US2011230422A1PendingUtilityA1

Purging of an ex vivo hematopoietic stem cell culture of cancer cells

66
Individually held — no corporate assignee on recordPriority: May 9, 2000Filed: Dec 23, 2009Published: Sep 22, 2011
Est. expiryMay 9, 2020(expired)· nominal 20-yr term from priority
Inventors:Christopher R. TudanAhmed MerzoukLakhdar ArabGeeta SaxenaConnie EavesJoanne CashmanIan Clark-LewisMary A. RichterMichael Clark-LewisHassan Salari
A61P 35/02C07K 14/522C12N 2501/21A61P 35/00C12N 5/0647A61K 48/00C07K 14/4703A61K 38/10A61P 43/00A61K 38/1709
66
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Claims

Abstract

A use of a composition comprising an SDF-1 peptide having the sequence KGVSLSYR is taught. The composition can be used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount.

Claims

exact text as granted — not AI-modified
1 . A composition comprising a peptide having KGVSLSYR (residues 1-8 of SEQ ID NO: 14), wherein the composition is used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount. 
     
     
         2 . The composition of  claim 1  comprising a peptide consisting of KGVSLSYRC (SEQ ID NO:14). 
     
     
         3 . The composition of  claim 1  comprising a peptide consisting of KGVSLSYRCPCRFFESH (SEQ ID NO:13). 
     
     
         4 . A composition comprising a dimer having the peptide of  claim 1 ,  2 , or  3 , wherein the composition is used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount. 
     
     
         5 . The composition of  claim 1  comprising a dimer consisting of SDF-1(1-8[P2G]) 2 . 
     
     
         6 . The composition of  claim 1  comprising a dimer consisting of SDF-1(1-9[P2G]) 2 . 
     
     
         7 . The composition of  claim 1  comprising a dimer consisting of: 
       
         
           
           
               
               
           
         
       
       wherein KGVSLSYR (SEQ ID NO: 3) is dimerized with the linker X. 
     
     
         8 . The composition of  claim 1  comprising a dimer consisting of: 
       
         
           
           
               
               
           
         
       
       wherein KGVSLSYRC (SEQ ID NO: 4) is dimerized with the linker X. 
     
     
         9 . The composition of  claim 1  comprising a dimer consisting of: 
       
         
           
           
               
               
           
         
       
       wherein KGVSLSYRCPCRFFESH (SEQ ID NO: 1) is dimerized using a linker X. 
     
     
         10 . The composition of  claim 7 ,  8 , or  9 , wherein the X comprises K. 
     
     
         11 . A composition comprising an SDF-1 analog that binds to a CXC chemokine receptor 4 (CXCR4), wherein the analog is selected from the group consisting of:
 1) a first SDF-1 analog consisting of:
 (i) an N-terminal region consisting of from 14 to about 17 amino acids that comprise a conserved KGVS (residues 1-4 in SEQ ID NO:1) motif in residue positions 1-4, and a conserved CPCRFF (residues 9-14 in SEQ ID NO:1) in residue positions 9-14; 
 (ii) a C-terminal region consisting of LKWIQEYLEKALN (residues 55-67 in SEQ ID NO:1); and 
 (iii) a linker consisting of either 4 natural amino acids or an aminoalkanoic acid having up to 20 carbons, where the linker connects the N-terminal region to the C-terminal region to form the SDF-1 analog; and 
   2) a second SDF-1 analog consisting of the first SDF-1 analog having conservative amino acid substitutions, wherein the conservative amino acid substitutions occur in any of residues 9-14 of the N-terminal region or the C-terminal region;   wherein the first or second SDF-1 analog is optionally modified with an acyl group, 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 composition is used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount.   
     
     
         12 . The composition of  claim 11 , wherein the N-terminal region of the SDF-1 analog consists of KGVSLSYRCPCRFF (residues 1-14 of SEQ ID NO:13). 
     
     
         13 . The composition of  claim 11 , wherein the N-terminal region of the SDF-1 analog consists of KGVSLSYRCPCRFFESH (SEQ ID NO:13). 
     
     
         14 . The composition of  claim 11 , wherein the linker is GGGG (residues 15-18 of SEQ ID NO: 74). 
     
     
         15 . The composition of  claim 11 , wherein the C-terminal region of the SDF-1 analog is cyclized at residue positions corresponding to K 56  and E 60  of SEQ ID NO: 1. 
     
     
         16 . The composition of  claim 11 , wherein the C-terminal region of the SDF-1 analog is cyclized at residue positions corresponding to E 60  and K 64  of SEQ ID NO:1. 
     
     
         17 . A composition comprising an SDF-1 analog that binds to a CXC chemokine receptor 4 (CXCR4), wherein the analog is selected from the group consisting of SEQ ID NOs: 74, 75, 137, 138, and 139, and wherein the composition is used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount. 
     
     
         18 . A composition comprising an SDF-1 analog that binds to a CXC chemokine receptor 4 (CXCR4), wherein the analog consists of:
 (i) an N-terminal region selected from the group consisting of:
 a) residues 1-14 of SEQ ID NO:1, 
 b) residues 1-15 of SEQ ID NO:1, 
 c) residues 1-16 of SEQ ID NO:1, and 
 d) residues 1-17 of SEQ ID NO:1; 
   (ii) a C-terminal region consisting of LKWIQEYLEKALN (residues 55-67 in SEQ ID NO:1); and   (iii) a linker consisting of either 4 natural amino acids or an aminoalkanoic acid having up to 20 carbons, where the linker connects the N-terminal region to the C-terminal region to form the SDF-1 analog;   wherein the SDF-1 analog is optionally modified with an acyl group, 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 composition is used to purge an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal by administering the composition to the ex vivo hematopoietic stem cell culture in an effective amount.   
     
     
         19 . The composition of  claim 18 , wherein the C-terminal region of the SDF-1 analog is cyclized at residue positions corresponding to K 56  and E 60  of SEQ ID NO: 1. 
     
     
         20 . The composition of  claim 18 , wherein the C-terminal region of the SDF-1 analog is cyclized at residue positions corresponding to E 60  and K 64  of SEQ ID NO: 1. 
     
     
         21 . The composition of  claim 18 ,  19 , or  20 , wherein the engraftment is for the treatment of a blood cancer. 
     
     
         22 . The composition of  claim 18 , wherein the blood cancer comprises a leukemia. 
     
     
         23 . The composition of  claim 18 , wherein the blood cancer comprises acute myelogenous leukemia. 
     
     
         24 . The composition of  claim 18 , wherein the blood cancer comprises a lymphoma. 
     
     
         25 . The composition of  claim 18 , wherein the engraftment is from an autologous donor. 
     
     
         26 . The composition of  claim 18 , wherein the mammal is murine. 
     
     
         27 . The composition of  claim 18 , wherein the mammal is human. 
     
     
         28 . A method of purging an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal, wherein the method comprises:
 obtaining the ex vivo hematopoietic stem cell culture from a donor; and,   administering the composition of  claim 1  to the ex vivo hematopoietic stem cell culture in an effective amount to purge the ex vivo hematopoietic stem cell culture of cancer cells for engraftment in the mammal.   
     
     
         29 . The method of  claim 28 , wherein the engraftment is for the treatment of a blood cancer. 
     
     
         30 . The method of  claim 28 , wherein the blood cancer comprises a leukemia. 
     
     
         31 . The method of  claim 28 , wherein the blood cancer comprises acute myelogenous leukemia. 
     
     
         32 . The method of  claim 28 , wherein the blood cancer comprises a lymphoma. 
     
     
         33 . The method of  claim 28 , wherein the donor is an autologous donor. 
     
     
         34 . The method of  claim 28 , wherein the mammal is murine. 
     
     
         35 . The method of  claim 28 , wherein the mammal is human. 
     
     
         36 . A method of purging an ex vivo hematopoietic stem cell culture of cancer cells for engraftment in a mammal, wherein the method comprises:
 obtaining the ex vivo hematopoietic stem cell culture from a donor; and,   administering the composition of  claim 7  to the ex vivo hematopoietic stem cell culture in an effective amount to purge the ex vivo hematopoietic stem cell culture of cancer cells for engraftment in the mammal.   
     
     
         37 . The method of  claim 36 , wherein X is lysine. 
     
     
         38 . The method of  claim 36 , wherein the engraftment is for the treatment of a blood cancer. 
     
     
         39 . The method of  claim 36 , wherein the blood cancer comprises a leukemia. 
     
     
         40 . The method of  claim 36 , wherein the blood cancer comprises acute myelogenous leukemia. 
     
     
         41 . The method of  claim 36 , wherein the blood cancer comprises a lymphoma. 
     
     
         42 . The method of  claim 36 , wherein the donor is an autologous donor. 
     
     
         43 . The method of  claim 36 , wherein the mammal is murine. 
     
     
         44 . The method of  claim 36 , wherein the mammal is human. 
     
     
         45 . A method of treating a mammal in need of an ex vivo hematopoietic stem cell engraftment, wherein the method comprises:
 obtaining an ex vivo hematopoietic stem cell culture from the mammal;   administering the composition of  claim 1  to the ex vivo hematopoietic stem cell culture in an effective amount to purge the ex vivo hematopoietic stem cell culture of cancer cells for engraftment in the mammal; and,   engrafting the purged ex vivo hematopoietic stem cell culture in the mammal.   
     
     
         46 . The method of  claim 45 , wherein the engraftment is for the treatment of a blood cancer. 
     
     
         47 . The method of  claim 45 , wherein the blood cancer comprises a leukemia. 
     
     
         48 . The method of  claim 45 , wherein the blood cancer comprises acute myelogenous leukemia. 
     
     
         49 . The method of  claim 45 , wherein the blood cancer comprises a lymphoma. 
     
     
         50 . The method of  claim 45 , wherein the donor is an autologous donor. 
     
     
         51 . The method of  claim 45 , wherein the mammal is murine. 
     
     
         52 . The method of  claim 45 , wherein the mammal is human. 
     
     
         53 . A method of treating a mammal in need of an ex vivo hematopoietic stem cell engraftment, wherein the method comprises:
 obtaining an ex vivo hematopoietic stem cell culture from the mammal;   administering the composition of  claim 7  to the ex vivo hematopoietic stem cell culture in an effective amount to purge the ex vivo hematopoietic stem cell culture of cancer cells for engraftment in the mammal; and,   engrafting the purged ex vivo hematopoietic stem cell culture in the mammal.   
     
     
         54 . The method of  claim 53 , wherein X is lysine. 
     
     
         55 . The method of  claim 53 , wherein the engraftment is for the treatment of a blood cancer. 
     
     
         56 . The method of  claim 53 , wherein the blood cancer comprises a leukemia. 
     
     
         57 . The method of  claim 53 , wherein the blood cancer comprises acute myelogenous leukemia. 
     
     
         58 . The method of  claim 53 , wherein the blood cancer comprises a lymphoma. 
     
     
         59 . The method of  claim 53 , wherein the donor is an autologous donor. 
     
     
         60 . The method of  claim 53 , wherein the mammal is murine. 
     
     
         61 . The method of  claim 53 , wherein the mammal is human.

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