METHOD AND COMPOSITIONS FOR ENHANCED ANTI-TUMOR EFFECTOR FUNCTIONING OF T CELLS

• US 20120148552A1
• Filed: 08/26/2009
• Published: 06/14/2012
• Est. Priority Date: 08/26/2008
• Status: Active Grant

• Current Assignee: City of Hope
• Original Assignee: City of Hope
• Inventors: Jensen, Michael
• Granted Patent: US 8,822,647 B2
• Time in Patent Office: Days
• US Class Current: 424/93.71
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/47 Brain; Nervous system
• 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: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/46444 Interleukins [IL]
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 14/5437 IL-13
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 14/7155 for interleukins [IL]
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/01 containing a localisation/targetting motif
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• 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: C07K 2319/74 containing a fusion for binding to a cell surface receptor

Abstract

Integration of costimulatory signaling domains within a tumor targeting chimeric antigen receptor (CAR), such as the IL13Rα2 specific IL13-zetakine (IL13ζ), enhances T cell-mediated responses against tumors even in the absence of expressed ligands for costimulatory receptors.

Claims

1-21. -21. (canceled)

22. A tumor-specific chimeric antigen receptor (CAR) which comprises a specific recognition element, an optional support or linker region, a transmembrane region, the signaling domain of CD3 zeta chain and the signalling domain of at least one additional costimulatory signaling receptor which is selected from the group consisting of CD28, 4-1BB and OX-40.

23. The CAR of claim 22 wherein said signaling domain comprises the signalling domains of two costimulatory signaling receptors.

24. The CAR of claim 23 wherein said two costimulatory signaling receptors are CD28 and 4-1BB.

25. The CAR of claim 22 wherein said transmembrane region is a human CD4 transmembrane region or a human CD28 transmembrane region.

26. The CAR of claim 22 wherein said support or linker region is a human IgG₄ Fc region.

27. The CAR of claim 22 wherein said specific recognition element is an IL13 molecule, an IL3 molecule or the extracellular binding domain of a single chain immunoglobulin that recognizes an antigen selected from the group consisting of Her/2Neu, α

3 integrin, CD20, CD19 and EGFRVIII.

28. The CAR of claim 27 wherein said specific recognition element is an IL13 molecule.

29. The CAR of claim 28 wherein said IL13 molecule contains the E13Y mutation.

30. The CAR of claim 22 which is IL13-CD28-4-1BBζ

.

31. The CAR of claim 29 which is IL13-CD28-4-1BBζ

.

32. An isolated polynucleic acid that encodes the CAR of claim 22.

33. An isolated polynucleic acid that encodes the CAR of claim 29.

34. An isolated T lymphocyte that expresses the CAR of claim 22.

35. An isolated T lymphocyte that expresses the CAR of claim 29.

36. A method of cancer immunotherapy which comprises administering to a patient in need thereof a T lymphocyte that expresses the CAR of claim 22.

37. A method of cancer immunotherapy which comprises administering to a patient in need thereof a T lymphocyte of claim 34.

38. A method of cancer immunotherapy which comprises administering to a patient in need thereof a T lymphocyte of claim 35.

39. A method of claim 37 wherein said cancer is selected from the group consisting of glioblastoma, medulloblastoma, breast cancer, head and neck cancer, kidney cancer, ovarian cancer, Kaposi'"'"'s sarcoma, acute myelogenous leukemia, and B-lineage malignancies.

40. A method of claim 38 wherein said cancer is selected from the group consisting of glioblastoma, medulloblastoma, breast cancer, head and neck cancer, kidney cancer, ovarian cancer, Kaposi'"'"'s sarcoma, acute myelogenous leukemia, and B-lineage malignancies.

41. A method of enhancing activity of a chimeric antigen receptor against a tumor, which comprises adding CD28 and 4-1BB signaling domains to said receptor.