Compositions and methods for treatment of celiac disease

Abstract

The invention provides agents and vaccines for treating and diagnosing celiac disease. In particular, the present invention provides a combination of three peptides that are useful for treating and diagnosing celiac disease in a large proportion of patients.

1 . An agent comprising
 i) a first peptide comprising the amino acid sequence LQPFPQPELPYPQPQ (SEQ ID NO:13), or a biologically active fragment or variant thereof,   ii) a second peptide comprising the amino acid sequence QPFPQPEQPFPWQP (SEQ ID NO:14), or a biologically active fragment or variant thereof, and   iii) a third peptide comprising the amino acid sequence PEQPIPEQPQPYPQQ (SEQ ID NO:16), or a biologically active fragment or variant thereof.   
     
     
         2 . The agent of  claim 1 , wherein the second peptide comprises the amino acid sequence PQQPFPQPEQPFPWQP (SEQ ID NO:320), or a biologically active fragment or variant thereof, and/or the third peptide comprises the amino acid sequence FPEQPIPEQPQPYPQQ (SEQ ID NO:321), or a biologically active fragment or variant thereof. 
     
     
         3 . The agent of  claim 1 , wherein the first, second and/or third peptides comprise an N terminal acetyl group or pyroglutamate group, and/or a C terminal amide group. 
     
     
         4 . The agent of  claim 3 , wherein the first, second and/or third peptides comprise an N terminal pyroglutamate group and a C terminal amide group. 
     
     
         5 . The agent of  claim 1 , wherein the first, second and/or third peptides are conjugated to a compound. 
     
     
         6 . The agent of  claim 5 , wherein the compound is an adjuvant, or an MHC molecule or binding fragment thereof. 
     
     
         7 . The agent of  claim 1 , wherein two or three of the first, second and third peptides, or the biologically active fragment or variant of one or more thereof, are on a single polypeptide chain. 
     
     
         8 . The agent of  claim 1  comprising one or more additional peptides comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:47, 48, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 75, 76, 77, 78, 79, 80, 81, 89, 90, 91, 92, 95, 102, 103, 104, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 136, 169, 170, 171, 172, 173, 174, 177, 178, 179, 180, 183, 184, 187, 188, 189, 190, 191, 192, 209, 210, or a biologically active fragment or variant of any one or more thereof. 
     
     
         9 . An agent comprising one or more polynucleotides encoding the agent of  claim 1 . 
     
     
         10 . An agent comprising
 i) a first peptide or a polynucleotide that encodes the first peptide,   ii) a second peptide or a polynucleotide that encodes the first peptide, and   iii) a third peptide or a polynucleotide that encodes the first peptide,   wherein the first peptide comprises the amino acid sequence LQPFPQPELPYPQPQ (SEQ ID NO: 13), or a biologically active fragment or variant thereof; the second peptide comprises the amino acid sequence QPFPQPEQPFPWQP (SEQ ID NO: 14), or a biologically active fragment or variant thereof; and the third peptide comprises the amino acid sequence PEQPIPEQPQPYPQQ (SEQ ID NO: 16), or a biologically active fragment or variant thereof.   
     
     
         11 . A substantially purified and/or recombinant peptide comprising an amino acid sequence as shown in any one or more of SEQ ID NO:16, 69, 73, 75, 78, 80, 87, 91, 92, 95, 96, 98, 100, 104, 107, 113, 116, 117, 123, 138, 144, 147, 149, 153, 155, 156, 159, 161, 163, 165, 179, 181, 185, 187, 189, 195, 196, 198, 202, 204, 205, 207, 209, 215, 223, or a biologically active fragment or variant of any one or more thereof. 
     
     
         12 . An isolated and/or exogenous polynucleotide encoding at least one peptide of  claim 11 . 
     
     
         13 . A vaccine comprising the agent of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         14 . (canceled) 
     
     
         15 . An isolated antigen presenting cell comprising the agent of  claim 1 . 
     
     
         16 . (canceled) 
     
     
         17 . A method of modulating a T cell response to a gluten peptide, inducing immune tolerance to a gluten peptide, treating celiac disease, or modifying cytokine secretion in a subject who is sensitive to gluten, comprising administering to the subject an effective amount of the agent of  claim 1 . 
     
     
         18 - 23 . (canceled) 
     
     
         24 . A method for diagnosing celiac disease in a subject, the method comprising contacting a sample from the subject with the agent of  claim 1 , and determining in vitro whether one or more of the peptides bind T cells in the sample, wherein the binding of one or more of the peptides to T cells indicates that the subject has, or is susceptible to, celiac disease. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 24 , wherein the method further comprises determining the efficacy of administering the composition to the subject. 
     
     
         27 . A kit comprising the agent of  claim 1 , and means to detect binding of one or more peptides to T cells. 
     
     
         28 . A method for producing an antigen presenting cell, the method comprising
 i) obtaining an antigen presenting cell, and   ii) contacting the cell in vitro with the agent of  claim 1 .   
     
     
         29 . (canceled) 
     
     
         30 . A method of preparing the vaccine of  claim 13 , the method comprising combining the first, second and third peptides, and optionally one or more additional peptides comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:47, 48, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 75, 76, 77, 78, 79, 80, 81, 89, 90, 91, 92, 95, 102, 103, 104, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 136, 169, 170, 171, 172, 173, 174, 177, 178, 179, 180, 183, 184, 187, 188, 189, 190, 191, 192, 209, 210, or a biologically active fragment or variant of any one or more thereof, with a pharmaceutically acceptable carrier, and optionally an adjuvant. 
     
     
         31 . A method of determining whether a composition or food is capable of causing celiac disease, the method comprising detecting the presence of the agent of  claim 1  in the composition or a food sample. 
     
     
         32 . A method of identifying a protease that can cleave a peptide as defined in  claim 1 , the method comprising contacting the peptide with a protease under conditions to effect specific cleavage of the peptide to produce a proteolytic product and detecting the proteolytic product produced. 
     
     
         33 . A method for improving the half life and/or bioavailability of a peptide when administered to a subject, the method comprising modifying the N terminus of the peptide to include an N terminal acetyl or pyroglutamate and modifying the C terminus of the peptide to include a C terminal amide. 
     
     
         34 . The method of  claim 33  in which the peptide is for administering to a subject to induce immune tolerance. 
     
     
         35 . A method of modulating a T cell response to a gluten peptide, inducing immune tolerance to a gluten peptide, treating celiac disease, or modifying cytokine secretion in a subject who is sensitive to gluten, comprising administering to the subject an effective amount of the composition of  claim 15 .