Tolerogenic synthetic nanocarriers to reduce immune responses to therapeutic proteins

Abstract

Disclosed are synthetic nanocarrier compositions, and related methods, comprising therapeutic protein APC presentable antigens and immunosuppressants that provide tolerogenic immune responses specific to therapeutic proteins.

1 . A composition comprising:
 (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and   (ii) a second population of synthetic nanocarriers that are coupled to therapeutic protein APC presentable antigens.   
     
     
         2 . The composition of  claim 1 , wherein the first population and second population are the same. 
     
     
         3 . The composition of  claim 1 , wherein the immunosuppressants comprise a statin, an mTOR inhibitor, a TGF-β signaling agent, a corticosteroid, an inhibitor of mitochondrial function, a P38 inhibitor, an NF-κβ inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor or a proteasome inhibitor. 
     
     
         4 . (canceled) 
     
     
         5 . The composition of  claim 1 , wherein the therapeutic protein APC presentable antigens comprise MHC Class I-restricted and/or MHC Class II-restricted epitopes of a therapeutic protein. 
     
     
         6 . (canceled) 
     
     
         7 . The composition of  claim 1 , wherein the therapeutic protein APC presentable antigens comprise B cell epitopes of a therapeutic protein. 
     
     
         8 . The composition of  claim 1 , wherein the therapeutic protein APC presentable antigens comprise substantially no B cell epitopes of a therapeutic protein. 
     
     
         9 . The composition of  claim 1 , wherein the therapeutic protein APC presentable antigens comprise a therapeutic protein for protein replacement or protein supplementation therapy, or a fragment thereof. 
     
     
         10 . The composition of  claim 1 , wherein the therapeutic protein APC presentable antigens comprise a/an infusible or injectable therapeutic protein, enzyme, enzyme cofactor, hormone, blood or blood coagulation factor, cytokine, interferon, growth factor, monoclonal antibody, polyclonal antibody or protein associated with Pompe's disease, or a fragment thereof. 
     
     
         11 - 18 . (canceled) 
     
     
         19 . The composition of  claim 1 , wherein the load of the immunosuppressant and/or therapeutic protein APC presentable antigen on average across the first and/or second population of synthetic nanocarriers is between 0.0001% and 50%. 
     
     
         20 . (canceled) 
     
     
         21 . The composition of  claim 1 , wherein the synthetic nanocarriers of the first population and/or second population comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles or peptide or protein particles. 
     
     
         22 - 31 . (canceled) 
     
     
         32 . The composition of  claim 1 , wherein the mean of a particle size distribution obtained using dynamic light scattering of the synthetic nanocarriers of the first and/or second population is a diameter greater than 100 nm. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . The composition of  claim 1 , wherein the aspect ratio of the synthetic nanocarriers of the first population and/or second population is greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7 or 1:10. 
     
     
         38 . (canceled) 
     
     
         39 . A dosage form comprising the composition of  claim 1 . 
     
     
         40 . A method comprising administering the composition of  claim 1  to a subject that is being administered or will be administered a therapeutic protein. 
     
     
         41 - 55 . (canceled) 
     
     
         56 . A method comprising:
 administering to a subject a composition comprising:
 (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers that are coupled to therapeutic protein APC presentable antigens, 
   wherein the composition is in an amount effective to reduce the generation of an undesired immune response against the therapeutic protein APC presentable antigens.   
     
     
         57 . A method comprising:
 reducing the generation of an undesired immune response in a subject by administering a composition comprising:
 (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers that are coupled to therapeutic protein APC presentable antigens. 
   
     
     
         58 . A method comprising:
 administering a composition to a subject according to a protocol that was previously shown to reduce the generation of an undesired immune response to therapeutic protein APC presentable antigens in one or more test subjects;   wherein the composition comprises:
 (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers that are coupled to the therapeutic protein APC presentable antigens. 
   
     
     
         59 - 103 . (canceled) 
     
     
         104 . A method comprising:
 (i) producing a first population of synthetic nanocarriers that are coupled to immunosuppressants, and   (ii) producing a second population of synthetic nanocarriers that are coupled to therapeutic protein APC presentable antigens.   
     
     
         105 - 110 . (canceled) 
     
     
         111 . A process for producing a composition or dosage form comprising:
 (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and   (ii) a second population of synthetic nanocarriers that are coupled to therapeutic protein APC presentable antigens,   the process comprising the steps as defined in the method of  claim 104 .   
     
     
         112 . A composition or dosage form obtainable by the method or process of  claim 104 . 
     
     
         113 - 116 . (canceled)