THROMBIN CLEAVABLE LINKER WITH XTEN AND ITS USES THEREOF
First Claim
1. A chimeric molecule comprising a von Willebrand Factor (VWF) protein, a heterologous moiety (H1), an extended recombinant polypeptide (XTEN) sequence, and a VWF linker connecting the VWF protein with the heterologous moiety, wherein the VWF linker comprises a polypeptide selected from:
- i. an a2 region from Factor VIII (FVIII);
ii. an a1 region from FVIII;
iii. an a3 region from FVIII;
iv. a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO;
3) and a PAR1 exosite interaction motif, wherein X is an aliphatic amino acid;
orv. any combination thereof, andwherein the XTEN sequence is connected to the VWF protein, the heterologous moiety (H1), the VWF linker, or any combination thereof.
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Accused Products
Abstract
The present invention provides a chimeric molecule comprising a VWF protein fused to a heterologous moiety via a VWF linker. The invention provides an efficient VWF linker that can be cleaved in the presence of thrombin. The chimeric molecule can further comprise a polypeptide chain comprising a FVIII protein and a second heterologous moiety, wherein the chain comprising the VWF protein and the chain comprising the FVIII protein are associated with each other. The invention also includes nucleotides, vectors, host cells, methods of using the chimeric proteins.
20 Citations
101 Claims
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1. A chimeric molecule comprising a von Willebrand Factor (VWF) protein, a heterologous moiety (H1), an extended recombinant polypeptide (XTEN) sequence, and a VWF linker connecting the VWF protein with the heterologous moiety, wherein the VWF linker comprises a polypeptide selected from:
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i. an a2 region from Factor VIII (FVIII); ii. an a1 region from FVIII; iii. an a3 region from FVIII; iv. a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO;
3) and a PAR1 exosite interaction motif, wherein X is an aliphatic amino acid;
orv. any combination thereof, and wherein the XTEN sequence is connected to the VWF protein, the heterologous moiety (H1), the VWF linker, or any combination thereof. - View Dependent Claims (2, 3, 4, 6, 12, 13, 18, 19, 25, 30, 36, 44, 46, 48, 49, 53, 57, 62, 68, 84, 86, 88, 91, 94, 98)
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5. (canceled)
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7. A chimeric molecule comprising a first polypeptide chain which comprises a VWF protein, a heterologous moiety (H1), and a VWF linker connecting the VWF protein and the heterologous moiety (H1) and a second polypeptide chain comprising a FVIII protein and an XTEN sequence, wherein the VWF linker in the first polypeptide chain comprises:
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i. an a2 region from FVIII; ii. an a1 region from FVIII; iii. an a3 region from FVIII; iv. a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO;
3) and a PAR1 exosite interaction motif, wherein X is an aliphatic amino acid;
orv. any combination thereof, and wherein the first polypeptide chain and the second polypeptide chain are associated with each other.
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8-11. -11. (canceled)
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14-17. -17. (canceled)
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20-24. -24. (canceled)
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26-29. -29. (canceled)
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31-35. -35. (canceled)
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37-43. -43. (canceled)
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45. (canceled)
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47. (canceled)
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50-52. -52. (canceled)
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54-56. -56. (canceled)
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58-61. -61. (canceled)
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63-67. -67. (canceled)
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69-83. -83. (canceled)
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85. (canceled)
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87. (canceled)
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89-90. -90. (canceled)
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92-93. -93. (canceled)
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95-97. -97. (canceled)
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99. (canceled)
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100. A method of improving FVIII activity of a chimeric FVIII protein comprising a VWF protein, a heterologous moiety (H1), and a VWF linker connecting the VWF protein and the heterologous moiety (H1) and a second polypeptide chain comprising a FVIII protein and an XTEN sequence, wherein the VWF linker in the first polypeptide chain comprises:
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vi. an a2 region from FVIII; vii. an a1 region from FVIII; viii. an a3 region from FVIII; ix. a thrombin cleavage site which comprises X-V-P-R (SEQ ID NO;
3) and a PAR1 exosite interaction motif, wherein X is an aliphatic amino acid;
orx. any combination thereof.
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101-111. -111. (canceled)
Specification