Chimeric antigen receptors targeting B-cell maturation antigen

• US 9,765,342 B2
• Filed: 03/15/2013
• Issued: 09/19/2017
• Est. Priority Date: 04/11/2012
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Kochenderfer, James Noble
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US14/389,677
• Publication Number:
  US 20150051266A1
• Time in Patent Office: 1,649 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70517 CD8
• CPC Class Codes: C07K 14/70521 CD28, CD152
• 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 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins

Abstract

The invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The invention also provides host cells, such as T-cells or natural killer (NK) cells, expressing the CAR and methods for destroying multiple myeloma cells.

Claims

1. A chimeric antigen receptor (CAR) comprising an antigen recognition moiety and a T-cell activation moiety, wherein the T-cell activation moiety comprises a transmembrane domain, wherein the antigen recognition moiety is directed against B-cell Maturation Antigen (BCMA).

2. The CAR of claim 1, wherein the antigen recognition moiety comprises a monoclonal antibody directed against BCMA, or an antigen-binding portion thereof.

3. The CAR of claim 2, wherein the antigen recognition moiety comprises a variable region of a monoclonal antibody directed against BCMA.

4. The CAR of claim 2, wherein the antigen recognition moiety comprises an antigen binding fragment of a monoclonal antibody directed against BCMA.

5. The CAR of claim 2, wherein the antigen recognition moiety comprises a single chain variable fragment (scFv) directed against BCMA.

6. The CAR of claim 1, wherein the transmembrane domain is a CD28 transmembrane domain or a CD8a transmembrane domain.

7. The CAR of claim 1, wherein the T-cell activation moiety comprises a T-cell signaling domain of any one of the following proteins:

a human CD8-alpha protein, a human CD28 protein, a human CD3-zeta protein, a human FcRγ

protein, a CD27 protein, an OX40 protein, a human 4-1BB protein, or any combination of the foregoing.

8. The CAR of claim 7, wherein the T-cell activation moiety comprises a T-cell signaling domain of a human 4-1BB protein.

9. The CAR of claim 7, wherein the T-cell activation moiety comprises a T-cell signaling domain of a human 4-1BB protein and a human CD3-zeta protein.

10. The CAR of claim 1, wherein the CAR comprises the amino acid sequence of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11 or SEQ ID NO;

12.

11. The CAR of claim 1, wherein the antigen recognition moiety comprises the (i) heavy chain complementarity determining region (CDR)1, (ii) heavy chain CDR2, (iii) heavy chain CDR3, (iv) light chain CDR1, (v) light chain CDR2, and (vi) light chain CDR3 of one amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

12. The CAR of claim 1, wherein the antigen recognition moiety comprises the (i) heavy Chain variable region and (ii) light chain variable region of one amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

13. A nucleic acid encoding the CAR of claim 1.

14. The nucleic acid of claim 13, wherein the CAR comprises the amino acid sequence set forth in SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, or SEQ ID NO;

12.

15. The nucleic acid of claim 13, wherein the antigen recognition moiety of the CAR comprises the (i) heavy chain CDR1, (ii) heavy Chain CDR2, (iii) heavy chain CDR3, (iv) light chain CDR1, (v) light chain CDR2, and (vi) light chain CDR3 of one amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

16. The nucleic acid of claim 13, wherein the antigen recognition moiety of the CAR comprises the (i) heavy chain variable region and (ii) light chain variable region of one amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

17. A vector comprising a nucleic acid sequence encoding the CAR of claim 1.

18. The vector of claim 17, wherein the antigen recognition moiety comprises the (i) heavy chain CDR1, (ii) heavy chain CDR2, (iii) heavy chain CDR3, (iv) light chain CDR1, (v) light chain CDR2, and (vi) light chain CDR3 of one amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, and SEQ ID NO;

12.

19. An isolated host cell which expresses the CAR of claim 1.