초록 ▼

The invention provides improved methods for cell therapy. In particular, the invention provides therapeutic compositions of enhanced hematopoietic stem and progenitor cells having improved engraftment and homing properties, and methods of making the therapeutic compositions. The invention further pr

The invention provides improved methods for cell therapy. In particular, the invention provides therapeutic compositions of enhanced hematopoietic stem and progenitor cells having improved engraftment and homing properties, and methods of making the therapeutic compositions. The invention further provides methods of improving the efficacy of hematopoietic stem and progenitor cell transplantation including transplanting the therapeutic composition to subjects in need of hematopoietic system reconstitution.

대표청구항 ▼

1. A human hematopoietic stem or progenitor cell that has been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cell by at least about 30 fold in the contacted hematopoietic stem or progenitor cell compared to a hematopoietic stem or progenitor cell that has not b

1. A human hematopoietic stem or progenitor cell that has been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cell by at least about 30 fold in the contacted hematopoietic stem or progenitor cell compared to a hematopoietic stem or progenitor cell that has not been contacted ex vivo with one or more agents that increase CXCR4 gene expression. 2. The hematopoietic stem or progenitor cell of claim 1, wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists; and (ii) one or more glucocorticoids. 3. The hematopoietic stem or progenitor cell of claim 2, wherein the one or more prostaglandin pathway agonists comprises PGE2 or a PGE2 analogue or derivative thereof. 4. The hematopoietic stem or progenitor cell of claim 2, wherein the one or more glucocorticoids is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6amethylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol. 5. The hematopoietic stem or progenitor cell of claim 1, wherein the cell is obtained from bone marrow, umbilical cord blood, mobilized peripheral blood, Wharton's jelly, placenta, or fetal blood. 6. A therapeutic composition comprising a population of cells comprising human hematopoietic stem or progenitor cells contacted ex vivo with one or more agents under conditions sufficient to increase CXCR4 expression in the human hematopoietic stem or progenitor cells by at least about 30 fold compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression. 7. The therapeutic composition of claim 6, wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists and (ii) one or more glucocorticoids. 8. The therapeutic composition of claim 6, wherein gene expression of CXCR4 is increased by at least about 40 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression. 9. The therapeutic composition of claim 7, wherein the one or more prostaglandin pathway agonists comprises PGE2 or a PGE2 analogue or derivative thereof. 10. The therapeutic composition of claim 7, wherein the one or more glucocorticoids is selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol. 11. The therapeutic composition of claim 6, wherein the hematopoietic stem or progenitor cells have been contacted for a time of at least about one hour with at least one of (i) one or more prostaglandin pathway agonists and (ii) one or more glucocorticoids. 12. The therapeutic composition of claim 6, wherein the population of cells comprises at least about 0.01% and no more than about 50% of CD34+ cells. 13. The therapeutic composition of claim 6, wherein the composition is not cultured. 14. A method of increasing hematopoietic stem or progenitor cell homing, engraftment, or reconstitution in a subject comprising administering to the subject a composition comprising a population of cells comprising human hematopoietic stem or progenitor cells wherein: a) the hematopoietic stem or progenitor cells have been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cells; andb) gene expression of CXCR4 is increased at least about 30 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression in the cells. 15. The method of claim 14, wherein the one or more agents comprise (i) one or more prostaglandin pathway agonists; and (ii) one or more glucocorticoids. 16. The method of claim 14, wherein the hematopoietic stem or progenitor cells are obtained from bone marrow, umbilical cord blood, mobilized peripheral blood, Wharton's jelly, placenta, or fetal blood. 17. The method of claim 15, wherein gene expression of CXCR4 is increased by at least about 40 fold in the contacted hematopoietic stem or progenitor cells compared to hematopoietic stem or progenitor cells that have not been contacted ex vivo with one or more agents that increase CXCR4 gene expression. 18. The method of claim 15, wherein the prostaglandin pathway agonist comprises PGE2 or a PGE2 analogue or derivative thereof. 19. The method of claim 15, wherein the one or more glucocorticoids are selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cloprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide hemihydrate, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide and ulobetasol. 20. The method of claim 15, wherein the hematopoietic stem or progenitor cells have been contacted with one or more prostaglandin pathway agonists and one or more glucocorticoids for a time of at least about one hour. 21. The method claim 15, wherein the population of cells comprises at least about 0.01% and no more than about 50% of CD34+ cells. 22. The method of claim 15, wherein the composition is not cultured. 23. The method of claim 15, wherein the subject: a) has acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), juvenile myelomonocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, severe aplastic anemia, Fanconi's anemia, paroxysmal nocturnal hemoglobinuria (PNH), pure red cell aplasia, amegakaryocytosis/congenital thrombocytopenia, severe combined immunodeficiency syndrome (SCID), Wiskott-Aldrich syndrome, beta-thalassemia major, sickle cell disease, Hurler's syndrome, adrenoleukodystrophy, metachromatic leukodystrophy, myelodysplasia, refractory anemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia, familial erythrophagocytic lymphohistiocytosis, or solid tumors;b) has breast cancer, ovarian cancer, brain cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, pancreatic cancer, or sarcoma;c) has received bone marrow ablative or non-myeolablative chemotherapy or radiation therapy; ord) is a bone marrow donor. 24. The hematopoietic stem or progenitor cell of claim 1, wherein the cell is contacted with the one or more agents at a temperature of about 22° C. to about 39° C. 25. The therapeutic composition of claim 1, wherein the cell is contacted with the one or more agents at a temperature of about 35° C. to about 39° C. 26. The therapeutic composition of claim 6, wherein the cell is contacted with the one or more agents at a temperature of about 22° C. to about 39° C. 27. The therapeutic composition of claim 6, wherein the cell is contacted with the one or more agents at a temperature of about 35° C. to about 39° C. 28. The therapeutic composition of claim 6, wherein the population of cells is not expanded ex vivo. 29. A human hematopoietic stem or progenitor cell having CXCR4 gene expression of at least 30-fold greater compared to basal CXCR4 gene expression of a control hematopoietic stem or progenitor cell. 30. The human hematopoietic stem or progenitor cell of claim 29, wherein the hematopoietic stem or progenitor cell has at least 40-fold greater CXCR4 gene expression compared to basal CXCR4 gene expression. 31. A population of cells comprising the human hematopoietic stem or progenitor cell of claim 29. 32. The population of cells of claim 31, wherein the population comprises at least about 0.01% and no more than about 50% CD34+ cells. 33. The population of cells of claim 31, wherein the cells are ready for administration to a human subject in need thereof. 34. A therapeutic composition comprising the human hematopoietic stem or progenitor cell of claim 29. 35. The hematopoietic stem or progenitor cell of claim 1, wherein the one or more prostaglandin pathway agonists comprises 16,16-dimethyl-PGE2. 36. The therapeutic composition of claim 9, wherein the one or more prostaglandin pathway agonists comprises 16,16-dimethyl-PGE2. 37. The therapeutic composition according to claim 11, wherein the one or more prostaglandin pathway agonists comprises 16,16-dimethyl-PGE2. 38. The method of claim 15, wherein the one or more prostaglandin pathway agonists comprises 16,16-dimethyl-PGE2. 39. The therapeutic composition of claim 6, wherein the hematopoietic stem or progenitor cells have been contacted for a time of two hours to six hours with at least one of (i) one or more prostaglandin pathway agonists and (ii) one or more glucocorticoids. 40. The method of claim 15, wherein the hematopoietic stem or progenitor cells have been contacted with one or more prostaglandin pathway agonists and one or more glucocorticoids for a time of two hours to six hours.