US2016017294A1PendingUtilityA1

Tumor-selective e1a and e1b mutants

53
Assignee: UNIV CALIFORNIAPriority: Mar 2, 2009Filed: May 26, 2015Published: Jan 21, 2016
Est. expiryMar 2, 2029(~2.6 yrs left)· nominal 20-yr term from priority
Inventors:Tony R. ReidFarah HedjranShantanu Kumar
A61P 35/00C12N 2710/10322A61K 48/005C12N 2710/10343C12N 2830/00C12N 2710/10021C12N 2710/10032A61K 35/761A61K 48/00C12N 2710/10341C12N 7/00C07K 14/005C12N 2710/10022C12N 2710/10321C12N 2710/10332C12N 5/16C12N 15/86C12N 15/861C12N 2830/008
53
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Claims

Abstract

Modified E1a regulatory sequences are provided, wherein at least one Pea3 binding site, or a functional portion thereof, is deleted. Also provided are modified E1a sequences that selectively express particular isoforms. Also provided is an E1b-19K clone insertion site. These modified sequences can be used individually, or in combination with one another, to provide tumor-selective expression of proteins.

Claims

exact text as granted — not AI-modified
1 .- 15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a recombinant adenovirus comprising a modified E1a regulatory sequence, wherein at least one Pea3 binding site, or a functional portion thereof, is deleted. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein at least one nucleotide in the range of −305 to −141 is retained. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein at least one of Pea3 II, Pea3 III, Pea3 IV, and Pea3 V, or a functional portion thereof is deleted. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein at least one of Pea3 II and Pea3 III, or a functional portion thereof is deleted. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein Pea3 II or a functional portion thereof, and Pea3 III or a functional portion thereof is deleted. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein at least one of Pea3 IV and Pea3 V, or a functional portion thereof is deleted. 
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein said recombinant adenovirus comprises deletion of nucleotides located upstream of a E1a initiation site, wherein the deletion comprises nucleotide −393 to −304, nucleotide −305 to −255, nucleotide −270 to −240, nucleotide −299 to −293, nucleotide −270 to −265, nucleotide −299 to −293, or nucleotide −270 to −265. 
     
     
         23 . The pharmaceutical composition of  claim 16 , wherein said recombinant virus selectively expresses an E1a isoform, wherein the sequence encoding the E1a isoform is operably linked to said modified E1a regulatory sequence. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein said recombinant adenovirus selectively expresses E1a-12S or E1a13S. 
     
     
         25 . The pharmaceutical composition of  claim 16 , wherein said recombinant adenovirus substantially excludes expression of an E1a isoform, wherein said sequence encoding said E1a isoform is operably linked to said modified E1a regulatory sequence. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein said excluded E1a isoform is E1a-12S or E1a-13S. 
     
     
         27 . The pharmaceutical composition of  claim 16 , wherein said recombinant adenovirus further comprises a DNA sequence inserted into an E1b-19K insertion site. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said insertion site is located between the start site of E1b-19K and the start site of E1b 55K. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein said E1b-19K insertion site comprises a deletion of 202 base pairs following the start site of E1b-19K. 
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein said DNA sequence is a sequence encoding a transgene, a cancer gene, or a mutated DNA sequence. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein said transgene is a tumor suppressor gene or a functional portion thereof, a toxin gene or a functional portion thereof, a cytokine gene or a functional portion thereof, a pro-drug activating gene or a functional portion thereof, or an apoptotic gene or a functional portion thereof. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein said transgene is IL-7, IL-12, IL-15, GMCSF, CD40L, CD70, GITRL, OX-40L or a functional portion thereof. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein said transgene is IL-2, IL-4, IL-5, IL-24, IL-27, CD80, CD137L or a functional portion thereof. 
     
     
         34 . The pharmaceutical composition of  claim 30 , wherein said transgene is a mutated p53 sequence. 
     
     
         35 . The pharmaceutical composition of  claim 30 , wherein said transgene is tumor necrosis factor, kras or a functional portion thereof. 
     
     
         36 . A method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of said pharmaceutical composition of  claim 16  or  27 . 
     
     
         37 . A recombinant adenovirus comprising a DNA sequence inserted into an E1b-19K insertion site, wherein said insertion site is located between the start site of E1b-19K and the start site of E1b 55K and wherein said E1b-19K insertion site comprises a deletion of at least about 100 base pairs. 
     
     
         38 . The recombinant adenovirus of  claim 37 , wherein said insertion site comprises a deletion of 202 base pairs following said start site of E1b-19K. 
     
     
         39 . The recombinant adenovirus of  claim 37 , wherein said DNA sequence is encoding a transgene, a cancer gene, or a mutated DNA sequence. 
     
     
         40 . The recombinant adenovirus of  claim 39 , wherein said transgene is a tumor suppressor gene or a functional portion thereof, a toxin gene or a functional portion thereof, a cytokine gene or a functional portion thereof, a pro-drug activating gene or a functional portion thereof, or an apoptotic gene or a functional portion thereof. 
     
     
         41 . The recombinant adenovirus of  claim 40 , wherein said transgene is IL-7, IL-12, IL-15, GMCSF, CD40L, CD70, GITRL, OX-40L or a functional portion thereof. 
     
     
         42 . The recombinant adenovirus of  claim 40 , wherein said transgene is IL-2, IL-4, IL-5, IL-24, IL-27, CD80, CD137L or a functional portion thereof. 
     
     
         43 . The recombinant adenovirus of  claim 39 , wherein said transgene is tumor necrosis factor, kras, or a functional portion thereof. 
     
     
         44 . The recombinant adenovirus of  claim 39 , wherein said transgene is a mutated p53 sequence. 
     
     
         45 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a recombinant virus of  claim 37 .

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