Immunomodulating compositions and methods of use thereof

Abstract

This invention is directed to β-1-6-glucans, compositions and devices comprising the same, and methods of use thereof in modulating immune responses. The β-1-6-glucans of certain embodiments of the invention are enriched for O-acetylated groups and/or conjugated to a solid support or linked to a targeting moiety.

What is claimed is: 
     
         1 . A composition comprising β-1-6-glucan enriched for O-acetylated groups. 
     
     
         2 . The composition of  claim 1 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         3 . The composition of  claim 1 , wherein said glucan is isolated or derived from a lichen, a fungus or a yeast. 
     
     
         4 . The composition of  claim 3 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         5 . The composition of  claim 1 , wherein said glucan is genetically engineered, or chemically synthesized or acetylated. 
     
     
         6 . The composition of  claim 1 , further comprising an adjuvant, an antigen, an immuno-modulatory compound, or a combination thereof. 
     
     
         7 . The composition of  claim 1 , wherein said glucan is conjugated to a particle. 
     
     
         8 . A method of modulating an immune response in a subject, said method comprising administering to said subject a composition comprising β-1-6-glucan optionally enriched for O-acetylated groups. 
     
     
         9 . The method of  claim 8 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         10 . The method of  claim 8 , wherein said glucan is isolated or derived from a lichen or a fungus, wherein said fungus is optionally a yeast. 
     
     
         11 . The method of  claim 10 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         12 . The method of  claim 8 , wherein said composition further comprises an adjuvant, an antigen, an immuno-modulatory compound, or a combination thereof. 
     
     
         13 . The method of  claim 8 , wherein said glucan is conjugated to a particle. 
     
     
         14 . The method of  claim 8 , wherein modulating said immune response comprises stimulating said immune response. 
     
     
         15 . The method of  claim 8 , wherein said immune response is an antigen-specific response. 
     
     
         16 . The method of  claim 8 , wherein said composition further comprises a chemotherapeutic compound. 
     
     
         17 . The method of  claim 8 , wherein said immune response is complement-dependent. 
     
     
         18 . The method of  claim 8 , wherein said immune response is directed against an infectious agent, a cancer, a preneoplastic lesion or a combination thereof. 
     
     
         19 . The method of  claim 18 , wherein said infectious agent causes sepsis. 
     
     
         20 . The method of  claim 18 , wherein said infectious agent is a parasite, helminth, virus or bacteria. 
     
     
         21 . The method of  claim 8 , wherein modulating said immune response comprises downmodulating or abrogating said immune response. 
     
     
         22 . The method of  claim 21 , wherein said composition further comprises an immunosuppressant. 
     
     
         23 . The method of  claim 21 , wherein said immune response is directed against an autoantigen or an allergen. 
     
     
         24 . The method of  claim 21 , wherein said immune response is directed against transplanted tissue or cells. 
     
     
         25 . A composition comprising β-1-6-glucan, wherein said glucan is conjugated to a particle. 
     
     
         26 . The composition of  claim 25 , wherein said glucan is enriched for O-acetylated groups. 
     
     
         27 . The composition of  claim 26 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         28 . The composition of  claim 25 , wherein said glucan is isolated or derived from a lichen, a yeast or a fungus. 
     
     
         29 . The composition of  claim 28 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         30 . The composition of  claim 25 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         31 . The composition of  claim 25 , further comprising an adjuvant, an antigen, an immuno-modulatory compound, or a combination thereof. 
     
     
         32 . The composition of  claim 25 , wherein said particle is a microsphere or nanoparticle. 
     
     
         33 . The composition of  claim 32 , wherein said microsphere has a diameter of about 0.1-15 microns. 
     
     
         34 . A method of modulating an immune response in a subject, said method comprising administering to said subject a composition comprising β-1-6-glucan, wherein said glucan is conjugated to a particle. 
     
     
         35 . The method of  claim 34 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         36 . The method of  claim 34 , wherein said glucan is isolated or derived from a lichen, a yeast or a fungus. 
     
     
         37 . The method of  claim 34 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         38 . The method of  claim 34 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         39 . The method of  claim 34 , further comprising an adjuvant, an antigen, an immuno-modulatory compound, or a combination thereof. 
     
     
         40 . The method of  claim 34 , wherein said glucan is conjugated to a solid support. 
     
     
         41 . The method of  claim 34 , wherein modulating said immune response comprises stimulating said immune response. 
     
     
         42 . The method of  claim 41 , wherein said immune response is an antigen-specific response. 
     
     
         43 . The method of  claim 41 , wherein said composition further comprises an immuno-stimulatory compound. 
     
     
         44 . The method of  claim 41 , wherein said composition further comprises a chemotherapeutic compound. 
     
     
         45 . The method of  claim 44 , wherein said immune response is directed against an infectious agent, a cancer, a preneoplastic lesion or a combination thereof. 
     
     
         46 . The method of  claim 34 , wherein said immune response is complement-dependent. 
     
     
         47 . The method of  claim 46 , wherein said infectious agent causes sepsis. 
     
     
         48 . The method of  claim 46 , wherein said infectious agent is a parasite, helminth, virus or bacteria. 
     
     
         49 . The method of  claim 34 , wherein modulating said immune response comprises downmodulating or abrogating said immune response. 
     
     
         50 . The method of  claim 49 , wherein said composition further comprises an immunosuppressant. 
     
     
         51 . The method of  claim 49 , wherein said immune response is directed against an autoantigen, an allergen, transplanted tissue or cells. 
     
     
         52 . A method of treating, delaying progression of, prolonging remission of, or reducing the incidence or severity of cancer in a subject, said method comprising administering to said subject a composition comprising purified β-1-6-glucan. 
     
     
         53 . The method of  claim 52 , wherein said β-1-6-glucan is enriched for O-acetylated groups. 
     
     
         54 . The method of  claim 53 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         55 . The method of  claim 52 , wherein said glucan is isolated or derived from a lichen or yeast or fungus. 
     
     
         56 . The method of  claim 52 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         57 . The method of  claim 52 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         58 . The method of  claim 52 , further comprising an adjuvant, an antigen, a peptide, an immuno-stimulatory compound, a chemotherapeutic or a combination thereof. 
     
     
         59 . The method of  claim 58 , wherein said antigen is a tumor-associated antigen. 
     
     
         60 . The method of  claim 58 , wherein said peptide is derived from a tumor-associated antigen. 
     
     
         61 . The method of  claim 58 , wherein said immuno-stimulatory compound is a cytokine. 
     
     
         62 . The method of  claim 58 , wherein said glucan is conjugated to a particle. 
     
     
         63 . The method of  claim 52 , wherein said subject has a hyperplastic or preneoplastic lesion. 
     
     
         64 . The method of  claim 52 , wherein said glucan is linked to a targeting moiety. 
     
     
         65 . The method of  claim 64 , wherein said targeting moiety specifically interacts with a tumor-associated antigen. 
     
     
         66 . A method of treating, delaying progression of, or reducing the incidence or severity of an infection in a subject, said method comprising administering to said subject a composition comprising purified β-1-6-glucan. 
     
     
         67 . The method of  claim 66 , wherein said β-1-6-glucan is enriched for O-acetylated groups. 
     
     
         68 . The method of  claim 67 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         69 . The method of  claim 68 , wherein said glucan is isolated or derived from a lichen or a yeast or a fungus. 
     
     
         70 . The method of  claim 68 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         71 . The method of  claim 68 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         72 . The method of  claim 68 , further comprising an adjuvant, an antigen, a peptide, an immuno-stimulatory compound, a chemotherapeutic or a combination thereof. 
     
     
         73 . The method of  claim 68 , wherein said antigen or peptide is derived from the source of said infection. 
     
     
         74 . The method of  claim 68 , wherein said immuno-stimulatory compound is a cytokine. 
     
     
         75 . The method of  claim 68 , wherein said chemotherapeutic compound is an antibiotic or antiviral compound. 
     
     
         76 . The method of  claim 68 , wherein said glucan is attached to a particle. 
     
     
         77 . The method of  claim 66 , wherein said immune response is complement-dependent. 
     
     
         78 . The method of  claim 66 , wherein said infectious agent causes sepsis. 
     
     
         79 . The method of  claim 66 , wherein said infectious agent is a parasite, helminth, virus or bacteria. 
     
     
         80 . A method of stimulating or enhancing heat shock protein expression in a cell, the method comprising contacting said cell with a composition comprising purified β-1-6-glucan, wherein said β-1-6-glucan is attached to a particle. 
     
     
         81 . The method of  claim 80 , wherein said glucan is enriched for O-acetylated glucan. 
     
     
         82 . The method of  claim 80 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         83 . The method of  claim 80 , wherein said glucan is isolated or derived from a lichen or yeast or fungus. 
     
     
         84 . The method of  claim 80 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         85 . The method of  claim 80 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         86 . The method of  claim 80 , wherein said cell is an antigen-presenting cell. 
     
     
         87 . The method of  claim 86 , wherein said cell is a neutrophil. 
     
     
         88 . The method of  claim 86 , wherein said cell is infected. 
     
     
         89 . A method of stimulating or enhancing heat shock protein expression in a cell, the method comprising contacting said cell with a composition comprising purified β-1-6-glucan, wherein said β-1-6-glucan is enriched for O-acetylated glucan. 
     
     
         90 . The method of  claim 89 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         91 . The method of  claim 89 , wherein said glucan is isolated or derived from a lichen or yeast or fungus. 
     
     
         92 . The method of  claim 89 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         93 . The method of  claim 89 , wherein said glucan is genetically engineered or chemically synthesized or acetylated 
     
     
         94 . The method of  claim 89 , wherein said cell is an antigen-presenting cell. 
     
     
         95 . The method of  claim 89 , wherein said cell is a neutrophil. 
     
     
         96 . The method of  claim 89 , wherein said cell is infected. 
     
     
         97 . A particle comprising β-1-6-glucan. 
     
     
         98 . The particle of  claim 97 , wherein the β-1-6-glucan is enriched for O-acetylated groups. 
     
     
         99 . The particle of  claim 97 , wherein the particle comprises at least 50% β-1-6-glucan by weight. 
     
     
         100 . The particle of  claim 97 , wherein the particle comprises glucan, and wherein at least 50% of the glucan is β-1-6-glucan 
     
     
         101 . The particle of  claim 97 , wherein the β-1-6-glucan is homogeneously distributed in the particle. 
     
     
         102 . The particle of  claim 97 , wherein the particle has a size appropriate for phagocytosis by neutrophils, monocytes, macrophages, or dendritic cells. 
     
     
         103 . A method of modulating the immune response of immune system cells comprising contacting the cells with the particle of  claim 97  in an amount sufficient to modulate the immune response. 
     
     
         104 . The method of  claim 103 , wherein said amount is sufficient to enhance phagocytosis, induce production of ROS, or induce expression of heat shock proteins. 
     
     
         105 . A method of modulating the immune response comprising administering the particle of  claim 97  to a subject in an amount sufficient to modulate the immune response. 
     
     
         106 . The method of  claim 105 , wherein said amount is sufficient to enhance phagocytosis, induce production of ROS, or induce expression of heat shock proteins. 
     
     
         107 . A composition comprising purified β-1-6-glucan, wherein the composition is a pharmaceutical composition, a food or food product, a food supplement, or a cosmetic composition. 
     
     
         108 . The composition of  claim 107 , wherein the composition comprises β-1-6-glucan that has been processed to increase its ability to modulate the immune response relative to unprocessed β-1-6-glucan. 
     
     
         109 . The composition of  claim 107 , wherein at least 50% of the glucan contained in the composition is β-1-6-glucan. 
     
     
         110 . A method of modulating the immune response comprising administering the particle of  claim 97  to a subject in an amount sufficient to modulate the immune response. 
     
     
         111 . The method of  claim 107 , wherein said amount is sufficient to enhance phagocytosis, induce production of ROS, or induce expression of heat shock proteins. 
     
     
         112 . A micelle comprising β-1,6-glucan, wherein said β-1,6-glucan is optionally enriched for O-acetylated glucan. 
     
     
         113 . A composition comprising β-1,6-glucan and a biodegradable polymer, wherein said biodegradable polymer degrades to form biologically active salicylate or alpha-hydroxy acid moieties and said β-1,6-glucan is optionally enriched for O-acetylated glucan. 
     
     
         114 . A particle comprising the composition of  claim 113 . 
     
     
         115 . A medical device comprising the composition of  claim 113 . 
     
     
         116 . A medical device wherein at least a portion of a surface of the implant or device comprises β-1-6-glucan, optionally enriched for O-acetylated glucan. 
     
     
         117 . The medical device of  claim 116 , wherein at least a portion of a surface is coated with a composition comprising a β-1-6-glucan, optionally enriched for O-acetylated glucan. 
     
     
         118 . The medical device of  claim 116 , wherein the device is selected from the group consisting of: catheter, stent, valve, pacemaker, central line, pessary, tube, shunt, feeding tube, drain, and orthopedic hardware devices. 
     
     
         119 . The medical device of  claim 116 , wherein the composition comprises a coating layer comprising a polymer and β-1-6-glucan, optionally enriched for O-acetylated glucan. 
     
     
         120 . The medical device of  claim 116 , wherein the composition comprises a coating layer comprising a polymer and β-1-6-glucan, optionally enriched for O-acetylated glucan, wherein the polymer is biodegradable. 
     
     
         121 . A method of treating a subject comprising implanting or introducing the medical device of claim  116  into the body of a subject in need thereof. 
     
     
         122 . A coated material comprising: (a) a substrate; and (b) a composition comprising a β-1-6-glucan physically associated with at least a portion of a surface of said substrate, wherein said composition is optionally in the form of a gel or film. 
     
     
         123 . The coated material of  claim 122 , wherein the composition comprises a polymer. 
     
     
         124 . The coated material of  claim 122 , wherein the composition comprises a biodegradable polymer. 
     
     
         125 . The coated material of  claim 122 , wherein the substrate is composed at least in part of metal, ceramic, or polymer. 
     
     
         126 . A method of treating a subject comprising contacting the body of a subject in need thereof with the coated material of  claim 122 . 
     
     
         127 . A composition comprising a β-1-6-glucan physically associated with a targeting moiety. 
     
     
         128 . The composition of  claim 127 , wherein said glucan is enriched for O-acetylated groups. 
     
     
         129 . The composition of  claim 128 , wherein said glucan contains at least 25% by weight O-acetylated glucan. 
     
     
         130 . The composition of  claim 127 , wherein said glucan is isolated or derived from a lichen or a yeast or a fungus. 
     
     
         131 . The composition of  claim 130 , wherein said glucan is isolated or derived from Umbilicariaceae. 
     
     
         132 . The composition of  claim 127 , wherein said glucan is genetically engineered or chemically synthesized or acetylated. 
     
     
         133 . The composition of  claim 127 , further comprising an adjuvant, an antigen, an immuno-modulatory compound, or a combination thereof. 
     
     
         134 . The composition of  claim 127 , wherein said phagocytic cell is a professional antigen-presenting cell. 
     
     
         135 . The composition of  claim 127 , wherein said phagocytic cell is a neutrophil. 
     
     
         136 . The composition of  claim 127 , wherein said targeting moiety is an antibody or antibody fragment. 
     
     
         137 . A method of modulating an immune response in a subject, said method comprising administering to said subject the composition of  claim 127 . 
     
     
         138 . The method of  claim 137 , wherein said glucan is conjugated to a particle. 
     
     
         139 . The method of  claim 137 , wherein modulating said immune response comprises stimulating said immune response. 
     
     
         140 . The method of  claim 139 , wherein said immune response is an antigen-specific response. 
     
     
         141 . The method of  claim 137 , wherein said composition further comprises an immuno-stimulatory compound. 
     
     
         142 . The method of  claim 137 , wherein said composition further comprises a chemotherapeutic compound. 
     
     
         143 . The method of  claim 137 , wherein said immune response is directed against an infectious agent, a cancer, a preneoplastic lesion or a combination thereof. 
     
     
         144 . The method of  claim 137 , wherein said immune response is complement-dependent. 
     
     
         145 . A method of treating, delaying progression of, or reducing the incidence or severity of an infection in a subject, said method comprising administering to said subject the composition of  claim 127 . 
     
     
         146 . The method of  claim 145 , further comprising an adjuvant, an antigen, a peptide, an immuno-stimulatory compound, a chemotherapeutic or a combination thereof. 
     
     
         147 . The method of  claim 146 , wherein said antigen or peptide is derived from the source of said infection. 
     
     
         148 . The method of  claim 146 , wherein said immuno-stimulatory compound is a cytokine. 
     
     
         149 . The method of  claim 146 , wherein said chemotherapeutic compound is an antibiotic or antiviral compound. 
     
     
         150 . A method of stimulating or enhancing heat shock protein expression in a cell, the method comprising contacting said cell with the composition of  claim 127 .