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US 2024/0190975 A1Published application
Chimeric antigen receptor that recognizes ccr8 as antigen
AssigneesShionogi & Co., Ltd., Osaka University
InventorsTetsuya Yoshida, Mai Yoshikawa, Miya Haruna, Morio Nagira, Koji Takahashi, Marina Hayashida, Hiroto Miwa, Yudai Sonoda, Naganari Ohkura, Shimon Sakaguchi, Hisashi Wada
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Abstract
The chimeric antigen receptor that recognizes CCR8 as an antigen of the present invention has cytotoxic activity against CCR8-expressing cells by being expressed in effector cells.
Claims44
1:
- A chimeric antigen receptor comprising an extracellular region that binds to CCR8, a transmembrane region, and an intracellular region, wherein the intracellular region comprises an intracellular signal region of a signaling molecule expressed in a lymphocyte that functions as an effector cell.
2:
- The chimeric antigen receptor according to claim 1, wherein the extracellular region that binds to CCR8 comprises an anti-CCR8-scFv region.
3:
- The chimeric antigen receptor according to claim 2, wherein the anti-CCR8-scFv region comprises:
- 1) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 24,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 25, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 26, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 27,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 29;
- 2) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 30,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 31, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 32, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 33,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 34;
- 3) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 35,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 36, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 37, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 38,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 39, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 40;
- 4) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 30,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 41, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 32, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 42,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 43;
- 5) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 44,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 45, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 46, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 47,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 48;
- or
- 6) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 56,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 57, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 58, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 59,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 60, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 61.
83 more elements
4:
- The chimeric antigen receptor according to claim 3, wherein the anti-CCR8-scFv region comprises:
- 1) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 24,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 25, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 26, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 27,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 29;
- 2) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 30,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 31, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 32, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 33,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 34;
- or
- 4) a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 30,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 41, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 32, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 42,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 43.
41 more elements
5:
- The chimeric antigen receptor according to claim 4, wherein the anti-CCR8-scFv region comprises:
- a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 24,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 25, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 26, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 27,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 29.
12 more elements
6:
- The chimeric antigen receptor according to claim 4, wherein the anti-CCR8-scFv region comprises:
- a light chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 30,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 31, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 32, and
- a heavy chain variable region including
- CDR1 having the amino acid sequence of SEQ ID NO:
- 33,
- CDR2 having the amino acid sequence of SEQ ID NO:
- 28, and
- CDR3 having the amino acid sequence of SEQ ID NO:
- 34.
12 more elements
7:
- The chimeric antigen receptor according to claim 2, wherein the anti-CCR8-scFv region comprises:
- 1) a light chain variable region having the amino acid sequence of SEQ ID NO:
- 12, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 13;
- 2) a light chain variable region having the amino acid sequence of SEQ ID NO:
- 14, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 15;
- or
- 3) a light chain variable region having the amino acid sequence of SEQ ID NO:
- 16, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 17.
11 more elements
8:
- The chimeric antigen receptor according to claim 7, wherein the anti-CCR8-scFv region comprises:
- 1) a light chain variable region having the amino acid sequence of SEQ ID NO:
- 12, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 13;
- or
- 2) a light chain variable region having the amino acid sequence of SEQ ID NO:
- 14, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 15.
7 more elements
9:
- The chimeric antigen receptor according to claim 8, wherein the anti-CCR8-scFv region comprises:
- a light chain variable region having the amino acid sequence of SEQ ID NO:
- 12, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 13.
2 more elements
10:
- The chimeric antigen receptor according to claim 8, wherein the anti-CCR8-scFv region comprises:
- a light chain variable region having the amino acid sequence of SEQ ID NO:
- 14, and
- a heavy chain variable region having the amino acid sequence of SEQ ID NO:
- 15.
2 more elements
11:
- The chimeric antigen receptor according to claim 2, wherein the light chain variable region and the heavy chain variable region are linked via the linker sequence of SEQ ID NO:
- 2 in the anti-CCR8-scFv region.
12:
- The chimeric antigen receptor according to claim 2, wherein the extracellular region that binds to CCR8 comprises a CD8A signal sequence region.
13:
- The chimeric antigen receptor according to claim 12, wherein the CD8A signal sequence region is present on an N-terminal side of the anti-CCR8-scFv region.
14:
- The chimeric antigen receptor according to claim 12, wherein the CD8A signal sequence region has the amino acid sequence of SEQ ID NO:
- 1.
15:
- The chimeric antigen receptor according to claim 2, wherein the anti-CCR8-scFv region and the transmembrane region are linked via a spacer sequence.
16:
- The chimeric antigen receptor according to claim 15, wherein the spacer sequence comprises a Flag epitope-containing sequence region.
17:
- The chimeric antigen receptor according to claim 16, wherein the Flag epitope-containing sequence region has the amino acid sequence of SEQ ID NO:
- 3.
18:
- The chimeric antigen receptor according to claim 15, wherein the spacer sequence comprises a CD8A hinge region.
19:
- The chimeric antigen receptor according to claim 18, wherein the CD8A hinge region has the amino acid sequence of SEQ ID NO:
- 4.
20:
- The chimeric antigen receptor according to claim 1, wherein the transmembrane region comprises a CD8A transmembrane region.
21:
- The chimeric antigen receptor according to claim 20, wherein the CD8A transmembrane region has the amino acid sequence of SEQ ID NO:
- 5.
22:
- The chimeric antigen receptor according to claim 1, wherein the transmembrane region comprises a CD28 transmembrane region and the intracellular region comprises a CD28 intracellular signal region.
23:
- The chimeric antigen receptor according to claim 22, wherein the CD28 transmembrane region has the amino acid sequence of SEQ ID NO:
- 6, and the CD28 intracellular signal region has the amino acid sequence of SEQ ID NO:
- 7.
24:
- The chimeric antigen receptor according to claim 1, wherein the intracellular region comprises at least one of intracellular signal regions of 4-1BB, 2B4, CD3ξ, and DAP10.
25:
- The chimeric antigen receptor according to claim 24, wherein the intracellular region comprises at least two of intracellular signal regions of 4-1BB, 2B4, CD3ξ, and DAP10.
26:
- The chimeric antigen receptor according to claim 25, wherein the intracellular region comprises intracellular signal regions of 4-1BB and CD3ξ.
27:
- The chimeric antigen receptor according to claim 25, wherein the intracellular region comprises intracellular signal regions of 2B4 and CD3ξ.
28:
- The chimeric antigen receptor according to claim 24, wherein the intracellular region comprises a 4-1BB intracellular signal region, and the 4-1BB intracellular signal region has the amino acid sequence of SEQ ID NO:
- 8.
29:
- The chimeric antigen receptor according to claim 24, wherein the intracellular region comprises a 2B4 intracellular signal region, and the 2B4 intracellular signal region has the amino acid sequence of SEQ ID NO:
- 9.
30:
- The chimeric antigen receptor according to claim 24, wherein the intracellular region comprises a CD3ξ intracellular signal region, and the CD3ξ intracellular signal region has the amino acid sequence of SEQ ID NO:
- 10.
31:
- The chimeric antigen receptor according to claim 24, wherein the intracellular region comprises a DAP10 intracellular signal region, and the DAP10 intracellular signal region has the amino acid sequence of SEQ ID NO:
- 11.
32:
- An effector cell expressing the chimeric antigen receptor according to claim 1.
33:
- The cell according to claim 32, wherein the effector cell is an NK cell.
34:
- The cell according to claim 32, wherein the effector cell is a T cell.
35:
- The cell according to claim 32, wherein the effector cell is a macrophage.
36:
- The cell according to claim 32, wherein the effector cell is derived from peripheral blood.
37:
- The cell according to claim 32, wherein the effector cell is differentiated from a stem cell.
38:
- The cell according to claim 36, wherein the stem cell is an iPS cell.
39:
- A pharmaceutical composition comprising the cell according to claim 32.
40:
- The pharmaceutical composition according to claim 39, for use in treating cancer.
41:
- The pharmaceutical composition according to claim 40, having an effect of depleting tumor-infiltrating Treg cells expressing CCR8.
42:
- The pharmaceutical composition according to claim 40, having an effect of depleting tumor cells expressing CCR8.
43:
- A polynucleotide encoding an amino acid sequence of the chimeric antigen receptor according to claim 1.
44:
- An expression vector comprising the polynucleotide according to claim 43.