Chimeric cytoplasmic signalling molecules derived from cd137

• US 20040038886A1
• Filed: 04/16/2003
• Published: 02/26/2004
• Est. Priority Date: 10/16/2000
• Status: Abandoned Application

• Current Assignee: Celltech R&D Ltd (UCB SA)
• Original Assignee: Celltech R&D Ltd (UCB SA)
• Inventors: Lawson, Alastair David Griffiths, Finney, Helene Margaret
• Application Number:
  US10/399,364
• Publication Number:
  US 20040038886A1
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Nucleic acids are described which code for chimeric cytoplasmic signalling molecules containing at least one cytoplasmic signalling sequence derived from CD137. The nucleic acids may be expressed in cells to produce chimeric receptors and other proteins which are able to regulate cell activation processes with improved efficiency. Such regulated cells are of use in medicine, for example in the treatment of infectious, inflammatory and autoimmune diseases.

Claims

1. A nucleic acid encoding a cytoplasmic signalling molecule comprising at least two cytoplasmic signalling sequences, wherein at least one cytoplasmic signalling sequence is derived from CD137.

2. A nucleic acid according to claim 1, wherein at least one cytoplasmic signalling sequence is a primary cytoplasmic signalling sequence.

3. A nucleic acid according to claim 2 wherein the primary signalling sequence contains an ITAM.

4. A nucleic acid according to claim 3, wherein the primary signalling sequence is derived from TCRζ

, FcRγ

, FcRβ

, CD3γ

, CD3δ

, CD3ε

, CD5, CD22, CD79a, CD79b or CD66d.

5. A nucleic acid according to claim 3, wherein the primary signalling sequence contains an ITIM.

6. A nucleic acid according to claim 1, wherein at least one cytoplasmic signalling sequence is a secondary cytoplasmic signalling sequence.

7. A nucleic acid according to claim 6, wherein the secondary cytoplasmic signalling sequence is derived from CD2, CD4, CD8, CD28, CD134 or CD154.

8. A nucleic acid according to any one of claims 2 to 7, which encodes three cytoplasmic signalling sequences.

9. A nucleic acid according to any one of claims 2 to 7, wherein the first cytoplasmic signalling sequence encoded for in reading frame is derived from CD137.

10. A nucleic acid according to claim 9, which encodes i) a cytoplasmic signalling sequence derived from CD137 followed in reading frame by ii) a cytoplasmic signalling sequence derived from TCRζ

.

11. A nucleic acid according to any one of claims 2 to 7, wherein the second cytoplasmic signalling sequence encoded for in reading frame is derived from CD137.

12. A nucleic acid according to claim 11, which encodes i) a cytoplasmic signalling domain derived from TCRζ

followed in reading frame by ii) a cytoplasmic signalling domain derived from CD137.

13. A nucleic acid according to claim 8, wherein the first cytoplasmic signalling sequence encoded for in reading frame is derived from CD137 or from a secondary cytoplasmic signalling sequence.

14. A nucleic acid encoding to claim 13 which encodes in reading frame i) a cytoplasmic signalling sequence derived from CD28, ii) a cytoplasmic signalling sequence derived from CD137, and iii) a cytoplasmic signalling domain derived from TCRζ

.

15. A nucleic acid encoding a chimeric receptor protein, which comprises an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic signalling domain, wherein the cytoplasmic signalling domain is encoded by a nucleic acid according to any one of claims 1 to 14.

16. A nucleic acid according to claim 15, wherein the extracellular ligand-binding domain is an antibody, or an antigen-binding fragment thereof.

17. A nucleic acid according to claim 16 wherein the antigen binding fragment is a Fab′

or scFv.

18. A nucleic acid according to any one of claims 15 to 17, wherein the transmembrane domain is derived from the α

, β

or ζ

chain of the T-cell receptor, CD28, CD3ε

, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.

19. A nucleic acid according to claim 18 wherein the transmembrane domain is derived from CD28.

20. A vector comprising a nucleic acid according to any one of the preceding claims.

21. A host cell containing a nucleic acid according to any one of claims 1 to 19, or a vector according to claim 20.

22. A peptide or polypeptide comprising a cytoplasmic signalling molecule encoded by a nucleic acid according to any one of claims 1 to 14.

23. A chimeric receptor protein encoded by a nucleic acid according to any one of claims 15 to 19.

24. A host cell expressing a peptide or polypeptide according to claim 22 or a chimeric receptor protein, according to claim 23.

25. A nucleic acid according to any one of claims 1 to 19, or a vector according to claim 20, for use in therapy.

26. A chimeric receptor protein according to claim 23, for use in therapy.

27. A composition comprising a peptide or polypeptide according to claim 22, a chimeric receptor protein according to claim 23, a nucleic acid according to any one of claims 1 to 19, or a vector according to claim 20, in conjunction with a pharmaceutically acceptable excipient.

28. The use of a peptide or polypeptide according to claim 22, a chimeric receptor protein according to claim 23, or a composition according to claim 27, in the manufacture of a medicament for the treatment or prevention of disease in humans or in animals.