Methods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organs

Abstract

The present invention is directed to methods for delivering cells to a target tissue in a mammal using glycoconjugate to traffic the cell to a desired organ in the mammal. The methods according to the present invention are especially applicable to administering lymphoid cells such as natural killer (NK) cells activated with interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells and/or tumor-infiltrating lymphocytes (TILs) and/or cytotoxic lymphocytes (CTLs), or stem cells such as those derived from the bone marrow or from umbilical cord tissue. The methods are also useful for targeting a gene of interest to a tissue in a mammal by introducing a cell containing the gene of interest and administering a glycoconjugate to the mammal.

1 . A method for delivering a stem cell or lymphoid cell to a target tissue in a mammal comprising the steps of: 
 (a) administering a glycoconjugate to a mammal;    (b) administering the cell to the mammal.    
     
     
         2 . The method of  claim 1 , wherein the cell is a hematopoietic stem cell.  
     
     
         3 . The method of  claim 2 , wherein the stem cell is obtained from the bone marrow, placenta, muscle, fat or an umbilical cord.  
     
     
         4 . The method of  claim 1  wherein the lymphoid cell is selected from the group consisting of a natural killer (NK) cell, a lymphokine-activated killer (LAK) cell, a tumor-infiltrating lymphocyte (TIL), a cytotoxic lymphocyte (CTL), and mixtures thereof.  
     
     
         5 . The method of  claim 1 , wherein the glycoconjugate is represented by the general formula P-(S)x-Gal, 
 wherein P is a peptide residue of a human serum glycoprotein and S is a sugar residue of a human serum glycoprotein; x is an integer from 1 to 100 and Gal is galactose residue.    
     
     
         6 . The method of  claim 1 , wherein the glycoconjugate is selected from the group consisting of an orosomucoid and an asialoorosomucoid.  
     
     
         7 . The method of  claim 1 , wherein the target tissue is a tissue of an organ selected from the group consisting of the heart, the liver, the lungs, and the kidneys.  
     
     
         8 . The method of  claim 1 , wherein the glycoconjugate is administered to the mammal prior to the cell.  
     
     
         9 . The method of  claim 1 , wherein the glycoconjugate and the cell are administered intravenously to the mammal.  
     
     
         10 . A method for targeting a hematopoietic stem cell to the heart of a mammal comprising the steps of: 
 (a) administering an asialo-orosomucoid to the mammal; and    (b) administering the cell to the mammal.    
     
     
         11 . The method of  claim 10 , wherein the cell is administered after the step of administering the asialo-orosomucoid.  
     
     
         12 . The method of  claim 10 , wherein the asialo-orosomucoid is administered via a vessel proximal to the heart.  
     
     
         13 . The method of  claim 12  wherein the asialo-orosomucoid is administered via a jugular vein.  
     
     
         14 . The method of  claim 10  wherein the heart of a mammal has suffered ischemic injury prior to administering the asialo-orosomucoid.  
     
     
         15 . A method for targeting a mesenchymal stem cell to the heart of a mammal comprising the steps of: 
 (a) administering an orosomucoid to the mammal; and    (b) administering the cell to the mammal.    
     
     
         16 . The method of  claim 15 , wherein the orosomucoid is administered via a vessel proximal to the heart.  
     
     
         17 . The method of  claim 16  wherein the orosomucoid is administered via a jugular vein.  
     
     
         18 . The method of  claim 15  wherein the heart of a mammal has suffered ischemic injury prior to administering the orosomucoid.  
     
     
         19 . The method of  claim 15 , wherein the cell is administered after the step of administering the orosomucoid.  
     
     
         20 . A method for targeting a hematopoietic stem cell to the liver of a mammal comprising the steps of: 
 (a) administering an orosomucoid to the mammal; and    (b) administering the cell to the mammal.    
     
     
         21 . The method of  claim 20 , wherein the cell is administered after the step of administering the orosomucoid.  
     
     
         22 . A method for targeting a mesenchymal stem cell to the liver of a mammal comprising the steps of: 
 (a) administering an asialoorosomucoid to the mammal; arid    (b) administering the cell to the mammal.    
     
     
         23 . The method of  claim 22 , wherein the cell is administered after the step of administering the orosomucoid.  
     
     
         24 . A method for targeting a gene of interest to a tissue in a mammal, wherein said ene of interest comprises a transgene, said method comprising the steps of: 
 (1) introducing a cell comprising the gene of interest to the mammal; and    (2) administering a glycoconjugate.    
     
     
         25 . The method of  claim 24 , wherein the cell is a hematopoietic stem cell.  
     
     
         26 . The method of  claim 24 , wherein the cell is a lymphoid cell.  
     
     
         27 . The method of  claim 26 , wherein the stem cell is obtained from the bone marrow, peripheral circulation or an umbilical cord.  
     
     
         28 . The method of  claim 24 , wherein the glycoconjugate is selected from the group consisting of an orosomucoid and an asialoorosomucoid.  
     
     
         29 . A method for treating a disease characterized by tissue damage in a mammal comprising the steps of: 
 (1) administering a stem cell to the mammal; and    (2) administering a glycoconjugate to the mammal.    
     
     
         30 . The method of  claim 29 , wherein the stem cell is obtained from the hone marrow, peripheral circulation or an umbilical cord.  
     
     
         31 . The method of  claim 29 , wherein the glycoconjugate is selected from the group consisting of an orosomucoid and an asialoorosomucoid.  
     
     
         32 . The method of  claim 29 , wherein the disease is selected from the group consisting of a heart disease, a lung disease, a liver disease a neurological disease and a kidney disease.  
     
     
         33 . The method of  claim 29 , wherein the disease is selected from the group consisting of myocardial infarction, emphysema, cystic fibrosis, hepatitis, stroke, nephritis and microalbuminuria.  
     
     
         34 . A pharmaceutical composition comprising a lymphoid cell or a stem cell and a glycoconjugate.  
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the glycoconjugate is selected from the group consisting of an orosomucoid and an asialoorosomucoid.  
     
     
         36 . The pharmaceutical composition of  claim 34 , wherein the cell is a stem cell.  
     
     
         37 . The pharmaceutical composition of  claim 34 , wherein the cell is a lymphoid cell.  
     
     
         38 . An article of manufacture, comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein 
 the pharmaceutical composition comprises a glycoconjugate that is therapeutically effective for targeting a cell to a desired organ, and wherein    the packaging material comprises a label which indicates that the pharmaceutical composition can be used for targeting a cell to a desired organ.    
     
     
         39 . The article of manufacture of  claim 38 , further comprising additional reagents for making cell suspensions to be administered to a mammal and printed instructions, for use in targeting cells.  
     
     
         40 . The article of manufacture of  claim 39  further comprising a quantity of stem cells suitable for targeting of such cells in a mammal.  
     
     
         41 . The article of manufacture of  claim 38 , wherein the glycoconjugate is selected from the group consisting of an orosomucoid and an asialoorosomucoid.  
     
     
         42 . The article of manufacture of  claim 40 , wherein the cell is a hematopoietic stem cell.  
     
     
         43 . A method to improve the efficiency of an adoptive immunotherapy using a lymphoid cell comprising modification of sialoglycoprotein determinants on the lymphoid cell surface.  
     
     
         44 . The method of  claim 43  wherein the modification comprises removal of sialic to generate new asialoglycoprotein determininants.  
     
     
         45 . The method of  claim 44  wherein the modification comprises removal of sialic acid by an enzyme.  
     
     
         46 . The method of  claim 45  wherein the modification comprises removal of sialic acid by a neuraminidase.  
     
     
         47 . The method of  claim 43  wherein the modification comprises addition of sialic acid by an enzyme.  
     
     
         48 . The method of  claim 43  wherein the adoptive immunotherapy is for a liver metastasis or a primary liver tumor. regional administration to the liver of activated lymphocytes.  
     
     
         49 . The method of  claim 6  wherein the glycoconjugate is administered via a vessel proximal to the organ wherein the target tissue is located.  
     
     
         50 . The method of  claim 6  wherein the organ is the liver and the glycoconjugate is administered viavia the hepatic artery or portal vein or peripheral vein