US2010227808A1PendingUtilityA1

Human kunitz-type inhibitor with enhanced antifibrinolytic activity

55
Assignee: STC UNMPriority: Apr 16, 2004Filed: Nov 12, 2008Published: Sep 9, 2010
Est. expiryApr 16, 2024(expired)· nominal 20-yr term from priority
Inventors:Walter KisielHitendra S. Chand
A61P 35/00A61P 31/16C07K 14/8114A61P 11/06A61K 38/00
55
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Claims

Abstract

A human Kunitz-type inhibitor polypeptide with enhanced antifibrinolytic activity, methods of making, and methods of use. The novel polypeptide is structurally similar to the KD1 domain of human tissue factor pathway inhibitor-2 (TFPI-2).

Claims

exact text as granted — not AI-modified
1 - 51 . (canceled) 
     
     
         52 . A polypeptide comprising:
 a KD1 domain consisting of a primary structure that is at least 86% identical to the primary structure of the wild-type KD1 domain of human tissue factor pathway inhibitor-2 (TFPI-2) (SEQ ID NO:2), or a biologically active subunit thereof;   wherein the polypeptide does not include a KD2 or KD3 domain of human TFPI-2.   
     
     
         53 . The polypeptide of  claim 52  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         54 . The polypeptide of  claim 53  comprising SEQ ID NO:3. 
     
     
         55 . The polypeptide of  claim 52  wherein the biologically active subunit of KD1 is characterized by a deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues at either or both of the amino-terminal or carboxy-terminal end relative to the wild-type KD1 sequence. 
     
     
         56 . The polypeptide of  claim 52  wherein the KD1 domain consists of a primary structure that is at least 90% identical to the primary structure of the wild-type KD1 domain of TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         57 . The polypeptide of  claim 56  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         58 . The polypeptide of  claim 52  wherein the KD1 domain consists of a primary structure that is at least 95% identical to the primary structure of the wild-type KD1 domain of TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         59 . The polypeptide of  claim 58  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         60 . A polypeptide comprising:
 a KD1 domain consisting of a primary structure that is at least 86% identical to the primary structure of the wild-type KD1 domain of human tissue factor pathway inhibitor-2 (TFPI-2) (SEQ ID NO:2), or a biologically active subunit thereof, wherein the polypeptide does not include a KD2 or KD3 domain of human TFPI-2; and   a multiply positively charged amino acid sequence disposed at either or both of the N-terminal or C-terminal end of the polypeptide.   
     
     
         61 . The polypeptide of  claim 60  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         62 . The polypeptide of  claim 60  wherein the KD1 domain consists of a primary structure that is at least 90% identical to the primary structure of the wild-type KD1 domain of TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         63 . The polypeptide of  claim 62  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         64 . The polypeptide of  claim 60  wherein the KD1 domain consists of a primary structure that is at least 95% identical to the primary structure of the wild-type KD1 domain of TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         65 . The polypeptide of  claim 64  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         66 . The polypeptide of  claim 60  wherein the multiply positively charged amino acid sequence comprises an amino acid sequence from the C-terminus of wild-type TFPI-2. 
     
     
         67 . The polypeptide of  claim 66  wherein the multiply positively charged amino acid sequence comprises amino acids 192 through 211 of SEQ ID NO:1. 
     
     
         68 . A polypeptide comprising:
 a KD1 domain consisting of a primary structure that is at least 86% identical to the primary structure of the wild-type KD1 domain of human tissue factor pathway inhibitor-2 (TFPI-2) (SEQ ID NO:2), or a biologically active subunit thereof; and   a multiply positively charged amino acid sequence disposed at either or both of the N-terminal or C-terminal end of the polypeptide.   
     
     
         69 . The polypeptide of  claim 68  wherein the KD1 domain comprises a lysine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         70 . The polypeptide of  claim 68  wherein the KD1 domain consists of a primary structure that is at least 90% identical to the primary structure of a wild-type KD1 domain of human TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         71 . The polypeptide of  claim 70  wherein the KD1 domain comprises a lysine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         72 . The polypeptide of  claim 68  wherein the KD1 domain consists of a primary structure that is at least 95% identical to the primary structure of the wild-type KD1 domain of TFPI-2 (SEQ ID NO:2), or a biologically active subunit thereof. 
     
     
         73 . The polypeptide of  claim 72  wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence. 
     
     
         74 . The polypeptide of  claim 68  wherein the multiply positively charged amino acid sequence comprises an amino acid sequence from the C-terminus of wild-type TFPI-2. 
     
     
         75 . The polypeptide of  claim 74  wherein the multiply positively charged amino acid sequence comprises amino acids 192 through 211 of SEQ ID NO:1. 
     
     
         76 . A polypeptide comprising:
 a KD1 domain consisting of a primary structure that is at least 86% identical to the primary structure of the wild-type KD1 domain of human tissue factor pathway inhibitor-2 (TFPI-2) (SEQ ID NO:2);   wherein the polypeptide includes a lysine instead of arginine at position 24 as defined for the wild-type KD1 amino acid sequence.   
     
     
         77 . A pharmaceutical composition comprising:
 the polypeptide of  claim 52 ; and   a pharmaceutically acceptable carrier.   
     
     
         78 . A pharmaceutical composition comprising:
 the polypeptide of  claim 60 ; and   a pharmaceutically acceptable carrier.   
     
     
         79 . A pharmaceutical composition comprising:
 the polypeptide of  claim 68 ; and   a pharmaceutically acceptable carrier.   
     
     
         80 . A pharmaceutical composition comprising:
 the polypeptide of  claim 76 ; and   a pharmaceutically acceptable carrier.

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