RECOMBINANT SEROTYPE 5 (Ad5) ADENOVIRAL VECTORS

Abstract

The invention relates to oncolytic adenovirus vectors and their uses in cancer therapy. The adenovirus vectors according to the invention have superior safety properties and have effective therapeutic activity. A production method for the inventive adenoviruses is also disclosed. The adenovirus vectors are useful in cancer therapy.

What is claimed is: 
     
         1 . A recombinant serotype 5 (Ad5) adenovirus comprising:
 (a) a nucleic acid sequence encoding the wild-type EIA adenoviral promoter or encoding a E2F-1 promoter replacing the wild-type EIA adenoviral promoter;   (b) a 24 by deletion (D24) in the Rb binding constant region 2 of E1;   (c) a deletion in gp19k/6.7K in E3;   (d) a nucleic acid sequence encoding a human CD40 ligand in the deletion in gp19k/6.7K, the nucleic acid sequence under the control of the E3 promoter; and   (e) a capsid modification wherein a region encoding Ad5 adenoviral fiber knob is replaced by the corresponding region from a serotype 3 (Ad3) adenovirus.   
     
     
         2 . The recombinant Ad5 adenovirus according to  claim 1 , wherein the nucleic acid sequence encodes the wild-type EIA adenoviral promoter. 
     
     
         3 . The recombinant Ad5 adenovirus according to  claim 1 , further comprising at least one element selected from the group consisting of an adenoviral immediate early gene, an adenoviral intermediate gene, and an adenoviral late gene. 
     
     
         4 . A method of treating a cancer comprising administering to a subject in need thereof an effective amount of the recombinant Ad5 adenovirus according to  claim 1 . 
     
     
         5 . The method of  claim 4 , wherein a first administration of the recombinant Ad5 adenovirus to the subject is followed by a subsequent administration or several administrations. 
     
     
         6 . The method of  claim 5 , wherein the subsequent administration comprises a different recombinant Ad5 adenovirus from the recombinant Ad5 adenovirus administered in the first administration. 
     
     
         7 . The method of  claim 4  comprising a first administration or several administrations of the recombinant Ad5 serotype adenovirus and a radiotherapy, a surgery, or administration of one or more agents selected from the group consisting of a virus sensitizer, a chemotherapeutic agent, verapamil, a calcium channel blocker, an anti-CD20 therapy, and an autophagy-inducing agent. 
     
     
         8 . The method of  claim 4 , wherein the recombinant Ad5 adenovirus is capable of replicating and having lytic activity in a target cell and wherein the recombinant Ad5 adenovirus is unable to bind Rb, thereby preventing virus replication outside a target cell. 
     
     
         9 . The method of  claim 4 , wherein the deletion in gp19k/6.7K in E3 disrupts the recombinant Ad5 adenovirus' ability to control a host immune response. 
     
     
         10 . A method of producing and recovering infectious recombinant Ad5 adenovirus particles comprising steps of:
 (a) providing a recombinant Ad5 adenovirus according to  claim 1  inside a host cell permissive for adenovirus replication,   (b) culturing the host cell under conditions that allow said recombinant Ad5 adenovirus to propagate and to produce infectious recombinant Ad5 adenovirus particles, and   (c) recovering said infectious recombinant Ad5 adenovirus particles.   
     
     
         11 . A pharmaceutical composition comprising the recombinant Ad5 adenovirus according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . The pharmaceutical composition of  claim 11  formulated to contain 5×10 10  to 5×10 11  viral particles. 
     
     
         13 . A virus particle comprising the recombinant Ad5 adenovirus according to  claim 1 . 
     
     
         14 . A host cell comprising the recombinant Ad5 adenovirus according to  claim 1 . 
     
     
         15 . A method for inducing immunity directed against a cancer cell, for treating a tumor, or for preventing a tumor's growth in a subject in need thereof comprising administering to the subject an effective amount of the recombinant Ad5 adenovirus according to  claim 1 .