Group B adenovirus encoding an anti-TCR-complex antibody or fragment
The present disclosure relates to a replication deficient oncolytic viral vector or replication capable group B oncolytic adenovirus selected from the group consisting of Ad11 and enadenotucirev, wherein the virus encodes an antibody or a binding fragment thereof for expression on the surface of a cancer cell, wherein said antibody or binding fragment is specific to a CD3 protein of a T-cell receptor complex (TCR), wherein the virus does not encode a B7 protein or an active fragment thereof, pharmaceutical compositions comprising the same, and use of any one of the same in treatment, particularly in the treatment of cancer.
1. A replication capable group B oncolytic adenovirus selected from the group consisting of Ad 11 and enadenotucirev (EnAd), wherein the adenovirus comprises a transgene encoding an antibody or a binding fragment thereof for expression on the surface of a cancer cell, wherein said antibody or binding fragment is specific to a CD3 protein of a T-cell receptor complex (TCR), and the gene encoding said antibody or binding fragment is located between the adenoviral gene L5 and the gene E4, and the encoded antibody further comprises a transmembrane domain or a GPI anchor, wherein the transgene encoding the anti-CD3 antibody or binding fragment is under the control of the endogenous major late promoter of the adenovirus, wherein the adenovirus encodes at least one further transgene, wherein the further transgene(s) encode(s) a protein independently selected from a cytokine, a chemokine, an antagonistic antibody molecule or binding fragment thereof, an agonistic antibody molecule or binding fragment thereof, and combinations thereof, and said one or more further transgenes are between the gene E4 and the gene L5 under the control of the major late promoter of the adenovirus, and wherein the anti-CD3 antibody or binding fragment thereof and protein encoded by the further transgene are expressed independently anchored at the surface of the cancer cell, wherein the adenovirus does not encode a B7 protein or an active fragment thereof.
2. The adenovirus of claim 1 , wherein the virus is Ad11.
3. The adenovirus according to claim 1 , wherein the virus is EnAd.
4. The adenovirus of claim 1 , wherein the virus is replication competent.
5. The adenovirus of claim 1 , wherein the transmembrane domain is selected from a sequence comprising one of SEQ ID NOs: 10 to 15.
6. The adenovirus of claim 1 , wherein the antibody or binding fragment is selected from a full-length antibody, a Fab, modified Fab, Fab′, modified Fab′, F(ab′)2, Fv, single domain antibody, scFv, bi, tri or tetra-valent antibody, Bis-scFv, diabody, triabody, tetrabody, humabody, disulfide stabilised forms of any one of the same and epitope-binding fragments thereof.
7. The adenovirus of claim 1 , wherein the antibody binding fragment is a single chain Fv.
8. The adenovirus of claim 1 , wherein the further transgene or transgenes are independently selected from FLT-3 ligand, IFN-α2, OX40, CD27, CD28, CD40, GITR, and 4-1 BB.
9. The adenovirus of claim 1 , wherein the at least one further transgene encodes a cytokine.
10. The adenovirus of claim 1 , wherein a second further transgene encodes a cytokine.
11. The adenovirus of claim 1 , wherein the cytokine is independently selected from IL-2, IFN-alpha, IFN-beta, IFN-gamma, Flt3 ligand, GM-CSF, IL-15, and IL-12.
12. The adenovirus of claim 1 , wherein the at least one further transgene encodes a chemokine.
13. The adenovirus of claim 12 , wherein the chemokine is independently selected from MIP-1 alpha, RANTES, IL-8, CCL5, CCL17, CCL20, CCL22, CXCL9, CXCL10, CXCL11, CXCL13, CXCL12, CCL2, CCL19 and CCL21.
14. The adenovirus of claim 13 , wherein the chemokine encoded is MIP-1 alpha.
15. The adenovirus of claim 14 , wherein the adenovirus comprises transgenes encoding a cytokine and chemokine combination selected from i) MIP-1α and Flt3, and ii) MIP-1α and IFNα.
16. The adenovirus of claim 1 , wherein the anti-CD3 antibody or binding fragment has at least a binding domain comprising a VH and a VL region from muromonab-CD3 (OKT3), otelixizumab, teplizumab or visilizumab.
17. A composition comprising a replication capable group B oncolytic adenovirus of claim 1 .
18. A method of treating a cancer patient comprising the step of: administering a therapeutically effective amount of a replication capable group B oncolytic adenovirus of claim 1 , wherein the adenovirus selectively infects cancer cells and expresses on the surface of the cells the encoded anti-CD3 antibody or binding fragment thereof.
19. The method of claim 18 , wherein the administration of the adenovirus results in in vivo stimulation of T cells to target the cancer cells.