US2009192082A1PendingUtilityA1

Cxcr4 antagonist treatment of hematopoietic cells

72
Individually held — no corporate assignee on recordPriority: May 9, 2000Filed: Aug 11, 2008Published: Jul 30, 2009
Est. expiryMay 9, 2020(expired)· nominal 20-yr term from priority
Inventors:Christopher R. TudanAhmed MerzoukLakhdar ArabGeeta SaxenaConnie EavesJoanne CashmanIan Clark-LewisHassan SalariMary A. RichterMichael Clark-Lewis
A61K 38/10A61P 35/02A61P 43/00C12N 2501/21A61K 38/1709A61P 35/00C07K 14/522A61K 48/00C07K 14/4703C12N 5/0647
72
PatentIndex Score
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Claims

Abstract

Compositions comprising a peptide consisting of an amino acid sequence derived from a P2G-substituted SDF-1 protein are taught. The amino acid sequence consists of a first sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif. The amino acid sequences may also consist of one or more optional components selected from the group consisting of a second sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif, wherein the second sequence is covalently joined to the first sequence with or without a linker; and, a third sequence consisting of LKWIQEYLEKALN, or conservative substitutions thereof, wherein the third sequence is covalently joined to the first sequence with the linker. Methods of increasing multiplication of hematopoietic cells and enhancing proliferation of hematopoietic cells during engraftment are also taught.

Claims

exact text as granted — not AI-modified
1 . A composition comprising a peptide consisting of an amino acid sequence derived from a P2G-substituted SDF-1 protein, wherein the amino acid sequence consists of
 a first sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1); and one or more optional components selected from the group consisting of   a second sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1), wherein the second sequence is covalently joined to the first sequence with or without a linker; and,   a third sequence consisting of LKWIQEYLEKALN (residues 55-67 in SEQ ID NO:1), or conservative substitutions thereof, wherein the third sequence is covalently joined to the first sequence with the linker;   
       wherein,
 the linker consists of 1 to 4 natural amino acids or an aminoalkanoic acid having up to 20 carbons; and 
 the peptide is optionally modified with one or more modifying groups selected from the group consisting of an acyl group, an acetyl group, an amide group, a detectable substance, a modifier capable of reducing the ability of the analog to act as a substrate for carboxypeptidases, or a modifier capable of reducing the ability of the analog to act as a substrate for aminopeptidases. 
 
     
     
         2 . The composition of  claim 1 , wherein the peptide is selected from the group consisting of SEQ ID NO:15 to SEQ ID NO:39. 
     
     
         3 . The composition of  claim 1 , wherein the peptide consists of the first sequence covalently joined to the second sequence with or without the linker. 
     
     
         4 . The composition of  claim 1 , wherein the peptide consists of a dimer selected from the group consisting of SEQ ID NO:40 to SEQ ID NO:50 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         5 . The composition of  claim 1 , wherein the peptide consists of a dimer selected from the group consisting of SEQ ID NO:51 to SEQ ID NO:72 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         6 . The composition of  claim 1 , wherein the peptide consists of a dimer having SEQ ID NO:134 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         7 . The composition of  claim 1 , wherein the peptide consists of a dimer having SEQ ID NO:135 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         8 . The composition of  claim 1 , wherein the peptide consists of a dimer having SEQ ID NO:136 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         9 . The composition of  claim 1 , wherein the peptide consists of the first sequence covalently joined to the third sequence with the linker. 
     
     
         10 . The composition of  claim 1 , wherein the peptide is selected from the group consisting of SEQ ID NOs: 74, 75, 137, 138, and 139, or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         11 . The composition of  claim 1 , wherein the peptide is selected from the group consisting of SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:76 to SEQ ID NO:122 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         12 . The composition of  claim 1 , wherein the peptide has at least 90% identity to any contiguous sequence of 10, 20, 30, 40, 50 or more amino acid residues composing a portion of a native SDF-1 sequence. 
     
     
         13 . The composition of  claim 1 , wherein the first sequence consists of KGVSLSYRCPCRFF (residues 1-14 of SEQ ID NO:13). 
     
     
         14 . The composition of  claim 1 , wherein the first sequence consists of KGVSLSYRCPCRFFESH (SEQ ID NO:13). 
     
     
         15 . The composition of  claim 1 , wherein the linker is GGGG (residues 15-18 of SEQ ID NO: 74). 
     
     
         16 . The composition of  claim 1 , wherein the third sequence is cyclized at residue positions corresponding to K 56  and E 60  of SEQ ID NO: 1. 
     
     
         17 . The composition of  claim 1 , wherein the peptide is SEQ ID NO:123 or SEQ ID NO:124 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         18 . The composition of  claim 1 , wherein the third sequence is cyclized at residue positions corresponding to E 60  and K 64  of SEQ ID NO:1. 
     
     
         19 . The composition of  claim 1 , wherein the peptide is SEQ ID NO:125 or SEQ ID NO:126 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         20 . A pharmaceutical composition comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a peptide selected from the group consisting of SEQ ID NOs: 74, 75, and 134-139 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         22 . A method of increasing multiplication of hematopoietic cells, wherein the method comprises contacting a hematopoietic cell with an effective amount of a composition comprising a peptide consisting of an amino acid sequence derived from a P2G-substituted SDF-1 protein, wherein the amino acid sequence consists of
 a first sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1); and one or more optional components selected from the group consisting of   a second sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1), wherein the second sequence is covalently joined to the first sequence with or without a linker; and,   a third sequence consisting of LKWIQEYLEKALN (residues 55-67 in SEQ ID NO:1), or conservative substitutions thereof, wherein the third sequence is covalently joined to the first sequence with the linker;   
       wherein,
 the linker consists of 1 to 4 natural amino acids or an aminoalkanoic acid having up to 20 carbons; and 
 the peptide is optionally modified with one or more modifying groups selected from the group consisting of an acyl group, an acetyl group, an amide group, a detectable substance, a modifier capable of reducing the ability of the analog to act as a substrate for carboxypeptidases, or a modifier capable of reducing the ability of the analog to act as a substrate for aminopeptidases; 
 and wherein, the cellular multiplication of the hematopoietic cells is greater after contacting the cells with the effective amount of the composition than after contacting the cells with only saline solution. 
 
     
     
         23 . The method of  claim 22 , wherein the peptide consists of a dimer having SEQ ID NO:134 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         24 . The method of  claim 22 , wherein the peptide consists of a dimer having SEQ ID NO:135 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         25 . The method of  claim 22 , wherein the peptide consists of a dimer having SEQ ID NO:136 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         26 . The method of  claim 22 , wherein the peptide consists of the first sequence covalently joined to the third sequence with the linker. 
     
     
         27 . The method of  claim 22 , wherein the peptide is selected from the group consisting of SEQ ID NOs: 74, 75, 137, 138, and 139, or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         28 . The method of  claim 22 , wherein the peptide has at least 90% identity to any contiguous sequence of 10, 20, 30, 40, 50 or more amino acid residues composing a portion of a native SDF-1 sequence. 
     
     
         29 . The method of  claim 22 , wherein the first sequence consists of KGVSLSYRCPCRFF (residues 1-14 of SEQ ID NO:13). 
     
     
         30 . The method of  claim 22 , wherein the first sequence consists of KGVSLSYRCPCRFFESH (SEQ ID NO:13). 
     
     
         31 . The method of  claim 22 , wherein the hematopoietic cells are human progenitor cells. 
     
     
         32 . A method of enhancing proliferation of hematopoietic cells during engraftment, wherein the method comprises administering to a mammal an effective amount of a composition comprising a peptide consisting of an amino acid sequence derived from a P2G-substituted SDF-1 protein, wherein the amino acid sequence consists of:
 a first sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1); and one or more optional components selected from the group consisting of   a second sequence consisting of 8 to 17 amino acids from the N-terminal portion of the SDF-1 protein and having a conserved KGVS motif (residues 1-4 in SEQ ID NO:1), wherein the second sequence is covalently joined to the first sequence with or without a linker; and,   a third sequence consisting of LKWIQEYLEKALN (residues 55-67 in SEQ ID NO:1), or conservative substitutions thereof, wherein the third sequence is covalently joined to the first sequence with the linker;   
       wherein,
 the linker consists of 1 to 4 natural amino acids or an aminoalkanoic acid having up to 20 carbons; and 
 the peptide is optionally modified with one or more modifying groups selected from the group consisting of an acyl group, an acetyl group, an amide group, a detectable substance, a modifier capable of reducing the ability of the analog to act as a substrate for carboxypeptidases, or a modifier capable of reducing the ability of the analog to act as a substrate for aminopeptidases; 
 and wherein, the proliferation of the hematopoietic cells is greater in the mammal after administering the effective amount of the composition than in the absence of the composition. 
 
     
     
         33 . The method of  claim 32 , wherein the peptide consists of a dimer having SEQ ID NO:134 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         34 . The method of  claim 32 , wherein the peptide consists of a dimer having SEQ ID NO:135 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         35 . The method of  claim 32 , wherein the peptide consists of a dimer having SEQ ID NO:136 or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         36 . The method of  claim 32 , wherein the peptide consists of the first sequence covalently joined to the third sequence with the linker. 
     
     
         37 . The method of  claim 32 , wherein the peptide is selected from the group consisting of SEQ ID NOs: 74, 75, 137, 138, and 139, or conservative substitutions thereof having the conserved KGVS motif. 
     
     
         38 . The method of  claim 32 , wherein the peptide has at least 90% identity to any contiguous sequence of 10, 20, 30, 40, 50 or more amino acid residues composing a portion of a native SDF-1 sequence. 
     
     
         39 . The method of  claim 32 , wherein the first sequence consists of KGVSLSYRCPCRFF (residues 1-14 of SEQ ID NO:13). 
     
     
         40 . The method of  claim 32 , wherein the first sequence consists of KGVSLSYRCPCRFFESH (SEQ ID NO:13). 
     
     
         41 . The method of  claim 32 , wherein the hematopoietic cells are human progenitor cells. 
     
     
         42 . The method of  claim 32 , wherein the hematopoietic cells are progenitor cells selected from the group consisting of CFU-GM cells, BFU-E cells, and LTC-IC cells.

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