IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
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출원번호 |
US-0699761
(2010-02-03)
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등록번호 |
US-8673860
(2014-03-18)
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발명자
/ 주소 |
- Schellenberger, Volker
- Silverman, Joshua
- Wang, Chia-wel
- Spink, Benjamin
- Stemmer, Willem P.
- Geething, Nathan C.
- To, Wayne
- Cleland, Jeffrey L.
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출원인 / 주소 |
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대리인 / 주소 |
Wilson Sonsini Goodrich & Rosati
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인용정보 |
피인용 횟수 :
26 인용 특허 :
84 |
초록
▼
The present invention relates to compositions comprising biologically active proteins linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of using such compositions in treatment of glucose-rel
The present invention relates to compositions comprising biologically active proteins linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of using such compositions in treatment of glucose-related diseases, metabolic diseases, coagulation disorders, and growth hormone-related disorders and conditions.
대표청구항
▼
1. An extended recombinant polypeptide (XTEN) comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:188, SEQ ID NO:204, SEQ ID NO:206, SEQ ID NO:210, SEQ ID NO:213, SEQ ID NO:215, SEQ ID NO:217, SEQ ID NO:387, SEQ ID NO:391, SEQ ID NO:393, SEQ ID NO:396, SEQ ID NO: 570, or S
1. An extended recombinant polypeptide (XTEN) comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:188, SEQ ID NO:204, SEQ ID NO:206, SEQ ID NO:210, SEQ ID NO:213, SEQ ID NO:215, SEQ ID NO:217, SEQ ID NO:387, SEQ ID NO:391, SEQ ID NO:393, SEQ ID NO:396, SEQ ID NO: 570, or SEQ ID NO:577, wherein the XTEN is characterized in that: (a) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid sequence of the XTEN; and(b) the XTEN sequence is substantially non-repetitive such that (i) the XTEN sequence contains no three contiguous amino acids that are identical unless the amino acids are serine residues, or (ii) at least 80% of the XTEN sequence comprises non-overlapping sequence motifs, each of the sequence motifs comprising from 9 to 14 amino acid residues, wherein any two contiguous amino acid residues does not occur more than twice in each of the sequence motifs. 2. The XTEN of claim 1, wherein the XTEN is further characterized in that: (a) the sum of asparagine and glutamine residues is less than 10% of the total amino acid sequence of the XTEN;(b) the sum of methionine and tryptophan residues is less than 2% of the total amino acid sequence of the XTEN; and/or(c) no one type of amino acid constitutes more than 30% of the XTEN sequence. 3. The XTEN of claim 1, wherein the XTEN has a subsequence score of less than 10. 4. The XTEN of claim 1, wherein the XTEN is further characterized in that: (a) the sequence motifs comprises four or more types of amino acids selected from glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P); and(b) the XTEN enhances pharmacokinetic properties of a biologically active protein (BP) when linked to the BP as a fusion protein wherein the pharmacokinetic properties are ascertained by measuring the blood concentration of the fusion protein after administration of a therapeutically effective dose to a subject in comparison to the corresponding BP not linked to XTEN and administered to a subject at a comparable dose. 5. The XTEN of claim 4, wherein the enhanced pharmacokinetic property is selected from an increase in terminal half-life of at least three-fold and blood concentrations that remain within the therapeutic window for the fusion protein for a period at least about three-fold longer compared to the corresponding BP not linked to XTEN. 6. The XTEN of claim 1, wherein the XTEN comprises an amino acid sequence at least 95% identical to SEQ ID NO:188, SEQ ID NO:204, SEQ ID NO:206, SEQ ID NO:210, SEQ ID NO:213, SEQ ID NO:215, SEQ ID NO:217, SEQ ID NO:387, SEQ ID NO:391, SEQ ID NO:393, SEQ ID NO:396, SEQ ID NO: 570, or SEQ ID NO:577. 7. An isolated fusion protein, comprising the XTEN of claim 1 or 6 linked to a BP. 8. The isolated fusion protein of claim 7, wherein the BP is selected from the group consisting of a glucose regulating peptide, a metabolic protein, and a growth hormone. 9. The isolated fusion protein of claim 8, wherein the glucose regulating peptide is exendin-4. 10. The isolated fusion protein of claim 7, wherein the BP is metabolic protein. 11. The isolated fusion protein of claim 7, wherein the BP is a growth hormone. 12. The isolated fusion protein of claim 7, further comprising a second XTEN sequence. 13. The isolated fusion protein of claim 7, further comprising a spacer sequence between the BP and XTEN, wherein the spacer sequence comprises between 1 to about 50 amino acid residues and optionally comprises a cleavage sequence. 14. The isolated fusion protein of claim 13, wherein the cleavage sequence is susceptible to cleavage by a protease selected from FXIa, FXIIa, kallikrein, FVIIa, FIXa, FXa, thrombin, elastase-2, granzyme B, MMP-12, MMP-13, MMP-17 or MMP-20, TEV, enterokinase, rhinovirus 3C protease, and sortase A. 15. A pharmaceutical composition comprising the fusion protein of claim 7, and at least one pharmaceutically acceptable carrier. 16. A kit, comprising a container comprising the pharmaceutical composition of claim 15, and instructions for the reconstitution and/or administration of the pharmaceutical composition to a subject. 17. The XTEN of claim 1, wherein the XTEN comprises SEQ ID NO:188, SEQ ID NO:204, SEQ ID NO:206, SEQ ID NO:210, SEQ ID NO:213, SEQ ID NO:215, SEQ ID NO:217, SEQ ID NO:387, SEQ ID NO:391, SEQ ID NO:393, SEQ ID NO:396, SEQ ID NO: 570, or SEQ ID NO:577. 18. The XTEN of claim 1, wherein the XTEN comprises SEQ ID NO:373, SEQ ID NO:375, SEQ ID NO:377, SEQ ID NO:378, SEQ ID NO:382, SEQ ID NO:384, SEQ ID NO:388, SEQ ID NO:389, SEQ ID NO:398, SEQ ID NO:401, SEQ ID NO:402, SEQ ID NO:403, SEQ ID NO:409, SEQ ID NO:762, SEQ ID NO:764, SEQ ID NO:765, SEQ ID NO:766, SEQ ID NO:767, or SEQ ID NO:768. 19. The XTEN of claim 1, wherein the XTEN comprises SEQ ID NO: 204 or SEQ ID NO: 206. 20. An extended recombinant polypeptide (XTEN) comprising an amino acid sequence which is SEQ ID NO:188, SEQ ID NO: 204, SEQ ID NO: 206, SEQ ID NO:563, SEQ ID NO:566, SEQ ID NO:569, SEQ ID NO:574, SEQ ID NO:577, SEQ ID NO:585, SEQ ID NO:590, SEQ ID NO:596, SEQ ID NO:597, SEQ ID NO:599, wherein the XTEN is characterized in that: (a) the sum of glycine (G), alanine (A), serine (S), threonine (T), glutamate (E) and proline (P) residues constitutes more than about 80% of the total amino acid sequence of the XTEN; and(b) the XTEN sequence is substantially non-repetitive such that (i) the XTEN sequence contains no three contiguous amino acids that are identical unless the amino acids are serine residues, or (ii) at least 80% of the XTEN sequence comprises non-overlapping sequence motifs, each of the sequence motifs comprising from 9 to 14 amino acid residues, wherein any two contiguous amino acid residues do not occur more than twice in each of the sequence motifs.
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