Methods for preventing or treating certain disorders by inhibiting binding of IL-4 and/or IL-13 to their respective receptors

1. A method of treating or ameliorating a disorder associated with an increase of the Th2 immune response, comprising administering to a subject in need thereof a composition comprising a mutein of human tear lipocalin, or a fragment, variant, fusion protein or conjugate thereof, wherein said mutein, or fragment, variant, fusion protein or conjugate thereof, is capable of exhibiting in vivo therapeutic activity in the subject, and wherein said mutein, or fragment or variant thereof has at least 90% identity to an amino acid sequence set forth in SEQ ID NO: 6.

2. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, binds to IL-4 receptor alpha chain.

3. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is cross-reactive with marmoset IL-4 receptor alpha chain.

4. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is not cross-reactive with mouse IL-4 receptor alpha chain, cynomolgus IL-4 receptor alpha chain, IL-23 receptor alpha chain, type I cytokine receptor with fibronectin type III domain, IL-6 receptor, or IL-18 receptor alpha chain.

5. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is capable of inhibiting in vivo human IL-13 induced transcript CCL11 (eotaxin).

6. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is more potent than an IL-4 mutant (R121D, Y124D) when inhibiting IL-13 induced transcript CCL11 (eotaxin) in vivo.

7. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is capable of exhibiting a functional activity at a level that is equal to or greater than an anti-IL-4 receptor alpha chain monoclonal antibody having the variable light and heavy chain sequences set forth in SEQ ID NOs: 14 and 15, respectively.

8. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, is capable of inhibiting IL-13 induced goblet cell metaplasia at a level that is equal to or greater than an anti-IL-4 receptor alpha chain monoclonal antibody having the variable light and heavy chain sequences set forth in SEQ ID NOs: 14 and 15, respectively.

9. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, has the following amino acid residues at amino acid positions corresponding to numbering of amino acid positions of mature human tear lipocalin (SEQ ID NO: 1): Ser at amino acid position 26, Arg at amino acid position 27, Cys at amino acid position 28, Arg at amino acid position 30, Ala at amino acid position 31, Val at amino acid position 32, Tyr at amino acid position 33, Asn at amino acid position 34, Phe at amino acid position 53, Ala at amino acid position 55, Gln at amino acid position 56, Arg at amino acid position 57, Lys at amino acid position 58, Trp at amino acid position 61, Lys at amino acid position 63, Tyr at amino acid position 64, Leu at amino acid position 66, Ser at amino acid position 80, Arg at amino acid position 83, Leu at amino acid position 104, Cys at amino acid position 105, Pro at amino acid position 106, and Gln at amino acid position 108.

10. The method of claim 1 , wherein the mutein, or fragment, variant, fusion protein or conjugate thereof, comprises a fragment of the amino acid sequence set forth in SEQ ID NO: 6 that lacks at least one of the N-terminal and/or C-terminal amino acid residues.

11. The method of claim 1 , wherein the mutein, or fragment or variant thereof, has at least 95% identity to an amino acid sequence set forth in SEQ ID NO: 6.

12. The method of claim 11 , wherein the mutein has the following amino acid residues at amino acid positions corresponding to numbering of amino acid positions of mature human tear lipocalin (SEQ ID NO: 1): Ser at amino acid position 26, Arg at amino acid position 27, Cys at amino acid position 28, Arg at amino acid position 30, Ala at amino acid position 31, Val at amino acid position 32, Tyr at amino acid position 33, Asn at amino acid position 34, Phe at amino acid position 53, Ala at amino acid position 55, Gln at amino acid position 56, Arg at amino acid position 57, Lys at amino acid position 58, Trp at amino acid position 61, Lys at amino acid position 63, Tyr at amino acid position 64, Leu at amino acid position 66, Ser at amino acid position 80, Arg at amino acid position 83, Leu at amino acid position 104, Cys at amino acid position 105, Pro at amino acid position 106, and Gln at amino acid position 108.

13. The method of claim 1 , wherein the fragment of the mutein lacks at least one of the N-terminal and/or C-terminal amino acid residues of the mutein.

14. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable formulation.

15. The method of claim 1 , wherein the composition is formulated for administration to the lung.

16. The method of claim 1 , wherein the composition is formulated for administration via aerosol inhalation.

17. The method of claim 1 , wherein the composition is administered to a subject in need thereof at a frequency selected from the group consisting of: up to four times daily, up to three times daily, up to twice daily, up to once daily, up to once every other day, up to once every third day, up to once every week, and up to once every other week.

18. The method of claim 1 , wherein said composition is administered to a subject in need thereof at a dosage level between 0.06-600 mg.

19. The method of claim 1 , wherein the disorder is selected from the group consisting of asthma, rhinitis, lung fibrosis, cystic fibrosis and chronic obstructive pulmonary disease.