Il-11r binding proteins and uses thereof

Abstract

To provide proteins comprising antigen binding sites of antibodies that bind to interleukin-11 (IL-11) receptor α (IL-11Rα), and to provide uses thereof, e.g., in therapy.SOLUTION: Provided is an IL-11Rα-binding protein comprising an antigen binding domain of an antibody, the antigen binding domain binding to or specifically binding to IL-11Rα and neutralizing IL-11 signaling, and the antigen binding domain being capable of binding to hIL-11R and cynoIL-11Rα.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Application Data This application is a joint publication of "IL-11R binding protein and its use" filed on February 7, 2013. Australian Patent Application No. 2013900389 entitled "For Use in a Combination of Fluorescent Light and Fluorescent Devices" and Australian Patent Application No. 2013900389 dated February 14, 2013 U.S. Patent Application No. 6,299,434, entitled "IL-11R BINDING PROTEINS AND USES THEREOF," filed on This application claims priority from US Pat. No. 1 / 764,756, the entire contents of which are incorporated herein by reference. Incorporated into the specification.

[0002] Sequence Listing This application is accompanied by a sequence listing which has been submitted in electronic format, the entire contents of which are incorporated by reference. No. 6,399,433, which is incorporated herein by reference.

[0003] Technical Field The present disclosure relates to a compound that binds to interleukin-11 (IL-11) receptor alpha (IL-11Rα). The present invention relates to a protein comprising an antigen-binding site of an antibody that binds to a nucleotide sequence of the ... do. [Background technology]

[0004] IL-11, among others, interacts with IL-27, IL-31, leukemia inhibitory factor (LIF), and oncogenic factors. IL-6 cytokines, including costatin M (OSM) and ciliary neurotrophic factor (CNTF) The IL-6 family of cytokines share a common signaling Signaling through the transduction receptor β subunit gp130 and specific receptor α subunits In the case of IL-11, its specific receptor α subunit IL-11R Binding of this cytokine to α induces homodimerization of gp130. Merization activates the JAK / STAT signaling pathway, upregulating signal transduction and transcription. STAT3 activation and, to a lesser extent, STAT This results in activation of 1.

[0005] IL-11 signaling is involved in hematopoiesis, immune response, inflammation, adipogenesis, osteoclastogenesis, and neuroprotection. It is known to play a role in the formation of megakaryocytes, their maturation, and the production of platelets. Various conditions, such as chemotherapy-induced thrombocytopenia, and arthritis, inflammatory bowel disease, It is being used clinically to treat various inflammatory disorders, including radiation-induced lung injury, sepsis, and psoriasis. However, clinical use of IL-11 has been associated with serious side effects, including edema. Furthermore, IL-11 has been shown to exert adverse effects in a variety of conditions. It has been shown that

[0006] For example, IL-11 has been found to act as an inhibitor of bone formation, It is essential for osteoclast formation and activity and bone resorption. Therefore, blocking IL-11 activity may improve bone resorption. As a treatment for porosis, and for example, in the treatment of metastatic bone cancer, myeloma, Paget's disease of bone and fractures and It has also been proposed to prevent bone resorption / promote bone formation in other conditions such as osteoarthritis and bone healing.

[0007] IL-11 signaling is implicated in a pathogenic role during the early stages of tuberculosis Blockade of IL-11 by anti-IL-11 antibodies has been shown to have a positive effect on M. tuberculosis-infected mice. It has been shown to reduce histopathology and neutrophil infiltration in lung tissue.

[0008] Antagonism of IL-11 has been shown to be effective in treating asthma, chronic obstructive pulmonary disease (COPD), rhinitis, and allergic and has also been proposed as a method for treating Th2-mediated disorders, including atopic dermatitis. In this regard, a mutant form of IL-11 that does not induce signaling has been used to Blocking this signaling has been shown to have therapeutic benefit in mouse models of asthma.

[0009] IL-11 and / or IL-11Rα are involved in the development of cancers in the following areas: liver cancer, pancreatic cancer, gastric cancer, osteosarcoma, endometrial cancer, and Moreover, as discussed above, IL-11-induced gp1 expression is overexpressed in ovarian cancer and ovarian cancer. Dimerization of 130 leads to activation of STAT3, which is involved in angiogenesis (e.g., VEGFR1, VEGFR2, VEGFR3, VEGFR4, VEGFR5, VEGFR6, VEGFR7, VEGFR8, VEGFR9, VEGFR10, VEGFR11, VEGFR12, VEGFR13, VEGFR14, VEGFR15, VEGFR16, VEGFR17, VEGFR18 F), cell cycle progression (e.g., cyclin D1) and cell survival (e.g., B Induce the expression of genes related to STAT3 activation (cl-XL, survival). This may be associated with hematological malignancies and tumors of epithelial origin. promotes gastric cell proliferation and survival, is associated with increased gastric angiogenesis, and promotes gastric tumorigenesis in mice. However, gastric inflammation, hyperplasia, and tumor formation were not observed in IL-11-unresponsive mice. The expression of IL-11 was suppressed in mice treated with IL-11 or a non-signaling mutant of IL-11.

[0010] IL-11 is also known to be involved in, for example, the inhibition of adipogenesis, the induction of cachexia (e.g., cancer cachexia), and the like. , induction of fever response, regulation of extracellular matrix metabolism, stimulation of acute phase reactants and embryo implantation. It is also involved in other biological processes.

[0011] Agents that neutralize IL-11 signaling may have therapeutic utility in any of a number of diverse conditions. It will be apparent to the skilled practitioner from the above that it is desirable because of its potential to provide benefits. Reagents that bind to IL-11Rα also bind soluble IL-11 throughout the subject and The ability to specifically target cells in vivo as opposed to the need for neutralization This is desirable because it has advantages.

[0012] Despite this desirability, a number of reagents that bind to IL-11Rα (e.g., antibodies ) does not neutralize IL-11 signaling. For example, Blanc et al. of Immunological Methods, 241:43-59,2000 ) have developed a panel of 14 mouse monoclonal antibodies against human IL-11Rα. However, none of them showed IL-11-induced BaF3 / gpl30 / IL-11R The failure to inhibit cell proliferation indicates that the antibody inhibits IL-11 signal transduction. The results show that the antibody does not neutralize IL-11Rα. 4D12, available from Anta Cruz Biotechnology, Inc., also inhibits IL-1 1 signaling. Summary of the Invention

[0013] In creating the present invention, the inventors have discovered that IL-11Rα binds to IL-1 Reagents that neutralize signal transduction of 1 (e.g., antibodies and proteins containing antigen-binding domains thereof) The present inventors have produced a series of antibodies with such activity. However, some of them strongly neutralized IL-11 signaling, e.g., IL-11 These antibodies inhibit the proliferation of human IL-11Rα (hIL-1 IL-11Rα) and cynomolgus monkey IL-11Rα (cynoIL-11Rα). The demonstrated efficacy of these compounds in primate models of human disease means that they can be used in primate models of human disease. The antibodies were also found to bind to overlapping epitopes. One of these antibodies can be affinity matured to confer additional desirable properties, e.g., IL-11 activation. Neutralization and / or improved affinity for signal transmission and / or sequences similar to human germline (e.g., unlikely to induce an immune response when administered to humans) Additional antibodies were produced.

[0014] Based on the above, the present inventors have generated a protein comprising the antigen-binding domain of an antibody. The antigen-binding domain is capable of binding or specifically binding to IL-11Rα. It is possible for a skilled practitioner to neutralize IL-11 signaling. It should be obvious.

[0015] In one embodiment, the present disclosure provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. The antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-1 1 signaling, wherein the antigen-binding domain binds to hIL-11Rα and cyn It is capable of binding to oIL-11Rα.

[0016] In one embodiment, the IL-11Rα binding protein is human IL-11 (hIL-11) and and / or neutralizes cynomolgus IL-11 (cynoIL-11) signaling.

[0017] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein has an IC5 of less than 10 μg / ml. At 0, IL-11 (e.g., For example, hIL-11 or cynoIL-11) mediated proliferation. ,I C 50 For example, IC 50 is 4μg / ml or less or 3. In one embodiment, the IC 50 is 3μg / ml or less or 2μg / ml For example, IC 50 For example, IC 50 is 0. 9 μg / ml or less, or 0.8 μg / ml or less, or 0.7 μg / ml or less. So, IC 50 In one embodiment, for each of the above examples, In conjunction with IC 50 is 10 pg / ml or more or 10 ng / ml or more.

[0018] In one embodiment, an IC 50 is less than 10 nM. For example, IC 50 is 8nM or less or In one embodiment, IC 50 is 6 nM or less or 6.5 nM or less. For example, IC 50 is less than 5 nM. For example, IC 50 The concentration is 4.5 nM or less. For example, IC 50 is 4 nM or less. In one embodiment, with respect to each of the above examples: I C 50 can be 10 pM or greater.

[0019] In one example, the IL-11Rα binding protein is the antibody 8E2 (shown in SEQ ID NO: 83). and a light chain comprising the sequence set forth in SEQ ID NO: 84). Approximately 1.5 times larger IC 50BaF3 expressing IL-11Rα and gp130 Inhibiting IL-11 (e.g., hIL-11 or cynoIL-11)-mediated proliferation of cells In one embodiment, IC 50 is at least about two times greater than antibody 8E2, or At least about 2.5 times greater, or at least about 3 times greater.

[0020] In one embodiment, the IL-11Rα binding protein is an antagonistic hIL-11 mutant protein. At least about 1.5 times larger than the protein (e.g., comprising the sequence set forth in SEQ ID NO:110). (i.e., IC50 value is about 1.5-fold smaller), or at least 2-fold greater, or 3-fold greater Twice as big as IC 50 In the I Inhibits proliferation mediated by I.C.I. 50 is nM In one embodiment, IC 50 is at least about 3.5 times higher than the mutant protein. twice as large or at least about four times as large.

[0021] In one embodiment, an IC 50 Approximately 0.3ng / ml of hIL-11 to approximately 5ng / ml of hIL-11 In the presence of IL-11 (e.g., about 0.3 ng / ml hIL-11 or about 0.5 ng / ml IL-11Rα and BaF3 cells expressing IL-11Rα and / or gp130 (e.g., 30) (e.g., approximately 1x10 4 Approximately 48 to 5 The measurement is performed by culturing for 0 hours, or for about 48 hours or for about 50 hours. The cells are cultured in the presence of a protein of the present disclosure (e.g., In one embodiment, proliferation is measured by the addition of 3H-thiol to DNA during the final 6 hours of culture. The neutralization of cynoIL-11 was measured by measuring the incorporation of cytoplasmic IL-11. In the assays performed to determine the level of cynoIL-11, the range was about 0.5 ng / ml to about 5 In the presence of about 0.5 ng / ml of cynoIL-11 (e.g., about 0.5 ng / ml of cynoIL-11 The cells can be cultured in the presence of about 5 ng / ml cynoIL-11 or about 5 ng / ml cynoIL-11. do.

[0022] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizing IL-11 signaling and binding to the polypeptide of SEQ ID NO:86, IL-11R The level of binding of IL-α binding protein to the polypeptides of SEQ ID NO: 3 and / or 85 is Lower than the level of binding of 11Rα binding protein.

[0023] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizing IL-11 signaling and binding to the IL-11R polypeptide of SEQ ID NO:89. The level of binding of IL-α binding protein to the polypeptides of SEQ ID NO: 3 and / or 85 is Lower than the level of binding of 11Rα binding protein.

[0024] In one embodiment, the level of binding is determined by Western blot analysis of cells expressing the polypeptide. and / or by fluorescence activated cell sorting (FACS).

[0025] In one embodiment, the polypeptide of SEQ ID NO: 86 or 89 of the IL-11Rα binding protein The level of binding to the IL-11Rα binding protein was determined by measuring the level of binding to the polypeptide of SEQ ID NO: 3 and / or SEQ ID NO: 85 of the IL-11Rα binding protein. At least about 10-fold, 20-fold, 50-fold, 100-fold, or It decreases by 150 or 200 times.

[0026] In one embodiment, the IL-11Rα binding protein is a polypeptide of SEQ ID NO: 86 or 89. does not detectably bind to

[0027] In one embodiment, the IL-11Rα binding protein is a polypeptide of SEQ ID NO: 87 or 88. For example, the polypeptide of SEQ ID NO: 87 or 88 of the IL-11Rα binding protein The level of binding to the peptide is similar to the level of binding to the polypeptide of SEQ ID NO: 3 and / or 85. Similar or nearly the same (e.g., within about 20% or 15% or 10% or 5% ).

[0028] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the antigen-binding domain is located on the first fragment of IL-11Rα. It binds to an epitope containing residues within the fibronectin III domain.

[0029] In one embodiment, the epitope is located within the immunoglobulin-like domain and the first domain of IL-11Rα. Contains residues within the fibronectin III domain.

[0030] In one example, the epitope comprises residues between amino acids 111-215 of SEQ ID NO:1.

[0031] In one example, the epitope comprises residues between amino acids 1-215 of SEQ ID NO:1.

[0032] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is inhibited by antibody 8E2 (shown in SEQ ID NO: 37). V containing the array to be H and V comprising the sequence shown in SEQ ID NO:5 L hIL-11 (including Competitively inhibits the binding of Rα and / or SEQ ID NO:3 and / or SEQ ID NO:85 to the polypeptide.

[0033] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is expressed by antibody 8E4 (shown in SEQ ID NO: 74). V containing the array to be H and V comprising the sequence shown in SEQ ID NO:73 L hIL-1 competitively inhibiting the binding of 1Rα and / or SEQ ID NO:3 and / or SEQ ID NO:85 to the polypeptide .

[0034] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is associated with antibody 8D10 (SEQ ID NO: 76). V containing the sequence shown H and V comprising the sequence shown in SEQ ID NO: 75 L (including hIL- Competitively inhibiting the binding of 11Rα and / or SEQ ID NO: 3 and / or 85 to the polypeptide do.

[0035] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is inhibited by antibody 8E2 (shown in SEQ ID NO: 37). V containing the array to be H and the heavy chain comprising the constant region of human IgG4 and V containing arrays L and a human light chain constant region comprising hIL-11Rα and / or Competitively inhibits binding to the polypeptides of SEQ ID NO: 3 and / or 85.

[0036] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is expressed by antibody 8E4 (shown in SEQ ID NO: 74). V containing the array to be H and a heavy chain comprising the constant region of human IgG4 and shown in SEQ ID NO: 73 V contains the sequence L hIL-11Rα and / or competitively inhibits binding to the polypeptides of SEQ ID NO:3 and / or 85.

[0037] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is associated with antibody 8D10 (SEQ ID NO: 76). V containing the sequence shown Hand a heavy chain comprising the constant region of human IgG4 and the heavy chain represented by SEQ ID NO: 75 V containing the sequence L hIL-11Rα and / or hIL-11Rα (including a light chain containing the human light chain constant region) or competitively inhibits binding to the polypeptides of SEQ ID NO: 3 and / or 85.

[0038] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is inhibited by antibody 8E2 (shown in SEQ ID NO: 83). and a light chain comprising the sequence shown in SEQ ID NO: 84. competitively inhibiting the binding of 1Rα and / or SEQ ID NO:3 and / or SEQ ID NO:85 to the polypeptide .

[0039] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is expressed by antibody 8E4 (shown in SEQ ID NO: 92). and a light chain comprising the sequence shown in SEQ ID NO:91. competitively inhibiting the binding of 1Rα and / or SEQ ID NO:3 and / or SEQ ID NO:85 to the polypeptide .

[0040] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the protein is inhibited by antibody 8D10 (SEQ ID NO: 94). and a light chain comprising the sequence shown in SEQ ID NO: 93. Competitively inhibiting the binding of 11Rα and / or SEQ ID NO: 3 and / or 85 to the polypeptide do.

[0041] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizing IL-11 signaling, and binding protein SEQ ID NO: 95 of IL-11Rα. The level of binding to the polypeptide of SEQ ID NO: 85 of the IL-11Rα binding protein was Lower than the level of binding to the peptide.

[0042] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizing IL-11 signaling, and binding to IL-11Rα protein SEQ ID NO: 96 The level of binding to the polypeptide of SEQ ID NO: 85 of the IL-11Rα binding protein was Lower than the level of binding to the peptide.

[0043] In one embodiment, the rate of binding of an IL-11Rα binding protein to a polypeptide comprising a substitution is The signal level is reduced by at least about 1.5 or 2 times.

[0044] In one embodiment, the rate of binding of an IL-11Rα binding protein to a polypeptide comprising a substitution is The level is reduced by at least about 3-fold or 4-fold or 5-fold or 10-fold.

[0045] In one embodiment, the IL-11Rα binding protein is detectably a polypeptide comprising the substitution. Do not combine.

[0046] In one embodiment, the level of binding can be measured using a biosensor, for example, surface plasmon resonance (SPRM). For example, IL-11Rα binding protein is immobilized and sequence no. The level of binding to the polypeptide of No. 85, 95 or 96 is measured. Affinity is determined by assessing the level of binding at several concentrations so that can be done.

[0047] In another embodiment, the level of binding is assessed using FACS. 5, 95 or 96 into a cell expressing a polypeptide of any one of the preceding claims, or Binding of IL-11Rα binding proteins to forms of IL-11Rα that contain the IL-11Rα cleavage site.

[0048] In one example, the IL-11Rα binding protein is a polypeptide of SEQ ID NO: 95 or 96. The polypeptide of SEQ ID NO:85 binds preferentially relative to its ability to bind to the polypeptide of SEQ ID NO:85.

[0049] In one example, the IL-11Rα binding protein binds to the polypeptide of SEQ ID NO:95. The polypeptide of SEQ ID NO:85 binds preferentially relative to its ability to bind to the polypeptide of SEQ ID NO:85.

[0050] In one example, the IL-11Rα binding protein is the antibody 8E2 (shown in SEQ ID NO:37). V contains the sequence H and V comprising the sequence shown in SEQ ID NO:5 L ) and / or 8E4( V comprising the sequence shown in SEQ ID NO:74 H and V comprising the sequence shown in SEQ ID NO:73 L Including ) and / or 8D10 (V H and SEQ ID NO: 75 V containing the array to be L 3 and / or 85. Synergistically inhibits

[0051] In one embodiment, the antigen binding domain comprises (i) a polypeptide of SEQ ID NO: 97 and / or (ii) a polypeptide of SEQ ID NO: 98, and / or (iii) a polypeptide of SEQ ID NO: 99 cross-reacts with

[0052] In one example, the IL-11Rα binding protein is murine IL-11Rα (SEQ ID NO:8). 2 or 102) and / or does not detectably bind to the polypeptide of SEQ ID NO:90.

[0053] In one example, the IL-11Rα binding protein is murine IL-11Rα (SEQ ID NO:8). 2 or 102) and / or cross-reacts with the polypeptide of SEQ ID NO:90.

[0054] In one embodiment, the IL-11Rα binding protein comprises human IL-11Rα and / or About 9 × 10 for polypeptides of numbers 3 and / or 85 -9 Affinity constant (K D ) For example, K D is about 8 x 10 -9 M or less or about 7 x 10 -9 M or less or about 6×10 -9 M or less or about 5 x 10 -9 In one embodiment, K D is about 4.8 x 10 -9 It is below M.

[0055] In another embodiment, the IL-11Rα binding protein is human IL-11Rα and / or a sequence About 2×10 for the polypeptides of sequence numbers 3 and / or 85 -9 Affinity constant (K D ) For example, K D is about 1 x 10 -9 M or less or about 9 x 10-10 M or less is about 8 x 10 -10 M or less or about 7 x 10 -10 In one embodiment, K D is about 5×10 -10 In one embodiment, K D is about 4 x 10 -10 M or less. In the embodiment, K D is about 3 x 10 -10 In one embodiment, K D is about 2 x 10 - 10 In one embodiment, K D is about 1.5 x 10 -10 It is below M.

[0056] In one embodiment, in relation to each of the preceding examples, D is 0.1 × 10 -12 M or more or 1 ×10 -12 It can be M or more.

[0057] In one embodiment, K D Biosensors are used to measure, for example, surface plasmon resonance. For example, an IL-11Rα binding protein is immobilized and the binding site of SEQ ID NO:85 is The level of binding to the polypeptide is measured.

[0058] In one embodiment, the IL-11Rα binding protein has a temperature transition midpoint (Tm) of about 60° C. or greater. For example, the Tm is about 61° C. or higher, e.g., about 6, such as about 63° C. or higher. 2° C. or higher. For example, the Tm is about 65° C. or higher. For example, the Tm is about 69° C. or higher. For example, the Tm is about 70° C. or higher. Proteins with higher Tm are also and thus, better storage and / or administration, e.g. For example, it provides reduced effects due to aggregation.

[0059] The present disclosure also or alternatively provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. and providing a protein, wherein the antigen-binding domain binds or specifically binds to IL-11Rα. and neutralizes IL-11 signaling, and the antigen-binding domain (i) at least about 40% to the sequence shown between amino acids 31 and 35 of SEQ ID NO: 37 % identical (or 50% identical or 60% identical or 70% identical or 8 0% identical or 90% identical or 95% identical or 98% identical or 9 9% identical or 100% identical) sequence, and At least about 76% identical to the sequence shown in amino acids 50 to 66 of SEQ ID NO:37 (or 80% identical or 90% identical or 95% identical or 98% identical or 99% identical or 100% identical) and At least about 55% identical to the sequence shown between amino acids 99 and 107 of 37 (or 60% identical or 70% identical or 80% identical or 90% identical or 95% identical or 98% identical or 99% identical or 100% identical a CDR3 comprising the sequence H ; (ii) at least about 95%, 96%, or 97% relative to the sequence set forth in SEQ ID NO: 37 or V containing a sequence that is 98% or 99% identical H ; (iii) at least about 4 amino acids 24 to 34 of SEQ ID NO:5 5% identical (or 50% identical or 55% identical or 60% identical or 70% identical or 80% identical or 90% identical or 95% identical or 98% identical, or 99% identical, or 100% identical) 5, CDR2 comprising a sequence shown in the amino acid sequence 50 to 56 of SEQ ID NO: 5, and At least about 44% identical (or 5% identical) to the sequence shown between amino acids 89 and 97 6% identical or 60% identical or 70% identical or 80% identical or 9 0% identical or 95% identical or 98% identical or 99% identical or 1 and CDR3 comprising a sequence that is 0.00% identical to L ; (iv) at least about 94% identical (or 95% identical) to the sequence set forth in SEQ ID NO:5 Identical or 96% identical or 97% identical or 98% identical or 99% V contains the same sequence L ; (v) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 74, and CDR2 comprising the sequence shown in amino acids 50 to 66 of SEQ ID NO: 74 and the amino acid sequence shown in SEQ ID NO: 74 and V comprising a CDR3 having a sequence represented by amino acids 99 to 115. H ; (vi) V comprising the sequence shown in SEQ ID NO: 74 H ; (vii) CDR1 comprising a sequence represented by amino acids 23 to 36 of SEQ ID NO: 73; and CDR2 comprising the sequence shown in amino acids 52 to 58 of SEQ ID NO: 73 and and CDR3 comprising the sequence shown between amino acids 91 and 101. L ; (viii) V comprising the sequence shown in SEQ ID NO: 73 L ; (ix) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 76, and the sequence CDR2 comprising the sequence shown in SEQ ID NO: 76 between amino acids 50 and 66, and and V comprising a CDR3 containing a sequence represented by amino acids 99 to 107. H ; (x) V comprising the sequence shown in SEQ ID NO: 76 H ; (xi) CDR1 comprising a sequence represented by amino acids 24 to 34 of SEQ ID NO: 75, and the sequence CDR2 comprising the sequence shown in SEQ ID NO: 75 between amino acids 50 to 57, and and V comprising a CDR3 containing a sequence represented by amino acids 89 to 97. L ; (xii) V comprising the sequence shown in SEQ ID NO: 75 L ; (xiii) V represented by (i) H and (iii) V L ; (xiv) V represented by (i) H and V shown in (iv). L ; (xv)(ii) V H and (iii) V L ; (xvi)(ii) V H and V shown in (iv). L ; (xvii) V as shown in (v) H and (vii) V L ; (xviii) V represented by (v) H and (viii) V L ; (xix) V represented by (vi) H and (vii) V L ; (xx)(vi) V H and (viii) V L ; (xxi) V represented by (ix) H and (xi) V L ; (xxii) V represented by (ix) Hand (xii) V L ; (xxiii) V represented by (x) H and (xi) V L or (xxiv) V represented by (x) H and (xii) V L ; Includes at least one of the following.

[0060] In one embodiment, the antigen binding domain comprises (i) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and at least about 80% identical to the sequence shown between amino acids 50 and 66 of No. 37 (or 90% identical or 95% identical or 98% identical or 99% identical or 100% identical thereto) and amino acids 99 to 10 of SEQ ID NO: 37. 7. At least about 55% identical (or 60% identical or is 70% identical or 80% identical or 90% identical or 95% identical or or 98% identical, or 99% identical, or 100% identical) V including H and CDR1 comprising the sequence shown in amino acids 24 to 34 of SEQ ID NO:5. 5, CDR2 comprising a sequence shown in the amino acid sequence 50 to 56 of SEQ ID NO: 5, and and V comprising a CDR3 containing the sequence shown between amino acids 89 and 97. L or SEQ ID NO:5 V containing the sequence indicated by L ; (ii) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and the sequence At least about 80% identical to the sequence shown between amino acids 50 and 66 of ID No. 37. (or 90% identical or 95% identical or 98% identical or 99% identical and CDR2 comprising a sequence identical to or 100% identical to amino acids 99-1 of SEQ ID NO: 37. and V comprising a CDR3 having the sequence shown in H and amino acids 24-3 of SEQ ID NO:5 CDR1 comprising the sequence shown between amino acids 50 and 56 of SEQ ID NO:5 and and CDR2 comprising a sequence represented by amino acids 89 to 97 of SEQ ID NO:5. DR3 and V L or V comprising the sequence shown in SEQ ID NO:5 L or (iii) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and CDR2 comprising the sequence shown in amino acids 50 to 66 of SEQ ID NO: 37 and At least about 55% identical to the sequence shown between amino acids 99 and 107 (or 60% identical or 70% identical or 80% identical or 90% identical or 95% identical or 98% identical or 99% identical or 100% identical) CDR3 comprising the sequence H and the sequence shown between amino acids 24 to 34 of SEQ ID NO:5 CDR1 comprising the sequence shown in SEQ ID NO:5 between amino acids 50 and 56 2 and CDR3 comprising a sequence represented by amino acids 89 to 97 of SEQ ID NO:5. L or V comprising the sequence shown in SEQ ID NO:5 L ;includes.

[0061] In one example, the antigen binding domain comprises: (i) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and CDR2 comprising the sequence shown in amino acids 50 to 66 of SEQ ID NO: 37 and the amino acid sequence shown in SEQ ID NO: 37. CDR3 containing a sequence between amino acids 99 and 107 and VH or SEQ ID NO:37 V containing the sequence shown H and for the sequence shown between amino acids 24 and 34 of SEQ ID NO:5 At least about 54% identical (or 60% identical or 70% identical or 80% identical) to % identical or 90% identical or 95% identical or 98% identical or 99 100% identical or 100% identical) to amino acid 5 of SEQ ID NO:5. CDR2 comprising a sequence shown between 0 and 56 and amino acids 89 to 97 of SEQ ID NO:5 At least about 66% identical (or 70% identical or 80% identical) to the sequence shown Identical or 90% identical or 95% identical or 98% identical or 99% CDR3 and V L ; (ii) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and the sequence CDR2 comprising the sequence shown in SEQ ID NO: 37 between amino acids 50 and 66, and CDR3 containing the sequence shown between amino acids 99 and 107 and V H or SEQ ID NO:37 V containing the sequence indicated by H and the sequence shown between amino acids 24 and 34 of SEQ ID NO:5 At least about 54% identical (or 60% identical or 70% identical or 8 0% identical or 90% identical or 95% identical or 98% identical or 9 9% identical or 100% identical) and the amino acid sequence of SEQ ID NO:5 CDR2 comprising the sequence shown in between 50 and 56 and amino acids 89 to 97 of SEQ ID NO:5 and V L or (iii) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 37, and CDR2 comprising the sequence shown in amino acids 50 to 66 of SEQ ID NO: 37 and CDR3 containing the sequence shown between amino acids 99 and 107 and V H or SEQ ID NO:3 V containing the sequence shown in 7 H and the sequence shown between amino acids 24 and 34 of SEQ ID NO:5 and CDR2 comprising a sequence represented by amino acids 50 to 56 of SEQ ID NO:5. 5, at least about 66% identical to the sequence set forth between amino acids 89 and 97 of SEQ ID NO:5 (or 70% identical or 80% identical or 90% identical or 95% identical or 98% identical or 99% identical or 100% identical CDR3 and V L ;includes.

[0062] In one embodiment, the protein is the V L Contains CDR1, CDR2 and CDR3 of MuV L and V of antibody 8E2 H V containing CDR1 and CDR2 H Includes.

[0063] In one embodiment, the protein is the V L Contains CDR1, CDR2 and CDR3 of MuV L and CDR1 and V of antibody 8E2 H V containing CDR1 and CDR3 H Includes.

[0064] In one embodiment, the protein is the V L Contains CDR1, CDR2 and CDR3 of MuV L and V of antibody 8E2 H V containing CDR2 and CDR3 H Includes.

[0065] In one embodiment, the protein is the V L V containing CDR1 and CDR3 L and V of antibody 8E2 H V containing CDR1, CDR2 and CDR3 H Includes.

[0066] In one embodiment, the antigen binding domain comprises (i) V comprising the sequence shown in SEQ ID NO: 71 H and V comprising the sequence shown in SEQ ID NO:35 L or (ii) V comprising the sequence shown in SEQ ID NO: 72 H and comprising the sequence shown in SEQ ID NO:36 V L ;includes.

[0067] Such IL-11Rα binding proteins have any of the functional activities described herein. A polypeptide of SEQ ID NO:3 containing one or more of the substitutions, e.g., as described above. can exhibit preferential binding to the polypeptide of SEQ ID NO:3 compared to the level of binding of .

[0068] In one embodiment, the differences between the reference sequence and the IL-11Rα binding protein are substitutions. do.

[0069] A skilled artisan may, for example, determine whether a particular region of a variable region is in the framework region of a variable region-containing protein. In this manner, it is possible to determine the site of a mutation in the IL-11Rα binding protein of the present disclosure. Furthermore, the present inventors have found that V H CDR1, CDR2 and / or CDR3 and V L and multiple sites in the CDR1 and / or CDR3 of the present disclosure. We have identified a number of mutations that maintain or improve the activity of the IL-11Rα binding protein. For example, mutations, e.g., substitutions, can be made in the HCDR1 and / or HCDR2 of antibody 8E2. one or more (e.g., 2 or 3 or 4) of R2 and / or the six N-terminal residues of HCDR3 or is within one or more (e.g., 2 or 3 or 4 or 5 or 6) of the six C-terminal residues. For example, mutations, e.g., substitutions, can be made in the six C-terminal amino acids of LCDR1 of antibody 8E2. at least one (e.g., 2 or 3 or 4 or 5 or 6) of LCDR3 and / or five of LCDR4 at least one (e.g., two or three or four or five) of the C-terminus of

[0070] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence QASQDX1X2X3 X4X5X6 (SEQ ID NO: 77), wherein X1=I or V; 2=N or D or G or S or A or H; X3=N or Y or I or K or M or Q or G or H; X4=Y or W; X5=L or V or I or M and X6=N or E.

[0071] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence X1QX2X3X4X5 X6PX7 (SEQ ID NO: 78), wherein X1=Q or E or S or T;X2=Y or H or F or N or S or W;X3=D or E;X4=N, D, F , S, E or T; X5=L or Q; X6=S or A or W or T or M or Q and X7= T or E or F or A or L or F or N or Q.

[0072] In one embodiment, X1 is Q and X2 is Y.

[0073] In one embodiment, X6 is S and X7 is T.

[0074] In one example, an IL-11Rα binding protein of the disclosure comprises the sequence X1X2SX3X4. X1=W or R; X2=Y or W or F; X4=M or I or V or T or L and X5=T or A.

[0075] In one example, the IL-11Rα binding protein of the disclosure has the sequence SIVPX1X2X3X 4TQYADSVKG, wherein X1=S or W or Y or H ;X2=G or A;X3=G or D or T and X4=H or Y or L or I or F .

[0076] In one example, the IL-11Rα binding protein of the disclosure has the sequence X1X2X3WGX4F X5X6, where X1=G or P; X2=P or E or V or is L or N or H; X3 = G or D; X4 = S or M or R or L; X5 = D or A or W and X6=L or V or F or Q or E or Y or T.

[0077] In one embodiment, X1 is G, X2 is P, and X3 is G.

[0078] In one embodiment, X5 is D and X6 is L.

[0079] In one embodiment, the IL-11Rα binding protein comprises one of the above consensus sequences. R, with the remaining CDRs from antibody 8E2.

[0080] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain is any one of SEQ ID NOs: 37 to 70, 74, and 76. V containing the sequence indicated by either H and / or any of SEQ ID NOs: 5 to 34, 73, or 75 V containing the sequence indicated by one of L Includes.

[0081] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain neutralizes signal transduction of (i) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally for CDR1 (including the N-terminal amino acid) H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (ii) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:5 L ; (iii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 38 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (iv) V comprising the sequence shown in SEQ ID NO: 38 H and V comprising the sequence shown in SEQ ID NO:5 L ; (v) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 39 (optionally for CDR1 (including the N-terminal amino acid) H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (vi) V comprising the sequence shown in SEQ ID NO: 39 Hand V comprising the sequence shown in SEQ ID NO:5 L ; (vii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 40 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (viii) V comprising the sequence shown in SEQ ID NO: 40 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (ix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 41 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains V L ; (x) V comprising the sequence shown in SEQ ID NO: 41 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 42 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains V L ; (xii) V comprising the sequence shown in SEQ ID NO: 42 H and comprising the sequence shown in SEQ ID NO:5 V L ; (xiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 43 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xiv) V comprising the sequence shown in SEQ ID NO: 43 H and comprising the sequence shown in SEQ ID NO:5 VL ; (xv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 44 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains V L ; (xvi) V comprising the sequence shown in SEQ ID NO: 44 H and comprising the sequence shown in SEQ ID NO:5 V L ; (xvii) CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 45 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xviii) V comprising the sequence shown in SEQ ID NO: 45 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 46 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xx) V comprising the sequence shown in SEQ ID NO: 46 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 47 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xxii) V comprising the sequence shown in SEQ ID NO: 47 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 48 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (xxiv) V comprising the sequence shown in SEQ ID NO: 48 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 49 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xxvi) V comprising the sequence shown in SEQ ID NO: 49 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 50 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (xxviii) V comprising the sequence shown in SEQ ID NO: 50 H and the sequence shown in SEQ ID NO:5 Contains V L ; (xxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 51 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xxx) V comprising the sequence shown in SEQ ID NO: 51 H and comprising the sequence shown in SEQ ID NO:5 V L ; (xxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 52 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xxxii) V comprising the sequence shown in SEQ ID NO: 52 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xxxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 53 (optionally CD (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO:5, V including 2 and 3 L ; (xxxiv) V comprising the sequence shown in SEQ ID NO: 53 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xxxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 54 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xxxvi) V comprising the sequence shown in SEQ ID NO: 54 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 55 (optionally (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO:5, V including 2 and 3 L ; (xxxviii) V comprising the sequence shown in SEQ ID NO: 55 H and the sequence shown in SEQ ID NO:5 V containing columns L ; (xxxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 56 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (xl) V comprising the sequence shown in SEQ ID NO: 56 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xli) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 57 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xlii) V comprising the sequence shown in SEQ ID NO: 57 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xliii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 58 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (xliv) V comprising the sequence shown in SEQ ID NO:58 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xlv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 59 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (xlvi) V comprising the sequence shown in SEQ ID NO:59 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (xlvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 60 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (xlviii) V comprising the sequence shown in SEQ ID NO: 60 H and the sequence shown in SEQ ID NO:5 Contains V L ; (xlix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 61 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (l) V comprising the sequence shown in SEQ ID NO: 61 H and V comprising the sequence shown in SEQ ID NO:5 L ; (li) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 62 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains V L ; (lii) V comprising the sequence shown in SEQ ID NO: 62 H and comprising the sequence shown in SEQ ID NO:5 V L ; (liii) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 63 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (liv) V comprising the sequence shown in SEQ ID NO:63 H and comprising the sequence shown in SEQ ID NO:5 V L ; (lv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 64 (optionally against CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains V L ; (lvi) V comprising the sequence shown in SEQ ID NO: 64 H and comprising the sequence shown in SEQ ID NO:5 V L ; (lvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 65 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (lviii) V comprising the sequence shown in SEQ ID NO: 65 H and the sequence shown in SEQ ID NO:5 Includes V L ; (lix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 66 (optionally including CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (lx) V comprising the sequence shown in SEQ ID NO:66 H and V comprising the sequence shown in SEQ ID NO:5 L ; (lxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 67 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (lxii) V comprising the sequence shown in SEQ ID NO: 67 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (lxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 68 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (lxiv) V comprising the sequence shown in SEQ ID NO:68 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (lxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 69 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (lxvi) V comprising the sequence shown in SEQ ID NO:69 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (lxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 70 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V, including 3 L ; (lxviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:5 Contains V L ; (lxix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 70 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (lxx) V comprising the sequence shown in SEQ ID NO: 70 H and comprising the sequence shown in SEQ ID NO:5 V L ; (lxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:6. V including 3 L ; (lxxii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:6 Includes V L ; (lxxiii) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO: 7, V including 2 and 3 L ; (lxxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:7 Includes V L ; (lxxv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:8. V including 3 L ; (lxxvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:8 Includes V L ; (lxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO: 9, V including 2 and 3 L ; (lxxviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:9 V containing columns L ; (lxxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 10, V including 2 and 3 L ; (lxxx) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 10 Includes V L ; (lxxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 11, V including 2 and 3 L ; (lxxxii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:11 V containing columns L ; (lxxxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally C (including amino acids N-terminal to DR1) V H and the CDR of the sequence shown in SEQ ID NO: 12 V including 1, 2 and 3 L ; (lxxxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:12 V containing columns L ; (lxxxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 13, V including 2 and 3 L ; (lxxxvi) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO: 13 V containing columns L ; (lxxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally C (including amino acids N-terminal to DR1) V H and the CDR of the sequence shown in SEQ ID NO: 14 V including 1, 2 and 3 L ; (lxxxviii) V comprising the sequence shown in SEQ ID NO: 37 H and SEQ ID NO: 14 V contains the sequence L ; (lxxxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CD (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO: 15 , 2 and 3 inclusive L ; (xc) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 15 V L ; (xci) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:16. V including 3 L ; (xcii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 16 Includes V L ; (xciii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 17, V including 2 and 3 L ; (xciv) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO: 17 Includes V L ; (xcv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:18. V including 3 L ; (xcvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 18 Includes V L ; (xcvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 19, V including 2 and 3 L ; (xcviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 19 V containing columns L ; (xcix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO: 20 and V, including 3 L ; (c) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO: 20 L ; (ci) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:21. V including 3 L ; (cii) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO:21. MuV L ; (ciii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO: 22 and V, including 3 L ; (civ) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 22 MuV L ; (cv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:23 V including 3 L ; (cvi) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO:23 MuV L ; (cvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO:24 and V, including 3 L ; (cviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:24 Contains V L ; (cix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally including CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:25. V including 3 L ; (cx) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 25 V L ; (cxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR3 of the sequence shown in SEQ ID NO:26. V including 3 L ; (cxii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:26 Includes V L ; (cxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 27, V including 2 and 3 L ; (cxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:27 Includes V L ; (cxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR3 of the sequence shown in SEQ ID NO:28. V including 3 L ; (cxvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:28 Includes V L ; (cxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR (including the N-terminal amino acid for 1) V H and CDR1 of the sequence shown in SEQ ID NO: 29, V including 2 and 3 L ; (cxviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:29 V containing columns L ; (cxix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO: 30 and V, including 3 L ; (cxx) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 30 MuV L ; (cxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO:31 and V, including 3 L ; (cxxii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:31 Contains V L ; (cxxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO: 32 , 2 and 3 inclusive L ; (cxxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:32 Contains V L ; (cxxv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO: 33 and V, including 3 L ; (cxxvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:33 Contains V L ; (cxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including the amino acid N-terminal to R1) V H and CDR1 of the sequence shown in SEQ ID NO: 34 , 2 and 3 inclusive L or (cxxviii) V comprising the sequence shown in SEQ ID NO: 37 H and SEQ ID NO:34 V containing arrays L ;includes.

[0082] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain neutralizes signal transduction of (i) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 49 (optionally for CDR1 (including the N-terminal amino acid) H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (ii) V comprising the sequence shown in SEQ ID NO: 49 H and V comprising the sequence shown in SEQ ID NO:5 L ; (iii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 53 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (iv) V comprising the sequence shown in SEQ ID NO: 53 H and V comprising the sequence shown in SEQ ID NO:5 L ; (v) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 57 (optionally for CDR1 (including the N-terminal amino acid) Hand CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (vi) V comprising the sequence shown in SEQ ID NO: 57 H and V comprising the sequence shown in SEQ ID NO:5 L ; (vii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 58 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (viii) V comprising the sequence shown in SEQ ID NO: 58 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (ix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:8 Contains V L ; (x) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:8 L ; (xi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:15. V including 3 L ; (xii) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 15. MuV L ; (xiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO: 16 and V, including 3 L ; (xiv) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 16 MuV L ; (xv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:18. V including 3 L ; (xvi) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO:18. MuV L ; (xvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO:29 and V, including 3 L or (xviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:29 Contains V L ;includes.

[0083] In one embodiment, the CDRs are as follows: (i) Heavy chain CDR1: amino acids 31-35 of the cited sequence; (ii) Heavy chain CDR2: amino acids 50 to 66 of the cited sequence (optionally, the five C-terminal one or more of the amino acids are replaced with another naturally occurring amino acid); (iii) heavy chain CDR3: amino acids 99 to 107 of the cited sequence; (iv) light chain CDR1: amino acids 24 to 34 of the cited sequence; (v) light chain CDR2: amino acids 50 to 56 of the reference sequence; and (vi) Light chain CDR3: amino acids 89 to 97 of the cited sequence.

[0084] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 49. V including 1, 2 and 3 H and V comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 L Includes.

[0085] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:5 L Includes.

[0086] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO:53. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in L Includes.

[0087] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:5 L Includes.

[0088] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO:57. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in L Includes.

[0089] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:5 L Includes.

[0090] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO:58. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in L Includes.

[0091] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:5 L Includes.

[0092] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 37. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in No. 8 L Includes.

[0093] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:8 L Includes.

[0094] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 37. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) Hand sequence number V comprising CDR1, 2 and 3 of the sequence shown in L Includes.

[0095] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:15 L Includes.

[0096] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 37. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in No. 16 L Includes.

[0097] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:16 L Includes.

[0098] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 37. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in No. 18 L Includes.

[0099] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:18 L Includes.

[0100] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises the CDR of the sequence shown in SEQ ID NO: 37. V including 1, 2, and 3 (optionally including amino acids N-terminal to CDR1) H and sequence number V comprising CDR1, 2 and 3 of the sequence shown in No. 29 L Includes.

[0101] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H and V comprising the sequence shown in SEQ ID NO:29 L Includes.

[0102] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V H In one embodiment, V L The nucleic acid sequence of the present invention is shown in SEQ ID NO: 18. nothing.

[0103] The present disclosure also provides an IL-11Rα binding protein comprising an antigen-binding domain of an antibody. wherein the antigen-binding domain binds or specifically binds IL-11Rα and binds to IL-11 and the antigen-binding domain comprises a V L In one embodiment, V H The nucleic acid sequence of the present invention is represented by SEQ ID NO: 37. nothing.

[0104] In one embodiment, the CDRs are as follows: (i) Heavy chain CDR1: amino acids 31-35 of the cited sequence; (ii) Heavy chain CDR2: amino acids 50 to 66 of the cited sequence (optionally, the five C-terminal one or more of the amino acids are replaced with another naturally occurring amino acid); (iii) heavy chain CDR3: amino acids 99 to 107 of the cited sequence; (iv) light chain CDR1: amino acids 24 to 34 of the cited sequence; (v) light chain CDR2: amino acids 50 to 56 of the reference sequence; and (vi) Light chain CDR3: amino acids 89 to 97 of the cited sequence.

[0105] In one embodiment, the IL-11Rα binding proteins described herein comprise at least one H and V LIncluding said V H and V L The antibodies combine to form an Fv that contains the antigen-binding domain. One skilled in the art will appreciate that an antigen-binding domain comprises the binding site of an antibody.

[0106] In one embodiment, V H and V L is found in a single polypeptide chain. For example, a protein teeth (i) Single chain Fv fragment (scFv); (ii) dimeric scFv (di-scFv); (iii) the constant region of an antibody, Fc or heavy chain constant domain (C H )2 and / or C H 3 or one of (i) or (ii) linked to (iv) (i) or (ii) linked to a protein that binds to an immune effector cell ) is one of;

[0107] In one embodiment, V H and V L are in separate polypeptide chains.

[0108] For example, proteins are (i) bispecific antibodies; (ii) trispecific antibodies; (iii) tetraspecific antibodies; (iv) Fab; (v) F(ab')2; (vi) Fv (vii) the constant region of an antibody, Fc or heavy chain constant domain (C H )2 and / or C H 3 one of (i) to (vi) connected to; (viii) (i) to (vi) linked to a protein that binds to an immune effector cell is one of;

[0109] The above proteins (described in the previous two lists) are also referred to as the antigen-binding domain of an antibody. It is possible.

[0110] In one embodiment, the protein is an antibody, e.g., a monoclonal antibody. In the present case, the antibody is a naked antibody.

[0111] In one embodiment, the protein (or antibody) is chimeric, deimmunized, or humanized. , human or primatized.

[0112] In one embodiment, the protein or antibody is human.

[0113] The present disclosure further or alternatively relates to a method for the treatment of cancer, comprising administering to a subject a subject a therapeutic agent that binds to IL-11Rα and mediates IL-11 signaling. and an antibody that neutralizes (i) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 49 (optionally for CDR1 (including the N-terminal amino acid) H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (ii) V comprising the sequence shown in SEQ ID NO: 49 H and V comprising the sequence shown in SEQ ID NO:5 L ; (iii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 53 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (iv) V comprising the sequence shown in SEQ ID NO: 53 H and V comprising the sequence shown in SEQ ID NO:5 L ; (v) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 57 (optionally for CDR1 (including the N-terminal amino acid) H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V L ; (vi) V comprising the sequence shown in SEQ ID NO: 57 H and V comprising the sequence shown in SEQ ID NO:5 L ; (vii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 58 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5. V including 3 L ; (viii) V comprising the sequence shown in SEQ ID NO: 58 H and comprising the sequence shown in SEQ ID NO:5 MuV L ; (ix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:8 Contains V L ; (x) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:8 L ; (xi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:15. V including 3 L ; (xii) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 15. MuV L ; (xiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V Hand CDR1, 2 of the sequence shown in SEQ ID NO: 16 and V, including 3 L ; (xiv) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO: 16 MuV L ; (xv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally corresponding to CDR1) (including the N-terminal amino acid)V H and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:18. V including 3 L ; (xvi) V comprising the sequence shown in SEQ ID NO: 37 H and comprising the sequence shown in SEQ ID NO:18. MuV L ; (xvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid)V H and CDR1, 2 of the sequence shown in SEQ ID NO:29 and V, including 3 L or (xviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:29 Contains V L ;includes.

[0114] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H In one embodiment, V L comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO:18. (xix) The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody is a V antibody having a sequence as set forth in SEQ ID NO:18. L In one embodiment So, V. Hcomprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO:37.

[0115] In one embodiment, the CDRs are as follows: (i) Heavy chain CDR1: amino acids 31-35 of the cited sequence; (ii) Heavy chain CDR2: amino acids 50 to 66 of the cited sequence (optionally, the five C-terminal one or more of the amino acids are replaced with another naturally occurring amino acid); (iii) heavy chain CDR3: amino acids 99 to 107 of the cited sequence; (iv) light chain CDR1: amino acids 24 to 34 of the cited sequence; (v) light chain CDR2: amino acids 50 to 56 of the reference sequence; and (vi) Light chain CDR3: amino acids 89 to 97 of the cited sequence.

[0116] Example V H and V L The sequence is shown in Table 1.

[0117] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 49 (optionally (including amino acids N-terminal to CDR1) V H and the CDR of the sequence shown in SEQ ID NO:5 V including 1, 2 and 3 L Includes.

[0118] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:5 V containing arrays L Includes.

[0119] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 53 (optionally (including amino acids N-terminal to CDR1) V H and the CDR of the sequence shown in SEQ ID NO:5 V including 1, 2 and 3 L Includes.

[0120] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:5 V containing arrays L Includes.

[0121] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 57 (optionally (including amino acids N-terminal to CDR1) V H and the CDR of the sequence shown in SEQ ID NO:5 V including 1, 2 and 3 L Includes.

[0122] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:5 V containing arrays L Includes.

[0123] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 58 (optionally (including amino acids N-terminal to CDR1) V H and the CDR of the sequence shown in SEQ ID NO:5 V including 1, 2 and 3 L Includes.

[0124] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:5 V containing arrays L Includes.

[0125] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including amino acids N-terminal to CDR1) V H and the CDR of the sequence shown in SEQ ID NO:8 V including 1, 2 and 3 L Includes.

[0126] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:8 V containing arrays L Includes.

[0127] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including amino acids N-terminal to CDR1) V H and the CD of the sequence shown in SEQ ID NO:15 V including R1, 2 and 3 L Includes.

[0128] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO: 15 V contains the sequence L Includes.

[0129] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including amino acids N-terminal to CDR1) V H and the CD of the sequence shown in SEQ ID NO:16 V including R1, 2 and 3 L Includes.

[0130] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO: 16 V contains the sequence L Includes.

[0131] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including amino acids N-terminal to CDR1) V H and the CD of the sequence shown in SEQ ID NO:18 V including R1, 2 and 3 L Includes.

[0132] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO: 18 V contains the sequence L Includes.

[0133] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally (including amino acids N-terminal to CDR1) V Hand the CD of the sequence shown in SEQ ID NO:29 V including R1, 2 and 3 L Includes.

[0134] The present disclosure also provides an antibody that binds to IL-11Rα and neutralizes IL-11 signaling. The antibody comprises a V H and SEQ ID NO:29 V contains the sequence L Includes.

[0135] In one embodiment, the CDRs are as follows: (i) Heavy chain CDR1: amino acids 31-35 of the cited sequence; (ii) Heavy chain CDR2: amino acids 50 to 66 of the cited sequence (optionally, the five C-terminal one or more of the amino acids are replaced with another naturally occurring amino acid); (iii) heavy chain CDR3: amino acids 99 to 107 of the cited sequence; (iv) light chain CDR1: amino acids 24 to 34 of the cited sequence; (v) light chain CDR2: amino acids 50 to 56 of the reference sequence; and (vi) Light chain CDR3: amino acids 89 to 97 of the cited sequence.

[0136] Reference herein to a protein or antibody that "binds to" IL-11Rα is intended to mean "specific A protein or protein that "binds" to or "specifically binds" to IL-11R provides literal support for antibodies.

[0137] The present disclosure also provides antigen-binding domains or antigen-binding fragments of the aforementioned antibodies.

[0138] In one example, the proteins or antibodies described herein contain a human constant region, e.g. , IgG1, IgG2, IgG3 or IgG4 IgG constant region. H and V L In the case of a protein or antibody containing V H can be linked to a heavy chain constant region, L is light The polypeptide may be linked to a polypeptide chain constant region.

[0139] The whole antibody (or the constant region or C H IL-11Rα binding protein (IL-11Rα-binding protein, including IL-11Rα-binding protein The C-terminal lysine of the heavy chain constant region of Alternatively, it may be removed by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody. The whole antibody (or IL-11Rα binding protein) has all of the C-terminal lysine residues removed. a population in which the C-terminal lysine residue has been removed, a population in which the C-terminal lysine residue has not been removed, and / or a population in which the C-terminal lysine residue has not been removed In some embodiments, the population may include a mixture of proteins with or without The population further includes proteins in which the C-terminal lysine residue of one of the heavy chain constant regions is removed. Similarly, a composition of whole antibodies may be obtained by analyzing a population of antibodies with or without a C-terminal lysine residue. The composition may include the same or similar mixtures of

[0140] In one embodiment, the protein or antibody described herein comprises a constant region of an IgG4 antibody. or a stabilized constant region of an IgG4 antibody. In one embodiment, the protein or antibody comprises Proline at position 241 (Kabat numbering system (Kabat et al., sequences of Proteins of Immunological In terest Washington DC United States Depar tment of Health and Human Services,1987 and / or 1991) contains the IgG4 constant region.

[0141] In one embodiment, the heavy chain constant region comprises the sequence from position 119 to position 445 of SEQ ID NO:83. In one embodiment, the protein or antibody described herein or the tag described herein The protein or antibody compositions may contain a mixture of sequences with or without a C-terminal lysine residue. The invention further comprises a heavy chain constant region, comprising, completely or partially, a stabilized heavy chain constant region.

[0142] In one example, the antibody of the disclosure comprises an IgG4 constant region or a stabilized IgG4 constant region. (e.g., as described above) H Including M, V L is linked or fused to a kappa light chain constant region.

[0143] The functional characteristics of the IL-11Rα binding protein of the present disclosure are utilized to apply the antibodies of the present disclosure mutatis mutandis. It will be.

[0144] In one embodiment, an IL-11Rα binding protein or antibody as described herein Isolated and / or recombinant.

[0145] In one example, the IL-11Rα binding protein or antibody of the disclosure may be coupled to another compound, e.g. For example, detectable labels or, for example, polyethylene glycol or albumin conjugates. The compound is conjugated to a protein, such as a protein, or to a compound that increases the half-life of an antibody. The compounds are described herein.

[0146] The present disclosure also provides nucleic acids encoding the IL-11Rα binding proteins or antibodies of the disclosure. also provides the polypeptide.

[0147] In one embodiment, such a nucleic acid is an expression vector in which the nucleic acid is operably linked to a promoter. Such an expression construct may be a vector, e.g., a plasmid. can be done.

[0148] In the examples of the disclosure relating to single polypeptide chain IL-11Rα binding proteins, The present construct can include a promoter linked to the nucleic acid encoding the polypeptide chain.

[0149] Implementation of the present disclosure with respect to multiple polypeptide chains that form an IL-11Rα binding protein In an example, the expression construct can include, for example, a V H Polyp containing A nucleic acid encoding a peptide and a V gene operably linked to, for example, a promoter. L Includes It includes a nucleic acid that encodes a polypeptide.

[0150] In another embodiment, the expression construct can comprise, for example, the following operably linked, in 5' to 3' order: Combined ingredients: (i) the promoter; (ii) a nucleic acid encoding a first polypeptide; (iii) an internal ribosome entry site; (iv) a nucleic acid encoding a second polypeptide; a bicistronic expression construct comprising In this case, the first polypeptide is V H and the second polypeptide comprises V L and vice versa It is.

[0151] The present disclosure also provides separate expression constructs, one of which is V H A first polypeptide comprising Code the other one is V L a separate expression construct encoding a second polypeptide comprising For example, the present disclosure also contemplates (i) a V operably linked to a promoter H The nucleic acid encoding a polypeptide comprising a first expression construct comprising: (ii) a V operably linked to a promoter L A nucleic acid encoding a polypeptide comprising a second expression construct comprising the gene encoding the polypeptide;

[0152] The present disclosure also provides isolated or recombinant human IL-11Rα binding proteins that express the disclosed IL-11Rα binding proteins. The present invention also provides cells of the

[0153] In one example, the cell is a cell that contains an expression construct of the disclosure, or (i) a V operably linked to a promoter H The nucleic acid encoding a polypeptide comprising a first expression construct comprising: (ii) a V operably linked to a promoter L A nucleic acid encoding a polypeptide comprising a second expression construct comprising: In so doing, the first and second polypeptides associate to form an IL-11Rα binding protein of the disclosure. Form.

[0154] Examples of cells of the present disclosure include bacterial cells, yeast cells, insect cells or mammalian cells.

[0155] The present disclosure further provides methods of making the IL-11Rα binding proteins or antibodies of the disclosure. For example, such methods include producing an IL-11Rα binding protein or antibody. The method involves maintaining the expression construct of the present disclosure under conditions sufficient to permit expression of the construct.

[0156] In one embodiment, the method of producing an IL-11Rα binding protein or antibody of the present disclosure comprises the steps of: -under conditions sufficient for the production and, optionally, secretion of the -11Rα binding protein or antibody. The method includes culturing the cells of the present disclosure in

[0157] In one embodiment, the method of producing an IL-11Rα binding protein or antibody of the disclosure further comprises: and optionally isolating the protein or antibody. and formulating the antibody into a pharmaceutical composition.

[0158] The present disclosure further relates to a method for the preparation of an IL-11Rα binding protein or antibody of the present disclosure, the method comprising the steps of: and a carrier.

[0159] In one embodiment, the composition comprises (i) an antibody of the disclosure comprising a C-terminal lysine residue from the heavy chain; (ii) an antibody of the present disclosure lacking a C-terminal lysine residue from a heavy chain; and / or (iii) containing a C-terminal lysine residue on one heavy chain and a C-terminal An antibody of the disclosure lacking lysine residues; and optionally a pharma- ceutically acceptable carrier.

[0160] The present disclosure also provides a method of treating or preventing an IL-11 mediated disease in a subject. and the method comprises administering an IL-11Rα binding protein, antibody, or composition of the disclosure. In this regard, the IL-11Rα binding proteins, antibodies or compositions can be used to prevent disease recurrence. This can be considered as preventing the disease.

[0161] In one embodiment, the IL-11 mediated disease is an autoimmune disease, an inflammatory disease, a debilitating disease, or a chronic inflammatory disorder. The disease is a bone disease or cancer.

[0162] Exemplary autoimmune diseases include arthritis, inflammatory bowel disease and psoriasis.

[0163] Exemplary inflammatory diseases include infection-induced inflammation (e.g., inflammation caused by Mycobacterium tuberculosis), gastrointestinal inflammation, and gastrointestinal inflammation. inflammation (e.g., associated with stomach cancer), inflammatory airway diseases (e.g., asthma, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease (COPD), rhinitis or allergies), or inflammatory dermatitis (e.g., atopic dermatitis) dermatitis).

[0164] Exemplary wasting diseases include cachexia (e.g., cachexia due to cancer or cachexia due to renal failure). or sarcopenia.

[0165] Exemplary bone diseases include osteoporosis (including postmenopausal osteoporosis), bone fractures, cancer (metastatic bone cancer, bone resorption / damage caused by myeloma or Paget's disease of bone, and cancer treatments (e.g. These include bone resorption / damage caused by osteoporosis (e.g., chemotherapy, hormone ablation or inhibition).

[0166] Exemplary cancers include hematological cancers, cancers of epithelial origin, liver cancer, pancreatic cancer, gastric cancer, osteosarcoma, endometrial cancer, and and ovarian cancer.

[0167] In one embodiment, the cancer or bone disease is cancer metastasis to bone.

[0168] The present disclosure also provides a method of inhibiting or neutralizing IL-11 in a subject, the method comprising: The method includes administering an IL-11Rα binding protein, antibody, or composition of the disclosure. In an embodiment, the subject suffers from an IL-11 mediated disease.

[0169] The present disclosure also provides a method of preventing pregnancy in a subject, the method comprising administering to a subject an IL-11R The method includes administering an alpha binding protein, antibody or composition.

[0170] In one embodiment, the methods described herein include administering a dose of about 0.05 mg / kg to about 30 mg / kg For example, administering an IL-11Rα binding protein or antibody between 0.1 Between about 0.2 mg / kg and 5 mg / kg of IL-1 In one embodiment, the method comprises administering a 1Rα binding protein or antibody to a subject in need thereof at about 0 The method includes administering 0.5 to 2 mg / kg of IL-11Rα binding protein or antibody.

[0171] The present disclosure also relates to a pharmaceutical composition comprising IL-11 as described herein. Uses of Rα binding proteins or antibodies are provided.

[0172] The present disclosure also relates to any of the uses in the manufacture of a medicament for treating an IL-11 mediated disease. The use of an IL-11Rα binding protein or antibody as described herein according to the examples Exemplary diseases are described herein.

[0173] The present disclosure also provides a method for treating IL-11-mediated diseases associated with cells expressing IL-11Rα. providing a method for localizing and / or detecting and / or diagnosing and / or prognosing a tumor; The method comprises determining whether a IL-11Rα-expressing antibody is present, and determining whether the antibody is a IL-11Rα-expressing antibody. and detecting in vivo such IL-11Rα binding proteins or antibodies. In this regard, the IL-11Rα binding protein or antibody is conjugated to a detectable tag.

[0174] In one embodiment, the method further comprises administering to the subject an IL-11Rα binding protein. nothing.

[0175] The present disclosure also provides a method for detecting IL-11Rα in a sample or detecting a gene encoding an IL-11Rα-expressing The present invention provides a method for detecting a cell containing a complex, the method comprising the steps of: Contacting the sample with a protein or antibody as described herein and detecting the complex. wherein detecting the complex includes detecting IL-11Rα or IL-1 in the sample. In one embodiment, the method is performed in vitro or in a test tube. do.

[0176] The present disclosure also provides a method of diagnosing or prognosing an IL-11 mediated disease, comprising: The method detects IL-11Rα or detects cells expressing IL-11Rα. carrying out a method as described herein according to any of the examples, wherein IL Detection of cells expressing IL-11Rα or IL-11Rα is diagnostic or prognostic of disease. In one embodiment, the method is performed in vitro or ex vivo. Such diseases are described herein.

[0177] The disclosure also includes, optionally together with instructions, for use in the methods as described herein. IL-11Rα binding protein as described herein according to any of the examples, Kits (eg, packages or articles of manufacture) containing the proteins or antibodies are also provided.

[0178] Key to the sequence table SEQ ID NO: 1: Amino acid sequence of human pre-IL-11Rα SEQ ID NO: 2: Amino acid sequence of cynomolgus monkey pre-IL-11Rα SEQ ID NO: 3: Amino acid sequence of a polypeptide containing amino acids 23 to 363 of SEQ ID NO: 1, ×HIS tag and serine at the position corresponding to position 248 of SEQ ID NO: 1 (referred to as "WT F / L" (also called SEQ ID NO: 4: Amino acid sequence of human gpl30 SEQ ID NO: 5: V of antibody 8E2 L Amino acid sequence of the chain SEQ ID NO: 6: V of antibody TS-303 L Amino acid sequence of the chain SEQ ID NO: 7: V of antibody TS-305 L Amino acid sequence of the chain SEQ ID NO: 8: V of antibody TS-306 L Amino acid sequence of the chain SEQ ID NO: 9: V of antibody TS-307 L Amino acid sequence of the chain SEQ ID NO: 10: V of antibody TS-310 L Amino acid sequence of the chain SEQ ID NO: 11: V of antibody TS-311 L Amino acid sequence of the chain SEQ ID NO: 12: V of antibody TS-312 L Amino acid sequence of the chain SEQ ID NO: 13: V of antibody TS-313 L Amino acid sequence of the chain SEQ ID NO: 14: V of antibody TS-322 L Amino acid sequence of the chain SEQ ID NO: 15: V of antibody TS-2 L Amino acid sequence of the chain SEQ ID NO: 16: V of antibody TS-4 L Amino acid sequence of the chain SEQ ID NO: 17: V of antibody TS-6 L Amino acid sequence of the chain SEQ ID NO: 18: V of antibody TS-7 L Amino acid sequence of the chain SEQ ID NO: 19: V of antibody TS-9 L Amino acid sequence of the chain SEQ ID NO: 20: V of antibody TS-13 L Amino acid sequence of the chain SEQ ID NO: 21: V of antibody TS-14 L Amino acid sequence of the chain SEQ ID NO: 22: V of antibody TS-17 L Amino acid sequence of the chain SEQ ID NO: 23: V of antibody TS-20 L Amino acid sequence of the chain SEQ ID NO: 24: V of antibody TS-21 L Amino acid sequence of the chain SEQ ID NO: 25: V of antibody TS-22 L Amino acid sequence of the chain SEQ ID NO: 26: V of antibody TS-29 L Amino acid sequence of the chain SEQ ID NO: 27: V of antibody TS-32 L Amino acid sequence of the chain SEQ ID NO: 28: V of antibody TS-49 L Amino acid sequence of the chain SEQ ID NO: 29: V of antibody TS-51 L Amino acid sequence of the chain SEQ ID NO: 30: V of antibody TS-55 L Amino acid sequence of the chain SEQ ID NO: 31: V of antibody TS-57 L Amino acid sequence of the chain SEQ ID NO: 32: V of antibody TS-58 L Amino acid sequence of the chain SEQ ID NO: 33: V of antibody TS-63 L Amino acid sequence of the chain SEQ ID NO: 34: V of antibody TS-64 L Amino acid sequence of the chain SEQ ID NO: 35: V of 8E2 antibody and derivatives L Consensus amino acid sequence of the chain SEQ ID NO: 36: V of 8E2 antibody and selected derivatives L Consensus amino acid sequence of the chain SEQ ID NO: 37: V of antibody 8E2 H Amino acid sequence of the chain SEQ ID NO: 38: V of antibody TS-66 H Amino acid sequence of the chain SEQ ID NO: 39: V of antibody TS-69 H Amino acid sequence of the chain SEQ ID NO: 40: V of antibody TS-71 H Amino acid sequence of the chain SEQ ID NO: 41: V of antibody TS-76 H Amino acid sequence of the chain SEQ ID NO: 42: V of antibody TS-79 H Amino acid sequence of the chain SEQ ID NO: 43: V of antibody TS-82 H Amino acid sequence of the chain SEQ ID NO: 44: V of antibody TS-88H Amino acid sequence of the chain SEQ ID NO: 45: V of antibody TS-89 H Amino acid sequence of the chain SEQ ID NO: 46: V of antibody TS-91 H Amino acid sequence of the chain SEQ ID NO: 47: V of antibody TS-92 H Amino acid sequence of the chain SEQ ID NO: 48: V of antibody TS-97 H Amino acid sequence of the chain SEQ ID NO: 49: V of antibody TS-101 H Amino acid sequence of the chain SEQ ID NO: 50: V of antibody TS-103 H Amino acid sequence of the chain SEQ ID NO: 51: V of antibody TS-104 H Amino acid sequence of the chain SEQ ID NO: 52: V of antibody TS-107 H Amino acid sequence of the chain SEQ ID NO: 53: V of antibody TS-108 H Amino acid sequence of the chain SEQ ID NO: 54: V of antibody TS-115 H Amino acid sequence of the chain SEQ ID NO: 55: V of antibody TS-129 H Amino acid sequence of the chain SEQ ID NO: 56: V of antibody TS-133 H Amino acid sequence of the chain SEQ ID NO: 57: V of antibody TS-134 H Amino acid sequence of the chain SEQ ID NO: 58: V of antibody TS-135 H Amino acid sequence of the chain SEQ ID NO: 59: V of antibody TS-136 H Amino acid sequence of the chain SEQ ID NO: 60: V of antibody TS-140 H Amino acid sequence of the chain SEQ ID NO: 61: V of antibody TS-143 H Amino acid sequence of the chain SEQ ID NO: 62: V of antibody TS-151 H Amino acid sequence of the chain SEQ ID NO: 63: V of antibody TS-156 H Amino acid sequence of the chain SEQ ID NO: 64: V of antibody TS-213 H Amino acid sequence of the chain SEQ ID NO: 65: V of antibody TS-214 H Amino acid sequence of the chain SEQ ID NO: 66: V of antibody TS-215 H Amino acid sequence of the chain SEQ ID NO: 67: V of antibody TS-218 H Amino acid sequence of the chain SEQ ID NO: 68: V of antibody TS-221 H Amino acid sequence of the chain SEQ ID NO: 69: V of antibody TS-222 H Amino acid sequence of the chain SEQ ID NO: 70: V of antibody TS-224 H Amino acid sequence of the chain SEQ ID NO: 71: V of 8E2 antibody and derivatives H Consensus amino acid sequence of the chain SEQ ID NO: 72: V of 8E2 antibody and selected derivatives H Consensus amino acid sequence of the chain SEQ ID NO: 73: V of antibody 8E4 L Amino acid sequence of the chain SEQ ID NO: 74: V of antibody 8E4 H Amino acid sequence of the chain SEQ ID NO: 75: V of antibody 8D10 L Amino acid sequence of the chain SEQ ID NO: 76: V of antibody 8D10 H Amino acid sequence of the chain SEQ ID NO: 77: V of 8E2 antibody and derivatives L Consensus amino acid sequence of CDR1 of each chain SEQ ID NO: 78: V of 8E2 antibody and derivatives L Consensus amino acid sequence of CDR3 of each chain SEQ ID NO: 79: V of 8E2 antibody and derivatives H Consensus amino acid sequence of CDR1 of each chain SEQ ID NO: 80: V of 8E2 antibody and derivatives H Consensus amino acid sequence of CDR2 of each chain SEQ ID NO: 81: V of 8E2 antibody and derivatives H Consensus amino acid sequence of CDR3 of each chain SEQ ID NO: 82: Amino acid sequence of Mus musculus pre-IL-11Rα SEQ ID NO: 83: Amino acid sequence of the heavy chain of antibody 8E2 SEQ ID NO: 84: Amino acid sequence of the light chain of antibody 8E2 SEQ ID NO: 85: A polypeptide containing amino acids 23 to 318 of human IL-11Rα (SEQ ID NO: 1). the amino acid sequence of the peptide, 8×HIS tag, and a sequence corresponding to position 248 of SEQ ID NO:1 Phosphorus (also called "WT Dl / 2") SEQ ID NO: 86: Amino acids 23 to 110 of human IL-11Rα (SEQ ID NO: 1) and Duck IL-11Rα (SEQ ID NO: 82) (serine at the position corresponding to position 206 of SEQ ID NO: 82) The amino acid sequence of the polypeptide containing amino acids 111 to 367 of the column SEQ ID NO: 87: Amino acids 23 to 215 of human IL-11Rα (SEQ ID NO: 1) and Amino acids 216 to 367 of mouse IL-11Rα (SEQ ID NO: 82) and an 8×HIS tag The amino acid sequence of the polypeptide comprising SEQ ID NO: 88: Human IL-11Rα (SEQ ID NO: 1) (position corresponding to position 248 of SEQ ID NO: 1) Amino acids 23 to 318 of mouse IL-11Rα (sequence number 64444) Amino acid sequence of the polypeptide containing amino acids 319 to 367 of 82) and an 8×HIS tag SEQ ID NO: 89: Mus musculus IL-11Rα (SEQ ID NO: 82) (position 206 of SEQ ID NO: 82) (sequence 10001) and human IL-11Rα (sequence 10001) Amino acid sequence of polypeptide containing amino acids 216 to 363 of No. 1 and 8×HIS tag column SEQ ID NO: 90: amino acids 24 to 367 of mouse IL-11Rα (SEQ ID NO: 82); A polypeptide comprising an 8×HIS tag and a serine at a position corresponding to position 206 of SEQ ID NO:82. Amino acid sequence of SEQ ID NO: 91: Amino acid sequence of the light chain of antibody 8E4 SEQ ID NO: 92: Amino acid sequence of the heavy chain of antibody 8E4 SEQ ID NO: 93: Amino acid sequence of the light chain of antibody 8D10 SEQ ID NO: 94: Amino acid sequence of the heavy chain of antibody 8D10 SEQ ID NO: 95: SEQ ID NO: 85 containing glutamic acid at the position corresponding to position 117 of SEQ ID NO: 1 The amino acid sequence of SEQ ID NO: 96: an arginine analog of SEQ ID NO: 85 containing an arginine at position 66 of SEQ ID NO: 1 Amino acid sequence SEQ ID NO: 97: Amino acid sequence of SEQ ID NO: 85 containing serine at the position corresponding to position 65 of SEQ ID NO: 1 Acid sequence SEQ ID NO: 98: Amino acid sequence of SEQ ID NO: 85 containing serine at the position corresponding to position 101 of SEQ ID NO: 1 Acid sequence SEQ ID NO: 99: an alanine analog of SEQ ID NO: 85 containing an alanine at the position corresponding to position 178 of SEQ ID NO: 1 Amino acid sequence SEQ ID NO: 100: Amino acid sequence of mature human IL-11Rα SEQ ID NO: 101: Amino acid sequence of mature cynomolgus monkey IL-11Rα SEQ ID NO: 102: Amino acid sequence of mature mouse IL-11Rα SEQ ID NO: 103: Consensus amino acid sequence of 8E2L1 shown in FIG. SEQ ID NO: 104: Consensus amino acid sequence of 8E2L3.1 shown in FIG. SEQ ID NO: 105: Consensus amino acid sequence of 8E2L3.2 shown in FIG. SEQ ID NO: 106: Consensus amino acid sequence of 8E2H1 shown in FIG. SEQ ID NO: 107: Consensus amino acid sequence of 8E2H2 shown in FIG. SEQ ID NO: 108: Consensus amino acid sequence of 8E2H3.1 shown in FIG. 2 SEQ ID NO: 109: Consensus amino acid sequence of 8E2H3.2 shown in FIG. 2 SEQ ID NO: 110: Amino acid sequence of an antagonistic IL-11 mutein [Brief description of the drawings]

[0179] [Figure 1] FIG. 1 is a diagrammatic representation showing the sequences of the CDRs of the VL of antibody 8E2 and their affinity maturation patterns. The consensus sequences listed (SEQ ID NOs: 103-105) represent the most commonly occurring amino acid at each position and were determined using MegAlign software. Outside of the consensus sequences, the sequences are derived from the antibodies shown in Table 1. [Diagram 2] FIG. 1 is a diagrammatic representation showing the sequences of the CDRs of the VH of antibody 8E2 and their affinity maturation patterns. The consensus sequences listed (SEQ ID NOs: 106-109) represent the most commonly occurring amino acid at each position and were determined using MegAlign software. Outside of the consensus sequences, the sequences are derived from the antibodies shown in Table 1. [Figure 3A-1] Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3A shows the sequences of the VL regions of 8E2 and its antibody derivatives and the consensus sequence of the VL regions of 8E2 and its antibody derivatives. The boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 3A-2] Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3A shows the sequences of the VL regions of 8E2 and its antibody derivatives and the consensus sequence of the VL regions of 8E2 and its antibody derivatives. The boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 3B] Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3B shows the sequences of the VL regions of 8E2 and select antibody derivatives and the consensus sequence of the VL regions of 8E2 and select antibody derivatives. The boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 3C-1]Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3C shows the sequences of the VH regions of 8E2 and its antibody derivatives and the consensus sequence of the VH regions of 8E2 and its antibody derivatives. The boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 3C-2] Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3C shows the sequences of the VH regions of 8E2 and its antibody derivatives and the consensus sequence of the VH regions of 8E2 and its antibody derivatives. The boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 3D] Figures 3A, B, C and D are diagrammatic representations showing the sequences of the variable regions of the 8E2 antibody and derivatives. Figure 3D shows the sequences of the VH regions of 8E2 and select antibody derivatives and the consensus sequence of the VH regions of 8E2 and select antibody derivatives. Boxed regions contain the CDRs (as shown) as defined by the Kabat numbering system. [Figure 4] FIG. 1 is a series of graphical representations showing that IL-11 stimulates STAT-3 phosphorylation in the human colorectal adenocarcinoma cell line DLD-1 and the gastric adenocarcinoma cell line MKN-28, and that antibodies of the present disclosure can inhibit this IL-11-mediated phosphorylation. Panels A and B show the levels of STAT-3 phosphorylation in DLD-1 and MKN-28 cells, respectively, following stimulation with increasing concentrations of hIL-11 for 15 minutes. Panels C and D show that increasing concentrations of 8E2 anti-IL-11R antibody (◯) inhibit IL-11-mediated STAT-3 phosphorylation in DLD-1 and MKN-28 cells, respectively. In contrast, the BM4 isotype control antibody (△) had no effect on IL-11-mediated STAT-3 phosphorylation. (Antibodies were added to cells prior to stimulation with hIL-11 (50 ng / ml). Means and standard deviations are shown.) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0180] overview Throughout this specification, unless specifically stated or otherwise required by context, a single References to a step, composition, group of steps or group of compositions include both one and more (i.e. The present invention is intended to encompass one or more of these steps, compositions, groups of steps or groups of compositions. should be interpreted as follows.

[0181] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It will be understood that the present disclosure includes all such variations and modifications. The present disclosure also relates to the steps, features, compositions and compounds referred to or illustrated herein. All of the components, individually or collectively, as well as any combination of steps or features, The present invention also includes any or all of the steps or features.

[0182] The present disclosure is provided by way of specific examples described herein, which are intended for purposes of illustration only. Functionally equivalent products, compositions and methods are clearly defined and should not be limited in scope by the above definition. Within the scope of this disclosure.

[0183] Any embodiment of the present disclosure herein may be combined with any other embodiment of the present disclosure unless specifically stated otherwise. The above examples should be construed as applying mutatis mutandis to the above examples.

[0184] Unless specifically defined, all technical and scientific terms used herein are techniques (e.g., cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry and biochemistry) shall be interpreted to have the same meaning as commonly understood by one of ordinary skill in the art of chemistry. It is.

[0185] Unless otherwise indicated, the recombinant proteins, cell culture, and immunological techniques utilized in this disclosure The methods are standard procedures well known to those skilled in the art. Such techniques are described, for example, in J. Perbal, A Practical Guide to Molecular Cloning,J ohn Wiley and Sons (1984), J. Sambrook et al., Mol ecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press (1989), T. A. Brown (editor), Essential Molecular Biology: A Practical Approach, Vol. 1 and 2, IRL Press ( 1991), D. M. Glover and B. D. Hames (eds.), DNA Cloning ing:A Practical Approach,Vol.1-4,IRL Pre ss (1995 and 1996), and FMAusubel et al. (editors), Curre nt Protocols in Molecular Biology,Greene Pub.Associates and Wiley-Interscience ( 1988, including all current updates, Ed Harlow and David Lan e(editor) Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory, (1988), and J.E. Coligan et al. (eds.) Current Protocols in Immun ology, John Wiley & Sons (including all current updates) This is described and explained throughout the literature in such sources.

[0186] Description and definitions of variable regions and portions thereof, immunoglobulins, antibodies and fragments thereof herein Kabat Sequences of Proteins of Immunol ogical Interest,National Institutes of H health, Bethesda, Md., 1987 and 1991, Bork et al., J. Molecular l.Biol.242,309-320,1994, Chothia and Lesk, J. Mol.Biol.196:901-917,1987, Chothia et al., Natur e, 342, 877-883, 1989 and / or Al-Lazikani et al., J. Mole. This is further clarified by the discussion in I. Biol. 273, 927-948, 1997. It is possible.

[0187] The term "and / or," for example, "X and / or Y," means "X and Y" or "X or only Y." means either "Y" or "Y" and does not provide clear support for either or both meanings. should be interpreted as follows.

[0188] Throughout this specification the word "comprise" or, for example, "comprises Variations such as "comprises" or "comprising" are used to refer to " " implies the inclusion of any element, integer or step, or group of elements, integers or steps, No exclusion of any other element, integer or step, or group of elements, integers or steps, is implied. It will be understood as follows.

[0189] As used herein, the term "derived from" does not necessarily mean directly derived from a particular source. indicates that a specified integer can be obtained from that source, even though it is not necessarily the case that should be interpreted as follows.

[0190] For example, references herein to ranges of residues will be understood to be inclusive. For example, a reference to "a range including amino acids 56 to 65" should be understood in an inclusive manner. That is, the range is 56, 57, 58, 59, 60, 61 , 62, 63, 64 and 65.

[0191] Selected Definitions For purposes of nomenclature only and not limitation, human precursor IL-11Rα (pre-IL-11R An example sequence of α) is provided in the NCBI reference sequence: NP_001136256.1 ( and SEQ ID NO: 1). Mature human IL-11Rα is represented by SEQ ID NO: 100. In the case of the sequence represented by NP_001136256.1, the mature protein consists of amino acids 1 to 22. Amino acid positions are designated herein by reference to pre-IL-11Rα. The position in mature IL-11Rα is often referred to as the signal sequence (in the case of SEQ ID NO: 1). It is easily determined by accounting for amino acids 1-22 in the cynomolgus monkey. An exemplary sequence of pre-IL-11Rα is provided in SEQ ID NO:2, and mature IL-11Rα is An exemplary sequence for mouse pre-IL-11Rα is provided in SEQ ID NO: 101. 82, and mature IL-11Rα is represented by SEQ ID NO: 102. The sequences of IL-11Rα that are suitable for use in the present invention may be obtained using the sequences provided herein and / or publicly available. The sequences may be determined using sequences provided in available databases and / or using standard techniques. (see, for example, Ausubel et al., (eds.), Current Proto cols in Molecular Biology, Greene Pub. As societies and Wiley-Interscience (1988, to date (including all updates in) or Sambrook et al., Molecular Cloning :A Laboratory Manual,Cold Spring Harbor (As described in Laboratory Press (1989)). Human IL-1 References to cynomolgus IL-11Rα may be abbreviated to hIL-11Rα, and to cynomolgus IL-11Rα. References to may be abbreviated to cynoIL-11Rα, and references to murine IL-11Rα References to soluble IL-11Rα may be abbreviated to IL-11Rα. a polypeptide comprising the extracellular region of α, for example, amino acids 23 to 363 of SEQ ID NO: 1, or In this study, the polypeptide with a serine substitution at position 248 was Soluble forms of the receptor containing amino acids 23 to 363 or 23 to 318 of SEQ ID NO:1 are used. (e.g., SEQ ID NO: 3 or 85), and a serinorin gene is inserted at a position corresponding to position 206 of SEQ ID NO: 82. The corresponding fragment of mIL-11Rα (e.g., SEQ ID NO: 90) with the substitution of These serine mutations were introduced into soluble polypeptides to produce poly(A)-receptor polypeptides. Improved peptide expression and prevented aggregation. Soluble receptors of SEQ ID NO: 3 and SEQ ID NO: 85 Various point mutations have also been utilized (see, for example, SEQ ID NOs: 95-99). The soluble polypeptides of the present disclosure bind to the relevant receptor when expressed on the surface of a cell. As demonstrated by the ability of the IL-11Rα binding protein of Thus, the mutant polypeptides are expressed as hIL-1Rα or mIL-11Rα. This is a model for studies using IL-11Rα and / or mIL-11Rα.

[0192] References herein to IL-11 include the native form of IL-11 and IL-11 Retains the ability to bind to Rα (e.g., hIL-11Rα) and induce signal transduction The present invention includes mutant forms thereof which are

[0193] References herein to specific domains of hIL-11Rα are as follows: Immunoglobulin-like (IG-like) domain: amino acids 23-110 of SEQ ID NO:1; First fibronectin III domain: amino acids 111-215 of SEQ ID NO:1; · second fibronectin III domain: amino acids 216-370 of SEQ ID NO:1; Transmembrane domain: amino acids 371 to 391 of SEQ ID NO:1; and · Cytoplasmic domain: amino acids 392-422 of SEQ ID NO:1; will be understood to mean

[0194] As used herein, the term "hIL-11 mutein" includes any of the following: The wild type residue at position 2 (AMSAG) was replaced by PAIDY, and the trinucleotide at position 147 The mutant form of hIL-11 in which ptophan is replaced by alanine (W147A) is included. For example, the mutein may comprise or be selected from the sequence set forth in SEQ ID NO: 110. Other examples of hIL-11 muteins include those disclosed in WO 2009 / 052588. Optionally, the mutein can contain additional sequences, e.g., Contains a xa-HIS tag.

[0195] The term "isolated protein" or "isolated polypeptide" refers to a polypeptide that is isolated from or derived from a Because of its source, it is not associated with the naturally associated components that accompany it in its native state. It is a protein or polypeptide that is substantially free of other proteins derived from the The protein may be rendered substantially free of naturally associated components using purification techniques known in the art. By "substantially purified" it is meant that the protein is The quality is substantially free of contaminants, e.g., at least about 70% or 75% free of contaminants. or 80% or 85% or 90% or 95% or 96% or 97% or 98% or 99% It means not to include.

[0196] The term "recombinant" should be understood to mean the product of artificial genetic recombination. Thus, in the context of a recombinant protein that contains an antigen-binding domain of an antibody, the term The term includes naturally occurring antibodies in a subject that are the product of natural recombination that occurs during cell maturation. However, if such an antibody is isolated, it is important to understand the antigen-binding domain of the antibody. Similarly, a protein should be considered an isolated protein containing the codon. If the nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein The recombinant protein is a recombinant protein that contains the antigen-binding domain of an antibody. For example, by artificial recombinant means when in a cell, tissue or subject in which it is expressed. This includes proteins expressed by

[0197] The term "protein" refers to a single polypeptide chain, i.e., a single molecule linked by peptide bonds. A series of adjacent amino acids or a series of polypeptides covalently or non-covalently bonded to each other The term "polypeptide complex" should be construed to include polypeptide chains (i.e., polypeptide complexes). For example, The polypeptide chains are covalently linked together using suitable chemical bonds or disulfide bonds. Examples of non-covalent bonds include hydrogen bonds, ionic bonds, van der Waals forces, and hydrophobic bonds. Interactions include:

[0198] The term "polypeptide" or "polypeptide chain" refers to a series of polypeptides linked by peptide bonds. It will be understood from the preceding paragraph that by "amino acid 1" means adjacent amino acids of

[0199] As used herein, the term "antigen-binding domain" refers to a domain capable of specifically binding to an antigen. The region of the antibody where H Or V L Or V H and V L Fv includes both The term antigen-binding domain should be construed as meaning the antigen-binding domain, not necessarily in the context of a whole antibody. For example, it may be in isolation (e.g., a domain antibody) or in a form such as, for example, an scFv. It may be in other forms as described herein.

[0200] For purposes of this disclosure, the term "antibody" includes an antigen-binding domain contained within an Fv. Specific binding to the same or a few closely related antigens (e.g., IL-11Rα) The term includes proteins that are capable of producing four-chain antibodies (e.g., two a light chain and two heavy chains), a recombinant antibody or a modified antibody (e.g., a chimeric antibody, a humanized antibody, Human antibodies, CDR-grafted antibodies, primatized antibodies, deimmunized antibodies, synhuma Antibodies generally contain constant domains. It can be composed of a constant region or a constant fragment or a crystallizable fragment (Fc). An exemplary form of an antibody contains a four-chain structure as its basic unit. Full-length antibodies are covalently linked. It contains two joined heavy chains (approximately 50-70 kDa) and two light chains (approximately 23 kDa each). The chains generally contain a variable region (if present) and a constant domain, and in mammals are either kappa light chains or lambda light chains. Heavy chains generally consist of a variable region and a hinge region, which is an additional constant domain. Mammalian heavy chains are of the following types: α, δ, ε, γ Each light chain is also covalently linked to one of the heavy chains. For example, two heavy chains and one heavy chain. The fatty and light chains are held together by interchain disulfide bonds and by noncovalent interactions The number of interchain disulfide bonds can vary among different types of antibodies. Each chain consists of an N-terminal The terminal variable regions (V H Or V L ) and one or more at the C-terminus The light chain constant domain (C, about 110 amino acids in length) L )teeth , the first constant domain of the heavy chain (C H Along with 1), Jisul The light chain variable region is aligned with the heavy chain variable region. The heavy chain of an antibody contains two or more additional C H Domain (for example, C H 2. C H 3, etc.), C H 1 and C H 2 regular domains The antibody may include any type (e.g., IgG, Ig E, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, The antibody may be of any class (IgG3, IgG4, IgA1 and IgA2) or subclass. In embodiments, the antibodies are murine (mouse or rat) antibodies or primate (e.g., human) antibodies. In one embodiment, the antibody heavy chain is missing a C-terminal lysine residue. The antibodies may be humanized, semi-humanized, chimeric, CDR-grafted, or deimmunized. can be.

[0201] The terms "full length antibody," "intact antibody," or "whole antibody" are used interchangeably. In particular, the term refers to an antibody in a substantially intact form as opposed to an antigen-binding fragment of an antibody. In general, all antibodies have heavy and light chains that contain the Fc region. The constant region is a constant region of the wild-type sequence. It may be a constant domain (e.g., a constant domain of the human wild-type sequence) or an amino acid thereof. It may be a variant of the amino acid sequence.

[0202] As used herein, a "variable region" refers to a region capable of specifically binding to an antigen. The term "antibody" refers to the light and / or heavy chain portions of an antibody as defined herein, which are complementary determining regions (CDs) of the antibody. R), i.e., CDR1, CDR2 and CDR3, and framework regions (FR) For example, a variable region may have three CDRs and three or four FRs (e.g., For example, FR1, FR2, FR3 and optionally FR4. H refers to the variable region of the heavy chain V L refers to the variable region of the light chain.

[0203] As used herein, the term "complementarity determining region" (synonym, CDR, i.e., C The presence of CDR1, CDR2 and CDR3 is a major contributor to specific antigen binding. The amino acid residues in the variable region of an antibody. H Or V L ) is CDR In one embodiment, each of the ribozymes typically has three CDRs, identified as CDR1, CDR2 and CDR3. The amino acid positions assigned to the CDRs and FRs are based on the Kabat Sequences o f Proteins of Immunological Interest,Nat ional Institutes of Health,Bethesda,Md., 1987 and 1991 (also referred to herein as the "Kabat numbering system"). In another embodiment, the amino acid positions assigned to the CDRs and FRs are defined as follows: The Chothia numbering scheme (http: / / www.bioinfo.org) rg.uk / mdex.html) according to the Kabat numbering system. So, V H The FR and CDR are as follows: residues 1 to 30 (FR1), 31 to 35 (CDR1) , 36~49(FR2), 50~65(CDR2), 66~94(FR3), 95~10 2 (CDR3) and 103-113 (FR4). According to the naming scheme, V L The FR and CDRs are as follows: residues 1-23 (FR1), 24-3 4(CDR1), 35~49(FR2), 50~56(CDR2), 57~88(FR3 ), 89-97 (CDR3) and 98-107 (FR4). The reference is not limited to the FR and CDR defined by the Kabat numbering system, but includes all sequences defined by the Ch. Othia and Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature, 342:877-883, 1989; and / or Al Canonical method of Lazikani et al., J. Mol. Biol. 273:927-948, 1997 Numbering scheme: Honnegher and Plukthun, J. Mol. Biol. 30 9:657-670, 2001; or the numbering system of Giudicelli et al., Nucl The IMGT method discussed in Eic Acids Res. 25:206-211 1997 In one embodiment, the CDRs are numbered according to Kabat numbering. Optionally, the heavy chain CDR2 is defined according to the Kabat numbering system. , does not contain the five C-terminal amino acids listed herein, or any of these amino acids In this regard, Padlan et al., FA SEB J., 9:133-139, 1995, the five C-terminal amino acids of the heavy chain CDR2 demonstrated that is generally not involved in antigen binding.

[0204] "Framework regions" (FR) are those variable region residues other than the CDR residues.

[0205] As used herein, the term "Fv" refers to a single polypeptide, whether composed of multiple polypeptides. Whether it is composed of a single polypeptide, L and V H The complex is composed of a complex having an antigen-binding domain. Any protein capable of forming a complex, i.e., binding specifically to an antigen The V that forms the antigen-binding domain should be interpreted as meaning L and V H is single The F of the present disclosure may be present in the same polypeptide chain or in different polypeptide chains. v (as well as any protein of the present disclosure) may bind or not bind the same antigen. The term also refers to fragments derived directly from an antibody, such as a fragment of an antibody that may or may not have multiple antigen-binding domains. and proteins corresponding to such fragments produced by recombinant means. In some embodiments, VH is the heavy chain constant domain (C H )1 Not and / or V L is the light chain constant domain (C L ) is not linked to the polypeptide. Exemplary Fv or proteins having Fab fragments, Fab' fragments, F(ab') fragments, , scFv, diabody, triabody, tetrabody, or higher order conjugates. or a constant region or domain thereof, e.g., C H 2 or C H 3. Domain "Fab fragments" include any of the above linked to a It consists of a monovalent antigen-binding fragment of an immunoglobulin and is produced by digestion of whole antibodies with the enzyme papain. The resulting fragments may be composed of intact light and heavy chains or recombinantly produced. "Fab' fragments" of antibodies can be produced by digesting whole antibodies with pepsin. The intact light chain and V H Weight including The resulting antibody molecule consists of a portion of the chain and a single constant domain. Two Fab' fragments are obtained by the addition of the Fab' fragment. Fab' fragments can also be produced by recombinant means. The F(ab')2 fragment of an antibody is held together by two disulfide bonds. It consists of a dimer of two Fab' fragments, which are synthesized by treating the whole antibody molecule with the enzyme pepsin and then reducing it. The Fab2 fragment can be obtained without the use of any of the following: H 3Dome A "single-chain Fv" or " "scFv" is a peptide that combines the variable regions of the light chain and the variable regions of the heavy chain in a flexible polypeptide linker. It is therefore a recombinant molecule containing a covalently linked variable region fragment (Fv) of an antibody.

[0206] As used herein, an IL-11Rα binding protein or an antigen-binding domain thereof The term "bind" in relation to the interaction of an antigen with an antibody is intended to mean that the interaction is with a specific structure on the antigen (e.g., For example, the presence of an antigenic determinant or epitope. For example, an antibody They recognize and bind to specific protein structures, rather than proteins in general. If the antibody binds to epitope "A", then the antibody is labeled with "A" and the protein is The presence of a molecule containing epitope "A" (or free, unlabeled "A") in the reaction is This will reduce the amount of labeled "A" that binds to the antibody.

[0207] As used herein, the term "specifically binds "specifically binds" or "binds specifically" means The IL-11Rα binding proteins of the present disclosure bind to IL-11Rα more frequently and rapidly than alternative antigens or cells. React with a specific antigen or a cell expressing a specific antigen for a long time and / or with high affinity. For example, IL-11 Rα-binding proteins bind to other interleukin receptors or to polyreactive natural antibodies (i.e. Naturally occurring antibodies known to bind a variety of antigens found naturally in humans ) with significantly greater affinity (e.g., 1.5-fold or 2x or 5x or 10x or 20x or 40x or 60x or 80x to 100x or 15x 0 or 200 times) IL-11Rα (e.g., hIL-11Rα or a polypeptide containing a region thereof) The present disclosure relates to a polypeptide that binds to a nucleotide sequence of the ... In the example, at least one variant of SEQ ID NO: 3, including the sequence shown in SEQ ID NO: 95, is .5x or 2x (for example, 5x or 10x or 20x or 50x or 100x or 20x) 0 times) with high affinity to hIL-11Rα or a polypeptide containing a domain thereof (e.g., hIL-11Rα The extracellular domain of IL-11Rα) or the polypeptide of the sequence shown in SEQ ID NO: 3 or 85 IL-11Rα binding proteins that "specifically bind" to one form of Although not necessarily a binding, reference to a bond means a specific bond and each term is unambiguous with respect to the other terms. should be understood to provide support for the

[0208] As used herein, the term "not detectably bind" refers to an IL-11Rα binding tag. Proteins, e.g., antibodies, less than 10%, 8%, 6%, or 5% above background. Background should be understood to mean binding to the candidate antigen at a level that is consistent with the antibody. The controls were assayed in the absence of protein and / or in the presence of a negative control protein (e.g., isotype The level of binding signal detected in the presence of a control antibody and / or a negative control antigen The level of binding can be the level of binding detected by IL-11Rα binding tag. Biosensor assays (e.g., Biacore) in which the protein is immobilized and contacted with the antigen. ) is used to detect the

[0209] As used herein, the term "does not significantly bind" refers to the IL-11Rα binding of the present disclosure. The level of binding of the fusion protein to the polypeptide is less than background, e.g., IL-1 The absence of 1Rα-binding protein and / or a negative control protein (e.g., isotype The level of binding signal detected in the presence of a negative control antibody and / or a negative control polypeptide This means that the level of binding is not statistically significantly higher than that detected in the presence of It should be understood that the level of binding can be determined by immobilizing the IL-11Rα binding protein and The antigen is detected using a biosensor assay (eg, Biacore).

[0210] As used herein, "reduced binding" or "lower levels of binding" with respect to an antigen. The phrase "binds" refers to an IL-11Rα binding protein, e.g., an antibody, that binds to a control epitope. At least about 1.5-fold, 2-fold, or 5-fold higher than the tope or antigen (e.g., SEQ ID NO:3) or with 10-fold or 20-fold or 50-fold or 100-fold or 200-fold lower affinity to the antigen (e.g. and variants of SEQ ID NO: 3 as described herein, such as variants comprising the sequence set forth in SEQ ID NO: 95. It should be understood to mean binding to a heterologous form.

[0211] The IL-11Rα binding protein or antibody may be a protein or antibody directed against another polypeptide. Dissociation constant of antibody (K D ) lower K D If you want to bind a polypeptide with In one embodiment, the IL-11Rα-binding protein may be considered to "preferentially bind" to the IL-11Rα-binding peptide. A protein or antibody is a polypeptide that binds to another polypeptide. D At least Approximately 1.5 times, 2 times, 5 times, 10 times, 20 times, 50 times, 100 times, or 200 times Large affinity (i.e., K D If you want to link a polypeptide with are considered to "preferentially bind" to the

[0212] As used herein, the terms "hIL-11Rα and cynoIL-11Rα" "Capable of binding to hIL-11Rα" means that the IL-11Rα binding protein is capable of binding to hIL-11Rα Cross-reacts with cynoIL-11Rα, i.e. binds to either protein will be understood to mean that.

[0213] For purposes of clarity and as will be apparent to those skilled in the art based on the illustrated subject matter herein. As such, references herein to "affinity" refer to the K D Reference to It is.

[0214] For purposes of clarity and as will be apparent to those skilled in the art based on the disclosure herein, Reference to "at least about affinity" refers to the affinity (or K D ) is equal to or greater than the quoted value (i.e. the value quoted for affinity is lower), i.e. an affinity of 2 nM is 3 This will be understood to mean greater than nM affinity. The term may be "affinity less than or equal to X," where X is a value recited herein.

[0215] "At least about IC 50 " is an IC 50 is less than or equal to the quoted value (i.e., I C 50 The values ​​quoted as are lower), i.e., IC of 2 μg / ml. 50 is 1μg / ml IC 50 would be understood to mean greater than. The term refers to an "IC less than or equal to X", where X is a value cited herein. 50 " It could be.

[0216] As used herein, the term "epitope" (synonym "antigenic determinant") refers to the site of an antibody. Region of IL-11Rα to which IL-11Rα binding proteins bind, including the antigen-binding domain This term should be understood to mean that the IL-11Rα binding protein It is not necessarily limited to the particular residues or structures that make contact. For example, the term includes IL- The region spanning the amino acids that contact the 11Rα binding protein and 5-10 outside this region In some embodiments, the epitope comprises 2-5 or 1-3 amino acids. When the IL-11Rα binding protein is folded, i.e., a “conformational epitope” " includes a series of non-contiguous amino acids located closely together. It will also be noted that the term "epitope" is not limited to peptides or polypeptides. For example, the term "epitope" includes, for example, a sugar side chain, a phosphoryl side chain, or a sulfonyl side chain. These include groupings of chemically active surfaces of molecules, such as aryl side chains, In examples, they may have particular three-dimensional structural characteristics and / or particular charge characteristics.

[0217] The term "competitively inhibits" refers to the ability of an IL-11Rα binding protein (or an antigen thereof) of the present disclosure to inhibit binding domain) of the cited antibody or IL-11Rα binding protein For example, this is understood to mean reducing or preventing binding to hIL-11Rα. This should be done by identifying IL-11Rα binding proteins to the same or overlapping epitopes. The binding of the IL-11Rα binding protein (or antigen-binding domain) to an antibody. The substance need not completely inhibit antibody binding, but rather, a statistically significant amount, e.g., At least about 10% or 20% or 30% or 40% or 50% or 60% or 70% or It is clear from the above that reducing binding by 80% or 90% or 95% is sufficient. Preferably, the IL-11Rα binding protein inhibits the binding of the antibody by at least about 30 %, more preferably at least about 50%, more preferably at least about 70%, More preferably, at least about 75%, and even more preferably, at least about 80% or 8 5%, and even more preferably at least about 90%. Methods are known in the art and / or described herein. For example, antibodies can be prepared by the methods described herein. The cells are exposed to IL-11Rα in the presence or absence of IL-11Rα binding protein. The results were greater in the presence of IL-11Rα binding protein than in its absence. If only a small amount of antibody binds, the protein is considered to competitively inhibit antibody binding. In one embodiment, competitive inhibition is not due to steric hindrance.

[0218] "Overlap" in the context of two epitopes refers to IL-11Rα binding to one epitope. IL-11 whose binding protein (or its antigen-binding domain) binds to another epitope It is possible to competitively inhibit the binding of Rα binding protein (or antigen binding domain) This is interpreted to mean that the two epitopes share a sufficient number of amino acid residues to For example, "overlapping" epitopes should be at least 1 or 2 or 3 or 4 or have 5 or 6 or 7 or 8 or 9 or 20 amino acids in common.

[0219] As used herein, the term "neutralizing" refers to a protein that inhibits IL-11R in a cell. Blocking, reducing or disrupting IL-11-mediated signal transduction through α The method for measuring neutralization is well known in the art. and / or as described herein.

[0220] As used herein, the term "condition" refers to a disruption or interruption of normal function. It is not limited to any particular disease, but will include any disease or disorder.

[0221] As used herein, an "IL-11 associated disorder" refers to an IL-11-associated disorder caused by excess IL-11 or IL-11. Any disease caused by or associated with administration of IL-11 or cells expressing IL-11 A skilled practitioner would be able to easily identify such a condition. Exemplary diseases are described herein.

[0222] As used herein, the terms "preventing," "prevent" or "prevention" include: IL-11Rα binding proteins of the present disclosure are administered to thereby treat at least one of the diseases. This term also includes stopping or preventing the onset of a condition. The present invention also encompasses treatment of subjects in remission for refractory disease.

[0223] As used herein, the terms “treating,” “treat,” or “treatment” include: The IL-11Rα binding proteins described herein are administered to treat certain diseases. Or reducing or eliminating at least one symptom of the disease.

[0224] As used herein, the term "subject" refers to any animal, including humans, e.g., mammals. Exemplary subjects include humans and non-human primates. For example, but not limited to, the subject may be a human.

[0225] antibody In one embodiment, the IL-11Rα binding protein as described herein according to any of the examples. is an antibody.

[0226] Methods for generating antibodies are known in the art and / or are described in detail by Harlow and Lane ( (Editor), Antibodies: A Laboratory Manual, Cold Described in Spring Harbor Laboratory, (1988) Generally, such methods may include the addition of any suitable or desired carrier, adjuvant or pharmaceutical IL-11Rα (e.g., hIL-11Rα) formulated with a suitable excipient. The antibody may be a region thereof (e.g., an extracellular region) or an immunogenic fragment thereof or an epitope thereof or That is, cells expressing or presenting an immunogen are cultured in a non-human animal, e.g., a mouse. Administered to mice, chickens, rats, rabbits, guinea pigs, dogs, horses, cows, goats, or pigs. The immunogen may be administered intranasally, intramuscularly, subcutaneously, intravenously, intradermally, intraperitoneally, or by any other known route. It may be administered by any route.

[0227] Polyclonal antibodies were isolated by collecting blood from immunized animals at various times after immunization. The body's production can be monitored. One or more further immunizations can be performed as necessary to determine the desired antibody titer. The process of boosting and titering is repeated until a suitable titer is achieved. Once a level of immunogenicity is achieved, the immunized animal is bled, the serum is isolated, stored, and and / or animals to generate monoclonal antibodies (mAbs).

[0228] Monoclonal antibodies are one exemplary form of antibody contemplated by the present disclosure. The term "monoclonal antibody" or "mAb" refers to a monoclonal antibody that binds to the same antigen, e.g., the same epitope within an antigen. The term refers to a homogenous population of antibodies capable of binding to a target polypeptide. It is not intended to be limited as to the method of making the compound.

[0229] mAbs can be produced by any one of a number of known techniques, e.g., U.S. Pat. No. 4,333,636. No. 196265 or the procedures exemplified in Harlow and Lane (1988) supra. may be used.

[0230] For example, a suitable animal is immunized with an immunogen under conditions sufficient to stimulate antibody producing cells. Rodents such as rabbits, mice and rats are exemplary animals. For example, the antibodies of the present disclosure can be expressed using mice genetically engineered not to express mouse antibodies. It is also possible to produce (for example, like).

[0231] Following immunization, mAbs are produced from somatic cells with the potential to produce antibodies, specifically B lymphocytes (B cells). These cells are selected for use in the b production protocol. It can be obtained from a lymph node biopsy or from a peripheral blood sample. By fusing immortal myeloma cells, typically from the same species, with B cells from the immunized animal, do.

[0232] Culture in selective media containing agents that block de novo synthesis of nucleotides in tissue culture media Exemplary agents include aminopterin, methotrexate, and and azaserine.

[0233] For example, flow cytometry and / or immunohistochemistry and / or immunoassays (e.g. For example, radioimmunoassays, enzyme immunoassays, cytotoxicity assays, plaque assays Functional selection of antibodies for specificity and / or potency, such as antibody screening, dot immunoassays, etc. The amplified hybrids are subjected to selection.

[0234] Alternatively, ABL-MYC technology (NeoClone, Madison WI 53713 mAb-secreting cells are generated using a mAb-secreting medium (e.g., Largaespada, USA) et al., J. Immunol. Methods. 197:85-95, 1996. As mentioned above.

[0235] Display libraries, e.g., those described in U.S. Pat. No. 6,300,064 and / or U.S. Pat. Screening a phage display library such as that described in US Pat. No. 5,885,793 For example, the present inventors have have isolated completely human antibodies from phage display libraries.

[0236] As described herein, some IL-11 antibodies of the present disclosure that bind hIL-11Rα. The Rα binding protein cross-reacts with cynoIL-11Rα and / or hIL-11R Binds to a polypeptide containing a mutant form of hIL-11Rα or a mutated region of hIL-11Rα These characteristics are consistent with the antibody or IL-11Rα binding protein. Can be used in quality generation.

[0237] For example, a phage display library can be screened with a polypeptide comprising SEQ ID NO:3. Then, IL-11Rα binding proteins are identified. A mutant form of the polypeptide in which the polypeptide does not detectably bind (e.g., position 117 of SEQ ID NO:1) A valine at a position corresponding to (including)) to remove cross-reactive proteins and / or IL-11Rα binding A mutant form of the polypeptide to which the fusion protein should bind (e.g., SEQ ID NO: 97, 98 or 99) to isolate proteins that cross-react correctly. A method for screening for immunity in a mammal can also be devised based on the above.

[0238] In another embodiment, a phage display library is screened or an animal is cultured. The extracellular domain of ynoIL-11Rα (or amino acids 23 to 215 or 1 of SEQ ID NO: 1) The IL-11Rα was identified by immunization with a polypeptide containing the region corresponding to 10-215 of the IL-11Rα gene. Binding proteins and / or antibodies are screened to identify hIL-11Rα or SEQ ID NO:3 and and / or those that cross-react with 85 polypeptides.

[0239] In a further embodiment, IL-11Rα or its extracellular domain (optionally 8E2 or 8D1 The phage (E4-binding variants) is then contacted with one of the antibodies described above. The display library is contacted with IL-11Rα or a region thereof and competes with the antibody for binding. Phages expressing a protein capable of binding to the target protein are selected.

[0240] In yet a further embodiment, the epitope of interest derived from hIL-11Rα is For example, a chimeric protein containing mouse IL-11Rα, which is substituted for mouse IL-11Rα. This chimeric protein was then used to induce an immune response against the mouse protein. Immunize mice (unlikely to induce HIV infection) and / or screen phage display libraries. The resulting antibodies / proteins are then screened to identify hIL-11Rα We identified a group of antibodies that bind to mouse IL-11Rα (specifically at the epitope of interest) but do not bind to mouse IL-11Rα. Determine.

[0241] The antibodies of the present disclosure can be synthetic antibodies. For example, the antibodies can be chimeric antibodies, humanized antibodies, human The antibody may be a humanized antibody, an analogous humanized antibody, a primatized antibody or a deimmunized antibody.

[0242] Deimmunized, chimeric, CDR-grafted, humanized, re-humanized, primatized , human and composite IL-11Rα binding proteins The IL-11Rα binding proteins of the present disclosure are grafted with FRs derived from a human antibody or of antibodies derived from non-human species (e.g., mouse or rat or non-human primate) inserted containing CDRs or grafted with FRs derived from another type of antibody (e.g., another type of human antibody) The CDRs of an antibody derived from a certain type of antibody (a certain type of human antibody) are inserted or inserted into the The term can be a CDR-grafted protein, for example, in which one or more CDRs have been grafted. The variable region may be a human variable region, a chimeric variable region, a similar human variable region, or one or more The present invention also encompasses composite IL-11Rα binding proteins that contain a primatized variable region or a primatized variable region. .

[0243] The IL-11Rα binding proteins of the present disclosure can be humanized proteins.

[0244] The term "humanized protein" refers to a protein that has non-human nucleotide sequences grafted or inserted into it that are derived from a human antibody. Contains the CDRs of an antibody derived from a human species (e.g., mouse or rat or non-human primate) It should be understood to refer to proteins that contain human-like variable regions (this type of antibody is referred to as " The humanized IL-11Rα binding proteins also fall within the category of “CDR-grafted antibodies.” and / or one or more residues of the human protein are modified by one or more amino acid substitutions; A protein in which one or more FR residues of the human protein are replaced by the corresponding non-human residues. Humanized proteins also contain residues that are not found in either human or non-human antibodies. Any additional regions of the protein (e.g., the Fc region) are generally human. Humanization can be performed by methods known in the art, e.g., U.S. Pat. No. 5,225,539, U.S. Pat. No. 6,054,297, U.S. Pat. No. 7,566,771 or U.S. Pat. No. 5,585,089 The term "humanized protein" can be used in any manner, for example as described in U.S. Pat. The term also encompasses hyper-humanized proteins, such as those described in US Pat. No. 5,578, also including, for example, For example, one or more humanized variable regions, and one or more, e.g., human variable regions, chimeric variable regions. , the analogous humanized variable region, or a composite protein comprising a primatized variable region.

[0245] The IL-11Rα binding protein of the present disclosure can be a human IL-11Rα binding protein. The term "human protein" as used herein refers to a protein that is produced in humans, e.g., in a human having variable regions and optionally constant regions of an antibody found in the germline or somatic cells, or a protein derived from a library produced using such a region. "The protein may be modified by introducing amino acid residues not encoded by the human sequence, e.g., Mutations introduced by random or site-directed mutagenesis in proteins (especially Conserved sequences at a small number of residues of interest, e.g., 1, 2, 3, 4, or 5 residues in a protein. These "human protein mutations" include those involving significant substitutions or mutations. The "proteins" do not necessarily have to be generated as a result of a human immune response; rather, they may be Recombinant means (e.g., screening a phage display library) and / or a vector comprising nucleic acid encoding the constant and / or variable regions of a human antibody. by transgenic animals (e.g., mice) and / or by guide selection (e.g., As described in U.S. Pat. No. 5,565,332, this The term also encompasses affinity matured forms of such antibodies. The target protein contains FRs derived from a human antibody or derived from the consensus sequence of human FRs. The FR includes a sequence similar to that described in U.S. Pat. No. 6,300,064 and / or U.S. Pat. No. 6,300,064, and one or more of the CDRs include a sequence similar to that described in U.S. Pat. or random or semi-random tampering as described in U.S. Pat. No. 6,248,516. It would also be considered to contain nicotinic acid.

[0246] An exemplary human IL-11Rα binding protein is an antibody that includes the following pair of variable regions: (i) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:5 L ; (ii) V comprising the sequence shown in SEQ ID NO: 38 H and V comprising the sequence shown in SEQ ID NO:5 L ; (iii) V comprising the sequence shown in SEQ ID NO: 39 H and V comprising the sequence shown in SEQ ID NO:5 L ; (iv) V comprising the sequence shown in SEQ ID NO: 40 H and V comprising the sequence shown in SEQ ID NO:5 L ; (v) V comprising the sequence shown in SEQ ID NO: 41 H and V comprising the sequence shown in SEQ ID NO:5 L ; (vi) V comprising the sequence shown in SEQ ID NO: 42 H and V comprising the sequence shown in SEQ ID NO:5 L ; (vii) V comprising the sequence shown in SEQ ID NO: 43 H and V comprising the sequence shown in SEQ ID NO:5 L ; (viii) V comprising the sequence shown in SEQ ID NO: 44 H and the sequence shown in SEQ ID NO:5 V L ; (ix) V comprising the sequence shown in SEQ ID NO: 45 H and V comprising the sequence shown in SEQ ID NO:5 L ; (x) V comprising the sequence shown in SEQ ID NO: 46 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xi) V comprising the sequence shown in SEQ ID NO: 47 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xii) V comprising the sequence shown in SEQ ID NO: 48 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xiii) V comprising the sequence shown in SEQ ID NO: 49 H and the sequence shown in SEQ ID NO:5 V L ; (xiv) V comprising the sequence shown in SEQ ID NO: 50 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xv) V comprising the sequence shown in SEQ ID NO: 51 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xvi) V comprising the sequence shown in SEQ ID NO: 52 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xvii) V comprising the sequence shown in SEQ ID NO: 53 H and the sequence shown in SEQ ID NO:5 V L ; (xviii) V comprising the sequence shown in SEQ ID NO: 54 H and the sequence shown in SEQ ID NO:5 MuV L ; (xix) V comprising the sequence shown in SEQ ID NO: 55 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xx) V comprising the sequence shown in SEQ ID NO: 56 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xxi) V comprising the sequence shown in SEQ ID NO: 57 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xxii) V comprising the sequence shown in SEQ ID NO: 58 H and the sequence shown in SEQ ID NO:5 V L ; (xxiii) V comprising the sequence shown in SEQ ID NO: 59 H and the sequence shown in SEQ ID NO:5 MuV L ; (xxiv) V comprising the sequence shown in SEQ ID NO: 60 H and the sequence shown in SEQ ID NO:5 VL ; (xxv) V comprising the sequence shown in SEQ ID NO: 61 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xxvi) V comprising the sequence shown in SEQ ID NO: 62 H and the sequence shown in SEQ ID NO:5 V L ; (xxvii) V comprising the sequence shown in SEQ ID NO: 63 H and the sequence shown in SEQ ID NO:5 MuV L ; (xxviii) V comprising the sequence shown in SEQ ID NO: 64 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xxix) V comprising the sequence shown in SEQ ID NO: 65 H and the sequence shown in SEQ ID NO:5 V L ; (xxx) V comprising the sequence shown in SEQ ID NO:66 H and V comprising the sequence shown in SEQ ID NO:5 L ; (xxxi) V comprising the sequence shown in SEQ ID NO: 67 H and the sequence shown in SEQ ID NO:5 V L ; (xxxii) V comprising the sequence shown in SEQ ID NO: 68 H and the sequence shown in SEQ ID NO:5 MuV L ; (xxxiii) V comprising the sequence shown in SEQ ID NO: 69 H and the sequence shown in SEQ ID NO:5 Includes V L ; (xxxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:5 MuV L ; (xxxv) V comprising the sequence shown in SEQ ID NO: 70 Hand the sequence shown in SEQ ID NO:5 V L ; (xxxvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:6 MuV L ; (xxxvii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:7 Includes V L ; (xxxviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:8 Contains V L ; (xxxix) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:9 MuV L ; (xl) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:10 L ; (xli) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:11 V L ; (xlii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 12 MuV L ; (xliii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:13 Includes V L ; (xliv) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO: 14 MuV L ; (xlv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 15 V L ; (xlvi) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO: 16 MuV L ; (xlvii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:17 Includes V L ; (xlviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:18 Contains V L ; (xlix) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO: 19 MuV L ; (l) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:20 L ; (li) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:21 L ; (lii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 22 V L ; (liii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 23 MuV L ; (liv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:24 V L ; (lv) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:25 L ; (lvi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:26 VL ; (lvii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 27 MuV L ; (lviii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:28 Includes V L ; (lix) V comprising the sequence shown in SEQ ID NO:37 H and the sequence shown in SEQ ID NO:29 V L ; (lx) V comprising the sequence shown in SEQ ID NO: 37 H and V comprising the sequence shown in SEQ ID NO:30 L ; (lxi) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:31 V L ; (lxii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 32 MuV L ; (lxiii) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO:33 Includes V L or (lxiv) V comprising the sequence shown in SEQ ID NO: 37 H and the sequence shown in SEQ ID NO: 34 MuV L .

[0247] Optionally, V H is linked to a heavy chain constant region, e.g., the heavy chain constant region of IgG4. In an embodiment, the heavy chain constant region lacks a C-terminal lysine residue.

[0248] Optionally, V L is linked to the light chain constant region.

[0249] The IL-11Rα binding proteins of the present disclosure may be analogous humanized proteins. The "humanized protein" was prepared by the method described in WO 2007 / 019620. The analogous humanized IL-11Rα binding protein refers to a protein prepared by The variable region comprises FRs derived from the variable region of an antibody of a New World primate and FRs derived from the variable region of an antibody of a non-New World primate. The CDRs are derived from the variable regions of antibodies from the primate family. For example, a humanized version of the IL-11R The α binding protein comprises a variable region of an antibody, the variable region being a variable region of an antibody of a New World primate. In one embodiment, the antibody comprises FRs derived from a corresponding region and CDRs derived from a mouse or rat antibody. The IL-11Rα binding protein is a humanized IL-11Rα binding protein in which one or both of the variable regions are humanized. The term refers to an antibody that binds IL-11Rα, for example, an antibody that contains one or more similar humanized variable regions, and one or more of, for example, a complex comprising a human variable region or a humanized variable region or a chimeric variable region. Synthetic proteins are also included.

[0250] The IL-11Rα binding proteins of the present disclosure can be primatized proteins. The "protein" refers to antibodies generated following immunization of a non-human primate (e.g., a cynomolgus monkey). Optionally, the variable regions of the non-human primate antibody are linked to human constant regions. , and the resulting primatized antibody is linked to the primatized antibody. Exemplary methods for producing primatized antibodies are described in U.S. Pat. The term also refers to, for example, one or more primatizable variable region, and one or more, e.g., a human variable region or a humanized variable region or a chimeric variable region. The present invention also includes a complex protein comprising:

[0251] In one example, the IL-11Rα binding protein of the disclosure is a chimeric protein. The term "chimeric protein" refers to a protein in which the antigen-binding domain is derived from a specific species (e.g., mouse or rat). or other rodents) or belong to a particular antibody class or subclass, The remainder of the protein may be derived from or derived from another species (e.g., human or non-human primate). In one embodiment, a chimeric protein is a protein that belongs to another class or subclass of organism. The protein is a V protein derived from a non-human antibody (e.g., a mouse antibody). H and / or V L Includes It is a chimeric antibody, the remaining regions of which are derived from a human antibody. Such chimeric proteins The creation of such substances is known in the art (see, e.g., U.S. Pat. No. 6,331,415; U.S. Pat. No. 6,331,415). No. 5,807,715; U.S. Pat. No. 4,816,567 and U.S. Pat. No. 4,816,397 This can be accomplished by standard means (such as those described above). Chimeric variable regions, and one or more, e.g., human variable regions or humanized variable regions or chimeric Also included are composite proteins that contain variable regions.

[0252] This disclosure also describes, for example, WO 2000 / 34317 and WO 2004 Deimmunized IL-11Rα binding proteins, such as those described in US Pat. No. 6,315,358, are also contemplated. Deimmunized antibodies and proteins may contain one or more epitopes, e.g., B cell epitopes. or T cell epitopes are eliminated (i.e., mutated) so that the subject develops antibodies or Reduce the likelihood of an immune response to the protein. For example, the IL-1 The 1Rα binding protein is analyzed to identify one or more B or T cell epitopes, and mutating one or more amino acids in the IL-11Rα binding protein to produce an immunogenic It reduces sexuality.

[0253] The "composite" protein is V H (e.g., human) and V L Another form of (e.g. It will be apparent to one skilled in the art from the foregoing disclosure that the present disclosure includes V H Form and V L All combinations of the above forms are expressly included.

[0254] Proteins containing antibody-binding domains Single Domain Antibodies In some embodiments, the proteins of the present disclosure are single domain antibodies (also referred to as "domain antibodies"). Single domain antibodies are or include (used interchangeably with "dAb"). It is a single polypeptide chain that contains all or part of the heavy chain variable region of an antibody. In the present embodiment, the single domain antibody is a human single domain antibody (Domantis, In c., Waltham, MA; see, e.g., U.S. Pat. No. 6,248,516).

[0255] Bispecific, trispecific, and tetraspecific antibodies In some embodiments, the proteins of the present disclosure are those disclosed in WO 98 / 044001 and / or Bispecific antibodies, trispecific antibodies, such as those described in WO 94 / 007921, is or comprises a heteroantibody, a tetrabody, or a higher order protein complex .

[0256] For example, a bispecific antibody is a protein that contains two associated polypeptide chains. , each polypeptide chain has the structure V L -XV H Or V H -XV L Including, where V L is anti The light chain variable region of the V H is the heavy chain variable region of an antibody, and X is V H and V L There is one pole A peptide that contains insufficient residues to be able to associate with a peptide chain (or form an Fv) anchor or absent, V of one polypeptide chain H is the V of the other polypeptide chain L to form an antigen-binding domain capable of specifically binding one or more antigens. i.e., forming an Fv molecule. L and V H is identical for each polypeptide chain Can be done, or V L and V H Bispecific antibodies (i.e., two Fs with different specificities) v) can be different in each polypeptide chain to form a

[0257] Single chain Fv (scFv) A skilled practitioner may recognize that an scFv is a single polypeptide chain with V H Area and V L Includes area and V that enables the scFv to form the desired structure for antigen binding. H and V L Between The polypeptide linker (i.e., a single polypeptide that associates with each other to form an Fv) Chain V H and V L For example, the linker might look like this: One of the more convenient linkers for scFvs contains more than 100 amino acid residues (Gl y4Ser)3.

[0258] The present disclosure also provides a method for the preparation of a compound having a single cysteine ​​residue in a V H FR or V L Introduced in FR, Cysteine ​​residues are linked by disulfide bonds to give a stable Fv; disulfide stabilization Also contemplated are Fvs which are synthesized by synthesis (or diFv or dsFv).

[0259] Alternatively or additionally, the present disclosure provides dimeric scFvs, i.e., non-covalently or covalently linked. For example, leucine zipper domains (e.g., those derived from Fos or Jun) can be used to Alternatively, for example, a protein may include a protein comprising two scFv molecules linked by a For example, as described in US Patent No. 20060263367, two scFvs are a peptide linker of sufficient length to allow the scFv to form and bind to the antigen are linked by

[0260] Heavy Chain Antibodies Heavy chain antibodies are distinct from many other forms of antibodies inasmuch as they contain heavy chains but no light chains. These antibodies are structurally distinct from the heavy chain-only antibodies. Antibodies are found, for example, in camelids and cartilaginous fish (also called IgNAR). can be.

[0261] The variable region present in naturally occurring heavy chain antibodies is the heavy chain variable region present in conventional four-chain antibodies. Area (“V H The light chain variable region present in conventional four-chain antibodies is ("V L To distinguish them from the "antibody domains" of camelids, camelid antibodies generally use the " V HH These are called "domains" and in IgNARs they are called V-NARs.

[0262] Heavy chain antibodies and variable regions thereof derived from camelids and their production and / or isolation and / or A general description of the method of use can be found, inter alia, in the following reference WO 94 / 04678: No. 6,313,633, WO 97 / 49805 and WO 97 / 49805. .

[0263] Heavy chain antibodies and their variable regions derived from cartilaginous fish and their production and / or isolation and / or A general description of the method of use can be found, inter alia, in WO 2005 / 118629. will be done.

[0264] Other antibodies and proteins containing their antigen-binding domains The present disclosure relates to, for example, (i) "Lock and key" bispecific tag, as described in U.S. Pat. No. 5,731,168. Protein; (ii) Heteroconjugate tandems, such as those described in U.S. Pat. No. 4,676,980. Pak quality; (iii) Chemical crosslinking agents, such as those described in U.S. Pat. No. 4,676,980. Heterocomplex proteins produced using the (iv) Fab3 (e.g., as described in EP19930302894) Other antibodies and proteins comprising the antigen-binding domain thereof, such as:

[0265] Mutations in proteins The present disclosure also relates to sequences having at least 80% identity to the sequences disclosed herein. Also provided is an IL-11Rα binding protein or a nucleic acid encoding same. The disclosed IL-11Rα binding proteins or nucleic acids have at least one amino acid sequence similar to that disclosed herein. Contains a sequence that is at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to The protein may be specific for IL-11Rα as described herein according to any of the examples. It bonds positively.

[0266] Alternatively or additionally, the IL-11Rα binding protein may be any of the compounds described herein according to any of the examples. V as described H Or V L At least about 80%, or about 85%, or about 9 0% or 95% or 97% or 98% or 99% identical CDRs (e.g., 3 CDRs ), the protein being IL-11Rα as described herein according to any of the examples. In this respect, the present inventors have found that the CDRs of the ribozyme-binding fragment ... can be specifically bound to the ribozyme-binding fragments of the ribozyme-binding fragments. We have generated a number of antibodies with the sequence shown in Fig. 1 to measure the binding of proteins to IL-11Rα. The methods are described herein.

[0267] For example, we have identified its HCDR1 (and any I, which shares at least 40% identity with HCDR1 (amino acids N-terminal to HCDR1) A group of L-11Rα binding proteins and their HCDR1s that share 80% identity have identified a distinct subgroup of proteins.

[0268] We also found that the sequence is 77% identical in its HCDR2 according to the Kabat numbering system. Classes of IL-11Rα binding proteins that share common identity and the Kabat numbering system IL-11Rα binding, which shares at least about 82% identity in its HCDR2 according to Subclasses of proteins have also been identified.

[0269] As discussed herein, the five C-terminal residues of the heavy chain CDR2 may be conserved or non-conserved. can be mutated to specific amino acid substitutions (31% of residues) (Padlan et al., FAS EB J.9:133-139, 1995) is also known in the art. The protein has at least about 47% identity to the heavy chain CDR2 sequences disclosed herein. The CDR2 may comprise

[0270] For example, we have identified a number of nucleotide sequences in the HCDR3 according to the Kabat numbering system. have identified a group of IL-11Rα binding proteins that share at least about 44% identity.

[0271] For example, the inventors have discovered that replacement without loss of function or improvement of function can be achieved. The resulting V H Several residues have been identified in In an example, the IL-11Rα binding protein has between amino acids 1 and 11 compared to SEQ ID NO:37. For example, the IL-11Rα binding protein may contain one or more amino acid substitutions compared to SEQ ID NO:37. Contains 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 amino acid substitutions For example, the IL-11Rα binding protein has three amino acid substitutions compared to SEQ ID NO:37. For example, the IL-11Rα binding protein contains four amino acid positions compared to SEQ ID NO:37. Includes conversion.

[0272] In one embodiment, the IL-11Rα binding protein has a 1:1 amino acid sequence in CDR3 compared to SEQ ID NO:37. For example, the IL-11Rα binding protein may contain an amino acid substitution between SEQ ID NO: 37 contains 1 or 2 or 3 or 4 amino acid substitutions compared to 37.

[0273] In one embodiment, the IL-11Rα binding protein has a 1:1 amino acid sequence in CDR2 compared to SEQ ID NO:37. For example, the IL-11Rα binding protein may contain between about 1 and about 3 amino acid substitutions. 37 contains 1, 2 or 3 amino acid substitutions in CDR3.

[0274] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The sequence of the variant comprises at least one tryptophan at position 54 of SEQ ID NO:37. include.

[0275] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. wherein the sequence of the variant includes at least a threonine at position 56 of SEQ ID NO:37. .

[0276] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The sequence of the variant comprises at least one additional aspartic acid at position 57 of SEQ ID NO:37. include.

[0277] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The sequence of the variant comprises at least one tryptophan at position 57 of SEQ ID NO:37. include.

[0278] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. wherein the sequence of the variant comprises at least a leucine at position 57 of SEQ ID NO:37.

[0279] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. wherein the sequence of the variant comprises at least a proline at position 99 of SEQ ID NO:37.

[0280] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The variant sequence includes a variant having at least one glutamic acid at position 100 of SEQ ID NO:37. include.

[0281] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. wherein the sequence of the variant includes at least a leucine at position 100 of SEQ ID NO:37. .

[0282] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The sequence of the variant includes at least one aspartic acid at position 101 of SEQ ID NO:37. Also includes.

[0283] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. wherein the sequence of the variant includes at least a leucine at position 104 of SEQ ID NO:37. .

[0284] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. The sequence of the variant includes at least an arginine at position 104 of SEQ ID NO:37. nothing.

[0285] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. and wherein the sequence of the variants is a tryptophan at position 54 with respect to SEQ ID NO:37. , containing at least an aspartic acid at position 56 and a leucine at position 57.

[0286] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. and wherein the sequence of the variants is a tryptophan at position 54 with respect to SEQ ID NO:37. , containing at least an aspartic acid at position 56 and a leucine at position 57.

[0287] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. and wherein the sequence of the variants is a tryptophan at position 54 with respect to SEQ ID NO:37. , containing at least a threonine at position 56 and a leucine at position 57.

[0288] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. and wherein the sequence of the variant comprises a proline at position 99 with respect to SEQ ID NO:37, Leucine at position 100, aspartic acid at position 101, and leucine at position 104 Also includes.

[0289] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:37. and wherein the sequence of the variant comprises a proline at position 99 with respect to SEQ ID NO:37, Leucine at position 100, aspartic acid at position 101, and arginine at position 104 are This includes at least

[0290] For example, we have found that at least one A group of IL-11Rα binding proteins sharing at least 45% identity, and their LCDRs 1 identifies another subgroup of proteins that share approximately 54% identity.

[0291] The inventors also identified at least one nucleotide sequence in its LCDR3 according to the Kabat numbering system. They also identified a class of IL-11Rα binding proteins that share approximately 55% or 56% identity. is.

[0292] For example, the inventors have discovered that replacement without loss of function or improvement of function can be achieved. The resulting V L Some residues have been identified in one example. In this case, the IL-11Rα binding protein has an amino acid sequence between 1 and 11 compared to SEQ ID NO:5. For example, the IL-11Rα binding protein may have one or two or more amino acid substitutions compared to SEQ ID NO:5. It contains 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 amino acid substitutions. For example, the IL-11Rα binding protein contains three amino acid substitutions compared to SEQ ID NO:5. For example, the IL-11Rα binding protein contains four amino acid substitutions compared to SEQ ID NO:5. For example, the IL-11Rα binding protein contains 5 amino acid substitutions compared to SEQ ID NO:5. .

[0293] In one embodiment, the IL-11Rα binding protein has 1 to 1 amino acids in CDR3 compared to SEQ ID NO:5. 4. For example, the IL-11Rα binding protein may contain the amino acid substitutions Contains 1 or 2 or 3 or 4 amino acid substitutions in CDR3 compared to:

[0294] In one embodiment, the IL-11Rα binding protein has 1 to 1 amino acids in CDR1 compared to SEQ ID NO:5. For example, the IL-11Rα binding protein may comprise an amino acid substitution between SEQ ID NO:5. Contains 1 or 2 or 3 or 4 or 5 amino acid substitutions in CDR3 compared to:

[0295] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. Mutants are included, the sequence of which at least comprises a valine at position 29 of SEQ ID NO:5.

[0296] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least an aspartic acid at position 30 of SEQ ID NO:5.

[0297] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least a lysine at position 31 of SEQ ID NO:5.

[0298] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. Mutants include those whose sequences include at least a valine at position 33 of SEQ ID NO:5.

[0299] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least a glutamic acid at position 34 of SEQ ID NO:5.

[0300] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. Mutants are included, the sequence of which includes at least an alanine at position 91 of SEQ ID NO:5.

[0301] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least a histidine at position 91 of SEQ ID NO:5.

[0302] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least a glutamic acid at position 91 of SEQ ID NO:5.

[0303] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least an aspartic acid at position 93 of SEQ ID NO:5.

[0304] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The variant includes a phenylalanine at position 93 of SEQ ID NO:5. .

[0305] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. Mutants include those whose sequences include at least a serine at position 93 of SEQ ID NO:5.

[0306] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. This includes variants, the sequence of which includes at least a glutamine at position 94 of SEQ ID NO:5.

[0307] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the variants include a valine at position 29 and a valine at position 30 relative to SEQ ID NO:5, respectively. At least one amino acid, at ... Also includes.

[0308] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the mutants include an alanine at position 91, an alanine at position 92, and an alpha-amino acid at position 93, respectively, relative to SEQ ID NO:5. at position 92, aspartic acid at position 93, and glutamine at position 94.

[0309] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the mutants each contain a histidine at position 91, a histidine at position 92, and a histidine at position 93 relative to SEQ ID NO:5. Contains at least glutamic acid at position 93, phenylalanine at position 94, and glutamine at position 95 .

[0310] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the mutants each contain a histidine at position 91, a histidine at position 92, and a histidine at position 93 relative to SEQ ID NO:5. It contains at least glutamic acid at position 93 and glutamine at position 94.

[0311] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the mutants each contain a histidine at position 91, a histidine at position 92, and a histidine at position 93 relative to SEQ ID NO:5. It contains at least glutamic acid at position 93 and glutamine at position 94.

[0312] In one embodiment, the IL-11Rα binding protein of the present disclosure has the sequence shown in SEQ ID NO:5. The sequences of the variants each contain a glutamic acid at position 92, a 9 Contains at least a serine at position 3 and a glutamine at position 94.

[0313] In another embodiment, the nucleic acids of the present disclosure have at least about 80% identity to the sequences set forth herein. % or 85% or 90% or 95% or 97% or 98% or 99% identical to any According to the examples, IL-11Rα binding proteins having the functions as described herein can be produced. The present disclosure also includes sequences that encode the nucleotide sequences exemplified herein as a result of the degeneracy of the genetic code. Also encompassed are nucleic acids encoding IL-11Rα binding proteins of the disclosure that differ in sequence.

[0314] Percentage of nucleic acid and polypeptide identities are calculated using a gap creation penalty of 5 and a gap extension penalty of 1. GAP with Nulty = 0.3 (Needleman and Wunsch. Mol. Biol. l.48,443-453,1970) analysis (GCG program). The query sequence is at least 50 residues long, and the GAP analysis is performed on a region of at least 50 residues. For example, if the query sequence is at least 100 residues long, GAP analysis aligns two sequences over a region of at least 100 residues. For example, , the two sequences are aligned over their entire length.

[0315] The present disclosure also provides a method for the production of a fusion protein comprising the steps of: Nucleic acids that hybridize to nucleic acids encoding L-11Rα binding proteins are also contemplated. As used herein, "moderate stringency" refers to a buffer solution containing 2×SSC at a temperature of 45° C. to 65° C. Hybridization and / or hybridization are performed in buffer, 0.1% (w / v) SDS, or equivalent conditions. "High stringency" is defined herein as 0.1×S SC buffer, 0.1% (w / v) SDS or lower salt concentration and at least 65°C is defined as hybridization and / or washing carried out under temperature or equivalent conditions. References herein to particular levels of stringency refer to SSCs known to those of skill in the art. Equivalent conditions using washing / hybridization solutions other than those described above are encompassed. For example, Methods for calculating the temperature at which a nucleic acid strand dissociates (also known as the melting temperature or Tm) are known in the art. Similar (e.g., within 5° C. or 10° C.) or equivalent to the Tm of a nucleic acid is considered to be high stringency. Intermediate stringency is should be considered to be within 10°C to 20°C or 10°C to 15°C of the calculated Tm of the nucleic acid. It is.

[0316] The present disclosure also includes sequences that contain one or more conservative amino acid substitutions compared to the sequences presented herein. Mutant forms of the IL-11Rα binding proteins of the present disclosure are also contemplated. The L-11Rα binding protein is 10 or less, for example, 9 or 8 or 7 or 6 or 5 or Conservative amino acid substitutions include 4 or 3 or 2 or 1 conservative amino acid substitutions. The amino acid residues are replaced by amino acid residues having similar side chains and / or hydrophobic and / or hydrophilic properties. It is something that can be replaced.

[0317] Basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., a sparginic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., a Alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine) and aromatic Contains aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine) Families of amino acid residues having similar side chains, including those that are hydrophobic, have been defined in the art. Marks are, for example, those described by Kyte and Doolittle, J. Mol. Biol., 157: 105-132, 1982, and the hydrophilicity index is described in, for example, U.S. Pat. It is described in issue 01.

[0318] The present disclosure also contemplates non-conservative amino acid changes. For example, of particular interest are Replacement of a charged amino acid with another charged amino acid and with a neutral or positively charged amino acid. In some embodiments, the IL-11Rα binding protein has 10 or fewer, e.g., 9 or contains 8 or 7 or 6 or 5 or 4 or 3 or 2 or 1 non-conservative amino acid substitutions.

[0319] In one embodiment, the mutation is in the antigen-binding domain of an IL-11Rα binding protein of the disclosure. In another embodiment, the mutation occurs within the FR of the IL-11Rα binding protein of the present disclosure. This occurs within the CDR of the protein.

[0320] Exemplary methods for generating mutant forms of IL-11Rα binding proteins include DNA (Thie et al., Methods Mol. Biol. 525:309-322, 2009) or RNA (Kopsidas et al., Immunol. Lett. 107:16 3-168,2006;Kopsidas et al. BMC Biotechnology,7 :18,2007; and WO 1999 / 058661) mutagenesis; Mutagenized cells, such as XL-1Red, XL-mutS and XL-mu Delivery of nucleic acid encoding a polypeptide into tS-Kanr bacterial cells (Stratagene) introduction; For example, see Stemmer, Nature, 370:389-91, 1994. DNA shuffling as described above; and For example, Dieffenbach (ed.) and Dveksler (ed.) (PCR Primer:A Laboratory Manual,Cold Spring H (Arbor Laboratories, NY, 1995) Examples include site-specific mutagenesis.

[0321] Measuring the biological activity, e.g., antigen binding, of the mutant IL-11Rα binding proteins of the present disclosure Exemplary methods for doing so will be apparent to one of skill in the art and / or may be described herein. For example, antigen binding, competitive inhibition of binding, affinity, association, dissociation and therapeutic efficacy will be discussed. Methods for measuring the sex are described herein.

[0322] Constant region The present disclosure relates to IL-11Rα binding proteins and and / or antibodies, including antigen-binding fragments of antibodies fused to Fc.

[0323] The sequences of constant regions useful for producing the proteins of the present disclosure can be obtained from a number of different sources. In some embodiments, the constant region of the protein or a portion thereof is derived from a human antibody. The constant region or a portion thereof may be any antibody, including IgM, IgG, IgD, IgA, and IgE. The antibody class and isotype of any antibody, including IgG1, IgG2, IgG3, and IgG4. In one embodiment, the constant region is of human isotype IgG4 or stabilized The antibody is an IgG4 constant region.

[0324] In one embodiment, the Fc region of the constant region is selected from the group consisting of, for example, native or wild-type human Ig It has a lower ability to induce effector functions compared to the Fc region of IgG1 or IgG3. In the examples, the effector functions include antibody-dependent cell-mediated cytotoxicity (ADCC) and / or or antibody-dependent cell-mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity ( CDC) to evaluate the level of effector function of proteins containing Fc regions. Methods are known in the art and / or described herein.

[0325] In one embodiment, the Fc region is an IgG4 Fc region (i.e., derived from the constant region of IgG4). For example, the Fc region of human IgG4. will be apparent to one of skill in the art and / or publicly available databases (e.g., available from the National Center for Biotechnology Information.

[0326] In one embodiment, the constant region is a stabilized IgG4 constant region. The "IgG4 constant region" reduces Fab arm exchange or inhibits Fab arm exchange or half IgG that has been modified to reduce its tendency to undergo antibody formation or to form half-antibodies 4 constant region. "Fab arm exchange" refers to the IgG4 complex The light chains (half molecules) associated with the heavy chains are exchanged for heavy / light chain pairs from another IgG4 molecule. This refers to the type of protein modification that occurs in human IgG4. Thus, an IgG4 molecule has two It is possible to obtain two distinct Fab arms that recognize distinct antigens (resulting in a bispecific molecule). Fab arm exchange occurs naturally in vivo and can be observed in purified blood cells or reduced glucose. It can be induced in vitro by reducing agents such as cations. "Half-antibodies" are IgG 4 When an antibody dissociates to form two molecules, each containing a single heavy chain and a single light chain, This occurs when

[0327] In one embodiment, the stabilized IgG4 constant region comprises a hinge region conformation according to the Kabat scheme. It contains a proline at position 241 of the eins of Immunological Interest Washingto n DC United States Department of Health and Human Services, 1987 and / or 1991). This position is It corresponds to position 228 of the hinge region according to the U numbering system (Kabat et al., Sequen ces of Proteins of Immunological Interes t Washington DC United States Department of Health and Human Services, 2001 and Edel Mann et al., Proc. Natl. Acad. USA, 63, 78-85, 1969). In human IgG4, this residue is generally serine. Following serine to proline substitution, The hinge region of gG4 contains the sequence CPPC. In this regard, those skilled in the art will recognize that the "hinge region" is The heavy chain of an antibody that connects the Fc and Fab regions, conferring flexibility on the two Fab arms. It will be noted that the constant region is a proline-rich portion. The hinge region contains the dimer between the heavy chains. It contains cysteine ​​residues involved in sulfide bonds. It is generally numbered according to Kabat numbering. It is defined as the stretch from Glu226 to Pro243 of human IgG1 according to the The hinge regions of other IgG isotypes have the same structure with cysteine ​​residues at the beginning and end. with the IgG1 sequence by forming inter-heavy chain disulfide (SS) bonds at can be arranged (see, for example, WO 2010 / 080538).

[0328] An additional example of a stabilized IgG4 antibody is the 409 heavy chain constant region of human IgG4. Arginine at position 1 (according to the EU numbering system) is lysine, threonine, methionine or rhodamine The antibody is an antibody in which the isoform is substituted with isoforms (see, for example, the antibody described in WO 2006 / 033386). The Fc region of the constant region may also or alternatively comprise a region at position 405 (EU numbering Alanine, valine, glycine, isoleucine and leucine are added at the positions corresponding to the amino acid sequence (according to the formula). Optionally, the hinge region comprises residues selected from the group consisting of 24 It contains a proline at position 1 (i.e., the CPPC sequence).

[0329] In another embodiment, the Fc region may have reduced effector function, i.e., "non-immunostimulatory." For example, the Fc region is 268, 3 IgG1 comprising a substitution at one or more positions selected from the group consisting of: In another embodiment, the Fc region has the following changes: E233P, L234V, One or more of the following changes: L235A and one or more of the deletion of G236, A327G, A The Fc region of IgG1 contains one or more of 330S and P331S (Armour et al., ur. J. Immunol. 29:2613-2624, 1999; Shields et al. J.Biol.Chem.276(9):6591-604,2001). immunostimulatory Additional examples of Fc regions that are not .177:1129-1138, 2006; and / or Hezareh J Virol. ;75:12161-12168,2001.

[0330] In another embodiment, the Fc region comprises at least one C domain, e.g., from an IgG4 antibody. H 2 domains and at least one C derived from an IgG1 antibody H Three-domain chimera Fc region, wherein the Fc region is 240, 262, 264, 266, 297, 299 , 307, 309, 323, 399, 409 and 427 (EU numbering) Substitutions at one or more selected amino acid positions (see, e.g., International Publication No. WO 2010 / 08 (As described in No. 5682). Example substitutions include 240F, 262L, 264T. , 266F, 297Q, 299A, 299K, 307P, 309K, 309M, 309P , 323F, 399S, and 427F.

[0331] Enhancement of effector functions In one embodiment, the IL-11Rα binding protein of the disclosure has effector function or high effector activity. The polypeptide may induce effector functions.

[0332] In the context of this disclosure, "effector functions" refer to the functions of the Fc region of an antibody that result in cell killing (e.g., A cell or protein that binds to the Fc region of an amino acid sequence variant of the Fc region of the native sequence Examples of effector functions induced by antibodies include complement antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); and activation of B cells.

[0333] In one example, the IL-11Rα binding protein of the disclosure is intended to be useful as an anti-IL-11Rα antibody, e.g., as an ADC. The expression of the cells in such a way that it is possible to induce effector functions such as C or CDC. It binds to IL-11Rα on the surface.

[0334] For example, IL-11Rα binding proteins may be used to mediate, for example, ADCC and / or CDC. Binds to IL-11Rα on the surface of cells long enough to induce effector functions It remains as it is.

[0335] In one example, the IL-11Rα binding protein of the disclosure may comprise, for example, a modified Fc by including a region capable of binding to immune effector cells. It is possible to induce effector function. For example, the level of effector function can be This is increased compared to the levels induced by the Fc region of human IgG1 or IgG3. The enhancement of effector function induced by the IL-11Rα binding proteins of the present disclosure includes: For example, blocking the action of IL-11Rα may be sufficient to block disease-causing killing or depleting autoreactive T cells, e.g., by killing autoreactive T cells This can result in a high therapeutic or preventive effect.

[0336] In one example, the Fc region of the IL-11Rα binding protein of the present disclosure comprises an unmodified Fc Modified to increase the level of effector function that is able to be induced compared to Such modifications may occur at the amino acid level and / or at the secondary structure level and / or at the tertiary structure level. The present invention relates to a method for the production of ribosomal proteins, such as ribosomal protein 1 (RIP1) or ribosomal protein 2 (RIP2) at the level of and / or glycosylation of the Fc region.

[0337] Those of skill in the art will appreciate that greater effector function can be achieved in any of a number of ways, e.g., by as a higher level effect, a more sustained effect, or a faster speed effect. It will be understood that the above may be represented as

[0338] In one embodiment, the Fc region may comprise one or more antigen-binding domains that enhance the ability to induce high effector function. In one embodiment, the Fc region comprises one or more amino acid modifications with greater affinity, e.g. In one embodiment, the Fc region binds to an FcγR, such as FcγRIII or FcγRIII. 230, 233, 234, 235, 239, 240, 243 numbered according to the U index , 264, 266, 272, 274, 275, 276, 278, 302, 318, 324 , 325, 326, 328, 330, 332, and 335 In one embodiment, the Fc region comprises at least one amino acid substitution in accordance with the EU The FcAsp1 gene contains the following amino acid substitutions S239D / I332E, numbered according to the index: The region has about a 14-fold higher affinity for FcγRIIIa compared to a wild-type Fc region, It has about 3.3 times higher ADCC induction ability than the wild-type Fc region. The Fc region contains the following amino acid substitutions, numbered according to the EU index of Kabat: S239 D / A330L / I332E. This F region contains FcγR It has approximately 138-fold higher affinity for IIIa, and approximately 323-fold higher affinity than the wild-type Fc region. It has the ability to induce ADCC.

[0339] Additional amino acid substitutions that enhance the ability of an Fc region to induce effector function are known in the art. As known and / or described, for example, in U.S. Pat. No. 6,737,056 or U.S. Pat. No. 7,317, It is described in issue 091.

[0340] In one embodiment, the glycosylation of the Fc region is altered to induce enhanced effector function. In this regard, native antibodies produced by mammalian cells have the Fc region C in the area H A branched biantennary oxidase (BIA) fragment commonly linked by an N-bond to Asn297 in the 2 domain Oligosaccharides usually contain various sugars, such as mannose, N-acetylglucosamine, and N-acetylglucosamine. Glucosamine (GlcNAc), galactose and sialic acid, and biantennary oligosaccharide structures In some embodiments, the fucose may be linked to a GlcNAc in the "stem" of The Fc region of the present disclosure is a glycan that lacks fucose linked (directly or indirectly) to the Fc region. Such variants contain fucosylated structures, i.e., the Fc region is "non-fucosylated." Methods for producing non-fucosylated antibodies include those that have an improved ability to induce CC. , (e.g., Yumane-Ohnuki et al., Biotechnol. Bioengineering α-1,6-fucosyltransferase (as described in Neer. 87:614-622, 2004) Antibody or its antigen-binding fragment in a cell line that cannot express furan transferase (FUT8) (e.g., Mori et al., Biotechnol. Bioengineering eer.,88:901-908,2004) Expressing the antibody or antigen-binding fragment thereof in a cell that expresses interfering RNA (e.g., For example, Kanda et al., J. Biotechnol., 130:300-310, 2007 As described in (2003), guanosine diphosphate (GDP)-mannose 4,6-dehydratase One approach is to express an antibody or its antigen-binding fragment in a cell that cannot express GMD. The present disclosure also provides the same results as those described in (e.g., Umana et al., Nat. Biotechnol. 17:176-180, 1999), for example, β-(1,4)-N -acetylglucosaminyltransferase III (GnT-III) expression Proteins with reduced levels of fucosylation produced using cell lines engineered to The use of is also contemplated.

[0341] Other methods include the use of antibodies capable of inducing enhanced Fc-mediated effector functions. Examples include the use of cell lines that naturally produce Duck embryonic stem cells for avian biology, WO 2008 / 129058; Avian EBX® Production of recombinant proteins in cells, WO 2008 / 142124).

[0342] The IL-11Rα binding proteins of the present disclosure also include a biantennary oligonucleotide linked to the FC region. Also included are those with bisected oligosaccharides in which the sugar is bisected by GlcNAc. Such proteins may have reduced fucosylation and / or improved ADCC function. Examples of such proteins are described, for example, in U.S. Pat. No. 6,602,684 and U.S. Pat. This is described in US Pat. No. 20050123546.

[0343] IL-1 with at least one galactose residue in the oligosaccharide linked to the FC region 1Rα binding proteins are also contemplated. Such proteins have improved CDC function. Such proteins may be used in the methods described in WO 1997 / 30087 and WO 1997 / 30088. This is described in No. 99 / 22764.

[0344] IL-11Rα binding protein is capable of inducing high levels of CDC. For example, hybrids of IgG1 and IgG3 have high CDC activity. (Natsume et al., Cancer Res. 68:3863) -3872,2008).

[0345] Alternatively, the IL-11Rα binding protein may be, for example, linked to CD3 or CD16. The fusion results in the formation of a protein (e.g., an antibody variable region) that binds to immune effector cells. They may also be combined or joined.

[0346] Methods for measuring effector function are known in the art. The level of sexuality 51 Cr release assay, europium release assay or 35 S release assay Each of these assays assesses the expression of IL-11Rα in Inject the cells with one or more of the referenced compounds sufficient to allow uptake of the compounds by the cells. The mixture is incubated for a period of time and under certain conditions. 35 In the case of S release assay, cells were 35 S-labeled Labeled amino acids in newly synthesized proteins along with thionine and / or cysteine The cells can then be cultured for a period of time sufficient for the IL-11Rα binding protein to be incorporated into the cells. In the presence or absence of proteins and immune effector cells, e.g., PBMCs and / or N The cells are then cultured in the presence of K cells. 51 Cr, Europium and / or 35 The amount of S in the presence of the protein compared to the absence of the protein is detected. An increase indicates that the molecule / agent that binds has an effector function. Exemplary publications disclosing assays for assessing the level of induced ADCC include Hellstrom et al. Proc. Natl. Acad. Sci. USA, 83:705 9-7063, 1986 and Bruggemann et al., J. Exp. Med. 166:1 351-1361, 1987.

[0347] Other assays to assess the level of ADCC induced by a protein include ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellT echnology, Inc. CA, USA) or CytoTox96 (registered trademark) non-release Examples of such assays include the radioactive cytotoxicity assay (Promega, WI, USA).

[0348] Alternatively or additionally, the effector function of the IL-11Rα binding protein may be, for example, , and its parent for one or more FcγRs as described in U.S. Pat. No. 7,317,091. It is assessed by measuring compatibility.

[0349] A C1q binding assay was performed to confirm that IL-11Rα binding protein binds C1q. To evaluate complement activation, a CDC assay was performed. (See, for example, Gazzano-Santoro et al., J. Immunol. (See Methods, 202:163, 1996).

[0350] Additional Modifications The present disclosure also relates to antibodies or IL-11Rα binding proteins comprising an Fc region or constant region. Additional modifications of are also contemplated.

[0351] For example, the antibody may contain one or more amino acid substitutions that increase the half-life of the protein. The antibody may comprise one or more nucleotides that increase the affinity of the Fc region for the neonatal Fc region (FcRn). For example, the Fc region may be capable of inhibiting apoptosis at low pH, e.g., pH 6. 0, which has high affinity for FcRn and promotes Fc / FcRn binding in endosomes. In one embodiment, the Fc region has an affinity of approximately p<0.05 relative to the affinity at approximately pH 7.4. H6.0 has high affinity for FcRn, which is expressed in the blood following cell recycling. These amino acid substitutions promote Fc re-release and reduce clearance from the blood. These are useful for extending the half-life of proteins by

[0352] Exemplary amino acid substitutions include T250Q and / or M428 according to the EU numbering system. L or T252A, T254S and T266F or M252Y, S254T and T256 Additional or alternative amino acid substitutions include For example, U.S. Patent Application Publication No. 20070135620 or U.S. Patent No. 7,083,784. It is described in.

[0353] Exemplary IL-11Rα Binding Proteins Exemplary variable region-containing IL-11Rα binding proteins produced by the present inventors are listed in Table 1. [Table 1-1] [Table 1-2]

[0354] Protein production In one embodiment, the IL-11Rα binding protein as described herein according to any of the examples. may be, for example, a TA, as described herein and / or known in the art. The hybridoma is cultured under conditions sufficient to produce the protein. can be.

[0355] Recombinant expression In another embodiment, the IL-11Rα binding protein as described herein according to any of the examples. Quality is recombinant.

[0356] In the case of a recombinant protein, the nucleic acid encoding it is cloned into an expression construct or expression vector. The resulting culture is then transferred to, for example, E. coli cells, yeast cells, insect cells, or e.g. , monkey COS cells, Chinese hamster ovary (CHO) cells, human embryonic kidney (HEK) cells ) cells or mammalian cells, such as myeloma cells, that do not otherwise produce the protein. Transfect the host cell. An exemplary cell used to express the protein is CHO The molecular cloning methods used to achieve these goals include: Mapping techniques are known in the art and are described, for example, in Ausubel et al., (eds.), Curren t Protocols in Molecular Biology,Greene Pub.Associates and Wiley-Interscience (1 988, including all current updates) or Sambrook et al., Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press (1989). A variety of cloning and in vitro amplification techniques are suitable for constructing recombinant nucleic acids. Methods for producing the bodies are also known in the art, see, for example, U.S. Pat. No. 4,816,567 or See U.S. Patent No. 5,530,101.

[0357] Isolation may be followed by further cloning (amplification of the DNA) or expression in a cell-free system or in cells. For expression in a mammalian cell, the nucleic acid is inserted into a promoter in an expression construct or expression vector and manipulated. The above-mentioned operations are performed in a manner that enables the linking of the two elements.

[0358] As used herein, the term "promoter" should be interpreted in its broadest context. These include, for example, the transcription of nucleic acids in response to developmental and / or external stimuli or in a tissue-specific manner. Additional regulatory elements that alter expression (e.g., upstream activating sequences, transcription factor binding sites, endogenous TA required for accurate transcription initiation with or without enhancers and silencers This includes the transcriptional regulatory sequences of genomic genes, including TA boxes or initiation elements. The term "promoter" refers to an activating gene that confers expression of a nucleic acid to which it is operably linked. Also used to describe recombinant, synthetic, or fusion nucleic acids or derivatives that enhance or Exemplary promoters can be used to further enhance expression and / or regulate the spatial expression and expression of the nucleic acid. and / or contain additional copies of one or more specific regulatory elements to alter temporal expression. It is possible.

[0359] As used herein, the term "operably linked" refers to an arrangement in which expression of a nucleic acid is promoted. By this means positioning a promoter relative to the nucleic acid such that it is controlled by the promoter.

[0360] A large number of vectors are available for expression in cells. The components of the vector generally include the following: Below: signal sequence, protein coding sequence (e.g., information provided herein) (derived from), enhancer elements, promoters, and transcription termination sequences, The present invention is not limited to these. A skilled artisan will be aware of suitable sequences for the protein sequence. Exemplary signal sequences include prokaryotic secretion signals (e.g., pelB, alfa, Calyphosphatase, penicillinase, Ipp, or heat-stable enterotoxin II), yeast Secretory signals (e.g., the invertase leader, the α-factor leader, or the acid phosphatase leader) leader of a ribozyme) or a mammalian secretory signal (e.g., the herpes simplex gD signal). ) are mentioned.

[0361] Exemplary promoters active in mammalian cells include the cytomegalovirus immediate early promoter CMV-IE, human elongation factor 1-α promoter (EF1), small nuclear RNA promoter promoter (U1a and U1b), α-myosin heavy chain promoter, simian virus 40 promoter SV40 promoter, Rous sarcoma virus promoter (RSV), adenovirus major late promoter promoter, β-actin promoter, CMV enhancer / β-actin promoter Hybrid regulatory elements including an immunoglobulin promoter or an active fragment thereof. An example of a useful mammalian host cell line is the SV40-transformed monkey kidney CV1 line (COS-7 ATCC CRL1651), human embryonic kidney line (293 cells or 293 cells subcloned for the purpose of inducing chromatin deficiency), baby hamster kidney cells (BHK, ATCC CL10) or Chinese hamster ovary cells (CHO).

[0362] For example, a yeast cell selected from the group including Pichia pastoris, Saccharomyces cerevisiae, and Schizosaccharomyces pombe. Exemplary promoters suitable for expression in yeast cells, such as yeast cells, include the ADH1 promoter, GAL1 promoter, GAL4 promoter, CUPl promoter, PHO5 promoter, Examples of such promoters include the nmt promoter, the RPR1 promoter, and the TEF1 promoter. However, the present invention is not limited to the above.

[0363] Means for introducing an isolated nucleic acid or an expression construct containing the same into a cell for expression are known to those skilled in the art. The technique used for a given cell depends on known successful techniques. Means of introducing recombinant DNA into cells include, among others, microinjection and DEAE / dextran. Mediated transfection, e.g., Lipofectamine (Gibco, MD, USA) and / or Or liposomes using Cellfectin (Gibco, MD, USA) PEG-mediated transfection, PEG-mediated DNA uptake, electroporation and D Microparticle bombardment using NA-coated tungsten or gold particles (Ag racetus Inc., WI, USA).

[0364] The host cells used to produce the proteins may be grown in a variety of culture media depending on the cell type used. For example, Ham's F10 (Sigma), basal medium (MEM), ), (Sigma), RPM1-1640 (Sigma), and Dulbecco's modified Eagle The medium (DMEM, Sigma) is suitable for culturing mammalian cells. Media for culturing the other cell types contemplated are known in the art.

[0365] Protein isolation Methods for isolating proteins are known in the art and / or described herein. will be done.

[0366] If the IL-11Rα binding protein is secreted into the culture medium, a commercially available protein-enriched fraction Filters, such as Amicon or Millipore Pellicon ultrafiltration filters. Supernatants from such expression systems can be first concentrated using filter units. Include a protease inhibitor such as PMSF at any of these steps to prevent proteolysis. Alternatively or additionally, the supernatant may be filtered. The protein can be separated from the cells expressing the protein by, for example, continuous centrifugation. .

[0367] The IL-11Rα binding protein prepared from cells can be purified by, for example, ion exchange, hydrolysis, or the like. hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, Dialysis, affinity chromatography (e.g., protein A affinity chromatography or protein The product can be purified using any of the above methods, including protein G chromatography, or any combination of the above. These methods are known in the art and are described, for example, in WO99 / 57134 or Ed. Harlow and David Lane (eds.), Antibodies: A Lab oratory Manual,Cold Spring Harbor Labora Tory, (1988).

[0368] The skilled artisan will appreciate that the protein may be tagged, e.g., with a polyhistidine tag, e.g. , hexahistidine tag, influenza virus hemagglutinin (HA) tag, or subunit Virus 5 (V5) tag or FLAG tag or glutathione-S-transferase It is also of interest that the peptides can be modified to include a (GST) tag to facilitate purification or detection. The resulting proteins may then be purified using methods known in the art, such as affinity purification. For example, hexaHis tags immobilized on solid or semi-solid supports are used to purify proteins. Specimens containing proteins specifically bind to nickel / nitrilotriacetic acid (Ni-NTA) The sample is then washed to remove unbound proteins, and the bound proteins are then contacted with the Proteins containing hexaHis tags are purified by eluting from the Additionally, affinity purification methods use ligands or antibodies that bind to the tag.

[0369] Complex In one embodiment, the IL-11Rα binding protein of the present disclosure is conjugated to a compound. For example, the compound may be a radioisotope, a detectable label, a therapeutic compound, a colloid, a toxin, a nucleic acid, Compounds that increase the half-life of IL-11Rα binding protein in a subject, peptides, proteins, and mixtures thereof.

[0370] Other compounds can be used that are capable of binding directly or indirectly to the IL-11Rα binding protein. Examples of compounds include: Radioisotopes (e.g., iodine-131, yttrium-90, or indium-11 1) a detectable label (e.g., a fluorescent dye molecule or a fluorescent nanocrystal or a quantum dot), Therapeutic compounds (e.g., chemotherapeutic or anti-inflammatory agents), colloids (e.g., gold), toxins ( For example, ricin toxin or tetanus toxoid), nucleic acids, peptides (for example, serum albumin binding peptide), protein (e.g., a protein comprising an antigen-binding domain of an antibody or serum albumin), compounds that increase the half-life of IL-11Rα binding protein in a subject ( For example, polyethylene glycol or other water-soluble polymers that have this activity) and their The present disclosure also provides a mixture of IL-11Rα binding proteins. Exemplary compounds and methods for such conjugation are known in the art and are described, for example, in the International Publication This is described in Publication No. 2010 / 059821.

[0371] The IL-11Rα binding protein can be bound to a nanoparticle (see, e.g., Kogan et al., Reviewed in Nanomedicine (Lond).2:287-306,2007 The nanoparticles can be metal nanoparticles.

[0372] IL-11Rα binding protein binds to antibody-targeted bacterial minicells (e.g., PCT / I B2005 / 000204).

[0373] Some exemplary compounds that can be conjugated to the IL-11Rα binding proteins of the present disclosure The items are listed in Table 2. [Table 2]

[0374] Assaying the activity of IL-11Rα binding proteins Binding to IL-11Rα and its mutants Some IL-11Rα binding proteins of the present disclosure bind to the extracellular domain of hIL-11Rα (e.g., For example, the region as described herein) and a specific extracellular region of hIL-11Rα. Mutant forms (e.g., SEQ ID NO:3 or SEQ ID NO:4, with or without certain point mutations) No. 85) and / or binds to both human and cynomolgus monkey IL-11Rα. It will be apparent to those skilled in the art from the disclosure herein. The method for evaluating the protein is, for example, Scopes (Protein purification: Principles and Practice, 3rd Edition, Springer Ve Such methods are known in the art, such as those described in Rlag, 1994. In general, IL-11Rα binding protein is immobilized and exposed to a labeled antigen. This involves washing to remove non-specifically bound proteins, followed by the labeling of The amount of IL-11Rα binding protein is detected. Panning-type assays can also be used. Alternatively or additionally, a surface plasmon resonance assay can be used.

[0375] The above-described assays can be used to detect hIL-11Rα or its extracellular domain (e.g., SEQ ID NO: 3) or the polypeptide of SEQ ID NO: 3 or SEQ ID NO: 85 or The level of binding of the protein to the mutant form of the polypeptide can also be detected.

[0376] In one example, the IL-11Rα binding protein of the disclosure comprises a polypeptide of SEQ ID NO:85. At least about 1.5-fold, or 2-fold, or 5-fold, or 10-fold, or 50-fold greater than that bound to the peptide or 100-fold or 150-fold or 160-fold or 200-fold lower levels of the polypeptide of SEQ ID NO:95 It binds to peptides.

[0377] In one embodiment, a protein of the present disclosure is a polypeptide that binds to SEQ ID NO:85. At least about 1.5 times, 2 times, 5 times, 10 times, 50 times, 100 times, or 1 Binds to the polypeptide of SEQ ID NO:96 at 50-fold, 160-fold, or 200-fold lower levels.

[0378] In one embodiment, a protein of the present disclosure is a polypeptide that binds to SEQ ID NO:85. At least about 1.5 times, 2 times, 5 times, 10 times, 50 times, 100 times, or 1 It binds to the polypeptide of SEQ ID NO:86 at a 50-fold, 160-fold, or 200-fold lower level.

[0379] In one embodiment, a protein of the present disclosure is a polypeptide that binds to SEQ ID NO:85. At least about 1.5 times, 2 times, 5 times, 10 times, 50 times, 100 times, or 1 Binds to the polypeptide of SEQ ID NO:89 at a 50-fold, 160-fold, or 200-fold lower level.

[0380] The level of binding is conveniently determined using a biosensor.

[0381] The present disclosure contemplates any combination of the foregoing features. The protein has all of the binding characteristics set forth in the above five paragraphs.

[0382] Epitope mapping In another embodiment, the epitopes to which the proteins described herein bind are mapped. Epitope mapping methods will be apparent to the skilled artisan. Epitopes, for example, IL-11Rα sequences including peptides containing 10 to 15 amino acids or A series of overlapping peptides spanning that region are then generated. The protein is exposed to each peptide and the peptides to which it binds are determined. This allows the determination of peptides that contain epitopes to which the protein binds. If a protein binds to a peptide, the protein binds a conformational epitope. obtain.

[0383] Alternatively or additionally, for example, alanine scanning mutagenesis or the use of evolutionarily conserved amino acids The amino acid residues in IL-11Rα were mutated by substitution of the amino acid to produce an IL-11Rα binding protein. Determine mutations that reduce or prevent protein binding. IL-11Rα binding protein Any mutation that reduces or prevents binding of the IL-11Rα binding protein. It is likely to be among the epitopes involved.

[0384] In this regard, as shown herein, a nucleotide sequence at position 117 of IL-11R relative to SEQ ID NO:1 is Mutation of valine reduced or prevented binding of 8E2 and 8D10. Testing of affinity matured mutants of IL-11R revealed that the V117 residue of IL-11R is resolved by mutation. These results confirmed that these residues are more important for binding than the other residues analyzed.

[0385] Another method to determine the region containing the epitope to which the IL-11Rα binding protein binds is is a form of IL-11Rα that is not bound by IL-11Rα binding proteins (e.g., mI The study involved replacing a region of hIL-11Rα with the corresponding region of hIL-11Rα. If the IL-11Rα binding protein does not bind to the mutant form of IL-11Rα, then In this case, residues that form part of the epitope of the protein are within the substituted region. It is possible.

[0386] Further methods for determining the region containing the epitope include using immobilized IL-11R of the present disclosure. The IL-11Rα or a region thereof is bound to the α-binding protein, and the resulting complex is then subjected to proteasome synthesis. The method involves digesting the IL-11Rα-binding protein with IL-11Rα-binding enzyme, which then binds the IL-11Rα-binding protein to immobilized IL-11Rα. The intact peptides are isolated and analyzed, for example using mass spectrometry, to determine their sequences. do.

[0387] Further methods include converting hydrogens in IL-11Rα or a region thereof to deuterons and The bound protein can be bound to an immobilized IL-11Rα binding protein of the present disclosure. The deuterons are then converted back to hydrogen, and the IL-11Rα or a region thereof is isolated and the enzyme is The enzyme is digested with 1,000 ng / ml and analyzed using mass spectrometry to identify the regions containing deuterons, which is the method of the present invention. The IL-11Rα binding protein described in the specification is protected from conversion to hydrogen by binding to the IL-11Rα binding protein. is.

[0388] Optionally, an immobilized IL-11Rα binding site for IL-11Rα or an epitope thereof. The dissociation constant (Kd), association constant (Ka) and / or affinity constant (K D ) is measured. "Kd" or "Ka" or "K for IL-11Rα binding protein D "teeth In one embodiment, the IL-11Rα binding assay is used to measure the IL-11Rα binding activity. In the case of "Kd," the assay is performed in the presence of a titration series of unlabeled IL-11Rα. Equilibrate IL-11Rα binding protein with the lowest concentration of labeled IL-11Rα at After washing to remove unbound IL-11Rα, the amount of label was measured and correlated with the protein The Kd of quality is shown.

[0389] In another example, Kd, ​​Ka or K D is immobilized IL-11Rα or a region thereof Surface plasmon resonance assay with or without immobilized IL-11Rα binding protein For example, BIAcore surface plasmon resonance (BIAcore, Inc., Pis The ELISA kit is measured using a ELISA kit (Cataway, NJ).

[0390] In some embodiments, the IL-11Rα binding proteins are characterized in that they bind IL-11Rα. Since they are likely to compete for D Or better yet, K DSand That is, a lower K D value).

[0391] Measuring competitive binding Proteins that competitively inhibit the binding of antibodies 8E2 and / or 8D10 and / or 8E4 Assays for measuring .alpha. will be apparent to the skilled artisan. One such method is Examples are given in the fine print.

[0392] For example, the antibody is conjugated to a detectable label, such as a fluorescent label or a radioactive label. The labeled antibody and the test IL-11Rα binding protein are then mixed to obtain IL-11Rα or a region thereof (e.g., as contained within a polypeptide comprising SEQ ID NO:3) or The labeled antibody is then contacted with a cell expressing IL-11R. The level of the labeled antibody is then measured. The labeled antibody is contacted with IL-11Rα or a region thereof in the absence of α-binding protein. The levels are compared to the levels measured in the absence of IL-11Rα binding protein. The level of labeled antibody was reduced in the presence of the test IL-11Rα binding protein. For example, IL-11Rα binding proteins competitively inhibit the binding of antibodies to IL-11Rα. It is considered that.

[0393] Optionally, the test IL-11Rα binding protein is conjugated to a different label to the antibody. The alternating label may be a IL-11Rα or a region thereof of the test IL-11Rα binding protein. This allows detection of the level of binding to the cells.

[0394] In another embodiment, the IL-11Rα binding protein comprises an antibody that binds IL-11Rα, a domain or Prior to contacting the cells, IL-11Rα or a region thereof (e.g., SEQ ID NO:3) may be (such as contained within a polypeptide comprising the The presence of IL-11Rα binding protein is greater than that of the absence of IL-11Rα binding protein. The reduction in the amount of bound antibody in the presence of the protein indicates that the protein is blocking the binding of the antibody to IL-11Rα. First, we used a labeled IL-11Rα binding protein to inhibit I The reverse assay can also be performed by binding an antibody to L-11Rα. Labeled IL-11Rα bound to IL-11Rα in the presence of antibody compared to in the absence The decreased amount of protein indicates that the IL-11Rα binding protein inhibits the antibody's binding to IL-11Rα. It is shown to competitively inhibit binding.

[0395] Any of the above-mentioned assays may further comprise the step of administering to the subject an antibody comprising IL-11Rα and / or SEQ ID NO:3 and / or SEQ ID NO: No. 85, and / or 8E2 and / or 8E3 as described herein. This can be performed on the extracellular domain of IL-11Rα to which 8D10 and / or 8E4 bind. Cut.

[0396] Measuring neutralization In some embodiments of the present disclosure, the protein is capable of neutralizing IL-11 signaling. It is possible.

[0397] To assess the ability of a protein to neutralize ligand signaling through a receptor A variety of assays are known in the art.

[0398] In one embodiment, the protein reduces or prevents binding of IL-11 to IL-11Rα. These assays utilize labeled IL-11 and / or labeled IL-11Rα binding. The assay can be performed as a competitive assay as described herein using the combined proteins. Cut.

[0399] In a further embodiment, the IL-11Rα binding protein is cultured in the presence of IL-11. Cells expressing IL-11Rα and gp130 (e.g., BaF3 cells) Reduce the proliferation of cells (e.g., cells engineered to express the protein) , about 1×10 4 cells) express IL-11 (e.g., about 0.3 ng / mL to about 5 ng / mL mL (e.g., between 0.3 ng / mL or 0.5 ng / mL for hIL-11) L or 5 ng / mL for cynoIL-11 or 0.5 ng / mL or 5 ng / mL) or about 1 ng / mL to about 5 ng / mL for mIL-11 (e.g., 1 ng / mL, 3 ng / mL, or 5 ng / mL)) and test IL- The cells are cultured in the presence or absence of 11Rα binding protein. Methods for the detection of thymidine incorporation are known in the art and include, for example, MTT reduction and / or thymidine incorporation. compared to levels seen in the absence of IL-11Rα binding protein. IL-11Rα binding protein reduces the level of proliferation and signaling in IL-11R By examining multiple concentrations of IL-11Rα binding protein, IC 50 , i.e., the concentration at which 50% of the maximum inhibition of cell proliferation occurs is determined. IC below μg / ml 50 In one embodiment, an IC 50 is less than 9μg / ml. For example, IC 50 For example, IC 50 is less than 7μg / ml For example, IC 50For example, IC 50 Less than 5μg / ml For example, IC 50 For example, IC 50 is 3μg In one embodiment, the IC 50 is 10 pages / ml or higher or 10ng / ml or higher.

[0400] Assays similar to those described in the previous paragraph are carried out with B9 or T10 cells. (Dams-Kozlowska et al., BMC Biotechnol, 12 :8,2012; and Yokote et al., J. AOAC,83:1053-1057,20 00). In the assay using T10 cells, proliferation was induced by the tetrazolium compound, 4-[3 -(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]- Measured by colorimetric detection of the reduction of l,3-benzenedisulfonate (WST-1). It can be determined.

[0401] In a further embodiment, IL-11Rα binding inhibits IL-11 mediated erythropoiesis. The ability of the protein to bind IL-11Rα is evaluated, for example, in the presence or absence of IL-11Rα binding protein. In the presence of Lin - CD34 + Cells (e.g., derived from umbilical cord blood) are contacted with IL-11. For example, by detecting the number of cells expressing CD235a using FACS. This determines the amount of erythropoiesis. IL-11Rα binding protein reduces the number of cells expressing CD235a compared with I It is considered to neutralize L-11 mediated signal transduction.

[0402] In yet a further embodiment, I inhibits IL-11-mediated phosphorylation of STAT3. Evaluate the ability of IL-11Rα binding proteins. For example, IL-11Rα and gp130 Cells expressing IL-11Rα were cultured in the presence of IL-11 and in the presence or absence of IL-11Rα binding protein. Then, Western blot analysis was performed using an antibody specific for phosphorylated STAT3. The level of STAT3 phosphorylation was assessed by blot or FACS. An exemplary assay that has been used is described in Dams-Kozlowska et al., BMC Biotech This was described in ol,12:8,2012.

[0403] In another embodiment, the cancer cells, e.g., gastric cancer cells or acute myeloid leukemia (AML) cells, The ability of IL-11Rα binding proteins to inhibit IL-11-mediated proliferation is assessed. In these assays, cancer cells (e.g., AGN or MKN45 gastric cancer cells) were treated with IL-1 1 in the presence or absence of an IL-11Rα binding protein. In the case of cells, the cells can also be cultured in the presence of G-CSF. and / or in the case of AML cells, the formation of L-CFUs. An exemplary assay that can be adapted to the present disclosure is: Zhang et al., Int. J. Biol. ScL, 8:383-393, 2012 and Ki Mura et al., Leukemia, 13:1018-1027, 1999.

[0404] Other methods of assessing neutralization of IL-11 signaling are contemplated by the present disclosure.

[0405] Measuring effector function As discussed herein, some IL-11Rα binding proteins of the present disclosure have reduced Having effector function or having effector function (or high effector function) Methods for assessing ADCC activity are known in the art.

[0406] In one embodiment, the level of ADCC activity is 51 Cr release assay, Europium release assay Say or 35 Each of these assays evaluates the I The cells expressing L-11R were treated with one or more of the compounds listed in the reference. The cells are then incubated for a time and under conditions sufficient for the incorporation of the 35 In the case of S release assay , cells expressing IL-11Rα 35 S-labeled methionine and / or cysteine with sufficient time for the labeled amino acid to be incorporated into newly synthesized proteins. The cells can then be cultured in the presence or absence of an IL-11Rα binding protein and in the presence or absence of an IL-11Rα binding protein. The presence of immune effector cells, e.g., peripheral blood mononuclear cells (PBMCs) and / or NK cells The cells are then cultured in the presence of 51 Cr, Europium and / or 35 IL-11Rα binding protein was detected in the absence of IL-11Rα. Little or no change in the presence of the binding protein indicates that the protein is a degraded effector. -function, and a higher amount ( or in the presence of an IL-11Rα binding protein containing an IgG1 Fc region) indicates effector function or high effector function. A Exemplary publications disclosing assays for assessing levels of DCC include Hells et al. trom et al. Proc. Natl. Acad. Sci. USA, 83:7059-706 3, 1986 and Bruggemann et al., J. Exp. Med. 166:1351-1 361,1987.

[0407] Other assays to assess the level of ADCC induced by a protein include ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellT echnology, Inc. CA, USA) or CytoTox96 (registered trademark) non-release Examples of such assays include the radioactive cytotoxicity assay (Promega, WI, USA).

[0408] A C1q binding assay was performed to confirm that IL-11Rα binding protein binds C1q. To evaluate complement activation, a CDC assay was performed. (See, for example, Gazzano-Santoro et al., J. Immunol. (See Methods, 202:163, 1996).

[0409] Determining half-life Some IL-11Rα binding proteins encompassed by the present disclosure have improved half-lives. For example, the modified IL-11Rα binding protein has an increased half-life compared to the unmodified IL-11Rα binding protein. The IL-11Rα binding proteins with improved half-lives are identified. Methods for doing so will be apparent to those skilled in the art. For example, I, which binds to the neonatal Fc receptor (FcRn), The ability of the L-11Rα binding protein to bind FcRn is evaluated. Increasing the activity of IL-11Rα increases the serum half-life of the IL-11Rα binding protein (see, e.g., Kim et al., (see, Eur. J. Immunol., 24:2429, 1994).

[0410] The half-lives of the IL-11Rα binding proteins of the present disclosure are described, for example, in Kim et al., Eur. J. Pharmacokinetic studies were performed according to the method described by I. Immunol., 24:542, 1994. According to this method, the expression of radioactively labeled IL-11Rα The binding protein is injected intravenously into mice and the binding activity is monitored as a function of time, for example, from 3 minutes to 72 hours after injection. The plasma concentration of the drug is measured periodically. The clearance curve obtained is biphasic, That is, it should be in the α and β phases. The β-phase clearance rate is calculated and compared to that of the wild-type or unmodified protein.

[0411] To evaluate the efficacy of treatment Assessing therapeutic efficacy in relation to measuring neutralization by IL-11Rα binding proteins An assay for this purpose is described above.

[0412] In another embodiment, an in vivo assay is used to evaluate the effectiveness of a protein to treat a disease. do.

[0413] For example, IL-11Rα binding proteins are examined in animal models of arthritis. Dell uses the mouse SKG line (Sakaguchi et al., Nature, 426:454- 460), type II collagen-induced arthritis model in rats, type II collagen-induced arthritis model in mice or antigen-induced arthritis models in some species (Bendele, J. Mus. culoskel Neuron Interact;1(4):377-385,20 In these assays, arthritis is induced and one or more symptoms of arthritis are observed. , e.g., IL-11R, which reduces inflammation in the joints and / or markers of inflammation in synovial fluid. The ability of IL-11Rα binding proteins to reduce arthritis symptoms is evaluated. The protein is involved in the progression of this disease or in diseases mediated by IL-11 (e.g., IL-11-mediated It is considered useful for treating chronic conditions such as inflammatory diseases.

[0414] The IL-11Rα binding protein may also or alternatively be used in, for example, a non-human mammal (e.g. For example, rodents (such as mice) have been examined in models of COPD in which they are exposed to cigarette smoke. Following exposure, the mammals are administered the IL-11Rα binding protein and standard Techniques are used to assess or estimate the level of lung inflammation and / or the number of neutrophils in the lungs. IL-11Rα binding proteins, which reduce lung inflammation and / or neutrophil numbers, may be involved in the prevention of lung inflammation and / or neutrophil counts. or COPD or IL-11-mediated diseases (e.g., IL-11-mediated inflammatory The present invention is considered to be useful in treating IL-11-mediated inflammatory diseases, such as pulmonary diseases. can be.

[0415] IL-11Rα binding proteins may also or alternatively be used to treat conditions such as asthma or airway hyperresponsiveness. This can be used to investigate any Th2-type inflammatory disease. An example model of allergic asthma For example, see Wang et al., J. Immunol. 165:2222, 2000. Following induction of inflammation, IL-11Rα binding proteins were expressed in mice. For example, the number of eosinophils in bronchoalveolar lavage fluid (BAL) was In vivo, symptoms of asthma, such as mucus secretion and / or goblet cell hyperplasia, are assessed. Other models of asthma are It is known in the art and includes, for example, those described in WO 2002 / 098216. Sheep models of inflammatory asthma, e.g., host dust mite protein-induced asthma A mouse model of allergic asthma (Fattouh et al., Am. J. Respir. Crit .Care Med.172:314-321,2005), IL-5 and eotaxin A mouse model of severe asthma in which nicotinamide-binding protein 1 (NICP) is overexpressed or delivered by aerosol in a mouse model of severe asthma. Mice receiving intratracheal instillation of poly-l-lysine are hypersensitive (Homma et al., Am. J. Physiol.Lung Cell Mol.Physiol.289:L413-L 418, 2005).

[0416] IL-11Rα binding proteins may also or alternatively be used in models of cancer, e.g., gastric cancer. For example, the mouse ( gpl30 Y757F / Y757F ) develop gastric tumors (Jenkins et al., Bloo d, 109:2380-2388, 2007). Mice (e.g., 8 weeks old) were treated with IL-1 1Rα binding protein and assess the number and weight of gastric polyps. Polyp size and / or weight-reducing IL-11Rα binding proteins are useful for treating cancer. Similar assays can be used to examine the effect on colon cancer, Prior to treatment with the L-11Rα binding protein, Greten et al. :285-296, 2004) Y757F / Y757F Mice were treated with azoxymethane (AOM) and then dextran sulfate sodium. Colon cancer is induced by treatment with sodium.

[0417] IL-11Rα binding proteins may also or alternatively be used as described, for example, in Li et al., Oncol As described in .Lett. 3:802-806, 2012, cancer metastasis or cancer-related This can be examined in models of bone disease.

[0418] Disease being treated The present disclosure relates to any disease caused or exacerbated by IL-11 in a subject. The present invention is intended to treat or prevent the disease.

[0419] In one embodiment, the disease is an autoimmune or inflammatory disease.

[0420] In one embodiment, the autoimmune disease is, for example, inflammatory arthritis, rheumatoid arthritis, or idiopathic arthritis. In one embodiment, the present invention relates to an autoimmune joint disease, such as juvenile idiopathic arthritis. In an example, the disease is rheumatoid arthritis.

[0421] In one embodiment, the autoimmune disease is an inflammatory disease, such as, for example, ulcerative colitis or Crohn's disease. and autoimmune colon diseases such as chronic bowel disease.

[0422] In one embodiment, the autoimmune disease is an autoimmune skin disease, such as, for example, psoriasis. be.

[0423] In one embodiment, the inflammatory disease is an inflammatory disorder, such as a lung disease associated with neutrophil infiltration. For example, the disease is asthma, chronic obstructive pulmonary disease (COPD), rhinitis or An allergy. In one embodiment, the disease is asthma.

[0424] Other exemplary inflammatory diseases include infection-induced inflammation (e.g., inflammation induced by Mycobacterium tuberculosis). inflammation of the stomach (e.g., associated with stomach cancer), or inflammatory dermatitis (e.g., Atopic dermatitis).

[0425] In one embodiment, the disease is a wasting disease, such as cachexia or sarcopenia. In one embodiment, the wasting disease is cachexia. For example, cachexia can be caused by rheumatoid arthritis, diabetes mellitus, Disease, heart disease, chronic kidney disease, chronic pulmonary inflammation, intestinal inflammation, inflammatory bowel disease, aging, sepsis, or A In one embodiment, the present invention relates to or is caused by a disease selected from the group consisting of IDS. The fluid may be associated with or caused by cancer.

[0426] In one embodiment, the disorder is a bone disorder, e.g., insufficient bone formation and / or excess bone. It is caused by catabolism. Example bone disorders include osteoporosis (including postmenopausal osteoporosis), fractures, and osteoporosis. , bone resorption / damage caused by cancer (metastatic bone cancer, myeloma, Paget's disease of bone), and cancer treatment Bone resorption / damage caused by medical treatment (e.g. chemotherapy, hormone ablation or inhibition) Examples include:

[0427] In one embodiment, the disease is cancer. Exemplary cancers include hematological cancers, cancers of epithelial origin, gastric cancer, and pancreatic cancer. , liver cancer, osteosarcoma, endometrial cancer and ovarian cancer.

[0428] In one embodiment, the subject is a patient who is resistant to treatment with another compound to treat a disease. For example, subjects suffering from autoimmune or inflammatory diseases corticosteroids and / or immunosuppressants and / or cyclophosphamide and / or methotrexate and / or anti-TNF antibody or soluble TNF receptor and / or anti-CD20 and / or anti-IL-6 antibody and / or anti-CD22 antibody. Not responding correctly or favorably.

[0429] composition In some embodiments, the IL-11Rα binding proteins as described herein are or in any other convenient dosage form. It can be administered orally, parenterally, by inhalation spray, absorption, adsorption, topically, rectally, or intranasally. The drug is administered intravenously, bucally, vaginally, intracerebroventricularly, or via an implanted reservoir. As used herein, "subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, Includes intrasternal and intracranial injection and infusion techniques.

[0430] Forms suitable for administering the IL-11Rα binding protein to a subject (e.g., pharmaceutical compositions) Methods for preparing such compounds are known in the art and are described, for example, in Remington's Pharma ceutical Sciences (18th edition, Mack Publishing C o., Easton, Pa., 1990) and the United States Pharmacopeia: National Formulary (Mack Publishing Company, Easton, Pa., 1984). This includes the methodology used.

[0431] The pharmaceutical compositions of the present disclosure can be administered, for example, intravenously or intraluminally into a body cavity or duct of an organ or joint. Compositions for administration are generally pharma- ceutical acceptable. A solution of the IL-11Rα binding protein dissolved in an acceptable carrier, e.g., an aqueous carrier, is A variety of aqueous carriers can be used, for example, buffered saline, etc. pH adjusters and buffers, toxicity adjusters, etc., such as sodium acetate, sodium chloride, etc. To approximate physiological conditions, such as calcium chloride, potassium chloride, sodium lactate, etc. These formulations may contain pharma- ceutically acceptable auxiliary substances as required. The concentration of the IL-11Rα binding protein shown can vary widely and is dependent on the administration method selected. Selection is based primarily on fluid volume, viscosity, weight, etc. according to the particular method and patient needs. Exemplary carriers include water, saline, Ringer's solution, and dextrose solution. and 5% human serum albumin. Non-aqueous media such as mixed oils and ethyl oleate. Liposomes may also be used as carriers. The vehicle must be isotonic and chemically stable. It may contain minor amounts of additives such as buffers and preservatives which enhance quality.

[0432] Once formulated, the IL-11Rα binding proteins of the disclosure may be administered in a manner compatible with the administration formulation. The formulations will be administered in amounts that are therapeutically / prophylactically effective at a therapeutically / prophylactically effective dose. Although the compounds are easily administered in a variety of dosage forms, such as in the form of an injectable solution of the compound, other pharma- ceutical acceptable forms are also contemplated. For example, tablets, pills, capsules, or other solid objects for oral administration, suppositories, pessaries, etc. Also contemplated are intranasal solutions or sprays, aerosols, inhalants, liposomal forms, and the like. "Sustained release" capsules or compositions may also be used. Sustained release formulations generally provide a sustained release effect over an extended period of time. The IL-11Rα binding proteins of the present disclosure are designed to provide a constant drug level. can be used to deliver

[0433] WO 2002 / 080967 describes the administration of the IL-11Rα binding proteins of the present disclosure. Also suitable are nebulized compositions and compositions comprising antibodies for the treatment of asthma, for example. The method of administering the substance is described.

[0434] Combination therapy In one example, the IL-11Rα binding protein of the disclosure is used in a combination treatment step or additional or as an additional component of a therapeutic formulation. It is administered in combination with another compound useful in treating the disease.

[0435] For example, the other compound is an anti-inflammatory compound. Alternatively or additionally, the other compound Alternatively or additionally, the other compound may be, for example, prednisolone. Alternatively or additionally, the active ingredient is a corticosteroid, such as benzodiazepine and / or prednisolone. The other compound is methotrexate. Alternatively or additionally, the other compound is cytochrome P450. Alternatively or additionally, the other compound is mycophenolate mofetil. Alternatively or additionally, the other compound is an anti-CD20 antibody (e.g., Rits Alternatively or additionally, the other compound is an anti-CD2 Alternatively or additionally, the other compound is an anti- TNF antibodies (e.g., infliximab or adalimumab or golimumab) or soluble Alternatively or additionally, the other compounds may be The agent is a CTLA-4 antagonist (e.g., abatacept, CTLA4-Ig). Alternatively or additionally, the other compound is an anti-IL-6 antibody. The compound may be, for example, a BLys antagonist, such as an anti-BLys antibody (e.g., belimumab). be.

[0436] In another embodiment, the other compound is a chemotherapeutic agent or other drug used to treat cancer. It is a drug.

[0437] In another embodiment, the proteins described herein can be administered prior to radiation therapy for the treatment of cancer. or administered later.

[0438] Dosage and timing of administration Suitable dosages of the IL-11Rα binding proteins of the present disclosure are This will vary depending on the protein, the disease being treated, and / or the subject being treated. For example, starting with a suboptimal dose and gradually modifying the dose to determine an optimal or useful dose. It is within the ability of a skilled physician to determine suitable dosages by Alternatively, cell culture assays or animal studies may be used to determine appropriate therapeutic / prophylactic doses. Using the derived data, the suitable dose is determined by determining whether the active compound has little or no toxicity. ED 50 The dosage will vary depending on the dosage form employed and the dosage utilized. The therapeutically / prophylactically effective dose may vary within this range depending on the route of administration used. The dose can be estimated initially from the results. The dose is formulated in animal models and determined in cell culture. The IC 50 (i.e., the concentration or amount of compound that achieves a half-maximal inhibition of symptoms). Such information can be used to refine useful doses in humans. Levels in plasma can be determined more accurately, for example by high performance liquid chromatography. This can be measured by fluoroscopy.

[0439] In some embodiments, the methods of the present disclosure include administering a prophylactically or therapeutically effective amount of any of the compounds described herein. This involves administering a protein that

[0440] The term "therapeutically effective amount" refers to an amount that, when administered to a subject in need of treatment, improves the prognosis and / or outcome of the subject. or ameliorate the condition and / or alleviate one or more symptoms of the conditions described herein. to a level below that recognized or accepted as a clinical diagnosis or clinical feature The amount administered to a subject will depend on the particular characteristics of the disease being treated, The type and stage of the disease being treated, the method of administration, and, for example, general condition, other diseases, age, The results will depend on the characteristics of the subject, such as sex, genotype, and weight. It will be possible to determine the appropriate dosage depending on the factors and other factors. The term should not be construed to limit the disclosure to a particular amount, e.g., weight or amount of protein. Rather, the present disclosure is not intended to be construed as a substitute for a full disclosure of any IL sufficient to achieve the results recited in the subject matter. The present invention encompasses any amount of -11Rα binding protein.

[0441] As used herein, the term "prophylactically effective amount" refers to a dose that reduces the severity of one or more detectable symptoms of a disease state. "protein" refers to an amount of protein sufficient to prevent, inhibit, or delay the onset of a disease. A skilled artisan will appreciate that such amounts may be, for example, L-11Rα binding proteins and / or specific subjects and / or types or severity of diseases or levels and / or predisposition (genetic or otherwise) to the disease. Thus, the term refers to a specific amount, e.g., by weight of protein. This disclosure should not be construed as limiting the disclosure to any specific amount or quantity, but rather, this disclosure is to be construed as limiting the disclosure to any specific amount or quantity. The present invention encompasses any amount of IL-11Rα binding protein sufficient to achieve the desired result. .

[0442] For in vivo administration of the IL-11Rα binding proteins described herein, The dosage ranged from about 10 ng / kg to about 100 mg / kg of body weight per day. For repeated administration over several days or more depending on the severity of the disease or disorder being treated. Alternatively, the treatment may be sustained until a desired suppression of symptoms is achieved.

[0443] In some embodiments, the IL-11Rα binding protein is administered at a dose of about 1 mg / kg to about 30 mg / kg. kg, for example, about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg or about 2 The IL-11R is then administered at an initial (or loading) dose of 1 mg / kg or 5 mg / kg. The α-binding protein is between about 0.01 mg / kg and 2 mg / kg, for example, about 0.05 mg / kg to about 1 mg / kg, for example, about 0.1 mg / kg to about 1 mg / kg, For example, a lower maintenance dose of about 0.1 mg / kg or 0.5 mg / kg or 1 mg / kg may be administered. Maintenance doses can be administered every 7 to 30 days, e.g., every 10 to 15 days. For example, it may be administered every 10 or 11 or 12 or 13 or 14 or 15 days.

[0444] In some embodiments, the IL-11Rα binding protein is administered in a concentration of from about 0.01 mg / kg to about 50 mg / kg, for example, between about 0.05 mg / kg and about 30 mg / kg, for example, Between about 0.1 mg / kg and about 20 mg / kg, for example, between about 0.1 mg / kg and about 10 mg / kg g / kg, for example, between about 0.1 mg / kg and about 2 mg / kg. For example, the IL-11Rα binding protein is administered at a concentration of about 0.01 mg / kg to about 5 mg / kg. For example, between about 0.1 mg / kg and about 2 mg / kg, for example, about 0.2 mg / kg or 0.3mg / kg or 0.5mg / kg or 1mg / kg or 1.5mg / kg In some embodiments, the dose is administered in a dose-dependent manner (e.g., without a high loading dose or a lower maintenance dose). In this case, multiple doses are administered, for example, every 7 to 30 days, for example, every 10 to 22 days, etc. For example, every 10 to 15 days, for example, 10 or 11 or 12 or 13 or 14 or 1 It is administered every 5 or 16 or 17 or 18 or 19 or 20 or 21 or 22 days. For example, the IL-11Rα binding protein may be administered every 7 days, every 14 days, or every 21 days. is administered.

[0445] In some embodiments, at the time the treatment regimen is initiated, the mammal has not been receiving any of the following treatments for 7 consecutive days or for 6 consecutive days. The IL-11Rα binding protein is administered on one or five consecutive days or on four consecutive days.

[0446] For mammals not responding adequately to treatment, multiple doses may be administered over a period of one week. Alternatively or additionally, increasing doses may be administered.

[0447] In another embodiment, for a mammal experiencing an adverse reaction, the initial (or loading) dose may be May be spread over a week or over a number of consecutive days.

[0448] Administration of an IL-11Rα binding protein according to the methods of the disclosure can, for example, the physiological state of the subject, whether the administration is for therapeutic or prophylactic purposes, and other factors known to the skilled practitioner. The administration of the IL-11Rα binding protein can be continuous or intermittent depending on the patient's condition. The pulses may be essentially continuous over a preselected period of time, or may be spaced apart over a series of intervals. The administration may be rapid, for example, during or after the onset of the disease.

[0449] IL-11Rα detection assay The IL-11Rα binding proteins of the present disclosure, for example, as discussed herein, The following assays can be performed with IL-11Rα binding protein conjugated to a suitable label: The assays described herein can be used to detect IL-11Rα or cells expressing it. Detection of the cells is useful for diagnosing or prognosing disease.

[0450] The immunoassays include those for diagnosing disease in a subject or for detecting IL-11Rα and / or its 1 is an exemplary assay format for detecting cells expressing a Western blotting antibody. Blot, enzyme-linked immunosorbent assay (ELISA), and fluorescence-linked immunosorbent assay (FL ISA), competitive assay, radioimmunoassay, lateral flow immunoassay, flow-through immunoassay Immunoassays, electrochemiluminescence assays, nephelometric assays, nephelometric assays and any immunoassay, including fluorescence-activated cell sorting (FACS)-based assays. Plan the form.

[0451] One suitable form of immunoassay is, for example, ELISA or FLISA.

[0452] In one form, such an assay involves administering an IL-11Rα binding protein of the disclosure to a solid support. A matrix, such as a polystyrene or polycarbonate microwell or decanter. Immobilization on a dipstick, membrane, or glass support (e.g., a glass slide) The test sample is then directly contacted with the IL-11Rα binding protein, and the sample is The method comprises the steps of: binding or capturing IL-11Rα or cells expressing IL-11Rα in a sample; Following washing to remove any unbound proteins, IL-11 was probed with different epitopes. The IL-11Rα binding proteins that bind to Rα or to different antigens on cells are captured. The detector protein is generally a protein that is capable of detecting IL-11Rα. In the case of LISA, for example, enzymes (e.g., horseradish peroxidase (HRP), alkaline phosphatase (AP), or β-galactosidase, or in the case of FLISA It is labeled with a detectable reporter molecule, such as a fluorescent dye molecule. A second labeled protein can be used that binds to the target protein. Following washing to remove proteins, in the case of ELISA, e.g. hydrogen peroxide, TMB or Toluidine or 5-bromo-4-chloro-3-indole-β-D-galactopyranoside The reporter molecule is detected by the addition of a substrate such as x-gal. Alternatively, the immobilized (capture) protein and detector protein can be used in the reverse manner.

[0453] The level of antigen in the sample is then measured using a calibrator that is made using a known amount of the marker. It is determined using a line or by comparison with a control sample.

[0454] The assays described above can be easily adapted to use chemiluminescence or electrochemiluminescence as the basis of detection. will be changed to.

[0455] As will be apparent to the skilled artisan, other detection methods based on immunosorbent assays are also contemplated herein. For example, detectable radioactive or detectable gold labels (e.g., colloidal gold) or, for example, liposomes encapsulating NAD+ for detection or activation. Immunosorbent assay as described above using lysinium-linked immunosorbent assay.

[0456] In some embodiments of the present disclosure, the level of IL-11Rα or cells expressing it is determined by measuring the surface Plasmon resonance detectors (e.g., BIAcore™, GE Healthcare e.g., U.S. Pat. No. 7,205,159. Flow-through devices, micro- or nano-immunoassay devices such as those described in US Pat. As described in U.S. Patent Application Publication No. 20030124619, lateral flow devices (such as For example, U.S. Patent Application Publication No. 20040228761 or U.S. Patent Application Publication No. 20040228761. No. 65926), or immunoturbidimetric assays (e.g., as described in U.S. Pat. No. 5,393,652). 571,728 or as described in U.S. Pat. No. 6,248,597. can be.

[0457] Samples and Controls As will be apparent to one of skill in the art, some of the examples described herein may be Thus, some degree of quantitation is required to determine the levels of -11Rα or cells expressing it. Such quantitation can be determined by including suitable control samples in the assays of the present disclosure. obtain.

[0458] In one embodiment, a suitable control sample is a sample from a healthy or normal subject.

[0459] In the present context, the term "healthy subject" refers to a subject suffering from a disease associated with IL-11Rα, e.g., inflammatory The term "immunoglobulin" should be construed to mean an individual who is known to be free of the disease.

[0460] The term "normal subject" refers to a subject having normal levels of IL-11Rα or IL-11Rα+ in a sample compared to a population of individuals. should be construed to mean an individual having cells which express it.

[0461] The present disclosure also provides methods for analyzing the effects of serotonin levels in normal and / or healthy subjects or populations of normal and / or healthy subjects. The control sample is also contemplated to be a data set obtained from

[0462] In one embodiment, the method of the present disclosure further comprises, for example, using the methods described herein. Determining the level of IL-11Rα in a control sample.

[0463] In one embodiment, the sample from the subject and the control sample are assayed at about or substantially the same time. do.

[0464] In one embodiment, any one or more samples may be subjected to the same method of the present disclosure as described herein. Assaying samples from subjects and control samples using the same method allows for comparison of results .

[0465] kit The disclosure further includes: (i) an IL-11Rα binding protein of the present disclosure or an expression construct encoding same; (ii) a cell of the present disclosure; or (iii) Pharmaceutical Compositions of the Disclosure The present invention also includes a kit comprising one or more of the above.

[0466] In the case of a kit for detecting IL-11Rα, the kit further comprises, for example, A detection means may be included which is linked to the IL-11Rα binding protein.

[0467] In the case of kits for therapeutic / prophylactic use, the kits further comprise a pharma- ceutically acceptable carrier. may include.

[0468] Optionally, the kits of the present disclosure are for use in the methods described herein according to any of the examples. It will be packaged with instructions.

[0469] The present disclosure includes the following non-limiting examples.

[0470] Non-limiting Examples Materials and Methods Phage display An antibody specific to human IL-11Rα was isolated from a human Fab-phagemid antibody library. Immobilized in the presence of wild-type hIL-11 or hIL-11 mutant proteins. hIL-11Rα-Fc (R&D Systems Catalog No. 1977-MR) Phages that bound to the IgG were eluted. Positive clones were reclassified as human IgG4 antibodies.

[0471] Proliferation assay of IL-11-responsive cells Using BaF3 cell lines responsive to hIL-11, cynoIL-11 and mIL-11 The ability of the antibodies to block the biological activity of IL-11 was examined. The three cell lines are described in WO 2009 / 052588.

[0472] The BaF3 cell lines, which are responsive to hIL-11 and cynoIL-11, were treated with wild-type Human and cynomolgus IL-11Rα and human gp130 and cynomolgus gp130, respectively The cells were stably transfected with a construct encoding p130. Cells were selected by growth in medium containing 11 and isolated by limiting dilution cloning. A number of stably transfected clones were derived from clonal cell lines expressing hIL-11 or The dose-responsive proliferation (thymidine incorporation) of cynoIL-11 was observed when cultured in the presence of cynoIL-11. One hIL-11-reactive clone and one cytochrome P450 clone were selected for analysis. One noIL-11-reactive clone from each was selected for antibody analysis.

[0473] Submaximal concentrations of IL-11 (hIL-11: 0. 3ng / mL or 0.5ng / mL or 5ng / mL; mIL-11: 1ng / mL, 3 ng / mL or 5ng / mL; cynoIL-11: 0.5ng / mL or 5ng / mL ) and increasing concentrations of purified monoclonal antibodies or hIL-11 muteins ( column number 110 and has an N-terminal hexaHis tag) in the presence of RPMI / 10% Approximately 1 × 10 in a 96-well plate using FCS / Glutamax / PenStrep 4 pcs IL-11-responsive BaF3 cells were seeded at 100 cells / well. Prior to the addition of cytokines, To determine the IL-11 expression level, cells were first incubated for 30 min in the presence of antibodies or hIL-11 mutant proteins. The cells were cultured at 37°C for approximately 48-50 h, with the final 6 h of culture being incubated at 37°C for 1 h. 3 Apply H-thymidine The cells were harvested onto glass fiber filters and the amount of radioactive thymidine incorporated into DNA was determined. Levels were measured by liquid scintillation counting. Assays were performed in duplicate and then The average value for each assay point was plotted.

[0474] Affinity maturation of antibody 8E2 Antibody 8E2 was affinity matured using the following method. H and V L Code The sequences are inserted into a phagemid construct to encode a germlined Fab and the CDRs - 18 codons (6 amino acid residues) in all CDRs except L2 are replaced with TAA stop codons By replacing the chromosome 1 gene with the chromosome 2 gene, a germline arrest template was created. ds in Enzymology:238:333-336,2000) The library was constructed using a method as previously described. Unkel et al., Methods in Enzymology:154:367-38 Each stop template was used as a template for the mutagenic oligonucleotide The plasmid was designed to simultaneously repair the stop codon and introduce a mutation at the planned site. The mutagenesis reaction was introduced into E. coli by poration and then transformed with helper phage. Phage production was initiated by precipitation with PEG / NaCl after overnight growth at 30°C. The phages were harvested by

[0475] The library was constructed by increasing the concentration of biotinylated polypeptides containing SEQ ID NO:3 and decreasing the number of The plasmid p53 was cycled through rounds of selection, with the concentration of target being reduced 10-fold each time.

[0476] Binding of antibodies to domain-swapped IL-11R mutant polypeptides We have generated various soluble forms of IL-11R that contain the hIL-11R and mIL-11R domains. The antibodies prepared by Western blotting included the sequences shown in SEQ ID NO: 3 and SEQ ID NO: 86 to 90. Using the antibodies 8E2, 8D10, and Binding of 8E4 was measured.

[0477] For Biacore analysis, anti-human IgG was used at approximately 10,000 to 12,000 RU. Immobilize on the sensor surface and measure 0.2 μg / mL to 0.5 μg / mL for 120 seconds per cycle. Each antibody was captured at concentrations ranging from 1 μM to 2.5 nM, including a buffer blank injection. The IL-11 receptor was injected into the capture antibody at various concentrations ranging from 0.1 to 0.2 μg / mL. The association was monitored for 3–5 min. The binding curves of each interaction were calculated using a 1:1 kinetic model. Approximate affinities were determined by line fitting.

[0478] Antibody binding to point mutants of soluble hIL-11R Amino acids derived from mIL-11 are synthesized as hIL-11 (SEQ ID NO: 85) (e.g., SEQ ID NO: The positions of the mutations relative to SEQ ID NO. 1 and references to the SEQ ID NOs of each polypeptide are shown. We created various point mutants of the soluble form of IL-11R by introducing the soluble form of IL-11R (see 5). and using Biacore analysis or FACS, these polypeptides or SEQ ID NO:3 Alternatively, binding of the antibody to the polypeptide of SEQ ID NO:85 was measured.

[0479] Anti-human IgG Fc specific antibody is chemically immobilized to a CM5 chip up to approximately 9000RU Antibodies were applied at approximately 0.3 to 1 μg / mL for 120 seconds in two spots on each flow cell. An adjacent spot consisting of anti-human IgG alone was used as a reference. The IL-11 receptor was injected into the capture antibody and reference spots at 40, 10, 5, and 2.5 nM. Blank injections of buffer only were also performed in duplicate. Injections were performed for 3 min to allow for further dissociation. Monitored for 5 min.

[0480] Binding curves were reference subtracted and buffer blanked before being fitted to a 1:1 kinetic model. I made it.

[0481] Antibody-mediated inhibition of IL-11 signaling in cancer cells DLD-1 cells (colorectal cancer cell line) and MKN-28 cells (gastric cancer cell line) were titrated. The cells were stimulated with hIL-11 (50 ng / mL) for 15 min. Prior to stimulation, increasing concentrations of 8E2 anti-IL-11R or BM4 isotype control antibody were administered. Cells were fixed, permeabilized, and stained with PE-conjugated anti-phosphatase. The cells were stained with STAT3 antibody and analyzed by flow cytometry. I went in pairs. EXAMPLES

[0482] Antibody isolation and characterization The three antibodies 8E2, 8D10 and 8E4 were used to measure IL-11 expression in transfected BaF3 cells. A single antibody was isolated from a Fab-phagemid library based on its ability to inhibit the proliferation of a Fab-dependent 8E4 also inhibited mouse IL-11-dependent proliferation of BaF3 cells.

[0483] 8E2, 8D10, and 8E4 were transfected with hIL-11Rα or cynoIL-11Rα. 8E4 bound to cells transfected with mIL-11Rα, whereas 8 E2 and 8D10 did not bind.

[0484] Of the three antibodies, 8E2 had the best thermal stability as assessed by differential scanning calorimetry. (69.8°C compared to between 63.2°C and 71.4°C for 8D10 and 8E4) (having a Tm between 76.6°C and 76.6°C).

[0485] 8E2 was selected and affinity matured. C was mutated using heavy and light chain libraries. We generated clones with DR (Figs. 1, 2 and 3). Of these affinity mutants, 62 Binding to hIL-11R was assessed by Biacore, and hIL-11 in BaF3 cells was The relative ability of each compound to inhibit proliferation induced by β-lactam serovar IgE was measured. The results are shown in Table 3. [Table 3-1] [Table 3-2]

[0486] hIL-11-induced increase in BaF3 cells compared with 8E2, 8D10 and 8E4 Improved ability to inhibit proliferation and improved activity against human IL-11Rα compared to 8E2 Ten affinity-matured antibodies (TS-306, TS-2, TS-4, T S-7, TS-14, TS-51, TS-101, TS-108, TS-134 and TS In selecting these affinity matured antibodies, the CDRs Sequences were also considered. Several clones were selected.

[0487] Human, cynomolgus monkey or mouse IL-11R-transfected BaF3 cells These antibodies were tested for inhibition of IL-11-induced proliferation in monkeys and / or mice. The binding to human and cynomolgus monkey IL-11R-transfected cells and flow cytometry were investigated. Mean fluorescence intensity was also measured by cytometry. Each of the clones further enhanced hIL-11 and cynoIL-11-induced proliferation. It potently inhibited IL-11R and bound to human and cynomolgus monkey IL-11R with great affinity. EXAMPLES

[0488] Comparison of hIL-11 mutant protein and antibody antagonism BaF3 cell line transfected with nucleic acids encoding human IL-11R and human gp130 Using the assay described above with 0.3 ng / ml human IL-11, several antibodies The antagonistic activity of hIL-11 mutein (containing SEQ ID NO: 110 and an N-terminal hexa The results are presented in Table 4. [Table 4]

[0489] The data presented in Table 4 showed that all of the antibodies tested were more potent than the hIL-11 mutant proteins. We also show that the mutant proteins and antibodies effectively inhibit IL-11 signaling. Due to the large difference in molecular weight between IC 50 Values ​​are expressed in nM. EXAMPLES

[0490] Epitope mapping Competitive ELISA and Biacore data show that 8E2, 8E4 and 8D10 inhibit hIL- These antibodies compete with each other for binding to hIL-11Rα and recognize the same region of hIL-11Rα. This indicates that.

[0491] Biacore data for domain swap (mouse / human) binding of 8E2 and 8D10 The amino acids 111 to 215 of hIL-11Rα (SEQ ID NO: 1) (Fn-type triplet domain) Main 1) is required, and replacing the mouse sequence with the human sequence in this region is It was shown to reduce the binding affinity of E4 (Table 5). [Table 5]

[0492] In the results presented in Table 5, references to "tight binding" refer to affinities of approximately 10 nM or less (K D ) References to "weak binding" refer to an affinity (K) of about 50 nM or greater. D )

[0493] by replacing native human amino acids with the corresponding mouse amino acid residues. It encompasses both the Ig-like domain of hIL-11Rα and fibronectin type 3 domain 1. 28 constructs were generated with single amino acid substitutions in the region. Five mutants of R (SEQ ID NO: 85) (P65S, K66R, L101S, V117E, A 178S) was expressed and purified (numbering relative to amino acid positions in SEQ ID NO: 1). The constructs were used to transfect cells which were then stained with 8E2, 8E4 and 8D10. Flow cytometry revealed that the binding of 8E2 and 8E10 was significantly correlated with the binding of V117E-transfected cells. It was shown that the expression level of β-lactamase was decreased in cells treated with β-lactamase.

[0494] Flow cytometry data was confirmed by Biacore. All of the sensorgrams were well fitted to a 1:1 binding model, but the derived K D Value Provided in Table 6.

[0495] The V117E mutant did not bind to 8E2 and 8D10 at the concentrations used in this assay. K of this interaction DThis residue is important for the binding of these two antibodies. Contribute to the interaction.

[0496] The K66R mutation was found to be identical to WT D1 / 2 (SEQ ID NO: 85) for antibodies 8E2 and 8D10. Compared to D The decrease in antibody binding This indicates some involvement of this residue in the

[0497] Mutants V117E and K66R also had significantly lower affinity than WT D1 / 2 (SEQ ID NO: 85). These residues bound to antibody 8E4 via the binding interaction with hIL-11Rα. This may contribute to the effect.

[0498] ANOVA and Tukey's multiple comparison test showed that the affinity of both V95E and K44R was All antibodies tested were significantly (p<0.0) higher than WT D1 / 2 (SEQ ID NO: 85). 5) showed that they were different.

[0499] All of the mutant forms of IL-11R examined in this example were able to bind IL-11. This means that the mutations did not induce substantial conformational changes in the receptor. This shows that. [Table 6] EXAMPLES

[0500] Comparison Data A non-neutralizing anti-IL-11R antibody (4D12; a commercially available antibody from Santa Cruz) ) was shown to bind to human IL-11Rα by ELISA. It was shown to bind to IL-11Rα-transfected BaF3 cells and express mouse IL-11 It was shown to bind to Rα-transfected 293 cells.

[0501] 4D12 was co-administered with 0.5 ng / ml hIL-11 or 3 ng / ml mIL-11R. Human or mouse IL-11-induced cell death in BaF3 cells incubated with It did not neutralize proliferation.

[0502] Competitive ELISA was used to compare the binding of 4D12 to IL-11Rα with that of 8D10 or 8E. It was shown that it does not compete with 2. EXAMPLES

[0503] Anti-IL-11R antibodies inhibit IL-11 signaling in cancer cells As shown in Figure 4, IL-11 inhibited the expression of IL-11 in DLD-1 colon cancer cells and MKN-28 gastric cancer cells. Figure 4 also shows that antibody 8E2 induces phosphorylation of STAT-3 in these cells. Inhibits phosphorylation of STAT-3 whereas an isotype control antibody does not show. The present invention includes the following embodiments. [1] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and said antigen-binding domain binds to hIL-11R and cynoIL-11Rα. The IL-11Rα binding protein is capable of [2] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. The protein neutralizes the I The IL-11R inhibits IL-11-mediated proliferation with an IC50 of 10 μg / ml or less. Alpha binding protein. [3] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and to the polypeptide of SEQ ID NO: 86 or 89 of the IL-11Rα binding protein. The level of binding of the IL-11Rα binding protein to the polypeptide of SEQ ID NO: 3 and / or SEQ ID NO: 85 The IL-11Rα-binding protein has a lower level of binding to a peptide. [4] The protein does not detectably bind to the polypeptide of SEQ ID NO: 86 or 89, An IL-11Rα binding protein as described in [3]. [5] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and said antigen-binding domain is a first fibronectin III domain of IL-11Rα. The IL-11Rα binding protein binds to an epitope that includes a residue within the IL-11Rα binding domain. [6] The epitope comprises an immunoglobulin-like domain of IL-11Rα and the first filtrate. The IL-11Rα-binding protein described in [5] above, which contains a residue in the pronectin III domain. Stuffy. [7] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and said protein (having a heavy chain comprising the sequence shown in SEQ ID NO: 83 and a heavy chain comprising the sequence shown in SEQ ID NO: 84) antibody 8E2 (containing a light chain having the sequence shown in SEQ ID NO: 92) and / or and a light chain comprising the sequence shown in SEQ ID NO: 91) antibody 8E4 and / or (sequence A heavy chain comprising the sequence shown in SEQ ID NO:94 and a light chain comprising the sequence shown in SEQ ID NO:93. competitively inhibiting the binding of antibody 8D10 to the polypeptides of SEQ ID NO: 3 and / or 85; IL-11Rα binding protein. [8] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and inhibiting the binding of said IL-11Rα binding protein to the polypeptide of SEQ ID NO:95. The level of binding of the IL-11Rα binding protein to the polypeptide of SEQ ID NO: 85 is The IL-11Rα binding protein is lower than the bell. [9] (a heavy chain comprising the sequence shown in SEQ ID NO: 83 and a light chain comprising the sequence shown in SEQ ID NO: 84) antibody 8E2 (containing a heavy chain having the sequence shown in SEQ ID NO: 92 and a heavy chain having the sequence shown in SEQ ID NO: 9 1) antibody 8E4 (containing a light chain having the sequence shown in SEQ ID NO: 94) and / or SEQ ID NO: 93 of antibody 8D10 (containing a heavy chain containing the sequence shown in SEQ ID NO: 94 and a light chain containing the sequence shown in SEQ ID NO: 95). The method according to the above [8], which competitively inhibits the binding of IL-3 and / or IL-85 to the polypeptide. 11Rα binding protein.

[10] The antigen-binding domain (i) a polypeptide of SEQ ID NO: 97 and / or (ii) a polypeptide of SEQ ID NO: 98, and / or (iii) a polypeptide of SEQ ID NO: 99 IL-11Rα-binding protein according to the above [8] or [9], which cross-reacts with

[11] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The IL-11 binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and wherein the antigen-binding domain is (i) at least about 40% to the sequence shown between amino acids 31 and 35 of SEQ ID NO: 37 100.degree. CDR 1 and amino acid 50 to 60 of SEQ ID NO:37, which are identical to each other. CDR2 comprising a sequence that is at least about 76% identical to a sequence set forth in any of the preceding claims. At least about 55% identical to the sequence shown between amino acids 99 and 107 of SEQ ID NO:37 and a VH comprising a CDR3 having a sequence identical to that of the VH; (ii) at least about 95%, 96%, or 97% relative to the sequence set forth in SEQ ID NO: 37 or a VH comprising a sequence that is 98% or 99% identical; (iii) at least about 4 amino acids 24 to 34 of SEQ ID NO:5 CDR1 containing a sequence that is 5% identical to amino acids 50 to 56 of SEQ ID NO:5 and CDR2 comprising the sequence shown between amino acids 89 to 97 of SEQ ID NO:5. and a VL comprising a CDR3 comprising a sequence that is at least about 44% identical; (iv) a V sequence having at least about 94% identity to the sequence set forth in SEQ ID NO:5; L; (v) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 74, and CDR2 comprising the sequence shown in amino acids 50 to 66 of SEQ ID NO: 74 and the amino acid sequence shown in SEQ ID NO: 74 and a VH having a CDR3 comprising a sequence represented by amino acids 99 to 115 of the sequence; (vi) a VH comprising the sequence set forth in SEQ ID NO: 74; (vii) CDR1 comprising a sequence represented by amino acids 23 to 36 of SEQ ID NO: 73; and CDR2 comprising the sequence shown in amino acids 52 to 58 of SEQ ID NO: 73 and and a VL comprising a CDR3 comprising the sequence set forth between amino acids 91 and 101; (viii) a VL comprising the sequence set forth in SEQ ID NO: 73; (ix) CDR1 comprising a sequence represented by amino acids 31 to 35 of SEQ ID NO: 76, and the sequence CDR2 comprising the sequence shown in SEQ ID NO: 76 between amino acids 50 and 66, and and a VH comprising a CDR3 comprising a sequence represented by amino acids 99 to 107; (x) a VH comprising the sequence set forth in SEQ ID NO: 76; (xi) CDR1 comprising a sequence represented by amino acids 24 to 34 of SEQ ID NO: 75, and the sequence CDR2 comprising the sequence shown in SEQ ID NO: 75 between amino acids 50 to 57, and and a VL comprising a CDR3 comprising the sequence set forth between amino acids 89 and 97; (xii) a VL comprising a sequence set forth in SEQ ID NO: 75; (xiii) VH designated in (i) and VL designated in (iii); (xiv) VH shown in (i) and VL shown in (iv); (xv) VH represented by (ii) and VL represented by (iii); (xvi) VH represented by (ii) and VL represented by (iv); (xvii) VH denoted by (v) and VL denoted by (vii); (xviii) VH designated (v) and VL designated (viii); (xix) VH represented by (vi) and VL represented by (vii); (xx) VH designated (vi) and VL designated (viii); (xxi) VH denoted by (ix) and VL denoted by (xi); (xxii) VH represented by (ix) and VL represented by (xii); (xxiii) VH represented by (x) and VL represented by (xi); or (xxiv) VH represented by (x) and VL represented by (xii); The IL-11Rα binding protein comprises at least one of the following:

[12] The antigen-binding domain, (i) a VH comprising a sequence as set forth in SEQ ID NO: 71 and a VL comprising a sequence as set forth in SEQ ID NO: 35 or (ii) a VH comprising the sequence set forth in SEQ ID NO: 72 and a V comprising the sequence set forth in SEQ ID NO: 36 L; the IL-11Rα binding protein described in

[0112] above.

[13] An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The IL-11 binding domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and said antigen-binding domain (i) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally for CDR1 VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains VL; (ii) a VH comprising the sequence shown in SEQ ID NO: 37 and a V comprising the sequence shown in SEQ ID NO: 5 L; (iii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 38 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (iv) VH comprising the sequence shown in SEQ ID NO: 38 and V comprising the sequence shown in SEQ ID NO: 5 L; (v) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 39 (optionally for CDR1 VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Contains VL; (vi) a VH comprising a sequence as set forth in SEQ ID NO: 39 and a V comprising a sequence as set forth in SEQ ID NO: 5 L; (vii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 40 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (viii) a VH comprising the sequence shown in SEQ ID NO: 40 and a VL comprising the sequence shown in SEQ ID NO: 5 MuVL; (ix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 41 (optionally corresponding to CDR1) VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 VL including; (x) a VH comprising a sequence shown in SEQ ID NO: 41 and a VL comprising a sequence shown in SEQ ID NO: 5 ; (xi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 42 (optionally corresponding to CDR1) VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 VL including; (xii) VH comprising the sequence shown in SEQ ID NO: 42 and the sequence shown in SEQ ID NO: 5 VL; (xiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 43 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xiv) VH comprising the sequence shown in SEQ ID NO: 43 and the sequence shown in SEQ ID NO: 5 VL; (xv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 44 (optionally corresponding to CDR1) VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 VL including; (xvi) VH comprising the sequence shown in SEQ ID NO: 44 and VH comprising the sequence shown in SEQ ID NO: 5 VL; (xvii) CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 45 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xviii) a VH comprising a sequence shown in SEQ ID NO: 45 and a sequence shown in SEQ ID NO: 5 Contains VL; (xix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 46 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (xx) VH comprising the sequence shown in SEQ ID NO: 46 and V comprising the sequence shown in SEQ ID NO: 5 L; (xxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 47 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (xxii) VH comprising the sequence shown in SEQ ID NO: 47 and VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (xxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 48 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xxiv) VH comprising the sequence shown in SEQ ID NO: 48 and VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (xxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 49 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (xxvi) VH comprising the sequence shown in SEQ ID NO: 49 and VL comprising the sequence shown in SEQ ID NO: 5 MuVL; (xxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 50 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xxviii) VH comprising a sequence shown in SEQ ID NO: 50 and a sequence shown in SEQ ID NO: 5 VL including; (xxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 51 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xxx) VH comprising the sequence shown in SEQ ID NO: 51 and VH comprising the sequence shown in SEQ ID NO: 5 VL; (xxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 52 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xxxii) a VH comprising a sequence shown in SEQ ID NO: 52 and a sequence shown in SEQ ID NO: 5 Contains VL; (xxxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 53 (optionally CD VH (including the amino acid N-terminal to R1) and CDR1 having the sequence shown in SEQ ID NO:5, VL, including 2 and 3; (xxxiv) a VH comprising a sequence shown in SEQ ID NO: 53 and a sequence shown in SEQ ID NO: 5 Contains VL; (xxxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 54 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xxxvi) a VH comprising a sequence shown in SEQ ID NO: 54 and a sequence shown in SEQ ID NO: 5 Contains VL; (xxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 55 (optionally VH (including the amino acid N-terminal to R1) and CDR1 having the sequence shown in SEQ ID NO:5, VL, including 2 and 3; (xxxviii) VH comprising the sequence shown in SEQ ID NO: 55 and the sequence shown in SEQ ID NO: 5 VL containing columns; (xxxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 56 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xl) VH comprising the sequence shown in SEQ ID NO: 56 and V comprising the sequence shown in SEQ ID NO: 5 L; (xli) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 57 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (xlii) a VH comprising the sequence shown in SEQ ID NO: 57 and a VL comprising the sequence shown in SEQ ID NO: 5 MuVL; (xliii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 58 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xliv) a VH comprising the sequence shown in SEQ ID NO: 58 and a VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (xlv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 59 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (xlvi) VH comprising the sequence shown in SEQ ID NO: 59 and VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (xlvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 60 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (xlviii) VH comprising a sequence shown in SEQ ID NO: 60 and a sequence shown in SEQ ID NO: 5 VL including; (xlix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 61 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (l) VH comprising the sequence shown in SEQ ID NO: 61 and VL comprising the sequence shown in SEQ ID NO: 5 ; (li) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 62 (optionally corresponding to CDR1) VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 VL including; (lii) a VH comprising the sequence shown in SEQ ID NO: 62 and a VH comprising the sequence shown in SEQ ID NO: 5 VL; (liii) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 63 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (liv) VH comprising the sequence shown in SEQ ID NO: 63 and VH comprising the sequence shown in SEQ ID NO: 5 VL; (lv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 64 (optionally against CDR1) VH (including the N-terminal amino acid) and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 VL including; (lvi) VH comprising the sequence shown in SEQ ID NO: 64 and VH comprising the sequence shown in SEQ ID NO: 5 VL; (lvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 65 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (lviii) a VH comprising a sequence shown in SEQ ID NO: 65 and a sequence shown in SEQ ID NO: 5 Contains VL; (lix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 66 (optionally including CDR1) VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (lx) VH comprising the sequence shown in SEQ ID NO: 66 and V comprising the sequence shown in SEQ ID NO: 5 L; (lxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 67 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (lxii) VH comprising the sequence shown in SEQ ID NO: 67 and VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (lxiii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 68 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (lxiv) VH comprising the sequence shown in SEQ ID NO: 68 and VH comprising the sequence shown in SEQ ID NO: 5 MuVL; (lxv) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 69 (optionally CDR1 VH (including the N-terminal amino acid to VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 VL including 3; (lxvi) VH comprising the sequence shown in SEQ ID NO: 69 and VL comprising the sequence shown in SEQ ID NO: 5 MuVL; (lxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 70 (optionally CDR VH (including the N-terminal amino acid of VH1) and CDR1, 2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (lxviii) VH comprising the sequence shown in SEQ ID NO: 37 and the sequence shown in SEQ ID NO: 5 VL including; (lxix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 70 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:5 and VL, including 3; (lxx) VH comprising the sequence shown in SEQ ID NO: 70 and VH comprising the sequence shown in SEQ ID NO: 5 VL; (lxxi) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO: 6 and VL, including 3; (lxxii) a VH comprising a sequence shown in SEQ ID NO: 37 and a sequence shown in SEQ ID NO: 6 Contains VL; (lxxiii) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally comprising CDR VH (including the amino acid N-terminal to R1) and CDR1 of the sequence shown in SEQ ID NO: 7, VL, including 2 and 3; (lxxiv) VH comprising the sequence shown in SEQ ID NO: 37 and the sequence shown in SEQ ID NO: 7 Contains VL; (lxxv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 VH (including the N-terminal amino acid of VH) and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO: 8 and VL, including 3; (lxxvi) a VH comprising the sequence shown in SEQ ID NO: 37 and a sequence shown in SEQ ID NO: 8 Contains VL; (lxxvii) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally VH (including the amino acid N-terminal to R1) and CDR1 of the sequence shown in SEQ ID NO: 9, VL, including 2 and 3; (lxxviii) VH comprising the sequence shown in SEQ ID NO: 37 and the sequence shown in SEQ ID NO: 9 VL containing columns; (lxxix) CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR VH having a sequence represented by SEQ I...

Claims

1. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and the antigen-binding domain binds to hIL-11R and cynoIL-11Rα. The IL-11Rα binding protein is capable of:

2. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. The protein inhibits IL-11Rα and gp130 expression in BaF3 cells. 11-mediated proliferation was suppressed by IC of 10 μg / ml or less. ５０ The IL-11Rα binding is inhibited by Synthetic protein.

3. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and binding of said IL-11Rα binding protein to the polypeptide of SEQ ID NO: 86 or 89. The level of the antibody is a polypeptide of SEQ ID NO: 3 and / or SEQ ID NO: 85 of the IL-11Rα binding protein. The IL-11Rα binding protein has a lower level of binding to tide.

4. 11. The method of claim 10, wherein the protein does not detectably bind to the polypeptide of SEQ ID NO: 86 or 89.

4. An IL-11Rα binding protein according to claim 3.

5. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and the antigen-binding domain is located within the first fibronectin III domain of IL-11Rα. The IL-11Rα binding protein binds to an epitope comprising residues of:

6. The epitope is an immunoglobulin-like domain of IL-11Rα and the first fibronectin. The IL-11Rα binding protein of claim 5, which comprises a residue within the nectin III domain. 。

7. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and the protein is a heavy chain comprising the sequence shown in SEQ ID NO:83 and a sequence shown in SEQ ID NO:

84. and / or antibody 8E2 (containing a light chain comprising the sequence shown in SEQ ID NO: 92) 91) antibody 8E4 and / or (SEQ ID NO: Antibody 8 comprising a heavy chain comprising the sequence shown in SEQ ID NO:94 and a light chain comprising the sequence shown in SEQ ID NO:93 The above-mentioned I competitively inhibits the binding of D10 to the polypeptides of SEQ ID NO: 3 and / or 85. L-11Rα binding protein.

8. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and determining the level of binding of said IL-11Rα binding protein to the polypeptide of SEQ ID NO:

95. the level of binding of said IL-11Rα binding protein to the polypeptide of SEQ ID NO:85 The lower the IL-11Rα binding protein.

9. (A heavy chain comprising the sequence shown in SEQ ID NO: 83 and a light chain comprising the sequence shown in SEQ ID NO: 84) and / or antibody 8E2 (containing a heavy chain having the sequence shown in SEQ ID NO: 92 and a heavy chain having the sequence shown in SEQ ID NO: 91) and / or antibody 8E4 (containing a light chain having the sequence shown in SEQ ID NO: 94) SEQ ID NO: 3 of antibody 8D10 and SEQ ID NO: 93 of antibody 8D10 The IL-11R polypeptide according to claim 8, which competitively inhibits the binding of IL-11R and / or IL-85 to the polypeptide of claim 8. Alpha binding protein.

10. The antigen-binding domain (i) a polypeptide of SEQ ID NO: 97 and / or (ii) a polypeptide of SEQ ID NO: 98 and / or (iii) a polypeptide of SEQ ID NO: 99 10. The IL-11Rα binding protein of claim 8 or 9, which cross-reacts with

11. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and wherein the antigen-binding domain comprises: (i) a sequence that is at least about 40% similar to the sequence set forth between amino acids 31 and 35 of SEQ ID NO:37; % identical to amino acids 50 to 60 of SEQ ID NO:

37. CDR2 comprising a sequence that is at least about 76% identical to a sequence set forth in any one of the preceding claims. At least about 55% identical to the sequence set forth between amino acids 99-107 of SEQ ID NO:37 and a V Ｈ ; (ii) at least about 95%, 96%, or 97% relative to the sequence set forth in SEQ ID NO: 37 or a V that contains a sequence that is 98% or 99% identical Ｈ ; (iii) at least about 4 amino acids to the sequence set forth in SEQ ID NO:5, CDR1 containing a sequence that is 5% identical to that shown between amino acids 50-56 of SEQ ID NO:5 and CDR2 comprising the sequence shown between amino acids 89-97 of SEQ ID NO:

5. and CDR3 comprising a sequence that is at least about 44% identical to Ｌ ; (iv) a V comprising a sequence that is at least about 94% identical to the sequence set forth in SEQ ID NO:5; Ｌ ； (v) a CDR1 comprising the sequence set forth between amino acids 31 and 35 of SEQ ID NO:74; and and a CDR2 comprising the sequence set forth between amino acids 50 to 66 of SEQ ID NO:74; and a VDR3 comprising the sequence shown between amino acids 99-115. Ｈ ; (vi) V comprising the sequence set forth in SEQ ID NO: 74 Ｈ ; (vii) a CDR1 comprising the sequence set forth between amino acids 23 and 36 of SEQ ID NO: 73; and a CDR2 comprising the sequence shown between amino acids 52-58 of SEQ ID NO:73; and CDR3 comprising the sequence shown between amino acids 91-101. Ｌ ; (viii) V comprising the sequence set forth in SEQ ID NO: 73 Ｌ ; (ix) a CDR1 comprising the sequence set forth between amino acids 31 and 35 of SEQ ID NO: 76; and the sequence A CDR2 comprising the sequence shown in SEQ ID NO: 76 between amino acids 50 and 66, and an A of SEQ ID NO: 76 and a CDR3 comprising the sequence shown between amino acids 99-107. Ｈ ; (x) a V having a sequence represented by SEQ ID NO: 76 Ｈ ; (xi) a CDR1 comprising the sequence set forth between amino acids 24 and 34 of SEQ ID NO: 75; and the sequence A CDR2 comprising the sequence shown between amino acids 50 to 57 of SEQ ID NO: 75 and an and a CDR3 comprising the sequence shown between amino acids 89-97. Ｌ ; (xii) a V having a sequence as set forth in SEQ ID NO: 75 Ｌ ; (xiii) V represented by (i) Ｈ and (iii) V Ｌ ; (xiv) V represented by (i) Ｈ and (iv) V Ｌ ; (xv) V represented by (ii) Ｈ and (iii) V Ｌ ; (xvi) V represented by (ii) Ｈ and (iv) V Ｌ ; (xvii) V represented by (v) Ｈ and (vii) V Ｌ ; (xviii) V represented by (v) Ｈ and (viii) V Ｌ ; (xix) (vi) V Ｈ and (vii) V Ｌ ; (xx) (vi) V Ｈ and (viii) V Ｌ ; (xxi) (ix) V Ｈ and V shown by (xi) Ｌ ; (xxii) (ix) V Ｈ and (xii) V Ｌ ; (xxiii) V represented by (x) Ｈ and V shown by (xi) Ｌ or (xxiv) V represented by (x) Ｈ and (xii) V Ｌ ; The IL-11Rα binding protein comprises at least one of the following:

12. The antigen-binding domain comprises: (i) a V comprising the sequence set forth in SEQ ID NO: 71 Ｈ and V comprising the sequence shown in SEQ ID NO:35 Ｌ or (ii) a V having a sequence as set forth in SEQ ID NO: 72 Ｈ and V comprising the sequence shown in SEQ ID NO:36 Ｌ 113. The IL-11Rα binding protein of claim 112, comprising:

13. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and the antigen-binding domain is (i) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (ii) a V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (iii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 38 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (iv) V comprising the sequence set forth in SEQ ID NO: 38 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (v) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 39 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (vi) V comprising the sequence set forth in SEQ ID NO: 39 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (vii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 40 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (viii) V comprising the sequence set forth in SEQ ID NO: 40 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (ix) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 41 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 V including Ｌ ; (x) a V having a sequence represented by SEQ ID NO: 41 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (xi) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 42 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 V including Ｌ ; (xii) V comprising the sequence shown in SEQ ID NO: 42 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (xiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 43 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xiv) V comprising the sequence shown in SEQ ID NO: 43 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (xv) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 44 (optionally including CDR1, (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 V including Ｌ ; (xvi) V comprising the sequence shown in SEQ ID NO: 44 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (xvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 45 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xviii) V comprising the sequence shown in SEQ ID NO: 45 Ｈ and the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (xix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 46 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xx) V comprising the sequence shown in SEQ ID NO: 46 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (xxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 47 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (xxii) V comprising the sequence set forth in SEQ ID NO: 47 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xxiii) CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 48 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (xxiv) V comprising the sequence set forth in SEQ ID NO: 48 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 49 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (xxvi) V comprising the sequence set forth in SEQ ID NO: 49 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 50 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (xxviii) V comprising the sequence set forth in SEQ ID NO: 50 Ｈ and the sequence shown in SEQ ID NO:5 V including Ｌ ; (xxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 51 (optionally including CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xxx) V comprising the sequence shown in SEQ ID NO:51 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (xxxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 52 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xxxii) V comprising the sequence set forth in SEQ ID NO:52 Ｈ and the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (xxxiii) comprises CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 53 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO:5, V including 2 and 3 Ｌ ; (xxxiv) V comprising the sequence set forth in SEQ ID NO:53 Ｈ and the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (xxxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 54 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xxxvi) V comprising the sequence shown in SEQ ID NO:54 Ｈ and the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (xxxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 55 (optionally comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 55) (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO:5, V including 2 and 3 Ｌ ; (xxxviii) V comprising the sequence set forth in SEQ ID NO:55 Ｈ and the sequence shown in SEQ ID NO:5 V containing columns Ｌ ; (xxxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 56 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (xl) V comprising the sequence set forth in SEQ ID NO:56 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (xli) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 57 (optionally in CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (xlii) V comprising the sequence set forth in SEQ ID NO:57 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xliii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 58 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (xliv) V comprising the sequence represented by SEQ ID NO:58 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xlv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO:59 (optionally in CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (xlvi) V comprising the sequence shown in SEQ ID NO:59 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (xlvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 60 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (xlviii) V comprising the sequence set forth in SEQ ID NO: 60 Ｈ and the sequence shown in SEQ ID NO:5 V including Ｌ ; (xlix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 61 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (l) V comprising the sequence shown in SEQ ID NO: 61 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (li) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 62 (optionally with respect to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 V including Ｌ ; (lii) V comprising the sequence set forth in SEQ ID NO: 62 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (liii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 63 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (liv) V comprising the sequence shown in SEQ ID NO:63 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (lv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 64 (optionally with respect to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 V including Ｌ ; (lvi) V comprising the sequence shown in SEQ ID NO: 64 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (lvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 65 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (lviii) V comprising the sequence set forth in SEQ ID NO: 65 Ｈ and the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (lix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 66 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (lx) V comprising the sequence shown in SEQ ID NO:66 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (lxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 67 (optionally in CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (lxii) V comprising the sequence set forth in SEQ ID NO:67 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (lxiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 68 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (lxiv) V comprising the sequence set forth in SEQ ID NO:68 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (lxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 69 (optionally in CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (lxvi) V comprising the sequence shown in SEQ ID NO:69 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (lxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 70 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:5 and V including 3 Ｌ ; (lxviii) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:5 V including Ｌ ; (lxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 70 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (lxx) V comprising the sequence shown in SEQ ID NO: 70 Ｈ and comprising the sequence shown in SEQ ID NO:5 V Ｌ ; (lxxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

6. V including 3 Ｌ ; (lxxii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:6 Includes V Ｌ ; (lxxiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 7, V including 2 and 3 Ｌ ; (lxxiv) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:7 Includes V Ｌ ; (lxxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

8. V including 3 Ｌ ; (lxxvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:8 Includes V Ｌ ; (lxxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO:9, V including 2 and 3 Ｌ ; (lxxviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:9 V containing columns Ｌ ; (lxxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 10, V including 2 and 3 Ｌ ; (lxxx) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO: 10 Includes V Ｌ ; (lxxxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 11, V including 2 and 3 Ｌ ; (lxxxii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:11 V containing columns Ｌ ; (lxxxiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally C (including the amino acids N-terminal to DR1) V Ｈ and the CDR of the sequence shown in SEQ ID NO: 12 V including 1, 2 and 3 Ｌ ; (lxxxiv) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:12 V containing columns Ｌ ; (lxxxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 13, V including 2 and 3 Ｌ ; (lxxxvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:13 V containing columns Ｌ ; (lxxxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally C (including the amino acids N-terminal to DR1) V Ｈ and the CDR of the sequence shown in SEQ ID NO: 14 V including 1, 2 and 3 Ｌ ; (lxxxviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and SEQ ID NO: 14 V containing the sequence Ｌ ; (lxxxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 15 , 2 and 3 Ｌ ; (xc) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:15 V Ｌ ; (xci) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally including CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

16. V including 3 Ｌ ; (xcii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO: 16 Includes V Ｌ ; (xciii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 17, V including 2 and 3 Ｌ ; (xciv) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO: 17 Includes V Ｌ ; (xcv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally in CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

18. V including 3 Ｌ ; (xcvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO: 18 Includes V Ｌ ; (xcvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 19, V including 2 and 3 Ｌ ; (xcviii) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO: 19 V containing columns Ｌ ; (xcix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO: 20 and V including 3 Ｌ ; (c) a V comprising the sequence shown in SEQ ID NO: 37 Ｈ and V comprising the sequence shown in SEQ ID NO:20 Ｌ ； (ci) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally with respect to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:21 V including 3 Ｌ ; (cii) a V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

21. MuV Ｌ ; (ciii) comprises CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:22 and V including 3 Ｌ ; (civ) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:22 MuV Ｌ ; (cv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally with respect to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:23 V including 3 Ｌ ; (cvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:23 MuV Ｌ ; (cvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:24 and V including 3 Ｌ ; (cviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:24 V including Ｌ ; (cix) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

25. V including 3 Ｌ ; (cx) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:25 V Ｌ ; (cxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

26. V including 3 Ｌ ; (cxii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:26 Includes V Ｌ ; (cxiii) comprises CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 27, V including 2 and 3 Ｌ ; (cxiv) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:27 Includes V Ｌ ; (cxv) comprising CDR1, 2 and 3 of the sequence shown in SEQ ID NO: 37 (optionally in CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

28. V including 3 Ｌ ; (cxvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:28 Includes V Ｌ ; (cxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR (including the N-terminal amino acid for 1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 29, V including 2 and 3 Ｌ ; (cxviii) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:29 V containing columns Ｌ ; (cxix) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO: 30 and V including 3 Ｌ ; (cxx) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

30. MuV Ｌ ; (cxxi) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:31 and V including 3 Ｌ ; (cxxii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:31 V including Ｌ ; (cxxiii) comprises CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 32 , 2 and 3 Ｌ ; (cxxiv) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:32 V including Ｌ ; (cxxv) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:33 and V including 3 Ｌ ; (cxxvi) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:33 V including Ｌ ; (cxxvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally comprising CDR (including the amino acid N-terminal to R1) V Ｈ and CDR1 of the sequence shown in SEQ ID NO: 34 , 2 and 3 Ｌ or (cxxviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and SEQ ID NO:34 V containing the sequence Ｌ IL-11Rα binding protein comprising:

14. An IL-11Rα binding protein comprising an antigen-binding domain of an antibody, The domain binds or specifically binds to IL-11Rα and mediates IL-11 signal transduction. and the antigen-binding domain is (i) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 49 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (ii) a V having a sequence as set forth in SEQ ID NO: 49 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (iii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 53 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (iv) V comprising the sequence set forth in SEQ ID NO:53 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (v) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 57 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (vi) V comprising the sequence shown in SEQ ID NO:57 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (vii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 58 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (viii) V comprising the sequence set forth in SEQ ID NO:58 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (ix) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:8 V including Ｌ ; (x) a V comprising the sequence shown in SEQ ID NO: 37 Ｈ and V comprising the sequence shown in SEQ ID NO:8 Ｌ ； (xi) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1, (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO: 15 V including 3 Ｌ ; (xii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

15. MuV Ｌ ; (xiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO: 16 and V including 3 Ｌ ; (xiv) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:16 MuV Ｌ ; (xv) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:18 V including 3 Ｌ ; (xvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

18. MuV Ｌ ; (xvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:29 and V including 3 Ｌ or (xviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:29 V including Ｌ IL-11Rα binding protein comprising:

15. At least the heavy chain variable region (V Ｈ ) and the light chain variable region (V Ｌ ) and V Ｈ and V Ｌ but combine to form an Fv comprising an antigen-binding domain, Ｈ and V Ｌ in a single polypeptide chain or Ｈ and V Ｌ Any one of claims 1 to 14, wherein 3. An IL-11Rα binding protein according to claim 1.

16. The V Ｈ and V Ｌ is in a single polypeptide chain, the protein is (i) single chain Fv fragment (scFv); (ii) dimeric scFv (di-scFv); (iii) the constant region of an antibody, Fc or heavy chain constant domain (C Ｈ ) 2 and / or C Ｈ 3 or one of (i) or (ii) linked to (iv) (i) or (ii) linked to a protein that binds to an immune effector cell ) or The V Ｈ and V Ｌ is in a separate polypeptide chain, the protein (i) bispecific antibody; (ii) trispecific antibody; (iii) tetraspecific antibody; (iv) Fab; (v)F(ab’) ２ ; (vi) Fv (vii) the constant region of an antibody, Fc or heavy chain constant domain (C Ｈ ) 2 and / or C Ｈ 3 one of (i)-(vi) linked to (viii) (i)-(vi) linked to a protein that binds to an immune effector cell or (ix) an antibody;

17. An antibody that binds to IL-11Rα and neutralizes IL-11 signal transduction, The antibody, (i) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 49 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (ii) a V having a sequence as set forth in SEQ ID NO: 49 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (iii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 53 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO:5 V including 3 Ｌ ; (iv) V comprising the sequence set forth in SEQ ID NO:53 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (v) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 57 (optionally with respect to CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:5 Includes V Ｌ ; (vi) V comprising the sequence shown in SEQ ID NO:57 Ｈ and V comprising the sequence shown in SEQ ID NO:5 Ｌ ； (vii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 58 (optionally including CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:

5. V including 3 Ｌ ; (viii) V comprising the sequence set forth in SEQ ID NO:58 Ｈ and comprising the sequence shown in SEQ ID NO:

5. MuV Ｌ ; (ix) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and 3 of the sequence shown in SEQ ID NO:8 V including Ｌ ; (x) a V comprising the sequence shown in SEQ ID NO: 37 Ｈ and V comprising the sequence shown in SEQ ID NO:8 Ｌ ； (xi) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including CDR1, (including the N-terminal amino acid) V Ｈ and CDR1, 2 and the sequence shown in SEQ ID NO: 15 V including 3 Ｌ ; (xii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

15. MuV Ｌ ; (xiii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO: 16 and V including 3 Ｌ ; (xiv) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:16 MuV Ｌ ; (xv) a sequence comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally including a sequence corresponding to CDR1) (including the N-terminal amino acid) V Ｈ and CDR1, 2 and CDR2 of the sequence shown in SEQ ID NO:18 V including 3 Ｌ ; (xvi) V comprising the sequence shown in SEQ ID NO: 37 Ｈ and comprising the sequence shown in SEQ ID NO:

18. MuV Ｌ ; (xvii) comprising CDR1, 2 and 3 of the sequence set forth in SEQ ID NO: 37 (optionally CDR1 (including the N-terminal amino acid) V Ｈ and CDR1, 2 of the sequence shown in SEQ ID NO:29 and V including 3 Ｌ or (xviii) V comprising the sequence set forth in SEQ ID NO: 37 Ｈ and the sequence shown in SEQ ID NO:29 V including Ｌ ;

18. The IL-11Rα binding protein according to any one of claims 1 to 16, which is conjugated to another compound. A protein or an antibody described in claim 17.

19. The IL-11Rα binding protein according to any one of claims 1 to 16 or claim 17 A nucleic acid encoding the antibody or its polypeptide described in .

20. 20. An expression construct comprising the nucleic acid of claim 19.

21. The IL-11Rα binding protein according to any one of claims 1 to 16 or claim 17 An isolated or recombinant cell expressing the antibody described in.

22. The IL-11Rα binding protein or the IL-11Rα binding protein according to any one of claims 1 to 16 or 18.

19. A composition comprising the antibody of claim 17 or 18 and a pharma- ceutically acceptable carrier.

23. A method for treating or preventing a disease mediated by IL-11 in a subject, comprising administering to a subject a composition comprising the compound of any one of claims 1 to 16. or 18, or the IL-11Rα binding protein according to claim 17 or 18. The method comprises administering an antibody described in claim 22 or a composition described in claim 23.

24. A method of contraception in a subject, comprising administering to a subject an IL-1 or IL-2 inhibitor according to any one of claims 1 to 16 or 18. -11Rα binding protein or the antibody according to claim 17 or 18 or the antibody according to claim 22 The method comprising administering a composition.

25. The IL-11Rα binding protein or the IL-11Rα binding protein according to any one of claims 1 to 16 or 18.

23. Use of an antibody according to claim 17 or 18 or a composition according to claim 22 in medicine.

26. The use of any one of claims 1 to 16 or 1 in the manufacture of a medicament for treating a disease mediated by IL-11. 8 or the IL-11Rα binding protein according to claim 17 or 18. Use of antibodies.

27. Any of claims 1 to 16 or 18 for use in the treatment of a disease mediated by IL-11 1 or the antibody or antibody according to claim 17 or 18.

23. The composition of claim 22.

28. Methods for localizing IL-11-mediated diseases associated with cells expressing IL-11Rα and and / or detection methods and / or diagnostic methods and / or prognostic methods, if any The IL-11Rα-binding protein according to claim 18, which is bound to a cell expressing IL-11Rα.

19. A method for detecting the IL-11Rα protein or the antibody according to claim 18 in vivo. The method, wherein the binding protein or antibody is conjugated to a detectable tag.

29. The method further comprises administering to a subject said IL-11Rα binding protein or antibody.

29. The method according to item 28.

30. A method for detecting IL-11Rα or cells expressing it in a sample, comprising: The sample is subjected to the IL-11Rα binding tag according to any one of claims 1 to 16 or 18 so as to obtain and detecting the complex. and detecting the complex in the sample. The method further comprising:

31. A method for diagnosing or prognosing a disease mediated by IL-11Rα, comprising the steps of: and detecting IL-11Rα or a cell expressing same by carrying out the method described above. The detection of IL-11Rα or cells expressing it is diagnostic or prognostic of the disease. How to write.

32. The IL-11 mediated disease is an autoimmune disease, an inflammatory disease, a wasting disease, 32. The method of claim 23, 28 or 31, which is a bone disease or cancer.

26. An IL-11Rα binding protein or a method for the use according to claim 27. is an antibody or composition.

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