Combination therapy of beta-glycolipids and antibodies for the treatment of immune-related disorders

Abstract

The present invention relates to a combination therapy for the treatment of immune-related disorders. More particularly, the invention relates to oral or mucosal synergistic compositions combining beta-glycolipids, preferably, β-glycosphingolipids with immunoglobulin molecules specific for at least one antigen derived from a component of the immune system, specifically an anti-CD3 antibody. The invention further provides methods kits and uses of the combined compositions of the invention for immuno-modulation and thereby for the treatment of immune-related disorders. In a preferred embodiment, anti-CD3 anti-body (OKT3) is orally administered in combination with β-glucosylceramide (also known as glycocerebroside) in an animal model of type 2 diabetes.

1 .- 32 . (canceled) 
     
     
         33 . A composition comprising a combination of at least one natural or synthetic beta-glycolipid and at least one immunoglobulin molecule specific for an epitope derived from a component of the immune system or any functional fragments thereof, said composition optionally further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive. 
     
     
         34 . The composition according to  claim 33 , wherein said beta-glycolipid is selected from the group consisting of a glucosylceramide, a monosaccharide ceramide, a galatosylceremide, a lactosyl-ceramide, a gal-gal-glucosyl-ceramide, GM2 ganglioside, GM3 ganglioside, globoside or any synthetic or natural β-glycolipid or any derivative or combination thereof, and wherein said immunoglobulin molecule is an antibody specifically recognizing any one of CD3, CD46, CD2, ICOS, CTLA-4, CD28, PD1 and CD94 and anti CD20 or any combination thereof. 
     
     
         35 . The composition according to  claim 34 , wherein said beta-glycolipid is glucosylceramide (GC) and said immunoglobulin molecule is an anti-CD3 antibody. 
     
     
         36 . The composition according to  claim 35 , wherein said composition is an immunomodulatory composition modulating the Th1/Th2, Th3 cell balance in a subject suffering from an immune-related disorder, thereby activating or inhibiting an immune response specifically directed toward said disorder in said subject. 
     
     
         37 . The composition according to  claim 36 , wherein said composition modulates the Th1/Th2, Th3 cell balance toward an anti-inflammatory Th2, Tr1/Th3 immune response in a subject suffering from an immune-related disorder, and wherein said composition leads to at least one of a decrease in at least one of IL-2, IL-17, IL-23, IFN-γ, IL-6 and an increase in at least one of TGF-β, and IL-10, in said subject. 
     
     
         38 . The combined composition according to  claim 37 , wherein said composition leads to at least one of a decrease in the serum levels of cholesterol, triglycerides, ALT, AST and Glucose, an increase in the serum levels of insulin and induction of at least one immune-related cell in a subject suffering from an immune-related disorder. 
     
     
         39 . The combined composition according to  claim 38 , wherein said immune related disorder is any one of Metabolic Syndrome or any of the conditions comprising the same, an autoimmune disease, graft rejection pathology, inflammatory disease, non alcoholic fatty liver disease, hyperlipidemia and atherosclerosis. 
     
     
         40 . A pharmaceutical composition for treating, preventing, ameliorating or delaying the onset of an immune-related disorder in a subject in need thereof, wherein said composition is as defined in  claim 33 , said composition is optionally suitable for oral or mucosal administration. 
     
     
         41 . A method of treating, preventing, ameliorating or delaying the onset of an immune-related disorder in a subject in need thereof comprising the step of administering to said subject a therapeutically effective amount of at least one of:
 (a) a combination of at least one natural or synthetic beta-glycolipid and at least one immunoglobulin molecule specific for an epitope derived from a component of the immune system or any functional fragments thereof;   (b) an immune-cell treated with (a) or with a composition comprising the same;   (c) an immune-cell obtained from a subject treated with any one of (a), (b) or with any combinations and mixtures thereof or with a composition comprising the same; and   (d) a composition comprising any one of (a), (b), (c) or any combinations and mixtures thereof, said composition optionally further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive.   
     
     
         42 . The method according to  claim 41 , wherein said beta-glycolipid is selected from the group consisting of a glucosylceramide, a monosaccharide ceramide, a galatosylceremide, a lactosyl-ceramide, a gal-gal-glucosyl-ceramide, GM2 ganglioside, GM3 ganglioside, globoside or any synthetic or natural β-glycolipid or any derivative or combination thereof, and wherein said immunoglobulin molecule is an antibody specifically recognizing any one of CD3, CD46, CD2, ICOS, CTLA-4, CD28, PD1 and CD94 and anti CD20 or any combination thereof. 
     
     
         43 . The method according to  claim 42 , wherein said beta-glycolipid is glucosylceramide (GC) and said immunoglobulin molecule is an anti-CD3 antibody. 
     
     
         44 . The method according to  claim 43 , wherein said combined composition is an immunomodulatory composition modulating the Th1/Th2Th3 cell balance in a subject suffering from an immune-related disorder, thereby activating or inhibiting an immune response specifically directed toward said disorder in said subject. 
     
     
         45 . The method according to  claim 44 , wherein said composition modulates the Th1/Th2, Th3 cell balance toward an anti-inflammatory Th2, Tr1/Th3 immune response in a subject suffering from an immune-related disorder and wherein said combined composition leads to at least one of a decrease in at least one of IL-2, IL-17, IL-23, IFN-γ, IL-6 and an increase in at least one of TGF-β, and IL-10, in said subject. 
     
     
         46 . The method according to  claim 45 , wherein said combined composition leads to at least one of a decrease in the serum levels of cholesterol, triglycerides, ALT, AST and Glucose, an increase in the serum levels of insulin and induction of at leas one immune-related cell, in a subject suffering from an immune-related disorder. 
     
     
         47 . The method according to  claim 41 , wherein said immune-cell is any one of APC (antigen presenting cell), adipocyte and T regulatory cell. 
     
     
         48 . The method according to  claim 41 , wherein said immune related disorder is any one of Metabolic Syndrome or any of the conditions comprising the same, an autoimmune disease, graft rejection pathology, inflammatory disease, non alcoholic fatty liver disease, hyperlipidemia and atherosclerosis. 
     
     
         49 . A pharmaceutical unit dosage form comprising at least one natural or synthetic beta-glycolipid and at least one immunoglobulin molecule specific for an epitope derived from a component of the immune system or any functional fragments thereof, and a pharmaceutically acceptable carrier or diluent, optionally, said unit dosage form is suitable for oral or mucosal administration. 
     
     
         50 . A kit for achieving a therapeutic effect in a subject suffering from an immune-related disorder comprising:
 (a) at least one natural or synthetic beta-glycolipid or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;   (b) at least one immunoglobulin molecule specific for an epitope derived from a component of the immune system or any functional fragments thereof, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and   (c) container means for containing said first and second dosage forms.   
     
     
         51 . A method of treating, preventing or delaying the onset of an immune-related disorder in a subject in need thereof comprising the step of administering to said subject a therapeutically effective amount of a first and a second unit dosage forms comprised in a kit according to  claim 50 . 
     
     
         52 . A method of inducing at least one of T regulatory cells and APC in a subject in need thereof comprising the step of administering to said subject a therapeutically effective amount of at least one of:
 (a) a combination of at least one natural or synthetic beta-glycolipid and at least one immunoglobulin molecule specific for an epitope derived from a component of the immune system or any functional fragments thereof;   (b) an immune-cell treated with any one of (a) or any composition comprising the same;   (c) an immune-cell obtained from a subject treated with any one of (a), (b) or any combination or mixtures thereof or any composition comprising the same; and   (d) a composition comprising any one of (a), (b), (c) or any combinations or mixtures thereof, said composition optionally further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive.