RELATED APPLICATION DATA

The present application claims priority from Australian Patent Application No. 2015904924 entitled "CD 131 binding proteins and uses thereof filed on 27 November 2015. The entire contents of which is hereby incorporated by reference.

SEQUENCE LISTING

The present application is filed with a Sequence Listing in electronic form. The entire contents of the Sequence Listing are hereby incorporated by reference.

FIELD

The present disclosure relates to CD 131 -binding proteins and compounds and uses thereof.

BACKGROUND

The pleiotropic cytokines interleukin (IL)-3 (IL-3), IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) play critical and overlapping roles in the differentiation and function of myeloid cells. They are important mediators of host defense and innate immunity, but can also contribute significantly to the development and progression of inflammatory pathologies including inflammatory airway diseases such as asthma, chronic rhinosinusitis with and without nasal polyposis (CRSwNP, CRSsNP), chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap syndrome (ACOS). GM-CSF has also been implicated in autoimmune conditions, such as rheumatoid arthritis and IL-3 has been implicated in conditions, such as leukemia. In asthma and COPD, GM-CSF expression is elevated in sputum, bronchoalveolar lavage fluid (BALF) and bronchial biopsies. IL-3 acts at the early stages of hematopoiesis and synergizes with other growth factors for hemopoietic development. It also modulates the activity of mature cell types such as monocytes, dendritic cells, megakaryocytes, mast cells and can activate eosinophils and prime basophils to release histamine. A growth factor for basophils, increased levels of IL-3 in BALF are typically present after allergen challenge. IL-5 is more cell type- specific, regulating the production and release of mature eosinophils from the bone marrow into the circulation. Elevated levels of IL-5 have been found in the serum and airway fluid of patients with asthma. In asthmatic subjects, IL-5 inhalation increased AHR as well as the recruitment of activated eosinophils to the airways.

Each of IL-3, IL-5 and GM-CSF all signal through a multimeric receptor made up of a common β chain (β0 chain or CD 131) and a cytokine specific a chain.

As a consequence of the evidence supporting a key role for cells of the myeloid lineage and IL-3, IL-5 and GM-CSF in the development and progression of inflammatory airway disease, a number of therapeutic antibodies targeting individual cytokines or receptor a-chains are in clinical development. While these agents may prove useful in selected subsets of patients it is likely that their broader application will be limited by both the redundant and overlapping function of the molecules that they target and by the variable nature of the inflammatory cell infiltrate that can underpin asthma. For example, studies of the anti-IL-5 antibody mepolizumab have shown that targeting only IL-5 has no effects on airway obstruction or airway hyperresponsiveness in patients with asthma.

It will be clear to the skilled artisan based on the foregoing that there is a need in the art for compounds (e.g., antibodies and antibody-derived proteins) that can treat conditions mediated by IL-3, IL-5 and/or GM-CSF.

SUMMARY

In producing the present invention, the inventors sought to produce reagents (e.g., antibodies and proteins comprising antigen binding domains thereof) that bind to CD131 and neutralize signaling by IL-3, IL-5 and GM-CSF. The inventors produced a series of antibodies having such activity, some of which potently neutralize signaling by IL-3, IL-5 and GM-CSF, e.g., prevent proliferation of TF-1 cell in response to each of those cytokines amongst numerous other assays. The inventors also performed epitope mapping and found that the antibodies bound to CD 131 within a region designated "Site 2" and also found that certain residues within Site 2 which are important for binding of IL-3, IL-5 and GM-CSF are also important for binding of the antibodies.

The inventors additionally showed that an antibody they had produced was capable of reducing survival of inflammatory cells from human subjects suffering from airway disease (e.g., asthma and/or nasal polyposis). This suppression in survival of inflammatory cells was greater than that observed using the current standard of care for inflammatory airway diseases, such as asthma (i.e., prednisolone). Using a xenograft model of nasal polyposis, the inventors showed that an antibody they produced reduced the size and weight of polyps and the number of B cells infiltrating polyps compared to a control antibody

The inventors also showed that neutralizing signaling of IL-3, IL-5 and GM-CSF is an effective manner of reducing survival of eosinophils, e.g., to treat eosinophilia. This was shown using an antibody of the disclosure that binds to CD131 or using a combination of antibodies against each of IL-3Ra, IL-5R and GM-CSF-R. While the combination of antibodies was effective in reducing survival of eosinophils, the antibody of the disclosure was more effective.

Based on the foregoing, it will be apparent to the skilled artisan that the inventors have produced a protein comprising an antigen binding domain of an antibody, the antigen binding domain capable of binding to or specifically binding to CD131 and neutralizing IL-3, IL-5 and GM-CSF signaling. The inventors have also produced methods for treating various conditions and/or reducing survival of eosinophils by neutralizing IL-3, IL-5 and GM-CSF signaling, e.g., using a protein of the disclosure.

In one example, the present disclosure provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD 131 -binding protein inhibits GM-CSF-induced proliferation of TF-1 erythroleukemic cells with an IC50 of at least 700nM.

In one example, the CD 131 -binding protein inhibits GM-CSF-induced proliferation of TF-1 cells with an IC50 of at least 600nM or 500nM. For example, the IC50 is at least about 460nM. For example, the IC50 is at least about 300nM or 200nM or ΙΟΟηΜ. For example, the IC50 is at least about 460nM. For example, the IC50 is at least about ΙΟηΜ or 5nM or InM. In one example, the IC50 is at least about InM. For example, the IC50 is at least about 0.9nM or 0.8nM or 0.6nM. In one example, the IC50 is at least about 0.5nM. In one example, the IC50 is at least about 0.4nM. In one example, the IC50 is at least about 0.3nM.

In one example, the CD131-binding protein inhibits IL-3-induced proliferation of TF-1 cells with an IC50 of at least 600nM or 500nM. For example, the IC50 is at least about 460nM. For example, the IC50 is at least about 300nM or 200nM or ΙΟΟηΜ. For example, the IC50 is at least about ΙΟηΜ or 5nM or InM. In one example, the IC50 is at least about InM. For example, the IC50 is at least about 0.9nM or 0.8nM or 0.6nM. In one example, the IC50 is at least about 0.5nM. In one example, the IC50 is at least about 0.2nM or at least about 0. InM. In one example, the IC50 is at least about 0.15nM.

In one example, the CD 131 -binding protein inhibits IL-5-induced proliferation of TF-1 cells with an IC50 of at least 600nM or 500nM. For example, the IC50 is at least about 460nM. For example, the IC50 is at least about 300nM or 200nM or ΙΟΟηΜ. For

example, the IC50 is at least about ΙΟηΜ or 5nM or InM. In one example, the IC50 is at least about 5nM. For example, the IC50 is at least about 4nM. In one example, the IC50 is at least about 4.5nM or at least about 4.6 or at least about 4.7nM. In one example, the IC50 is at least about 4.6nM.

Methods for determining the IC50 include culturing TF-1 cells (e.g., about lxlO4

TF-1 cells) in the presence of the CD131-binding protein (e.g., for at least about 3 minutes or 1 hour, such as about 30 minutes) prior to adding the relevant growth factor (GM-CSF, IL-3 and/or IL-5) and culturing the cells further (e.g., for at least about 48 hours or at least about 72 hours or at least about 96 hours, e.g., for about 72 hours) and then determining cell proliferation. Cell proliferation can be determined by growing the cells in the presence of 3 [H] -thymidine for about 6 hours and determining 3 [H]-thymidine incorporation, e.g., by liquid- scintillation counting. By determining proliferation in a variety of concentrations of the CD 131 -binding protein an IC50 can be determined.

In one example, the present disclosure provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF to a degree greater than antibody BION-1 (as disclosed in Sun et ah, Blood, 94: 1943-1951, 1999).

The present disclosure additionally provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to an epitope within Site 2 of CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF. In this regard, the skilled artisan will be aware that Site 2 of CD131 is made up of residues from two CD131 polypeptides that form a dimer, e.g., Site 2 comprises residues within loops A-B and E-F of domain 1 of one CD131 polypeptide and residues within loops B-C and F-G of another CD131 polypeptide.

In one example, the antigen binding domain binds to an epitope formed upon dimerization of two CD 131 polypeptides. For example, the antigen binding domain binds to residues within domain 1 of a CD 131 polypeptide and residues within domain 4 of another CD 131 polypeptide.

In one example, the antigen binding domain binds to an epitope comprising one or more of amino acids corresponding to residues 39 and/or 103 of SEQ ID NO: 1.

In another example, the antigen binding domain binds to an epitope comprising one or more of amino acids corresponding to residues 338, 365, 367 and 368 of SEQ ID NO: 1.

In a further example, the antigen binding domain binds to an epitope formed upon dimerization of two CD 131 polypeptides, wherein the epitope comprises one or more (or all) of amino acids corresponding to residues 39 and 103 of one CD131 polypeptide and residues 338, 365, 367 and 368 of the other CD131 polypeptide.

In another example, present disclosure provides a CD 131 -binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to an epitope within Site 2 of CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, wherein the antigen binding domain binds to an epitope comprising amino acids involved in binding of IL-3, IL-5 and/or GM-CSF to CD131. For example, the amino acids correspond to residues 39, 103, 338, 365, 367 and 368 of SEQ ID NO: 1. For example, the amino acid corresponds to residue 39 of SEQ ID NO: 1. For example, the residues correspond to residues 39 and 103 of one CD131 polypeptide and residues 338, 365, 367 and 368 of another CD131 polypeptide. For example, the residues correspond to residue 39 of one CD131 polypeptide and residue 365 and/or residue 367 of another CD131 polypeptide.

The present disclosure additionally provides a compound that binds to or specifically binds to an epitope within Site 2 of CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF. For example, the compound binds to an epitope formed upon dimerization of two CD131 polypeptides. For example, the compound binds to residues within domain 1 of a CD 131 polypeptide and residues within domain 4 of another CD 131 polypeptide.

In one example, the compound binds to an epitope comprising one or more of amino acids corresponding to residues 39 and/or 103 of SEQ ID NO: 1.

In another example, the compound binds to an epitope comprising one or more of amino acids corresponding to residues 365 and 367 of SEQ ID NO: 1.

In another example, the compound binds to an epitope comprising one or more of amino acids corresponding to residues 338, 365, 367 and 368 of SEQ ID NO: 1.

In a further example, the compound binds to an epitope formed upon dimerization of two CD 131 polypeptides, wherein the epitope comprises one or more (or all) of amino acids corresponding to residues 39 and 103 of one CD131 polypeptide and residues 338, 365, 367 and 368 of the other CD131 polypeptide.

The present disclosure also provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein binds to one or more (or all) of the following mutant polypeptide(s):

(i) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 119

(ii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 123

(iii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 124

(iv) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 135 (v) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 131

(vi) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 136

(vii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 137

(viii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 139

(ix) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 145, at a level that is reduced compared to the level of binding of the CD 131 -binding protein to a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

The present disclosure also provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein binds to a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 137 at a level that is reduced compared to the level of binding of the CD131-binding protein to a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

The present disclosure also provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein binds to a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 139 at a level that is reduced compared to the level of binding of the CD131-binding protein to a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

In one example, the level of binding (e.g., as determined by KD) of the CD131-binding protein to the mutant polypeptide is reduced by at least about 3 fold or 4 fold or 5 fold or 10 fold. For example, the level of binding to the mutant polypeptide is reduced by at least about 20 fold or 50 fold or 100 fold.

In one example, the affinity (KD) of the CD 131 -binding protein for the mutant polypeptide is about 4xl0"6 or greater, e.g., 4.5xl0"6 or lxlO"5.

In one example, the disclosure provides a CD 131 -binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein preferentially binds to binds to polypeptide

comprising a sequence set forth in SEQ ID NO: 192 compared to one or more (or all) of the following mutant polypeptide(s):

(i) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 119;

(ii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 124;

(iii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 131;

(iv) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 137;

(v) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 139; or

(vi) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 140.

In one example, the CD 131 -binding protein does not detectably bind or does not significantly bind to the mutant polypeptide. For example, the CD131-binding protein does not detectably bind to does not significantly bind to one or more of the following mutant polypeptide(s):

(i) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 119;

(ii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 124;

(iii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 131; or

(iv) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 137.

In one example, a CD131-binding protein of the disclosure binds to or cross-reacts with a polypeptide comprising a sequence set forth in any one of SEQ ID NOs: 117, 118, 120-123, 125-130, 132-136, 138 or 140-148.

In one example, a CD131-binding protein of the disclosure binds to a polypeptide comprising a sequence set forth in SEQ ID NO: 127 with a higher affinity than it does to a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

In one example, a CD131-binding protein of the disclosure binds to or cross-reacts with one or more of the following mutant polypeptide(s):

(i) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 135;

(ii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 136; and/or

(iii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 138.

The present disclosure also provides a compound that binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the compound binds to one or more (or all) of the following mutant polypeptide(s):

(i) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 119;

(ii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 124;

(iii) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 131;

(iv) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 137;

(v) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 139;

(vi) a mutant polypeptide comprising a sequence set forth in SEQ ID NO: 140, at a level that is reduced compared to the level of binding of the compound to a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

Methods for determining binding of a CD131-binding protein to a polypeptide will be apparent to the skilled artisan. For example, the polypeptide is immobilized on a solid or semi-solid surface and the CD131-binding protein is contacted to the immobilized polypeptide. Binding is then determined, e.g., by surface plasmon resonance.

The present disclosure additionally provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein competitively inhibits binding of antibody 9A2 (comprising a VL comprising a sequence set forth in SEQ ID NO: 5 and a VH comprising a sequence set forth in SEQ ID NO: 20) to CD131 and/or a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

In one example, the present disclosure provides a CD 131 -binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein competitively inhibits binding of antibody 9A2 (comprising a VL comprising a sequence set forth in SEQ ID NO: 5 and a human kappa light chain constant region and a VH comprising a sequence set forth in SEQ ID NO: 20 and a human IgG4 constant region) to CD131 and/or a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

The present disclosure additionally provides a CD 131 -binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the CD131-binding protein competitively inhibits binding of antibody 9A2 (comprising a light chain comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain comprising a sequence set forth in SEQ ID NO: 20) to CD131 and/or a polypeptide comprising a sequence set forth in SEQ ID NO: 192.

The present disclosure additionally provides a compound that binds to or specifically binds to CD131 and neutralizes signaling by IL-3, IL-5 and GM-CSF and competitively inhibits binding of one or more of the following antibodies to CD 131 and/or a polypeptide comprising a sequence set forth in SEQ ID NO: 192:

(i) an antibody comprising a VL comprising a sequence set forth in SEQ ID NO: 5 and a VH comprising a sequence set forth in SEQ ID NO: 20;

(ii) an antibody comprising a VL comprising a sequence set forth in SEQ ID NO: 5 and a human kappa light chain constant region and a VH comprising a sequence set forth in SEQ ID NO: 20 and a human IgG4 constant region; and/or

(iii) an antibody comprising a light chain comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain comprising a sequence set forth in SEQ ID NO: 20.

The present disclosure additionally or alternatively provides a CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by IL-3, IL-5 and GM-CSF, and wherein the antigen binding domain comprises at least one of:

(i) a VH comprising a complementarity determining region (CDR) 1 comprising a sequence at least about 40% identical to a sequence set forth between amino acids 26-35 of SEQ ID NO: 20, a CDR2 comprising a sequence at least about 65% identical to a sequence set forth between amino acids 50-66 of SEQ ID NO: 20 and a CDR3 comprising a sequence at least about 44% identical to a sequence set forth between amino acids 99-106 of SEQ ID NO: 20;

(ii) a VH comprising a sequence at least about 89% or 90% or 91% or 92% or 93% or 94% or 95% or 96% or 97% or 98% or 99% identical to a sequence set forth in any one of SEQ ID NOs: 20, 25, 37, 59, 63, 64, 65, 68, 69, 72 or 101;

(iii) a VL comprising a CDR1 comprising a sequence at least about 45% identical to a sequence set forth between amino acids 24-34 of SEQ ID NO: 5, a CDR2 comprising a sequence set forth between amino acids 44-51 of SEQ ID NO: 5 and a CDR3 comprising a sequence at least about 44% identical to a sequence set forth between amino acids 89-97 of SEQ ID NO: 5;

(iv) a VL comprising a sequence at least about 94% or 95% or 96% or 97% or 98% or 99% identical to a sequence set forth in SEQ ID NO: 5;

(v) a VH comprising a CDR1 comprising a sequence set forth between amino acids 26-35 of SEQ ID NO: 180, a CDR2 comprising a sequence set forth between amino acids 50-66 of SEQ ID NO: 180 and a CDR3 comprising a sequence set forth between amino acids 99-106 of SEQ ID NO: 180;

(vi) a VH comprising a sequence set forth in SEQ ID NO: 180;

(vii) a VL comprising a CDR1 comprising a sequence set forth between amino acids 24-34 of SEQ ID NO: 177, a CDR2 comprising a sequence set forth between amino acids 44-51 of SEQ ID NO: 177 and a CDR3 comprising a sequence set forth between amino acids 89-97 of SEQ ID NO: 177;

(viii) a VL comprising a sequence set forth in SEQ ID NO: 177;

(ix) a VL comprising an amino acid sequence set forth in SEQ ID NO: 5;

(x) a VH as set forth in (i) and a VL as set forth in (iii);

(xi) a VH as set forth in (i) and a VL as set forth in (iv);

(xii) a VH as set forth in (i) and a VL as set forth in (ix);

(xiii) a VH as set forth in (ii) and a VL as set forth in (iii);

(xiv) a VH as set forth in (ii) and a VL as set forth in (iv);

(xv) a VH as set forth in (ii) and a VL as set forth in (ix);

(xvi) a VH as set forth in (v) and a VL as set forth in (vii);

(xvii) a VH as set forth in (v) and a VL as set forth in (viii);

(xviii) a VH as set forth in (v) and a VL as set forth in (ix);

(xix) a VH as set forth in (vi) and a VL as set forth in (vii);

(xx) a VH as set forth in (vi) and a VL as set forth in (viii); or

(xxi) a VH as set forth in (vi) and a VL as set forth in (ix).

In one example, reference in the foregoing paragraph(s) to CDRs within a defined sequence (i.e., SEQ ID NO) will be understood as follows:

• For a VH, CDRl is between amino acids 26-35; CDR2 is between amino acids 50-66; and CDR3 is between amino acids 99-106; and

• For a VL, CDRl is between amino acids 24-34; CDR2 is between amino acids 44-51; and CDR3 is between amino acids 89-97.

In one example, the antigen binding domain comprises a VH comprising a sequence set forth in SEQ ID NO: 193 and a VL comprising a sequence set forth in SEQ ID NO: 5.

CLAIMS:

1. A CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), and wherein the CD131-binding protein inhibits GM-CSF-induced proliferation of TF-1 erythroleukemic cells with an IC50 of at least 700nM.

2. A CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to an epitope within site 2 of CD 131 and neutralizes signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF).

3. The CD131-binding protein of claim 2, wherein the antigen binding domain binds to an epitope formed upon dimerization of two CD 131 polypeptides.

4. The CD131-binding protein of claim 3, wherein the antigen binding domain binds to residues within domain 1 of a CD 131 polypeptide and residues within domain 4 of another CD 131 polypeptide.

5. A CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), and wherein the CD131-binding protein binds to one or more (or all) of the following mutant polypeptide(s):
6. The CD 131 -binding protein of claim 5, wherein the CD 131 -binding protein does not detectably bind to the mutant polypeptide.

7. A CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), and wherein the CD131-binding protein competitively inhibits binding of antibody 9A2 (comprising a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 20).

8. A CD131-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain binds to or specifically binds to CD 131 and neutralizes signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), and wherein the antigen binding domain comprises at least one of: 9. The CD131-binding protein of claim 8, wherein the antigen binding domain comprises a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 193 and a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5.17. The CD 131 -binding protein of any one of claims 1 to 14 or the antibody of claim 15 or 16, which is conjugated to another compound.

18. A nucleic acid encoding the CD 131 -binding protein of any one of claims 1 to 14 or the antibody of claim 15 or 16 or a polypeptide thereof.

19. An expression construct comprising the nucleic acid of claim 18.

21. An isolated or recombinant cell expressing the CD131-binding protein of any one of claims 1 to 14 or the antibody of claim 15 or 16.

22. A composition comprising a CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 and a pharmaceutically acceptable carrier.

23. A method for treating or preventing a CD131-mediated condition in a subject, the method comprising administering the CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 or the composition of claim 22.

24. Use of the CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 or the composition of claim 22 in medicine.

25. Use of the CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 in the manufacture of a medicament to treat a CD131-mediated condition.

26. The CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 or the composition of claim 22 for use in the treatment of a CD131-mediated condition.

27. A method for localizing and/or detecting and/or diagnosing and/or prognosing a CD131-mediated condition associated with a cell expressing CD131, the method comprising detecting in vivo the CD 131 -binding protein of claim 17 or the antibody of claim 17 bound to the CD131 expressing cell, if present, wherein the CD131-binding protein or antibody is conjugated to a detectable tag.

28. The method of claim 27 additionally comprising administering the CD 131-binding protein or antibody to the subject.

29. A method for detecting CD131 or a cell expressing same in a sample, the method comprising contacting the sample with the CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 such that a complex forms and detecting the complex, wherein detection of the complex is indicative of CD131 or a cell expressing same in the sample.

30. A method for diagnosing or prognosing a CD131-mediated condition, the method comprising performing the method of claim 29 to detect CD131 or a cell expressing same in a sample from a subject, wherein detection of the CD 131 or cell expressing same is diagnostic or prognostic of the condition.

31. The method of any one of claims 23, 27 or 30 or the use of claim 25 or the CD 131-binding protein or the antibody or the composition for use of claim 26, wherein the

CD131-mediated condition is an autoimmune condition, an inflammatory condition, an allergic condition or cancer.

32. A method for depleting or reducing eosinophils in a subject, the method comprising neutralizing signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in a subject.

33. A method of treating eosinophilia in a subject, the method comprising neutralizing signaling by interleukin (IL) 3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in the subject.

34. The method of claim 32 or 33 comprising administering one or more inhibitors of IL-3 and/or IL-5 and/or GM-CSF.

35. The method of any one of claims 32 to 34 comprising administering the CD131-binding protein of any one of claims 1 to 14 or 17 or the antibody of any one of claims 15 to 17 or the composition of claim 22.