Tolerogenic synthetic nanocarriers to reduce antibody responses

Abstract

Disclosed are synthetic nanocarrier compositions, and related methods, comprising MHC Class II-restricted epitopes and immunosuppressants that provide tolerogenic immune responses, such as a reduction in CD4+ T cell help specific to an antigen.

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 MHC Class II-restricted epitopes of an antigen that generates an undesired humoral immune response.   
     
     
         2 . The composition of  claim 1 , wherein the first population and the second population are the same. 
     
     
         3 . The composition of  claim 1 , wherein the composition comprises substantially no B cell epitopes of the antigen that generate an undesired humoral immune response. 
     
     
         4 . The composition of  claim 3 , wherein the undesired humoral immune response is the generation of antigen-specific antibodies. 
     
     
         5 . The composition of  claim 3 , wherein the undesired humoral immune response is CD4+ T cell proliferation and/or activity and/or B cell proliferation and/or activity. 
     
     
         6 . The composition of  claim 1 , wherein the first population and/or second population of synthetic nanocarriers are also coupled to MHC Class I-restricted epitopes. 
     
     
         7 . 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 phosphodiesterasse 4 inhibitor, an HDAC inhibitor or a proteasome inhibitor. 
     
     
         8 . (canceled) 
     
     
         9 . The composition of  claim 1 , wherein the antigen is an allergen, autoantigen or therapeutic protein, or is associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease. 
     
     
         10 . (canceled) 
     
     
         11 . The composition 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). 
     
     
         12 . (canceled) 
     
     
         13 . 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. 
     
     
         14 - 23 . (canceled) 
     
     
         24 . 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. 
     
     
         25 - 28 . (canceled) 
     
     
         29 . 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. 
     
     
         30 . (canceled) 
     
     
         31 . A dosage form comprising the composition of  claim 1 . 
     
     
         32 . A method comprising administering the composition of  claim 1 . 
     
     
         33 - 35 . (canceled) 
     
     
         36 . 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 MHC Class II-restricted epitopes of an antigen that generates an undesired humoral immune response,   wherein the composition is in an amount effective to reduce an undesired humoral immune response to the antigen in the subject.   
     
     
         37 . A method comprising:
 reducing an undesired humoral immune response to an antigen 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 MHC Class II-restricted epitopes of the antigen.   
     
     
         38 . A method comprising:
 administering a composition to a subject according to a protocol that was previously shown to reduce an undesired humoral immune response to an antigen 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 MHC Class II-restricted epitopes of the antigen.   
     
     
         39 - 73 . (canceled) 
     
     
         74 . 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 MHC Class II-restricted epitopes of an antigen that generates an undesired humoral immune response.   
     
     
         75 - 82 . (canceled) 
     
     
         83 . A process for producing a composition or dosage form comprising the steps of:
 (i) coupling a first population of synthetic nanocarriers to immunosuppressants, and   (ii) coupling a second population of synthetic nanocarriers to MHC Class II-restricted epitopes of an antigen that generates an undesired humoral immune response.   
     
     
         84 . (canceled) 
     
     
         85 . A composition or dosage form obtainable by the method or process of  claim 74 . 
     
     
         86 - 89 . (canceled)