Compositions and methods for cell transplantation

Abstract

The present invention relates to compositions and methods for cell transplantation. In particular, the present invention provides a composition comprising procoagulant cells and at least one antithrombin activator, preferably unfractionated heparin, as well as at least one thrombin inhibitor, preferably bivalirudin.

1 . A combination comprising cells having procoagulant activity, as determined by thromboelastometry, at least one antithrombin activator, and at least one thrombin inhibitor. 
     
     
         2 . The combination according to  claim 1 , wherein said cells are selected from the group consisting of stem cells and progenitor cells. 
     
     
         3 . The combination according to  claim 1 , wherein the cells are adult liver-derived progenitor or stem cells, mesenchymal stem cells (preferably bone marrow mesenchymal stem cells), skin fibroblasts, or liver myofibroblasts. 
     
     
         4 . The combination according to  claim 1 , wherein the cells express tissue factor. 
     
     
         5 . The combination according to  claim 1 , wherein the cells comprise a procoagulant activity component independent of the expression of tissue factor by the cells and/or comprise a procoagulant activity component resistant to heparin. 
     
     
         6 . A combination comprising at least one antithrombin activator, at least one thrombin inhibitor, and cells selected from the group consisting of adult liver progenitor cells and liver myofibroblasts. 
     
     
         7 . The combination according to  claim 1  configured for separate, simultaneous or sequential in any order administration of said cells, at least one antithrombin activator and at least one thrombin inhibitor to a subject. 
     
     
         8 . The combination according to  claim 1 , wherein the antithrombin activator is selected from the group consisting of unfractionated heparin, low molecular weight heparin and fondaparinux, preferably unfractionated heparin. 
     
     
         9 . The combination according to  claim 1 , wherein the thrombin inhibitor is selected from the group consisting of bivalirudin and hirudin, preferably bivalirudin. 
     
     
         10 . A pharmaceutical composition comprising the combination according to  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         11 . (canceled) 
     
     
         12 . A method for treatment of thrombosis or thrombotic complications caused by transplantation of cells as defined in  claim 1 , or a method for transplantation of cells as defined in  claim 1 , or a method for inhibiting procoagulant activity of the cells as defined in  claim 1  in vivo comprising administering the combination according to  claim 1  or a pharmaceutical composition comprising the combination according to  claim 1  and one or more pharmaceutically acceptable excipients to a subject in need thereof. 
     
     
         13 . The method according to  claim 12 , wherein the antithrombin activator is unfractionated heparin to be administered to a subject via a cell suspension comprising about 5-15 IU/ml, preferably about 8-12 IU/ml, more preferably about 10 IU/ml or by intravenous administration at about 10-30 IU/kg/hr, preferably about 15-25 IU/kg/hr, more preferably about 20 IU/kg/hr and/or wherein the thrombin inhibitor is bivalirudin or hirudin to be administered to a subject respectively at between about 0.50 and about 3.00 mg/kg body weight or between about 0.2 and 0.6 mg/kg body weight. 
     
     
         14 . The method according to  claim 12 , wherein (a) a composition comprising a cell suspension of the cells in an aqueous solution containing the at least one antithrombin activator is to be prepared; (b) an aqueous solution containing the at least one thrombin inhibitor is to be prepared; and (c) the composition as defined in (a) and the solution as defined in (b) is to be administered simultaneously, separately or sequentially to a subject. 
     
     
         15 . A method for inhibiting in vitro the procoagulant activity of cells as defined in  claim 1  comprising providing a combination comprising said cells, at least one antithrombin activator, and at least one thrombin inhibitor. 
     
     
         16 . A kit of parts or an article of manufacture comprising the combination according to  claim 1  and optionally comprising one or more pharmaceutically acceptable excipients. 
     
     
         17 . A method for treatment of thrombosis or thrombotic complications caused by transplantation of cells as defined in  claim 1 , or a method for transplantation of cells as defined in  claim 1 , or a method for inhibiting procoagulant activity of the cells as defined in  claim 1  in vivo comprising administering a combination comprising at least one antithrombin activator and at least one thrombin inhibitor, or a pharmaceutical composition comprising said combination and one or more pharmaceutically acceptable excipients to a subject in need thereof. 
     
     
         18 . The method according to  claim 17 , wherein the antithrombin activator is selected from the group consisting of unfractionated heparin, low molecular weight heparin and fondaparinux, preferably unfractionated heparin. 
     
     
         19 . A method for inhibiting in vitro the procoagulant activity of cells as defined in  claim 1  comprising contacting said cells with a combination comprising at least one antithrombin activator and at least one thrombin inhibitor. 
     
     
         20 . The method according to  claim 17 , wherein the thrombin inhibitor is selected from the group consisting of bivalirudin and hirudin, preferably bivalirudin. 
     
     
         21 . The method according to  claim 12 , wherein the antithrombin activator is selected from the group consisting of unfractionated heparin, low molecular weight heparin and fondaparinux, preferably unfractionated heparin. 
     
     
         22 . The method according to  claim 12 , wherein the thrombin inhibitor is selected from the group consisting of bivalirudin and hirudin, preferably bivalirudin. 
     
     
         23 . The method according to  claim 17 , wherein the antithrombin activator is unfractionated heparin to be administered to a subject via a cell suspension comprising about 5-15 IU/ml, preferably about 8-12 IU/ml, more preferably about 10 IU/ml or by intravenous administration at about 10-30 IU/kg/hr, preferably about 15-25 IU/kg/hr, more preferably about 20 IU/kg/hr and/or wherein the thrombin inhibitor is bivalirudin or hirudin to be administered to a subject respectively at between about 0.50 and about 3.00 mg/kg body weight or between about 0.2 and 0.6 mg/kg body weight. 
     
     
         24 . The method according to  claim 17 , wherein (a) a composition comprising a cell suspension of the cells in an aqueous solution containing the at least one antithrombin activator is to be prepared; (b) an aqueous solution containing the at least one thrombin inhibitor is to be prepared; and (c) the composition as defined in (a) and the solution as defined in (b) is to be administered simultaneously, separately or sequentially to a subject.