Chimeric antigen receptor to which anti-cotinine antibody is linked, and use thereof
The present invention relates to chimeric antibody receptors with anti-cotinine antibodies linked, and use thereof. A T cell presenting the chimeric antibody receptor on the surface secretes interferon gamma specifically for a target molecule of a cotinine-conjugated binding molecule that is added together therewith and induces cell death of the cell expressing the target molecule by the T cell. On the contrary, by administering a cytotoxic agent conjugated with cotinine, cell death of the chimeric antigen receptor T cell is induced. Therefore, if necessary, a cytotoxic agent conjugated with cotinine can be administered to remove the chimeric antigen receptor T cells that have been already administered, thereby suppressing immune side effects due to hyperactivity of T cells. Thus, the chimeric antigen receptor to which the anti-cotinine antibody is linked can be effectively and safely used for the treatment of cancer.
1. An isolated chimeric antigen receptor comprising, in the order from the N-terminus to the C-terminus of the chimeric antigen receptor, the following (a)-(d):
(a) an anti-cotinine single chain Fv (scFv) antibody, wherein the anti-cotinine scFv antibody comprises the amino acid sequence of SEQ ID NO: 1;
(b) a CD8 (cluster of differentiation 8) hinge domain comprising the sequence of SEQ ID NO: 3;
(c) a transmembrane domain of CD28 comprising the sequence of SEQ ID NO: 5 or 7; and
(d) a signal transduction domain selected from the group consisting of the following (i)-(iii):
(i) a CD28 cytoplasmic region comprising the sequence of SEQ ID NO: 9 or 11,
(ii) a CD3 zeta cytoplasmic region comprising the sequence of SEQ ID NO: 13, and
(iii) a CD28 cytoplasmic region comprising the sequence of SEQ ID NO: 9 or 11 and a CD3 zeta cytoplasmic region comprising the sequence of SEQ ID NO: 13.
2. The isolated chimeric antigen receptor of claim 1 , wherein the signal transduction domain is the (iii) CD28 cytoplasmic region comprising the sequence of SEQ ID NO: 9 or 11 and CD3 zeta cytoplasmic region comprising the sequence of SEQ ID NO: 13.
3. The isolated chimeric antigen receptor of claim 1 , wherein the chimeric antigen receptor comprises the amino acid sequence of SEQ ID NO: 15 or SEQ ID NO: 17.
4. An isolated nucleic acid molecule encoding the chimeric antigen receptor of claim 1 .
5. An isolated expression vector comprising the nucleic acid molecule of claim 4 .
6. The isolated expression vector of claim 5 , wherein the expression vector is a virus vector.
7. The isolated expression vector of claim 6 , wherein the virus vector is an adenovirus vector, a retrovirus vector, a lentivirus vector, or an adeno-associated virus vector.
8. An isolated virus comprising the nucleic acid molecule of claim 4 .
9. An isolated cell transduced with the virus of claim 8 .
10. The isolated cell of claim 9 , wherein the cell is a T cell, a natural killer cell, or a macrophage.