Protease variants for pharmaceutical use
The invention relates to novel variants of a protease derived from Nocardiopsis sp. (SEQ ID NO: 1) and closely related proteases, as well as their pharmaceutical use. The variants show improved performance in the treatment of pancreatic exocrine insufficiency (PEI). The variants may be combined with a lipase and/or an amylase. Other examples of medical indications are: Treatment of digestive disorders, pancreatitis, cystic fibrosis, diabetes type I, and/or diabetes type II.
1. A non-naturally-occurring protease having at least 90% sequence identity to the sequence of amino acids 1-188 of SEQ ID NO:1, and which, as compared to amino acids 1-188 of SEQ ID NO:1, comprises at least one substitution selected from the group consisting of A1T; I3V; T41A; E53K; Q54L; Q54D; S99P; P124L; M131V; and T151I.
2. The protease of claim 1 , which comprises A1T.
3. The protease of claim 1 , which comprises I3V.
4. The protease of claim 1 , which comprises T41A.
5. The protease of claim 1 , which comprises E53K.
6. The protease of claim 1 , which comprises Q54L or Q54D.
7. The protease of claim 1 , which comprises S99P.
8. The protease of claim 1 , which comprises P124L.
9. The protease of claim 1 , which comprises M131 V.
10. The protease of claim 1 , which comprises T151I.
11. The protease of claim 1 , which has at least 95% identity to amino acids 1-188 of SEQ ID NO:1.
12. A pharmaceutical composition comprising a protease of claim 1 and at least one pharmaceutically acceptable auxiliary material.
13. The composition of claim 12 , further comprising a lipase or an amylase.
14. The composition of claim 13 , wherein
(a) the lipase has at least 70% identity to a lipase having amino acids 1-269 of SEQ ID NO:2; and/or
(b) the amylase has at least 70% identity to an amylase selected from the group consisting of
(i) an amylase having amino acids 1-481 of SEQ ID NO:3,
(ii) an amylase having amino acids 1-483 of SEQ ID NO:4, and
(iii) an amylase having amino acids 1-513 of SEQ ID NO:5.
15. A feed composition comprising the protease of claim 1 .
16. A method for the treatment of digestive disorders, pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I, and/or diabetes type II, comprising administering a therapeutically effective amount of a protease of claim 1 .
17. The method of claim 16 , further comprising administering a therapeutically effective amount of a lipase or an amylase.