Enhancing t cell activation using altered mhc-peptide ligands

Abstract

Materials and Methods for identifying and using MHC molecule variants for activating self-reactive T cells in a peptide-specific manner, and their use to focus autoimmune cellular responses against diseases such as cancers and persisting viral infections, are described.

1 . A method for treating a subject in need thereof, comprising administering to the subject:
 (a) a cell expressing on its surface a variant of a major histocompatibility complex (MHC) molecule, the variant comprising one or more amino acid changes from wild-type in the part of the MHC molecule that interacts with a T cell receptor, wherein the cell has been identified as having the ability to activate a T cell in the presence of an epitope from the subject; and   (b) the epitope or a polypeptide comprising the epitope,   
       wherein the subject has a pathological condition that is amenable to therapy by a T cell immune response. 
     
     
         2 . The method of  claim 1 , wherein the subject is a human. 
     
     
         3 . The method of  claim 1 , wherein at least one of the one or more amino acid changes is at a residue of the MHC molecule that, on the surface of a cell expressing the MHC molecule, is accessible for interaction with a TCR. 
     
     
         4 . The method of  claim 1 , wherein the MHC molecule is an HLA-A0201 MHC class I molecule, and wherein at least one of the one or more amino acid changes is at position 72, 76, 79, 154, 158, 162, or 166 of the molecule. 
     
     
         5 . The method of  claim 1 , wherein the epitope is from a polypeptide associated with the pathological condition. 
     
     
         6 . The method of  claim 1 , wherein the pathological condition is cancer and the epitope is from a polypeptide expressed by a cancer cell, or wherein the pathological condition is caused by an infectious microorganism and the epitope is from a polypeptide expressed by a cell infected with the infectious microorganism. 
     
     
         7 . The method of  claim 1 , wherein the epitope is from a survivin, GP100, MelA, survivin-2B, livin/ML-IAP, Bcl-2, Mcl-1, BcI-X(L), mucin-1, NY-ESO-1, telomerase, CEA, MART-1, HER-2/neu, bcr-abl, PSA, PSCA, tyrosinase, p53, hTRT, leukocyte proteinase-3, hTRT, gpl OO, MAGE antigens, GASC, JMJD2C, JARD2 (JMJ), JHDM3a, WT-1,CA 9, or protein kinase polypeptide. 
     
     
         8 . A composition comprising:
 (a) a cell expressing on its surface a variant of an MHC molecule, the variant comprising one or more amino acid changes from wild-type in the part of the MHC molecule that interacts with a T cell receptor, wherein the cell has been identified as having the ability to activate a T cell in the presence of a particular peptide epitope; and   (b) a pharmaceutically acceptable carrier;   and optionally, the peptide epitope.   
     
     
         9 . The composition of  claim 8 , wherein at least one of the one or more amino acid changes is at a residue of the MHC molecule that is accessible for interaction with a TCR. 
     
     
         10 . The composition of  claim 8 , wherein the MHC molecule is an HLA-A0201 MHC class I molecule, and wherein at least one of the one or more amino acid changes is at position 72, 76, 79, 154, 158, 162, or 166 of the molecule. 
     
     
         11 . The composition of  claim 8 , wherein the peptide epitope is from a polypeptide expressed by a cancer cell or by a cell infected with an infectious microorganism. 
     
     
         12 . The composition of  claim 8 , wherein the peptide epitope is from a survivin, GP100, MelA, survivin-2B, livin/ML-IAP, Bcl-2, Mcl-1, BcI-X(L), mucin-1, NY-ESO-1, telomerase, CEA, MART-1, HER-2/neu, bcr-abl, PSA, PSCA, tyrosinase, p53, hTRT, leukocyte proteinase-3, hTRT, gpl OO, MAGE antigens, GASC, JMJD2C, JARD2 (JMJ), JHDM3a, WT-1,CA 9, or protein kinase polypeptide. 
     
     
         13 . The composition of  claim 8 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of water, saline solution, binding agents, fillers, lubricants, disintegrates, and wetting agents. 
     
     
         14 . The composition of  claim 8 , further comprising an adjuvant selected from the group consisting of Freund's adjuvant, aluminum hydroxide, lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, cytokines, and bacterial products. 
     
     
         15 . A method comprising contacting a cell in a subject with a virus particle comprising a nucleic acid that encodes a variant of an MHC molecule, the variant comprising one or more amino acid changes from wild-type in a portion of the MHC molecule that interacts with a T cell receptor. 
     
     
         16 . The method of  claim 15 , wherein the subject is a human. 
     
     
         17 . The method of  claim 15 , wherein the virus is an adenovirus. 
     
     
         18 . The method of  claim 15 , wherein the MHC molecule is a class I MHC molecule. 
     
     
         19 . A variant of an MHC molecule, comprising one or more amino acid changes from wild-type in the part of the MHC molecule that interacts with a T cell receptor, wherein the MHC molecule, in the presence of a particular epitope, has been identified as having the ability to activate a T cell. 
     
     
         20 . A method of selecting a MHC molecule variant for activation of an immune response, the method comprising:
 providing a panel of cells, each cell of the panel expressing on its surface a variant of an MHC molecule, the variant comprising one or more amino acid changes from wild-type in the part of the MHC molecule that interacts with a T cell receptor;   testing the ability of each cell of the panel to activate a T cell in the presence of a selected peptide epitope; and   selecting the MHC molecule expressed by a cell of the panel that activates a T cell in the presence of the peptide epitope.