Granted Patent B2

US 12,258,417 · App. 16/329,125 · Granted Mar 25, 2025

Inventors: Brian Robert Champion (Abingdon, GB); Alice Claire Noel Bromley (Abingdon, GB); Joshua David Freedman (Chigwell, GB); Kerry David Fisher (Witney, GB); Leonard William Seymour (Wootton by Woodstock, GB)

Assignee: AKAMIS BIO LIMITED

C07K16/30A61K35/761A61K39/39558A61P35/00C07K14/521C07K16/2809C07K16/40C12N15/86C12N15/861A61K35/768A61K38/00A61K2039/505A61K2039/5256A61K2039/585A61K2300/00C07K2317/31C07K2317/56C07K2317/622C07K2317/73C07K2317/75C07K2319/92C12N2710/10332C12N2710/10343C12N2830/60C12N2840/44

Abstract

Claims (37)

1. An oncolytic adenovirus comprising a sequence of formula (I):

5′ITR-B 1 -B A -B 2 -B X -B B -B Y -B 3 -3′ITR  (I)

wherein:

B 1 is a bond or comprises: E1A, E1B or E1A-E1B;

B A comprises: E2B-L1-L2-L3-E2A-L4;

B 2 is a bond or comprises: E3;

B X is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both;

B B comprises: L5;

B Y is a bond or a DNA sequence comprising: a restriction site, one or more transgenes or both;

B 3 is a bond or comprises: E4;

wherein the adenovirus encodes:

a tumour antigen-specific Bispecific T cell Engager comprising at least two binding domains, Bd1 and Bd2, wherein at least one of the binding domains is specific to a component of a T-cell receptor complex (TCR) and at least one of the binding domains is specific to a tumour antigen, and

a tumour stromal antigen-specific Bispecific T cell Engager comprising at least two binding domains, Bd3 and Bd4, wherein at least one of the binding domains is specific to a component of a T-cell receptor complex (TCR) and at least one of the binding domains is specific to a tumour stromal antigen;

wherein both Bispecific T cell Engagers are encoded in position B Y ; and

the adenovirus is Enadenotucirev (EnAd) or serotype 11 adenovirus (Ad11).

2. An oncolytic adenovirus according to claim 1 , wherein the adenovirus is EnAd.

3. An oncolytic adenovirus according to claim 1 , wherein the component of the T-cell receptor complex (TCR) is CD3 in the tumour antigen-specific bispecific T cell engager, the tumour stromal antigen-specific bispecific T cell engager or both.

4. An oncolytic adenovirus according to claim 3 , wherein the component of the T-cell receptor complex (TCR) in the tumour antigen-specific bispecific T cell engager, the tumour stromal antigen-specific bispecific T cell engager or both is selected from the group comprising CD3ε, CD3γ and CD3δ.

5. An oncolytic adenovirus according to claim 1 , wherein the Bd2 in the tumour antigen-specific Bispecific T cell Engager and Bd4 in the tumour stromal antigen-specific Bispecific T cell Engager bind different antigens of interest.

6. An oncolytic adenovirus according to claim 1 , wherein the tumour antigen-specific Bispecific T cell Engager comprises a binding domain that is specific to a tumour antigen selected from the group consisting of CEA, MUC-1, EpCAM, HER receptors HER1, HER2, HER3, HER4, PEM, A33, G250, carbohydrate antigens Le y , Le x , Le b , PSMA, TAG-72, STEAP1, CD166, CD24, CD44, E-cadherin, SPARC, ErbB2 and ErbB3.

7. An oncolytic adenovirus according to claim 6 , wherein the binding domain is specific to EpCAM.

8. An oncolytic adenovirus according to claim 1 , wherein the tumour stromal antigen-specific Bispecific T cell Engager comprises a binding domain that is specific to a tumour stromal antigen selected from the group consisting of fibroblast activation protein (FAP), TREM1, IGFBP7, FSP-1, platelet-derived growth factor-α receptor (PDGFR-α), platelet-derived growth factor-β receptor (PDGFR-β) and vimentin.

9. An oncolytic adenovirus according to claim 8 , wherein the binding domain is specific to FAP.

10. An oncolytic adenovirus according to claim 1 , wherein the adenovirus is replication competent.

11. An oncolytic adenovirus according to claim 1 , wherein the adenovirus is replication deficient.

12. An oncolytic adenovirus according to claim 1 , wherein a transgene is under the control of an endogenous promoter.

13. An oncolytic adenovirus according to claim 1 wherein the tumour antigen-specific bispecific T cell engager, the tumour stromal antigen-specific bispecific T cell engager, or both, comprises a VH domain comprising an amino acid sequence as set forth in SEQ ID NO: 8, and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 9.

14. An oncolytic adenovirus according to claim 13 , wherein the tumour antigen-specific bispecific T cell engager, the tumour stromal antigen-specific bispecific T cell engager, or both, comprises an scFv comprising an amino acid sequence as set forth in SEQ ID NO: 7.

15. An oncolytic adenovirus according to claim 1 , wherein the tumour stromal antigen-specific bispecific T cell engager comprises a VH domain comprising an amino acid sequence as set forth in SEQ ID NO: 13 and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 12.

16. An oncolytic adenovirus according to claim 15 , wherein the tumour stromal antigen-specific bispecific T cell engager comprises an scFv comprising an amino acid sequence as set forth in SEQ ID NO: 11, or 75.

17. An oncolytic adenovirus according to claim 1 wherein the tumour antigen-specific bispecific T cell engager comprises a VH domain comprising an amino acid sequence as set forth in SEQ ID NO: 18, and a VL comprising an amino acid sequence as set forth in SEQ ID NO: 17.

18. An oncolytic adenovirus according to claim 17 , wherein the tumour antigen-specific bispecific T cell engager comprises an scFv comprising an amino acid sequence as set forth in SEQ ID NO: 16, or 73.

19. An oncolytic adenovirus according to claim 1 , wherein the adenovirus comprises a sequence shown in SEQ ID NO: 120.

20. An oncolytic adenovirus according to claim 1 , wherein the adenovirus encodes at least one further transgene.

21. An oncolytic adenovirus according to claim 20 , wherein the further transgene(s) encodes a cytokine, chemokine and/or an immunomodulator.

22. A composition comprising an adenovirus according to claim 1 , and a diluent or carrier.

23. A composition according to claim 22 , wherein the composition comprises a second oncolytic virus.

Assignments (3)

Priority Claims (4)

Continuity (1)

References Cited (274)