Chimeric receptors with 4-1BB stimulatory signaling domain

• US 8,399,645 B2
• Filed: 07/12/2012
• Issued: 03/19/2013
• Est. Priority Date: 11/05/2003
• Status: Active Grant

• Current Assignee: St Jude Children's Research Hospital Incorporated (Abbott Laboratories)
• Original Assignee: St Jude Children's Research Hospital Incorporated (Abbott Laboratories)
• Inventors: Campana, Dario, Imai, Chihaya
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US13/548,148
• Publication Number:
  US 20120282256A1
• Time in Patent Office: 250 Days
• Field of Search: None
• US Class Current: 536/23.4
• CPC Class Codes: A61K 2239/22 Intracellular domain
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/4613 Natural-killer cells [NK or NK-T]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/464412 CD19 or B4
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70517 CD8
• CPC Class Codes: C07K 14/70578 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 2502/11 blood or immune system cells
• CPC Class Codes: C12N 2502/99 genetically modified cells
• CPC Class Codes: C12N 5/0646 Natural killers cells [NK], NKT cells

Abstract

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

Claims

1. A polynucleotide encoding a chimeric receptor comprising:

(a) an extracellular ligand-binding domain comprising an anti-CD19 single chain variable fragment (scFv) domain;

(b) a transmembrane domain; and

(c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ

signaling domain.

6. The polynucleotide of claim 1 wherein the signaling domain is a human 4-1BB signaling domain.

7. The polynucleotide of claim 6, Wherein the 4-1BB signaling domain comprises amino acids 214-255 of SEQ ID NO:

2.

8. The polynucleotide of claim 7, wherein the nucleotide sequence encoding the human 4-1BB signaling domain comprises nucleotide residues 129-893 of SEQ ID NO:

1.

9. The polynucleotide of claim 1, wherein the transmembrane domain is the transmembrane domain of CD8α

.

10. The polynucleotide of claim 9, wherein the extracellular ligand-binding domain further comprises a signal peptide of CD8α

.

20. The polynucleotide of claim 1, wherein the chimeric receptor further comprises a hinge domain.

2. A vector comprising a polynucleotide encoding a chimeric receptor comprising:

(a) an extracellular ligand-binding domain comprising an anti-CD19 single chain variable fragment (scFv) domain, (b) a transmembrane domain, and (c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ

signaling domain, wherein the polynucleotide encoding the chimeric receptor is operatively linked to at least one regulatory element for expression of the chimeric receptor.

11. The vector of claim 2 which is a viral vector.

12. The vector of claim 11 which is a retroviral vector.

21. The vector of claim 2, wherein the chimeric receptor further comprises a hinge domain.

3. An isolated host cell comprising a polynucleotide encoding a chimeric receptor comprising:

(a) an extracellular ligand-binding domain comprising an anti-CD19 single chain variable fragment (scFv) domain;

(b) a transmembrane domain; and

(c) a cytoplasmic domain comprising a 4-1BB signaling domain and a CD3ζ

signaling domain.

4. The isolated host cell of claim 3 which is a T lymphocyte or an NK cell.

5. The isolated host cell of claim 3 which is a T lymphocyte.

13. The isolated host cell of claim 3 which is an NK cell.

14. The isolated host cell of claim 3 which is an autologous cell isolated from a patient having a cancer of B cell origin.

15. The isolated host cell of claim 14, wherein the autologous cell is an autologous T lymphocyte.

16. The isolated host cell of claim 15, wherein the autologous T lymphocyte is derived from a blood or tumor sample of a patient having a cancer of B cell origin and activated and expanded in vitro.

17. The isolated host cell of claim 5, wherein the T lymphocyte is an activated T lymphocyte.

18. The isolated host cell of claim 5, wherein the T lymphocyte is isolated from a blood or tumor sample of a patient having a cancer of B cell origin.

19. The isolated host cell of claim 18 wherein the host cell is isolated from a patient having lymphoblastic leukemia, B-lineage acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia or B-cell non-Hodgkin'"'"'s lymphoma.

22. The isolated cell of claim 3, wherein the chimeric receptor further comprises a hinge domain.