Compositions employing alternative reading frame polypeptides for the treatment of cancer and infectious disease

Abstract

Provided are alternative reading frame (ARF) polypeptides as well as antigen presenting cell (APC) and dendritic cell (DC) based compositions that comprise ARF polypeptides. ARF polypeptides and ARF polypeptide-based compositions are useful in the treatment of cancer and infectious disease.

1 - 18 . (canceled) 
     
     
         19 . A fusion protein comprising,
 two or more alternative reading frame (ARF) polypeptides wherein each of said ARF polypeptides comprises at least 9 amino acids of an ARF polypeptide derived from a polynucleotide selected from the group consisting of human tyrosine kinase receptor (hHER-2, SEQ ID NO: 2); human telomerase reverse transcriptase (hTERT, SEQ ID NO: 4); mouse telomerase reverse transcriptase (mTERT, SEQ ID NO: 6); human transient receptor potential cation channel 8 (hTrpP8, SEQ ID NO: 8); human prostatic acid phosphatase (hPAP, SEQ ID NOs: 10); human prostatic acid phosphatase (hPAP, SEQ ID NOs: 12); human carbonic anhydrase IX (hCA9, SEQ ID NO: 295); human carcinoembryonic antigen (hCEA, SEQ ID NO: 302); human prostate-specific membrane antigen (hPSMA; SEQ ID NO: 345), human prostate-specific antigen (hPSA, SEQ ID NO: 369); human p53 cellular tumor antigen (hp53; SEQ ID NO: 381); human P-glycoprotein (hPGY1; SEQ ID NO: 392); human alpha-fetoprotein (hAFP; SEQ ID NO: 424); human mucin precursor (hMUC1; SEQ ID NO: 441); human preferentially expressed antigen of melanoma (hPRAME; SEQ ID NO: 452); human ephrin receptor (hEPHA3; SEQ ID NO: 468); human peptidyl-prolyl isomerase and essential mitotic regulator (hPIN1; SEQ ID NO: 496); human BASE (hBASE; SEQ ID NO: 504); human prostate stem cell antigen (hPSCA; SEQ ID NO: 515); human SURVIVIN (hSURVIVIN; SEQ ID NO: 549); human WTI (hWTI; SEQ ID NO: 557); human SGA-M1 (hSGA-M1; SEQ ID NO: 566); human RCAS1 (hRCAS1; SEQ ID NO: 579); and human CYP1B1 (hCYP1B1; SEQ ID NO: 592) or a complement of any of the foregoing polynucleotides,   wherein the ARF polypeptide corresponds to a polypeptide generated by an in vivo translational error resulting in frame-shifting of the initiation complex at a normal rf0 AUG codon one base (rf1) or two bases (rf2) forward or one base (rf2) or two bases (rf1) backward.   
     
     
         20 . The fusion protein of  claim 19 , wherein each of said ARF polypeptides comprises at least 10, 11, 12, 13, 14, or 15 amino acids. 
     
     
         21 . The fusion protein of  claim 19 , wherein each of said ARF polypeptides comprises at least 16, 17, 18, 19, or 20 amino acids. 
     
     
         22 . The fusion protein of  claim 19 , wherein each of said ARF polypeptides comprises at least 25, 30, 35, 40, 45, or 50 amino acids. 
     
     
         23 . The fusion protein of  claim 19 , wherein each of said ARF polypeptides comprises at least 75, 100, 150, or 200 amino acids. 
     
     
         24 . The fusion protein of  claim 19 , wherein the fusion protein is capable of priming antigen presenting cells (APCs) or dendritic cells (DCs) to elicit an immune response. 
     
     
         25 . The fusion protein of  claim 24 , wherein said immune response is a cytotoxic T-cell (CTL) response. 
     
     
         26 . The fusion protein of  claim 19 , wherein translation of said ARF polypeptides initiates at nucleotide 2 of the normal rf0 initiation codon. 
     
     
         27 . The fusion protein of  claim 19 , wherein translation of said ARF polypeptides initiates at nucleotide 3 of the normal rf0 initiation codon. 
     
     
         28 . The fusion protein of  claim 19 , wherein translation of said ARF polypeptides initiates at an AUG at an internal ribosome entry site (IRES) located 3′ to a site of normal ribosomal entry. 
     
     
         29 . The fusion protein of  claim 19 , further comprising a polypeptide moiety that facilitates the binding of the ARF polypeptide or fusion protein to an antigen presenting cell (APC) or to a dendritic cell (DC). 
     
     
         30 . The fusion protein of  claim 19 , wherein the fusion protein comprises a C- or N-terminal moiety having at least a portion of an APC/DC binding protein. 
     
     
         31 . The fusion protein of  claim 19 , further comprising a polypeptide moiety selected from the group consisting of GM-CSF, IL-1, TNF, IL-4, CD40L, CTLA4, CD28, FLT-3 ligand, a functional fragment, derivative or variant thereof. 
     
     
         32 . The fusion protein of  claim 19  wherein the fusion protein comprises a peptide linker sequence. 
     
     
         33 . The fusion protein of  claim 32  wherein the peptide linker is from 1 to 50 amino acids in length. 
     
     
         34 . A method for eliciting an immune response in a patient, the methods comprising the steps of: (1) obtaining a sample containing antigen presenting cells (APCs); (2) isolating from the sample the APCs; (3) priming the APCs ex vivo with an ARF polypeptide fusion protein of  claim 19  wherein the stimulated APCs are capable of stimulating an immune response in vivo; and (4) administering the primed APCs to the patient. 
     
     
         35 . The method of  claim 34  wherein, the immune response is a cytotoxic T-cell response. 
     
     
         36 . A method for inhibiting proliferation of a tumor cell in a cancer patient the methods comprising the steps of: (1) obtaining from the cancer patient a sample containing antigen presenting cells (APCs); (2) isolating the APCs from the sample; (3) priming the APCs ex vivo with one or more ARF polypeptide fusion protein of  claim 19  wherein the primed APCs are capable of stimulating an immune response in vivo; and (4) administering the primed APCs to the cancer patient. 
     
     
         37 . The method of  claim 36  wherein the tumor cell is selected from a soft tissue sarcoma, a lymphoma, and/or a cancer of the brain, esophagus, uterus, cervix, bone, lung, endometrium, bladder, breast, larynx, colon/rectum, stomach, ovary, pancreas, adrenal gland or prostate.