Dendritic cell asgpr targeting immunotherapeutics for multiple sclerosis

Abstract

Methods and compositions for treating multiple sclerosis using dendritic cell anti-ASGPR antibodies fused to myelin basic protein or myelin oligodendrocyte glycoprotein provided.

What is claimed is: 
     
         1 . A method of inducing immune tolerance to at least one myelin sheath protein in a patient comprising administering to the patient an effective amount of a composition comprising a dendritic cell targeting complex comprising a dendritic cell antibody, or targeting fragment thereof, attached to the at least one myelin sheath protein, or antigenic fragment thereof. 
     
     
         2 . The method of  claim 1 , wherein at least one myelin sheath protein is myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin associated glycoprotein (MAG). 
     
     
         3 . The method of  claim 2 , wherein at least one myelin sheath protein is MBP. 
     
     
         4 . The method of  claim 2 , wherein at least one myelin sheath protein is MOG. 
     
     
         5 . The method of any of  claims 1 - 4 , wherein the dendritic cell antibody specifically binds asialoglycoprotein receptor (ASGPR). 
     
     
         6 . The method of any of  claims 1 - 5 , wherein the composition comprises multiple dendritic cell targeting complexes. 
     
     
         7 . The method of  claim 6 , wherein the multiple dendritic cell targeting complexes comprise different myelin sheath proteins or different antigenic fragments of one or more myelin sheath proteins. 
     
     
         8 . The method of  claim 6  or  7 , wherein each myelin sheath protein or antigen fragment is separately attached to a dendritic cell antibody, or a targeting fragment thereof. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein the dendritic cell antibody is attached to the myelin sheath protein using a peptide linker. 
     
     
         10 . The method of any of  claims 1 - 9 , wherein the composition further comprises at least one tolerogenic adjuvant. 
     
     
         11 . The method of  claim 10 , wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 
     
     
         12 . The method of  claim 11 , wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 
     
     
         13 . The method of  claim 11 , wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 
     
     
         14 . The method of any of  claims 10 - 13 , wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit,  Escherichia coli  heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 
     
     
         15 . The method of any of  claims 1 - 14 , wherein the dendritic cell antibody is attached to at least one myelin sheath protein through binding polypeptides. 
     
     
         16 . The method of  claim 15 , wherein the binding polypeptides are dockerin and cohesin. 
     
     
         17 . The method of any of  claims 1 - 16 , comprising more than one administration of the composition. 
     
     
         18 . The method of any of  claims 1 - 16 , wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, mucosally, and/or using a nebulizer. 
     
     
         19 . The method of any of  claims 1 - 18 , wherein the subject exhibits one or more symptoms of a demyelinating disease. 
     
     
         20 . The method of any of  claims 1 - 19 , wherein the subject has been diagnosed with a demyelinating disease. 
     
     
         21 . The method of any of  claims 1 - 20 , wherein the subject is at risk for a demyelinating disease. 
     
     
         22 . The method of any of  claims 19 - 21 , wherein the demyelinating disease affects the central nervous system. 
     
     
         23 . The method of  claim 22 , wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 
     
     
         24 . The method of  claim 22 , wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 
     
     
         25 . The method of  claim 24 , wherein the demyelinating disease is multiple sclerosis. 
     
     
         26 . The method of any of  claims 19 - 21 , wherein the demyelinating disease affects the peripheral nervous system. 
     
     
         27 . The method of  claim 26 , wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 
     
     
         28 . The method of any of  claims 1 - 24 , further comprising preparing the composition. 
     
     
         29 . The method of any of  claims 1 - 28 , further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 
     
     
         30 . A method for treating a demyelinating disease in a subject comprising administering to the subject a pharmaceutically acceptable vaccine composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 
     
     
         31 . The method of  claim 30 , wherein the ASGPR antibody, or binding fragment thereof, is fused to MBP or MOG, or an antigenic fragment thereof. 
     
     
         32 . The method of  claim 30  or  31 , wherein the subject is administered the vaccine composition multiple times. 
     
     
         33 . The method of  claim 32 , wherein the composition is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, nasally, by injection, by inhalation, muscosally, and/or using a nebulizer. 
     
     
         34 . The method of any of  claims 30 - 33 , wherein the subject exhibits one or more symptoms of a demyelinating disease. 
     
     
         35 . The method of any of  claims 30 - 33 , wherein the subject has been diagnosed with a demyelinating disease. 
     
     
         36 . The method of any of  claims 30 - 33 , wherein the subject is at risk for a demyelinating disease. 
     
     
         37 . The method of any of  claims 34 - 36 , wherein the demyelinating disease affects the central nervous system. 
     
     
         38 . The method of  claim 37 , wherein the demyelinating disease is an idiopathic inflammatory demyelinating disease. 
     
     
         39 . The method of  claim 38 , wherein the demyelinating disease is multiple sclerosis, neuropathy, central pontine myelinolysis, tabes dorsalis, transverse myelitis, Devic's disease, progressive multifocal leukoencephalopathy, optic neuritis, or leukodystrophy. 
     
     
         40 . The method of  claim 39 , wherein the demyelinating disease is multiple sclerosis. 
     
     
         41 . The method of any of  claims 34 - 36 , wherein the demyelinating disease affects the peripheral nervous system. 
     
     
         42 . The method of  claim 41 , wherein the demyelinating disease is Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy. Charcot-Marie-Tooth Disease, copper deficiency, or progressive inflammatory neuropathy. 
     
     
         43 . The method of any of  claims 30 - 42 , further comprising preparing the composition. 
     
     
         44 . The method of any of  claims 30 - 43 , further comprising measuring antibodies against the at least one myelin sheath protein in the subject after administering the composition. 
     
     
         45 . A composition comprising at least a first ASGPR antibody, or binding fragment thereof, attached to myelin basic protein (MBP) and/or myelin oligodendrocyte glycoprotein (MOG), or antigenic fragment thereof. 
     
     
         46 . The composition of  claim 45 , wherein the dendritic cell antibody is attached to the myelin sheath protein or antigenic fragment thereof using a peptide linker. 
     
     
         47 . The composition of any of  claims 45 - 46 , wherein the composition further comprises at least one tolerogenic adjuvant. 
     
     
         48 . The composition of  claim 47 , wherein the tolerogenic adjuvant is attached to the dendritic cell targeting complex. 
     
     
         49 . The composition of  claim 48 , wherein the tolerogenic adjuvant is conjugated to the dendritic cell targeting complex. 
     
     
         50 . The composition of  claim 48 , wherein the tolerogenic adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one myelin sheath protein. 
     
     
         51 . The composition of any of  claims 47 - 50 , wherein the tolerogenic adjuvant is selected from IL-10, dexamethasone, FK506 (Tacrolimus), cholera toxin B subunit, Escherichia coli heat-labile enterotoxin B subunit, IFN-beta, glucocorticoids, vitamin D3, and vitamin D3 analogues. 
     
     
         52 . The composition of any of  claims 45 - 51 , wherein the dendritic cell antibody is attached to at least one myelin sheath protein or antigenic fragment thereof through binding polypeptides. 
     
     
         53 . The composition of  claim 52 , wherein the binding polypeptides are dockerin and cohesin.