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 derivative of IL-22 comprising a fatty acid covalently attached to an IL-22 protein, wherein
(i) the IL-22 is a variant of native mature human IL-22 (hIL-22; SEQ ID NO. 1), wherein the variant comprises 1, 2, or 3 amino acid substitutions within SEQ ID NO. 1, including an A1C substitution;
(ii) when the variant comprises 2 or 3 amino acid substitutions, the substitutions other than the A1C substitution are:
conservative substitutions; and/or
located at one or more positions selected from positions 21, 35, 64, 113 and 114 of hIL-22; and
(iii) the fatty acid is covalently attached to the substituted Cys residue at position 1.
2. A derivative as claimed in claim 1 , wherein the fatty acid is covalently attached to the Cys residue at position 1 by a linker.
3. A derivative as claimed in claim 2 , wherein the linker comprises:
(i) one or more amino acids, which may include Glu and/or Lys;
(ii) an oxyethylene glycine unit or multiple linked oxyethylene glycine units, which may include 2-5 such units;
(iii) one or more oligo (ethylene glycol) (OEG) residues;
(iv) an ethylenediamine (C 2 DA) group;
(v) an acetamide (Ac) group;
(vi)
wherein R represents the fatty acid and * designates a point of attachment of the linker to the IL-22 protein;
(vii)
wherein R represents the fatty acid and * designates a point of attachment of the linker to the IL-22 protein;
and/or
(viii)
wherein R represents the fatty acid and * designates a point of attachment of the linker to the IL-22 protein.
4. A derivative as claimed in claim 1 , wherein:
the fatty acid is of Formula I:
HOOC—(CH 2 ) x —CO—*,
the variant comprises an N-terminal G-P-G and a Cys residue at position 1 of hIL-22, x is 14, 16 or 18, the fatty acid is covalently attached to the substituted Cys residue at position 1 by a linker and * designates a point of attachment to the linker.
5. A pharmaceutical composition comprising a derivative as claimed in claim 1 and a pharmaceutically acceptable vehicle, wherein:
the pharmaceutical composition is suitable for administration by inhalation, by injection, topically or ocularly.
6. A pharmaceutical composition as claimed in claim 5 , for use in therapy.
7. A pharmaceutical composition as claimed in claim 5 , for use in a method of treating a metabolic, liver, pulmonary, gut, kidney or skin disease, disorder, or condition.
8. A pharmaceutical composition for use as claimed in claim 7 , wherein:
(i) the metabolic disease, disorder or condition is obesity, diabetes type 1, diabetes type 2, hyperlipidaemia, hyperglycaemia or hyperinsulinaemia;
(ii) the liver disease, disorder or condition is non-alcoholic fatty liver disease (NAFLD), 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, inflammatory disease or GvHD.
9. A pharmaceutical composition for use as claimed in claim 7 , said method comprising administering a daily or weekly dose of between 0.001 μg/kg of body weight and 10 mg/kg of body weight of the derivative.
10. A pharmaceutical composition of claim 5 , wherein the injection is intraperitoneal, subcutaneous, or intravenous.
11. A derivative as claimed in claim 1 , for use in therapy.
12. A derivative as claimed in claim 1 , for use in a method of treating a metabolic, liver, pulmonary, gut, kidney or skin disease, disorder, or condition.
13. A derivative for use as claimed in claim 12 , wherein:
(i) the metabolic disease, disorder or condition is obesity, diabetes type 1, diabetes type 2, hyperlipidemia, hyperglycemia or hyperinsulinemia;
(ii) the liver disease, disorder or condition is non-alcoholic fatty liver disease (NAFLD), 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, inflammatory disease or GvHD.
14. A derivative for use as claimed in claim 12 , said method comprising administering a daily or weekly dose of between 0.001 μg/kg of body weight and 10 mg/kg of body weight of the derivative.
15. A derivative as claimed in claim 1 , wherein the substitutions are selected from the group consisting of N21D, N21Q, N35D, N35H, N35Q, N64D, N64Q, N64W, Q113R, and K114R.