Methods for providing polymeric synthetic nanocarriers for generating antigen-specific tolerance immune responses

Abstract

Disclosed are synthetic nanocarrier compositions that provide controlled release of immunosuppressants as well as related methods. The synthetic nanocarrier compositions may also include antigen in some embodiments.

1 . A composition, comprising:
 (i) synthetic nanocarriers that comprise an immunosuppressant coupled thereto, and (ii) an APC presentable antigen;   wherein the synthetic nanocarriers are adapted to release the immunosuppressant according to the following relationship:   wt % (1 hr) is from 0.01 to 60% and wt % (24 hr) is from 25 to 100%,   wherein wt % (1 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at a pH for 1 hour divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour, expressed as weight percent, and taken as an average across the synthetic nanocarriers,   wherein wt % (24 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours, expressed as weight percent, and taken as an average across the synthetic nanocarriers; and   wherein the pH ranges from 4.5 to 6.5.   
     
     
         2 . The composition of  claim 1 , wherein wt % (1 hr) is from 10 to 60%. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein wt % (24 hr) is from 20 to 90%. 
     
     
         7 - 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein the aqueous environment is 0.5% wt/v sodium dodecyl sulfate in 100 mM pH 4.5 sodium citrate buffer. 
     
     
         11 - 49 . (canceled) 
     
     
         50 . A dosage form comprising the composition of  claim 1 . 
     
     
         51 . A method comprising administering the dosage form of  claim 50  to a subject. 
     
     
         52 . (canceled) 
     
     
         53 . A method comprising:
 providing a composition to a subject that comprises:   (i) synthetic nanocarriers that comprise an immunosuppressant coupled thereto, and   (ii) an APC presentable antigen; and   releasing the immunosuppressant from the synthetic nanocarriers, wherein the synthetic nanocarriers have been adapted to release the immunosuppressant according to the following relationship:   wt % (1 hr) is from 0.01 to 60% and wt % (24 hr) is from 25 to 100%,   wherein wt % (1 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at a pH for 1 hour divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour, expressed as weight percent, and taken as an average across the synthetic nanocarriers,   wherein wt % (24 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours, expressed as weight percent, and taken as an average across the synthetic nanocarriers; and   wherein the pH ranges from 4.5 to 6.5.   
     
     
         54 - 61 . (canceled) 
     
     
         62 . A composition as defined in  claim 1  or a dosage form thereof for use in therapy or prophylaxis. 
     
     
         63 . A composition as defined in  claim 1  or a dosage form thereof for use in a method as defined herein. 
     
     
         64 . A composition as defined in  claim 1  or a dosage form thereof for use in a method of therapy or prophylaxis of an autoimmune disease, an inflammatory disease, an allergy, or graft versus host disease. 
     
     
         65 . A composition as defined in  claim 1  or a dosage form thereof for use in a method of therapy or prophylaxis in a subject who has undergone or will undergo transplantation. 
     
     
         66 . A composition as defined in  claim 1  or a dosage form thereof for use in a method of therapy or prophylaxis in a subject that has received, is receiving or will receive a therapeutic protein against which the subject has experienced, is experiencing or is expected to experience an undesired immune response 
     
     
         67 . The composition of  claim 1 , wherein the method of therapy or prophylaxis is as defined herein. 
     
     
         68 . A composition as defined in  claim 1  or a dosage form thereof for use in a method of therapy or prophylaxis comprising administration by intravenous, transmucosal, intraperitoneal, oral, subcutaneous, pulmonary, intranasal, intradermal or intramuscular administration. 
     
     
         69 . A composition as defined in  claim 1  or a dosage form thereof for use in a method of therapy or prophylaxis comprising administration by inhalation, intravenous, subcutaneous or transmucosal administration. 
     
     
         70 . Use of a composition as defined in  claim 1  or a dosage form thereof for the manufacture of a medicament for use in a method as defined herein. 
     
     
         71 . A method of providing synthetic nanocarriers, comprising:
 (i) preparing synthetic nanocarriers that comprise an immunosuppressant coupled thereto, and, optionally, an APC presentable antigen; and   (ii) determining whether or not the synthetic nanocarriers release the immunosuppressant according to the following relationship:   wt % (1 hr) is from 0.01 to 60% and wt % (24 hr) is from 25 to 100%,   wherein wt % (1 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at a pH for 1 hour divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 1 hour, expressed as weight percent, and taken as an average across the synthetic nanocarriers,   wherein wt % (24 hr) is the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours divided by the sum of the weight of immunosuppressant released upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours plus a weight of immunosuppressant retained in the synthetic nanocarriers upon exposure of the synthetic nanocarriers to an in vitro aqueous environment at 37° C. at the pH for 24 hours, expressed as weight percent, and taken as an average across the synthetic nanocarriers; and   wherein the pH ranges from 4.5 to 6.5.   
     
     
         72 - 76 . (canceled) 
     
     
         77 . A process for producing synthetic nanocarriers comprising the method steps as defined in  claim 71 . 
     
     
         78 . Synthetic nanocarriers made according to  claim 71 . 
     
     
         79 - 80 . (canceled) 
     
     
         81 . Use of the synthetic carriers of  claim 78  for the manufacture of a medicament for use in a method as defined herein.