Oncolytic adenovirus encoding a b7 protein

Abstract

The present disclosure provides a replication competent oncolytic adenovirus with selectivity for cancer cells, wherein the adenovirus comprises a transgene under the control of a promoter endogenous to the virus, wherein the transgene comprises a DNA sequence encoding a B7 protein or an active fragment thereof, compositions comprising same, methods of generating the viruses, and use of the viruses and compositions in treatment, particularly in the treatment of cancer.

1 .- 23 . (canceled) 
     
     
         24 . A replication competent oncolytic group B adenovirus with selectivity for cancer cells, wherein the virus has a formula (I):
   5′ITR-B 1 -B A -B 2 -B X -B B -B Y -B 3 -3′ITR  (I)
   wherein:   B 1  comprises: E1A, E1B or E1A-E1B;   B A  is E2B-L1-L2-L3-E2A-L4;   B 2  is absent or comprises E3 or a transgene under an endogenous or exogenous promoter;   B X  is absent or a DNA sequence comprising: a restriction site, one or more transgenes or both;   B B  comprises L5;   B Y  comprises:
 a transgene encoding a B7 protein selected from B7-1 or an active fragment thereof, B7-2 or an active fragment thereof, or combinations thereof; and 
 a second transgene; 
   B 3  is absent or comprises E4;
 wherein said transgenes in B Y  are located between the stop codon-polyA recognition site of the adenovirus L5 gene and the stop codon-polyA recognition site of the adenovirus E4 gene, 
 wherein said transgenes are under the control of the endogenous major late promoter. 
   
     
     
         25 . A replication competent oncolytic virus according to  claim 24 , wherein B Y  further comprises a third transgene. 
     
     
         26 . A replication competent oncolytic virus according to  claim 24 , wherein the virus is a chimeric virus. 
     
     
         27 . A replication competent oncolytic virus according to  claim 26 , wherein the virus backbone is enadenotucirev. 
     
     
         28 . A replication competent oncolytic virus according to  claim 24 , wherein the B7-1 protein or active fragment thereof, B7-2 protein or active fragment, or combinations thereof, comprises a transmembrane sequence selected from the group comprising a transmembrane domain from a PDGF receptor, or a GPI anchor suitable for anchoring the protein or fragment in a cell membrane. 
     
     
         29 . A replication competent oncolytic virus according to  claim 24 , wherein the second transgene encodes a polypeptide independently selected from the group comprising a cytokine, a chemokine, an antagonistic antibody molecule or fragment thereof, and an agonistic antibody molecule or fragment thereof. 
     
     
         30 . A replication competent oncolytic virus according to  claim 25 , wherein the third transgene is independently selected from the group comprising a cytokine, a chemokine, an antagonistic antibody molecule or fragment thereof, and an agonistic antibody molecule or fragment thereof. 
     
     
         31 . A replication competent oncolytic virus according to  claim 24 , wherein the second transgene encodes a cytokine independently selected from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12. 
     
     
         32 . A replication competent oncolytic virus according to  claim 25 , wherein the third transgene encodes a cytokine independently selected from the group comprising IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12. 
     
     
         33 . A replication competent oncolytic virus according to  claim 24 , wherein the second transgene encodes a chemokine selected from the group comprising MIP-1 alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21. 
     
     
         34 . A replication competent oncolytic virus according to  claim 25 , wherein the third transgene encodes a chemokine selected from the group comprising MIP-1 alpha, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21. 
     
     
         35 . A replication competent oncolytic virus according to  claim 34 , wherein the second and third transgene encode Mip1α and IFNα respectively. 
     
     
         36 . A replication competent oncolytic virus according to  claim 35 , wherein the B7 protein is B7-1 or an active fragment thereof. 
     
     
         37 . A pharmaceutical composition comprising a replication competent oncolytic adenovirus according to  claim 24 , and a diluent or carrier. 
     
     
         38 . A method of treating a patient comprising administering a therapeutically effective amount of a replication competent adenovirus according to  claim 24 . 
     
     
         39 . A method of treating a patient comprising administering a therapeutically effective amount of a composition according to  claim 37 . 
     
     
         40 . A method of treating a patient according  claim 38 , wherein the patient is a cancer patient. 
     
     
         41 . A method of treating a patient according to  claim 39 , wherein the patient is a cancer patient.