Brachyury protein, non-poxvirus non-yeast vectors encoding brachyury protein, and their use

Abstract

Brachyury protein can be used to induce Brachyury-specific CD4+ T cells in vivo and ex vivo. It is also disclosed that Brachyury protein can be used to stimulate the production of both Brachyury-specific CD4+ T cells and Brachyury-specific CD8+ T cells in a subject, such as a subject with cancer. In some embodiments, the methods include the administration of a Brachyury protein. In additional embodiments, the methods include the administration of a nucleic acid encoding the Brachyury protein, such as in a non-pox non-yeast vector. In further embodiments, the methods include the administration of host cells expressing the Brachyury protein.

1 . A method for inducing an immune response to Brachyury comprising administering to a human subject, wherein the human subject has cancer, an effective amount of
 (a) a polypeptide comprising at least 15 consecutive amino acids of the amino acid sequence set forth in SEQ ID NO: 1 that specifically binds a Major Histocompatibility Class (MHC) II molecule, or through internalization and cross-presentation can bind to MHC Class I;   (b) a nucleic acid encoding the polypeptide;   (c) a bacterial host cell expressing the polypeptide; or   (d) a non-pox non-yeast vector encoding the polypeptide,   
       thereby inducing the immune response, wherein the immune response comprises a Brachyury specific CD4+ T cell response. 
     
     
         2 . The method of  claim 1 , wherein the immune response further comprises a Brachyury specific CD8+ T cell response. 
     
     
         3 . The method of  claim 1 , further comprising measuring the Brachyury specific CD4+ T cell response. 
     
     
         4 . The method of  claim 1 , wherein the cancer is a breast cancer, small intestine cancer, stomach cancer, kidney cancer, bladder cancer, uterus cancer, ovarian cancer, testes cancer, lung cancer, colon cancer, prostate cancer, chronic lymphocytic leukemia (CLL), a B cell lymphoma, a Burkitt's lymphoma or a Hodgkin's lymphoma. 
     
     
         5 . The method of  claim 1 , comprising administering to the subject a protein comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1. 
     
     
         6 . The method of  claim 1 , comprising administering to the subject an effective amount of the polypeptide sufficient to induce Brachyury specific CD4+ T cells and/or Brachyury specific CD8+ T cells. 
     
     
         7 . The method of  claim 1 , wherein administering to the subject an effective amount of the polypeptide comprises administering an effective amount of dendritic cells presenting epitopes of the protein. 
     
     
         8 . The method of  claim 1 , comprising administering to the subject an effective amount of a nucleic acid encoding the polypeptide sufficient to induce Brachyury specific CD4+ T cells. 
     
     
         9 . The method of  claim 1 , comprising administering to the subject an effective amount of the non-pox non-yeast vector encoding the polypeptide sufficient to induce Brachyury specific CD4+ T cells and/or CD8+ T cells. 
     
     
         10 . The method of  claim 1 , comprising administering to the subject a liposome comprising the polypeptide. 
     
     
         11 . The method of  claim 1 , wherein the polypeptide comprises 15 to 435 consecutive amino acids of the amino acid sequence set forth as SEQ ID NO: 1. 
     
     
         12 . The method of  claim 1 , wherein the polypeptide comprises at least 20 consecutive amino acids of the amino acid sequence set forth as SEQ ID NO: 1. 
     
     
         13 . The method of  claim 1 , comprising administering to the subject the non-pox non-yeast vector encoding the protein, and wherein the non-pox non-yeast vector is a viral vector. 
     
     
         14 . The method of  claim 13 , wherein the viral vector is an adenovirus, an alphavirus, a lentivirus, a measles virus or a poliovirus vector. 
     
     
         15 . A method for treating or preventing cancer in a human subject, comprising administering to the subject an effective amount of
 (a) a polypeptide comprising at least 15 consecutive amino acids of the amino acid sequence set forth in SEQ ID NO: 1;   (b) a nucleic acid encoding the polypeptide;   (c) a host cell expressing the polypeptide; or   (d) a non-pox non-yeast vector encoding the polypeptide,   
       thereby treating or preventing the cancer in the human subject. 
     
     
         16 . The method of  claim 15 , wherein the cancer is a breast cancer, small intestine cancer, stomach cancer, kidney cancer, bladder cancer, uterus cancer, ovarian cancer, testes cancer, lung cancer, colon cancer, prostate cancer, chronic lymphocytic leukemia (CLL), a B cell lymphoma, a Burkitt's lymphoma or a Hodgkin's lymphoma. 
     
     
         17 . The method of  claim 15 , comprising administering to the subject a protein comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1. 
     
     
         18 . The method of  claim 15 , comprising administering to the subject an effective amount of the polypeptide sufficient to induce Brachyury specific CD4+ T cells and/or Brachyury specific CD8+ T cells. 
     
     
         19 . The method of  claim 15 , wherein administering to the subject an effective amount of the polypeptide comprises administering an effective amount of dendritic cells presenting epitopes of the protein. 
     
     
         20 . The method of  claim 15 , comprising administering to the subject an effective amount of a nucleic acid encoding the polypeptide sufficient to induce Brachyury specific CD4+ T cells. 
     
     
         21 . The method of  claim 15 , comprising administering to the subject an effective amount of the non-pox non-yeast vector encoding the polypeptide sufficient to induce Brachyury specific CD4+ T cells and/or CD8+ T cells. 
     
     
         22 . The method of  claim 15 , comprising administering to the subject a liposome comprising the polypeptide. 
     
     
         23 . The method of  claim 15 , wherein the polypeptide comprises 15 to 435 consecutive amino acids of the amino acid sequence set forth as SEQ ID NO: 1. 
     
     
         24 . The method of  claim 15 , wherein the polypeptide comprises at least 20 consecutive amino acids of the amino acid sequence set forth as SEQ ID NO: 1. 
     
     
         25 . The method of  claim 15 , comprising administering to the subject the non-pox non-yeast vector encoding the protein, and wherein the non-pox non-yeast vector is a viral vector. 
     
     
         26 . The method of  claim 25 , wherein the viral vector is an adenovirus, an alphavirus, a lentivirus, a measles virus or a poliovirus vector.