阅读说明：本技术 携带双特异性T细胞衔接器（BiTE）的腺病毒 (Adenovirus carrying bispecific T cell engager (BITE) ) 是由 B·查皮尔 A·C·N·布罗姆利 于 2018-08-28 设计创作，主要内容包括：一种包括式(I)的序列的腺病毒：5’ITR-B<Sub>1</Sub>-B<Sub>A</Sub>-B<Sub>2</Sub>-B<Sub>X</Sub>-B<Sub>B</Sub>-B<Sub>Y</Sub>-B<Sub>3</Sub>-3’ITR (I)其中B<Sub>Y</Sub>包括含有四个转基因的转基因盒,所述基因编码FAP-BITE、CXL10、CXL9和IFN。本公开还扩展到包括所述病毒的药物组合物,以及使用所述病毒或调配物进行治疗。(An 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 Y Comprising a transgene cassette comprising four transgenes encoding FAP-BITE, CXL10, CXL9 and IFN. The disclosure also extends to pharmaceutical compositions comprising the viruses, and to treatments using the viruses or formulations.)

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

5'ITR-B₁-B_A-B₂-B_X-B_B-B_Y-B₃-3'ITR(I)

wherein:

B₁is a key or comprises: E1A, E1B, or E1A to E1B;

B_Acomprises-E2B-L1-L2-L3-E2A-L4;

B₂is a key or comprises: e3;

B_Xis a bond or a DNA sequence comprising: a restriction site, one or more transgenes, or both;

B_Bincluding L5;

B_Ycomprising a transgene cassette comprising four transgenes encoding FAP-BITE, CXL10, CXL9 and IFN;

B₃is a key or comprises: E4.

2. the adenovirus according to claim 1, wherein the encoded FAB-BITE comprises anti-CD 3 as set forth in SEQ ID NO. 5 or a sequence at least 95% identical thereto as set forth in SEQ ID NO. 5.

3. The adenovirus of claim 1 or 2, wherein the FAP-BITE comprises anti-FAP as set forth in SEQ ID No.9 or a sequence at least 95% identical thereto, such as SEQ ID No. 9.

4. The adenovirus according to claim 1, wherein the encoded FAB-BITE comprises a sequence selected from SEQ ID NOs 75, 76 or a sequence at least 95% identical to any one thereof.

5. The adenovirus according to any one of claims 1 to 4, wherein the transgene cassette encodes CXL10 shown in SEQ ID NO 100 or a sequence at least 95% identical thereto, as set forth in SEQ ID NO 100.

6. The adenovirus according to any one of claims 1 to 5, wherein the transgene cassette encodes CXCL9 shown in SEQ ID NO 99 or a sequence at least 95% identical thereto, such as SEQ ID NO 99.

7. The adenovirus according to any one of claims 1 to 6, wherein the transgene cassette encodes IFN α as set forth in SEQ ID No.98 or a sequence at least 95% identical thereto, as set forth in SEQ ID No. 98.

8. The adenovirus according to any one of claims 1-7, wherein the transgene is operably linked.

9. The adenovirus according to any one of claims 1 to 8, wherein the transgenes are separated by 3 different high efficiency self-cleaving peptides.

10. The adenovirus of claim 9, wherein the self-cleaving peptide is independently selected from E2A, F2A, P2A, and T2A.

11. The adenovirus according to any one of claims 1 to 10, wherein the relative order of transgenes from L5 to E4 is FAP-BITE, CXL10, CXL9 and IFN α, e.g. as shown in figure XC.

12. The adenovirus according to any one of claims 1 to 11, wherein the transgene cassette has the polynucleotide sequence shown in SEQ ID No. 95 or a polynucleotide encoding the same amino acid sequence, in particular SEQ ID No. 95.

13. The adenovirus according to any one of claims 1-12, wherein the adenovirus comprises SEQ ID NO 84.

14. The adenovirus according to any one of claims 1-13, wherein the adenovirus is replication competent.

15. The adenovirus according to any one of claims 1-14, wherein the adenovirus is oncolytic.

16. The adenovirus according to any one of claims 1-15, wherein the virus has a hexon and fiber from Ad 11.

17. A pharmaceutical composition comprising an adenovirus according to any one of claims 1 to 16 and an excipient, diluent or carrier.

18. An adenovirus according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 for use in therapy, for example for use in the treatment of cancer.

19. A method of treating a patient comprising administering an adenovirus according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17.

20. Use of an adenovirus according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the treatment of cancer.