METHODS AND COMPOSITIONS INVOLVING INTERLEUKIN-6 RECEPTOR ALPHA-BINDING SINGLE CHAIN VARIABLE FRAGMENTS

1 . A chimeric interleukin 6 receptor alpha (IL-6Rα) binding protein comprising a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10).

2 . The chimeric IL-6Rα binding protein, wherein the binding protein is an scFv, (scFv)2, scFvFc, Fab, Fab′, or F(ab) 2 .

3 . The chimeric IL-6Rα binding protein of claim 1 , wherein the binding protein is one polypeptide.

4 . The chimeric IL-6Rα binding protein of claim 3 , wherein the one polypeptide is a single chain variable fragment (scFv).

5 . The chimeric IL-6Rα binding protein of claim 1 , wherein the heavy chain variable region is on the N-terminal side of the light chain variable region.

6 . The chimeric IL-6Rα binding protein of claim 1 , wherein the light chain variable region is on the N-terminal side of the heavy chain variable region.

7 . The chimeric IL-6Rα binding protein of any of claims 1 - 6 , wherein the linker comprises the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO:11).

8 . The chimeric IL-6Rα binding protein of any of claims 1 - 7 , further comprising a leader peptide.

9 . The chimeric IL-6Rα binding protein of any of claims 1 - 8 , further comprising an isolation tag.

10 . An chimeric interleukin 6 receptor alpha (IL-6Rα) binding protein comprising a leader peptide, heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10), wherein the heterologous linker comprises the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO:11) and the IL-6Rα binding protein is a single chain antibody fragment (scFv).

11 . A T cell expressing the chimeric IL-6Rα binding protein of any of claims 1 - 10 .

12 . A nucleic acid molecule encoding the chimeric IL-6Rα binding protein of any of claims 1 - 10 .

13 . The nucleic acid molecule of claim 12 , further comprising a promoter controlling expression of the chimeric IL-6R binding protein.

14 . The nucleic acid molecule of claim 13 , wherein the promoter is constitutive.

15 . The nucleic acid molecule of claim 13 , wherein the promoter responds positively to at least one cytokine or to T-cell activation.

16 . The nucleic acid molecule of claim 15 , where the at least one cytokine is IL-6, TNF-α, IFN-γ, IL-1β, IL-2, IL-8, or IL-10 or the promoter responds positively to NFAT-1 or NF-κB.

17 . An expression construct comprising the nucleic acid molecule of any of claims 12 - 16 .

18 . The expression construct of claim 14 , wherein the expression construct is a viral vector.

19 . The expression construct of claim 14 , wherein the expression construct is a plasmid.

20 . A recombinant T cell comprising the nucleic acid expression construct of any of claims 17 - 19 .

21 . A T cell comprising a heterologous expression construct encoding an IL-6 receptor alpha single chain variable fragment comprising a leader peptide, a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10), wherein the heterologous linker comprises the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO:11).

22 . The T cell of claim 21 , wherein the expression construct comprises a cytokine-responsive promoter or promoter that increases expression when T cells are activated.

23 . The T cell of claim 22 , wherein the promoter responds positively to one or more of the following: NFAT-1, NF-κB, IL-6, TNF-α, IFN-γ, IL-1β, IL-2, IL-8, and IL-10.

24 . A method for reducing the risk of cytokine release syndrome comprising administering to a patient at risk for cytokine release syndrome a composition comprising an isolated IL-6 receptor alpha (IL-6Rα) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL-6Rα binding protein.

25 . The method of claim 24 , wherein the patient has cancer.

26 . The method of claim 24 or 25 , wherein the patient has or will receive adoptive T-cell therapy.

27 . The method of claim 26 , wherein the patient has or will receive lymphodepletion.

28 . The method of claim 24 , wherein the patient has an autoimmune disease.

29 . The method of any of claims 24 - 28 , wherein the isolated IL-6Rα binding protein comprises a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10).

30 . The method of claim 29 , wherein the IL-6Rα binding protein is an scFv, (scFv)2, scFvFc, Fab, Fab′, or F(ab) 2 .

31 . The method of any of claims 24 - 30 , wherein the heavy chain variable region is on the N-terminal side of the light chain variable region.

32 . The method of any of claims 24 - 30 , wherein the light chain variable region is on the N-terminal side of the heavy chain variable region.

33 . The method of any of claims 24 - 32 , wherein isolated IL-6Rα binding protein comprises a linker comprising the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO:11).

34 . The method of any of claims 24 - 33 , wherein the isolated chimeric IL-6Rα binding protein comprises a leader peptide.

35 . The method of any of claims 24 - 34 , wherein the isolated chimeric IL-6Rα binding protein comprises an isolation tag.

36 . The method of any of claims 24 - 35 , wherein the patient is administered T cell comprising a heterologous nucleic acid molecule encoding an IL-6Rα binding protein.

37 . The method of claim 36 , wherein the T cells are autologous.

38 . The method of claims 24 - 37 , wherein the heterologous nucleic acid molecule encodes a chimeric IL-6Rα binding polypeptide comprising a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10).

39 . The method of any of claims 24 - 38 , wherein the nucleic acid molecule comprises a promoter controlling expression of the chimeric IL-6R binding protein.

40 . The method of claim 39 , wherein the promoter is constitutive.

41 . The method of claim 39 , wherein the promoter responds positively to at least one cytokine or to T cell activation

42 . The method of claim 41 , wherein the promoter is responsive to NFAT-1, NF-κB, IL-6, TNF-α, IFN-γ, IL-1β, IL-2, IL-8, or IL-10.

43 . The method of any of claims 24 - 42 , wherein the nucleic acid molecule is an expression construct.

44 . The method of claim 43 , wherein the expression construct is a viral vector.

45 . The method of claim 43 , wherein the expression construct is a plasmid.

46 . The method of any of claims 24 - 45 , further comprising administering to the patient an antihistamine, a corticosteroid, a steroid, acetaminophen, furosemide, and/or intravenous fluids.

47 . The method of any of claims 24 - 46 , wherein the patient has one or more symptoms of cytokine release syndrome.

48 . A method for reducing the toxicity of adoptive cell therapy in a cancer patient comprising administering to the patient a composition comprising a composition comprising an isolated IL-6 receptor alpha (IL-6Rα) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL-6Rα binding protein.

49 . A method for treating an autoimmune disease in a patient comprising administering to the patient a composition comprising a composition comprising an isolated IL-6 receptor alpha (IL-6Rα) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL-6Rα binding protein.

50 . A method for treating a cancer patient comprising administering to the patient a composition comprising a composition comprising an isolated IL-6 receptor alpha (IL-6Rα) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL-6Rα binding protein, wherein the patient has been or will be treated with immunotherapy.

51 . The method of claim 50 , wherein the immunotherapy is adoptive cell therapy.

52 . The method of claim 50 , wherein the patient has symptoms of cytokine release syndrome.

53 . A method for reducing the toxicity of one or more cytokines comprising administering to a patient with an autoimmune disease or condition or a patient being treated with immunotherapy an effective amount of a composition comprising a single chain variable fragment comprising an isolated IL-6Rα binding protein comprises a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10). AMENDMENTS This listing of claims will replace all prior versions, and listings of claims in the application. CLAIMS: 1 . (Original) A chimeric interleukin 6 receptor alpha (IL- 6 Ra) binding protein comprising a heavy chain variable region comprising CDR 1 (SEQ ID NO: 5 ), CDR 2 (SEQ ID NO: 6 ), and CDR 3 (SEQ ID NO: 7 ) attached by a heterologous linker to a light chain variable region comprising CDR 4 (SEQ ID NO: 8 ), CDR 5 (SEQ ID NO: 9 ), and CDR 6 (SEQ ID NO: 10 ). 2 - 10 . (Canceled) 11 . (Currently Amended) A T cell expressing the chimeric IL- 6 Ra binding protein of any of elaims 1 - 10 claim 1 . 12 . (Currently Amended) A nucleic acid molecule encoding the chimeric IL- 6 Ra binding protein of any of claims 1 - 10 claim 1 . 13 - 19 . (Canceled) 20 . (Currently Amended) A recombinant T cell comprising the nucleic acid expression construct of any of claims 17 - 19 of claim 12 . 21 - 23 . (Canceled) 24 . (Original) A method for reducing the risk of cytokine release syndrome comprising administering to a patient at risk for cytokine release syndrome a composition comprising an isolated IL- 6 receptor alpha (IL- 6 Ra) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL- 6 Ra binding protein. 25 . (Original) The method of claim 24 , wherein the patient has cancer. 26 . (Currently Amended) The method of claim 24 er 25 , wherein the patient has or will receive adoptive T-cell therapy. 27 . (Original) The method of claim 26 , wherein the patient has or will receive lymphodepletion. 28 . (Original) The method of claim 24 , wherein the patient has an autoimmune disease. 29 . (Currently Amended) The method of any of elaims 24 28 claim 24 , wherein the isolated IL- 6 Ra binding protein comprises a heavy chain variable region comprising CDR 1 (SEQ ID NO: 5 ), CDR 2 (SEQ ID NO: 6 ), and CDR 3 (SEQ ID NO: 7 ) attached by a heterologous linker to a light chain variable region comprising CDR 4 (SEQ ID NO: 8 ), CDR 5 (SEQ ID NO: 9 ), and CDR 6 (SEQ ID NO: 10 ). 30 . (Original) The method of claim 29 , wherein the IL- 6 Ra binding protein is an scFv, (scFv) 2 , scFvFc, Fab, Fab', or F(ab) 2 . 31 - 32 . (Canceled) 33 . (Currently Amended) The method of any of elaims 24 - 32 claim 24 , wherein isolated IL- 6 Ra binding protein comprises a linker comprising the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO: 11 ). 34 . (Currently Amended) The method of any of elaims 24 33 claim 24 , wherein the isolated chimeric IL- 6 Ra binding protein comprises a leader peptide and/or an isolation tag. 35 . (Canceled) 36 . (Currently Amended) The method of any of elaims 24 35 claim 24 , wherein the patient is administered T cell comprising a heterologous nucleic acid molecule encoding an IL- 6 Ra binding protein. 37 . (Original) The method of claim 36 , wherein the T cells are autologous. 38 . (Currently Amended) The method of elaims 24 37 claim 24 , wherein the heterologous nucleic acid molecule encodes a chimeric IL- 6 Ra binding polypeptide comprising a heavy chain variable region comprising CDR 1 (SEQ ID NO: 5 ), CDR 2 (SEQ ID NO: 6 ), and CDR 3 (SEQ ID NO: 7 ) attached by a heterologous linker to a light chain variable region comprising CDR 4 (SEQ ID NO: 8 ), CDR 5 (SEQ ID NO: 9 ), and CDR 6 (SEQ ID NO: 10 ). 39 - 45 . (Canceled) 46 . (Currently Amended) The method of any of elaims 24 45 claim 24 , further comprising administering to the patient an antihistamine, a corticosteroid, a steroid, acetaminophen, furosemide, and/or intravenous fluids. 47 . (Currently Amended) The method of any of elaims 24 - 46 claim 24 , wherein the patient has one or more symptoms of cytokine release syndrome. 48 . (Canceled) 49 . (Original) A method for treating an autoimmune disease in a patient comprising administering to the patient a composition comprising a composition comprising an isolated IL- 6 receptor alpha (IL- 6 Ra) binding protein or cells comprising a heterologous nucleic acid molecule encoding the IL- 6 Ra binding protein. 50 - 52 . (Canceled) 53 . (Original) A method for reducing the toxicity of one or more cytokines comprising administering to a patient with an autoimmune disease or condition or a patient being treated with immunotherapy an effective amount of a composition comprising a single chain variable fragment comprising an isolated IL- 6 Ra binding protein comprises a heavy chain variable region comprising CDR 1 (SEQ ID NO: 5 ), CDR 2 (SEQ ID NO: 6 ), and CDR 3 (SEQ ID NO: 7 ) attached b y a heterologous linker to a light chain variable region comprising CDR 4 (SEQ ID NO: 8 ), CDR 5 (SEQ ID NO: 9 ), and CDR 6 (SEQ ID NO: 10 ).