THERAPEUTIC DERIVATIVES OF INTERLEUKIN-22
The invention relates to novel derivatives of Interleukin-22 (IL-22), particularly those comprising a fatty acid covalently attached to an IL-22 protein, and their use in therapy.
1 . A method of treating a disease, disorder, or condition in a subject, wherein the method comprises administering an effective amount of a derivative of IL-22 to the subject, and wherein the derivative of IL-22. comprises a fatty acid covalently attached to an IL-22 protein, wherein:
(i) the IL-22 protein is native mature human IL-22 (hIL-22; SEQ ID NO. 1) or a variant thereof, wherein the variant (a) comprises a variation within SEQ ID NO. 1 and has at least 10% sequence identity with hIL-22, and/or (b) comprises a variation relative to SEQ ID NO. 1; and
(ii) the fatty acid is covalently attached to a Cys residue in the IL-22 protein.
2 . The method of claim 1 , wherein the fatty acid is covalently ched to the Cys residue by a linker.
3 . The method of claim 1 , wherein the disease, disorder or condition is a metabolic, liver ; pulmonary, gut, kidney or skin disease, disorder or condition.
4 . The method of claim 3 , wherein:
(i) the metabolic disease, disorder or condition is obesity, diabetes type I, diabetes type 2, hyperlipidemia, hyperglycemia or hyperinsulinemia;
(ii) the liver disease, disorder or condition is non-alcoholic fatty liver disease (NAELD), non-alcoholic steatohepatitis (NASH), cirrhosis, alcoholic hepatitis, acute liver failure, chronic liver failure, acute-on-chronic liver failure (ACLF), acetaminophen induced liver toxicity, acute liver injury, sclerosing cholangitis, biliary cirrhosis or a pathological condition caused by surgery or transplantation;
(iii) the pulmonary disease, disorder or condition is chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, a chemical injury, a viral infection, a bacterial infection or a fungal infection;
(iv) the gut disease, disorder or condition is inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, graft- versus-host-disease (GVHD), a chemical injury, a viral infection or a bacterial infection;
(v) the kidney disease, disorder or condition is acute kidney disease or chronic kidney disease; or
(vi) the skin disease, disorder or condition is a wound, inflammatorydisease or GvHD.
5 . The method of claim 1 , wherein the method comprises administering a daily dose of between 0.001 μg/kg of body weight and 10 mg/kg of body weight of the derivative to the subject.
6 . The method of claim 2 , wherein
(i) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 1);
(ii) the variant has the sequence set forth in SEQ ID NO. 17, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue at position −7 relative to hIL-22 (identified herein as Derivative 2);
(iii) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 3);
(iv) the variant has the sequence set forth in SEQ ID NO. 17, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue at position −7 relative to hIL-22 (identified herein as Derivative 4);
(v) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-γGlu-γGlu-γGlu-OEG-OEG-εLys-αAc, the fatty acid is a C14 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 5);
(vi) the variant has the sequence set forth in SEQ ID NO. 18, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 6);
(vii) the variant has the sequence set forth in SEQ ID NO. 19, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 7);
(viii) the variant has the sequence set forth in SEQ ID NO. 20, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 6 of hIL-22 (identified herein as Derivative 8);
(ix) the variant has the sequence set forth in SEQ ID NO. 21, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 33 of hIL-22 (identified herein as Derivative 9); or
(x) the variant has the sequence set forth in SEQ ID NO. 18, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 10).
7 . A method of treating a disease, disorder, or condition in a subject, wherein the method comprises administering an effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a derivative of IL-22, and wherein the derivative of IL-22 comprises a fatty acid coxal eptly attached to an IL-22 protein, wherein:
(i) the IL-22 protein is native mature human IL-22 (hIL-22; SEQ ID NO. 1) or a variant thereof, wherein the variant (a) comprises a variation within SEQ ID NO. 1 and has at least 10% sequence identity with hIL-22, and/or (b) comprises a variation relative to SEQ ID NO. 1; and
(ii) the fatty acid is covalently attached to a Cys residue in the IL-22 protein.
8 . The method of claim 7 , wherein the fatty acid is covalently attached to the Cys residue by a linker.
9 . The method of claim 8 , wherein
(i) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 1);
(ii) the variant has the sequence set forth in SEQ ID NO. 17, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue at position -7 relative to hIL-22 (identified herein as Derivative 2);
(iii) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 3);
(iv) the variant has the sequence set forth in SEQ ID NO. 17, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue at position −7 relative to hIL-22 (identified herein as Derivative 4);
(v) the variant has the sequence set forth in SEQ ID NO. 16, the linker is γGlu-γGlu-γGlu-γGlu-OEG-OEG-εLys-αAc, the fatty acid is a C14 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 5);
(vi) the variant has the sequence set forth in SEQ ID NO. 18, the linker is γGlu-OEG-OEG-C2DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 6);
(vii) the variant has the sequence set forth in SEQ ID NO. 19, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 7);
(viii) the variant has the sequence set forth in SEQ ID NO. 20, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 6 of hIL-22 (identified herein as Derivative 8);
(ix) the variant has the sequence set forth in SEQ ID NO. 21, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C18 diacid and the linker is attached to the Cys residue substituted at position 33 of hIL-22 (identified herein as Derivative 9); or
(x) the variant has the sequence set forth in SEQ ID NO. 18, the linker is γGlu-OEG-OEG-C 2 DA-Ac, the fatty acid is a C16 diacid and the linker is attached to the Cys residue substituted at position 1 of hIL-22 (identified herein as Derivative 10).
10 . The method of claim 6 , wherein the disease, disorder or condition is a metabolic, liver, pulmonary, gut, kidney or skin disease, disorder or condition.
11 . The method of claim 7 , wherein the disease, disorder or condition is a metabolic, liver, pulmonary, gut, kidney or skin disease, disorder or condition.
12 . The method of claim 9 , wherein the disease, disorder or condition is a metabolic, liver, pulmonary, gut, kidney or skin disease, disorder or condition.
13 . A method for preparing a derivative of IL-22, comprising covalently attaching a fatty acid to an 1L-22 protein, wherein:
(i) the IL-22 protein is native mature human IL-22 (hIL-22; SEQ ID NO. 1) or a variant thereof, wherein the variant (a) comprises a variation within SEQ ID NO. 1 and has at least 10% sequence identity with hIL-22, and/or (b) comprises a variation relative to SEQ ID NO. 1; and
(ii) the fatty acid is covalently attached to a Cys residue in the IL-22 protein.