CHIMERIC ANTIGEN RECEPTOR
Chimeric Antigen Receptors (CARs) comprising a costimulatory sequence which is, or which is derived from, the intracellular domain of CD226, or a fragment thereof, are disclosed. Also disclosed are compositions comprising such CARs, and uses and methods using the same.
1 . A chimeric antigen receptor (CAR), comprising a costimulatory sequence which is, or which is derived from, the intracellular domain of CD226, or a fragment thereof.
2 . The CAR according to claim 1 , wherein the costimulatory sequence which is, or which is derived from, the intracellular domain of CD226, or a fragment thereof comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:16, 58 or 59.
3 . The CAR according to claim 1 or claim 2 , wherein the CAR additionally comprises a costimulatory sequence which comprises or consists of an amino acid sequence which is, or which is derived from, the intracellular domain of CD28.
4 . The CAR according to any one of claims 1 to 3 , wherein the CAR additionally comprises a costimulatory sequence which comprises or consists of an amino acid sequence which is, or which is derived from, the intracellular domain of 4-1BB.
5 . The CAR according to any one of claims claim 1 to 4 , wherein the CAR comprises a costimulatory sequence which comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:17.
6 . The CAR according to any one of claims 1 to 5 , wherein the CAR comprises a costimulatory sequence which comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:18.
7 . The CAR according to any one of claims 1 to 6 , wherein the CAR additionally comprises a dimerization domain.
8 . The CAR according to claim 7 , wherein the dimerization domain is an inducible dimerization domain.
9 . The CAR according to claim 7 or claim 8 , wherein the dimerization domain comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:20.
10 . The CAR according to any one of claims 1 to 9 , wherein the CAR comprises a transmembrane domain which comprises or consists of an amino acid sequence which is, or which is derived from, the transmembrane domain of CD28, CD8a or CD226.
11 . The CAR according to any one of claims 1 to 10 , wherein the CAR comprises a transmembrane domain which comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:11, 10 or 57.
12 . The CAR according to any one of claims 1 to 11 , wherein the CAR additionally comprises a hinge region which is, or which is derived from, the human IgG1 hinge region.
13 . The CAR according to claim 12 , wherein the hinge region comprises or consists of an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:19.
14 . The CAR according to any one of claims 1 to 13 , wherein the CAR comprises an antigen-binding domain which comprises:
a heavy chain variable region sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:1, and
a light chain variable region sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:5.
15 . The CAR according to any one of claims 1 to 13 , wherein the CAR comprises an antigen-binding domain which comprises:
a heavy chain variable region sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:48, and
a light chain variable region sequence having at least 85% sequence identity to the amino acid sequence of SEQ ID NO:52.
16 . A chimeric antigen receptor (CAR) according to any one of A, B, C, D, E, F, G or H, I, J, K, L or M as shown in Table 1, or V, W, X, Z, AA, BB, CC, DD, EE, FF, GG, HH, II, JJ, KK, LL or MM as shown in Table 3.
17 . A chimeric antigen receptor (CAR) comprising, or consisting of, an amino acid sequence having at least 60% sequence identity to the amino acid sequence of SEQ ID NO:22, 23, 24, 25, 26, 27, 28, 29, 38, 39, 40, 41, 42, 81, 83, 84, 85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97 or 98.
18 . A chimeric antigen receptor (CAR) comprising, or consisting of, an amino acid sequence having at least 60% sequence identity to the amino acid sequence of SEQ ID NO:30, 31, 32, 33, 34, 35, 36, 37, 43, 44, 45, 46, 47, 62, 64, 65, 66, 67, 69, 70, 71, 73, 74, 75, 76, 77, 78 or 79.
19 . A nucleic acid encoding the chimeric antigen receptor (CAR) according to any one of claims 1 to 18 .
20 . A vector comprising the nucleic acid of claim 19 .
21 . A cell comprising the chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , the nucleic acid according to claim 19 , or the vector according to claim 20 .
22 . A method for producing a cell expressing a chimeric antigen receptor (CAR), comprising introducing into a cell a nucleic acid according to claim 19 , or a vector according to claim 20 , and culturing the cell under conditions suitable for expression of the nucleic acid or vector by the cell.
23 . A cell which is obtained or obtainable by the method according to claim 22 .
24 . A pharmaceutical composition comprising a chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , a vector according to claim 20 , or a cell according to claim 21 or claim 23 , and a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.
25 . A chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , a vector according to claim 20 , a cell according to claim 21 or claim 23 , or a pharmaceutical composition according to claim 24 , for use in a method of treating or preventing a disease or disorder.
26 . Use of a chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , a vector according to claim 20 , a cell according to claim 21 or claim 23 , or a pharmaceutical composition according to claim 24 , in the manufacture of a medicament for treating or preventing a disease or disorder.
27 . A method of treating or preventing a disease or disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , a vector according to claim 20 , a cell according to claim 21 or claim 23 , or a pharmaceutical composition according to claim 24 .
28 . A method of treating or preventing a disease or disorder in a subject, comprising:
(a) isolating at least one T cell from a subject;
(b) modifying the at least one T cell to express or comprise a chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , or a vector according to claim 20 , and;
(c) administering the modified at least one T cell to a subject.
29 . A method of treating or preventing a disease or disorder in a subject, comprising:
(a) isolating at least one T cell from a subject;
(b) introducing into the at least one T cell a nucleic acid according to claim 19 , or a vector according to claim 20 , thereby modifying the at least one T cell and;
(c) administering the modified at least one T cell to a subject.
30 . The CAR, nucleic acid, vector, cell, or pharmaceutical composition for use according to claim 25 , the use according to claim 26 , or the method according to any one of claims 27 to 29 , wherein the disease or disorder is a cancer.
31 . The CAR, nucleic acid, vector, cell, or pharmaceutical composition for use, the use, or the method according to according to claim 30 , wherein the cancer is a GPC3-expressing cancer or an EpCAM-expressing cancer.
32 . A kit of parts comprising a predetermined quantity of a chimeric antigen receptor (CAR) according to any one of claims 1 to 18 , a nucleic acid according to claim 19 , a vector according to claim 20 , a cell according to claim 21 or claim 23 , or a pharmaceutical composition according to claim 24 .