Agonist and antagonist peptides of carcinoembryonic antigen (cea)

Abstract

The invention provides a peptide comprising an agonist of a MHC Class I binding native sequence having amino acid substitution(s) and enhanced immunogenicity compared to the native sequence. The invention also provides methods comprising the administration of the peptide.

1 .- 29 . (canceled) 
     
     
         30 . A method for treating a host having a tumor expressing carcinoembryonic antigen (CEA) or epitope thereof comprising introducing cytotoxic T lymphocytes specific for CEA or epitope thereof to the host and at a periodic interval thereafter introducing to the host a peptide comprising an agonist of the MHC Class I binding native sequence YLSGANLNL (SEQ ID NO: 1), wherein the agonist has an amino acid substitution at any of positions 1, 3, 4, 5, 6, 7, and 8 and the agonist has enhanced immunogenicity compared to the native sequence, such that the host is treated. 
     
     
         31 . The method according to  claim 30  wherein the peptide is selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and combinations thereof. 
     
     
         32 . A method of inhibiting a carcinoembryonic antigen (CEA) epitope-expressing carcinoma cell in a patient comprising administering to the patient an effective amount of a peptide comprising an agonist of the MHC Class I binding native sequence YLSGANLNL (SEQ ID NO: 1), wherein the agonist has an amino acid substitution at any of positions 1, 3, 4, 5, 6, 7, and 8 and the agonist has enhanced immunogenicity compared to the native sequence, such that a CEA epitope-expressing carcinoma cell is inhibited. 
     
     
         33 . The method according to  claim 32  further comprising administration of an immunostimulatory molecule. 
     
     
         34 . The method according to  claim 33  wherein the immunostimulatory molecule is selected from the group consisting of IL-2, B7.1, B7.2, ICAM-1, LFA-3, CD72, GMCSF, TNFα, INFγ, IL-12, IL-6, and combinations thereof. 
     
     
         35 . The method according to  claim 32  further comprising administration of an adjuvant. 
     
     
         36 . The method according to  claim 32  wherein the carcinoma cell is a gastrointestinal, breast, pancreatic, bladder, ovarian, lung, or prostate carcinoma cell. 
     
     
         37 . The method according to  claim 32  further comprising the administration of a vector comprising the gene encoding CEA. 
     
     
         38 . A method of inhibiting or killing carcinoembryonic antigen (CEA) epitope-expressing carcinoma cells comprising:
 A) generating CEA epitope or agonist peptide-specific cytotoxic T lymphocytes in vitro by stimulation of lymphocytes from a source with an effective amount of a peptide comprising an agonist of the MHC Class I binding native sequence YLSGANLNL (SEQ ID NO: 1), wherein the agonist has an amino acid substitution at any of positions 1, 3, 4, 5, 6, 7, and 8 and the agonist has enhanced immunogenicity compared to the native sequence, alone or in combination with an immunostimulatory molecule; and   B) adoptively transferring the CEA epitope or agonist peptide-specific cytotoxic T lymphocytes alone or in combination with the agonist peptide into a mammal in an amount sufficient to inhibit or kill the CEA epitope expressing carcinoma cells.   
     
     
         39 . A method of inhibiting or killing carcinoembryonic antigen (CEA) epitope-expressing carcinoma cells in a mammal comprising:
 A) generating CEA epitope or agonist peptide-specific cytotoxic T lymphocytes in vivo by administration of an effective amount of (i) a peptide comprising an agonist of the MHC Class I binding native sequence YLSGANLNL (SEQ ID NO: 1), wherein the agonist has an amino acid substitution at any of positions 1, 3, 4, 5, 6, 7, and 8 and the agonist has enhanced immunogenicity compared to the native sequence, (ii) a vector comprising the nucleic acid sequence encoding CEA or (iii) agonist peptide pulsed antigen presenting cells; and   B) at a periodic interval providing the agonist peptide alone or in combination with an adjuvant; wherein the CEA epitope or agonist peptide-specific cytotoxic T lymphocytes so generated inhibit or kill CEA epitope expressing carcinoma cells.   
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . A method of inhibiting carcinoembryonic antigen (CEA) specific immune responses comprising administration of a peptide comprising an antagonist of the MHC Class I binding native sequence YLSGANLNL (SEQ ID NO: 1), wherein the antagonist varies at least one amino acid position from SEQ ID NO: 1 and the antagonist inhibits CEA-specific immune responses in an amount effective to inhibit the CEA-specific immune responses. 
     
     
         43 . The method according to  claim 42  wherein cytotoxic T lymphocytes specific for CEA or epitopes thereof are inhibited. 
     
     
         44 . The method of  claim 32  wherein the peptide is selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and combinations thereof. 
     
     
         45 . The method of  claim 38  wherein the peptide is selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and combinations thereof. 
     
     
         46 . The method of  claim 39  wherein the peptide is selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and combinations thereof.