Toxin peptide therapeutic agents
Disclosed is a DNA encoding a composition of matter of the formula (X 1 ) a —(F 1 ) d —(X 2 ) b —(F 2 ) e —(X 3 ) c (I) and multimers thereof, in which F 1 and F 2 are half-life extending moieties, and d and e are each independently 0 or 1, provided that at least one of d and e is 1; X 1 , X 2 , and X 3 are each independently -(L) f -P-(L) g -, and f and g are each independently 0 or 1; P is a ShK peptide analog of no more than about 80 amino acid residues in length; L is an optional linker; and a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1. A DNA encoding the ShK peptide analog is disclosed. Also disclosed are an expression vector comprising the DNA, and a host cell comprising the expression vector.
1. A DNA encoding a composition of matter for extending the half-life of a polypeptide, of the formula
(X 1 ) a —(F 1 ) d —(X 2 ) b —(F 2 ) e —(X 3 ) c
or multimers thereof, wherein:
F 1 and F 2 are half-life extending moieties selected from:
(i) a human IgG Fc domain or a portion thereof,
(ii) a transthyretin protein domain, and
(iii) a human serum albumin (HSA) protein domain;
and d and e are each independently 0 or 1, provided that at least one of d and e is 1;
X 1 , X 2 , and X 3 are each independently -(L) f -P-(L) g -, and f and g are each independently 0 or 1;
P is a polypeptide of no more than about 80 amino acid residues in length, comprising the amino acid sequence of SEQ ID NO: 914, SEQ ID NO: 915, SEQ ID NO: 916, or SEQ ID NO: 917;
L is a linker; and
a, b, and c are each independently 0 or 1, provided that at least one of a, b and c is 1.
2. The DNA of claim 1 of a formula selected from
P-(L) g -F 1 ,
F 1 -(L) f -P,
P-(L) g -F 1 -(L) f -P,
F 1 -(L) f -P-(L) g -F 2 ,
F 1 -(L) f -P-(L) g -F 2 -(L) f -P,
F 1 —F 2 -(L) f -P,
P-(L) g -F 1 —F 2 , and
P-(L) g -F 1 —F 2 -(L) f -P.
3. The DNA of claim 1 , wherein F 1 or F 2 , or both, comprises a human IgG Fc domain or a portion thereof.
4. The DNA of claim 3 , wherein the human IgG Fc domain comprises a human IgG1 Fc domain.
5. The DNA of claim 4 , wherein the human IgG Fc domain comprises a human IgG2 Fc domain.
6. The DNA of claim 1 , wherein F 1 and F 2 are different half-life extending moieties.
7. The DNA of claim 1 , wherein claim 1 , wherein any f or any g is 1, and L is a peptide linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 79, 84, and 637 through 656.
8. The DNA of claim 1 , wherein F 1 or F 2 , or both, comprises a human serum albumin protein domain or a transthyretin protein domain.
9. The DNA of claim 1 , wherein P comprises the amino acid sequence of SEQ ID NO: 914.
10. The DNA of claim 1 , wherein P comprises the amino acid sequence of SEQ ID NO: 915.
11. The DNA of claim 1 , wherein P comprises the amino acid sequence of SEQ ID NO: 916.
12. The DNA of claim 1 , wherein P comprises the amino acid sequence of SEQ ID NO: 917.
13. A DNA encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 914, SEQ ID NO: 915, SEQ ID NO: 916, or SEQ ID NO: 917.
14. The DNA of claim 13 , wherein the DNA encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 914.
15. The DNA of claim 13 , wherein the DNA encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 915.
16. The DNA of claim 13 , wherein the DNA encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 916.
17. The DNA of claim 13 , wherein the DNA encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 917.
18. An expression vector comprising the DNA of claim 1 or claim 13 .
19. A host cell comprising the expression vector of claim 18 .
20. The host cell of claim 19 , wherein the cell is a eukaryotic cell.
21. The host cell of claim 20 , wherein the cell is a mammalian cell.
22. The host cell of claim 21 , wherein the cell is a CHO cell.
23. The host cell of claim 19 , wherein the cell is a prokaryotic cell.
24. The host cell of claim 23 , wherein the cell is an E. coli cell.