Chimeric antigen receptor comprising anti c-met antibody or antigen binding fragment thereof, and use thereof
The present invention relates to a chimeric antigen receptor comprising a c-Met binding domain, and a use thereof. The chimeric antigen receptor comprising a c-Met domain, of the present invention, can be effectively usable as an agent for treating various diseases associated with c-Met expression.
1 . A nucleic acid molecule coding for an anti-c-Met chimeric antigen receptor, comprising:
a c-Met-binding domain, a transmembrane domain, and an intracellular signaling domain,
wherein the c-Met-binding domain is an antibody or an antigen binding fragment thereof binding specifically to c-Met,
wherein the antibody or the antigen binding fragment thereof comprises a heavy chain variable region (VH) consisting of the amino acid sequence of SEQ ID NO: 21; and a light chain variable region (VL) consisting of the amino acid sequence of SEQ ID NO: 22.
2 . The nucleic acid molecule of claim 1 , wherein the chimeric antigen receptor further comprises a leader sequence (LS).
3 . The nucleic acid molecule of claim 2 , wherein the leader sequence is a leader sequence of hCD8 alpha, a leader sequence of hGM-CSF receptor alpha-chain, or a leader sequence of 3E8 antibody.
4 . The nucleic acid molecule of claim 2 , wherein the leader sequence is a leader sequence comprising the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26, 28, or 30.
5 . The nucleic acid molecule of claim 1 , wherein the c-Met-binding domain is linked to the transmembrane domain by a hinge region, a spacer region, or a combination thereof.
6 . The nucleic acid molecule of claim 5 , wherein the hinge region and the spacer region is a hinge of IgG1, a hinge of IgG4, a hinge of IgD, a hinge of CD8 alpha, IgG1 CH3, an extracellular domain of CD28, or a combination thereof.
7 . The nucleic acid molecule of claim 5 , wherein the hinge region or the spacer region comprises the amino acid sequence encoded by the nucleotide sequence of 32, 34, 36, 38, 40, or 44.
8 . The nucleic acid molecule of claim 1 , wherein the chimeric antigen receptor comprises a transmembrane domain of a protein selected from the group consisting of a T-cell receptor, CD28, CD3, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
9 . The nucleic acid molecule of claim 8 , wherein the transmembrane domain comprises the amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 42, 46, or 47.
10 . The nucleic acid molecule of claim 1 , wherein the intracellular signaling domain comprises a signaling domain of CD3 zeta.
11 . The nucleic acid molecule of claim 10 , wherein the signaling domain of CD3 zeta comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 55, 57, or 59.
12 . The nucleic acid molecule of claim 1 , wherein the intracellular signaling domain further comprises as a costimulatory domain a signaling domain of a protein selected from the group consisting of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137).
13 . The nucleic acid molecule of claim 12 , wherein the costimulatory domain comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 49, 51, or 53.
14 . An anti-c-Met chimeric antigen receptor molecule comprising a polypeptide encoded by the nucleic acid molecule of claim 1 .
15 . An effector cell, having the anti-c-Met chimeric antigen receptor molecule of claim 14 expressed on a surface thereof.
16 . The effector cell of claim 15 , wherein the effector cell is selected from the group consisting of dendritic cells, killer dendritic cells, mast cells, natural killer cells, B lymphocytes, T lymphocytes, macrophages, and progenitor cells thereof.