Method of modifying the immune response

Abstract

Methods of neutralising circulating antibody and mitigating the risk of clinically significant adverse responses to incompatible transfusions and transplantations are described. The methods comprise the administration to the subject of dispersible antigen-lipid constructs.

1 - 58 . (canceled) 
     
     
         59 . A method of neutralizing one or more populations of circulating antibody in a subject comprising the step of administering to the subject by intravascular injection a construct of the structure F—S 1 —S 2 -L where F is the epitope of a carbohydrate antigen reactive with the one or more populations of circulating antibody, S 1 —S 2  is a spacer covalently linking F to L and selected to provide a construct that is dispersible in water and preferentially partitions into plasma relative to a naturally occurring glycolipid, and L is a di-acyl or di-alkyl glycerophospholipid. 
     
     
         60 . The method of  claim 59  where the administering to the subject is by intravenous injection. 
     
     
         61 . The method of  claim 60  where the administering to the subject is prior to transfusion or transplantation. 
     
     
         62 . The method of  claim 61  here the administering to the subject is prior to transfusion or transplantation of donor cells, tissues or organs expressing the carbohydrate antigen. 
     
     
         63 . The method of  claim 62  where the administering to the subject is prior to transfusion or transplantation of donor cells, tissues or organs predetermined to express the carbohydrate antigen. 
     
     
         64 . The method of  claim 63  where the method is to provide at least a transient tolerance in the subject of the transfusion or graft expressing the antigen. 
     
     
         65 . The method of  claim 59  where F is selected from the group consisting of: glycotopes of blood group antigens. 
     
     
         66 . The method of  claim 65  where F is selected from the group consisting of:
 GalNAcα3(Fucα2)Galβ-; 
 Galα3(Fucα2)Galβ-; 
 GalNα3(Fucα2)Galβ-; 
 Fucα2Galβ-; 
 Galβ4GlcNAcβ3(Galβ4GlcNAcβ6)Galβ-; 
 Galβ4GlcNAcβ3-; 
 Galβ4Glcβ-; 
 Galβ3GlcNAcβ-; 
 Galβ3(Fucα4)GlcNAcβ-; 
 Fucα2Galβ3(Fucα4)GlcNAcβ-; 
 GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galβ4(Fucα3)GlcNAcβ-; 
 Fucα2Galβ4(Fucα3)GlcNAcβ-; 
 NeuAcα2-3Galβ3(Fucα4)GlcNAcβ-; 
 NeuAcα2-3Galβ4(Fucα3)GlcNAcβ-; 
 GalNAcβ4(NeuAcα2-3)Galβ4-; 
 Galβ3GalNAcα; 
 NeuAcα2-3Galβ4-; 
 NeuAcα2-6Galβ4-; 
 Galα4Galβ4-; 
 GalNAcβ3Galα4Galβ4-; 
 Galα4Galβ4GlcNAcβ3-; 
 Galβ3GalNAcβ3Galα4-; 
 NeuAcα2-3Galβ3GalNAcβ3Galα4-; 
 Galα3Galβ-; 
 GalNAcα3GalNAcβ3Galα4-; and 
 GalNAcβ3GalNAcβ3Galα4-. 
 
     
     
         67 . The method of  claim 66  where F is selected from the group consisting of: glycotopes of the ABO blood group antigens. 
     
     
         68 . The method of  claim 59  where S1 is 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl, and S2 is —CO(CH2)2CO—, —CO(CH2)3CO—, —CO(CH2)4CO— or —CO(CH2)5CO—. 
     
     
         69 . The method of  claim 68  where L is a phosphatidyl ethanolamine. 
     
     
         70 . The method of  claim 69  where L is derived from one or more cis-desaturated fatty acids. 
     
     
         71 . The method of  claim 70  where L is 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE). 
     
     
         72 . The method of  claim 71  where the construct includes the substructure: 
       
         
           
           
               
               
           
         
         where * is other than H. 
       
     
     
         73 . The method of  claim 72  where the construct is of the structure: 
       
         
           
           
               
               
           
         
         designated Atri-sp1-sp2-DOPE (I). 
       
     
     
         74 . A pharmaceutical preparation suitable for intravascular administration to a subject in order to neutralize one or more populations of circulating antibody comprising a dispersion of a construct of the structure F—S1-S2-L where F is the epitope of a carbohydrate antigen reactive with the one or more populations of circulating antibody, S1-S2 is a spacer covalently linking F to L selected to provide a construct that is dispersible in water and preferentially partitions into plasma relative to a naturally occurring glycolipid, and L is a di-acyl or di-alkyl glycerophospholipid. 
     
     
         75 . The pharmaceutical preparation of  claim 74  where the construct is at a concentration of at least 10 μmol. 
     
     
         76 . The pharmaceutical preparation of  claim 75  where the construct is at a concentration of at least 15 μmol. 
     
     
         77 . The pharmaceutical preparation of  claim 76  where the construct is at a concentration of at least 17.5 μmol. 
     
     
         78 . The pharmaceutical preparation of  claim 74  where the dispersion is in human red cell transfusion medium. 
     
     
         79 . The pharmaceutical preparation of  claim 74  where F is selected from the group consisting of glycotopes of blood group antigens. 
     
     
         80 . The pharmaceutical preparation of  claim 74  where F is selected from the group consisting of:
 GalNAcα3(Fucα2)Galβ-; 
 Galα3(Fucα2)Galβ-; 
 GalNα3(Fucα2)Galβ-; 
 Fucα2Galβ-; 
 Galβ4GlcNAcβ3(Galβ4GlcNAcβ6)Galβ3-; 
 Galβ4GlcNAcβ3-; 
 Galβ4Glcβ-; 
 Galβ3GlcNAcβ-; 
 Galβ3(Fucα4)GlcNAcβ-; 
 Fucα2Galβ3(Fucα4)GlcNAcβ-; 
 GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galβ4(Fucα3)GlcNAcβ-; 
 Fucα2Galβ4(Fucα3)GlcNAcβ-; 
 NeuAcα2-3Galβ3(Fucα4)GlcNAcβ-; 
 NeuAcα2-3Galβ4(Fucα3)GlcNAcβ-; 
 GalNAcβ4(NeuAcα2-3)Galβ4-; 
 Galβ3GalNAcα-; 
 NeuAcα2-3Galβ4-; 
 NeuAcα2-6Galβ4-; 
 Galα4Galβ4-; 
 GalNAcβ3Galα4Galβ4-; 
 Galα4Galβ4GlcNAcβ3-; 
 Galβ3GalNAcβ3Galα-4-; 
 NeuAcα2-3Galβ3GalNAcβ3Galα4-; 
 Galα3Galβ-; 
 GalNAcα3GalNAcβ3Galα4-; and 
 GalNAcβ3GalNAcβ3Galα4-. 
 
     
     
         81 . The pharmaceutical preparation of  claim 80  where F is selected from the group consisting of glycotopes of the ABO blood group antigens. 
     
     
         82 . The pharmaceutical preparation of  claim 74  where S1 is 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl, and S2 is —CO(CH2)2CO—, —CO(CH2)3CO—, —CO(CH2)4CO— or —CO(CH2)5CO—. 
     
     
         83 . The pharmaceutical preparation of  claim 82  where L is a phosphatidyl ethanolamine. 
     
     
         84 . The pharmaceutical preparation of  claim 83  where L is derived from one or more cis-desaturated fatty acids. 
     
     
         85 . The pharmaceutical preparation of  claim 84  where L is 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE). 
     
     
         86 . The pharmaceutical preparation of  claim 85  where the construct includes the substructure: 
       
         
           
           
               
               
           
         
         where * is other than H. 
       
     
     
         87 . The pharmaceutical preparation of  claim 86  where the construct is of the structure: 
       
         
           
           
               
               
           
         
         designated A tri -sp 1 -sp 2 -DOPE (I). 
       
     
     
         88 . A method of modifying the profile of circulating antibody in the plasma of a mammal comprising the step of administering to the mammal by intravascular injection a construct of the structure F—S1-S2-L where F is the epitope of a carbohydrate antigen (glycotope) reactive with one or more populations of circulating antibody, S1-S2 is a spacer covalently linking F to L selected to provide an antigen-lipid construct that is dispersible in water and preferentially partitions into the plasma relative to naturally occurring glycolipids, and L is a diacyl- or dialkyl-glycerophospholipid. 
     
     
         89 . The method of  claim 88  where the administering to the mammal is by intravenous injection. 
     
     
         90 . The method of  claim 88  where F is selected from the group consisting of glycotopes of blood group antigens. 
     
     
         91 . The method of  claim 90  where F is selected from the group consisting of:
 GalNAcα3(Fucα2)Galβ-; 
 Galα3(Fucα2)Galβ-; 
 GalNα3(Fucα2)Galβ-; 
 Fucα2Galβ-; 
 Galβ4GlcNAcβ3(Galβ4GlcNAcβ6)Galβ-; 
 Galβ4GlcNAcβ3-; 
 Galβ4Glcβ-; 
 Galβ3GlcNAcβ-; 
 Galβ3(Fucα4)GlcNAcβ-; 
 Fucα2Galβ3(Fucα4)GlcNAcβ-; 
 GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ-; 
 Galβ4(Fucα3)GlcNAcβ-; 
 Fucα2Galβ4(Fucα3)GlcNAcβ-; 
 NeuAcα2-3Galβ3(Fucα4)GlcNAcβ-; 
 NeuAcα2-3Galβ4(Fucα3)GlcNAcβ-; 
 GalNAcβ4(NeuAcα2-3)Galβ4-; 
 Galβ3GalNAcα-; 
 NeuAcα2-3Galβ-4-; 
 NeuAcα2-6Galβ4-; 
 Galα4Galβ-4-; 
 GalNAcβ3Galα4Galβ-4-; 
 Galα4Galβ4GlcNAcβ3-; 
 Galβ3GalNAcβ3Galα4-; 
 NeuAcα2-3Galβ3GalNAcβ3Galα4-; 
 Galα3Galβ-; 
 GalNAcα3GalNAcβ3Galα4-; and 
 GalNAcβ3GalNAcβ3Galα4-. 
 
     
     
         92 . The method of  claim 91  where F is selected from the group consisting of glycotopes of the ABO blood group antigens. 
     
     
         93 . The method of  claim 88  where L is a phosphatidyl ethanolamine. 
     
     
         94 . The method of  claim 93  where L is derived from one or more cis-desaturated fatty acids. 
     
     
         95 . The method of  claim 94  where L is 1,2-O-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE). 
     
     
         96 . The method of  claim 93  where the construct includes the substructure: 
       
         
           
           
               
               
           
         
         where * is other than H. 
       
     
     
         97 . The method of  claim 96  where construct is the structure: 
       
         
           
           
               
               
           
         
         designated Atri-sp1-sp2-DOPE (I).