SIGNAL TRANSDUCTION MODIFYING PROTEIN

• US 20190309046A1
• Filed: 11/27/2017
• Published: 10/10/2019
• Est. Priority Date: 11/28/2016
• Status: Abandoned Application

• Current Assignee: Autolus Limited (Autolus Therapeutics Plc)
• Original Assignee: Autolus Limited (Autolus Therapeutics Plc)
• Inventors: Cordoba, Shaun, Kokalaki, Evangelia, Baldan, Vania, Thomas, Simon, Stavrou, Maria
• Application Number:
  US16/463,258
• Publication Number:
  US 20190309046A1
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/70514 CD4
• CPC Class Codes: C07K 14/70517 CD8
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12N 9/16 acting on ester bonds (3.1)
• CPC Class Codes: C12Y 207/11001 Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
• CPC Class Codes: C12Y 301/03048 Protein-tyrosine-phosphatase (3.1.3.48)

Abstract

The present invention provides signal transduction modifying protein which comprises a domain which binds a phosphorylated immunoreceptor tyrosine-based inhibition motif (pITIM). The signal transduction modifying protein lacks a functional phosphatase domain. The present invention also provides cells which express such a signal transduction modifying protein, and cells which co-express such a signal transduction modifying protein together with a chimeric antigen receptor (CAR).

Claims

1. A signal transduction modifying protein which comprises:

(i) a domain which binds a phosphorylated immunoreceptor tyrosine-based inhibition motif (pITIM); and

(ii) a membrane localisation domain.

7. A signal transduction modifying protein according to claim 1, wherein the pITIM-binding domain comprises a SHP-1 SH2 domain which lacks a functional phosphatase domain or a SHP-2 SH2 domain which lacks a functional phosphatase domain.

12. A signal transduction protein according to claim 7, in which the phosphatase domain is partially or completely deleted.

13. A signal transduction modifying protein according to claim 7, which comprises an inactivated phosphatase domain.

14. A signal transduction modifying protein according to claim 13, wherein the phosphatase domain comprises one or more amino acid mutations compared to a wild-type phosphatase domain, rendering it non-functional.

20. A cell which comprises a signal transduction modifying protein according to claim 1.

21. A cell according to claim 20 which comprises two signal modifying proteins;

wherein the pITIM-binding domain of the first signal transduction modifying protein comprises a SHP-1 SH2 domain; and

the pITIM-binding domain of the second signal transduction modifying protein comprises a SHP-2 SH2 domain.

22. A cell according to claim 20, which also comprises a chimeric antigen receptor (CAR).

23. A nucleic acid sequence which encodes a signal transduction modifying protein according to claim 1.

24. A nucleic acid construct which comprises:

i) a first nucleic acid sequence according to claim 23; and

ii) a second nucleic acid sequence which encodes a chimeric antigen receptor (CAR).

25. A vector which comprises a nucleic acid sequence according to claim 23 or a nucleic acid construct according to claim 24.

26. A pharmaceutical composition comprising a plurality of cells according to claim 20.

28. A method for treating and/or preventing a disease, which comprises the step of administering a pharmaceutical composition according to claim 26 to a subject.

29. A method according to claim 28 which also comprises the step of administering an immune checkpoint inhibitor to the subject, which immune checkpoint inhibitor inhibits a non-ITIM-mediated pathway.

30. A method according to claim 29, wherein the immune checkpoint inhibitor is or comprises a CTLA4 pathway inhibitor.

31. A method according to claim 30 wherein the CTLA4 pathway inhibitor is a CTLA4 antibody.

32. A method according to claim 28, which comprises the following steps:

(i) isolation of a cell containing sample from a subject;

(ii) transduction or transfection of the cells with a nucleic acid sequence according to claim 23;

a nucleic acid construct according to claim 24;

or a vector according to claim 25; and

(iii) administration the cells from (ii) to the subject.

34. A method according to claim 28, wherein the disease is cancer.

35. A method for making a cell according to claim 20, which comprises the step of introducing a vector according to claim 25 into the cell.

36. A method according to claim 35, wherein the cell is from a sample isolated from a subject.

2-6. -6. (canceled)

8-11. -11. (canceled)

15-19. -19. (canceled)

27. (canceled)

33. (canceled)