0125] In another embodiment, an IL-1β binding protein described herein is selected from the group consisting of: an immunoglobulin molecule, an scFv, a monoclonal antibody, a humanized antibody, a chimeric antibody, a humanized antibody, a Fab fragment, an Fab′ fragment, an F(ab′)₂, an Fv, and a disulfide linked Fv.

[0126] In an aspect of the invention, a binding protein described herein is capable of modulating a biological function of IL-1. In another aspect, a binding protein described herein is capable of neutralizing IL-1.

[0127] In an embodiment, a binding protein described herein has an on rate constant (K_on) to IL-1β selected from the group consisting of: at least about 10²M⁻¹s⁻¹; at least about 10³M⁻¹s⁻¹; at least about 10⁴M⁻¹s⁻¹; at least about 10⁵M⁻¹s⁻¹; and at least about 10⁶M⁻¹s⁻¹; as measured by surface plasmon resonance.

[0128] In another embodiment, a binding protein described herein has an off rate constant (K_off) to IL-1β selected from the group consisting of: at most about 10⁻³s⁻¹; at most about 10⁻⁴s⁻¹; at most about 10⁻⁵s⁻¹; and at most about 10⁻⁶s⁻¹, as measured by surface plasmon resonance.

[0129] In another embodiment, a binding protein described herein 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.

[0130] In one aspect, the invention provides a binding protein construct that comprises a binding protein described herein and further comprises a linker or an immunoglobulin constant domain. In an embodiment, the binding protein construct comprises a binding protein, wherein the 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 DVD-Ig™, and an Fv.

[0131] In an embodiment, a 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.

[0132] In another embodiment, a 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.

[0133] The invention also provide a binding protein conjugate that comprises a binding protein construct described herein and further comprises an agent selected from the group consisting of an immunoadhesion molecule, an imaging agent, a therapeutic agent, and a cytotoxic agent. Imaging agents that are useful as agent moieties in binding protein conjugates described herein include, but are not limited to, a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin. In an embodiment, a radiolabel is selected from the group consisting of: ³H, ¹⁴C, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁶Ho, and ¹⁵³Sm.

[0134] In another embodiment, a binding protein conjugate comprises an agent that 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.

[0135] In an embodiment, a binding protein, binding protein construct, or binding protein conjugate described herein possesses a human glycosylation pattern.

[0136] Binding proteins, binding protein constructs, and binding protein conjugates described herein may exist as soluble proteins or as crystals. In an embodiment, such crystals are carrier-free pharmaceutical controlled released crystals. In another embodiment, a crystalline form of a binding protein, binding protein construct, or binding protein conjugate described herein has a greater in vivo half-life than its soluble counterpart. In another embodiment, a crystal of a binding protein, binding protein construct, or binding protein conjugate described herein retains biological activity of its soluble counterpart.

[0137] Compositions of the invention include a composition for the release of a crystallized binding protein, binding protein construct, or binding protein conjugate described herein, comprising:

[0138] (a) a formulation, wherein said formulation comprises a crystallized binding protein, binding protein construct, or binding protein conjugate described herein, and an ingredient; and

[0139] (b) at least one polymeric carrier.

[0140] Polymeric carriers useful in compositions of the invention include, without limitation, 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.

[0141] In another aspect, an ingredient of a composition of the invention is selected from the group consisting of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol.

[0142] The invention also provides pharmaceutical compositions comprising a binding protein, a binding protein construct, or binding protein conjugate described herein, and a pharmaceutically acceptable carrier. Pharmaceutical compositions of the invention may further comprise at least one additional agent. In an embodiment, such an additional agent includes, but is not limited to, therapeutic agent, imaging agent, cytotoxic agent, angiogenesis inhibitors; kinase inhibitors; co-stimulation molecule blockers; adhesion molecule blockers; anti-cytokine antibody or functional fragment thereof; methotrexate; cyclosporin; rapamycin; FK506; 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, a cytokine, and a cytokine antagonist.

[0143] In an embodiment, a pharmaceutical composition of the invention comprises a pharmaceutically acceptable carrier, wherein the carrier also serves as an adjuvant to increase the absorption or dispersion of the binding protein, binding protein construct, or binding protein conjugate in the composition. An exemplary adjuvant is hyaluronidase.

[0144] In another embodiment, a pharmaceutical composition further comprises at least one additional therapeutic agent for treating a disorder in which IL-1β activity is detrimental.

[0145] In an embodiment, the invention provides isolated nucleic acids encoding one or more amino acid sequences of a binding protein described herein. Such nucleic acids may be inserted into a vector for carrying out various genetic analyses or for expressing, characterizing, or improving one or more properties of a binding protein described herein. A vector may comprise a one or more nucleic acid molecules encoding one or more amino acid sequences of a binding protein described herein in which the one or more nucleic acid molecules is operably linked to appropriate transcriptional and/or translational sequences that permit expression of the binding protein in a particular host cell carrying the vector. Examples of vectors for cloning or expressing nucleic acids encoding amino acid sequences of binding proteins described herein include, but are not limited, pcDNA, pTT, pTT3, pEFBOS, pBV, pJV, and pBJ.

[0146] The invention also provides a host cell comprising a vector comprising a nucleic acid encoding one or more amino acid sequences of a binding protein described herein. Host cells useful in the invention may be prokaryotic or eukaryotic. An exemplary prokaryotic host cell is Escherichia coli. Eukaryotic cells useful as host cells in the invention include protist cell, animal cell, plant cell, and fungal cell. An exemplary fungal cell is a yeast cell, including Saccharomyces cerevisiae. An exemplary animal cell useful as a host cell according to the invention includes, but is not limited to, a mammalian cell, an avian cell, and an insect cell. Preferred mammalian cells include CHO and COS cells. An insect cell useful as a host cell according to the invention is an insect Sf9 cell.

[0147] In another aspect, the invention provides a method of producing a binding protein described herein comprising culturing a host cell comprising a vector encoding the binding protein in culture medium under conditions sufficient to produce the binding protein capable of binding IL-1α and/or IL-1β. The protein so produced can be isolated and used in various compositions and methods described herein.

[0148] In another embodiment, the invention provides a method for reducing human IL-1 activity comprising contacting human IL-1 with a binding protein described herein, such that human IL-1 activity is reduced.

[0149] Another embodiment of the invention provides a method for treating a subject for a disorder by administering to the subject a binding protein described herein such that treatment is achieved.

[0150] In another embodiment, a binding protein described herein is useful for treating a disorder selected from the group consisting of: diabetes; uveitis; neuropathic pain; osteoarthritic pain; inflammatory pain; rheumatoid arthritis; osteoarthritis; juvenile chronic arthritis; septic arthritis; Lyme arthritis; psoriatic arthritis; reactive arthritis; spondyloarthropathy; systemic lupus erythematosus (SLE); Crohn's disease; ulcerative colitis; inflammatory bowel disease; autoimmune diabetes; insulin dependent diabetes mellitus; thyroiditis; asthma; allergic diseases; psoriasis; dermatitis; scleroderma; graft versus host disease; organ transplant rejection; acute immune disease associated with organ transplantation; chronic immune disease associated with organ transplantation; sarcoidosis; atherosclerosis; disseminated intravascular coagulation (DIC); Kawasaki's disease; Grave's disease; nephrotic syndrome; chronic fatigue syndrome; Wegener's granulomatosis; Henoch-Schoenlein purpurea; microscopic vasculitis of the kidneys; chronic active hepatitis; autoimmune uveitis; septic shock; toxic shock syndrome; sepsis syndrome; cachexia; infectious diseases; parasitic diseases; acute transverse myelitis; Huntington's chorea; Parkinson's disease; Alzheimer's disease; stroke; primary biliary cirrhosis; hemolytic anemia; malignancies; heart failure; myocardial infarction; Addison's disease; sporadic polyglandular deficiency type I; polyglandular deficiency type II (Schmidt's syndrome); acute respiratory distress syndrome (ARDS); alopecia; alopecia greata; seronegative arthropathy; arthropathy; Reiter's disease; psoriatic arthropathy; ulcerative colitic arthropathy; enteropathic synovitis; chlamydia; Yersinia and Salmonella associated arthropathy; spondyloarthropathy; atheromatous disease/arteriosclerosis; atopic allergy; autoimmune bullous disease; pemphigus vulgaris; pemphigus foliaceus; pemphigoid; linear IgA disease; autoimmune haemolytic anaemia; Coombs positive haemolytic anaemia; acquired pernicious anaemia; juvenile pernicious anaemia; myalgic encephalitis/Royal Free disease; chronic mucocutaneous candidiasis; giant cell arteritis (GCA); primary sclerosing hepatitis; cryptogenic autoimmune hepatitis; acquired immunodeficiency syndrome (AIDS); acquired immunodeficiency related diseases; hepatitis B; hepatitis C; common varied immunodeficiency (common variable hypogammaglobulinaemia); dilated cardiomyopathy; female infertility; ovarian failure; premature ovarian failure; fibrotic lung disease; cryptogenic fibrosing alveolitis; post-inflammatory interstitial lung disease; interstitial pneumonitis; connective tissue disease associated interstitial lung disease; mixed connective tissue disease associated lung disease; systemic sclerosis associated interstitial lung disease; rheumatoid arthritis associated interstitial lung disease; systemic lupus erythematosus associated lung disease; dermatomyositis/polymyositis associated lung disease; Sjögren's disease associated lung disease; ankylosing spondylitis associated lung disease; vasculitic diffuse lung disease; haemosiderosis associated lung disease; drug-induced interstitial lung disease; fibrosis; radiation fibrosis; bronchiolitis obliterans; chronic eosinophilic pneumonia; lymphocytic infiltrative lung disease; postinfectious interstitial lung disease; gouty arthritis; autoimmune hepatitis; type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis); type-2 autoimmune hepatitis (anti-LKM antibody hepatitis); autoimmune mediated hypoglycaemia; type B insulin resistance with acanthosis nigricans; hypoparathyroidism; osteoarthrosis; primary sclerosing cholangitis; psoriasis type 1; psoriasis type 2; idiopathic leucopaenia; autoimmune neutropaenia; renal disease NOS; glomerulonephritides; microscopic vasculitis of the kidneys; Lyme disease; discoid lupus erythematosus; idiopathic male infertility; nitric oxide-associated male infertility; sperm autoimmunity; multiple sclerosis (all subtypes, including primary progressive, secondary progressive, relapsing remitting); sympathetic ophthalmia; pulmonary hypertension secondary to connective tissue disease; Goodpasture's syndrome; pulmonary manifestation of polyarteritis nodosa; acute rheumatic fever; rheumatoid spondylitis; Still's disease; systemic sclerosis; Sjörgren's syndrome; Takayasu's disease/arteritis; autoimmune thrombocytopaenia (AITP); idiopathic thrombocytopaenia; autoimmune thyroid disease; hyperthyroidism; goitrous autoimmune hypothyroidism (Hashimoto's disease); atrophic autoimmune hypothyroidism; primary myxoedema; phacogenic uveitis; primary vasculitis; vitiligo; acute liver disease; chronic liver disease; alcoholic cirrhosis; alcohol-induced liver injury; cholestasis; idiosyncratic liver disease; drug-induced hepatitis; non-alcoholic steatohepatitis; allergy; group B Streptococci (GBS) infection; mental disorders (e.g., depression and schizophrenia); Th2 Type and Th1 Type mediated diseases; acute and chronic pain (different forms of pain); cancer (such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate, and rectal cancer); hematopoietic malignancies; leukemia; lymphoma; abetalipoproteinemia; acrocyanosis; acute and chronic parasitic or infectious processes; acute leukemia; acute lymphoblastic leukemia (ALL); T-cell ALL; FAB ALL; acute myeloid leukemia (AML); acute or chronic bacterial infection; acute pancreatitis; acute renal failure; adenocarcinomas; atrial ectopic beats; AIDS dementia complex; alcohol-induced hepatitis; allergic conjunctivitis; allergic contact dermatitis; allergic rhinitis; allograft rejection; alpha-1-antitrypsin deficiency; amyotrophic lateral sclerosis; anemia; angina pectoris; anterior horn cell degeneration; anti-CD3 therapy; antiphospholipid syndrome; anti-receptor hypersensitivity reactions; aortic and peripheral aneurysms; aortic dissection; arterial hypertension; arteriosclerosis; arteriovenous fistula; ataxia; atrial fibrillation (sustained or paroxysmal); atrial flutter; atrioventricular block; B cell lymphoma; bone graft rejection; bone marrow transplant (BMT) rejection; bundle branch block; Burkitt's lymphoma; burns; cardiac arrhythmias; cardiac stun syndrome; cardiac tumors; cardiomyopathy; cardiopulmonary bypass inflammation response; cartilage transplant rejection; cerebellar cortical degenerations; cerebellar disorders; chaotic or multifocal atrial tachycardia; chemotherapy associated disorders; chronic myelocytic leukemia (CML); chronic alcoholism; chronic inflammatory pathologies; chronic lymphocytic leukemia (CLL); chronic obstructive pulmonary disease (COPD); chronic salicylate intoxication; colorectal carcinoma; congestive heart failure; conjunctivitis; contact dermatitis; cor pulmonale; coronary artery disease; Creutzfeldt-Jakob disease; culture negative sepsis; cystic fibrosis; cytokine therapy associated disorders; dementia pugilistica; demyelinating diseases; dengue hemorrhagic fever; dermatitis; dermatologic conditions; diabetes mellitus; diabetic arteriosclerotic disease; diffuse Lewy body disease; dilated congestive cardiomyopathy; disorders of the basal ganglia; Down's syndrome in middle age; drug-induced movement disorders induced by drugs which block CNS dopamine receptors; drug sensitivity; eczema; encephalomyelitis; endocarditis; endocrinopathy; epiglottitis; Epstein-Barr virus infection; erythromelalgia; extrapyramidal and cerebellar disorders; familial hemophagocytic lymphohistiocytosis; fetal thymus implant rejection; Friedreich's ataxia; functional peripheral arterial disorders; fungal sepsis; gas gangrene; gastric ulcer; glomerular nephritis; graft rejection of any organ or tissue; gram negative sepsis; gram positive sepsis; granulomas due to intracellular organisms; hairy cell leukemia; Hallervorden-Spatz disease; Hashimoto's thyroiditis; hay fever; heart transplant rejection; hemochromatosis; hemodialysis; hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura; hemorrhage; hepatitis A; His bundle arrhythmias; HIV infection/HIV neuropathy; Hodgkin's disease; hyperkinetic movement disorders; hypersensitivity reactions; hypersensitivity pneumonitis; hypertension; hypokinetic movement disorders; hypothalamic-pituitary-adrenal axis evaluation; idiopathic Addison's disease; idiopathic pulmonary fibrosis (IPF); antibody mediated cytotoxicity; asthenia; infantile spinal muscular atrophy; inflammation of the aorta; influenza a; ionizing radiation exposure; iridocyclitis/uveitis/optic neuritis; ischemia-reperfusion injury; ischemic stroke; juvenile rheumatoid arthritis; juvenile spinal muscular atrophy; Kaposi's sarcoma; kidney transplant rejection; legionella; leishmaniasis; leprosy; lesions of the corticospinal system; lipedema; liver transplant rejection; lymphedema; malaria; malignant lymphoma; malignant histiocytosis; malignant melanoma; meningitis; meningococcemia; metabolic syndrome migraine headache; idiopathic migraine headache; mitochondrial multisystem disorder; mixed connective tissue disease; monoclonal gammopathy; multiple myeloma; multiple systems degenerations (Menzel; Dejerine-Thomas; Shy-Drager; and Machado-Joseph); myasthenia gravis; mycobacterium avium intracellulare; mycobacterium tuberculosis; myelodysplastic syndrome; myocardial infarction; myocardial ischemic disorders; nasopharyngeal carcinoma; neonatal chronic lung disease; nephritis; nephrosis; neurodegenerative diseases; neurogenic I muscular atrophies; neutropenic fever; non-Hodgkin's lymphoma; occlusion of the abdominal aorta and its branches; occlusive arterial disorders; OKT3® therapy; orchitis/epididymitis; orchitis/vasectomy reversal procedures; organomegaly; osteoporosis; pancreas transplant rejection; pancreatic carcinoma; paraneoplastic syndrome/hypercalcemia of malignancy; parathyroid transplant rejection; pelvic inflammatory disease; perennial rhinitis; pericardial disease; peripheral atherosclerotic disease; peripheral vascular disorders; peritonitis; pernicious anemia; pneumocystis carinii pneumonia; pneumonia; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome); post perfusion syndrome; post pump syndrome; post-MI cardiotomy syndrome; preeclampsia; progressive supranucleo palsy; primary pulmonary hypertension; radiation therapy; Raynaud's phenomenon; Raynaud's disease; Refsum's disease; regular narrow QRS tachycardia; renovascular hypertension; reperfusion injury; restrictive cardiomyopathy; sarcomas; senile chorea; senile dementia of Lewy body type; seronegative arthropathies; shock; sickle cell anemia; skin allograft rejection; skin changes syndrome; small bowel transplant rejection; solid tumors; specific arrhythmias; spinal ataxia; spinocerebellar degenerations; streptococcal myositis; structural lesions of the cerebellum; subacute sclerosing panencephalitis; syncope; syphilis of the cardiovascular system; systemic anaphylaxis; systemic inflammatory response syndrome; systemic onset juvenile rheumatoid arthritis; telangiectasia; thromboangitis obliterans; thrombocytopenia; toxicity; transplants; trauma/hemorrhage; type III hypersensitivity reactions; type IV hypersensitivity; unstable angina; uremia; urosepsis; urticaria; valvular heart diseases; varicose veins; vasculitis; venous diseases; venous thrombosis; ventricular fibrillation; viral and fungal infections; viral encephalitis/aseptic meningitis; viral-associated hemophagocytic syndrome; Wernicke-Korsakoff syndrome; Wilson's disease; xenograft rejection of any organ or tissue; acute coronary syndromes; acute idiopathic polyneuritis; acute inflammatory demyelinating polyradiculoneuropathy; acute ischemia; adult Still's disease; alopecia greata; anaphylaxis; anti-phospholipid antibody syndrome; aplastic anemia; arteriosclerosis; atopic eczema; atopic dermatitis; autoimmune dermatitis; autoimmune disorder associated with Streptococcus infection; autoimmune enteropathy; autoimmune hearing loss; autoimmune lymphoproliferative syndrome (ALPS); autoimmune myocarditis; autoimmune premature ovarian failure; blepharitis; bronchiectasis; bullous pemphigoid; cardiovascular disease; catastrophic antiphospholipid syndrome; celiac disease; cervical spondylosis; chronic ischemia; cicatricial pemphigoid; clinically isolated syndrome (CIS) with risk for multiple sclerosis; conjunctivitis; childhood onset psychiatric disorder; dacryocystitis; dermatomyositis; diabetic retinopathy; disk herniation; disk prolapse; drug induced immune hemolytic anemia; endocarditis; endometriosis; endophthalmitis; episcleritis; erythema multiforme; erythema multiforme major; gestational pemphigoid; Guillain-Barré syndrome (GBS); hay fever; Hughes syndrome; idiopathic Parkinson's disease; idiopathic interstitial pneumonia; IgE-mediated allergy; immune hemolytic anemia; inclusion body myositis; infectious ocular inflammatory disease; inflammatory demyelinating disease; inflammatory heart disease; inflammatory kidney disease; iritis; keratitis; keratojunctivitis sicca; Kussmaul disease or Kussmaul-Meier disease; Landry's paralysis; Langerhan's cell histiocytosis; livedo reticularis; macular degeneration; microscopic polyangiitis; Morbus Bechterev; motor neuron disorders; mucous membrane pemphigoid; multiple organ failure; myasthenia gravis; myelodysplastic syndrome; myocarditis; nerve root disorders; neuropathy; non-A non-B hepatitis; optic neuritis; osteolysis; pauciarticular JRA; peripheral artery occlusive disease (PAOD); peripheral vascular disease (PVD); peripheral artery; disease (PAD); phlebitis; polyarteritis nodosa (or periarteritis nodosa); polychondritis; polymyalgia rheumatica; poliosis; polyarticular JRA; polyendocrine deficiency syndrome; polymyositis; polymyalgia rheumatica (PMR); post-pump syndrome; primary Parkinsonism; secondary Parkinsonism; prostatitis; pure red cell aplasia; primary adrenal insufficiency; recurrent neuromyelitis optica; restenosis; rheumatic heart disease; SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis); secondary amyloidosis; shock lung; scleritis; sciatica; secondary adrenal insufficiency; silicone associated connective tissue disease; Sneddon-Wilkinson dermatosis; spondylitis ankylosans; Stevens-Johnson syndrome (SJS); systemic inflammatory response syndrome; temporal arteritis; toxoplasmic retinitis; toxic epidermal necrolysis; transverse myelitis; TRAPS (tumor necrosis factor receptor type 1 (TNFR)-associated periodic syndrome); type B insulin resistance with acanthosis nigricans; type 1 allergic reaction; type II diabetes; urticaria; usual interstitial pneumonia (UIP); vernal conjunctivitis; viral retinitis; Vogt-Koyanagi-Harada syndrome (VKH syndrome); wet macular degeneration; wound healing; Yersinia and Salmonella associated arthropathy.

[0151] In a further embodiment of a method of treatment described herein, the step of administering to the subject a binding protein or binding protein construct or binding protein conjugate described herein is by at least one mode selected from parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, and transdermal.

[0152] Another aspect of the invention is a method of treating a patient suffering from a disorder in which IL-1 is detrimental comprising the step of administering a binding protein, binding protein construct, or binding protein conjugate described herein before, concurrently with, or after the administration of a second agent, wherein the second agent is selected from the group consisting of inhaled steroids; beta-agonists; short-acting or long-acting beta-agonists; antagonists of leukotrienes or leukotriene receptors; ADVAIR; IgE inhibitors; anti-IgE antibodies; XOLAIR; phosphodiesterase inhibitors; PDE4 inhibitors; xanthines; anticholinergic drugs; mast cell-stabilizing agents; Cromolyn; IL-4 inhibitors; IL-5 inhibitors; eotaxin/CCR3 inhibitors; antagonists of histamine or its receptors including H1, H2, H3, and H4; antagonists of prostaglandin D or its receptors DP1 and CRTH2; TNF antagonists; a soluble fragment of a TNF receptor; ENBREL®; TNF enzyme antagonists; TNF converting enzyme (TACE) inhibitors; muscarinic receptor antagonists; TGF-beta antagonists; interferon gamma; perfenidone; chemotherapeutic agents, methotrexate; leflunomide; sirolimus (rapamycin) or an analog thereof, CCI-779; COX2 or cPLA2 inhibitors; NSAIDs; immunomodulators; p38 inhibitors; TPL-2, MK-2 and NFkB inhibitors; budenoside; epidermal growth factor; corticosteroids; cyclosporine; sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1 antibodies; anti-IL-6 antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies or agonists of TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, EMAP-II, GM-CSF, FGF, or PDGF; antibodies of CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; FK506; rapamycin; mycophenolate mofetil; ibuprofen; prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; IRAK, NIK, IKK, p38, or MAP kinase inhibitors; IL-1β converting enzyme inhibitors; TNF-α converting enzyme inhibitors; T-cell signaling inhibitors; metalloproteinase inhibitors; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors; soluble p55 TNF receptor; soluble p75 TNF receptor; sIL-1RI; sIL-1RII; sIL-6R; anti-inflammatory cytokines; IL-4; IL-10; IL-11; and TGF-β.

[0153] Another aspect of the invention provides at least one IL-1 anti-idiotype antibody to at least one IL-1 binding protein described herein. The anti-idiotype antibody includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule such as, but not limited to, at least one CDR of a heavy or light chain or ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a binding protein of the invention.

[0154] This invention pertains to IL-1β binding proteins, including, but not limited to, anti-IL-1β antibodies, or antigen-binding portions thereof, that bind IL-1β and multivalent, multispecific binding proteins such as DVD-Ig™ that bind IL-1β and another target. Various aspects of the invention relate to antibodies and antibody fragments, DVD-Ig binding proteins, and pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such IL-1β binding proteins, including antibodies, DVD-Ig binding proteins, and fragments thereof. Methods of using the IL-1β binding proteins of the invention to detect human IL-1β; to inhibit human IL-1β, either in vitro or in vivo; and to regulate gene expression are also encompassed by the invention.

[0155] The invention also encompasses any binding protein or antibody capable of competing with an IL-1β binding protein described herein.

[0156] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

[0157] Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well known and commonly used in the art. The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0158] That the present invention may be more readily understood, select terms are defined below.

[0159] The term “polypeptide” refers to any polymeric chain of amino acids. The terms “peptide” and “protein” are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids. The term “polypeptide” encompasses native or artificial proteins, protein fragments and polypeptide analogs of a protein sequence. A polypeptide may be monomeric or polymeric The term “polypeptide” encompasses fragments and variants (including fragments of variants) thereof, unless otherwise contradicted by context. For an antigenic polypeptide, a fragment of polypeptide optionally contains at least one contiguous or nonlinear epitope of polypeptide. The precise boundaries of the at least one epitope fragment can be confirmed using ordinary skill in the art. The fragment comprises at least about 5 contiguous amino acids, such as at least about 10 contiguous amino acids, at least about 15 contiguous amino acids, or at least about 20 contiguous amino acids. A variant of polypeptide is as described herein.

[0160] The term “isolated protein” or “isolated polypeptide” is a protein or polypeptide that by virtue of its origin or source of derivation is not associated with naturally associated components that accompany it in its native state; is substantially free of other proteins from the same species; is expressed by a cell from a different species; or does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components. A protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.

[0161] The term “recovering” refers to the process of rendering a chemical species such as a polypeptide substantially free of naturally associated components by isolation, e.g., using protein purification techniques well known in the art.

[0162] The term “human IL-1α” (abbreviated herein as hIL-1α, or IL-1α), includes a pleiotropic cytokine involved in various immune responses, inflammatory processes, and hematopoiesis. For example, IL-1α includes the human cytokine produced by activated macrophages; it stimulates thymocyte proliferation by inducing IL-2 release, B-cell maturation and proliferation, and fibroblast growth factor activity. The term human IL-1α is intended to include recombinant human IL-1α (rh IL-1α) that can be prepared by standard recombinant expression methods.

[0163] The term “human IL-1β” (abbreviated herein as hIL-1β, or IL-1β) includes a pleiotropic cytokine involved in various immune responses, inflammatory processes, and hematopoiesis. The term human IL-1β includes recombinant human IL-1β (rh IL-1β) that can be prepared by standard recombinant expression methods.

[0164] The amino acid sequences of human IL-1α and IL-1β are shown in Table 1.

[0165]

TABLE 1
Sequence of Human IL-1α and Human IL-1β
	Sequence	Sequence
Protein	Identifier	123456789012345678901234567890
Human	SEQ ID	SAPFSFLSNVKYNFMRIIKYEFILNDALNQ
mature	NO: 1	SIIRANDQYLTAAALHNLDEAVKFDMGAYK
IL-1α		SSKDDAKITVILRISKTQLYVTAQDEDQPV
		LLKEMPEIPKTITGSETNLLFFWETHGTKN
		YFTSVAHPNLFIATKQDYWVCLAGGPPSIT
		DFQILENQA
Human	SEQ ID	APVRSLNCTLRDSQQKSLVMSGPYELKALH
mature	NO: 2	LQGQDMEQQVVFSMSFVQGEESNDKIPVAL
IL-1β		GLKEKNLYLSCVLKDDKPTLQLESVDPKNY
		PKKKMEKRFVFNKIEINNKLEFESAQFPNW
		YISTSQAENMPVFLGGTKGGQDITDFTMQF
		VSS

[0166] The term “biological activity” refers to all inherent biological properties of the IL-1 cytokine, e.g., IL-1α and/or IL-1β. Biological properties of IL-1α and IL-1β include, but are not limited to, binding to an IL-1 receptor.

[0167] The terms “specific binding” or “specifically binding” in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody.

[0168] The term “antibody” broadly refers to any immunoglobulin (Ig) molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivation thereof, which retains the essential epitope binding features of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. Nonlimiting embodiments of which are discussed below.

[0169] In a full-length antibody, each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains: CH1, CH2, and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG 3, IgG4, IgA1 and IgA2) or subclass.

[0170] The term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, which may be generated by papain digestion of an intact antibody. The Fc region may be a native sequence Fc region or a variant Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain, and a CH3 domain, and optionally comprises a CH4 domain. Replacements of amino acid residues in the Fc portion to alter antibody effector function are known in the art (Winter et al., U.S. Pat. Nos. 5,648,260 and 5,624,821). The Fc portion of an antibody mediates several important effector functions, for example, cytokine induction, ADCC, phagocytosis, complement dependent cytotoxicity (CDC), and half-life/clearance rate of antibody and antigen-antibody complexes. In some cases these effector functions are desirable for therapeutic antibody but in other cases might be unnecessary or even deleterious, depending on the therapeutic objectives. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC and CDC via binding to FcγRs and complement C1q, respectively. Neonatal Fc receptors (FcRn) are the critical components determining the circulating half-life of antibodies. In still another embodiment at least one amino acid residue is replaced in the constant region of the antibody, for example the Fc region of the antibody, such that effector functions of the antibody are altered. The dimerization of two identical heavy chains of an immunoglobulin is mediated by the dimerization of CH3 domains and is stabilized by the disulfide bonds within the hinge region (Huber et al., Nature, 264: 415-420 (1976); Thies et al., J. Mol. Biol., 293: 67-79 (1999)). Mutation of cysteine residues within the hinge regions to prevent heavy chain-heavy chain disulfide bonds will destabilize dimerization of CH3 domains. Residues responsible for CH3 dimerization have been identified (Dall'Acqua et al., Biochemistry, 37: 9266-9273 (1998)). Therefore, it is possible to generate a monovalent half-Ig. Interestingly, these monovalent half Ig molecules have been found in nature for both IgG and IgA subclasses (Seligmann et al., Ann. Immunol., 129 C: 855-870 (1978); Biewenga et al., Clin. Exp. Immunol., 51: 395-400 (1983)). The stoichiometry of FcRn: Ig Fc region has been determined to be 2:1 (West et al., Biochemistry, 39: 9698-9708 (2000)), and half Fc is sufficient for mediating FcRn binding (Kim et al., Eur. J. Immunol., 24: 542-548 (1994)). Mutations to disrupt the dimerization of CH3 domain may not have greater adverse effect on its FcRn binding as the residues important for CH3 dimerization are located on the inner interface of CH3 b sheet structure, whereas the region responsible for FcRn binding is located on the outside interface of CH2-CH3 domains. However, the half Ig molecule may have certain advantage in tissue penetration due to its smaller size than that of a regular antibody. In one embodiment, at least one amino acid residue is replaced in the constant region of the binding protein of the invention, for example the Fc region, such that the dimerization of the heavy chains is disrupted, resulting in half DVD Ig molecules. The anti-inflammatory activity of IgG is completely dependent on sialylation of the N-linked glycan of the IgG Fc fragment. The precise glycan requirements for anti-inflammatory activity has been determined, such that an appropriate IgG1 Fc fragment can be created, thereby generating a fully recombinant, sialylated IgG1 Fc with greatly enhanced potency (Anthony et al., Science, 320:373-376 (2008)).

[0171] The term “antigen-binding portion” of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hIL-1β). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multi-specific formats; specifically binding to two or more different antigens (e.g., hIL-1β and a different antigen molecule, such as hIL-1β and hIL-1α). Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab′)₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature, 341: 544-546 (1989); PCT Publication No. WO 90/05144), which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, for example, Bird et al., Science, 242: 423-426 (1988); and Huston et al., Proc. Natl. Acad. Sci. USA, 85: 5879-5883 (1988)). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see, for example, Holliger et al., Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993); Poljak, R. J., Structure, 2: 1121-1123 (1994)). Such antibody binding portions are known in the art (Kontermann and Dübel eds., Antibody Engineering (Springer-Verlag, New York, 2001), p. 790 (ISBN 3-540-41354-5)). In addition single chain antibodies also include “linear antibodies” comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata et al., Protein Eng., 8(10): 1057-1062 (1995); and U.S. Pat. No. 5,641,870)).

[0172] An immunoglobulin constant (C) domain refers to a heavy (CH) or light (CL) chain constant domain. Murine and human IgG heavy chain and light chain constant domain amino acid sequences are known in the art.

[0173] The term “IL-1β binding protein construct” (or “binding protein construct”) refers to a polypeptide comprising one or more of the antigen binding portions of the invention linked to a linker or an immunoglobulin constant domain. A “linker polypeptide” comprises two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions. Such linker polypeptides are well known in the art (see e.g., Holliger et al., Proc. Natl. Acad. Sci. USA, 90: 6444-6448 (1993); Poljak, R. J., Structure, 2: 1121-1123 (1994)). An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art and represented in Table 2.

[0174]

TABLE 2
Sequence of Human IgG Heavy Chain Constant
Domain and Light Chain Constant Domain
	Sequence	Sequence
Protein	Identifier	123456789012345678901234567890
Ig gamma-1	SEQ ID	ASTKGPSVFFLAPSSKSTSGGTAALGCLVK
constant	NO: 3	DYFPEPVTVSWNSGALTSGVHTFPAVLQSS
region		GLYSLSSVVTVPSSSLGTQTYICNVNHKPS
		NTKVDKKVEPKSCDKTHTCPPCPAPELLGG
		PSVFLFPPKPKDTLMISRTPEVTCVVVDVS
		HEDPEVKFNWYVDGVEVHNAKTKPREEQYN
		STYRVVSVLTVLHQDWLNGKEYKCKVSNKA
		LPAPIEKTISKAKGQPREPQVYTLPPSREE
		MTKNQVSLTCLVKGFYPSDIAVEWESNGQP
		ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
		QQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Ig gamma-1	SEQ ID	ASTKGPSVFPLAPSSKSTSGGTAALGCLVK
constant	NO: 4	DYFPEPVTVSWNSGALTSGVHTFPAVLQSS
region		GLYSLSSVVTVPSSSLGTQTYICNVNHKPS
mutant		NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG
		PSVFLFPPKPKDTLMISRTPEVTCVVVDVS
		HEDPEVKFNWYVDGVEVHNAKTKPREEQYN
		STYRVVSVLTVLHQDWLNGKEYKCKVSNKA
		LPAPIEKTISKAKGQPREPQVYTLPPSREE
		MTKNQVSLTCLVKGFYPSDIAVEWESNGQP
		ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
		QQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Ig Kappa	SEQ ID	TVAAPSVFIFPPSDEQLKSGTASVVCLLNN
constant	NO: 5	FYPREAKVQWKVDNALQSGNSQESVTEQDS
region		KDSTYSLSSTLTLSKADYEKHKVYACEVTH
		QGLSSPVTKSFNRGEC
Ig Lambda	SEQ ID	QPKAAPSVTLFPPSSEELQANKATLVCLIS
constant	NO: 6	DFYPGAVTVAWKADSSPVKAGVETTTPSKQ
region		SNNKYAASSYLSLTPEQWKSHRSYSCQVTH
		EGSTVEKTVAPTECS

[0175] Still further, an IL-1β binding protein, such as an antibody or antigen-binding portion thereof, may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antigen-binding portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov et al., Human Antibod. Hybridomas, 6: 93-101 (1995)) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov et al., Mol. Immunol., 31: 1047-1058 (1994)). Antibody portions, such as Fab and F(ab′)₂ fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antigen-binding portions thereof, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques.

[0176] An “isolated antibody” is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hIL-1β is substantially free of antibodies that specifically bind antigens other than hIL-1β). An isolated antibody that specifically binds hIL-1β may, however, have cross-reactivity to other antigens, such as IL-1β molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0177] The term “monoclonal antibody” or “mAb” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each mAb is directed against a single determinant on the antigen. The modifier “monoclonal” is not to be construed as requiring production of the antibody by any particular method.

[0178] The term “human antibody” includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody” does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0179] The term “recombinant human antibody” includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further in Section II C, below), antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom, H. R., Trends Biotechnol., 15: 62-70 (1997); Azzazy and Highsmith, Clin. Biochem., 35: 425-445 (2002); Gavilondo and Larrick, BioTechniques, 29: 128-145 (2000); Hoogenboom and Chames, Immunol. Today, 21: 371-378 (2000)), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al., Nucl. Acids Res., 20: 6287-6295 (1992); Kellermann and Green, Curr. Opin. Biotechnol., 13: 593-597 (2002); Little et al., Immunol. Today, 21: 364-370 (2000)); or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0180] The term “chimeric antibody” refers to antibodies that comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.

[0181] The term “CDR-grafted antibody” refers to antibodies that comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.

[0182] The term “CDR” refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions. The term “CDR set” as used herein refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987); and Chothia et al., Nature, 342: 877-883 (1989)) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2, and L3 or H1, H2, and H3 where the “L” and the “H” designates the light chain and the heavy chains regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan et al. (FASEB J., 9: 133-139 (1995)) and MacCallum et al. (J. Mol. Biol., 262(5): 732-745 (1996)). Still other CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although exemplary embodiments use Kabat or Chothia defined CDRs.

[0183] The terms “Kabat numbering”, “Kabat definitions”, and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al., Ann. NY Acad. Sci., 190: 382-391 (1971); and Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.

[0184] The growth and analysis of extensive public databases of amino acid sequences of variable heavy and light regions over the past twenty years have led to the understanding of the typical boundaries between framework regions (FR) and CDR sequences within variable region sequences and enabled persons skilled in this art to accurately determine the CDRs according to Kabat numbering, Chothia numbering, or other systems. See, e.g., Martin, “Protein Sequence and Structure Analysis of Antibody Variable Domains,” Chapter 31, In Antibody Engineering, (Kontermann and Dübel, eds.) (Springer-Verlag, Berlin, 2001), especially pages 432-433. A useful method of determining the amino acid sequences of Kabat CDRs within the amino acid sequences of variable heavy (VH) and variable light (VL) regions is provided below:

[0185] To identify a CDR-L1 amino acid sequence:

• • [0186] Starts approximately 24 amino acid residues from the amino terminus of the VL region;
  • [0187] Residue before the CDR-L1 sequence is always cysteine (C);
  • [0188] Residue after the CDR-L1 sequence is always a tryptophan (W) residue, typically Trp-Tyr-Gln (W-Y-Q), but also Trp-Leu-Gln (W-L-Q), Trp-Phe-Gln (W-F-Q), and Trp-Tyr-Leu (W-Y-L);
  • [0189] Length is typically 10 to 17 amino acid residues.

[0190] To identify a CDR-L2 amino acid sequence:

• • [0191] Starts always 16 residues after the end of CDR-L1;
  • [0192] Residues before the CDR-L2 sequence are generally Ile-Tyr (1-Y), but also Val-Tyr (V-Y), Ile-Lys (1-K), and Ile-Phe (1-F);
  • [0193] Length is always 7 amino acid residues.

[0194] To identify a CDR-L3 amino acid sequence:

• • [0195] Starts always 33 amino acids after the end of CDR-L2;
  • [0196] Residue before the CDR-L3 amino acid sequence is always a cysteine (C);
  • [0197] Residues after the CDR-L3 sequence are always Phe-Gly-X-Gly (F-G-X-G) (SEQ ID NO:11), where X is any amino acid;
  • [0198] Length is typically 7 to 11 amino acid residues.

[0199] To identify a CDR-H1 amino acid sequence:

• • [0200] Starts approximately 31 amino acid residues from amino terminus of VH region and always 9 residues after a cysteine (C);
  • [0201] Residues before the CDR-H1 sequence are always Cys-X-X-X-X-X-X-X-X (SEQ ID NO:12), where X is any amino acid;
  • [0202] Residue after CDR-H1 sequence is always a Trp (W), typically Trp-Val (W-V), but also Trp-Ile (W-I), and Trp-Ala (W-A);
  • [0203] Length is typically 5 to 7 amino acid residues.

[0204] To identify a CDR-H2 amino acid sequence:

• • [0205] Starts always 15 amino acid residues after the end of CDR-H1;
  • [0206] Residues before CDR-H2 sequence are typically Leu-Glu-Trp-Ile-Gly (L-E-W-I-G) (SEQ ID NO:23), but other variations also;
  • [0207] Residues after CDR-H2 sequence are Lys/Arg-Leu/Ile/Val/Phe/Thr/Ala-Thr/Ser/Ile/Ala (K/R-L/I/V/F/T/A-T/S/I/A);
  • [0208] Length is typically 16 to 19 amino acid residues.

[0209] To identify a CDR-H3 amino acid sequence:

• • [0210] Starts always 33 amino acid residues after the end of CDR-H2 and always 3 after a cysteine (C)′
  • [0211] Residues before the CDR-H3 sequence are always Cys-X-X (C-X-X), where X is any amino acid, typically Cys-Ala-Arg (C-A-R);
  • [0212] Residues after the CDR-H3 sequence are always Trp-Gly-X-Gly (W-G-X-G) (SEQ ID NO:24), where X is any amino acid;
  • [0213] Length is typically 3 to 25 amino acid residues.

[0214] As used herein, the term “canonical” residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al. (J. Mol. Biol., 196: 901-917 (1987)); and Chothia et al. (J. Mol. Biol., 227: 799-817 (1992)), both are incorporated herein by reference). According to Chothia et al., critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.

[0215] An “affinity matured” antibody is an antibody with one or more alterations in one or more CDRs thereof which result in an improvement in the affinity of the antibody for a target antigen, compared to a parent antibody which does not possess the alteration(s). Exemplary affinity matured antibodies will have nanomolar or even picomolar affinities for the target antigen. A variety of procedures for producing affinity matured antibodies are known in the art. For example, Marks et al., BioTechnology, 10: 779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by Barbas et al., Proc. Nat. Acad. Sci. USA, 91: 3809-3813 (1994); Schier et al., Gene, 169: 147-155 (1995); Yelton et al., J. Immunol., 155: 1994-2004 (1995); Jackson et al., J. Immunol., 154(7): 3310-3319 (1995); Hawkins et al., J. Mol. Biol., 226: 889-896 (1992). Selective mutation at selective mutagenesis positions and at contact or hypermutation positions with an activity enhancing amino acid residue is described in U.S. Pat. No. 6,914,128 B1.

[0216] The term “multivalent binding protein” denotes a binding protein comprising two or more antigen binding sites. A multivalent binding protein is preferably engineered to have three or more antigen binding sites, and is generally not a naturally occurring antibody. The term “multispecific binding protein” refers to a binding protein capable of binding two or more related or unrelated targets. “Dual variable domain” (“DVD”) binding proteins of the invention comprise two or more antigen binding sites and are tetravalent or multivalent binding proteins. DVDs may be monospecific, i.e., capable of binding one antigen, or multispecific, i.e., capable of binding two or more antigens. A DVD binding protein comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides is referred to as a “DVD immunoglobulin” or “DVD-Ig”. Each half of a DVD-Ig comprises a heavy chain DVD polypeptide and a light chain DVD polypeptide, and two or more antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of six CDRs involved in antigen binding per antigen binding site.

[0217] A description of the design, expression, and characterization of DVD-Ig molecules is provided in PCT Publication No. WO 2007/024715; U.S. Pat. No. 7,612,181; and Wu et al., Nature Biotechnol., 25: 1290-1297 (2007). A preferred example of such DVD-Ig molecules comprises a heavy chain that comprises the structural formula 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 0 or 1, but preferably 1; and a light chain that comprises the structural formula 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, and X2 does not comprise an Fc region; and n is 0 or 1, but preferably 1. Such a DVD-Ig may comprise two such heavy chains and two such light chains, wherein each chain comprises variable domains linked in tandem without an intervening constant region between variable regions, wherein a heavy chain and a light chain associate to form tandem functional antigen binding sites, and a pair of heavy and light chains may associate with another pair of heavy and light chains to form a tetrameric binding protein with four functional antigen binding sites. In another example, a DVD-Ig molecule may comprise heavy and light chains that each comprise three variable domains (VD1, VD2, VD3) linked in tandem without an intervening constant region between variable domains, wherein a pair of heavy and light chains may associate to form three antigen binding sites, and wherein a pair of heavy and light chains may associate with another pair of heavy and light chains to form a tetrameric binding protein with six antigen binding sites.

[0218] A DVD-Ig binding protein may bind one or more epitopes of IL-1β. A DVD-Ig binding protein may also bind an epitope of IL-1β and an epitope of a second target antigen other than an IL-1β polypeptide.

[0219] The term “bispecific antibody”, as used herein, refers to full-length antibodies that are generated by quadroma technology (see Milstein and Cuello, Nature, 305: 537-540 (1983)), by chemical conjugation of two different monoclonal antibodies (see Staerz et al., Nature, 314: 628-631 (1985)), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (see Holliger et al., Proc. Natl. Acad. Sci. USA, 90(14): 6444-6448 (1993)), resulting in multiple different immunoglobulin species of which only one is the functional bispecific antibody. By molecular function, a bispecific antibody binds one antigen (or epitope) on one of its two binding arms (one pair of HC/LC), and binds a different antigen (or epitope) on its second arm (a different pair of HC/LC). By this definition, a bispecific antibody has two distinct antigen binding arms (in both specificity and CDR sequences), and is monovalent for each antigen it binds.

[0220] The term “dual-specific antibody”, as used herein, refers to full-length antibodies that can bind two different antigens (or epitopes) in each of its two binding arms (a pair of HC/LC) (see PCT Publication No. WO 02/02773). Accordingly a dual-specific binding protein has two identical antigen binding arms, with identical specificity and identical CDR sequences, and is bivalent for each antigen to which it binds.

[0221] A “functional antigen binding site” of a binding protein is one that is capable of binding a target antigen. The antigen binding affinity of the antigen binding site is not necessarily as strong as the parent antibody from which the antigen binding site is derived, but the ability to bind antigen must be measurable using any one of a variety of methods known for evaluating antibody binding to an antigen. Moreover, the antigen binding affinity of each of the antigen binding sites of a multivalent antibody herein need not be quantitatively the same.

[0222] The term “cytokine” is a generic term for proteins that are released by one cell population and that act on another cell population as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones, such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones, such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; a tumor necrosis factor such as tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor-beta (TNF-β); mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-alpha (NGF-α); platelet-growth factor; placental growth factor; transforming growth factors (TGFs) such as TGF-alpha (TGF-α) and TGF-beta (TGF-β); insulin-like growth factor-1 and -11; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-alpha (IFN-α), interferon-beta (IFN-β), and interferon-gamma (IFN-γ); colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-33; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.

[0223] As used herein, the terms “donor” and “donor antibody” refer to an antibody providing one or more CDRs. In an exemplary embodiment, the donor antibody is an antibody from a species different from the antibody from which the framework regions are obtained or derived. In the context of a humanized antibody, the term “donor antibody” refers to a non-human antibody providing one or more CDRs.

[0224] As used herein, the term “framework” or “framework sequence” refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations. The six CDRs (CDR-L1, -L2, and -L3 of light chain and CDR-H1, -H2, and -H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying the particular sub-regions as FR1, FR2, FR3 or FR4, a framework region, as referred by others, represents the combined FR's within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region.

[0225] As used herein, the terms “acceptor” and “acceptor antibody” refer to the antibody providing or nucleic acid sequence encoding at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions. In some embodiments, the term “acceptor” refers to the antibody amino acid providing or nucleic acid sequence encoding the constant region(s). In yet another embodiment, the term “acceptor” refers to the antibody amino acid providing or nucleic acid sequence encoding one or more of the framework regions and the constant region(s). In a specific embodiment, the term “acceptor” refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions. In accordance with this embodiment, an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody. An acceptor framework region and/or acceptor constant region(s) may be, e.g., derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well known in the art, antibodies in development, or antibodies commercially available).

[0226] Human heavy chain and light chain acceptor sequences are known in the art. In one embodiment of the invention,the human heavy chain and light chain acceptor sequences are selected from the sequences listed from V-base (vbase.mrc-cpe.cam.ac.uk/) or from IMGT®, the international ImMunoGeneTics information system® (imgt.cines.fr/itextes/IMGTrepertoire/LocusGenes/). In an embodiment of the invention, the human heavy chain and light chain acceptor sequences are selected from the sequences described in Table 3 and Table 4.

[0227]

TABLE 3
Heavy Chain Acceptor Sequences
SEQ
ID		Sequence
NO:	Protein region	123456789012345678901234567890
7	FR1	EVQLVESGGGVVQPGRSLRLSCSSSGFIFS
8	FR2	WVRQAPGKGLEWVA
9	FR3	RFTISRDNSKNTLFLQMDSLRPEDTGVYFC
		AR
10	FR4	WGQGTPVTVSS
240	VH3-7 FR1	EVQLVESGGGLVQPGGSLRLSCAASGFTFS
241	VH3-7 FR2	WVRQAPGKGLEWVA
242	VH3-7 FR3	RFTISRDNAKNSLYLQMNSLRAEDTAVYYC
		AR
243	JH4 FR4	WGQGTLVTVSS
244	VH3 CONSENSUS	EVQLVESGGGLVQPGGSLRLSCAASGFTFS
	FR1
245	VH3 CONSENSUS	WVRQAPGKGLEWVS
	FR2
246	VH3 CONSENSUS	RFTISRDNSKNTLYLQMNSLRAEDTAVYYC
	FR3	AR
247	JH4 FR4	WGQGTLVTVSS
248	VH1-46 FR1	QVQLVQSGAEVKKPGASVKVSCKASGYTFT
249	VH1-46 FR2	WVRQAPGQGLEWMG
250	VH1-46 FR3	RVTMTRDTSTSTVYMELSSLRSEDTAVYYC
		AR
251	JH4 FR4	WGQGTLVTVSS
252	VH3-30 FR1	QVQLVESGGGVVQPGRSLRLSCAASGFTFS
253	VH3-30 FR2	WVRQAPGKGLEWVA
254	VH3-30 FR3	RFTISRDNSKNTLYLQMNSLRAEDTAVYYC
		AR
255	JH3 FR4	WGQGTMVTVSS
256	VH3 CONSENSUS	EVQLVESGGGLVQPGGSLRLSCAASGFTFS
	FR1
257	VH3 CONSENSUS	WVRQAPGKGLEWVS
	FR2
258	VH3 CONSENSUS	RFTISRDNSKNTLYLQMNSLRAEDTAVYYC
	FR3	AR
259	JH3 FR4	WGQGTMVTVSS
260	VH2-70/JH6 FR1	EVTLRESGPALVKPTQTLTLTCTFSGFSLS
261	VH2-70/JH6 FR2	WIRQPPGKALEWLA
262	VH2-70/JH6 FR3	RLTISKDTSKNQVVLTMTNMDPVDTATYYC
		AR
263	VH2-70/JH6 FR4	WGQGTTVTVSS
264	VH2-26/JH6 FR1	EVTLKESGPVLVKPTETLTLTCTVSGFSLS
265	VH2-26/JH6 FR2	WIRQPPGKALEWLA
266	VH2-26/JH6 FR3	RLTISKDTSKSQVVLTMTNMDPVDTATYYC
		AR
267	VH2-26/JH6 FR4	WGQGTTVTVSS
268	VH3-72/JH6 FR1	EVQLVESGGGLVQPGGSLRLSCAASGFTFS
269	VH3-72/JH6 FR2	WVRQAPGKGLEWVG
270	VH3-72/JH6 FR3	RFTISRDDSKNSLYLQMNSLKTEDTAVYYC
		AR
271	VH3-72/JH6 FR4	WGQGTTVTVSS
272	VH3-21/JH6 FR1	EVQLVESGGGLVKPGGSLRLSCAASGFTFS
273	VH3-21/JH6 FR2	WVRQAPGKGLEWVS
274	VH3-21/JH6 FR3	RFTISRDNAKNSLYLQMNSLRAEDTAVYYC
		AR
275	VH3-21/JH6 FR4	WGQGTTVTVSS
276	VH1-69/JH6 FR1	EVQLVQSGAEVKKPGSSVKVSCKASGGTFS
277	VH1-69/JH6 FR2	WVRQAPGQGLEWMG
278	VH1-69/JH6 FR3	RVTITADKSTSTAYMELSSLRSEDTAVYYC
		AR
279	VH1-69/JH6 FR4	WGQGTTVTVSS
280	VH1-18/JH6 FR1	EVQLVQSGAEVKKPGASVKVSCKASGYTFT
281	VH1-18/JH6 FR2	WVRQAPGQGLEWMG
282	VH1-18/JH6 FR3	RVTMTTDTSTSTAYMELRSLRSDDTAVYYC
		AR
283	VH1-18/JH6 FR4	WGQGTTVTVSS
284	IGHV4-59 FR1	EVQLQESGPGLVKPSETLSLTCTVSGGSIS
285	IGHV4-59 FR2	WIRQPPGKGLEWIG
286	IGHV4-59 FR3	RVTISVDTSKNQFSLKLSSVTAADTAVYYC
		AR
287	IGHV4-59/JH FR4	WGQGTLVTVSS
288	IGHV3-66 FR1	EVQLVESGGGLVQPGGSLRLSCAVSGGSIS
289	IGHV3-66 FR2	WIRQAPGKGLEWIG
290	IGHV3-66 FR3	RVTISVDTSKNSFYLQMNSLRAEDTAVYYC
		AR
291	IGHV3-66/JH FR4	WGQGTLVTVSS
292	IGHV4-59 FR1	EVQLQESGPGLVKPGETLSLTCTVSGGSIS
293	IGHV4-59 FR2	WIRQAPGKGLEWIG
294	IGHV4-59 FR3	RVTISVDTSKNQFYLKLSSVRAEDTAVYYC
		AR
295	IGHV4-59/JH FR4	WGQGTLVTVSS
296	IGHV5-51 FR1	EVQLVQSGTEVKKPGESLKISCKVSGGSIS
297	IGHV5-51 FR2	WIRQMPGKGLEWIG
298	IGHV5-51 FR3	QVTISVDTSFNTFFLQWSSLKASDTAMYYC
		AR
299	IGHV5-51/JH FR4	WGQGTMVTVSS
300	IGHV2-70 FR1	EVTLRESGPALVKPTQTLTLTCTVSGGSIS
301	IGHV2-70 FR2	WIRQPPGKGLEWIG
302	IGHV2-70 FR3	RVTISVDTSKNQFVLTMTNMDPVDTATYYC
		AR
303	IGHV2-70/JH FR4	WGQGTTVTVSS
304	IGHV3-15 FR1	EVQLLESGGGLVKSGGSLRLSCAASGFTFR
305	IGHV3-15 FR2	WVRQAPGKGLEWVA
306	IGHV3-15 FR3	RFTISRDNSKNTLYLQLNSLRAEDTAVYYC
		AK
307	IGHV3-15/JH FR4	WGQGTMVTVSS
308	IGHV3-43 FR1	EVQLVESGGGVVQPGGSLRLSCAASGFTFG
309	IGHV3-43 FR2	WVRQAPGKGLEWVA
310	IGHV3-43 FR3	RFTISRDNSKNTLYLQLNSLRAEDTAVYYC
		AK
311	IGHV3-43/JH FR4	WGQGTMVTVSS
312	VH1-18/JH6 FR4	WGQGTTVTVSS
313	VH7-4.1/JH6 FR1	QVQLVQSGSELKKPGASVKVSCKASGYTFT
314	VH7-4.1/JH6 FR2	WVRQAPGQGLEWMG
315	VH7-4.1/JH6 FR3	RFVFSLDTSVSTAYLQISSLKAEDTAVYYC
		AR
316	VH7-4.1/JH6 FR4	WGQGTTVTVSS

[0228]

TABLE 4
Light Chain Acceptor Sequences
SEQ
ID		Sequence
NO:	Protein region	123456789012345678901234567890
13	FR1	DIQMTQSPSSLSASVGDRVTITC
14	FR2	WYQQTPGKAPKLLIY
15	FR3	GVPSRFSGSGSGTDYTFTISSLQPEDIATY
		YC
16	FR4	FGQGTKLQIT
25	O2 FR1	DIQMTQSPSSLSASVGDRVTITC
317	O2 FR2	WYQQKPGKAPKLLIY
318	O2 FR3	GVPSRFSGSGSGTDFTLTISSLQPEDFATY
		YC
319	JK2 FR4	FGQGTKLEIK
320	L2 FR1	EIVMTQSPATLSVSPGERATLSC
321	L2 FR2	WYQQKPGQAPRLLIY
322	L2 FR3	GIPARFSGSGSGTEFTLTISSLQSEDFAVY
		YC
323	JK2 FR4	FGQGTKLEIK
324	B3/JK4 FR1	DIVMTQSPDSLAVSLGERATINC
325	B3/JK4 FR2	WYQQKPGQPPKLLIY
326	B3/JK4 FR3	GVPDRFSGSGSGTDFTLTISSLQAEDVAVY
		YC
327	B3/JK4 FR4	FGGGTKVEIKR
328	L2/JK4 FR1	EIVMTQSPATLSVSPGERATLSC
329	L2/JK4 FR2	WYQQKPGQAPRLLIY
330	L2/JK4 FR3	GIPARFSGSGSGTEFTLTISSLQSEDFAVY
		YC
331	L2/JK4 FR4	FGGGTKVEIKR
332	L15/JK4 FR1	DIQMTQSPSSLSASVGDRVTITC
333	L15/JK4 FR2	WYQQKPEKAPKSLIY
334	L15/JK4 FR3	GVPSRFSGSGSGTDFTLTISSLQPEDFATY
		YC
335	L15/JK4 FR4	FGGGTKVEIKR
336	L5/JK4 FR1	DIQMTQSPSSVSASVGDRVTITC
337	L5/JK4 FR2	WYQQKPGKAPKLLIY
338	L5/JK4 FR3	GVPSRFSGSGSGTDFTLTISSLQPEDFATY
		YC
339	L5/JK4 FR4	FGGGTKVEIKR
340	IGLV3-1 FR1	SYELTQPPSVSVSPGQTASITC
341	IGLV3-1 FR2	WYQQKPGQSPVLVIY
342	IGLV3-1 FR3	GIPERFSGSNSGDTATLTISGTQPMDEADY
		YC
343	IGLV3-1/JL FR4	FGYGTKVTVL
344	IGLV3-1 FR1	SYELTQPPSVSVSPGQTASITC
345	IGLV3-1 FR2	WYQQKPGQSPVLVIY
346	IGLV3-1 FR3	GIPERFSGSNSGDTATLTISGTQPMDEADY
		YC
347	IGLV3-1/JL FR4	GGGTKLTVLG
348	IGLV3-1 FR1	YELTQPPSVSVSPGQTASITC
349	IGLV3-1 FR2	WYQQKPGQSPVLVIY
350	IGLV3-1 FR3	GIPERFSGSNSGDTATLTISGTQPMDEADY
		YC
351	IGLV3-1/JL FR4	GGGTKLTVLG
352	IGLV3-1 FR1	LYVLTQPPSVSVSPGQTASITC
353	IGLV3-1 FR2	WYQQKPGQSPVLVIY
354	IGLV3-1 FR3	GIPERFSGSNSGDTATLTISGTQTMDEADY
		LC
355	IGLV3-1/JL FR4	FGGGTKVTVLG
356	IGKV6D-21 FR1	EYVLTQSPDFQSVTPKEKVTITC
357	IGKV6D-21 FR2	WYQQKPDQSPKLVIY
358	IGKV6D-21 FR3	GVPSRFSGSNSGDDATLTINSLEAEDAATY
		YC
359	IGKV6D-21/JK FR4	FGQGTKVEIKR
360	IGKV3D-15 FR1	EYVLTQSPATLSVSPGERATLSC
361	IGKV3D-15 FR2	WYQQKPGQSPRLVIY
362	IGKV3D-15 FR3	DIPARFSGSNSGDEATLTISSLQSEDFAVY
		YC
363	IGKV3D-15/JK FR4	FGQGTRLEIKR
364	IGKV4-1 FR1	DYVLTQSPDSLAVSLGERATINC
365	IGKV4-1 FR2	WYQQKPGQSPKLVIY
366	IGKV4-1 FR3	GIPDRFSGSNSGDDATLTISSLQAEDVAVY
		YC
367	IGKV4-1/JK FR4	FGGGTKVEIKR
368	IGLV3-1 FR1	LPVLTQPPSVSVSPGQTASITC
369	IGLV3-1 FR2	WYQQKPGQSPVLVIY
370	IGLV3-1 FR3	GIPERFSGSNSGNTATLTISGTQTMDEADY
		LC
371	IGLV3-1/JL FR4	FGGGTKVTVL
372	IGLV3-1 FR1	SYELTQPPSVSVSPGQTASITC
373	IGLV3-1 FR2	WYQQKPGQSPVLVIY
374	IGLV3-1 FR3	GIPERFSGSNSGNTATLTISGTQTMDEADY
		LC
375	IGLV3-1/JL FR4	FGGGTKLTVL
376	1-33/018/JK2 FR1	DIQMTQSPSSLSASVGDRVTITC
377	1-33/018/JK2 FR2	WYQQKPGKAPKLLIY
378	1-33/018/JK2	GVPSRFSGSGSGTDFTFTISSLQPEDIATY
	FR3	YC
379	1-33/018/JK2	FGQGTKLEIKR
	FR4
380	1-33/018/JK4	FGGGTKVEIKR
	FR4