Proteases for Pharmaceutical Use
The pharmaceutical use of proteases related to amino acids 1-274 of SEQ ID NO: 2, the serine protease derived from Bacillus licheniformis , which is also designated subtilisin Carlsberg, optionally in combination with a lipase and/or an amylase. Examples of medical indications are: Treatment of digestive disorders, pancreatic exocrine insufficiency (PEI), pancreatitis, cystic fibrosis, diabetes type I, and/or diabetes type II.
1 . An isolated protease having at least 50% identity to amino acids 1-274 of SEQ ID NO: 2, for use as a medicament.
2 . The protease of claim 1 , wherein
(a) the protease comprises an amino acid sequence selected from the group consisting of amino acids 1-274 of SEQ ID NO: 2, amino acids 1-274 of SEQ ID NO: 5, amino acids 1-275 of SEQ ID NO: 6, amino acids 1-275 of SEQ ID NO: 7, amino acids 1-275 of SEQ ID NO: 8, amino acids 1-275 of SEQ ID NO: 9, amino acids 1-275 of SEQ ID NO: 10, amino acids 1-269 of SEQ ID NO: 11, amino acids 1-269 of SEQ ID NO: 12, and amino acids 1-268 of SEQ ID NO: 13; and/or
(b) the protease is a variant of an amino acid sequence selected from the group consisting of amino acids 1-274 of SEQ ID NO: 2, amino acids 1-274 of SEQ ID NO: 5, amino acids 1-275 of SEQ ID NO: 6, amino acids 1-275 of SEQ ID NO: 7, amino acids 1-275 of SEQ ID NO: 8, amino acids 1-275 of SEQ ID NO: 9, amino acids 1-275 of SEQ ID NO: 10, amino acids 1-269 of SEQ ID NO: 11, amino acids 1-269 of SEQ ID NO: 12, and amino acids 1-268 of SEQ ID NO: 13, wherein the variant differs from the respective amino acid sequence by no more than twenty-five amino acids, and wherein:
(i) the variant comprises at least one substitution, deletion and/or insertion of one or more amino acids as compared to the respective amino acid sequence; and/or
(ii) the variant comprises at least one small deletion as compared to the respective amino acid sequence; and/or
(iii) the variant comprises at least one small N- or C-terminal extension as compared to the respective amino acid sequence; and/or
(c) the protease is an allelic variant of a protease having amino acids selected from the group consisting of amino acids 1-274 of SEQ ID NO: 2, amino acids 1-274 of SEQ ID NO:
5, amino acids 1-275 of SEQ ID NO: 6, amino acids 1-275 of SEQ ID NO: 7, amino acids 1-275 of SEQ ID NO: 8, amino acids 1-275 of SEQ ID NO: 9, amino acids 1-275 of SEQ ID NO: 10, amino acids 1-269 of SEQ ID NO: 11, amino acids 1-269 of SEQ ID NO: 12, and amino acids 1-268 of SEQ ID NO: 13; and/or
(d) the protease is a fragment of a protease having amino acids selected from the group consisting of amino acids 1-274 of SEQ ID NO: 2, amino acids 1-274 of SEQ ID NO: 5, amino acids 1-275 of SEQ ID NO: 6, amino acids 1-275 of SEQ ID NO: 7, amino acids 1-275 of SEQ ID NO: 8, amino acids 1-275 of SEQ ID NO: 9, amino acids 1-275 of SEQ ID NO: 10, amino acids 1-269 of SEQ ID NO: 11, amino acids 1-269 of SEQ ID NO: 12, and amino acids 1-268 of SEQ ID NO: 13.
3 . The protease of claim 1 , wherein the protease has an amino acid sequence selected from the group consisting of amino acids 1-274 of SEQ ID NO: 2, amino acids 1-274 of SEQ ID NO: 5, amino acids 1-275 of SEQ ID NO: 6, amino acids 1-275 of SEQ ID NO: 7, amino acids 1-275 of SEQ ID NO: 8, amino acids 1-275 of SEQ ID NO: 9, amino acids 1-275 of SEQ ID NO: 10, amino acids 1-269 of SEQ ID NO: 11, amino acids 1-269 of SEQ ID NO: 12, and amino acids 1-268 of SEQ ID NO: 13.
4 . The protease of claim 3 , wherein the protease has amino acids 1-274 of SEQ ID NO: 2.
5 . A pharmaceutical composition comprising a protease of claim 1 and at least one pharmaceutically acceptable auxiliary material.
6 . The composition of claim 5 , further comprising an amylase.
7 . The composition of claim 6 , wherein the amylase has at least 70% identity to an amylase selected from the group consisting of:
(a) an amylase having amino acids 1-481 of SEQ ID NO: 16,
(b) an amylase having amino acids 1-481 of SEQ ID NO: 17, and
(c) an amylase having amino acids 1-483 of SEQ ID NO: 18.
8 . The composition of claim 5 , further comprising a lipase.
9 . The composition of claim 8 , wherein the lipase has at least 70% identity to a lipase having amino acids 1-269 of SEQ ID NO: 15
10 . The composition of claim 5 , further comprising a lipase and an amylase.
11 . The composition of claim 10 , wherein
(a) the lipase has at least 70% identity to a lipase having amino acids 1-269 of SEQ ID NO: 15; and
(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: 16,
(ii) an amylase having amino acids 1-481 of SEQ ID NO: 17, and
(iii) an amylase having amino acids 1-483 of SEQ ID NO: 18.
12 . The composition of claim 10 , wherein
(a) the protease has amino acids 1-274 of SEQ ID NO: 2;
(b) the lipase comprises amino acids 2-269 of SEQ ID NO: 15; and
(c) the amylase is an amylase selected from the group consisting of:
(i) an amylase comprising amino acids 1-481 of SEQ ID NO: 16,
(ii) an amylase having amino acids 1-481 of SEQ ID NO: 17, and
(iii) an amylase having amino acids 1-483 of SEQ ID NO: 18.
13 . 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 .
14 . The method of claim 13 , further comprising administering a therapeutically effective amount of an amylase.
15 . The method of claim 13 , further comprising administering a therapeutically effective amount of a lipase.
16 . The method of claim 13 , further comprising administering a therapeutically effective amount of a lipase and an amylase.
17 . An isolated protease in accordance with claim 1 having at least 90% identity to amino acids 1-274 of SEQ ID NO: 2.
18 . An isolated protease in accordance with claim 1 having at least 95% identity to amino acids 1-274 of SEQ ID NO: 2.