Tolerogenic synthetic nanocarriers for antigen-specific deletion of t effector cells

Abstract

Disclosed are synthetic nanocarrier methods, and related compositions, comprising administering immunosuppressants and MHC Class I-restricted and/or MHC Class II-restricted epitopes that can generate tolerogenic immune responses (e.g., antigen-specific T effector cell deletion).

1 . A method comprising:
 (A) administering to a subject according to a protocol that was previously shown to reduce the number or activity of antigen-specific T effector cells in one or more test subjects:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; or 
   (B) reducing the number or activity of antigen-specific T effector cells in a subject by administering:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; or 
   (C) administering to a subject:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; 
 in an amount effective to reduce the number or activity of antigen-specific T effector cells. 
   
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the first population and the second population are the same population. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the antigen is a therapeutic protein, an autoantigen or an allergen, or is associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection or graft versus host disease. 
     
     
         9 . The method of  claim 1 , wherein the subject has undergone or will undergo transplantation. 
     
     
         10 . The method of  claim 1 , wherein the subject has or is at risk of having an undesired immune response against a therapeutic protein that is being administered or will be administered to the subject. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . The method 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. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the load of the immunosuppressants and/or epitopes on average across the first and/or second population of synthetic nanocarriers is between 0.0001% and 50% (weight/weight). 
     
     
         17 . (canceled) 
     
     
         18 . The method 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. 
     
     
         19 - 28 . (canceled) 
     
     
         29 . The method 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. 
     
     
         30 - 33 . (canceled) 
     
     
         34 . The method 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. 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein the T effector cells are CD4+ and/or CD8+ T cells. 
     
     
         37 . A method comprising:
 (i) producing a first population of synthetic nanocarriers coupled to immunosuppressants, and   (ii) producing a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; and   (iii) evaluating the effect of the first and second population of synthetic nanocarriers on antigen-specific T effector cell number or activity.   
     
     
         38 - 43 . (canceled) 
     
     
         44 . A process for producing a composition or dosage form comprising the steps of:
 (i) coupling a first population of synthetic nanocarriers to immunosuppressants,   (ii) coupling a second population of synthetic nanocarriers to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen, and   (iii) evaluating the effect of the first and second population of synthetic nanocarriers on antigen-specific T effector cell number or activity.   
     
     
         45 . (canceled) 
     
     
         46 . A composition or dosage form obtainable by the method of  claim 37  . 
     
     
         47 . A composition comprising:
 (i) a first population of synthetic nanocarriers coupled to immunosuppressants;   (ii) a second population of synthetic nanocarriers coupled to MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; and   (iii) a pharmaceutically acceptable excipient,   
       wherein the synthetic nanocarriers are is in an amount effective to reduce the number or activity of antigen-specific T effector cells in a subject. 
     
     
         48 - 52 . (canceled) 
     
     
         53 . A method comprising:
 (A) administering to a subject, according to a protocol that was previously shown to reduce the number or activity of antigen-specific T effector cells in one or more test subjects:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; or 
   (B) reducing the number or activity of antigen-specific T effector cells in a subject by administering:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; or 
   (C) administering to a subject:
 (i) a population of synthetic nanocarriers coupled to immunosuppressants, and 
 (ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; 
 in an amount effective to reduce the number or activity of antigen-specific T effector cells. 
   
     
     
         54 . The method of  claim 53 , wherein the antigen is a therapeutic protein, an autoantigen or an allergen, or is associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease. 
     
     
         55 . The method of  claim 53 , wherein the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection or graft versus host disease. 
     
     
         56 . The method of  claim 53 , wherein the subject has or is at risk of having an undesired immune response against a therapeutic protein that is being administered or will be administered to the subject.