TREATMENT OF CANCER USING A CD123 CHIMERIC ANTIGEN RECEPTOR

• US 20180312595A1
• Filed: 10/06/2017
• Published: 11/01/2018
• Est. Priority Date: 08/19/2014
• Status: Active Grant

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Brogdon, Jennifer, Gill, Saar, Glass, David Jonathan, Kenderian, Saad, Loew, Andreas, Mannick, Joan, Milone, Michael, Murphy, Leon, Porter, David L., Ruella, Marco, Wang, Yongqiang, Wu, Qilong, Zhang, Jiquan
• Granted Patent: US 10,703,819 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• 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 2239/48 Blood cells, e.g. leukemia or lymphoma
• 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 39/464412 CD19 or B4
• CPC Class Codes: A61K 39/464419 Receptors for interleukins [IL]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• 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: C12N 5/0636 : T lymphocytes

Abstract

The invention provides compositions and methods for treating diseases associated with expression of CD123. The invention also relates to chimeric antigen receptor (CAR) specific to CD123, vectors encoding the same, and recombinant cells comprising the CD123 CAR. The invention also includes methods of administering a genetically modified cell expressing a CAR that comprises a CD123 binding domain.

Claims

1-51. -51. (canceled)

52. A method of providing an anti-tumor immunity in a mammal, comprising administering to the mammal an effective amount of a cell comprising:

(a) an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a CD123 binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said CD123 binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any CD123 heavy chain binding domain amino acid sequence listed in Table 9, Table 2, or Table 6, or

(b) an isolated CAR polypeptide molecule encoded by the nucleic acid molecule of (a).

59. The method of claim 52, wherein the cell comprises:

(i) an mRNA encoding the CAR polypeptide;

or

(ii) a lentiviral vector comprising the nucleic acid molecule, or encoding the CAR polypeptide.

61. The method of claim 52, wherein the cell is administered in combination with second therapeutic agent or procedure chosen from one or more of chemotherapy, a targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, a cytokine, surgical procedure, a radiation procedure, an agonist of a costimulatory molecule, an inhibitor of an immune checkpoint molecule, a vaccine, or a second CAR-based immunotherapy.

62. The method of claim 61, wherein the cell is administered in combination with:

(i) an agonist of a costimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand;

or

(ii) an inhibitor of an immune checkpoint molecule chosen from one or more of PD1, PD-L1, PD-L2, CTLA4, TIM3, CEACAM-1, CEACAM-3, CEACAM-5, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, or TGFR.

64. The method of claim 61, wherein the cell is administered in combination with a PD-1 inhibitor, a TIM-3 inhibitor, a CEACAM-1 inhibitor, or a combination thereof.

65. The method of claim 64, wherein:

(i) the PD-1 inhibitor and the TIM-3 inhibitor are administered in combination;

or

(ii) the TIM-3 inhibitor and the CEACAM-1 inhibitor are administered in combination.

67. The method of claim 61, wherein:

(i) the agonist or the inhibitor is an antibody molecule; and

/or

(ii) the inhibitor is administered subsequent to the administration of the cell.

70. The method of claim 52, wherein the cell is administered in combination with a CD19 inhibitor.

71. The method of claim 70, wherein the CD19 inhibitor is a CD19 CAR-expressing cell or an anti-CD19 antibody molecule.

76. The method of claim 70, wherein:

(i) the cell is administered after administration of the CD19 inhibitor;

or

(ii) the cell is administered concurrently with the CD19 inhibitor.

78. The method of claim 52, wherein the cell expresses a CD19 CAR and the CD123 CAR.

91. The method of claim 52, further comprising transplanting a cell or a bone marrow, into the mammal.

103. The method of claim 52, wherein said CD123 binding domain of (a) further comprises a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any CD123 light chain binding domain amino acid sequence listed in Table 9, Table 2, or Table 6.

104. The method of claim 103, wherein said LC CDR1, LC CDR2, and LC CDR3 of (a) are the LC CDR sequences listed in Tables 11, 13, 4 or 8.

105. The method of claim 52, wherein said HC CDR1, HC CDR2, and HC CDR3 of (a) are the HC CDR sequences listed in Tables 10, 12, 3, or 7.

106. The method of claim 52, wherein the nucleic acid molecule of (a) encodes a CAR comprising:

(A) (i) the amino acid sequence of any light chain variable region listed in Table 9 or 2;

(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of any of the light chain variable regions provided in Table 9 or 2;

or

(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the light chain variable regions provided in Table 9 or 2;

(B) (i) the amino acid sequence of any heavy chain variable region listed in Table 9 or 2;

(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of any of the heavy chain variable regions provided in Table 9 or 2;

or

(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of any of the heavy chain variable regions provided in Table 9 or 2; and

/or

(C) the amino acid sequence of any light chain variable region listed in Table 9 or 2, and the amino acid sequence of any heavy chain variable region listed Table 9 or 2.

107. The method of claim 52, wherein:

(i) the encoded CD123 binding domain of (a) comprises the amino acid sequence selected from a group consisting of SEQ ID NO;

480, 483, 485, 478, 158, 159, 160, 157, 217, 218, 219, 216, 276, 277, 278, or 275;

(ii) the encoded CD123 binding domain of (a) comprises an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications to any of SEQ ID NO;

480, 483, 485, 478, 158, 159, 160, 157, 217, 218, 219, 216, 276, 277, 278, or 275;

(iii) the encoded CD123 binding domain of (a) comprises an amino acid sequence with 95-99% identity to any of SEQ ID NO;

480, 483, 485, 478, 158, 159, 160, 157, 217, 218, 219, 216, 276, 277, 278, or 275; and

/or

(iv) the CD123 binding domain of (a) comprises a nucleotide sequence selected from a group consisting of SEQ ID NO;

479, 481, 482, 484, or a nucleotide sequence with 95-99% identity thereof.

108. The method of claim 52, wherein:

(a) the encoded CAR of (a) includes a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154;

or

(b) the encoded transmembrane domain of (a) comprises the amino acid sequence of SEQ ID NO;

6, an amino acid sequence comprises at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO;

6, or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO;

6;

or

(c) the nucleic acid sequence encoding the transmembrane domain of (a) comprises the nucleotide sequence of SEQ ID NO;

17, or a nucleotide sequence with 95-99% identity thereof.

109. The method of claim 52, wherein the encoded CD123 binding domain of (a) is connected to the transmembrane domain by a hinge region, and wherein

(i) the encoded hinge region comprises the amino acid sequence of SEQ ID NO:

2, or an amino acid sequence comprising at least one, two, or three modifications, but no more than 20, 10, or 5 modifications, or an amino acid sequence with 95-99% identity thereof;

or

(ii) the nucleic acid sequence encoding the hinge region comprises the nucleotide sequence of SEQ ID NO;

13, or a nucleotide sequence with 95-99% identity thereof.

110. The method of claim 52, wherein the encoded costimulatory domain of (a) is a functional signaling domain obtained from a protein selected from the group consisting of a MHC class I molecule, a TNF receptor protein, an Immunoglobulin-like protein, a cytokine receptor, an integrin, a signaling lymphocytic activation molecule (SLAM protein), an activating NK cell receptor, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83.

111. The method of claim 110, wherein:

(i) the encoded costimulatory domain of (a) comprises the amino acid sequence of SEQ ID NO;

7, or an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO;

7, or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO;

7;

or

(ii) the nucleic acid sequence encoding the costimulatory domain comprises the nucleotide sequence of SEQ ID NO;

18, or a nucleotide sequence with 95-99% identity thereof.

112. The method of claim 52, wherein:

(i) the encoded intracellular signaling domain of (a) comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta;

(ii) the encoded intracellular signaling domain of (a) comprises the amino acid sequence of SEQ ID NO;

7 and/or the amino acid sequence of SEQ ID NO;

9 or SEQ ID NO;

10;

or an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO;

7 and/or the amino acid sequence of SEQ ID NO;

9 or SEQ ID NO;

10;

or an amino acid sequence with 95-99% identity to the amino acid sequence of SEQ ID NO;

7 and/or the amino acid sequence of SEQ ID NO;

9 or SEQ ID NO;

10;

or

(iii) the encoded intracellular signaling domain of (a) comprises the amino acid sequence of SEQ ID NO;

7 and the amino acid sequence of SEQ ID NO;

9 or SEQ ID NO;

10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain; and

/or

(iv) the nucleic acid sequence encoding the intracellular signaling domain of (a) comprises the nucleotide sequence of SEQ ID NO;

18, or a nucleotide sequence with 95-99% identity thereof, and/or the nucleotide sequence of SEQ ID NO;

20 or SEQ ID NO;

21, or a nucleotide sequence with 95-99% identity thereof.

113. The method of claim 52, wherein the nucleic acid molecule of (a) further comprises a leader sequence which encodes the amino acid sequence of SEQ ID NO:

1.

114. The method of claim 52, wherein the nucleic acid molecule of (a) encodes a CAR comprising:

(i) the amino acid sequence of any of SEQ ID NOs;

99, 100, 101, or 98;

(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications to any of SEQ ID NOs;

99, 100, 101, or 98;

or

(iii) an amino acid sequence with 95-99% identity to any of SEQ ID NOs;

99, 100, 101, or 98.

115. The method of claim 52, wherein the nucleic acid molecule of (a) comprises the nucleotide sequence of any of SEQ ID NOs:

39, 40, 41, or 38, or a nucleotide sequence with 95-99% identity to any of SEQ ID NOs;

39, 40, 41, or 38.

116. The method of claim 52, wherein the administering to the mammal comprises an effective amount of a population of immune effector cells.

117. The method of claim 52, wherein the encoded CD123 binding domain of (a) comprises:

(a) a heavy chain variable domain comprising three complementary determining regions of heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) present in order of HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1 comprises the amino acid sequence of SEQ ID NO;

487, HC CDR2 comprises the amino acid sequence of SEQ ID NO;

492, and HC CDR3 comprises the amino acid sequence of SEQ ID NO;

497; and

a light chain variable domain comprising three complementary determining regions of light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) present in order of LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises the amino acid sequence of SEQ ID NO;

502, LC CDR2 comprises the amino acid sequence of SEQ ID NO;

507, and LC CDR3 comprises the amino acid sequence of SEQ ID NO;

512;

or

(b) a heavy chain variable domain comprising three complementary determining regions of heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) present in order of HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1 comprises the amino acid sequence of SEQ ID NO;

517, HC CDR2 comprises the amino acid sequence of SEQ ID NO;

522, and HC CDR3 comprises the amino acid sequence of SEQ ID NO;

527; and

a light chain variable domain comprising three complementary determining regions of light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) present in order of LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises the amino acid sequence of SEQ ID NO;

532, LC CDR2 comprises the amino acid sequence of SEQ ID NO;

537, and LC CDR3 comprises the amino acid sequence of SEQ ID NO;

542;

or

(c) a heavy chain variable domain comprising three complementary determining regions of heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) present in order of HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1 comprises the amino acid sequence of SEQ ID NO;

335, HC CDR2 comprises the amino acid sequence of SEQ ID NO;

363, and HC CDR3 comprises the amino acid sequence of SEQ ID NO;

391; and

a light chain variable domain comprising three complementary determining regions of light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) present in order of LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1 comprises the amino acid sequence of SEQ ID NO;

419, LC CDR2 comprises the amino acid sequence of SEQ ID NO;

447, and LC CDR3 comprises the amino acid sequence of SEQ ID NO;

475.

53. (canceled)

54. A method of treating a mammal having a disease associated with expression of CD123, comprising administering to the mammal an effective amount of a cell comprising:

(a) an isolated nucleic acid molecule encoding a CAR, wherein the CAR comprises a CD123 binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said CD123 binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any CD123 heavy chain binding domain amino acid sequence listed in Table 9, Table 2, or Table 6, or

(b) an isolated CAR polypeptide molecule encoded by the nucleic acid molecule of (a).

55. The method of claim 54, wherein the disease associated with CD123 expression is:

(i) a cancer or malignancy,

(ii) a precancerous condition, or

(ii) a non-cancer related indication associated with expression of CD123.

56. The method of claim 54, wherein the disease is a hematologic cancer, a leukemia, or a pre-leukemia.

57. The method of claim 54, wherein the disease is chosen from one or more of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia (B-cell acute lymphoid leukemia, BALL), acute lymphoblastic T-cell leukemia (T-cell acute lymphoid leukemia (TALL), B-cell prolymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin lymphoma, a histiocytic disorder, a mast cell disorder, a myelodysplasia, a myelodysplastic syndrome, a myeloproliferative neoplasm, a plasma cell myeloma, a plasmacytoid dendritic cell neoplasm, or a combination thereof.

72. The method of any of claim 54, wherein the disease is a CD19-negative cancer.

75. The method of claim 54, wherein the disease is relapsing and refractory ALL.

58. (canceled)

60. (canceled)

63. (canceled)

66. (canceled)

68-69. -69. (canceled)

73-74. -74. (canceled)

77. (canceled)

79-90. -90. (canceled)

92-102. -102. (canceled)