Treatment of cancer using a CD123 chimeric antigen receptor

Patent metadata

Field	Value
Publication number	US-9815901-B2
Application number	US-201514830392-A
Country	US
Kind code	B2
Filing date	Aug 19, 2015
Priority date	Aug 19, 2014
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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.

First claim

What is claimed is:

1. 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) 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.

2. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising:
(i) the amino acid sequence of the light chain variable region of SEQ ID NO: 276; or
(ii) an amino acid sequence with 95-99% identity to the amino acid sequence of the light chain variable region of SEQ ID NO: 276.

3. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising:
(i) the amino acid sequence of the heavy chain variable region of SEQ ID NO: 217; or
(ii) an amino acid sequence with 95-99% identity to the amino acid sequence of the heavy chain variable region of SEQ ID NO: 217.

4. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising the amino acid sequence of the light chain variable region of SEQ ID NO: 276, and the amino acid sequence of the heavy chain variable region of SEQ ID NO: 217.

5. The isolated nucleic acid molecule of claim 1 , wherein the encoded CD123 binding domain comprises:
(i) the amino acid sequence of SEQ ID NO:480;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 10 modifications to SEQ ID NO: 480; or
(iii) an amino acid sequence with 95-99% identity to SEQ ID NO: 480.

6. The isolated nucleic acid molecule of claim 1 , wherein the CD123 binding domain comprises a nucleotide sequence chosen from SEQ ID NO: 479 and 481, or a nucleotide sequence with 95-99% identity thereof.

7. The isolated nucleic acid molecule of claim 1 , wherein:
(i) the encoded CAR comprises 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, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154; or
(ii) the encoded transmembrane domain comprises 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
(iii) the nucleic acid sequence encoding the transmembrane domain comprises nucleotides 928-999 of sequence of SEQ ID NO: 40, or a nucleotide sequence with 95-99% identity thereof.

8. The isolated nucleic acid molecule of claim 1 , wherein the encoded CD123 binding domain is connected to the transmembrane domain by a hinge region, wherein
(i) the encoded hinge region comprises the amino acid sequence of SEQ ID NO:2, or an amino acid sequence with 95-99% identity to SEQ ID NO: 2; or
(ii) the nucleic acid sequence encoding the hinge region comprises nucleotides 793-927 of sequence of SEQ ID NO: 40, or a nucleotide sequence with 95-99% identity thereof.

9. The isolated nucleic acid molecule of claim 1 , wherein the encoded intracellular domain comprises a costimulatory domain, wherein the costimulatory domain comprises a functional signaling domain derived 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, and PAG/Cbp.

10. The isolated nucleic acid molecule of claim 9 , wherein the costimulatory domain comprises 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.

11. The isolated nucleic acid molecule of claim 9 , wherein the nucleic acid sequence encoding the costimulatory domain comprises nucleotides 1000-1125 of sequence of SEQ ID NO: 40, or a nucleotide sequence with 95-99% identity thereof.

12. The isolated nucleic acid molecule of claim 1 , wherein the encoded intr

Assignees

• Brogdon Jennifer
• Gill Saar
• Glass David
• Kenderian Saad
• Loew Andreas
• Mannick Joan
• Milone Michael C
• Murphy Leon
• Porter David L
• Ruella Marco
• Wang Yongqiang
• Wu Qilong
• Zhang Jiquan
• Novartis Ag
• Univ Pennsylvania

Inventors

• Brogdon Jennifer
• Gill Saar
• Glass David
• Kenderian Saad
• Loew Andreas
• Mannick Joan
• Milone Michael C
• Murphy Leon
• Porter David L
• Ruella Marco
• Wang Yongqiang
• Wu Qilong
• Zhang Jiquan

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title