US2023330198A1PendingUtilityA1
Rna for treatment of autoimmune diseases

Assignee: BioNTech SEPriority: Apr 11, 2017Filed: Jun 12, 2023Published: Oct 19, 2023
Est. expiryApr 11, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Ugur Sahin Sebastian Kreiter Christina Krienke Jutta Petschenka Lena Mareen Kranz Mustafa Diken
C12N 2310/335A61K 2039/55555A61K 2039/53C12N 15/11C12N 15/117C12N 15/101A61P 25/00A61P 37/06A61K 48/005A61K 48/0033A61K 39/0008A61K 2039/6018A61K 9/1272A61P 37/00
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Claims
Abstract

The present invention relates to non-immunogenic RNA. This RNA forms the basis for the development of therapeutic agents for inducing tolerance towards an autoantigen and thus, for the treatment of autoimmune diseases.
Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A method of treating an autoimmune disease in a subject, comprising administering to the subject non-immunogenic RNA encoding a peptide or polypeptide comprising an autoantigen or a fragment thereof, or a variant of the autoantigen or fragment. 
     
     
         2 . The method of claim I, wherein the autoimmune disease is a T cell-mediated autoimmune disease. 
     
     
         3 . A method of inducing tolerance to autoreactive T cells in a subject, comprising administering to the subject non-immunogenic RNA encoding a peptide or polypeptide comprising an autoantigen or a fragment thereof, or a variant of the autoantigcn or fragment. 
     
     
         4 . The method of  claim 3 , wherein the subject has an autoimmune disease. 
     
     
         5 . The method of any one of  claims 1 ,  2  and  4  wherein the autoimmune disease is an autoimmune disease of the CNS. 
     
     
         6 . The method of any one of  claims 1 ,  2 ,  4  and  5 , wherein the autoimmune disease is Multiple Sclerosis. 
     
     
         7 . The method of any one of  claims 1  to  6 , wherein the non-immunogenic RNA when administered does not result in activation of dendritic cells, activation of T cells and/or secretion of 1FN-alpha. 
     
     
         8 . The method of any one of  claims 1  to  7 , wherein the non-immunogenic RNA is rendered non-immunogenic by the incorporation of modified nucleotides and the removal of dsRNA. 
     
     
         9 . The method of  claim 8 , wherein the modified nucleotides suppress RNA-mediated activation of innate immune receptors. 
     
     
         10 . The method of  claim 8  or  9 , wherein the modified nucleotides comprise a replacement of one or more uridines with a nucleoside comprising a modified nucleobase. 
     
     
         11 . The method of  claim 10 , wherein the modified nucleobase is a modified uracil. 
     
     
         12 . The method of  claim 10  or  11 , wherein the nucleoside comprising a modified nucleobase is selected from the group consisting of 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thin-uridine (s2U), 4-thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyTuridine, 5-halo-uridine (e.g., 5-iodo-uridineor 5-bromo-uridine), uridine 5-oxyacetic acid (emo5U), uridine 5-oxyacetic acid methyl ester (incino5U), 5-carboxymethyl-uridine (cm5U), 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-uridinc (chm5U), 5-carboxyhydroxymethylmridine methyl ester (mchm5U), 5methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (un5s2U), 5-methylaminomethyl-uridine (mnm5U), 1-ethyl-pseudouridine, 5-methylaminomethyl-2-thio-uridine (namn5s2U), 5-methylaminomethyl-2-seleno-uridine (nnm5se2U), 5-carhamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl-uridine (enmm5U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine (cm5U), 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine (rm5s2U), 1-taurinomethyl-4-thio-pseudouridine, 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pseudouridine (m1s4y), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3y), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5.6-dihydrouridine, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2-inethoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridinc, N1-methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3 U), 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp3 NO, 5-(isopentenylaminomethyDuridine (inm5U), 5-(isopentenylaminomethyl)-2-thio-uridinc (inm5s2U), a-thio-uridine, 2′-0-methyl-uridine (Urn), 5,T-O-dimethyl-uridine (m5Um), T-0-methyl-5 pseudouridine (win). 2-thio-2′-O-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-T-0-methyl-uridine (mcm5Urn), 5-carbamoylmethyl-2c 0-methyl-uridine (ncm5Um), 5-carboxymethylaminomethyl-21-0-methyl-uridine (emnin5Ifin), 3,21-0-dimethyl-uridine (rn3Um), 5-(isopentcnylaminomethyl)-21-0-methyl-tiridine (inm5 Um), 1-thio-uridine, deoxythymidine, T-F-ara-uridine, 2′-F10 uridine, 2′-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, and 543-(1-E-propenylamino)unidine. 
     
     
         13 . The method of any one of  claims 10  to  12 , wherein the nucleoside comprising a modified nucleobase is pseudouridine (NO, NI-methyl-pseudouridine (m′ NO or 5-methyl-uridine (m5U). 
     
     
         14 . The method of any one of  claims 10  to  13 , wherein the nucleoside comprising a modified nucleobase is 1-methyl-pseudouridine. 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the non-immunogenic RNA is inRNA. 
     
     
         16 . The method of any one of claims I to  15 , wherein the non-immunogenic RNA is in vitro transcribed RNA. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein the autoantigen is associated with an autoimmune disease. 
     
     
         18 . The method of any one of  claims 1  to  17 , wherein the autoantigen is a T cell-antigen. 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the autoantigen is CNS-derived. 
     
     
         20 . The method of any one of  claims 1  to  19 , wherein the autoantigen is a myelin antigen. 
     
     
         21 . The method of any one of  claims 1  to  20 , wherein the autoantigen is Myelin Oligodendrocyte Glycoprotein (MOG). 
     
     
         22 . The method of ally one of  claims 1  to  21 , wherein the peptide or polypeptide comprising an autoantigen or a fragment thereof; or a variant of the autoantigen or fragment comprises amino acids 35 to 55 of Myelin Oligodendrocyte Glycoprotein (MOG). 
     
     
         23 . The method of any one of claims I to 22, wherein the non-immunogenic RNA is transiently expressed in cells of the subject. 
     
     
         24 . The method of any one of  claims 1  to  23 , wherein the non-immunogenic RNA is delivered to dendritic cells. 
     
     
         25 . The method of  claim 24 , wherein the dendritic cells are immature dendritic cells. 
     
     
         26 . The method of any one of  claims 1  to  25 , wherein the non-immunogenic RNA is formulated in a delivery vehicle. 
     
     
         27 . The method of  claim 26 , wherein the delivery vehicle comprises particles. 
     
     
         28 . The method of  claim 26  or  27 , wherein the delivery vehicle comprises a lipid. 
     
     
         29 . The method of  claim 28 , wherein the lipid comprises a cationic lipid. 
     
     
         30 . The method of  claim 28  or  29 , wherein the lipid forms a complex with and/or encapsulates the non-immunogenic RNA. 
     
     
         31 . The method of any one of claims I to 30, wherein the non-immunogenic RNA is formulated in liposomes. 
     
     
         32 . A pharmaceutical composition comprising non-immunogenic RNA encoding a peptide or polypeptide comprising an autoantigen or a fragment thereof, or a variant of the autoantigen or fragment. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the non-immunogenic RNA when administered does not result in activation of dendritic cells, activation of T cells and/or secretion of IFN-alpha. 
     
     
         34 . The pharmaceutical composition of  claim 32  or  33 , wherein the non-immunogenic RNA is rendered non-immunogenic by the incorporation of modified nucleotides and the removal of dsRNA. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the modified nucleotides suppress RNA-mediated activation of innate immune receptors. 
     
     
         36 . The pharmaceutical composition of  claim 34  or  35 , wherein the modified nucleotides comprise a replacement of one or more uridines with a nucleoside comprising a modified nucleobase. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the modified nucleobase is a modified uracil. 
     
     
         38 . The pharmaceutical composition of  claim 36  or  37 , wherein the nucleoside comprising a modified nucleobase is selected from the group consisting of 3-methyl-uridine (m311), 5-methoxy-uridinc (mo5U), 5-aza-uridine, 6-aza-uridine, 230 thio-5-aza-uridine, 2-thio-uridine (s2U), 4-thio-uridine (s4U). 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridineor 5-bromo-uridine), uridine 5-oxyacetic acid (cmo5U), uridinc 5-oxyacetic acid methyl ester (memo5U), 5-carboxyincthyl-uridine (cin5U), I-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-undine (chm5U), 5-earboxyhydroxymethyl-uridine methyl ester (mchm5U),5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-24hio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nn5s2U), 5-methylaminomethyl-uridine (mnin5U), 1-ethyl-pseudouridine, 5-methylaminomethyl-2-thio-uridine (nnin5s2U), 5-methylaminomethyl-2-selcno-uridine (mnin5se2U), 5-carbamoylmethyl-uridine (ncin5U), 5-carboxymethylaminomethyl-uridine (enmun5U), 5-carboxymethylaminomethyl-2-thio-midine (cmnrn5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine (tm5U), 1-taurinomethyl-pscudouridine, 5-tatninomethyl-2-thio-uridine (rm5s211), 1-taurinom ethyl-4-thio-pseuclouridine, 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pscudouridine I s4y), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3 v), 2-thio-1-methyl-pseudo uridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridinc, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-rnethoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-incthoxy-2-thio-pseudouridine, N1-methyl-pscudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3U), I-methyl-343-amino-3-carboxypropyl)pseudouridine (acp3 y), 5-(isopentenylaminomethyl)uridine (inm5U), 5-(isopentenylaminomethyl)-2-thio-uridine (inm5s2U), a-thio-uridine, 21-O-methyl-uridine (Urn), 5,2′-O-dimethyl-uridine (m5Um), T-O-methyl-pseudouridine (ym), 2-thio-2′-O-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-T-O-methyl-uridine (mcm5Um), 5-arbamoylmethyl-2′-O-methyl-uridine (ncm5Um), 5-carboxymethylaminomethyl-r-O-methyl-uridine (cmnm5Um), 3,2′-O-dimethyl-uridine (m3Um), 5-(isopentenylaminomethyl)-T-O-methyl-uridine (inni51.1m), 1-thio-uridine, deoxythymidine, 2′-F-ara-uridine, 2′-F-uridine, 2′-OH-ara-uridine, 5(2-carbomethoxyvinyl) uridine, and 5-[3-(1-E-propenyl amino)uridine. 
     
     
         39 . The pharmaceutical composition of any one of  claims 36  to  38 , wherein the nucleoside comprising a modified nutlet-base is pseudouridine (y), N I-methyl-pseudouridinc (na 1  y) or 5-methyl-uridine (m5U). 
     
     
         40 . The pharmaceutical composition of any one of  claims 36  to  39 , wherein the nucleoside comprising a modified nucleobase is I-methyl-pseudouridine. 
     
     
         41 . The pharmaceutical composition of any one of  claims 32  to  40 , wherein the non-immunogenic RNA is mRNA. 
     
     
         42 . The pharmaceutical composition of any one of  claims 32  to  41 , wherein the non-immunogenic RNA is in vitro transcribed RNA. 
     
     
         43 . The pharmaceutical composition of any one of  claims 32  to  42 , wherein the autoantigen is associated with an autoimmune disease. 
     
     
         44 . The pharmaceutical composition of any one of  claims 32  to  43 , wherein the autoantigen is a T cell-antigen. 
     
     
         45 . The pharmaceutical composition of any one of  claims 32  to  44 , wherein the autoantigen is CNS-derived. 
     
     
         46 . The pharmaceutical composition of any one of  claims 32  to  45 , wherein the autoantigen is a myelin antigen. 
     
     
         47 . The pharmaceutical composition of any one of  claims 32  to  46 , wherein the autoantigen is Myelin Oligodendrocyte Glycoprotein (MOG). 
     
     
         47 . The pharmaceutical composition of any one of  claims 32  to  48 , wherein the non-immunogenic RNA is transiently expressed in cells of a subject to whom the pharmaceutical composition is administered. 
     
     
         48 . The pharmaceutical composition of any one of  claims 32  to  47 , wherein the peptide or polypeptide comprising an autoantigen or a fragment thereof, or a variant of the autoantigen or fragment comprises amino acids 35 to 55 of Myelin Oligodendrocyte Glycoprotein (MOG). 
     
     
         50 . The pharmaceutical composition of any one of  claims 32  to  49 , wherein the non-immunogenic RNA is delivered to dendritic cells of a subject to whom the pharmaceutical composition is administered. 
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein the dendritic cells arc immature dendritic cells. 
     
     
         52 . The pharmaceutical composition of any one of  claims 32  to  51 , wherein the non-immunogenic RNA is formulated in a delivery vehicle. 
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the delivery vehicle comprises particles. 
     
     
         54 . The pharmaceutical composition of  claim 52  or  53 , wherein the delivery vehicle comprises a lipid. 
     
     
         55 . The pharmaceutical composition of  claim 54 , wherein the lipid comprises a cationic lipid. 
     
     
         56 . The pharmaceutical composition of  claim 54  or  55 , wherein the lipid lbrms a complex with and/or encapsulates the non-immunogenic RNA. 
     
     
         57 . The pharmaceutical composition of any one of  claims 32  to  56 , wherein the non-immunogenic RNA is formulated in liposomes. 
     
     
         58 . The pharmaceutical composition of any one of  claims 32  to  57  for use in the method of any one of  claims 1  to  31 .
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