Granted Patent B2

US 12,428,486 · App. 17/353,648 · Granted Sep 30, 2025

Inventors: Blythe D. Sather (Seattle, WA); Eric L. Smith (New York, NY); Rupesh Amin (Seattle, WA); Aye Chen (Seattle, WA); Kimberly Harrington (Seattle, WA); Collin Hauskins (Seattle, WA); Erik Hess (Seattle, WA); Cyr De Imus (Seattle, WA); Jon Jones (Seattle, WA); Audrey Olshefsky (Seattle, WA); Stefan Ponko (Seattle, WA); Ruth Salmon (Seattle, WA); Semih Tareen (Seattle, WA); Rebecca Wu (Seattle, WA); Yan Chen (Seattle, WA); Steven M. Shamah (Seattle, WA); Csaba Pazmany (Seattle, WA); Jui Dutta-Simmons (Seattle, WA); Mariana Cota Stirner (Seattle, WA); Melissa Works (Seattle, WA)

Assignees: Juno Therapeutics, Inc.; Memorial Sloan Kettering Cancer Center

C07K16/2878A61K39/395A61K40/11A61K40/31A61K40/4215A61P35/00C07K14/7051C07K14/70521C07K14/70578C12N5/0636C12Q1/6848A61K38/00A61K2039/505C07K2317/524C07K2317/528C07K2317/53C07K2317/565C07K2317/622C07K2317/73C07K2319/02C07K2319/03C07K2319/30C07K2319/33C12N2510/00

Abstract

Claims (43)

1. A chimeric antigen receptor comprising:

(a) an extracellular antigen-binding domain that specifically binds B cell maturation antigen (BCMA), wherein the extracellular antigen-binding domain comprises a variable heavy chain (V H ) region and a variable light chain (V L ) region, wherein:

(i) the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS:593, 594, and 595, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS:601, 602, and 603, respectively;

(ii) the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS:507, 513, and 517, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS:589, 590, and 591, respectively;

(iii) the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS:2, 5, and 10, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS:33, 43, and 421, respectively;

(iv) the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS:1, 4, and 7, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS:380, 400, and 416, respectively; or

(v) the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS:2, 5, and 157, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS:178, 183, and 194, respectively;

(b) a spacer comprising a sequence of a hinge region, a C H 2 region and a C H 3 region of an immunoglobulin constant region;

(c) a transmembrane domain; and

(d) an intracellular signaling region;

wherein the spacer is located between the extracellular antigen binding domain and the transmembrane domain.

2. The chimeric antigen receptor of claim 1 , wherein the spacer comprises an IgG4/2 chimeric hinge or a modified IgG4 hinge comprising at least one amino acid replacement compared to human IgG4 hinge region, an human IgG2/4 chimeric C H 2 region, and a human IgG4 C H 3 region.

3. The chimeric antigen receptor of claim 1 , wherein the spacer comprises the sequence set forth in SEQ ID NO: 649.

4. The chimeric antigen receptor of claim 1 , wherein the extracellular-antigen binding domain that specifically binds BCMA comprises an scFv.

5. The chimeric antigen receptor of claim 1 , wherein:

(A) the V H region and the V L region comprise amino acid sequences having at least 90% identity to the amino acid sequences set forth in SEQ ID NOS:617 and 618, respectively;

(B) the V H region and the V L region comprise amino acid sequences having at least 90% identity to SEQ ID NOS:609 and 610, respectively;

(C) the V H region and the V L region comprise amino acid sequences having at least 90% identity to SEQ ID NOS: 115 and 536, respectively;

(D) the V H region and the V L region comprise amino acid sequences having at least 90% identity to SEQ ID NOS:519 and 535, respectively; or

(E) the V H region and the V L region comprise amino acid sequences having at least 90% identity to SEQ ID NOS:256 and 267, respectively.

6. The chimeric antigen receptor of claim 1 , wherein the transmembrane domain is from a human CD28.

7. The chimeric antigen receptor of claim 1 , wherein the intracellular signaling region comprises an activating cytoplasmic signaling domain that comprises an immunoreceptor tyrosine-based activation motif (ITAM).

8. The chimeric antigen receptor of claim 7 , wherein the activating cytoplasmic signaling domain comprises a cytoplasmic signaling domain of a CD3-zeta (CD3ζ) chain, or a functional variant thereof.

9. The chimeric antigen receptor of claim 7 , wherein the intracellular signaling region further comprises an intracellular signaling domain of a T cell costimulatory molecule.

10. The chimeric antigen receptor of claim 9 , wherein the costimulatory molecule is a CD28, a 4-1BB or an ICOS.

11. The chimeric antigen receptor of claim 9 , wherein the costimulatory molecule is a 4-1BB.

12. The chimeric antigen receptor of claim 1 , wherein the spacer is encoded by a polynucleotide that comprises the sequence set forth in SEQ ID NO:622.

13. An engineered cell, comprising the chimeric antigen receptor of claim 1 .

14. The engineered cell of claim 13 , wherein the engineered cell is a T cell.

15. A composition comprising the engineered cell of claim 13 .

16. A composition comprising the engineered cell of claim 14 .

17. The composition of claim 16 , wherein the composition comprises CD4+ and CD8 + T cells.

18. The composition of claim 16 , wherein the composition comprises CD4+ and CD8 + T cells and the ratio of CD4+ to CD8 + T cells is 1:3 to 3:1.

19. A method of treatment, comprising administering the composition of claim 15 to a subject having a cancer, wherein the cancer is multiple myeloma.

20. The method of claim 6 , wherein the composition comprises a dose of engineered cells comprising between 1×10 7 CAR-expressing T cells and 2×10 9 CAR-expressing T cells.

21. The chimeric antigen receptor of claim 1 , wherein the spacer comprises a sequence that has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO:649.

22. A chimeric antigen receptor comprising:

(a) an extracellular antigen-binding domain that specifically binds B cell maturation antigen (BCMA), wherein the extracellular antigen-binding domain comprises a variable heavy chain (V H ) region and a variable light chain (V L ) region, wherein:

the V H region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOS: 593, 594, and 595, respectively, and the V L region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOS: 601, 602, and 603, respectively;

(b) a spacer that comprises the sequence set forth in SEQ ID NO: 649;

(c) a transmembrane domain from a human CD28; and

(d) an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3ζ chain, and an intracellular signaling domain of a 4-1BB;

wherein the spacer is located between the extracellular antigen binding domain and the transmembrane domain.

Assignments (2)

Continuity (12)

References Cited (400)

Cited By (2)

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