Yeast-Based Vaccines as Immunotherapy

Abstract

Compositions and methods for treating and/or preventing a variety of diseases and conditions that are amenable to immunotherapy and, in one particular embodiment, compositions and methods for treating and/or preventing cancer in an animal are described. Specifically improvements related to the use of a yeast-based vaccine comprising a yeast vehicle and an antigen that is selected to elicit an antigen-specific cellular and humoral immune response in an animal, for use in prophylactic and/or therapeutic vaccination and the prevention and/or treatment of a variety of diseases and conditions are disclosed.

1 . A method to treat an infectious disease, comprising administering a therapeutic composition to an animal that has an infectious disease, the therapeutic composition comprising:
 a) a yeast vehicle; and   b) a fusion protein expressed by the yeast vehicle, the fusion protein comprising:
 i) at least one antigen from an infectious disease pathogen; and 
 ii) a peptide linked to the N-terminus of the antigen or immunogenic domain thereof, the peptide consisting of between two and six amino acid residues that are heterologous to the antigen or immunogenic domain thereof, wherein the peptide stabilizes the expression of the fusion protein in the yeast vehicle or prevents posttranslational modification of the expressed fusion protein, and wherein the peptide does not negatively impact an immune response against the antigen or immunogenic domain thereof;
 wherein the first six amino acids of the fusion protein consist of an amino acid sequence of M-X 2 -X 3 -X 4 -X 5 -X 6 ; 
 wherein M is methionine; 
 wherein X 2  is any amino acid except glycine, proline, lysine or arginine; 
 wherein X 3  is any amino acid except methionine, lysine or arginine; 
 wherein X 4  is any amino acid except methionine, lysine or arginine; 
 wherein X 5  is any amino acid except methionine, lysine or arginine; and 
 wherein X 6  is any amino acid except methionine. 
 
   
     
     
         2 . The method of  claim 1 , wherein X 6  is a proline. 
     
     
         3 . The method of  claim 1 , wherein the peptide consists of an amino acid sequence of M-A-D-E-A-P (SEQ ID NO:1). 
     
     
         4 . The method of  claim 1 , wherein the infectious disease pathogen is selected from the group consisting of: a virus, a bacterium, a fungus, and a parasite. 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the yeast vehicle is a whole, killed yeast. 
     
     
         10 . The method of  claim 1 , wherein yeast vehicle is from  Saccharomyces cerevisiae.    
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the therapeutic composition is administered in combination with another therapeutic treatment for the infectious disease. 
     
     
         14 - 20 . (canceled) 
     
     
         21 . A therapeutic composition, comprising:
 a) a whole yeast formulated for injection; and   b) a fusion protein expressed by the whole yeast, the fusion protein comprising:
 i) at least one cancer antigen; and 
 ii) a yeast protein linked to the N-terminus of the cancer antigen, wherein the yeast protein consists of between about two and about 200 amino acids of a yeast alpha factor signal leader sequence, wherein the yeast protein stabilizes the expression of the fusion protein in the yeast vehicle or prevents posttranslational modification of the expressed fusion protein. 
   
     
     
         22 . The method of  claim 21 , wherein the cancer antigen is from a cancer selected from: melanomas, squamous cell carcinoma, breast cancers, head and neck carcinomas, thyroid carcinomas, soft tissue sarcomas, bone sarcomas, testicular cancers, prostatic cancers, ovarian cancers, bladder cancers, skin cancers, brain cancers, angiosarcomas, hemangiosarcomas, mast cell tumors, primary hepatic cancers, lung cancers, pancreatic cancers, gastrointestinal cancers, renal cell carcinomas, hematopoietic neoplasias or metastatic cancers thereof. 
     
     
         23 . The method of  claim 21 , wherein the cancer antigen is selected from: MAGE, NY-ESO-1, gp100, tyrosinase, EGF-R, PSA, PMSA, CEA, HER2/neu, Muc-1, hTERT, MART1, TRP-1, TRP-2, BCR-abl, or mutant oncogenic forms of p53 (TP53), p73, ras, BRAF, APC (adenomatous polyposis coli), myc, VHL (von Hippel's Lindau protein), Rb-1 (retinoblastoma), Rb-2, BRCA1, BRCA2, AR (androgen receptor), Smad4, MDR1, or Flt-3. 
     
     
         24 . A method to reduce tumor burden, increase survival, or inhibit tumor growth in a subject that has cancer, comprising administering, by injection, to a subject that has a cancer a therapeutic composition comprising:
 a) a whole yeast; and   b) a fusion protein expressed by the whole yeast, the fusion protein comprising:
 i) at least one cancer antigen; and 
 ii) a yeast protein linked to the N-terminus of the cancer antigen, wherein the yeast protein consists of between about two and about 200 amino acids of a yeast alpha factor signal leader sequence, wherein the yeast protein stabilizes the expression of the fusion protein in the yeast vehicle or prevents posttranslational modification of the expressed fusion protein.