Methods to enhance delivery and engraftment of stem cells including the identification of specific prostagandin e2 receptors

Abstract

The receptor EP 4 is identified as the PGE 2 receptor that is most responsible enhancing the homing and engraftment of hematopoietic stem and progenitor cells. Treatment of graft sources and graft recipients with compounds that preferentially target the EP 4 receptor provide effective methods of increasing engraftment success while minimizing adverse side effects that may Obe associated with therapies that include the use of less selective molecules such as PGE 2 and dmPGE 2 . One effective molecule used in such therapies is 5-[(1E,3R)-4,4-ditluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-1-[6-(2H-tetrazol-5R-yl)hexyl]-2-pyrrolidinone or a pharmaceutically acceptable salt thereof (L-902, 685).

1 . A method of treating a donor, donor cells or a recipient of hematopoietic stem or progenitor cells, comprising the steps of:
 providing at least one compound that preferentially interacts with a PGE 2  EP 4  receptor on a hematopoietic stem or progenitor cell, or a pharmaceutically acceptable salt thereof; and   administering a therapeutically acceptable dose of said at least one compound to a patient where the patient is a donor or a recipient of the hematopoietic stem or progenitor cells.   
     
     
         2 . The method according to  claim 1 , wherein the compound increases the homing and/or engraftment of the hematopoietic stem or progenitor cells. 
     
     
         3 . The method according to  claim 1 , wherein said at least one compound is selected from the groups consisting of: 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5 -[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxocyclopentyl]sulfanylpropylsulfanyl]acetic acid; methyl 4-[2-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl]- 5 -oxocyclopentyl]ethyl sulfanyl]butanoate; 16-(3-Methoxymethyl)phenyl-ω-tetranor-5-thiaPGE; 5-{3-[(2S)-2-(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylate; [4′-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]; and ((Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}hept- 5 -enoic acid) or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method according to  claim 1 , wherein said at least one compound is 5-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-146-(2H-tetrazol-5R-yl)hexyl]-2-pyrrolidinone or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method according to  claim 1 , wherein the patient is the recipient of a graft wherein the graft includes at least one type of cell selected from the group consisting of hematopoietic stem cells and progenitor cells, wherein the cells have been treated with said at least one compound that preferentially binds to the PGE2 EP4 receptor. 
     
     
         6 . The method according to  claim 1 , wherein the patient is a human. 
     
     
         7 . The method according to  claim 1 , wherein the patient is an animal. 
     
     
         8 . A method of treating a patient, comprising the steps of:
 providing a therapeutically effective amount of a PGE2 EP4 agonist or a pharmaceutically acceptable salt thereof; and   harvesting a hematopoietic stem or progenitor cell from a donor; and   contacting said PGE2 EP4 agonist with a hematopoietic stem or progenitor cell, wherein said hematopoietic stem or progenitor cell was harvested from the donor.   
     
     
         9 . The method according to  claim 8 , wherein said at least one compound is selected from the groups consisting of: 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxocyclopentyl]sulfanylpropylsulfanyl]acetic acid; methyl 4-[2-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl]-5-oxocyclopentyl]ethyl sulfanyl]butanoate; 16-(3-Methoxymethyl)phenyl-ω-tetranor-5-thiaPGE; 5-{3-[(2S)-2-(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylate; [4′-[3 -butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]; and ((Z)-7-(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoic acid) or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 8 , wherein said at least one compound is 5-[(1E,3R)-4,4-difluoro-3-hydroxy-4-phenyl-1-buten-1-yl]-1-[6-(2H-tetrazol-5R-yl)hexyl]-2-pyrrolidinone or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 8 , further comprising the step of:
 administering the hematopoietic stem or progenitor cell to a patient, wherein said cells are administered to a recipient after the cells have been contacted with said therapeutically effective amount of a PGE2 EP4 agonist or a pharmaceutically acceptable salt thereof   
     
     
         12 . The method according to  claim 8 , wherein the therapeutically effective amount of said PGE2 EP4 agonist or a pharmaceutically acceptable salt thereof is between about 0.001 μM to about 10 μM per about 1.0×106 per ml to about 1.0×107 per ml of said hematopoietic stem or progenitor cells. 
     
     
         13 . The method according to  claim 8 , wherein the hematopoietic stem or progenitor cells are harvested from marrow, umbilical cord or peripheral blood. 
     
     
         14 . The method according to  claim 8 , wherein the donor is a human. 
     
     
         15 . The method according to  claim 8 , wherein the donor is an animal. 
     
     
         16 . The method according to  claim 11 , wherein the donor and the recipient of the hematopoietic stem or progenitor cell are the same human or animal patient. 
     
     
         17 .- 24 . (canceled)