St2 antigen binding proteins

Abstract

To provide ST2 antigen binding proteins.SOLUTION: Described herein compositions and methods related to antigen binding proteins that bind to human ST2, including antibodies. In particular embodiments, the disclosure provides fully human anti-ST2 antibodies, derivatives and variants thereof. Further provided are nucleic acids encoding such antibodies and antibody fragments, variants and derivatives. Also provided are methods for preparing and using such antibodies including methods for treating and preventing autoimmune disease and inflammatory disorders.SELECTED DRAWING: Figure 8

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61 / 792,619, filed March 15, 2013, and U.S. Provisional Patent Application No. 61 / 649,147, filed May 18, 2012, which are hereby incorporated by reference in their entireties.

[0002] Sequence Listing Reference This application is filed in electronic format via EFS-Web with a Sequence Listing. The Sequence Listing is provided as a text file entitled A1712WOPCT_ST25.txt, created on May 17, 2013, and sized at 189,804 bytes. The information contained in the electronic Sequence Listing is incorporated herein by reference in its entirety. [Background technology]

[0003] ST2 is the binding receptor for interleukin-33 (IL-33), also known as NF-HEV or IL-1F11, a cytokine related to IL-1 and IL-18. ST2 is expressed both as a soluble, non-signaling variant (soluble ST2 or ST2) and as a full-length transmembrane form (FL ST2, ST2, or ST2L) that mediates cellular responses to IL-33. The latter form is expressed in a wide range of cell types involved in pathological inflammation in a number of disease situations. These include lymphocytes, in particular T helper cells, natural killer (NK) and natural killer T (NKT) cells that express IL-5 and IL-13, as well as many so-called innate immune cells, such as mast cells, basophils, eosinophils, macrophages, and innate helper cells (also known as nuocytes (Neill, Wong et al. 2010)). IL-33 binding to ST2 on these cells leads to recruitment of a widely expressed co-receptor known as IL-1R accessory protein (AcP) and activation of proinflammatory signaling similar to IL-1 and IL-18. IL-33 can thus directly activate cells expressing ST2 or enhance their activation in the presence of other activating stimuli. Examples of cellular responses induced by IL-33 include the production of inflammatory cytokines such as IL-5, IL-6, IL-13, TNF, IFN-γ, and GM-CSF, as well as the production of chemokines such as CXCL8, CCL17, and CCL24. IL-33 has also been shown to enhance acute allergic responses by increasing mast cell and basophil activation caused by IgE receptor signaling or other mast cell and basophil activating factors. IL-33 also enhances the recruitment, survival, and adhesiveness of ST2-expressing immune cells, and is therefore important in inducing and sustaining cellular inflammation in local tissues.

[0004] The proinflammatory effects of IL-33 on innate and adaptive immune cells ultimately promote many pathological processes. In the lung, these include increased airway inflammation, mucus production, airway hyperresponsiveness, and fibrotic remodeling. IL-33 may also contribute to local inflammation in the joints, as well as skin and joint hypernociception, by promoting the production of proinflammatory cytokines ( Verri, Guerrero et al. 2008 ; Xu, Jiang et al. 2008 ). Excess IL-33 has been associated with pathological collagen deposition and fibrosis, and also contributes to epithelial damage in the setting of inflammatory bowel disease. Through its potent actions on basophils and IgE-sensitized mast cells, IL-33 may also induce anaphylactic shock ( Pushparaj, Tay et al. 2009 ), may play a causative role in allergic diseases. Many of these diseases are chronic and progressive in nature and difficult to treat, so there is a need for more effective treatments.

[0005] Consistent with its identified biological effects, there are several lines of evidence that the IL-33 / ST2 pathway contributes to human disease. For example, abnormally high expression of IL-33 is found in diseases involving inflammation of mucosal tissues and joint inflammation. These include asthma ( Prefontaine, Lajoie-Kadoch et al. 2009 ; Prefontaine, Nadigel et al. 2010 ), inflammatory bowel disease ( Beltran, Nunez et al. 2010 ; Pastorelli, Garg et al. 2010 ; Sponheim, Pollheimer et al. 2010 ), and rheumatoid arthritis ( Palmer, Talabot-Ayer et al. 2009 ; Matsuyama, Okazaki et al. 2010 IL-33 expression is associated with psoriatic skin ( Theoharides, Zhang et al. 2010 ) and the skin of patients with atopic dermatitis ( Pushparaj, Tay et al. 2009 ) and in systemic sclerosis ( Yanaba, Yoshizaki et al. 2011 )( Manetti, Ibba-Manneschi et al. 2009 ) and liver fibrosis ( Marvie, Lisbonne et al. 2009 Circulating levels of soluble ST2 are also elevated in a number of disease states, further implicating this cytokine pathway in these diseases. Examples include asthma ( Kuroiwa, Arai et al. 2001 ; Oshikawa, Kuroiwa et al. 2001 ; Ali, Zhang et al. 2009 ), chronic obstructive pulmonary disease (Hacker, Lambers et al. 2009 ), pulmonary fibrosis ( Tajima, Oshikawa et al. 2003 ), sepsis and trauma ( Brunner, Krenn et al. 2004 ), HIV infection ( Miyagaki, Sugaya et al. 2011 ), systemic lupus erythematosus ( Mok, Huang et al.2010 ), inflammatory bowel disease ( Beltran, Nunez et al. 2010 ), as well as rheumatoid arthritis, sclerosis, Wegener's granulomatosis and Behçet's disease ( Kuroiwa, Arai et al. 2001 ), and cardiovascular disease ( Shah and Januzzi 2010 IL-33 enhances eosinophilic inflammation, and this pathway is thought to be involved in rhinosinusitis and nasal polyposis ( Plager, Kahl et al. 2010 ), and eosinophilic bronchitis ( Oshikawa, Kuroiwa et al. 2001 There is evidence that eosinophils are involved in eosinophil-related diseases such as

[0006] Further evidence linking the IL-33 / ST2 pathway to human disease has been provided by genetic studies, which have identified genetic polymorphisms in IL-33 and / or ST2 in the general population that are significantly associated with increased disease risk or parameters of disease severity. Several large genome-wide association studies have linked genetic variations in ST2 (IL1RL1) or IL-33 with increased risk of asthma ( Gudbjartsson, Bjornsdottir et al. 2009 ; Moffatt, Gut et al. 2010 ; Wu, Romieu et al. 2010 ), and other studies have linked this pathway to increased asthma severity ( Ali, Zhang et al. 2009 ) and bronchial hyperresponsiveness ( Reijmerink, Postma et al. 2008 ) genetic association. Similar findings have been reported in the study of atopic dermatitis ( Shimizu, Matsuda et al. 2005 ), rhinosinusitis ( Sakashita, Yoshimoto et al. 2008 ; Castano R 2009 ), and nasal polyposis ( Buysschaert, Grulois et al. 2010 have implicated this pathway in allergic diseases such as rheumatoid arthritis, bronchitis, and bronchitis. Taken together, the association with several human diseases and the ability of this cytokine system to promote many forms of harmful inflammation mean that it is a useful target for therapeutic intervention. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Neill, DR, SH Wong, et al. (2010). “Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.” Nature 464(7293): 1367-1370 [Non-Patent Document 2] Verri, WA, Jr., AT Guerrero, et al. (2008). “IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice.” Proc Natl Acad Sci USA 105(7): 2723-2728 Summary of the Invention [Means for solving the problem]

[0008] The present invention provides anti-ST2 antigen binding proteins, e.g., antibodies and functional fragments thereof, with properties suitable for commercial production and therapeutic use in humans. The anti-ST2 antigen binding proteins are particularly useful in methods for treating diseases and disorders associated with the IL-33 / ST2 system. Provided herein are ST2-binding antibodies that bind to ST2 with high affinity and effectively block the binding of IL-33, thereby reducing IL-33-mediated signal transduction in cells.

[0009] In a first embodiment, the ST2 antigen binding protein comprises a) a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164 or SEQ ID NO:165; b) a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146 or SEQ ID NO:147, or c) the light chain variable domain of a) and the heavy chain variable domain of b).

[0010] Preferred antigen binding proteins of the first aspect are those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 95 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 29; a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 96 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 30. a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO:97; a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO:31; a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO:98. those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 99 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 33; those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 100 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 34; those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 101 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 35;those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 102 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 36; those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 103 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 37; those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 104 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 38; those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 163 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 145; those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 164 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 146; and those comprising a light chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 165 and a heavy chain variable domain that has at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 147. ;

[0011] In a second embodiment, the ST2 antigen binding protein comprises a) a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165; b) a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; or c) the light chain variable domain of a) and the heavy chain variable domain of b).

[0012] Preferred antigen binding proteins of the second aspect include those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 95 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 29; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 96 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 30; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 97 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 31; those comprising a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:32; those comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:99 and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:33; those comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:100 and a light chain variable domain and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:34; those comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:101 and a light chain variable domain and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO:35;comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 102 and a light chain variable domain and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 36; comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 103 and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 37; comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 104 and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 38; those comprising a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 39; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 163 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 145; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 164 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 146; and those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 165 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 147.

[0013] In a third embodiment, the ST2 antigen binding protein comprises a) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 128; b) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129; c) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 108; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 130. d) an LCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR3 sequence set forth in SEQ ID NO: 131; e) an LCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR1 sequence set forth in SEQ ID NO: 110. and LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 132; f) LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 111; LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 122;and an LCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR3 sequence set forth in SEQ ID NO: 133; g) an LCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR3 sequence set forth in SEQ ID NO: 134; h) an LCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR1 sequence set forth in SEQ ID NO: 113. an LCDR1 having the following amino acid additions, deletions, or substitutions: an LCDR2 having three or fewer amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 124; and an LCDR3 having three or fewer amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 135; i) an LCDR1 having three or fewer amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 having three or fewer amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 having an addition, deletion or substitution of 3 or less amino acids from the LCDR3 sequence set forth in SEQ ID NO: 136; j) an LCDR1 having an addition, deletion or substitution of 3 or less amino acids from the LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 having an addition, deletion or substitution of 3 or less amino acids from the LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 having an addition, deletion or substitution of 3 or less amino acids from the LCDR3 sequence set forth in SEQ ID NO: 137; k) an LCDR1 having an addition, deletion or substitution of 3 or less amino acids from the LCDR1 sequence set forth in SEQ ID NO: 116. LCDR1 having the following amino acid additions, deletions, or substitutions: LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 127; and LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 138; l) LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 166; LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 169;and an LCDR3 having an addition, deletion or substitution of 3 or less amino acids from the LCDR3 sequence set forth in SEQ ID NO: 172; m) an LCDR1 having an addition, deletion or substitution of 3 or less amino acids from the LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 having an addition, deletion or substitution of 3 or less amino acids from the LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 having an addition, deletion or substitution of 3 or less amino acids from the LCDR3 sequence set forth in SEQ ID NO: 173; or n) an LCDR1 having an addition, deletion or substitution of 3 or less amino acids from the LCDR1 sequence set forth in SEQ ID NO: 168. a light chain variable domain comprising: an LCDR1 having an addition, deletion or substitution of no more than 1 amino acid; an LCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR3 sequence set forth in SEQ ID NO: 174; and o) an HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 40; an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 51, and HCDR3 having an addition, deletion or substitution of up to 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 62; p) HCDR1 having an addition, deletion or substitution of up to 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 41; HCDR2 having an addition, deletion or substitution of up to 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 52; and HCDR3 having an addition, deletion or substitution of up to 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 63; q) HCDR1 sequence set forth in SEQ ID NO: 42 HCDR1 having no more than three amino acid additions, deletions or substitutions from the sequence set forth in SEQ ID NO: 53; HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 53; and HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 64; r) HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 43; HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 54;and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 65;s) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 44; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 55; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 66;t) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 45; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 56; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 67;u) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 46; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 57; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 68; v) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 47; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 58; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 69; w) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 48; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 59; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 70; x) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 49; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 60;and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 71; y) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 50; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 61; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 72; z) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 148; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 151; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 154, or a substitution; aa) an HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 149; an HCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 152; and an HCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 155; or bb) an HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 150; an HCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 153; and an HCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 156.

[0014] Preferred ST2 antigen binding proteins of the third aspect are those comprising a) a light chain variable domain and o) a heavy chain variable domain; those comprising b) a light chain variable domain and p) a heavy chain variable domain; those comprising c) a light chain variable domain and q) a heavy chain variable domain; those comprising d) a light chain variable domain and r) a light chain variable domain; those comprising e) a light chain variable domain and s) a heavy chain variable domain; those comprising f) a light chain variable domain and t) a heavy chain variable domain; those comprising g) a light chain variable domain and u) a heavy chain variable domain. those comprising the light chain variable domain of i) and the heavy chain variable domain of w); those comprising the light chain variable domain of j) and the heavy chain variable domain of x); those comprising the light chain variable domain of k) and the heavy chain variable domain of y); those comprising the light chain variable domain of l) and the heavy chain variable domain of z); those comprising the light chain variable domain of m) and the heavy chain variable domain of aa); and those comprising the light chain variable domain of n) and the heavy chain variable domain of bb).

[0015] In a fourth aspect of the invention, the ST2 antigen binding protein of the first, second or third aspect is administered at a concentration of 1×10 -10 It binds to human ST2 with an affinity of less than or equal to M.

[0016] In a fifth aspect of the invention, the ST2 antigen binding protein of the first, second, third or fourth aspect inhibits binding of human ST2 to human IL-33.

[0017] In a sixth aspect of the invention, the ST2 antigen binding protein of the first, second, third, fourth or fifth aspect reduces ST2 signalling mediated by human IL-33 in cells expressing human ST2.

[0018] In a seventh aspect of the invention, the ST2 antigen binding protein of the sixth aspect reduces cynomolgus ST2 signalling mediated by IL-33 in cells expressing cynomolgus ST2.

[0019] In an eighth aspect of the invention, the ST2 antigen-binding protein of the first, second, third, fourth, fifth, sixth or seventh aspect is an antibody, such as a human antibody. Preferred antibodies are an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 84 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 18, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 19, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 86 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 20; an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 87 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 21; an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 88 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 22; an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 89 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 23, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 90 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 24, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 91 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 92, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 93 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 94, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 95 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 96, These include an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 91 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 25, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 92 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 26, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 93 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 27, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 94 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 28, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 160 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 142, an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 161 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 143, and an antibody comprising a light chain having the amino acid sequence set forth in SEQ ID NO: 162 and a heavy chain having the amino acid sequence set forth in SEQ ID NO: 144.

[0020] In a ninth aspect, the present invention provides an isolated nucleic acid encoding one or more polypeptide components of an ST2 antigen binding protein, such as an antibody light chain or an antibody heavy chain.

[0021] a) a light chain variable domain having at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 163, SEQ ID NO: 164, or SEQ ID NO: 165;

[0022] b) a heavy chain variable domain having at least 95% identity to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147;

[0023] c) a light chain variable domain having 5 or fewer amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165;

[0024] d) a heavy chain variable domain having five or fewer amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147;

[0025] e) a light chain variable domain;

[0026] i) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 128;

[0027] ii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129;

[0028] iii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 108; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 130;

[0029] iv) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 131;

[0030] v) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 110; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 121; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 132;

[0031] vi) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 111; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 122; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 133;

[0032] vii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 134;

[0033] viii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 113; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 124; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 135;

[0034] ix) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 136;

[0035] x) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 137;

[0036] xi) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 116; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 127; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 138;

[0037] xii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 166; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 169; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 172;

[0038] xiii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 173; or

[0039] xiv) a light chain variable domain comprising an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 168; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 174; or

[0040] f) a heavy chain variable domain,

[0041] i) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 40; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 51; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 62;

[0042] ii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 63;

[0043] iii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 42; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 53; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 64;

[0044] iv) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 43; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 54; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 65;

[0045] v) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 44; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 55; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 66;

[0046] vi) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 45; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 56; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 67;

[0047] vii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 46; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 57; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 68;

[0048] viii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 47; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 58; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 69;

[0049] ix) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 48; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 59; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 70;

[0050] x) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 49; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 60; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 71;

[0051] xi) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO:50; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO:61; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO:72;

[0052] xii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 148; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 151; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 154;

[0053] xiii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 149; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 152; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 155; or

[0054] xiv) encoding a polypeptide comprising a heavy chain variable domain comprising an HCDR1 with no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 150; an HCDR2 with no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 153; and an HCDR3 with no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 156.

[0055] In certain embodiments of the ninth aspect, the polypeptide encodes an antibody light chain and is at least 80%, at least 90%, at least 95%, or 100% identical to the nucleotide sequence set forth in SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:157, SEQ ID NO:158, or SEQ ID NO:159. In other embodiments of the ninth aspect, the polypeptide encodes an antibody heavy chain and is at least 80%, at least 90%, at least 95%, or 100% identical to the nucleotide sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:139, SEQ ID NO:140, or SEQ ID NO:141.

[0056] In a tenth aspect, the invention provides an expression vector comprising one or more isolated nucleic acids of the eighth aspect. In certain embodiments, the expression vector encodes an antibody light chain, an antibody heavy chain, or both an antibody light chain and an antibody heavy chain.

[0057] In an eleventh aspect, the present invention provides a recombinant host cell comprising one or more isolated nucleic acids of the ninth aspect operably linked to a promoter, including a recombinant host cell comprising one or more expression vectors of the tenth aspect of the invention. In a preferred embodiment, the recombinant host cell secretes an antibody that binds to ST2. Preferred host cells are mammalian host cells, including CHO cell lines.

[0058] In a twelfth aspect, the present invention provides a method of treating an autoimmune or inflammatory disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of an ST2 antigen binding protein of any one of the first, second, third, fourth, fifth, sixth, seventh or eighth aspects. In a preferred embodiment, the ST2 antigen binding protein is an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 95 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 29 (e.g., Ab1), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 96 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 30 (e.g., Ab2), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 97 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 31 (e.g., Ab3), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 98 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 32 (e.g., Ab4), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 99 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 33 (e.g., Ab5), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 100 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 34 (e.g., Ab6), for example, Ab6), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 101 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 35 (for example, Ab7), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 102 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 36 (for example, Ab8), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 103 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 37 (for example, Ab9), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 38 (for example, Ab10), an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 105 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 39 (for example, Ab11); an antibody comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 163 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 145 (for example, Ab30);an antibody (e.g., Ab32) comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 164 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 146; or an antibody (e.g., Ab33) comprising the amino acid sequence of the light chain variable domain set forth in SEQ ID NO: 165 and the amino acid sequence of the heavy chain variable domain set forth in SEQ ID NO: 147. In a preferred embodiment, the ST2 antigen binding protein inhibits the binding of IL-33 to ST2. In a particularly preferred embodiment, the autoimmune or inflammatory disease is asthma, inflammatory bowel disease, rheumatoid arthritis, psoriasis, atopic dermatitis, fibrosis, chronic obstructive pulmonary disease, systemic lupus erythematosus, sclerosis, Wegener's granulomatosis, Behcet's disease, sinusitis, nasal polyposis, eosinophilic bronchitis, and cardiovascular disease;

[0059] In a thirteenth aspect, the invention provides a method of producing the ST2 antigen binding protein of any one of the first, second, third, fourth, fifth, sixth, sixth, seventh or eighth aspects by culturing a recombinant host cell of the eleventh aspect and isolating the ST2 antigen binding protein from the culture.

[0060] In a fourteenth aspect, the present invention provides an ST2 antigen binding protein of any one of the first, second, third, fourth, fifth, sixth, seventh, or eighth aspects that cross-competes with an antibody selected from the group consisting of:

[0061] a) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 84 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18;

[0062] b) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19;

[0063] c) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 86 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 20;

[0064] d) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 87 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 21;

[0065] e) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 88 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 22;

[0066] f) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 89 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 23;

[0067] g) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 90 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24;

[0068] h) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 91 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 25;

[0069] i) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 92 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 26;

[0070] j) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 93 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 27;

[0071] k) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 94 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 28;

[0072] l) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 142;

[0073] m) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 161 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 143; and

[0074] n) An antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 162 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 144.

[0075] In a fifteenth aspect, the present invention provides an isolated ST2 antigen-binding protein, preferably an antibody or antigen-binding fragment thereof, that binds to a polypeptide comprising human ST2 domain 1 and domain 2 (SEQ ID NO: 175), wherein binding is significantly inhibited when a single mutation is introduced into human ST2 domain 1 or domain 2 of the polypeptide, the single mutation being selected from the group consisting of L14R, I15R, S33R, E43R, V47R, A62R, G65R, T79R, D92R, D97R, V104R, G138R, N152R, and V176R. By "significantly inhibited" it is meant that the difference measured in binding is statistically significant. In a preferred embodiment, binding is significantly inhibited for two or more members of the group, including all members of the group. In certain embodiments of the fifteenth aspect, binding is also significantly activated when a single mutation is introduced into human ST2 domain 1 or domain 2 of the polypeptide, the single mutation being selected from the group consisting of L53R, R72A, and S73R. By "significantly activated" it is meant that the difference measured in binding is statistically significant. In preferred embodiments, binding is significantly activated for all members of the group. In certain embodiments of the fifteenth aspect, the ST2 binding protein cross-competes with an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO:85 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:19 for binding to human ST2. In particularly preferred embodiments, the antigen binding protein is an antigen binding protein of the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect.

[0076] In a sixteenth aspect, the present invention provides an antigen binding protein of the first, second, third, fourth, fifth, sixth, seventh, eighth, fourteenth or fifteenth aspect, wherein the ST2 binding protein, preferably an antibody or antigen binding fragment thereof, binds to a portion of ST2 comprising amino acids 33-44 and / or 88-94 of SEQ ID NO:1, as determined by hydrogen / deuterium exchange analysis.

[0077] In a seventeenth aspect, the present invention provides an antigen binding protein, preferably an antibody or antigen binding fragment thereof, of the first, second, third, fourth, fifth, sixth, seventh, eighth, fourteenth, fifteenth or sixteenth aspect, which binds to ST2 to form an interface, wherein the interface formed by said binding comprises ST2 residues selected from the group consisting of K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79 and Y81. In a preferred embodiment of the seventeenth aspect, the interface formed by the bond comprises ST2 residues P19, R20, Q21, G22, K23, and / or Y26, ST2 residues I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and / or Y81, or ST2 residues P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81. The interface may be determined by the difference in solvent exposure between bound and unbound ST2, with interface residues defined as amino acids that have a difference of more than 10% and that form water-mediated hydrogen bonds with the antibody or that have at least one atom within 5 Å of the antibody.

[0078] In an eighteenth aspect, the present invention relates to a) a light chain variable domain having at least 90% or at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 96, b) a heavy chain variable domain having at least 90% or at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 30; c) the light chain variable domain of a) and the heavy chain variable domain of b), d) a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 96; e) a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 30; f) the light chain variable domain of d) and the heavy chain variable domain of e), g) an LCDR1 with no more than 3 amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107. and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 129; h) a heavy chain variable domain comprising an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 63; or i) an isolated ST2 antigen-binding protein, preferably an antibody or antigen-binding fragment thereof, comprising the light chain variable domain of g) and the heavy chain variable domain of h).

[0079] In a preferred embodiment of the eighteenth aspect, the light chain variable region comprises D28 or a conservative substitution thereof, I29 or a conservative substitution thereof, S30 or a conservative substitution thereof, N31 or a conservative substitution thereof, Y32 or a conservative substitution thereof, Y49 or a conservative substitution thereof, D50 or a conservative substitution thereof, N53 or a conservative substitution thereof, E55 or a conservative substitution thereof, T56 or a conservative substitution thereof, D91 or a conservative substitution thereof, D92 or a conservative substitution thereof, N93 or a conservative substitution thereof, F94 or a conservative substitution thereof, or L96 or a conservative substitution thereof. In other preferred embodiments, the light chain variable region comprises D28 or a conservative substitution thereof, N31 or a conservative substitution thereof, D50 or a conservative substitution thereof, N53 or a conservative substitution thereof, E55 or a conservative substitution thereof, D91 or a conservative substitution thereof, and D92 or a conservative substitution thereof. In yet other preferred embodiments, the light chain variable region comprises D28, N31, D50, N53, E55, D91, and D92.

[0080] An eighteenth embodiment also includes an ST2 binding protein, preferably an antibody or antigen-binding fragment thereof, wherein the heavy chain variable region comprises W33 or a conservative substitution thereof, I50 or a conservative substitution thereof, D57 or a conservative substitution thereof, R59 or a conservative substitution thereof, H99 or a conservative substitution thereof, G100 or a conservative substitution thereof, T101 or a conservative substitution thereof, S102 or a conservative substitution thereof, S103 or a conservative substitution thereof, D104 or a conservative substitution thereof, Y105 or a conservative substitution thereof, or Y106 or a conservative substitution thereof; the heavy chain variable region comprises S102 or a conservative substitution thereof, S103 or a conservative substitution thereof, D104 or a conservative substitution thereof, and Y105 or a conservative substitution thereof; the heavy chain variable region comprises S102, S103, D104, and Y105.

[0081] In certain embodiments of the eighteenth aspect, the ST2 antigen binding protein is at least 1×10 -10The antibody specifically binds to human ST2 with an affinity of M or less, inhibits the binding of human ST2 to human IL-33, reduces ST2 signaling mediated by human IL-33 in cells expressing human ST2, inhibits the binding of cynomolgus ST2 to cynomolgus IL-33, reduces cynomolgus ST2 signaling mediated by IL-33 in cells expressing cynomolgus ST2, and / or is a human antibody. In a preferred embodiment of the present invention, for example, the following items are provided: (Item 1) a) a light chain variable domain having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165; b) a heavy chain variable domain having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; or c) An isolated ST2 antigen-binding protein comprising the light chain variable domain of a) and the heavy chain variable domain of b). (Item 2) 2. The ST2 antigen-binding protein according to item 1, wherein the light chain variable domain has at least 95% identity to an amino acid sequence set forth in SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 163, SEQ ID NO: 164, or SEQ ID NO: 165. (Item 3) 3. The ST2 antigen-binding protein according to item 1 or 2, wherein the heavy chain variable domain has at least 95% identity to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147. (Item 4) a) a light chain variable domain having no more than 10 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165; b) a heavy chain variable domain having 10 or fewer amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; or c) An isolated ST2 antigen-binding protein comprising the light chain variable domain of a) and the heavy chain variable domain of b). (Item 5) 5. The ST2 antigen binding protein according to item 4, wherein the light chain variable domain has an addition, deletion or substitution of 5 or fewer amino acids from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165. (Item 6) 6. The ST2 antigen-binding protein according to item 4 or 5, wherein the heavy chain variable domain has an addition, deletion or substitution of no more than 5 amino acids from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147. (Item 7) 7. The ST2 antigen-binding protein according to any one of items 1 to 6, wherein the light chain variable domain comprises the amino acid sequence set forth in SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 163, SEQ ID NO: 164, or SEQ ID NO: 165. (Item 8) 8. The ST2 antigen-binding protein according to any one of items 1 to 7, wherein the heavy chain variable domain comprises the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147. (Item 9) a) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 128; b) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129; c) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 108; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 130; d) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 131; e) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 110; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 121; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 132; f) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 111; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 122; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 133; g) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 134; h) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 113; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 124; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 135; i) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 136; j) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 137; k) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 116; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 127; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 138; l) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 166; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 169; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 172; m) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 173; or n) a light chain variable domain comprising: an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 168; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 174; And o) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 40; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 51; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 62; p) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 63; q) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 42; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 53; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 64; r) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 43; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 54; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 65; s) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 44; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 55; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 66; t) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 45; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 56; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 67; u) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 46; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 57; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 68; v) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 47; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 58; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 69; w) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 48; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 59; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 70; x) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 49; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 60; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 71; or y) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 50; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 61; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 72; z) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 148; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 151; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 154; aa) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 149; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 152; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 155; or bb) An isolated ST2 antigen binding protein comprising a heavy chain variable domain comprising: HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 150; HCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 153; and HCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 156. (Item 10) 10. The ST2 antigen-binding protein of item 9, comprising the light chain variable domain of a) and the heavy chain variable domain of o). (Item 11) 11. The ST2 antigen binding protein of claim 10, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 sequence set forth in SEQ ID NO: 128; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 40; an HCDR2 sequence set forth in SEQ ID NO: 51; and an HCDR3 sequence set forth in SEQ ID NO: 62. (Item 12) 10. The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of b) and the heavy chain variable domain of p). (Item 13) 13. The ST2 antigen binding protein of item 12, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 sequence set forth in SEQ ID NO: 129; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 sequence set forth in SEQ ID NO: 63. (Item 14) 10. The ST2 antigen-binding protein of item 9, comprising the light chain variable domain of c) and the heavy chain variable domain of q). (Item 15) 15. The ST2 antigen binding protein of item 14, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 108; an LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 sequence set forth in SEQ ID NO: 130; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 42; an HCDR2 sequence set forth in SEQ ID NO: 53; and an HCDR3 sequence set forth in SEQ ID NO: 64. (Item 16) 10. The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of d) and the heavy chain variable domain of r). (Item 17) 17. The ST2 antigen binding protein of item 16, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 sequence set forth in SEQ ID NO: 131; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 43; an HCDR2 sequence set forth in SEQ ID NO: 54; and an HCDR3 sequence set forth in SEQ ID NO: 65. (Item 18) 10. The ST2 antigen-binding protein according to claim 9, comprising a light chain variable domain according to e) and a heavy chain variable domain according to s). (Item 19) 19. The ST2 antigen binding protein of item 18, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 110; an LCDR2 sequence set forth in SEQ ID NO: 121; and an LCDR3 sequence set forth in SEQ ID NO: 132; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 44; an HCDR2 sequence set forth in SEQ ID NO: 55; and an HCDR3 sequence set forth in SEQ ID NO: 66. (Item 20) 10. The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of f) and the heavy chain variable domain of t). (Item 21) 21. The ST2 antigen binding protein of item 20, wherein the light chain variable domain comprises an LCDR1 as set forth in SEQ ID NO: 111; an LCDR2 sequence as set forth in SEQ ID NO: 122; and an LCDR3 sequence as set forth in SEQ ID NO: 133; and the heavy chain variable domain comprises an HCDR1 as set forth in SEQ ID NO: 45; an HCDR2 sequence as set forth in SEQ ID NO: 56; and an HCDR3 sequence as set forth in SEQ ID NO: 67. (Item 22) 10. The ST2 antigen-binding protein of item 9, comprising the light chain variable domain of g) and the heavy chain variable domain of u). (Item 23) 23. The ST2 antigen binding protein of claim 22, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 sequence set forth in SEQ ID NO: 134; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 46; an HCDR2 sequence set forth in SEQ ID NO: 57; and an HCDR3 sequence set forth in SEQ ID NO: 68. (Item 24) The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of h) and the heavy chain variable domain of v). (Item 25) 25. The ST2 antigen binding protein of item 24, wherein the light chain variable domain comprises an LCDR1 as set forth in SEQ ID NO: 113; an LCDR2 sequence as set forth in SEQ ID NO: 124; and an LCDR3 sequence as set forth in SEQ ID NO: 135; and the heavy chain variable domain comprises an HCDR1 as set forth in SEQ ID NO: 47; an HCDR2 sequence as set forth in SEQ ID NO: 58; and an HCDR3 sequence as set forth in SEQ ID NO: 69. (Item 26) 10. The ST2 antigen-binding protein of item 9, comprising the light chain variable domain of i) and the heavy chain variable domain of w). (Item 27) 27. The ST2 antigen binding protein of claim 26, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 sequence set forth in SEQ ID NO: 136; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 48; an HCDR2 sequence set forth in SEQ ID NO: 59; and an HCDR3 sequence set forth in SEQ ID NO: 70. (Item 28) The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of j) and the heavy chain variable domain of x). (Item 29) 29. The ST2 antigen binding protein of item 28, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 sequence set forth in SEQ ID NO: 137; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 49; an HCDR2 sequence set forth in SEQ ID NO: 60; and an HCDR3 sequence set forth in SEQ ID NO: 71. (Item 30) The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of item k) and the heavy chain variable domain of item y). (Item 31) 31. The ST2 antigen binding protein of item 30, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 116; an LCDR2 sequence set forth in SEQ ID NO: 127; and an LCDR3 sequence set forth in SEQ ID NO: 138; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 50; an HCDR2 sequence set forth in SEQ ID NO: 61; and an HCDR3 sequence set forth in SEQ ID NO: 72. (Item 32) The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of l) and the heavy chain variable domain of z). (Item 33) 33. The ST2 antigen binding protein of claim 32, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 166; an LCDR2 sequence set forth in SEQ ID NO: 169; and an LCDR3 sequence set forth in SEQ ID NO: 172; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 148; an HCDR2 sequence set forth in SEQ ID NO: 151; and an HCDR3 sequence set forth in SEQ ID NO: 154. (Item 34) 10. The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of m) and the heavy chain variable domain of aa). (Item 35) 35. The ST2 antigen binding protein of item 34, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 sequence set forth in SEQ ID NO: 173; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 149; an HCDR2 sequence set forth in SEQ ID NO: 152; and an HCDR3 sequence set forth in SEQ ID NO: 155. (Item 36) The ST2 antigen-binding protein according to item 9, comprising the light chain variable domain of n) and the heavy chain variable domain of bb). (Item 37) 37. The ST2 antigen binding protein of item 36, wherein the light chain variable domain comprises an LCDR1 sequence set forth in SEQ ID NO: 168; an LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 sequence set forth in SEQ ID NO: 174; and the heavy chain variable domain comprises an HCDR1 sequence set forth in SEQ ID NO: 150; an HCDR2 sequence set forth in SEQ ID NO: 153; and an HCDR3 sequence set forth in SEQ ID NO: 156. (Item 38) The antigen-binding protein is at 1×10 -10 38. The ST2 antigen-binding protein according to any of items 1 to 37, which specifically binds to human ST2 with an affinity of M or less. (Item 39) 39. The ST2 antigen-binding protein according to any of items 1 to 38, wherein the antigen-binding protein inhibits binding of human ST2 to human IL-33. (Item 40) 40. The ST2 antigen-binding protein according to any of items 1 to 39, wherein the antigen-binding protein reduces ST2 signaling mediated by human IL-33 in cells expressing human ST2. (Item 41) 40. The ST2 antigen-binding protein of item 39, wherein the antigen-binding protein inhibits binding of cynomolgus ST2 to cynomolgus IL-33. (Item 42) 42. The ST2 antigen-binding protein of claim 41, wherein the antigen-binding protein reduces cynomolgus ST2 signaling mediated by IL-33 in cells expressing cynomolgus ST2. (Item 43) 43. The ST2 antigen-binding protein according to any one of items 1 to 42, wherein the antigen-binding protein is an antibody. (Item 44) 44. The ST2 antigen-binding protein according to claim 43, wherein the antibody is a human antibody. (Item 45) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 84 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 18. (Item 46) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 85 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 19. (Item 47) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 86 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 20. (Item 48) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 87 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 21. (Item 49) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 88 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 22. (Item 50) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 89 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 23. (Item 51) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 90 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 24. (Item 52) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 91 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 25. (Item 53) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 92 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 26. (Item 54) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 93 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 27. (Item 55) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 94 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 28. (Item 56) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 160 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 142. (Item 57) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 161 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 143. (Item 58) 45. The ST2 antigen-binding protein according to claim 44, comprising a light chain and a heavy chain, wherein the light chain comprises the amino acid sequence set forth in SEQ ID NO: 162 and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 144. (Item 59) 1. An isolated nucleic acid encoding a polypeptide, said polypeptide comprising: a) a light chain variable domain having at least 95% identity to the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165; b) a heavy chain variable domain having at least 95% identity to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; c) a light chain variable domain having five or fewer amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165; d) a heavy chain variable domain having five or fewer amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; e) a light chain variable domain, i) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 128; ii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129; iii) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 108; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 130; iv) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 131; v) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 110; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 121; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 132; vi) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 111; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 122; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 133; vii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 134; viii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 113; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 124; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 135; ix) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 136; x) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 137; xi) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 116; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 127; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 138; xii) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 166; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 169; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 172; xiii) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 173; or xiv) a light chain variable domain comprising an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 168; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 174; or f) a heavy chain variable domain, i) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 40; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 51; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 62; ii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 63; iii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 42; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 53; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 64; iv) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 43; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 54; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 65; v) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 44; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 55; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 66; vi) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 45; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 56; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 67; vii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 46; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 57; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 68; viii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 47; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 58; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 69; ix) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 48; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 59; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 70; x) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 49; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 60; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 71; xi) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO:50; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO:61; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO:72; xii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 148; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 151; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 154; xiii) an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 149; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 152; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 155; or xiv) An isolated nucleic acid comprising a heavy chain variable domain comprising: an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 150; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 153; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 156. (Item 60) 60. The isolated nucleic acid of claim 59, wherein the polypeptide comprises an antibody light chain. (Item 61) 61. The isolated nucleic acid of claim 60, wherein the light chain is encoded by a nucleic acid comprising a nucleotide sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:157, SEQ ID NO:158, or SEQ ID NO:159. (Item 62) 62. The isolated nucleic acid of claim 61, wherein the light chain is encoded by a nucleic acid comprising a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:157, SEQ ID NO:158, or SEQ ID NO:159. (Item 63) 63. The isolated nucleic acid of claim 62, wherein the light chain is encoded by a nucleic acid comprising a nucleotide sequence at least 95% identical to the nucleotide sequence set forth in SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:157, SEQ ID NO:158, or SEQ ID NO:159. (Item 64) 64. The isolated nucleic acid of claim 63, wherein the light chain is encoded by a nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 157, SEQ ID NO: 158, or SEQ ID NO: 159. (Item 65) 60. The isolated nucleic acid of claim 59, wherein the polypeptide comprises an antibody heavy chain. (Item 66) 66. The isolated nucleic acid of claim 65, wherein the heavy chain is encoded by a nucleic acid comprising a nucleotide sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:139, SEQ ID NO:140, or SEQ ID NO:141. (Item 67) 67. The isolated nucleic acid of claim 66, wherein the heavy chain is encoded by a nucleic acid comprising a nucleotide sequence at least 90% identical to the nucleotide sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:139, SEQ ID NO:140, or SEQ ID NO:141. (Item 68) 68. The isolated nucleic acid of claim 67, wherein the heavy chain is encoded by a nucleic acid comprising a nucleotide sequence at least 95% identical to the nucleotide sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:139, SEQ ID NO:140, or SEQ ID NO:141. (Item 69) 69. The isolated nucleic acid of claim 68, wherein the heavy chain is encoded by a nucleic acid comprising the nucleotide sequence set forth in SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:139, SEQ ID NO:140, or SEQ ID NO:141. (Item 70) 70. An expression vector comprising the isolated nucleic acid according to any one of items 59 to 69. (Item 71) 71. The expression vector of claim 70, wherein the isolated nucleic acid encodes an antibody light chain. (Item 72) 71. The expression vector of claim 70, wherein the isolated nucleic acid encodes an antibody heavy chain. (Item 73) Item 74. The expression vector according to Item 71, further comprising an isolated nucleic acid encoding an antibody heavy chain. 70. A recombinant host cell comprising the isolated nucleic acid according to any of items 59 to 69 operably linked to a promoter. (Item 75) A recombinant host cell comprising the expression vector according to any one of items 70 to 73. (Item 76) 76. The recombinant host cell according to claim 75, wherein the host cell comprises an expression vector according to claims 71 and 72. (Item 77) 77. The recombinant host cell of item 76, wherein the host cell secretes an antibody that binds to ST2. (Item 78) 78. The recombinant host cell according to any of items 74 to 77, wherein the cell is of mammalian origin. (Item 79) 79. The recombinant host cell of item 78, wherein the cell is a Chinese Hamster Ovary (CHO) cell line. (Item 80) 59. A method for treating an autoimmune or inflammatory disease, comprising administering a therapeutically effective amount of the ST2 antigen-binding protein according to any one of items 1 to 58 to a patient in need thereof. (Item 81) 81. The method of claim 80, wherein the ST2 antigen binding protein is an antibody. (Item 82) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 95 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 29. (Item 83) 83. The method of claim 82, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 84 and a heavy chain amino acid sequence set forth in SEQ ID NO: 18. (Item 84) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 96 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 30. (Item 85) 85. The method of claim 84, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain amino acid sequence set forth in SEQ ID NO: 19. (Item 86) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 97 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 31. (Item 87) 87. The method of claim 86, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 86 and a heavy chain amino acid sequence set forth in SEQ ID NO: 20. (Item 88) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 98 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 32. (Item 89) 89. The method of claim 88, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 87 and a heavy chain amino acid sequence set forth in SEQ ID NO: 21. (Item 90) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 99 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 33. (Item 91) 91. The method of claim 90, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 88 and a heavy chain amino acid sequence set forth in SEQ ID NO: 22. (Item 92) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 100 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 34. (Item 93) 93. The method of claim 92, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 89 and a heavy chain amino acid sequence set forth in SEQ ID NO: 23. (Item 94) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 101 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 35. (Item 95) 95. The method of claim 94, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 90 and a heavy chain amino acid sequence set forth in SEQ ID NO: 24. (Item 96) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 102 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 36. (Item 97) 97. The method of claim 96, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 91 and a heavy chain amino acid sequence set forth in SEQ ID NO: 25. (Item 98) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 103 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 37. (Item 99) 99. The method of claim 98, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 92 and a heavy chain amino acid sequence set forth in SEQ ID NO: 26. (Item 100) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 104 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 38. (Item 101) 101. The method of claim 100, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 93 and a heavy chain amino acid sequence set forth in SEQ ID NO: 27. (Item 102) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 105 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 39. (Item 103) 103. The method of claim 102, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 94 and a heavy chain amino acid sequence set forth in SEQ ID NO: 28. (Item 104) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 163 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 145. (Item 105) 105. The method of claim 104, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 160 and a heavy chain amino acid sequence set forth in SEQ ID NO: 142. (Item 106) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 164 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 146. (Item 107) 107. The method of claim 106, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 161 and a heavy chain amino acid sequence set forth in SEQ ID NO: 143. (Item 108) 82. The method of claim 81, wherein the antibody comprises the amino acid sequence of a light chain variable domain set forth in SEQ ID NO: 165 and the amino acid sequence of a heavy chain variable domain set forth in SEQ ID NO: 147. (Item 109) 109. The method of claim 108, wherein the antibody comprises a light chain amino acid sequence set forth in SEQ ID NO: 162 and a heavy chain amino acid sequence set forth in SEQ ID NO: 144. (Item 110) 109. The method of any of items 80 to 109, wherein the antigen-binding protein inhibits binding of IL-33 to ST2. (Item 111) 111. The method of claim 110, wherein the autoimmune or inflammatory disease is asthma, atopic dermatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, sepsis and trauma, HIV infection, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, sclerosis, Wegener's granulomatosis, Behcet's disease, cardiovascular disease, sinusitis, nasal polyposis, or eosinophilic bronchitis. (Item 112) 1. A method of producing an ST2 antigen binding protein, comprising: a) culturing a recombinant host cell according to any one of items 74 to 79; b) isolating the ST2 antigen-binding protein from said culture. (Item 113) a) an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19, or b) An isolated ST2 antigen-binding protein that cross-competes with an antibody, comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO:93 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:27. (Item 114) 114. The ST2 antigen-binding protein according to Item 113, wherein the ST2 binding protein is an ST2 binding protein according to any one of Items 1 to 58. (Item 115) The ST2 antigen-binding protein of claim 113 or 114, wherein the ST2 antigen-binding protein cross-competes with an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19. (Item 116) 1. An isolated ST2 antigen binding protein that binds to a polypeptide comprising human ST2 domain 1 and domain 2 (SEQ ID NO: 175), wherein binding is significantly inhibited when a single mutation is introduced into human ST2 domain 1 or domain 2 of the polypeptide, wherein the single mutation is L14R, I15R, S33R, E43R, V47R, A62R, G65R, T79R, D92R, D97R, V104R, G138R, N152R, or V176R. (Item 117) 117. The isolated ST2 antigen binding protein of claim 116, wherein binding is significantly inhibited due to two or more of the single mutations. (Item 118) 118. The isolated ST2 antigen binding protein of claim 117, wherein binding is significantly inhibited due to all of the single mutations. (Item 119) 117. The isolated ST2 antigen-binding protein of claim 116, wherein a single mutation introduced into human ST2 domain 1 or domain 2 of the polypeptide significantly activates binding, wherein the single mutation is L53R, R72A, or S73R. (Item 120) 120. The isolated ST2 antigen-binding protein of item 119, wherein binding is significantly activated for all members of the group. (Item 121) 17. The isolated ST2 antigen-binding protein of claim 116, wherein the ST2-binding protein cross-competes with an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO: 85 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19 for binding to human ST2. (Item 122) The isolated ST2 antigen-binding protein according to any one of Items 116 to 121, wherein the ST2-binding protein is an ST2-binding protein according to any one of Items 1 to 58. (Item 123) 1. An isolated ST2 antigen binding protein that binds ST2 comprising amino acids 19-322 of SEQ ID NO:1 within amino acids 33-44 or 88-94 of SEQ ID NO:1, as determined by hydrogen / deuterium exchange analysis. (Item 124) 124. The isolated ST2 antigen binding protein according to claim 123, wherein the ST2 binding protein binds within amino acids 33-44 and 88-94 of SEQ ID NO:1 as determined by hydrogen / deuterium exchange analysis. (Item 125) Item 125. The isolated ST2 antigen-binding protein according to Item 124, wherein the ST2 binding protein is an ST2 binding protein according to any one of Items 1 to 58. (Item 126) 1. An isolated ST2 antigen-binding protein that binds to ST2 to form an interface, wherein the interface formed by said binding comprises ST2 residues K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, or Y81. (Item 127) 127. The isolated ST2 antigen-binding protein of claim 126, wherein the interface formed by said binding comprises ST2 residues P19, R20, Q21, G22, K23, or Y26. (Item 128) 128. The isolated ST2 antigen-binding protein of claim 127, wherein the interface formed by said binding comprises ST2 residues P19, R20, Q21, G22, K23, and Y26. (Item 129) 127. The isolated ST2 antigen-binding protein of claim 126, wherein the interface formed by said binding comprises ST2 residues I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, or Y81. (Item 130) 130. The isolated ST2 antigen-binding protein of claim 129, wherein the interface formed by said binding comprises ST2 residues I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81. (Item 131) 127. The isolated ST2 antigen-binding protein of claim 126, wherein the interface formed by said binding comprises ST2 residues P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81. (Item 132) 132. The isolated ST2 antigen binding protein of claim 131, wherein the interface formed by said binding comprises ST2 residues K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81. (Item 133) 132. The isolated ST2 antigen-binding protein according to any one of items 126 to 131, wherein the interface is determined by the difference in solvent exposure between bound and unbound ST2, and interface residues are defined as amino acids that have a difference of more than 10% and that form water-mediated hydrogen bonds with the antibody. (Item 134) 132. The isolated ST2 antigen-binding protein according to any of items 126 to 131, wherein the interface residues are defined as amino acids having at least one atom within 5 Å of the antibody. (Item 135) a) a light chain variable domain having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 96; b) a heavy chain variable domain having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 30; or c) an isolated ST2 antigen-binding protein comprising the light chain variable domain of a) and the heavy chain variable domain of b). (Item 136) 136. The isolated ST2 antigen-binding protein of claim 135, wherein the light chain variable domain has at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 96. (Item 137) 137. The isolated ST2 antigen-binding protein according to claim 135 or 136, wherein the heavy chain variable domain has at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 30. (Item 138) a) a light chain variable domain having no more than 10 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 96; b) a heavy chain variable domain having no more than 10 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 30; or c) an isolated ST2 antigen-binding protein comprising the light chain variable domain of a) and the heavy chain variable domain of b). (Item 139) 139. The isolated ST2 antigen binding protein of claim 138, wherein the light chain variable domain has no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:96. (Item 140) 140. The isolated ST2 antigen binding protein of claim 138 or 139, wherein the heavy chain variable domain has no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 30. (Item 141) a) a light chain variable domain comprising: an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129; b) a heavy chain variable domain comprising an HCDR1 having no more than three amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 41; an HCDR2 having no more than three amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 52; and an HCDR3 having no more than three amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 63; or c) An isolated ST2 antigen-binding protein comprising the light chain variable domain of a) and the heavy chain variable domain of b). (Item 142) 142. The isolated ST2 antigen-binding protein according to any of Items 135 to 141, wherein the light chain variable region comprises D28 or a conservative substitution thereof, I29 or a conservative substitution thereof, S30 or a conservative substitution thereof, N31 or a conservative substitution thereof, Y32 or a conservative substitution thereof, Y49 or a conservative substitution thereof, D50 or a conservative substitution thereof, N53 or a conservative substitution thereof, E55 or a conservative substitution thereof, T56 or a conservative substitution thereof, D91 or a conservative substitution thereof, D92 or a conservative substitution thereof, N93 or a conservative substitution thereof, F94 or a conservative substitution thereof, or L96 or a conservative substitution thereof. (Item 143) 143. The isolated ST2 antigen binding protein of claim 142, wherein the light chain variable region comprises D28 or a conservative substitution thereof, N31 or a conservative substitution thereof, D50 or a conservative substitution thereof, N53 or a conservative substitution thereof, E55 or a conservative substitution thereof, D91 or a conservative substitution thereof, and D92 or a conservative substitution thereof. (Item 144) 144. The isolated ST2 antigen binding protein of claim 143, wherein the light chain variable region comprises D28, N31, D50, N53, E55, D91, and D92. (Item 145) 145. The isolated ST2 antigen-binding protein according to any of Items 135 to 144, wherein the heavy chain variable region comprises W33 or a conservative substitution thereof, I50 or a conservative substitution thereof, D57 or a conservative substitution thereof, R59 or a conservative substitution thereof, H99 or a conservative substitution thereof, G100 or a conservative substitution thereof, T101 or a conservative substitution thereof, S102 or a conservative substitution thereof, S103 or a conservative substitution thereof, D104 or a conservative substitution thereof, Y105 or a conservative substitution thereof, or Y106 or a conservative substitution thereof. (Item 146) 146. The isolated ST2 antigen binding protein of claim 145, wherein the heavy chain variable region comprises S102 or a conservative substitution thereof, S103 or a conservative substitution thereof, D104 or a conservative substitution thereof, and Y105 or a conservative substitution thereof. (Item 147) 147. The isolated ST2 antigen binding protein of claim 146, wherein the heavy chain variable region comprises S102, S103, D104, and Y105. (Item 148) The antigen-binding protein is at 1×10 -10 148. The ST2 antigen-binding protein according to any of items 113 to 147, which specifically binds to human ST2 with an affinity of M or less. (Item 149) 149. The ST2 antigen-binding protein according to any of Items 113 to 148, wherein the antigen-binding protein inhibits binding of human ST2 to human IL-33. (Item 150) 150. The ST2 antigen-binding protein according to any one of items 113 to 149, wherein the antigen-binding protein reduces ST2 signaling mediated by human IL-33 in cells expressing human ST2. (Item 151) 150. The ST2 antigen-binding protein of item 149, wherein the antigen-binding protein inhibits binding of cynomolgus ST2 to cynomolgus IL-33. (Item 152) 152. The ST2 antigen binding protein of claim 151, wherein the antigen binding protein reduces cynomolgus ST2 signaling mediated by IL-33 in cells expressing cynomolgus ST2. (Item 153) 153. The ST2 antigen-binding protein according to any of Items 113 to 152, wherein the antigen-binding protein is an antibody. (Item 154) 154. The ST2 antigen binding protein according to claim 153, wherein the antibody is a human antibody. [Brief description of the drawings]

[0082]

Figure 1

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Figure 3

Figure 4

Figure 5

Figure 6

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Figure 8

Figure 9A

Figure 9B

Figure 10

[0083] The headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All references cited in the body of this specification are expressly incorporated herein by reference in their entirety.

[0084] Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation, protein purification, and the like. Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The following procedures and techniques may generally be performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Sambrook et al.,2001,Molecular Cloning:A Laboratory Manuel,3 rded., Cold Spring Harbor Laboratory Press, cold Spring Harbor, NY, incorporated herein by reference for any purpose. Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0085] ST2 The antigen binding proteins described herein bind to ST2. ST2 is expressed as both a soluble, non-signaling variant (soluble ST2 or sST2) and a full-length transmembrane form (FL ST2, ST2, or ST2L). An exemplary human ST2L amino acid sequence is provided herein in Table 1. The protein is composed of several domains: amino acids 1-18, which correspond to a leader sequence that can be cleaved during processing of the protein in mammalian cells; amino acids 19-331, which correspond to an extracellular domain; amino acids 332-350, which correspond to a transmembrane domain; and amino acids 351-556, which correspond to an intracellular domain. In a preferred embodiment, the antigen binding protein binds to the extracellular domain of ST2L and prevents the interaction of ST2 with IL-33. An exemplary human IL-33 amino acid sequence is provided in Table 1.

[0086] IL-33 signals through a heterodimeric receptor that includes ST2L and AcP. An exemplary human AcP amino acid sequence is provided in Table 1. This protein is also composed of several domains: amino acids 1-20, which correspond to a leader sequence that can be cleaved during processing of the protein in mammalian cells; amino acids 21-367, which correspond to an extracellular domain; amino acids 368-388, which correspond to a transmembrane domain; and amino acids 389-570, which correspond to an intracellular domain. In an exemplary embodiment, the ST2 antigen binding protein binds to ST2L and prevents signaling mediated by IL-33 in cells expressing ST2L and AcP. Table 1 [Table 1]

[0087] Exemplary embodiments of the invention bind with high affinity to both human and cynomolgus ST2, including those that bind with high affinity and block the interaction of cynomolgus IL-33 with cynomolgus ST2. These characteristics allow for beneficial toxicity studies in non-human primates.

[0088] An exemplary amino acid sequence of cynomolgus ST2L is provided in Table 2. The protein is composed of several domains: amino acids 1-18, which correspond to a leader sequence that can be cleaved during processing of the protein in mammalian cells; amino acids 19-331, which correspond to an extracellular domain; amino acids 332-350, which correspond to a transmembrane domain; and amino acids 351-556, which correspond to an intracellular domain.

[0089] An exemplary amino acid sequence of cynomolgus AcP is provided in Table 2. The protein is composed of several domains: amino acids 1-20, which correspond to a leader sequence that can be cleaved during processing of the protein in mammalian cells; amino acids 21-367, which correspond to an extracellular domain; amino acids 368-388, which correspond to a transmembrane domain; and amino acids 389-570, which correspond to an intracellular domain.

[0090] An exemplary amino acid sequence of cynomolgus IL-33 is provided in Table 2. Table 2 [Table 2]

[0091] ST2 antigen-binding protein The present invention provides antigen-binding proteins that specifically bind to ST2. Antigen-binding protein embodiments include peptides and / or polypeptides that specifically bind to ST2. Such peptides or polypeptides optionally include one or more post-translational modifications. Antigen-binding protein embodiments include antibodies and fragments thereof that specifically bind to ST2, as variously defined herein. These include antibodies that specifically bind to human ST2, including those that inhibit IL-33 from binding to and / or activating ST2.

[0092] The antigen-binding protein of the present invention specifically binds to ST2. As used herein, "specifically binds" means that the antigen-binding protein binds to ST2 preferentially over other proteins. In some embodiments, "specifically binds" means that the ST2 antigen-binding protein has a higher affinity for ST2 than it does for other proteins. The ST2 antigen-binding protein that specifically binds to ST2 is 1×10 -7 M or less, 2×10 -7 M or less, 3×10 -7 M or less, 4×10 -7 M or less, 5×10 -7 M or less, 6×10 -7 M or less, 7×10 -7 M or less, 8×10 -7 M or less, 9×10 -7 M or less, 1×10 -8 M or less, 2×10 -8 M or less, 3×10 -8 M or less, 4×10 -8 M or less, 5×10 -8 M or less, 6×10-8 Less than M, 7×10 -8 Less than M, 8×10 -8 Less than M, 9×10 -8 Less than M, 1×10 -9 Less than M, 2×10 -9 Less than M, 3×10 -9 Less than M, 4×10 -9 Less than M, 5×10 -9 Less than M, 6×10 -9 Less than M, 7×10 -9 Less than M, 8×10 -9 Less than M, 9×10 -9 Less than M, 1×10 -10 Less than M, 2×10 -10 Less than M, 3×10 -10 Less than M, 4×10 -10 Less than M, 5×10 -10 Less than M, 6×10 -10 Less than M, 7×10 -10 Less than M, 8×10 -10 Less than M, 9×10 -10 Less than M, 1×10 -11 Less than M, 2×10 -11 Less than M, 3×10 -11 Less than M, 4×10 -11 Less than M, 5×10 -11 Less than M, 6×10 -11 Less than M, 7×10 -11 Less than M, 8×10 -11 Less than M, 9×10 -11 Less than M, 1×10 -12 Less than M, 2×10 -12 Less than M, 3×10 -12 Less than M, 4×10 -12 Less than M, 5×10 -12 Less than M, 6×10 -12 Less than M, 7×10 -12 Less than M, 8×10 -12 Less than M, or 9×10 -12 May have binding affinity for human ST2 less than M.

[0093] Methods for measuring the binding affinity of antigen-binding proteins are well known in the art. A commonly used method for determining affinity is surface plasmon resonance (SPR) (Morton and Myszka "Kinetic analysis of macromolecular interactions using surface plasmon resonance"). plasmon resonance biosensors”Methods in Enzymology (1998) 295, 268-294), biolayer interferometry (Abdiche et al. “Determining Kinetics and Affinities of Protein Interactions Using "A Parallel Real-time Label-free Biosensor, the Octet" Analytical Biochemistry (2008) 377, 209-217), equilibrium exclusion assay (KinExA) (Darling and Brault "Kinetic exclusion assay technology: characterization of molecular interactions" Assay and Drug Dev Tech (2004) 2, 647-657), isothermal calorimetry (Pierce et al "Isothermal Titration Calorimetry of Protein-Protein Interactions" Methods (1999) 19, 213-221), and analytical ultracentrifugation (Lebowitz et al "Modern analytical ultracentrifugation in protein science: A tutorial review" Protein Science (2002), 11:2067-2079). Example 3 provides an exemplary method. .

[0094] When reference is made to various embodiments of ST2-binding antibodies described herein, it should be understood that ST2-binding fragments thereof are also included. ST2-binding fragments include any of the antibody fragments or domains described herein that retain the ability to specifically bind to ST2. ST2-binding fragments may be any of the scaffolds described herein.

[0095] In certain therapeutic embodiments, the ST2 antigen binding protein inhibits binding of ST2 to IL-33 and / or inhibits one or more biological activities associated with ST2 binding to IL-33, such as, for example, IL-33-mediated signal transduction. Such antigen binding proteins are said to be "neutralizing." In certain embodiments, a neutralizing ST2 antigen binding protein specifically binds to ST2 and inhibits binding of ST2 to IL-33 by a level in the range of 10% to 100%, e.g., at least about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 10 , 96, 97, 98, 99% or more. For example, ST2 antigen binding proteins can be tested for neutralizing capacity by determining the ability of the antigen binding protein to block binding of IL-33 to ST2 or to the co-receptors ST2 and AcP (see, e.g., IL-33 blocking assay in Example 6). Alternatively, ST2 antigen binding protein can be tested for neutralizing ability in an assay that measures the effect of the presence of ST2 antigen binding protein in an assay that measures biological functions mediated by IL-33.For example, the ability of IL-33 to induce intracellular signaling or biological responses such as increasing the mRNA expression or secretion of mediators such as cytokines and chemokines from cells such as eosinophils, basophils, T cells, mast cells, NK cells, NKT cells, neutrophils, or natural helper cells.Alternatively, the ability of IL-33 to promote the differentiation, proliferation, survival, chemotaxis, shape change, or adhesiveness of cells such as eosinophils, basophils, T cells, mast cells, NK cells, NKT cells, neutrophils, or natural helper cells.Alternatively, the ability of IL-33 to induce cell surface expression of certain markers of cell activation, such as CD11b, on cells such as eosinophils, basophils, T cells, mast cells, NK cells, NKT cells, neutrophils, or natural helper cells. Exemplary methods are provided in Examples 7-10.

[0096] As variously defined herein, embodiments of antigen binding proteins include a scaffold structure with one or more complementarity determining regions (CDRs). Embodiments further include antigen binding proteins comprising a scaffold structure with one or more antibody variable domains, either heavy or light chain. Embodiments include Ab1 light chain variable domain (LCv), Ab2 LCv, Ab3 LCv, Ab4 LCv, Ab5 LCv, Ab6 LCv, Ab7 LCv, Ab8 LCv, Ab9 LCv, Ab10 LCv, Ab11 LCv, Ab12 LCv, Ab13 LCv, Ab14 LCv, Ab15 LCv, Ab16 LCv, Ab17 LCv, Ab18 LCv, Ab19 LCv, Ab20 LCv, Ab21 LCv, Ab22 LCv, Ab23 LCv, Ab24 LCv, Ab25 LCv, Ab26 LCv, Ab27 LCv, Ab28 LCv, Ab29 LCv, Ab30 LCv, Ab31 LCv, Ab32 LCv, Ab33 LCv, Ab34 LCv, Ab35 LCv, Ab36 LCv, Ab37 LCv, Ab38 LCv, Ab39 LCv, Ab310 LCv, Ab32 LCv, Ab34 LCv, Ab35 LCv, Ab36 LCv, Ab37 LCv, Ab38 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab310 LCv, Ab32 LCv, Ab33 LCv, Ab34 LCv, Ab35 LCv, Ab36 LCv, Ab37 LCv, Ab38 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab39 LCv, Ab39 LC LCv, Ab4 LCv, Ab5 LCv, Ab6 LCv, Ab7 LCv, Ab8 and / or a heavy chain variable domain selected from the group consisting of Ab1 heavy chain variable domain (HCv), Ab2 HCv, Ab3 HCv, Ab4 HCv, Ab5 HCv, Ab6 HCv, Ab7 HCv, Ab8 HCv, Ab9 HCv, Ab10 HCv, Ab11 HCv, Ab30HCv, Ab32HCv, and Ab33HCv (SEQ ID NOs: 29-39, 145-147, respectively), and fragments, derivatives, muteins, and variants thereof.

[0097] An exemplary light chain that comprises the Ab1 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:84.

[0098] An exemplary light chain that comprises the Ab2 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:85.

[0099] An exemplary light chain that comprises the Ab3 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:86.

[0100] An exemplary light chain that comprises the Ab4 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:87.

[0101] An exemplary light chain that comprises the Ab5 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:88.

[0102] An exemplary light chain that comprises the Ab6 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:89.

[0103] An exemplary light chain that comprises the Ab7 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:90.

[0104] An exemplary light chain that comprises the Ab8 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:91.

[0105] An exemplary light chain that comprises the Ab9 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:92.

[0106] An exemplary light chain that comprises the Ab10 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:93.

[0107] An exemplary light chain that comprises the Ab11 LCv is a light chain that comprises the amino acid sequence set forth in SEQ ID NO:94.

[0108] An exemplary light chain comprising the Ab30 LCv is a light chain comprising the amino acid sequence set forth in SEQ ID NO:160.

[0109] An exemplary light chain comprising the Ab32 LCv is a light chain comprising the amino acid sequence set forth in SEQ ID NO:161.

[0110] An exemplary light chain comprising the Ab33 LCv is a light chain comprising the amino acid sequence set forth in SEQ ID NO:162.

[0111] An exemplary heavy chain comprising the Ab1 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:18.

[0112] An exemplary heavy chain that comprises the Ab2 HCv is a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:19.

[0113] An exemplary heavy chain that comprises the Ab3 HCv is a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:20.

[0114] An exemplary heavy chain that comprises the Ab4 HCv is a heavy chain that comprises the amino acid sequence set forth in SEQ ID NO:21.

[0115] An exemplary heavy chain comprising the Ab5 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:22.

[0116] An exemplary heavy chain comprising the Ab6 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:23.

[0117] An exemplary heavy chain comprising the Ab7 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:24.

[0118] An exemplary heavy chain comprising the Ab8 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:25.

[0119] An exemplary heavy chain comprising the Ab9 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:26.

[0120] An exemplary heavy chain comprising Ab10 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:27.

[0121] An exemplary heavy chain comprising the Ab11 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:28.

[0122] An exemplary heavy chain comprising the Ab30 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:142.

[0123] An exemplary heavy chain comprising the Ab32 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:143.

[0124] An exemplary heavy chain comprising the Ab33 HCv is a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:144.

[0125] Further examples of contemplated scaffolds include fibronectin, neocarzinostatin CBM4-2, lipocalin, T cell receptor, protein A domain (protein Z), Im9, TPR protein, zinc finger domain, pVIII, avian pancreatic polypeptide, GCN4, WW domain, Src homology domain 3, PDZ domain, TEM-1 beta-lactamase, thioredoxin, staphylococcal nuclease, PHD finger domain, CL-2, BPTI, APPI, HPSTI, ecotin, LACI-D1, LDTI, MTI-II, scorpion toxin, insect defensin-A peptide, EETI-II, Min-23, CBD, PBP, cytochrome b-562, Ldl receptor domain, gamma-crystallin, ubiquitin, transferrin, and or C-type lectin-like domain. Non-antibody scaffolds and their use as therapeutic agents are reviewed in Gebauer and Skerra, Curr. Opin. Chem. Biol., 13:245-255 (2009) and Binz et al., Nat. Biotech., 23(10):1257-1268 (2005), which are incorporated by reference in their entireties.

[0126]

[0023] Embodiments of the invention include antibodies comprising the following variable domains: Ab1 LCv / Ab1 HCv (SEQ ID NO:95 / SEQ ID NO:29), Ab2 LCv / Ab2 HCv (SEQ ID NO:96 / SEQ ID NO:30), Ab3 LCv / Ab3 HCv (SEQ ID NO:97 / SEQ ID NO:31), Ab4 LCv / Ab4 HCv (SEQ ID NO:98 / SEQ ID NO:32), Ab5 LCv / Ab5 HCv (SEQ ID NO:99 / SEQ ID NO:33), Ab6 LCv / Ab6 HCv (SEQ ID NO:100 / SEQ ID NO:34), Ab7 LCv / Ab7 HCv (SEQ ID NO:101 / SEQ ID NO:35), Ab8 LCv / Ab8 HCv (SEQ ID NO:102 / SEQ ID NO:36), Ab9 LCv / Ab9 HCv (SEQ ID NO:103 / SEQ ID NO:37), Ab10 LCv / Ab10 Ab30 LCv / Ab30 HCv (SEQ ID NO:163 / SEQ ID NO:145), Ab32 LCv / Ab32 HCv (SEQ ID NO:164 / SEQ ID NO:146), Ab33 LCv / Ab33 HCv (SEQ ID NO:165 / SEQ ID NO:147), and combinations thereof, as well as fragments, derivatives, muteins, and variants thereof.

[0127] Exemplary antibodies of the invention include Ab1 (SEQ ID NO:84 / SEQ ID NO:18), Ab2 (SEQ ID NO:85 / SEQ ID NO:19), Ab3 (SEQ ID NO:86 / SEQ ID NO:20), Ab4 (SEQ ID NO:87 / SEQ ID NO:21), Ab5 (SEQ ID NO:88 / SEQ ID NO:22), Ab6 (SEQ ID NO:89 / SEQ ID NO:23), Ab7 (SEQ ID NO:90 / SEQ ID NO:24), Ab8 (SEQ ID NO:91 / SEQ ID NO:25), Ab9 (SEQ ID NO:92 / SEQ ID NO:26), Ab10 (SEQ ID NO:93 / SEQ ID NO:27), Ab11 (SEQ ID NO:94 / SEQ ID NO:28), Ab30 (SEQ ID NO:160 / SEQ ID NO:142), Ab32 (SEQ ID NO:161 / SEQ ID NO:143), and Ab33 (SEQ ID NO:162 / SEQ ID NO:144).

[0128] Typically, each variable domain of the light or heavy chain of an antibody comprises three CDRs. The heavy chain variable domain comprises a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), and a heavy chain CDR3 (HCDR3). The light chain variable domain comprises a light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2), and a light chain CDR3 (LCDR3). In certain embodiments, the antigen binding protein comprises one or more CDRs contained within the preferred variable domains described herein.

[0129] Examples of such CDRs include, but are not limited to, the following CDRs:

[0130] CDRs of Ab1 LCv: LCDR1 (SEQ ID NO: 106), LCDR2 (SEQ ID NO: 117), and LCDR3 (SEQ ID NO: 128);

[0131] CDRs of Ab2 LCv: LCDR1 (SEQ ID NO: 107), LCDR2 (SEQ ID NO: 118), and LCDR3 (SEQ ID NO: 129);

[0132] CDRs of Ab3 LCv: LCDR1 (SEQ ID NO: 108), LCDR2 (SEQ ID NO: 119), and LCDR3 (SEQ ID NO: 130);

[0133] CDRs of Ab4 LCv: LCDR1 (SEQ ID NO: 109), LCDR2 (SEQ ID NO: 120), and LCDR3 (SEQ ID NO: 131);

[0134] CDRs of Ab5 LCv: LCDR1 (SEQ ID NO:110), LCDR2 (SEQ ID NO:121), and LCDR3 (SEQ ID NO:132);

[0135] CDRs of Ab6 LCv: LCDR1 (SEQ ID NO:111), LCDR2 (SEQ ID NO:122), and LCDR3 (SEQ ID NO:133);

[0136] CDRs of Ab7 LCv: LCDR1 (SEQ ID NO:112), LCDR2 (SEQ ID NO:123), and LCDR3 (SEQ ID NO:134);

[0137] CDRs of Ab8 LCv: LCDR1 (SEQ ID NO: 113), LCDR2 (SEQ ID NO: 124), and LCDR3 (SEQ ID NO: 135);

[0138] CDRs of Ab9 LCv: LCDR1 (SEQ ID NO:114), LCDR2 (SEQ ID NO:125), and LCDR3 (SEQ ID NO:136);

[0139] CDRs of Ab10 LCv: LCDR1 (SEQ ID NO: 115), LCDR2 (SEQ ID NO: 126), and LCDR3 (SEQ ID NO: 137);

[0140] CDRs of Ab11 LCv: LCDR1 (SEQ ID NO:116), LCDR2 (SEQ ID NO:127), and LCDR3 (SEQ ID NO:138);

[0141] CDRs of Ab30 LCv: LCDR1 (SEQ ID NO: 166), LCDR2 (SEQ ID NO: 169), and LCDR3 (SEQ ID NO: 172);

[0142] CDRs of Ab32 LCv: LCDR1 (SEQ ID NO: 167), LCDR2 (SEQ ID NO: 170), and LCDR3 (SEQ ID NO: 173);

[0143] CDRs of Ab33 LCv: LCDR1 (SEQ ID NO: 168), LCDR2 (SEQ ID NO: 171), and LCDR3 (SEQ ID NO: 174);

[0144] CDRs of Ab1 HCv: HCDR1 (SEQ ID NO: 40), HCDR2 (SEQ ID NO: 51), and HCDR3 (SEQ ID NO: 62);

[0145] CDRs of Ab2 HCv: HCDR1 (SEQ ID NO:41), HCDR2 (SEQ ID NO:52), and HCDR3 (SEQ ID NO:63);

[0146] CDRs of Ab3 HCv: HCDR1 (SEQ ID NO:42), HCDR2 (SEQ ID NO:53), and HCDR3 (SEQ ID NO:64);

[0147] CDRs of Ab4 HCv: HCDR1 (SEQ ID NO:43), HCDR2 (SEQ ID NO:54), and HCDR3 (SEQ ID NO:65);

[0148] CDRs of Ab5 HCv: HCDR1 (SEQ ID NO:44), HCDR2 (SEQ ID NO:55), and HCDR3 (SEQ ID NO:66);

[0149] CDRs of Ab6 HCv: HCDR1 (SEQ ID NO:45), HCDR2 (SEQ ID NO:56), and HCDR3 (SEQ ID NO:67);

[0150] CDRs of Ab7 HCv: HCDR1 (SEQ ID NO:46), HCDR2 (SEQ ID NO:57), and HCDR3 (SEQ ID NO:68);

[0151] CDRs of Ab8 HCv: HCDR1 (SEQ ID NO:47), HCDR2 (SEQ ID NO:58), and HCDR3 (SEQ ID NO:69);

[0152] CDRs of Ab9 HCv: HCDR1 (SEQ ID NO:48), HCDR2 (SEQ ID NO:59), and HCDR3 (SEQ ID NO:70);

[0153] CDRs of Ab10 HCv: HCDR1 (SEQ ID NO:49), HCDR2 (SEQ ID NO:60), and HCDR3 (SEQ ID NO:71);

[0154] CDRs of Ab11 HCv: HCDR1 (SEQ ID NO:50), HCDR2 (SEQ ID NO:61), and HCDR3 (SEQ ID NO:72);

[0155] CDRs of Ab30 HCv: HCDR1 (SEQ ID NO: 148), HCDR2 (SEQ ID NO: 151), and HCDR3 (SEQ ID NO: 154);

[0156] CDRs of Ab32 HCv: HCDR1 (SEQ ID NO: 149), HCDR2 (SEQ ID NO: 152), and HCDR3 (SEQ ID NO: 155); and

[0157] CDRs of Ab33 HCv: HCDR1 (SEQ ID NO: 150), HCDR2 (SEQ ID NO: 153), and HCDR3 (SEQ ID NO: 156).

[0158] In some embodiments, the antigen binding protein is A) a polypeptide, e.g., an LCDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 166, 167, and 168; an LCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 169, 170, and 171; and / or an LCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 172, 173, and 174. and / or B) a polypeptide, such as a heavy chain comprising an HCDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 148, 149, and 150; an HCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 151, 152, and 153; and / or an HCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 154, 155, and 156.

[0159] In a further embodiment, the antigen binding protein comprises A) a light chain amino acid sequence comprising an LCDR1, LCDR2, and LCDR3 of any of Ab1 LCv, Ab2 LCv, Ab3 LCv, Ab4 LCv, Ab5 LCv, Ab6 LCv, Ab7 LCv, Ab8 LCv, Ab9 LCv, Ab10 LCv, Ab11 LCv, Ab30 LCv, Ab32 LCv, and Ab33 LCv, and B) a light chain amino acid sequence comprising an LCDR1, LCDR2, and LCDR3 of any of Ab1 HCv, Ab2 HCv, Ab3 HCv, Ab4 HCv, Ab5 HCv, Ab6 HCv, Ab7 HCv, Ab8 HCv, Ab9 HCv, Ab10 HCv, Ab11 HCv, Ab30 HCv, Ab32 HCv, and Ab33 LCv. The heavy chain amino acid sequence includes HCDR1, HCDR2, and HCDR3 of any of HCv.

[0160] In certain embodiments, the CDRs comprise no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six amino acid additions, deletions, or substitutions from the exemplary CDRs described herein.

[0161] Embodiments of the invention include antibodies comprising a light chain variable domain selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165. Embodiments of the invention include antibodies comprising a heavy chain variable domain selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147. Further embodiments of the invention include antibodies comprising A) a light chain variable domain selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165, and B) a heavy chain variable domain selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147.

[0162] The antibody of the present invention can comprise any constant region known in the art. The light chain constant region can be, for example, a kappa-type or lambda-type light chain constant region, for example, a human kappa-type or lambda-type light chain constant region. The heavy chain constant region can be, for example, an alpha-type, delta-type, epsilon-type, gamma-type, or mu-type heavy chain constant region, for example, a human alpha-type, delta-type, epsilon-type, gamma-type, or mu-type heavy chain constant region. In one embodiment, the light or heavy chain constant region is a fragment, derivative, variant, or mutein of a naturally occurring constant region.

[0163] Embodiments of the invention include antibodies comprising a light chain variable region selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165 with no more than one, two, three, four, five, six, seven, eight, nine, or ten amino acid additions, deletions, or substitutions.Embodiments of the invention include antibodies comprising a heavy chain variable region selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147 with no more than one, two, three, four, five, six, seven, eight, nine, or ten amino acid additions, deletions, or substitutions. Further embodiments of the invention include antibodies comprising A) a light chain variable region selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165 with no more than one, two, three, four, five, six, seven, eight, nine, or ten amino acid additions, deletions, or substitutions; and B) a heavy chain variable region selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147 with no more than one, two, three, four, five, six, seven, eight, nine, or ten amino acid additions, deletions, or substitutions.

[0164] In one variation, the antigen binding protein comprises an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165. In another variation, the antigen binding protein comprises an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147.In a further embodiment, the antigen binding protein comprises: A) a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165; and a light chain variable region amino acid sequence selected from the group consisting of: SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 163, 164, and 165; and and B) an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 145, 146, and 147.

[0165] In certain embodiments, the antigen binding protein comprises a light chain and / or a heavy chain CDR3. In some embodiments, the antigen binding protein comprises an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 172, 173, 174, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 154, 155, and 156. In certain embodiments, the amino acid sequence contains no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six amino acid additions, deletions, or substitutions from the exemplary sequences set forth in SEQ ID NOs: 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 172, 173, 174, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 154, 155, and 156. Thus, embodiments of the present invention include antigen binding proteins comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 172, 173, 174, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 154, 155, and 156.

[0166] In certain embodiments, the antigen binding protein comprises a light chain and / or a heavy chain CDR2. In some embodiments, the antigen binding protein comprises an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 169, 170, 171, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 151, 152, and 153. In certain embodiments, the amino acid sequence contains no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six amino acid additions, deletions, or substitutions from the exemplary sequences set forth in SEQ ID NOs: 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 169, 170, 171, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 151, 152, and 153. Thus, embodiments of the present invention include antigen binding proteins comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 169, 170, 171, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 151, 152, and 153.

[0167] In certain embodiments, the antigen binding protein comprises a light chain and / or a heavy chain CDR1. In some embodiments, the antigen binding protein comprises an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 166, 167, 168, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 148, 149, and 150. In certain embodiments, the amino acid sequence contains no more than one, no more than two, no more than three, no more than four, no more than five, or no more than six amino acid additions, deletions, or substitutions from the exemplary sequences set forth in SEQ ID NOs: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 166, 167, 168, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 148, 149, and 150. Thus, embodiments of the present invention include antigen binding proteins comprising an amino acid sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group of sequences set forth in SEQ ID NOs: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 166, 167, 168, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 148, 149, and 150.

[0168] The antigen-binding proteins of the present invention include conventional antibody scaffolds, including human and monoclonal antibodies, bispecific antibodies, diabodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, antibody fusions (sometimes referred to as "antibody conjugates"), and fragments of each. The above-mentioned CDRs, including various combinations of CDRs, may be grafted onto any of the subsequent scaffolds.

[0169] As used herein, the term "antibody" refers to various forms of monomeric or multimeric proteins comprising one or more polypeptide chains that specifically bind to an antigen, as variously described herein. In certain embodiments, the antibody is produced by recombinant DNA technology. In further embodiments, the antibody is produced by enzymatic or chemical cleavage of a naturally occurring antibody. In another aspect, the antibody is selected from the group consisting of a) human antibody; b) humanized antibody; c) chimeric antibody; d) monoclonal antibody; e) polyclonal antibody; f) recombinant antibody; g) antigen-binding fragment; h) single-chain antibody; i) diabody; j) triabody, k) tetrabody, l) Fab fragment; m) F(ab')2 fragment, n) IgA antibody, o) IgD antibody, p) IgE antibody, q) IgG1 antibody, r) IgG2 antibody, s) IgG3 antibody, t) IgG4 antibody, and u) IgM antibody.

[0170] A variable region or domain contains at least three heavy or light chain CDRs surrounded by framework regions (referred to as FR1, FR2, FR3, and FR4 framework regions). Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service NIH, Bethesda, MD. The structural unit of a conventional antibody typically comprises a tetramer. Each tetramer typically consists of two identical pairs of polypeptide chains, each pair having one "light" chain and one "heavy" chain. The amino-terminal portion of each chain contains a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa or lambda light chains. Heavy chains are classified as μ, δ, γ, α, or ε, which define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. Embodiments of the invention include all such classes and subclasses of antibodies that incorporate the variable domains or CDRs of an antigen binding protein as described herein.

[0171] Some naturally occurring antibodies, such as those found in camels and llamas, are dimers consisting of two heavy chains and no light chains. The present invention encompasses dimeric antibodies of two heavy chains or fragments thereof capable of binding to ST2.

[0172] The variable regions of heavy and light chains typically exhibit the same overall structure of three hypervariable regions, i.e., relatively conserved framework regions (FRs) bound by complementarity determining regions or CDRs. The CDRs are primarily responsible for antigen recognition and binding. The CDRs from the two chains of each pair are aligned by the framework regions, allowing binding to a specific epitope. From the N-terminus to the C-terminus, both light and heavy chains contain the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain follows the definition of Kabat.

[0173] CDRs constitute the main surface contact points for antigen binding. CDR3 or light chain, and especially CDR3 of heavy chain, may constitute the most important determinant in antigen binding within the light chain and heavy chain variable region. In some antibodies, heavy chain CDR3 is considered to constitute the main contact area between antigen and antibody. In order to change the binding characteristics of the antibody or to determine which residues contribute to antigen binding, an in vitro selection scheme can be used in which only CDR3 is changed.

[0174] Naturally occurring antibodies typically contain a signal sequence that directs the antibody into the cellular pathway for protein secretion and that is typically not present in the mature antibody. Polynucleotides encoding antibodies of the invention may encode a naturally occurring or a heterologous signal sequence, as described below.

[0175] In one embodiment, the antigen binding protein is an antibody comprising one to six of the exemplary CDRs described herein. The antibody of the present invention may be any type of antibody, including IgM, IgG (including IgG1, IgG2, IgG3, IgG4), IgD, IgA, or IgE antibodies. In a specific embodiment, the antigen binding protein is an IgG type antibody, for example, an IgG1 antibody.

[0176] In some embodiments, for example, when the antigen binding protein is an antibody with complete heavy and light chains, the CDRs are all derived from the same species, for example, human. Alternatively, for example, in embodiments where the antigen binding protein contains less than six CDRs from the sequences outlined above, the additional CDRs may be derived from other species or may be different human CDRs from those shown in the exemplary sequences. For example, the HCDR3 and LCDR3 regions from the appropriate sequences identified herein may be used with HCDR1, HCDR2, LCDR1, and LCDR2 optionally selected from alternative species, or different human antibody sequences, or combinations thereof. For example, the CDRs of the present invention can replace the CDR regions of commercial chimeric or humanized antibodies.

[0177] Particular embodiments utilize a scaffold component of an antigen-binding protein that is a human component. In some embodiments, however, the scaffold component may be a mixture from different species. Thus, when the antigen-binding protein is an antibody, such an antibody may be a chimeric antibody and / or a humanized antibody. In general, both "chimeric antibody" and "humanized antibody" refer to an antibody that combines regions from more than one species. For example, a "chimeric antibody" traditionally contains a mouse (or sometimes a rat) variable region(s) and a human constant region(s).

[0178] "Humanized antibody" generally refers to a non-human antibody in which the variable domain framework region has been replaced with a sequence found in a human antibody. Typically, in a humanized antibody, the entire antibody, except for one or more CDRs, is encoded by a polynucleotide of human origin or is identical to such an antibody except within one or more CDRs. CDRs encoded in part or in whole by a nucleic acid originating from a non-human organism are grafted into the beta-sheet framework of a human antibody variable region to generate an antibody whose specificity is determined by the grafted CDRs. The generation of such antibodies is described, for example, in International Publication No. WO 92 / 11018, Jones 1986, Nature 321:522-525, Verhoeyen et al., 1988, Science 239:1534-1536. Humanized antibodies can also be generated using mice with genetically engineered immune systems. Roque et al., 2004, Biotechnol. Prog. 20:639-654. In the exemplary embodiments described herein, the identified CDRs are human, and thus in this context both humanized and chimeric antibodies contain some non-human CDRs: for example, a humanized antibody may be made that contains HCDR3 and LCDR3 regions, one or more of the other CDR regions being of a different species origin.

[0179] In one embodiment, the ST2 antigen binding protein is a multispecific antibody, in particular a bispecific antibody, sometimes also referred to as a "diabody." These are antibodies that bind to two or more different antigens, or different epitopes on a single antigen. In certain embodiments, bispecific antibodies bind to ST2 and an antigen on a human effector cell (e.g., a T cell). Such antibodies are useful in targeting effector cell responses to ST2-expressing cells, such as tumor cells that express ST2. In a preferred embodiment, the antigen on the human effector cell is CD3. U.S. Pat. No. 7,235,641. Methods for making bispecific antibodies are known in the art. One such method involves engineering the Fc portion of the heavy chain to form a "knob" and a "hole" that promotes heterodimerization of the heavy chains when co-expressed in a cell. U.S. Pat. No. 7,695,963. Other methods also involve engineering the Fc portion of the heavy chain, but using electrostatic steering to promote heterodimerization while preventing heavy chain heterodimerization when co-expressed in cells, International Publication No. WO 09 / 089,004, which is incorporated herein by reference in its entirety.

[0180] In one embodiment, the ST2 antigen binding protein is a minibody. Minibodies are miniaturized antibody-like proteins that contain an scFv linked to a CH3 domain. Hu et al., 1996, Cancer Res. 56:3055-3061.

[0181] In one embodiment, the ST2 antigen binding protein is a domain antibody: see, for example, U.S. Patent No. 6,248,516. A domain antibody (dAb) is a functional binding domain of an antibody that corresponds to the variable region of either the heavy (VH) or light (VL) chain of a human antibody. dABs have a molecular weight of about 13 kDa, or less than one-tenth the size of a full antibody. dABs are well expressed in a variety of hosts, including bacteria, yeast, and mammalian cell systems. Moreover, dAbs are highly stable and retain activity even after being subjected to harsh conditions such as lyophilization or heat denaturation. See, e.g., U.S. Patent Nos. 6,291,158; 6,582,915; 6,593,081; 6,172,197; U.S. Patent Application No. 2004 / 0110941; European Patent No. 0368684; U.S. Patent No. 6,696,245, International Publication Nos. WO04 / 058821, WO04 / 003019, and WO03 / 002609.

[0182] In one embodiment, the ST2 antigen binding protein is an antibody fragment, i.e., a fragment of any of the antibodies outlined herein that retains binding specificity to ST2. In various embodiments, the antibody binding protein includes, but is not limited to, F(ab), F(ab'), F(ab')2, Fv, or single chain Fv fragments. At a minimum, an antibody as meant herein includes a polypeptide capable of specifically binding to ST2, including all or part of a light or heavy chain variable region, e.g., one or more CDRs.

[0183] Further examples of antibody fragments that bind to ST2 include, but are not limited to, (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) an Fd fragment consisting of the VH and CH1 domains, (iii) an Fv fragment consisting of the VL and VH domains of a single antibody; (iv) a dAb fragment consisting of a single variable portion (Ward et al., 1989, Nature 341:544-546), (v) an isolated CDR region, (vi) an F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, and (vii) a single chain Fv molecule (scFv) in which the VH and VL domains are linked by a peptide linker that can associate the two domains to form an antigen-binding site (Bird et al., 1988, Science 242:423-426, Huston et al., 2002). al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883), (viii) bispecific single chain Fv dimers (PCT / US92 / 09965), and (ix) "diabodies" or "triabodies," which are multivalent or multispecific fragments constructed by gene fusion (Tomlinson et.al., 2000, Methods Enzymol. 326:461-479; International Publication No. WO 94 / 13804; Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448). Antibody fragments may be modified. The molecules may be stabilized, for example, by the incorporation of disulfide bridges linking the VH and VL domains (Reiter et al., 1996, Nature Biotech. 14:1239-1245). Aspects of the invention include embodiments in which the non-CDR components of these fragments are human sequences.

[0184] In one embodiment, the ST2 antigen binding protein is a fully human antibody. In this embodiment, the particular structure includes the illustrated complete heavy and light chains including the CDR regions, as outlined above. Further embodiments utilize one or more of the CDRs of the present invention, with other CDRs, framework regions, J and D regions, constant regions, etc., derived from other human antibodies. For example, the CDRs of the present invention can replace the CDRs of any number of human antibodies, particularly commercial antibodies.

[0185] Single chain antibodies may be formed by linking fragments of the heavy and light chain variable domains (Fv regions) via an amino acid bridge (a short peptide linker) to produce a single polypeptide chain. Such a single chain Fv (scFv) comprises two variable domain polypeptides (V L and V H These have been prepared by fusing DNA encoding a peptide linker between DNA encoding the variable domains. The resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of the flexible linker between the two variable domains (Kortt et al., 1997, Prot. Eng. 10:423; Kortt et al., 2001, Biomol. Eng. 18:95-108). L and V HBy combining polypeptides containing the above, multimeric scFvs that bind different epitopes can be formed (Kriangkum et al., 2001, Biomol. Eng. 18:31-40). Techniques developed for the production of single-chain antibodies include those described in U.S. Patent No. 4,946,778; Bird, 1988, Science 242:423; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879; Ward et al., 1989, Nature 334:544, de Graaf et al., 2002, Methods Mol Biol. 178:379-87. Antibodies provided herein, including but not limited to, Ab1 LCv / Ab1 HCv (SEQ ID NO:95 / SEQ ID NO:29), Ab2 LCv / Ab2 HCv (SEQ ID NO:96 / SEQ ID NO:30), Ab3 LCv / Ab3 HCv (SEQ ID NO:97 / SEQ ID NO:31), Ab4 LCv / Ab4 HCv (SEQ ID NO:98 / SEQ ID NO:32), Ab5 LCv / Ab5 HCv (SEQ ID NO:99 / SEQ ID NO:33), Ab6 LCv / Ab6 HCv (SEQ ID NO:100 / SEQ ID NO:34), Ab7 LCv / Ab7 HCv (SEQ ID NO:101 / SEQ ID NO:35), Ab8 LCv / Ab8 HCv (SEQ ID NO:102 / SEQ ID NO:36), Ab9 LCv / Ab9 HCv (SEQ ID NO:103 / SEQ ID NO:37), Ab10 LCv / Ab10 HCv (SEQ ID NO:104 / SEQ ID NO:38), Ab2 LCv / Ab2 HCv (SEQ ID NO:105 / SEQ ID NO:39), Ab10 LCv / Ab10 HCv (SEQ ID NO:106 / SEQ ID NO:39), Ab11 LCv / Ab11 HCv (SEQ ID NO:107 / SEQ ID NO:39), Ab12 LCv / Ab12 HCv (SEQ ID NO:109 / SEQ ID NO:31), Ab13 LCv / Ab13 HCv (SEQ ID NO:108 / SEQ ID NO:32), Ab14 LCv / Ab14 HCv (SEQ ID NO:109 / SEQ ID NO:33), Ab15 LCv / Ab15 Encompassed by the present invention are single chain antibodies derived from Ab11 LCv / Ab11 HCv (SEQ ID NO:104 / SEQ ID NO:38), Ab30 LCv / Ab30 HCv (SEQ ID NO:163 / SEQ ID NO:145), Ab32 LCv / Ab32 HCv (SEQ ID NO:164 / SEQ ID NO:146), Ab33 LCv / Ab33 HCv (including scFvs comprising the variable domain combination of SEQ ID NO:165 / SEQ ID NO:147) and combinations thereof.

[0186] In one embodiment, the ST2 antigen-binding protein is an antibody fusion protein (sometimes referred to herein as an "antibody conjugate"). The conjugate partner may be proteinaceous or non-proteinaceous: the latter is usually produced using functional groups on the antigen-binding protein and on the conjugate partner. In certain embodiments, the antibody is conjugated to a non-proteinaceous chemical (drug) to form an antibody-drug conjugate.

[0187] In one embodiment, the ST2 antigen binding protein is an antibody analog, sometimes referred to as a "synthetic antibody". For example, various studies have utilized either alternative protein scaffolds or artificial scaffolds with CDR grafts. Such scaffolds include, but are not limited to, mutations introduced to stabilize the three-dimensional structure of the binding protein, and fully synthetic scaffolds, for example, made of biocompatible polymers. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics, Volume 53, Issue 1:121-129; Roque et al., 2004, Biotechnol. Prog. 20:639-654. Additionally, studies based on peptide antibody mimics ("PAMs") and antibody mimics utilizing fibronectin components as scaffolds can be used.

[0188] "Protein" as used herein means at least two covalently linked amino acids, including proteins, polypeptides, oligopeptides, and peptides. In some embodiments, the two or more covalently linked amino acids are linked by peptide bonds. Proteins may be composed of naturally occurring amino acids and peptide bonds (e.g., when proteins are made recombinantly using expression systems and host cells, as outlined below). Alternatively, proteins may include "peptide or protein analogs" such as synthetic amino acids (e.g., homophenylalanine, citrulline, ornithine, and norleucine) or peptidomimetic structures, i.e., peptoids, that can be resistant to proteases or other physiological and / or storage conditions (see Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367, incorporated herein by reference). Such synthetic amino acids may be incorporated in particular when antigen-binding proteins are synthesized in vitro by conventional methods well known in the art. Additionally, any combination of peptidomimetics, synthetic and naturally occurring residues / structures may be used. "Amino acid" also includes imino acid residues such as proline and hydroxyproline. The "R group" or "side chain" of an amino acid may be in either the (L) or (S) configuration. In specific embodiments, the amino acid may be in the (L) or (S) configuration.

[0189] In certain aspects, the present invention provides recombinant antigen-binding proteins that bind to ST2, and in some embodiments, recombinant human ST2 or portions thereof. In this context, a "recombinant protein" is a protein that is made using recombinant technology, using any technique and method known in the art, i.e., by expression of a recombinant nucleic acid as described herein. Methods and techniques for the production of recombinant proteins are well known in the art. Embodiments of the present invention include recombinant antigen-binding proteins that bind to wild-type ST2 and its variants.

[0190] "Consisting essentially of," as used herein, means that the amino acid sequence can vary by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% from the sequence of the recited SEQ ID NO: and still retain biological activity.

[0191] In some embodiments, the antigen binding proteins of the present invention are isolated or substantially pure proteins. An "isolated" protein is free from at least some of the materials with which it is normally associated in its natural state, for example constituting at least about 5% by weight, or at least about 50% by weight, of the total protein in a given sample. It is understood that an isolated protein may constitute 5-99.9% by weight of the total protein content, depending on the circumstances. For example, the protein may be made at significantly higher concentrations by using an inducible promoter or a high expression promoter, such that the protein is made at high concentration levels. This definition includes the production of antigen binding proteins in a wide variety of organisms and / or host cells known in the art.

[0192] With respect to amino acid sequences, sequence identity and / or sequence similarity are determined as described by Smith and The local sequence identity algorithm of Waterman, 1981, Adv. Appl. Math. 2:482; the sequence identity alignment algorithm of Needleman and Wunsch, 1970, J. Mol. Biol. 48:443; and Lipman, 1988, Proc. Nat. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described by Devereux et al., 1984, Nucl. Acid Res. 12:387-395, preferably using default settings, or by inspection. Preferably, percent identity is calculated by FastDB based on the following parameters: mismatch penalty = 1; gap penalty = 1; gap size penalty = 0.33; and joining penalty = 30 ("Current Methods in Sequence Comparison and Analysis" Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp 127-149 (1988), Alan R. Liss, Inc.).

[0193] One example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle, 1987, J. Mol. Evol. 35:351-360; this method is similar to that described by Higgins and Sharp, 1989, CABIOS 5:151-153. Useful PILEUP parameters include a default gap weighting=3.00, a default gap length weighting=0.10, and weighted end gaps.

[0194] Another example of a useful algorithm is the BLAST algorithm described in Altschul et al., 1990, J. Mol. Biol. 215:403-410; Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402 and Karin et al., 1993, Proc. Natl. Acad. Sci. USA 90:5873-5787. A particularly useful BLAST program is the WU-BLAST-2 program, taken from Altschul et al., 1996, Methods in Enzymology 266:460-480. WU-BLAST-2 uses several search parameters, most of which are set to default values. Adjustable parameters are set with the following values: overlap span=1, overlap fragment=0.125, word threshold (T)=II. The HSP S and HSP S2 parameters are dynamic values ​​and are established by the program itself depending on the composition of the particular sequence and the composition of the particular database against which the subject sequence is searched, although the values ​​may be adjusted to increase sensitivity.

[0195] An additional useful algorithm is Gapped BLAST, reported by Altschul et al., 1993, Nucl. Acids Res. 25:3389-3402. Gapped BLAST uses the BLOSUM-62 substitution score; a threshold T parameter set to 9; a two-hit method to initiate ungapped extensions, imposing a cost of 10+k on the gap length k; and X set to 16. u , and X, which was set to 40 in the database search phase of the algorithm and 67 in the output phase of the algorithm. g The gapped alignment is started with a score corresponding to approximately 22 bits.

[0196] Typically, the amino acid homology, similarity, or identity between the individual variant CDRs to the sequences set forth herein is at least 80%, with increasing homology or identity of at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and near 100% being preferred. Similarly, "percent (%) nucleic acid sequence identity" with respect to the nucleic acid sequences of the binding proteins identified herein is defined as the percentage of nucleotide residues of a candidate sequence that are identical to the nucleotide residues of the coding sequence of the antigen binding protein. A particular method utilizes the BLASTN module of WU-BLAST-2 set to default parameters, with overlap span and overlap fragment set to 1 and 0.125, respectively.

[0197] Typically, the nucleic acid sequence homology, similarity or identity between the nucleotide sequence encoding each variant CDR and those set forth herein will be at least 80%, more typically at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, with increasing homology or identity of nearly 100% being preferred.

[0198] Thus, a "variant CDR" is one that has the specified homology, similarity or identity to a parent CDR of the invention and shares a biological function, including but not limited to, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the specificity and / or activity of the parent CDR.

[0199] The site or region for introducing amino acid sequence diversity is predetermined, but the mutation itself is not necessarily predetermined.For example, to optimize the performance of a mutation at a given site, random mutagenesis may be performed at the target codon or region, and the CDR variants of the expressed antigen-binding protein may be screened for the optimal combination of desired activity.Techniques for making substitution mutations at a predetermined site of DNA with a known sequence are well known, such as M13 primer mutagenesis and PCR mutagenesis.The screening of mutants is performed using an assay of antigen-binding protein activity, such as binding of ST2.

[0200] Amino acid substitutions are typically of single residues; insertions are usually on the order of about 1 to about 20 amino acid residues, although much larger insertions can be tolerated. Deletions range from about 1 to about 20 amino acid residues, although in some cases deletions can be much larger.

[0201] Substitution, deletion, insertion, or any combination thereof can be used to arrive at the final derivative or variant. Usually, these changes are made to a few amino acids to minimize the change in the molecule, especially the change in the immunogenicity and specificity of the antigen-binding protein. However, larger changes can be tolerated in certain situations. Conservative substitutions are generally made according to the following chart shown in Table 3. Table 3 [Table 3]

[0202] Substantial alterations in function or immunological identity are made by selecting substitutions that are less conservative than those shown in Table 3. For example, substitutions may be made that more significantly affect the structure of the polypeptide backbone, e.g., alpha helix or beta sheet structure, in the area of ​​the change; the charge or hydrophobicity of the molecule at the target site; or the bulk of the side chains. In general, the substitutions that are predicted to result in the most significant changes in the properties of a polypeptide are those in which a hydrophilic residue, e.g., seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl, or alanyl; (b) cysteine ​​or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g., glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) a residue having no side chain, e.g., glycine.

[0203] The variants typically exhibit the same qualitative biological activity and induce the same immune response as the naturally occurring analogues, but the variants are also selected to modify the characteristics of the antigen-binding protein, if necessary. Alternatively, the variants may be designed to change the biological activity of the antigen-binding protein. For example, glycosylation sites may be altered or removed as described herein.

[0204] Other derivatives of ST2 antibodies within the scope of the present invention include covalent or aggregate conjugates of ST2 antibodies or fragments thereof with other proteins or polypeptides, such as by expressing recombinant fusion proteins that contain heterologous polypeptides fused to the N-terminus or C-terminus of the ST2 antibody polypeptide. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, such as the yeast α-factor leader, or a peptide such as an epitope tag. Fusion proteins containing ST2 antibodies may include a peptide (e.g., poly-His) added to facilitate purification or identification of the ST2 antibody. ST2 antibody polypeptides may also be linked to a FLAG peptide, as described in Hopp et al., Bio / Technology 6:1204, 1988, and U.S. Pat. No. 5,011,912. FLAG peptides are highly antigenic and provide an epitope that is reversibly bound by specific monoclonal antibodies (mAbs), allowing for rapid assay and easy purification of expressed recombinant proteins. Reagents useful for preparing fusion proteins in which the FLAG peptide is fused to a given polypeptide are commercially available (Sigma, St. Louis, Mo.).

[0205] In one embodiment, oligomers are prepared using immunoglobulin-derived polypeptides. Preparation of fusion proteins containing specific heterologous polypeptides fused to various portions of antibody-derived polypeptides (including Fc domains) is described, for example, in Ashkenazi et al., 1991, PNAS USA 88:10535; Byrn et al., 1990, Nature 344:677; and Hollenbaugh et al., 1992 "Construction of Immunoglobulin Fusion Proteins", in Current Protocols in Immunology, Suppl. 4, pages 10.19.1 to 10.19.11.

[0206] One embodiment of the present invention is directed to a dimer comprising two fusion proteins made by fusing the ST2-binding fragment of the ST2 antibody to the Fc region of an antibody. The dimer can be made, for example, by inserting a gene fusion encoding the fusion protein into an appropriate expression vector, expressing the gene fusion in a host cell transformed with the recombinant expression vector, and assembling the expressed fusion protein to closely resemble an antibody molecule, whereby interchain disulfide bonds form between the Fc portions to give rise to a dimer.

[0207] The term "Fc polypeptide" as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Also included are truncated forms of such polypeptides that contain the hinge region that promotes dimerization. Fusion proteins (and oligomers formed therefrom) that contain Fc portions offer the advantage of easy purification by affinity chromatography on protein A or protein G columns.

[0208] One suitable Fc polypeptide described in PCT Application WO93 / 10151 (herein incorporated by reference) is a single chain polypeptide that extends from the N-terminal hinge region to the natural C-terminus of the Fc region of a human IgG antibody. Another useful Fc polypeptide is the Fc mutein described in U.S. Patent No. 5,457,035 and Baum et al., 1994, EMBO J. 13:3992-4001. The amino acid sequence of this mutein is identical to that of the natural Fc sequence presented in International Publication WO93 / 10151, except that amino acid 19 is changed from Leu to Ala, amino acid 20 is changed from Leu to Glu, and amino acid 22 is changed from Gly to Ala. The mutein exhibits low affinity to Fc receptors.

[0209] In other embodiments, the variable portions of the heavy and / or light chains of the ST2 antibody may be substituted for the variable portions of the antibody heavy and / or light chains.

[0210] Another method for preparing oligomeric ST2 antibody derivatives involves the use of leucine zippers. Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found. Leucine zippers were originally identified in several DNA-binding proteins (Landschulz et al., 1988, Science 240:1759) and have since been found in a variety of different proteins. Among the known leucine zippers are naturally occurring peptides and derivatives that dimerize or trimerize. Examples of leucine zipper domains suitable for producing soluble oligomeric proteins are described in PCT Application No. WO94 / 10308, and the leucine zipper derived from pulmonary surfactant protein D (SPD) is described in Hoppe et al., 1994, FEBS Letters 344:191 (incorporated herein by reference). The use of modified leucine zippers that allow stable trimerization of heterologous proteins fused thereto is described in Fanslow et al., 1994, Semin. Immunol. 6:267-78. In one approach, a recombinant fusion protein containing an ST2 antibody fragment or derivative fused to a leucine zipper peptide is expressed in a suitable host cell, and the soluble oligomeric ST2 antibody fragment or derivative that forms is recovered from the culture supernatant.

[0211] Covalent modifications of antigen-binding proteins are included within the scope of the present invention and are typically, but not necessarily, performed post-translationally. For example, some types of covalent modifications of antigen-binding proteins are introduced into the molecule by reacting specific amino acid residues of the antigen-binding protein with organic derivatizing agents capable of reacting with selected side chains or N- or C-terminal residues.

[0212] Cysteinyl residues most commonly are reacted with α-haloacetates (and corresponding amines), such as chloroacetic acid or chloroacetamide, to give carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residues are also derivatized by reaction with bromotrifluoroacetone, α-bromo-β-(5-imidozoyl)propionic acid, chloroacetylphosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-1,3-diazole.

[0213] Histidyl residues are derivatized by reaction with diethylpyrocarbonate at pH 5.5-7.0 because this agent is relatively specific for the histidyl side chain. Para-bromophenacyl bromide is also useful, with the reaction preferably being performed in 0.1 M sodium cacodylate at pH 6.0.

[0214] Lysinyl and amino terminal residues are reacted with succinic anhydride or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl residue. Other suitable reagents for derivatizing alpha amino-containing residues include imidoesters such as methylpicolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pendandione; and transaminase-catalyzed reactions with glyoxylic acid.

[0215] Arginyl residues are modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. a Due to the high pH of arginine residues, derivatization of arginine residues must be performed in alkaline conditions. Furthermore, these reagents may react with lysine groups as well as the arginine epsilon-amino group.

[0216] The specific modification of tyrosyl residues, with particular interest in introducing spectral labels into tyrosyl residues, can be made by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly, N-acetylimidizole and tetranitromethane are used to form O-acetyltyrosyl species and 3-nitro derivatives, respectively. Tyrosyl residues can be 125 I or 131 1. Iodination with 1H to prepare labeled proteins for use in radioimmunoassays, the Chloramine T method described above being preferred;

[0217] Carboxyl side groups (aspartyl or glutamine) are reacted with carbodiimides (R'-N= C=N--R'), where R and R' are optionally different alkyl groups, such as 1-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimide or 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide. Furthermore, aspartyl and glutamine residues are converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.

[0218] Derivatization with bifunctional agents is useful for crosslinking antigen-binding proteins to water-insoluble support matrices or surfaces for use in a variety of methods. Commonly used crosslinking agents include bifunctional maleimides such as 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, e.g., esters with 4-azidosalicylic acid, homobifunctional imidoesters (including disuccinimidyl esters such as 3,3'-dithiobis(succinimidyl propionate)), and bis-N-maleimido-1,8-octane. Derivatizing agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate result in photoactivatable intermediates capable of forming crosslinks in the presence of light. Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and reactive substrates described in U.S. Patent Nos. 3,969,287, 3,691,016, 4,195,128, 4,247,642, 4,229,537, and 4,330,440 are utilized for immobilization of proteins.

[0219] Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues is within the scope of the invention.

[0220] Other modifications include hydroxylation of proline and lysine, phosphorylation of the hydroxyl group of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (TECreighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, 1983, pp. 79-86), acetylation of the N-terminal amine, and amidation of either C-terminal carboxyl group.

[0221] Another type of covalent modification of antigen binding proteins that falls within the scope of the present invention involves altering the glycosylation pattern of the protein. As is known in the art, glycosylation patterns can depend both on the sequence of the protein (e.g., the presence or absence of particular glycosylated amino acid residues, as described below), or on the host cell or organism in which the protein is produced. Specific expression systems are described below.

[0222] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tri-peptide sequences asparagine-X-serine and asparagine-X-threonine (X is any amino acid except proline) are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tri-peptide sequences in a polypeptide forms a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0223] Addition of glycosylation sites to the antigen binding protein is conveniently accomplished by altering the amino acid sequence to include one or more of the above-mentioned tri-peptide sequences (for N-linked glycosylation sites). Alterations may also be made by the addition or substitution of one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). To facilitate this, the amino acid sequence of the antigen binding protein is preferably altered by changes at the DNA level, specifically by mutating the DNA encoding the target polypeptide at preselected bases to form codons that are translated into the desired amino acids.

[0224] Another means of increasing the number of carbohydrate moieties of an antigen-binding protein is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. These methods are described in International Publication No. WO 87 / 05330, published September 11, 1987, and in Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp. 259-306.

[0225] Removal of carbohydrate moieties present on the starting antigen-binding protein may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linked sugar (N-acetylglucosamine or N-acetylgalactosamine) while leaving the polypeptide intact. Chemical deglycosylation has been described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52, and by Edge et al., 1981, Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties on the polypeptide can be accomplished by the use of various endo- and exo-glucosidases as described by Thotakura et al., 1987, Meth. Enzymol. 138:350. Glycosylation at potential glycosylation sites can be prevented by the use of the compound tunicamycin, as described by Duskin et al., 1982, J. Biol. Chem. 257:3105. Tunicamycin blocks the formation of protein-N-glycosidic linkages.

[0226] Another type of covalent modification of antigen binding proteins involves linking the antigen binding protein to various nonproteinaceous polymers, including, but not limited to, various polyols, such as polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner described in U.S. Patent Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337. Additionally, amino acid substitutions may be made at various positions within the antigen binding protein to facilitate the addition of polymers such as PEG, as is known in the art.

[0227] In some embodiments, the covalent modification of the antigen binding proteins of the invention comprises the addition of one or more labels.

[0228] The term "labeling group" refers to any detectable label. Examples of suitable labeling groups include, but are not limited to, radioisotopes or radionuclides (e.g., 3 H, 14 C. 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I), fluorescent groups (e.g., FITC, rhodamine, lanthanide fluorophores), enzymatic groups (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotinyl groups, or predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags). In some embodiments, the labeling group is attached to the antigen binding protein via spacer arms of various lengths to reduce potential steric hindrance. A variety of methods for labeling proteins are known in the art and can be used in practicing the present invention.

[0229] Generally, labels are divided into various classes depending on the assay in which they are detected: a) isotopic labels, which may be radioisotopes or heavy isotopes; b) magnetic labels (e.g., magnetic particles); c) redox-active moieties; d) optical dyes; enzymatic groups (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase); e) biotinylation groups; and f) predetermined polypeptide epitopes recognized by secondary reporters (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags, etc.). In some embodiments, the labeling group is attached to the antigen-binding protein via spacer arms of various lengths to reduce potential steric hindrance. A variety of methods for labeling proteins are known in the art and can be used in practicing the present invention.

[0230] Specific labels include optical dyes, including but not limited to chromophores, fluorophores, and fluorophores, the latter being often specific. Fluorophores can be either "small molecule" fluorescers or proteinaceous fluorescers.

[0231] "Fluorescent label" refers to any molecule that can be detected by its inherent fluorescent properties. Suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosine, coumarin, methyl-coumarin, pyrene, malachite green, stilbene, Lucifer Yellow, Cascade Blue J, Texas Red, IAEDANS, EDANS, BODIPY FL, LCRed640, Cy5, Cy5.5, LC Red 705, Oregon Green, Alexa-Fluor dyes (Alexa Fluor 350, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680), Cascade Blue, Cascade Yellow, and R-Phycoerythrin (PE) (Molecular Suitable optical dyes, including fluorophores, include those listed in the Molecular Probes catalogue, which is expressly incorporated herein by reference. It is described in the Handbook by Richard P. Haugland.

[0232] Suitable proteinaceous fluorescent labels include, but are not limited to, green fluorescent proteins including GFP from Renilla, Penaeus, or Aequorea species (Chalfie et al., 1994, Science 263:802-805), EGFP (Clontech Laboratories, Inc., Genbank Accession Number U55762), blue fluorescent protein (BFP, Quantum Biotechnologies, Inc. 1801 de Maisonneuve Blvd. West, 8th Floor, Montreal, Quebec, Canada H3H 1J9; Stauber, 1998, Biotechniques 24:462-471; Heim et al., 1996, Curr. Biol. 6:178-182), enhanced yellow fluorescent protein (EYFP, Clontech Laboratories, Inc.), luciferase (Ichiki et al., 1993, J. Immunol. 150:5408-5417), β-galactosidase (Nolan et al., 1999, J. Immunol. 150:5408-5417), and β-galactosidase (Nolan et al., 1999, J. Immunol. 150:5408-5417). al., 1988, Proc. Natl. Acad. Sci. USA 85:2603-2607) and Renilla reniformis (International Publication Nos. WO 92 / 15673, WO 95 / 07463, WO 98 / 14605, WO 98 / 26277, WO 99 / 49019, U.S. Patent Nos. 5,292,658, 5,418,155, 5,683,888, 5,741,668, 5,777,079, 5,804,387, 5,874,304, 5,876,995, 5,925,558). All of the above cited references are expressly incorporated herein by reference.

[0233] Exemplary antigen binding proteins described herein have characteristics based on the different epitopes on ST2 to which they bind. The term "epitope" refers to the amino acids of a target molecule that are contacted by an antigen binding protein, e.g., an antibody, when the antigen binding protein binds to the target molecule. Epitopes can be contiguous or discontinuous (e.g., (i) in a single-chain polypeptide, amino acid residues that are not contiguous with each other in the polypeptide sequence but are bound by the antigen binding protein in the context of the target molecule, or (ii) in a multimeric receptor that includes two or more individual components, e.g., ST2 and AcP, amino acid residues that are present in one or more of the individual components but are still bound by the antigen binding protein. Epitope determinants may include chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural characteristics, and / or specific charge characteristics. Typically, an antigen binding protein specific for a particular target molecule selectively recognizes an epitope on the target molecule in a complex mixture of proteins and / or macromolecules.

[0234] Methods for characterizing epitopes bound by antigen binding proteins are well known in the art and include, but are not limited to, binning (cross-competition) (Miller et al “Epitope binning of murine monoclonal antibodies by a multiplexed pairing assay” J Immunol Methods (2011) 365, 118-25), peptide mapping (e.g., PEPSPOT™) (Albert et al “ The B-cell Epitope of the Monoclonal Anti-Factor VIII Antibody ESH8 Characterized by Peptide Array Analysis"2008 Thromb Haemost 99,634-7), mutagenesis methods such as chimeras (Song et al "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients" J. Virol. (2010) 84,6935-6942), alanine scanning (Cunningham and Wells "High-resolution epitope mapping of HGH-receptor interactions by alanine-scanning mutagenesis" Science (1989) 244,1081-1085), arginine scanning (Lim et al “A diversity of antibody epitopes can induce signaling through the erythropoietin receptor”Biochemistry(2010)49,3797-38 04), HD exchange method (Coates et al “Epitope mapping by amide hydrogen / deuterium exchange coupled with immobilization of antibody, on-line proteolysis, liquid chromatography and mass spectrometry” Rapid Commun. Mass Spectrom.(2009)23 639-647), NMR cross-saturation method (Mor gan et al "Precise epitope mapping of malaria parasite inhibitory antibodies by TROSY NMR cross-saturation" Biochemistry (2005) 44, 518-23), and crystallography (Gerhardt et al "Structure of IL-17A in complex with a potent, fully human neutralizing antibody" J. Mol. Biol (2009) 394, 905-21). Methods vary in the level of detail they provide regarding the amino acids that comprise the epitope.

[0235] The antigen binding proteins of the present invention include those that have an epitope that overlaps with the exemplary antigen binding proteins described herein, such as Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33. In certain embodiments, the antigen binding protein has the same epitope as the exemplary antigen binding protein. In other embodiments, the antigen binding protein only binds to the same subset of amino acids as the exemplary antigen binding protein.

[0236] In certain embodiments, the ST2 antigen binding protein has an epitope identical or overlapping with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33, and has a) at least 90% similarity to the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165. a) a light chain variable domain that has at least 90% identity, at least 95% identity or identity to the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; or c) a light chain variable domain of a) and a heavy chain variable domain of b).

[0237] In certain embodiments, the ST2 antigen binding protein has an epitope identical or overlapping with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33, a light chain variable domain that is at least 90% identical, at least 95% identical, or identical to the amino acid sequence set forth in SEQ ID NO:95, and a light chain variable domain that is at least 90% identical, at least 95% identical, or identical to the amino acid sequence set forth in SEQ ID NO:29. a heavy chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 96 and a heavy chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 30; a light chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 97 and a heavy chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 31. those comprising a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:98 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:32; those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:99 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:33; those comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:100 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO:34;comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 101 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 35; comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 102 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 36; comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 103 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 37; comprising a light chain variable domain and sequence having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 104. comprising a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 38; comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 105 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 39; comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 163 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 145; comprising a light chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 164 and a heavy chain variable domain having at least 90% identity, at least 95% identity or identical to the amino acid sequence set forth in SEQ ID NO: 146;and those comprising a light chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 165 and a heavy chain variable domain having at least 90% identity, at least 95% identity, or identical to the amino acid sequence set forth in SEQ ID NO: 147;

[0238] In certain embodiments, the ST2 antigen binding protein has an epitope identical or overlapping with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33, and comprises: a) 10 amino acids from the amino acid sequence set forth in SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:163, SEQ ID NO:164, or SEQ ID NO:165. a) a light chain variable domain having the following or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:145, SEQ ID NO:146, or SEQ ID NO:147; or c) a light chain variable domain of a) and a heavy chain variable domain of b).

[0239] In certain embodiments, the ST2 antigen binding protein has an epitope identical or overlapping with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33, and includes a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:95 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:29; a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:96 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:30; a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:97 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:31. those comprising a heavy chain variable domain with no more than 0 or no more than 5 amino acid additions, deletions, or substitutions; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:98 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:32; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:99 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:33; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:100 and a light chain variable domain and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO:34;comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 101 and a light chain variable domain and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 35; comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 102 and a light chain variable domain and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 36; comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 103 and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 37; a light chain having no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 104. those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 105 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 39; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 163 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 145; those comprising a light chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 164 and a heavy chain variable domain with no more than 10 or no more than 5 amino acid additions, deletions or substitutions from the amino acid sequence set forth in SEQ ID NO: 146;and those comprising a light chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 165 and a heavy chain variable domain having no more than 10 or no more than 5 amino acid additions, deletions, or substitutions from the amino acid sequence set forth in SEQ ID NO: 147;

[0240] In certain embodiments, the ST2 antigen binding protein has an epitope identical to or overlapping with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33 and has a) an LCDR1 having no more than three amino acid additions, deletions, or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 106; an LCDR2 having no more than three amino acid additions, deletions, or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 117; and an LCDR3 having no more than three amino acid additions, deletions, or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 128. a) an LCDR1 having up to three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 107; an LCDR2 having up to three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 118; and an LCDR3 having up to three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 129; c) an LCDR1 having up to three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 108. an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 119; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 130; d) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 109; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 120; and an LCDR3 sequence set forth in SEQ ID NO: 131. e) an LCDR1 having up to 3 amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 110; an LCDR2 having up to 3 amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 121; and an LCDR3 having up to 3 amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 132; f) an LCDR1 having up to 3 amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 111;an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 122; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 133; g) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 112; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 123; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 134. h) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 113; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 124; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 135; i) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 114; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 125; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 136; j) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 115; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 126; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 137. k) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 116; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 127; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 138; l) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 166;m) an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 169; and an LCDR3 having no more than three amino acid additions, deletions or substitutions from the LCDR3 sequence set forth in SEQ ID NO: 172; m) an LCDR1 having no more than three amino acid additions, deletions or substitutions from the LCDR1 sequence set forth in SEQ ID NO: 167; an LCDR2 having no more than three amino acid additions, deletions or substitutions from the LCDR2 sequence set forth in SEQ ID NO: 170; and an LCDR3 sequence set forth in SEQ ID NO: 173. or n) an LCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR1 sequence set forth in SEQ ID NO: 168; an LCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR2 sequence set forth in SEQ ID NO: 171; and an LCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the LCDR3 sequence set forth in SEQ ID NO: 174; and o) an HCDR1 sequence set forth in SEQ ID NO: 40, HCDR1 having an addition, deletion or substitution of up to 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 51; and HCDR3 having an addition, deletion or substitution of up to 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 62; p) HCDR1 having an addition, deletion or substitution of up to 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 41; HCDR2 having an addition, deletion or substitution of up to 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 52; and HCDR3 having an addition, deletion or substitution of up to 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 63. q) an HCDR1 having an addition, deletion or substitution of no more than three amino acids from the HCDR1 sequence set forth in SEQ ID NO: 42; an HCDR2 having an addition, deletion or substitution of no more than three amino acids from the HCDR2 sequence set forth in SEQ ID NO: 53; and an HCDR3 having an addition, deletion or substitution of no more than three amino acids from the HCDR3 sequence set forth in SEQ ID NO: 64; r) an HCDR1 having an addition, deletion or substitution of no more than three amino acids from the HCDR1 sequence set forth in SEQ ID NO: 43;HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 54; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 65; s) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 44; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 55; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 66; t) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 45; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 56; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 67; u) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 46; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 57; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 68; v) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 47; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 58; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 69; w) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 48; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 59; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 70; x) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 49;HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 60; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 71; y) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 50; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 61; and HCDR3 having no more than 3 amino acid additions, deletions or substitutions from the HCDR3 sequence set forth in SEQ ID NO: 72; z) HCDR1 having no more than 3 amino acid additions, deletions or substitutions from the HCDR1 sequence set forth in SEQ ID NO: 148; HCDR2 having no more than 3 amino acid additions, deletions or substitutions from the HCDR2 sequence set forth in SEQ ID NO: 151; and set forth in SEQ ID NO: 154. aa) an HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 149; a HCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 152; and a HCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 155; or bb) an HCDR1 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR1 sequence set forth in SEQ ID NO: 150; a HCDR2 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR2 sequence set forth in SEQ ID NO: 153; and a HCDR3 having an addition, deletion or substitution of no more than 3 amino acids from the HCDR3 sequence set forth in SEQ ID NO: 156.

[0241] Preferred ST2 antigen binding proteins as described immediately above include those comprising a) a light chain variable domain and o) a heavy chain variable domain; those comprising b) a light chain variable domain and p) a heavy chain variable domain; those comprising c) a light chain variable domain and q) a heavy chain variable domain; those comprising d) a light chain variable domain and r) a heavy chain variable domain; those comprising e) a light chain variable domain and s) a heavy chain variable domain; those comprising f) a light chain variable domain and t) a heavy chain variable domain; those comprising g) a light chain variable domain and u) a heavy chain variable domain. those comprising the light chain variable domain of h) and the heavy chain variable domain of v); those comprising the light chain variable domain of i) and the heavy chain variable domain of w); those comprising the light chain variable domain of j) and the heavy chain variable domain of x); those comprising the light chain variable domain of k) and the heavy chain variable domain of y); those comprising the light chain variable domain of l) and the heavy chain variable domain of z); those comprising the light chain variable domain of m) and the heavy chain variable domain of aa); and those comprising the light chain variable domain of n) and the heavy chain variable domain of bb).

[0242] Antigen-binding proteins with identical or overlapping epitopes often cross-compete for binding to antigens. Thus, in certain embodiments, the antigen-binding proteins of the present invention cross-compete with Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab30, Ab32, or Ab33. "Cross-compete" or "cross-compete" means that the antigen-binding proteins compete for the same epitope or binding site on the target. Such competition can be determined by an assay in which a reference antigen-binding protein (e.g., an antibody or antigen-binding portion thereof) prevents or inhibits the specific binding of a test antigen-binding protein (and vice versa). Many types of competitive binding assays can be used to determine whether a test molecule competes with a reference molecule for binding. Examples of assays that can be utilized include solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competitive assays (see, e.g., Stahli et al. (1983) Methods in Enzymology 9:242-253), solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol. 137:3614-3619), solid-phase direct label assays, solid-phase direct label sandwich assays, Luminex (Jia et al “A novel method of Multiplexed Competitive Antibody Binning for the characterization of monoclonal antibodies” J. Immunological Methods (2004) 288, 91-98), and surface plasmon resonance. ((Song et al“Epitope Mapping of Ibalizumab,a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Exemplary methods for determining cross-competition are described in Example 5. Typically, when a competing antigen-binding protein is present in excess, it inhibits binding of a reference antigen-binding protein to a common antigen by at least 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more.

[0243] Ab2 binds with high affinity to human and cynomolgus ST2 and blocks IL-33 binding to ST2, thus blocking IL-33-mediated ST2 signaling. Antibodies against epitopes that are the same, similar, or overlapping with those of Ab2 may share these unique characteristics. In a preferred embodiment, the ST2 antigen binding protein cross-competes with Ab2 for binding to ST2. Exemplary ST2 antigen binding proteins that cross-compete with Ab2 include Ab1, Ab3, Ab5, Ab7, Ab8, and Ab30 (see Example 5). When attempting to find an antibody that binds to an epitope that is overlapping, similar, or identical to that of Ab2, one or more antibodies may be screened for cross-competition with Ab2. Furthermore, when creating variants against antibodies that cross-react with Ab2, such antibodies may be screened to determine whether cross-competition is maintained after diversification, suggesting that the epitope of the variant is not significantly altered from the parent molecule. Thus, in certain embodiments, the invention provides antibody variants that cross-compete with Ab2 for binding to ST2.

[0244] Antibodies with overlapping, similar, or identical epitopes other than cross-competing with each other can be similarly affected by ST2 mutagenesis. Certain mutations can inhibit antibody binding, while other mutations can enhance or activate binding. In Example 11, arginine / alanine mutagenesis of a portion of the extracellular domain of ST2 was performed to determine the effect on the exemplary antibody. ST2 binding proteins with characteristics that are affected by mutagenesis in a similar manner to the exemplary antibody are included within the scope of the present invention.

[0245] In certain embodiments, the binding of ST2 antigen-binding protein is inhibited by a single mutation in ST2, and the single mutation is selected from the group consisting of L14R, I15R, S33R, E43R, V47R, A62R, G65R, T79R, D92R, D97R, V104R, G138R, N152R, and V176R. In preferred embodiments, any or all of two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more of the single mutations in the group inhibit the binding of ST2 binding protein individually. In other embodiments, the binding of ST2 antigen-binding protein is activated by a single mutation in ST2, and the single mutation is selected from the group consisting of L53R, R72A, and S73R. In preferred embodiments, all of the single mutations in the group activate the binding of ST2 binding protein individually. In a preferred embodiment, the ST2 antigen binding protein shares the attributes of Ab2 and is inhibited by any of L14R, I15R, S33R, E43R, V47R, A62R, G65R, T79R, D92R, D97R, V104R, G138R, N152R, and V176R, and activated by any of L53R, R72A, and S73R.

[0246] Another method to characterize antibodies based on their epitopes is amide hydrogen / deuterium exchange (HDX). HDX has been widely used to study protein conformation and dynamics, protein-ligand interactions, and protein-protein interactions (Zhang and Smith 1993, Engen and Smith 2001). Because the replacement of one hydrogen with a deuterium results in a mass increase of 1 Da for each exchange, mass spectrometry detection provides a powerful tool to determine the extent of the exchange. The degree of HDX can be easily measured at the peptide level by analysis of the proteolysis of the protein by combining tandem mass spectrometry with liquid chromatography under controlled conditions (Engen and Smith 2001, Baerga-Ortiz, Hughes et al. 2002, Codreanu, Ladner et al. 2003). al.2002, Hamuro, Coales et al.2006, Coales, Tuske et al.2009, Zhang, Zhang et al.2012).

[0247] Comparison of antigen HDX profiles between proteolysis of ST2 in the absence and presence of antibody (free vs. bound) can reveal sites of interaction. Specifically, when antibody binds to ST2, solvent-exposed amide hydrogens in free ST2 can become protected, and as a result, slower exchange rates are observed. Thus, regions that gain less deuterium in the presence of antibody than in its absence are potential binding epitopes. Once epitopes are determined, other factors such as exchange rates in the free state, knowledge of antigen protein structure, and results of other epitope mapping efforts are considered.

[0248] Binding of Ab2 to ST2 was analyzed by HDX as described in Example 12. Analysis showed that Ab2 binds to a portion of the ST2 structure including amino acids 33-44 and 88-94 of SEQ ID NO:1 (amino acids 15-26 and 70-76 of mature ST2, respectively) of amino acids 19-322 of SEQ ID NO:1, altering its exchange rate. Antibodies against overlapping, similar or identical epitopes as those of Ab2 also bind to amino acids within SEQ ID NO:1 33-44 and 88-94, altering its exchange rate. In certain embodiments, an ST2 binding protein, e.g., an antibody, binds to ST2 and protects any of amino acids 33-44 of SEQ ID NO:1 when analyzed by HDX. In other embodiments, any of amino acids 88-94 is protected. Both show partial overlap with the binding epitope with Ab2. In a preferred embodiment, both any of 33-44 and any of 88-94 are protected. In certain embodiments, an ST2 binding protein, e.g., an antibody, binds to ST2 and protects all of amino acids 33-44 of SEQ ID NO:1 when analyzed by HDX. In other embodiments, all of amino acids 88-94 are protected. Both exhibit similar binding epitopes with Ab2. In preferred embodiments, both all of 33-44 and all of 88-94 are protected and exhibit the same or nearly the same epitope as for Ab2.

[0249] The binding of Ab2 to ST2 was further analyzed using X-ray crystallography. X-ray crystallography was consistent with the HDX analysis. The interface between Ab and antigen can be determined / defined in several ways. In Example 13, the interface was determined using solvent exposure difference and by distance. ST2 residues in the interface with Ab2 determined by solvent exposure difference or distance less than 5 Å are K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81 (corresponding to the positions of mature ST2 (lacking the leader sequence)). In certain embodiments, the ST2 binding protein forms an interface with ST2 that overlaps with the interface of Ab2, including those in which any of K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, or Y81 are present in the interface. In some embodiments, the ST2 binding protein forms an interface with ST2, and P19, R20, Q21, G22, K23, and / or Y26 are present in the interface. In other embodiments, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and / or Y81 are present in the interface. In a preferred embodiment, K1, F2, P19, R20, Q21, G22, K23, Y26, I70, V71, R72, S73, P74, T75, F76, N77, R78, T79, and Y81 are present within the interface.

[0250] The crystal structure showed that certain amino acid residues formed hydrogen bonds or salt bridges with amino acids of Ab2. These residues include K1, R20, K23, Y26, T75, N77, R78, and T79. In certain embodiments, the ST2 antigen binding protein forms hydrogen bonds or salt bridges with one or more of K1, R20, K23, Y26, T75, N77, R78, and T79.

[0251] The crystal structure further provides information on which residues of Ab2 form an interface with ST2. Figure 10 shows residues in the light and heavy chain variable regions that form an interface with ST2. Also shown are residues that form hydrogen bonds or salt bridges with amino acids in ST2. This information can be used to design variants of Ab2, including those that contain variable domains with 90% identity, 95% identity, and 10 or less insertions, deletions, and / or substitutions in the light or heavy chain variable domains of Ab2. It may be desirable to maintain amino acids in the interface while altering non-interface residues. Thus, variants of Ab2 that maintain binding to ST2 can be designed and created with one or more amino acid additions, substitutions, and / or deletions in one or more CDRs of Ab2.

[0252] In some embodiments, the ST2 binding protein comprises a variant of the Ab2 light chain variable region (SEQ ID NO: 96) in which D28, I29, S30, N31, Y32, Y49, D50, N53, E55, T56, D91, D92, N93, F94, and / or L96 remain unchanged or contain conservative substitutions thereof, and / or a variant of the Ab2 heavy chain variable region (SEQ ID NO: 30) in which W33, I50, D57, R59, H99, G100, T101, S102, S103, D104, Y105, and / or Y106 remain unchanged or contain conservative mutations. In a preferred embodiment, D28, N31, D50, N53, E55, D91, and D92 of the light chain variable region remain unchanged and S102, S103, D104, and Y105 of the heavy chain remain unchanged.

[0253] Polynucleotides encoding ST2 antigen-binding proteins Nucleic acids encoding ST2 antigen binding proteins, including antibodies, as defined herein are encompassed by the invention. Preferred nucleic acids include those encoding the exemplary light and heavy chains described herein.

[0254] An exemplary nucleic acid encoding Ab1 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:73.

[0255] An exemplary nucleic acid encoding Ab2 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:74.

[0256] An exemplary nucleic acid encoding Ab3 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:75.

[0257] An exemplary nucleic acid encoding Ab4 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:76.

[0258] An exemplary nucleic acid encoding Ab5 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:77.

[0259] An exemplary nucleic acid encoding Ab6 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:78.

[0260] An exemplary nucleic acid encoding Ab7 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:79.

[0261] An exemplary nucleic acid encoding Ab8 LC is a nucleic acid comprising the sequence set forth in SEQ ID NO:80.

[0262] An exemplary nucleic acid encoding Ab9 LC is a nucleic acid comprising the sequence set forth in SEQ ID NO:81.

[0263] An exemplary nucleic acid encoding Ab10 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:82.

[0264] An exemplary nucleic acid encoding Ab11 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:83.

[0265] An exemplary nucleic acid encoding Ab30 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:157.

[0266] An exemplary nucleic acid encoding Ab32 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:158.

[0267] An exemplary nucleic acid encoding Ab33 LC is the nucleic acid comprising the sequence set forth in SEQ ID NO:159.

[0268] An exemplary nucleic acid encoding Ab1 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:7.

[0269] An exemplary nucleic acid encoding Ab2 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:8.

[0270] An exemplary nucleic acid encoding Ab3 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:9.

[0271] An exemplary nucleic acid encoding Ab4 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:10.

[0272] An exemplary nucleic acid encoding Ab5 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:11.

[0273] An exemplary nucleic acid encoding Ab6 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:12.

[0274] An exemplary nucleic acid encoding Ab7 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:13.

[0275] An exemplary nucleic acid encoding Ab8 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:14.

[0276] An exemplary nucleic acid encoding Ab9 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:15.

[0277] An exemplary nucleic acid encoding Ab10 HC is the nucleic acid comprising the sequence set forth in SEQ ID NO:16.

[0278] An exemplary nucleic acid encoding Ab11 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:17.

[0279] An exemplary nucleic acid encoding Ab30 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:139.

[0280] An exemplary nucleic acid encoding Ab32 HC is a nucleic acid comprising the sequence set forth in SEQ ID NO:140.

[0281] An exemplary nucleic acid encoding Ab33 HC is the nucleic acid comprising the sequence set forth in SEQ ID NO:141.

[0282] Aspects of the invention include polynucleotide variants (eg, due to degeneracy) that encode the amino acid sequences described herein.

[0283] Aspects of the present invention include various embodiments, including but not limited to the following exemplary embodiments.

[0284] 1. An isolated polynucleotide, the polynucleotide encoding one or more polypeptides comprising an amino acid sequence selected from the group consisting of:

[0285] A.1. A light chain variable domain sequence that is at least 90% identical to a light chain variable domain sequence set forth in SEQ ID NOs: 95-105, 163-165;

[0286] 2. A heavy chain variable domain sequence that is at least 90% identical to a heavy chain variable domain sequence set forth in SEQ ID NOs: 29 to 39, 145 to 147;

[0287] 3. A light chain variable domain of (1) and a heavy chain variable domain of (2); and

[0288] B. A light chain variable domain comprising CDR1, CDR2, CDR3 and / or a heavy chain variable domain comprising CDR1, CDR2, CDR3 that are the same or differ by a total of no more than three amino acid additions, substitutions, and / or deletions in each CDR from the following sequences:

[0289] 1. Light chain CDR1 (SEQ ID NO:106), CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:128), or heavy chain CDR1 (SEQ ID NO:40), CDR2 (SEQ ID NO:51), CDR3 (SEQ ID NO:62) of Ab1;

[0290] 2. light chain CDR1 (SEQ ID NO:107), CDR2 (SEQ ID NO:118), CDR3 (SEQ ID NO:129), or heavy chain CDR1 (SEQ ID NO:41), CDR2 (SEQ ID NO:52), CDR3 (SEQ ID NO:63) of Ab2;

[0291] 3. Light chain CDR1 (SEQ ID NO:108), CDR2 (SEQ ID NO:119), CDR3 (SEQ ID NO:130), or heavy chain CDR1 (SEQ ID NO:42), CDR2 (SEQ ID NO:53), CDR3 (SEQ ID NO:64) of Ab3;

[0292] 4. Light chain CDR1 (SEQ ID NO:109), CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:131), or heavy chain CDR1 (SEQ ID NO:43), CDR2 (SEQ ID NO:54), CDR3 (SEQ ID NO:65) of Ab4;

[0293] 5. Light chain CDR1 (SEQ ID NO:110), CDR2 (SEQ ID NO:121), CDR3 (SEQ ID NO:132), or heavy chain CDR1 (SEQ ID NO:44), CDR2 (SEQ ID NO:55), CDR3 (SEQ ID NO:66) of Ab5;

[0294] 6. Light chain CDR1 (SEQ ID NO:111), CDR2 (SEQ ID NO:122), CDR3 (SEQ ID NO:133), or heavy chain CDR1 (SEQ ID NO:45), CDR2 (SEQ ID NO:56), CDR3 (SEQ ID NO:67) of Ab6;

[0295] 7. Light chain CDR1 (SEQ ID NO:112), CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:134), or heavy chain CDR1 (SEQ ID NO:46), CDR2 (SEQ ID NO:57), CDR3 (SEQ ID NO:68) of Ab7;

[0296] 8. Light chain CDR1 (SEQ ID NO:113), CDR2 (SEQ ID NO:124), CDR3 (SEQ ID NO:135), or heavy chain CDR1 (SEQ ID NO:47), CDR2 (SEQ ID NO:58), CDR3 (SEQ ID NO:69) of Ab8;

[0297] 9. Light chain CDR1 (SEQ ID NO:114), CDR2 (SEQ ID NO:125), CDR3 (SEQ ID NO:136), or heavy chain CDR1 (SEQ ID NO:48), CDR2 (SEQ ID NO:59), CDR3 (SEQ ID NO:70) of Ab9;

[0298] 10. Light chain CDR1 (SEQ ID NO:115), CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:137), or heavy chain CDR1 (SEQ ID NO:49), CDR2 (SEQ ID NO:60), CDR3 (SEQ ID NO:71) of Ab10;

[0299] 11. Light chain CDR1 (SEQ ID NO:116), CDR2 (SEQ ID NO:127), CDR3 (SEQ ID NO:138), or heavy chain CDR1 (SEQ ID NO:50), CDR2 (SEQ ID NO:61), CDR3 (SEQ ID NO:72) of Ab11;

[0300] 12. Light chain CDR1 (SEQ ID NO: 166), CDR2 (SEQ ID NO: 169), CDR3 (SEQ ID NO: 172), or heavy chain CDR1 (SEQ ID NO: 148), CDR2 (SEQ ID NO: 151), CDR3 (SEQ ID NO: 154) of Ab30;

[0301] 13. The light chain CDR1 (SEQ ID NO: 167), CDR2 (SEQ ID NO: 170), CDR3 (SEQ ID NO: 173), or the heavy chain CDR1 (SEQ ID NO: 149), CDR2 (SEQ ID NO: 152), CDR3 (SEQ ID NO: 155) of Ab32; and

[0302] 14. Light chain CDR1 (SEQ ID NO: 168), CDR2 (SEQ ID NO: 171), CDR3 (SEQ ID NO: 174), or heavy chain CDR1 (SEQ ID NO: 150), CDR2 (SEQ ID NO: 153), CDR3 (SEQ ID NO: 156) of Ab33.

[0303] In a preferred embodiment, the polypeptide encoded by the isolated nucleic acid is a component of an antigen-binding protein that binds to ST2.

[0304] Nucleotide sequences corresponding to the amino acid sequences described herein, used as probes or primers for isolating nucleic acids or as query sequences for database searches, can be obtained by "reverse translation" from the amino acid sequence or by identifying regions of amino acid identity with a polypeptide whose encoding DNA sequence has been identified. Well-known polymerase chain reaction (PCR) procedures can be used to isolate and amplify DNA sequences encoding ST2 antigen binding proteins, or the desired combination of ST2 antigen binding protein polypeptide fragments. Oligonucleotides that define the desired termini of the combination of DNA fragments are used as 5' and 3' primers. The oligonucleotides can additionally contain recognition sites for restriction endonucleases to facilitate insertion of the amplified combination of DNA fragments into an expression vector. PCR techniques are described in Saiki et al., Science 239:487 (1988); Recombinant DNA Methodology, Wu et al., eds., Academic Press, Inc., San Diego (1989), pp. 189-196; and PCR Protocols: A Guide to Methods and Applications, Innis et.al., eds., Academic Press, Inc. (1990).

[0305] The nucleic acid molecules of the present invention include both single-stranded and double-stranded forms of DNA and RNA, and corresponding complementary sequences.DNA includes, for example, cDNA, genomic DNA, chemically synthesized DNA, DNA amplified by PCR, and combinations thereof.The nucleic acid molecules of the present invention include full-length genes or cDNA molecules, and combinations of fragments thereof.The nucleic acids of the present invention are preferentially derived from human sources, but the present invention also includes those derived from non-human species.

[0306] In the case of nucleic acids isolated from naturally occurring sources, an "isolated nucleic acid" is a nucleic acid that is separated from adjacent gene sequences present in the genome of the organism from which the nucleic acid is isolated. In the case of nucleic acids that are enzymatically synthesized or chemically synthesized from a template, such as PCR products, cDNA molecules, or oligonucleotides, it is understood that the nucleic acid obtained from such a process is an isolated nucleic acid. An isolated nucleic acid molecule refers to a nucleic acid molecule in the form of an isolated fragment or as a component of a larger nucleic acid construct. In one preferred embodiment, the nucleic acid is substantially free of endogenous contaminants. It is preferred that the nucleic acid molecule is derived from DNA or RNA that has been isolated at least once, in a substantially pure form and in an amount or concentration that allows the identification, manipulation, and recovery of its component nucleotide sequences by standard biochemical methods (such as those outlined in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1989)). Such sequences are desirably provided and / or constructed in the form of an open reading frame uninterrupted by internal non-translated sequences, or introns, that are typically present in eukaryotic genes. Sequences of non-translated DNA may be present 5' or 3' to the open reading frame, provided that such sequences do not interfere with manipulation or expression of the coding region.

[0307] The present invention also includes nucleic acids that hybridize under moderately stringent conditions, and more preferably under highly stringent conditions, to nucleic acids encoding ST2 antigen binding proteins as described herein. Basic parameters influencing the selection of hybridization conditions, and guidelines for devising suitable conditions, are described by Sambrook,, Fritsch, and Maniatis (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, chapters 9 and 11; and Current Protocols in Molecular Biology, 1995, Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4) and can be readily determined by one of skill in the art, e.g., based on DNA length and / or base composition. One method of achieving moderately stringent conditions involves the use of a pre-wash solution containing 5×SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0), a hybridization buffer of about 50% formamide, 6×SSC, and a hybridization temperature of about 55° C. (or other similar hybridization solutions such as those containing about 50% formamide, with a hybridization temperature of about 42° C.), and wash conditions in 0.5×SSC, 0.1% SDS at about 60° C. Generally, highly stringent conditions are defined as hybridization conditions as above, but with a wash of 0.2×SSC, 0.1% SDS at about 68° C. SSPE (1xSSPE is 0.15 M NaCl, 10 mM NaH2PO4, and 1.25 mM EDTA, pH 7.4) may be substituted for SSC (1xSSC is 0.15 M NaCl and 15 mM sodium citrate) in the hybridization and washing buffers, and washing is performed for 15 minutes after hybridization is completed.It should be understood that washing temperature and washing salt concentration can be adjusted as necessary to achieve the desired degree of stringency by applying basic principles governing hybridization reactions and duplex stability, as known to those skilled in the art and as described in detail below (see, for example, Sambrook et al., 1989). When hybridizing a nucleic acid to a target nucleic acid of known sequence, the length of the hybrid is assumed to be the length of the hybridizing nucleic acid. When hybridizing a nucleic acid of known sequence, the length of the hybrid can be determined by aligning the sequences of the nucleic acids to identify the region(s) of optimal sequence complementarity. The hybridization temperature for hybrids predicted to be less than 50 base pairs in length should be 5-10°C lower than the melting temperature (Tm) of the hybrid, with Tm being determined according to the following equation: For hybrids less than 18 base pairs, Tm(°C)=2(number of A+T bases)+4(number of G+C bases). For hybrids of more than 18 base pairs, Tm(°C)=81.5+16.6(log 10 [Na + ])+0.41(%G+C)-(600 / N), where N is the number of bases in the hybrid and [Na + ] is the concentration of sodium ions in the hybridization buffer ([Na +

[0036] =0.165M). Preferably, each such hybridizing nucleic acid has a length that is at least 15 nucleotides (or, more preferably, at least 18 nucleotides, or at least 20 nucleotides, or at least 25 nucleotides, or at least 30 nucleotides, or at least 40 nucleotides, or most preferably at least 50 nucleotides) or at least 25% (more preferably, at least 50%, or at least 60%, or at least 70%, most preferably at least 80%) of the length of the nucleic acid of the invention to which it hybridizes, and is at least 60% (more preferably, at least 70%, at least Preferably, the hybridization sequence has at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, and most preferably at least 99.5%) sequence identity, as described in more detail above, where sequence identity is determined by comparing the sequences of hybridizing nucleic acids when aligned to maximize overlap and identity while minimizing sequence gaps.

[0308] The variants according to the invention are typically prepared by site-directed mutagenesis of nucleotides in the DNA encoding the antigen-binding protein using cassette or PCR mutagenesis, or other techniques well known in the art, to generate DNA encoding the variant, followed by expression of the recombinant DNA in cell culture as outlined herein. However, antigen-binding protein fragments containing variant CDRs having up to about 100-150 residues may also be prepared by in vitro synthesis using established techniques. The variants typically exhibit the same qualitative biological activity, e.g., binding to ST2, as the naturally occurring analogue, although variants may be selected with modified characteristics, as outlined in more detail below.

[0309] As will be appreciated by those skilled in the art, due to the degeneracy of the genetic code, a very large number of nucleic acids can be generated, all of which encode the CDRs (as well as the heavy and light chains or other components of the antigen-binding protein) of the present invention. Thus, having identified a particular amino acid sequence, one skilled in the art can create any number of different nucleic acids by simply modifying the sequence of one or more codons in a manner that does not change the amino acid sequence of the encoded protein.

[0310] The present invention also provides expression systems and constructs in the form of plasmids, expression vectors, transcription or expression cassettes comprising at least one polynucleotide as described above. Additionally, the present invention provides host cells comprising such expression systems or constructs.

[0311] Typically, expression vectors used in any of the host cells contain sequences for plasmid maintenance and sequences for cloning and expressing exogenous nucleotide sequences. Such sequences, collectively referred to in certain embodiments as "flanking sequences", typically include one or more of the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcription termination sequence, a complete intron sequence containing donor and acceptor splicing sites, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element. Each of these sequences is described below.

[0312] Optionally, the vector may contain a "tag" coding sequence, i.e., an oligonucleotide molecule located at the 5' or 3' end of the ST2 antigen binding protein coding sequence, which encodes polyHis (such as hexaHis) for which commercially available antibodies exist, or another "tag", e.g., FLAG, HA (influenza virus hemagglutinin), or myc. This tag is typically fused to the polypeptide upon expression of the polypeptide and can serve as a means for affinity purification or detection of the ST2 antigen binding protein from host cells. Affinity purification may be achieved, for example, by column chromatography using antibodies against the tag as an affinity matrix. Optionally, the tag may then be removed from the purified ST2 antigen binding protein by various means, such as using specific peptidases for cleavage.

[0313] Flanking sequences can be homologous (i.e., derived from the same species and / or strain as the host cell), heterologous (i.e., derived from a species other than the host cell species or strain), hybrid (i.e., a combination of flanking sequences from more than one source), synthetic, or natural. Thus, the source of a flanking sequence can be any prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, or any plant, so long as the flanking sequence is functional in and can be activated by the host cell machinery.

[0314] Flanking sequences useful in the vector of the present invention can be obtained by any of several methods well known in the art. Typically, flanking sequences useful herein have been previously identified by mapping and / or by restriction endonuclease digestion, and can therefore be isolated from suitable tissue sources using appropriate restriction endonucleases. In some cases, the full-length nucleotide sequence of the flanking sequence may be known. Herein, flanking sequences may be synthesized using the methods described herein for synthesizing or cloning nucleic acids.

[0315] Whether all or only a portion of the flanking sequence is known, the flanking sequence can be obtained using polymerase chain reaction (PCR) and / or by screening a genomic library with suitable probes, such as oligonucleotides and / or flanking sequence fragments from the same or another species. If the flanking sequence is unknown, a fragment of DNA containing the flanking sequence may be isolated from a larger piece of DNA that may contain, for example, a coding sequence or even another gene(s). Isolation may be accomplished by generating the appropriate DNA fragment by restriction endonuclease digestion, followed by isolation using agarose gel purification, Qiagen® column chromatography (Chatsworth, Calif.), or other methods known to those of skill in the art. The selection of suitable enzymes to accomplish this purpose will be readily apparent to those of skill in the art.

[0316] Replication origins are typically part of commercially purchased prokaryotic expression vectors, and origins aid in the amplification of vectors in host cells. If the vector of choice does not contain a replication origin site, one may be chemically synthesized based on a known sequence and ligated into the vector. For example, the replication origin from plasmid pBR322 (New England Biolabs, Beverly, Mass.) is suitable for most Gram-negative bacteria, and various viral origins (e.g., SV40, polyoma, adenovirus, vesicular stomatitis virus (VSV), or papillomavirus such as HPV or BPV) are useful for cloning vectors in mammalian cells. Usually, the replication origin component is not required for mammalian expression vectors (e.g., the SV40 origin is often used simply because it also contains the viral early promoter).

[0317] Transcription termination sequence is typically located at the 3' end of the polypeptide coding region and serves to terminate transcription.Usually, the transcription termination sequence of prokaryotic cells is a GC-rich fragment followed by a poly-T sequence.This sequence can be easily cloned from a library or even purchased commercially as part of a vector, but can also be easily synthesized using methods for nucleic acid synthesis such as those described herein.

[0318] A selectable marker gene encodes a protein necessary for the survival and growth of a host cell grown in a selective culture medium. Typical selectable marker genes encode (a) a protein that confers resistance to antibiotics or other toxins, such as ampicillin, tetracycline, or kanamycin in the case of prokaryotic host cells; (b) a protein that complements auxotrophic deficiencies of the cell; or (c) a protein that supplies a critical nutrient that is unavailable from a complex or defined medium. Particular selectable markers are the kanamycin resistance gene, the ampicillin resistance gene, and the tetracycline resistance gene. Advantageously, the neomycin resistance gene can also be used for selection in both prokaryotic and eukaryotic host cells.

[0319] Other selectable genes may be used to amplify the expressed genes. Amplification is the process in which genes required for the production of proteins critical for growth or cell survival are repeated in tandem in the chromosomes of successive generations of recombinant cells. Examples of suitable selectable markers for mammalian cells include dihydrofolate reductase (DHFR) and promoterless thymidine kinase genes. Mammalian cell transformants are placed under selection pressure that is uniquely adapted to the survival of only transformants by the selectable gene present in the vector. Selection pressure is imposed by culturing the transformed cells under conditions in which the concentration of the selection agent in the medium is successively increased, thereby resulting in the amplification of both the selectable gene and another gene, such as DNA encoding an antigen-binding protein antibody that binds to the ST2 polypeptide. As a result, an increased amount of polypeptide, such as ST2 antigen-binding protein, is synthesized from the amplified DNA.

[0320] A ribosome binding site is usually necessary for translation initiation of mRNA and is characterized by a Shine-Dalgarno sequence (prokaryotes) or a Kozak sequence (eukaryotes). This element is typically located 3' to the promoter and 5' to the coding sequence of the polypeptide to be expressed. In certain embodiments, one or more coding regions may be operably linked to an internal ribosome binding site (IRES), allowing translation of two open reading frames from a single RNA transcript.

[0321] In some cases, for example, when glycosylation is desired in a eukaryotic host cell expression system, various pre- or pro-sequences can be manipulated to improve glycosylation or yield. For example, the peptidase cleavage site of a particular signal peptide may be changed, or a pro-sequence may be added, which may also affect glycosylation. The final protein product may have one or more additional amino acids at position -1 (relative to the first amino acid of the mature protein) upon expression, which may not be completely removed. For example, the final protein product may have one or two amino acid residues found in the peptidase cleavage site attached to the amino terminus. Alternatively, the use of some enzyme cleavage sites may result in a slightly truncated form of the desired polypeptide when the enzyme cleaves such a region in the mature polypeptide.

[0322] The expression and cloning vectors of the invention typically contain a promoter that is recognized by the host organism and operably linked to the molecule encoding the ST2 antigen binding protein. A promoter is conventionally a non-transcribed sequence located upstream (i.e., 5') of the start codon of a structural gene (usually within about 100-1000 bp) that controls transcription of the structural gene. Promoters are classified into one of two classes: inducible and constitutive. Inducible promoters initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, such as the presence or absence of a nutrient or a change in temperature. Constitutive promoters, on the other hand, transcribe the genes to which they are operably linked uniformly, i.e., with little or no control over gene expression. Numerous promoters that are recognized by a variety of potential host cells are well known. A suitable promoter is operably linked to DNA encoding the heavy or light chains comprising the ST2 antigen binding protein of the invention by removing the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into the vector.

[0323] Suitable promoters for use with yeast hosts are also well known in the art. Yeast enhancers are advantageously used with yeast promoters. Suitable promoters for use with mammalian host cells are well known, including, but not limited to, those obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, and most preferably simian virus 40 (SV40). Other suitable mammalian promoters include heterologous mammalian promoters, such as heat shock promoters and actin promoters.

[0324] Additional promoters of interest include, but are not limited to, the SV40 early promoter (Benoist and Chambon, 1981, Nature 290:304-310); the CMV promoter (Thornsen et al., 1984, Proc. Natl. Acad. USA 81:659-663); the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797); the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. USA 78:1444-1445); promoters and control sequences from metallothionein genes (Prinster et al., 1982, Nature 296:39-42); and prokaryotic promoters such as the β-lactamase promoter (Villa-Kamaroff et al., 1982, Nature 296:39-42). al., 1978, Proc. Natl. Acad. Sci. USA 75:3727-3731); or the tac promoter (DeBoer et al., 1983, Proc. Natl. Acad. Sci. USA 80:21-25).Also of interest are the following animal transcriptional control regions that exhibit tissue specificity and have been utilized in transgenic animals: the elastase I gene control region, active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulin gene control region, active in pancreatic β cells (Hanahan, 1985, Nature 315:115-122); the immunoglobulin gene control region, active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658; Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Hepatology 7:425-515); al., 1987, Mol. Cell. Biol. 7:1436-1444); mouse mammary tumor virus control region active in testicular, breast, lymphoid, and mast cells (Leder et al., 1986, Cell 45:485-495); albumin gene control region active in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276); alpha-fetoprotein gene control region active in liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science 253:53-58); alpha-1 antitrypsin gene control region active in liver (Kelsey et al., 1987, Genes and. Devel. 1:161-171); the beta-globin gene control region, which is active in myeloid cells (Mogram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94); the myelin basic protein gene control region, which is active in oligodendrocyte cells in the brain (Readhead et al., 1987, Cell 48:703-712); the myosin light chain-2 gene control region, which is active in skeletal muscle (Sani, 1985, Nature 314:283-286); and the gonadotropin-releasing hormone gene control region, which is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378).

[0325] Enhancer sequences may be inserted into vectors to increase transcription of DNA encoding the light or heavy chain constituting the ST2 antigen binding protein of the present invention by higher eukaryotes. Enhancers are cis-acting elements of DNA, usually about 10-300 bp in length, that act on promoters to increase transcription. Enhancers are relatively orientation and position independent, and are found at both 5' and 3' positions of transcription units. Several enhancer sequences are known that are available from mammalian genes (e.g., globin, elastase, albumin, alpha-fetoprotein, and insulin). However, typically enhancers from viruses are used. SV40 enhancers, cytomegalovirus early promoter enhancers, polyoma enhancers, and adenovirus enhancers known in the art are exemplary facilitating elements for eukaryotic promoter activation. Enhancers may be located in vectors either 5' or 3' of the coding sequence, but are typically located at the 5' site of the promoter. To promote extracellular secretion of the antibody, a sequence encoding a suitable native or heterologous signal sequence (leader sequence or signal peptide) can be incorporated into the expression vector. The choice of signal peptide or leader depends on the type of host cell in which the antibody is produced, and a heterologous signal sequence can replace the native signal sequence. Examples of signal peptides that are functional in mammalian host cells include the signal sequence of interleukin 7 (IL-7) described in U.S. Pat. No. 4,965,195; the signal sequence of interleukin 2 receptor described in Cosman et al., 1984, Nature 312:768; the interleukin 4 receptor signal peptide described in European Patent No. 0 367 566; the type I interleukin 1 receptor signal peptide described in U.S. Pat. No. 4,968,607; the type II interleukin 1 receptor signal peptide described in European Patent No. 0 460 846.

[0326] Vectors may contain one or more elements that promote expression when the vector is integrated into the host cell genome. Examples include EASE elements (Aldrich et al.2003 Biotechnol Prog.19:1433-38) and matrix attachment regions (MARs). MARs mediate the organization of chromatin structure and can shield the integrated vector from "position" effects. Thus, MARs are particularly useful when the vector is used to generate stable transformants. Many natural and synthetic MAR-containing nucleic acids are known in the art (e.g., U.S. Patent Nos. 6,239,328, 7,326,567, 6,177,612, 6,388,066, 6,245,974, 7,259,010, 6,037,525, 7,422,874, 7,129,062).

[0327] The expression vector of the present invention may be constructed from a starting vector, such as a commercially available vector. Such vector may or may not contain all of the desired flanking sequences. If one or more of the flanking sequences described herein are not already present in the vector, they may be obtained separately and linked to the vector. The method used to obtain each of the flanking sequences is well known to those skilled in the art.

[0328] After the vector is constructed and the nucleic acid molecules encoding the light, heavy, or light and heavy chains that constitute the ST2 antigen binding sequence are inserted into the appropriate sites of the vector, the completed vector may be inserted into a suitable host cell for amplification and / or polypeptide expression. Transformation of the expression vector of the ST2 antigen binding protein into the selected host cell can be accomplished by well-known methods, including transfection, infection, calcium phosphate co-precipitation, electroporation, microinjection, lipofection, DEAE-dextran mediated transfection, or other known techniques. The method selected will depend, in part, on the type of host cell used. These and other suitable methods are well known to those of skill in the art and are described, for example, in Sambrook et al., 2001 (see above).

[0329] When cultured under appropriate conditions, the host cells synthesize ST2 antigen-binding proteins, which can then be recovered from the medium (if the host cells secrete the protein into the medium) or directly from the host cells that produce it (if the protein is not secreted). The selection of an appropriate host cell depends on a variety of factors, such as the desired expression level, the polypeptide modifications (such as glycosylation or phosphorylation) that are desired or necessary for activity, and the ease of folding into biologically active molecules. The host cells can be eukaryotic or prokaryotic.

[0330] Mammalian cell lines that can be used as hosts for expression are well known in the art and include, but are not limited to, immortalized cell lines available from the American Type Culture Collection (ATCC) and any cell lines used in expression systems known in the art that can be used to produce recombinant polypeptides of the present invention. In general, host cells are transformed with recombinant expression vectors that contain DNA encoding the desired anti-ST2 antibody polypeptide. Among them, prokaryotic cells, yeast cells, or higher eukaryotic cells are host cells that can be used. Prokaryotes include gram-negative or gram-positive bacteria, such as E. coli or Bacillus. Higher eukaryotic cells include insect cells and established cell lines of mammalian origin. Examples of suitable mammalian host cells include the COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al., 1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells or their derivatives, such as Veggie CHO and related cell lines grown in serum-free medium (Rasmussen et al., 1998, Cytotechnology 28:31), HeLa cells, the BHK (ATCC CRL 10) cell line, McMahan cells, and the like. Examples of such cell lines include the CVI / EBNA cell line (ATCC CCL 70) derived from the African green monkey kidney cell line CVI as described in et al., 1991, EMBO J. 10:2821, human fetal kidney cells, such as 293, 293 EBNA, or MSR 293, human epidermal A431 cells, human Colo205 cells, other transformed primate cell lines, normal diploid cells, cell lines derived from in vitro culture of primary tissues, primary explants, HL-60, U937, HaK, or Jurkat cells. Optionally, when it is desired to use the polypeptide in various signal transduction or reporter assays, mammalian cell lines, such as HepG2 / 3B, KB, NIH 3T3, or S49, can be used for the expression of the polypeptide. Alternatively, it is possible to produce the polypeptide in lower eukaryotes, such as yeast, or in prokaryotes, such as bacteria. Suitable yeasts include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing a heterologous polypeptide. Suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing a heterologous polypeptide. If the polypeptide is made in yeast or bacteria, it may be desirable to modify the polypeptide produced therein, for example by phosphorylation or glycosylation of appropriate sites, to obtain a functional polypeptide. Such covalent attachment can be accomplished using known chemical or enzymatic methods. The polypeptide can also be produced by operably linking the isolated nucleic acid of the invention to suitable control sequences of one or more insect expression vectors and utilizing an insect expression system. Materials and methods for baculovirus / insect cell expression systems are commercially available in kit form from, for example, Invitrogen, San Diego, Calif., USA (MaxBac® kit), and such methods are described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987) and Luckow and Summers, Bio / Technology 6:47 (1988), are well known in the art. Cell-free translation systems can also be utilized to produce polypeptides using RNA derived from the nucleic acid constructs disclosed herein. Suitable cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cell hosts are described in Pouwels et al. (Cloning (Vecters: A Laboratory Manual, Elsevier, New York, 1985). Preferably, a host cell containing an isolated nucleic acid of the invention operably linked to at least one expression control sequence is a "recombinant host cell."

[0331] In certain embodiments, cell lines may be selected by determining which cell lines have high expression levels and constitutively produce antigen binding proteins with ST2 binding properties, hi another embodiment, cell lines derived from the B cell lineage that do not make their own antibodies but have the ability to make and secrete heterologous antibodies may be selected.

[0332] ST2 antigen-binding protein that depletes cells In a preferred embodiment, ST2 antigen binding protein binds to ST2 and inhibits the binding of IL-33, thereby reducing the signal transduction mediated by IL-33 in cells expressing ST2.However, in certain embodiments, ST2 antigen binding protein binds to ST2 and targets cells expressing ST2 for depletion.Of course, ST2 antigen binding protein can also inhibit the binding of IL-33 and target ST2 cells for depletion.

[0333] The ST2 antigen binding protein that depletes cells is particularly useful for treating diseases associated with overexpression of ST2, such as inflammatory diseases or tumors that express ST2.Methods for targeting cells using antigen binding proteins, such as antibodies, are well known in the art.Exemplary embodiments are described below.

[0334] Antibody Drug Conjugates The embodiment of the present invention includes antibody drug conjugates (ADCs). Usually, ADCs include antibodies conjugated to chemotherapeutic agents, such as cytotoxic agents, cytostatic agents, toxins, or radioactive agents. Linker molecules can be used to conjugate drugs to antibodies. A variety of linkers and drugs useful in ADC technology are known in the art and can be used in the embodiments of the present invention. (See U.S. Patent Application Publication Nos. 20090028856; 2009 / 0274713; 2007 / 0031402; International Publication Nos. WO2005 / 084390; WO2009 / 099728; U.S. Patent Nos. 5,208,020; 5,416,064; 5,475,092; 5,585,499; 6436931; 6,372,738; and 6,340,701, all of which are incorporated herein by reference).

[0335] Linker In certain embodiments, the ADC comprises a linker composed of one or more linker moieties. Exemplary linker moieties include 6-maleimidocaproyl, maleimidopropanoyl, valine-citrulline, alanine-phenylalanine, p-aminobenzyloxycarbonyl, and those resulting from conjugation with linker reagents including, but not limited to, N-succinimidyl 4-(2-pyridylthio)pentanoate ("SPP"), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate ("SMCC", also referred to herein as "MCC"), and N-succinimidyl (4-iodo-acetyl)aminobenzoate ("SIAB").

[0336] Linkers can be "cleavable" or "non-cleavable" linkers (Ducry and Stump, Bioconjugate Chem. 2010, 21, 5-13: incorporated herein by reference in its entirety). Cleavable linkers are designed to release drugs when subjected to certain environmental factors, for example, when internalized into target cells. Cleavable linkers include acid-labile linkers, protease-sensitive linkers, photolabile linkers, dimethyl linkers, or disulfide-containing linkers. Non-cleavable linkers tend to remain covalently associated with at least one amino acid of the antibody and the drug upon internalization by and degradation within target cells. An exemplary non-cleavable linker is MCC.

[0337] Drugs In certain embodiments, the antibody is conjugated to a chemotherapeutic agent. Exemplary chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN.TM.); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictin; spongiostatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine; ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine; phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., the calicheamicins, particularly calicheamicin gamma 1, and calicheamicin theta I (e.g., the Angew See Chem. Intl. Ed. Engl. 33:183-186 (1994); the dynemycins, including dynemycin A; the esperamicins;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin). , epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues, such as pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides. Cid;Aminolevulinic acid;Amsacrine;Bestravcil;Bisantrene;Edatrexate;Defofamine;Demecolcine;Diaziquone;Elfomithine;Elliptinium acetate;Epothilone;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Maytansinoids, such as maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK.RTM.; razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel (TAXOL.TM., Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE.RTM., Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylomithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit the action of hormones on tumors, such as anti-estrogens (including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and toremifene (Fareston)); and anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; siRNAs, and pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Other chemotherapeutic agents that may be used with the present invention are disclosed in U.S. Patent Application Publication No. 20080171040 or 20080305044, which are incorporated herein by reference in their entireties.;

[0338] It is contemplated that an antibody may be conjugated to two or more different chemotherapeutic agents, or a pharmaceutical composition may include a mixture of antibodies, in which case the antibody components are identical except that they are conjugated to different chemotherapeutic agents. Such embodiments may be useful for targeting multiple biological pathways with target cells.

[0339] In a preferred embodiment, the ADC comprises an antibody conjugated to one or more maytansinoid molecules, which are mitotic inhibitors that act by inhibiting tubulin polymerization. Maytansinoids, including various modifications, are described in U.S. Patent Nos. 3,896,111; 4,151,042; 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,309,428; 4,310,428; 4,320,428; 4,330,428; 4,340,428; 4,350,428; 4,360,428; 4,370,428; 4,380,428; 4,390,430; 4,410,430; 4,420,430; 4,430,430; 4,410,430; 4,42 ... Nos. 313946; 4315929; 4317821; 4322348; 4331598; 4361650; 4364866; 4424219; 4450254; 4362663; 4371533, and International Publication No. WO 2009 / 099728. Maytansinoid drug moieties can be isolated from natural sources, produced using recombinant technology, or prepared synthetically. Exemplary maytansinoids are C-19-dec...

Claims

[Claim 1] A kit or method as described in the specification.

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