Recombinant serotype 5 (Ad5) adenoviral vectors
AssigneeTargovax Oy
InventorsTuuli Ranki, Akseli Hemminki, Vincenzo Cerullo, Anniina Koski
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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.
Claims29
A recombinant serotype 5 (Ad5) adenovirus comprising:
- a) a nucleic acid sequence encoding an E2F-1 promoter replacing the natural E1A adenoviral promoter;
- b) at least a 24 bp deletion (D24) in the Rb binding constant region 2 of E1;
- c) at least a deletion in gp19k/6.7K in E3;
- and
- d) a nucleic acid sequence encoding an immunostimulatory transgene inserted in the deletion in gp19k/6.7K.
A recombinant Ad5 adenovirus comprising the nucleic acid sequence according to SEQ ID NO:
- 1, 2, 3, 4, 5, 6, or 7.
A method of producing and recovering infectious recombinant Ad5 adenovirus articles comprising the steps of
- a) providing a recombinant Ad5 adenovirus comprising
- i) a nucleic acid sequence encoding an E2F-1 promoter replacing the natural EIA adenoviral promoter;
- ii) at least a 24 bp deletion (D24) in the Rb binding constant region 2 of E1;
- iii) at least a deletion in gp19k/6.7K in E3;
- and
- iv) a nucleic acid sequence encoding an immunostimulatory transgene inserted in the deletion in gp19k/6.7K,
- b) culturing the host cell under conditions allowing said recombinant Ad5 adenovirus to propagate and to produce infectious recombinant Ad5 adenovirus particles, and
- c) recovering said infectious recombinant Ad5 adenovirus particles.
A method of treating a cancer comprising sequentially administering recombinant Ad5 adenoviruses, each adenovirus comprising:
- a) a nucleic acid sequence encoding E2F-1 promoter replacing the natural EIA adenoviral promoter;
- b) at least a 24 bp deletion (D24) in the Rb binding constant region 2 of E1;
- c) at least a deletion in gp19k/6.7K in E3;
- d) a nucleic acid sequence encoding an immunostimulatory transgene inserted in the deletion in gp19k/6.7K;
- and
- e) a nucleic acid element which activates TLR9 comprising a CpG island inserted in an E3 region downstream of the immunostimulatory transgene;
- wherein to avoid neutralizing antibodies in a subject a subsequent administration comprises a recombinant Ad5 adenovirus having a different fiber knob of the capsid compared to the recombinant Ad5 adenovirus used in the first administration, thereby treating the cancer.
A method of producing and recovering infectious recombinant Ad5 adenovirus particles comprising the steps of
- a) providing a recombinant adenovirus comprising the nucleic acid sequence according to SEQ ID NO:
- 1, 2, 3, 4, 5, 6, or 7 inside a host cell permissive for adenovirus replication,
- b) culturing the host cell under conditions allowing said recombinant Ad5 adenovirus to propagate and to produce infectious recombinant Ad5 adenovirus particles, and
- c) recovering said infectious recombinant Ad5 adenovirus particles.
Dependencies are inferred from the claim text.