LONG-ACTING POLYPEPTIDES AND METHODS OF PRODUCING AND ADMINISTERING SAME
A polypeptide and polynucleotides comprising at least two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to a non-human peptide-of-interest are disclosed. Pharmaceutical compositions comprising the non-human polypeptides and polynucleotides of the invention and methods of using both human and non-human polypeptides and polynucleotides are also disclosed.
1 . A method of reducing the dosing frequency of a growth hormone in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide consisting of a growth hormone, one chorionic gonadotrophin carboxy terminal peptide (CTP) attached to the amino terminus of said growth hormone, and two chorionic gonadotrophin CTPs attached to the carboxy terminus of said growth hormone, and wherein said polypeptide optionally consists of a signal peptide attached to the amino terminus of said one CTP, thereby reducing the dosing frequency of a growth hormone in a subject.
2 . The method of claim 1 , wherein the sequence of at least one CTP consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 and SEQ ID NO: 18.
3 . The method of claim 1 , wherein said at least one CTP is glycosylated.
4 . The method of claim 1 , wherein said at least one CTP is truncated.
5 . The method of claim 1 , wherein the sequence of said signal peptide is as set forth in SEQ ID NO: 19.
6 . The method of claim 1 , wherein at least one CTP is optionally attached to said growth hormone via a linker.
7 . The method of claim 6 , wherein the linker is a peptide bond.
8 . The method of claim 1 , wherein said polypeptide is administered once weekly or once bi-weekly.
9 . The method of claim 1 , wherein said subject is a human child.
10 . The method of claim 1 , wherein said growth hormone is human growth hormone (hGH).
11 . A method of improving the area under the curve (AUC) of a growth hormone in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide consisting of a growth hormone, one chorionic gonadotrophin carboxy terminal peptide (CTP) attached to the amino terminus of said growth hormone, and two chorionic gonadotrophin CTPs attached to the carboxy terminus of said growth hormone, and wherein said polypeptide optionally consists of a signal peptide attached to the amino terminus of said one CTP, thereby reducing the dosing frequency of a growth hormone in a subject.
12 . The method of claim 11 , wherein the sequence of at least one CTP consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 and SEQ ID NO: 18.
13 . The method of claim 11 , wherein said at least one CTP is glycosylated.
14 . The method of claim 11 , wherein said at least one CTP is truncated.
15 . The method of claim 11 , wherein the sequence of said signal peptide is as set forth in SEQ ID NO: 19.
16 . The method of claim 11 , wherein at least one CTP is optionally attached to said growth hormone via a linker.
17 . The method of claim 16 , wherein the linker is a peptide bond.
18 . The method of claim 11 , wherein said polypeptide is administered once weekly or once bi-weekly.
19 . The method of claim 11 , wherein said subject is a human child.
20 . The method of claim 11 , wherein said growth hormone is human growth hormone (hGH).
21 . A method of treating a subject in need of GH therapy, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide comprising a polynucleotide, said polynucleotide consisting of a growth hormone, one chorionic gonadotrophin carboxy terminal peptide (CTP) attached to the amino terminus of said growth hormone, and two chorionic gonadotrophin CTPs attached to the carboxy terminus of said growth hormone, and wherein said polypeptide optionally consists of a signal peptide attached to the amino terminus of said one CTP, thereby reducing the dosing frequency of a growth hormone in a subject.
22 . The method of claim 21 , wherein the sequence of at least one CTP consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 and SEQ ID NO: 18.
23 . The method of claim 21 , wherein said at least one CTP is glycosylated.
24 . The method of claim 21 , wherein said at least one CTP is truncated.
25 . The method of claim 21 , wherein the sequence of said signal peptide is as set forth in SEQ ID NO: 19.
26 . The method of claim 21 , wherein at least one CTP is optionally attached to said growth hormone via a linker.
27 . The method of claim 26 , wherein the linker is a peptide bond.
28 . The method of claim 21 , wherein said polypeptide is administered once weekly or once bi-weekly.
29 . The method of claim 21 , wherein said subject is a human child.
30 . The method of claim 21 , wherein said growth hormone is human growth hormone (hGH).
31 . A method of increasing insulin-like growth factor (IGF-1) levels in a subject, comprising administering to said subject a therapeutically effective amount of a polypeptide consisting of a growth hormone, one chorionic gonadotrophin carboxy terminal peptide (CTP) attached to the amino terminus of said growth hormone, and two chorionic gonadotrophin CTPs attached to the carboxy terminus of said growth hormone, and wherein said polypeptide optionally consists of a signal peptide attached to the amino terminus of said one CTP, thereby increasing insulin-like growth factor (IGF-1) levels in a subject.
32 . The method of claim 31 , wherein the sequence of at least one CTP consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 17 and SEQ ID NO: 18.
33 . The method of claim 31 , wherein said at least one CTP is glycosylated.
34 . The method of claim 31 , wherein said at least one CTP is truncated.
35 . The method of claim 31 , wherein the sequence of said signal peptide is as set forth in SEQ ID NO: 19.
36 . The method of claim 31 , wherein at least one CTP is optionally attached to said growth hormone via a linker
37 . The method of claim 36 , wherein the linker is a peptide bond.
38 . The method of claim 31 , wherein said polypeptide is administered once weekly or once bi-weekly.
39 . The method of claim 31 , wherein said subject is a human child.
40 . The method of claim 31 , wherein said growth hormone is a human growth hormone.