Fully-human t-cell receptor specific for the 369-377 epitope derived from the Her2/neu (ERBB2) receptor protein
View Patent ↗The present invention relates to compositions and methods for treating HER2/Neu (ERBB2) expressing cancer cells. In some embodiments, the invention includes an isolated T cell receptor (TCR) having high affinity for and that specifically binds ERBB2 369-377 epitope on a target cell. Other embodiments include a T cell or a population of T cells modified to express ERBB2-specific TCR. Further embodiments include methods of using ERBB2-specific TCR gene transfer for treating ERBB2 expressing cancer cells. Also included are methods and pharmaceutical compositions comprising the modified T cells for adoptive therapy.
1. A nucleic acid encoding a T cell receptor (TCR) having affinity for a tyrosine-protein kinase HER2/Neu (ERBB2), wherein the TCR comprises a TCR alpha chain and a TCR beta chain,
wherein the TCR alpha chain is encoded by a nucleotide sequence comprising the sequence set forth in SEQ ID NO: 1, and
wherein the TCR beta chain is encoded by a nucleotide sequence comprising the sequence set forth in SEQ ID NO: 3.
2. The nucleic acid of claim 1 , wherein the nucleotide sequence encoding at least one of the TCR chains is codon optimized.
3. A nucleic acid comprising a nucleotide sequence which is the exact complementary sequence of the nucleic acid of claim 1 .
4. A recombinant expression vector comprising at least one of the nucleotide sequences of the nucleic acid of claim 1 .
5. A modified mammalian cell comprising the recombinant expression vector of claim 4 .
6. The modified mammalian cell of claim 5 , wherein the cell is selected from the group consisting of a peripheral blood mononuclear cell, a cord blood cell, a primary T cell, and a cell of a T cell line.
7. The modified mammalian cell of claim 5 , wherein the cell is a tumor infiltrating lymphocyte (TIL).
8. A population of cells comprising the cell of claim 7 .
9. A recombinant expression vector comprising at least one of the nucleotide sequences of the nucleic acid of claim 1 operably linked to an exogenous promoter selected from the group consisting of a constitutive promoter, an inducible promoter, and a tissue-specific promoter.
10. The nucleic acid of claim 1 , wherein the nucleotide sequence encoding the TCR alpha chain and the nucleotide sequence encoding the TCR beta chain are linked by a sequence encoding a peptide linker.
11. The nucleic acid of claim 10 , wherein the peptide linker is a 2A peptide.
12. The nucleic acid of claim 1 , wherein the nucleic acid comprises the nucleotide sequence set forth in SEQ ID NO: 5.
13. A recombinant expression vector comprising the nucleic acid of claim 1 , wherein the sequence encoding the TCR alpha chain and/or the sequence encoding the TCR beta chain are operably linked to a heterologous regulatory sequence selected from the group consisting of a constitutive promoter, an inducible promoter, and a tissue-specific promoter.