BCMA CHIMERIC ANTIGEN RECEPTORS
First Claim
Patent Images
1. A chimeric antigen receptor (CAR) comprising:
- an extracellular domain that comprises a humanized anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment thereof that binds one or more epitopes of a human BCMA polypeptide;
a transmembrane domain, one or more intracellular co-stimulatory signaling domains, and a primary signaling domain.
3 Assignments
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Accused Products
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
40 Citations
86 Claims
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1. A chimeric antigen receptor (CAR) comprising:
- an extracellular domain that comprises a humanized anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment thereof that binds one or more epitopes of a human BCMA polypeptide;
a transmembrane domain, one or more intracellular co-stimulatory signaling domains, and a primary signaling domain. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86)
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2. The CAR of claim 1, wherein the humanized anti-BCMA antibody or antigen binding fragment that binds the human BCMA polypeptide is selected from the group consisting of:
- a Camel Ig, Ig NAR, Fab fragments, Fab′
fragments, F(ab)′
2 fragments, F(ab)′
3 fragments, Fv, single chain Fv antibody (“
scFv”
), bis-scFv, (scFv)2, minibody, diabody, triabody, tetrabody, disulfide stabilized Fv protein (“
dsFv”
), and single-domain antibody (sdAb, Nanobody).
- a Camel Ig, Ig NAR, Fab fragments, Fab′
-
3. The CAR of claim 2, wherein the humanized anti-BCMA antibody or antigen binding fragment that binds the human BCMA polypeptide is an scFv.
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4. The CAR of any one of claims 1 to 3, wherein the humanized anti-BCMA antibody or antigen binding fragment thereof comprises one or more CDRs as set forth in any one of SEQ ID NOs:
- 1-3.
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5. The CAR of any one of claims 1 to 4, wherein the humanized anti-BCMA antibody or antigen binding fragment thereof comprises one or more CDRs as set forth in any one of SEQ ID NOs:
- 4-6.
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6. The CAR of any one of claims 1 to 5, wherein the humanized anti-BCMA antibody or antigen binding fragment thereof comprises a variable light chain sequence as set forth in any one of SEQ ID NOs:
- 7-9.
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7. The CAR of claim 6, wherein the variable light chain sequence comprises the CDR sequences set forth in SEQ ID NOs:
- 1-3.
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8. The CAR of any one of claims 1 to 7, wherein the humanized anti-BCMA antibody or antigen binding fragment thereof comprises a variable heavy chain sequence as set forth in any one of SEQ ID NOs:
- 10-14.
-
9. The CAR of claim 8, wherein the variable heavy chain sequence comprises the CDR sequences set forth in SEQ ID NOs:
- 4-6
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10. The CAR of any one of claims 1 to 9, wherein the transmembrane domain is from a polypeptide selected from the group consisting of:
- alpha, beta or zeta chain of the T-cell receptor, CD3ε
, CD3ζ
, CD4, CD5, CD8α
, CD9, CD 16, CD22, CD27, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD 134, CD137, CD152, CD 154, and PD1.
- alpha, beta or zeta chain of the T-cell receptor, CD3ε
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11. The CAR of any one of claims 1 to 9, wherein the transmembrane domain is from a polypeptide selected from the group consisting of:
- CD8α
;
CD4, CD45, PD1, and CD152.
- CD8α
-
12. The CAR of any one of claims 1 to 11, wherein the transmembrane domain is from CD8α
- .
-
13. The CAR of any one of claims 1 to 11, wherein the transmembrane domain is from PD1.
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14. The CAR of any one of claims 1 to 11, wherein the transmembrane domain is from CD152.
-
15. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains are from a co-stimulatory molecule selected from the group consisting of:
- CARD11, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD137 (4-1BB), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270 (HVEM), CD273 (PD-L2), CD274 (PD-L1), CD278 (ICOS), DAP10, LAT, NKD2C SLP76, TRIM, and ZAP70.
-
16. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains are from a co-stimulatory molecule selected from the group consisting of:
- CD28, CD134, and CD137.
-
17. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains are from a co-stimulatory molecule selected from the group consisting of:
- CD28, CD134, and CD137.
-
18. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains is from CD28.
-
19. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains is from CD134.
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20. The CAR of any one of claims 1 to 14, wherein the one or more co-stimulatory signaling domains is from CD137.
-
21. The CAR of any one of claims 1 to 20, further comprising a hinge region polypeptide.
-
22. The CAR of claim 21, wherein the hinge region polypeptide comprises a hinge region of CD8α
- .
-
23. The CAR of claim 21, wherein the hinge region polypeptide comprises a hinge region of PD1.
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24. The CAR of claim 21, wherein the hinge region polypeptide comprises a hinge region of CD152.
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25. The CAR of any one of claims 1 to 24, further comprising a spacer region.
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26. The CAR of claim 25, wherein the spacer region polypeptide comprises CH2 and CH3 regions of IgG1 or IgG4.
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27. The CAR of any one of claims 1 to 26, further comprising a signal peptide.
-
28. The CAR of claim 27, wherein the signal peptide comprises an IgG1 heavy chain signal polypeptide, a CD8α
- signal polypeptide, or a human GM-CSF receptor alpha signal polypeptide.
-
29. The CAR of any one of claims 1 to 28, comprising an amino acid sequence as set forth in any one of SEQ ID NOs:
- 15-29, 71, and 73.
-
30. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 15.
-
31. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 16.
-
32. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 17.
-
33. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 18.
-
34. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 19.
-
35. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 20.
-
36. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 21.
-
37. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 22.
-
38. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 23.
-
39. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 24.
-
40. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 25.
-
41. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 26.
-
42. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 27.
-
43. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 28.
-
44. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 29.
-
45. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 71.
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46. The CAR of any one of claims 1 to 29, comprising an amino acid sequence as set forth in SEQ ID NO:
- 73.
-
47. A polynucleotide encoding a CAR of any one of claims 1 to 46.
-
49. A vector comprising the polynucleotide of claim 47 or claim 48.
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50. The vector of claim 49, wherein the vector is an expression vector.
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51. The vector of claim 49, wherein the vector is an episomal vector.
-
52. The vector of claim 49, wherein the vector is a viral vector.
-
53. The vector of claim 49, wherein the vector is a retroviral vector.
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54. The vector of claim 49, wherein the vector is a lentiviral vector.
-
55. The vector of claim 49, wherein the lentiviral vector is selected from the group consisting essentially of:
- human immunodeficiency virus 1 (HIV-1);
human immunodeficiency virus 2 (HIV-2), visna-maedi virus (VMV) virus;
caprine arthritis-encephalitis virus (CAEV);
equine infectious anemia virus (EIAV);
feline immunodeficiency virus (FIV);
bovine immune deficiency virus (BIV); and
simian immunodeficiency virus (SIV).
- human immunodeficiency virus 1 (HIV-1);
-
56. The vector according to any one of claims 52 to 55, comprising a left (5′
- ) retroviral LTR, a Psi (Ψ
) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a retroviral export element;
a promoter operably linked to the polynucleotide of claim 26 or claim 27; and
a right (3′
) retroviral LTR.
- ) retroviral LTR, a Psi (Ψ
-
57. The vector of claim 56, further comprising a heterologous polyadenylation sequence.
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58. The vector of claim 56 or claim 57, further comprising a hepatitis B virus posttranscriptional regulatory element (HPRE) or woodchuck post-transcriptional regulatory element (WPRE).
-
59. The vector of any one of claims 56 to 58, wherein the promoter of the 5′
- LTR is replaced with a heterologous promoter.
-
60. The vector of claim 59, wherein the heterologous promoter is a cytomegalovirus (CMV) promoter, a Rous Sarcoma Virus (RSV) promoter, or an Simian Virus 40 (SV40) promoter.
-
61. The vector of any one of claims 56 to 60, wherein the 5′
- LTR or 3′
LTR is a lentivirus LTR.
- LTR or 3′
-
62. The vector of any one of claims 56 to 61, wherein the 3′
- LTR comprises one or more modifications.
-
63. The vector of any one of claims 56 to 62, wherein the 3′
- LTR comprises one or more deletions.
-
64. The vector of any one of claims 56 to 63, wherein the 3′
- LTR is a self-inactivating (SIN) LTR.
-
65. The vector of any one of claims 56 to 64, wherein the polyadenylation sequence is a bovine growth hormone polyadenylation or signal rabbit β
- -globin polyadenylation sequence.
-
66. The vector of any one of claims 59 to 65, wherein the polynucleotide of claim 57 or claim 58 comprises an optimized Kozak sequence.
-
67. The vector of any one of claims 56 to 66, wherein the promoter operably linked to the polynucleotide of claim 57 or claim 58 is selected from the group consisting of:
- a cytomegalovirus immediate early gene promoter (CMV), an elongation factor 1 alpha promoter (EF1-α
), a phosphoglycerate kinase-1 promoter (PGK), a ubiquitin-C promoter (UBQ-C), a cytomegalovirus enhancer/chicken beta-actin promoter (CAG), polyoma enhancer/herpes simplex thymidine kinase promoter (MC1), a beta actin promoter (β
-ACT), a simian virus 40 promoter (SV40), and a myeloproliferative sarcoma virus enhancer, negative control region deleted, d1587rev primer-binding site substituted (MND) promoter.
- a cytomegalovirus immediate early gene promoter (CMV), an elongation factor 1 alpha promoter (EF1-α
-
68. An immune effector cell comprising the vector of any one of claims 49 to 67.
-
69. The immune effector cell of claim 68, wherein the immune effector cell is selected from the group consisting of:
- a T lymphocyte and a natural killer (NK) cell.
-
70. A composition comprising the immune effector cell of claim 68 or claim 69 and a physiologically acceptable excipient.
-
71. A method of generating an immune effector cell comprising a CAR according to any one of claims 1 to 46 comprising introducing into an immune effector cell the vector of an one of claims 49 to 67.
-
72. The method of claim 71, further comprising stimulating the immune effector cell and inducing the cell to proliferate by contacting the cell with antibodies that bind CD3 and antibodies that bind to CD28;
- thereby generating a population of immune effector cells.
-
73. The method of claim 72, wherein the immune effector cell is stimulated and induced to proliferate before introducing the vector.
-
74. The method of claim 72, wherein the immune effector cells comprise T lymphocytes.
-
75. The method of claim 72, wherein the immune effector cells comprise NK cells.
-
76. A method of treating a B cell related condition in a subject in need thereof, comprising administering to the subject a therapeutically effect amount of the composition of claim 70.
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77. The method of claim 76, wherein the B cell related condition is multiple myeloma, non-Hodgkin'"'"'s lymphoma, B cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, post-transplant lymphoproliferative disorder, an immunoregulatory disorder, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenia purpura, anti-phospholipid syndrome, Chagas'"'"' disease, Grave'"'"'s disease, Wegener'"'"'s granulomatosis, poly-arteritis nodosa, Sjogren'"'"'s syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, anti-phospholipid syndrome, ANCA associated vasculitis, Goodpasture'"'"'s disease, Kawasaki disease, autoimmune hemolytic anemia, and rapidly progressive glomerulonephritis, heavy-chain disease, primary or immunocyte-associated amyloidosis, or monoclonal gammopathy of undetermined significance.
-
78. The method of claim 76, wherein the B cell related condition is a B cell malignancy.
-
79. The method of claim 78, wherein the B cell malignancy is multiple myeloma (MM) or non-Hodgkin'"'"'s lymphoma (NHL).
-
80. The method of claim 79, wherein the MM is selected from the group consisting of:
- overt multiple myeloma, smoldering multiple myeloma, plasma cell leukemia, non-secretory myeloma, IgD myeloma, osteosclerotic myeloma, solitary plasmacytoma of bone, and extramedullary plasmacytoma.
-
81. The method of claim 79, wherein the NHL is selected from the group consisting of:
- Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma.
-
82. The method of claim 76, wherein the B cell related condition is a plasma cell malignancy.
-
83. The method of claim 76, wherein the B cell related condition is an autoimmune disease.
-
84. The method of claim 83, wherein the autoimmune disease is systemic lupus erythematosus.
-
85. The method of claim 83, wherein the B cell related condition is rheumatoid arthritis.
-
86. The method of claim 83, wherein the B cell related condition is idiopathic thrombocytopenia purpura, or myasthenia gravis, or autoimmune hemolytic anemia.
-
2. The CAR of claim 1, wherein the humanized anti-BCMA antibody or antigen binding fragment that binds the human BCMA polypeptide is selected from the group consisting of:
- an extracellular domain that comprises a humanized anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment thereof that binds one or more epitopes of a human BCMA polypeptide;
-
48. A polynucleotide encoding a CAR, wherein the polynucleotide sequence is set forth in any one of SEQ ID NOs:
- 30-44, 70, and 72.
Specification
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Current Assignee2seventy Bio, Inc. (bluebird bio, Inc.)
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Original Assigneebluebird bio, Inc.
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InventorsMorgan, Richard, Friedman, Kevin
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Application NumberUS15/328,278Publication NumberTime in Patent OfficeDaysField of SearchUS Class CurrentCPC Class CodesA61K 2039/5156 expressing foreign proteinsA61K 2039/572 cytotoxic responseA61K 2239/48 Blood cells, e.g. leukemia ...A61K 38/177 Receptors; Cell surface ant...A61K 38/1774 Immunoglobulin superfamily ...A61K 39/3955 against proteinaceous mater...A61K 39/4611 T-cells, e.g. tumor infiltr...A61K 39/4631 Chimeric Antigen Receptors ...A61K 39/464417 Receptors for tumor necrosi...A61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 19/02 for joint disorders, e.g. a...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 29/00 Non-central analgesic, anti...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 7/00 : Drugs for disorders of the ...A61P 7/06 : AntianaemicsA61P 9/00 : Drugs for disorders of the ...C07K 14/70503 : Immunoglobulin superfamilyC07K 14/7051 : T-cell receptor (TcR)-CD3 c...C07K 14/70517 : CD8C07K 14/70521 : CD28, CD152C07K 14/70578 : NGF-receptor/TNF-receptor s...C07K 16/2878 : against the NGF-receptor/TN...C07K 2317/24 : containing regions, domains...C07K 2317/524 : CH2 domainC07K 2317/526 : CH3 domainC07K 2317/53 : HingeC07K 2317/56 : variable (Fv) region, i.e. ...C07K 2317/565 : Complementarity determining...C07K 2317/622 : Single chain antibody (scFv)C07K 2317/73 : Inducing cell death, e.g. a...C07K 2319/02 : containing a signal sequenceC07K 2319/03 : containing a transmembrane ...C07K 2319/10 : containing a tag for extrac...C07K 2319/33 : fusions for targeting to sp...C12N 15/86 : Viral vectorsC12N 2740/15043 : viral genome or elements th...C12N 2830/48 : regulating transport or exp...C12N 2830/50 : regulating RNA stability, n...C12N 2830/60 : from viruses