Anti-human papillomavirus 16 E6 T cell receptors
View Patent ↗Disclosed is a T cell receptor (TCR) having antigenic specificity for an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E6, E6 29-38 . Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells are also provided. Antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention are also provided. Also disclosed are methods of detecting the presence of a condition in a mammal and methods of treating or preventing a condition in a mammal, wherein the condition is cancer, HPV 16 infection, or HPV-positive premalignancy.
1. A T cell receptor (TCR) having antigenic specificity for human papillomavirus (HPV) 16 E6 and comprising a human variable region and a murine constant region, wherein the TCR comprises the alpha chain complementarity determining region (CDR) 1 amino acid sequence of SEQ ID NO: 3, the alpha chain CDR2 amino acid sequence of SEQ ID NO: 4, the alpha chain CDR3 amino acid sequence of SEQ ID NO: 5, the beta chain CDR1 amino acid sequence of SEQ ID NO: 6, the beta chain CDR2 amino acid sequence of SEQ ID NO: 7, and the beta chain CDR3 amino acid sequence of SEQ ID NO: 8.
2. The TCR of claim 1 , wherein the TCR has antigenic specificity for HPV 16 E6 29-38 comprising the amino acid sequence of SEQ ID NO: 2.
3. The TCR of claim 1 , comprising the amino acid sequences of SEQ ID NOs: 15 and 16.
4. The TCR of claim 1 , comprising the amino acid sequences of SEQ ID NOs: 17 and 18.
5. An isolated or purified TCR having antigenic specificity for HPV 16 E6 and comprising the alpha chain CDR1 amino acid sequence of SEQ ID NO: 3, the alpha chain CDR2 amino acid sequence of SEQ ID NO: 4, the alpha chain CDR3 amino acid sequence of SEQ ID NO: 5, the beta chain CDR1 amino acid sequence of SEQ ID NO: 6, the beta chain CDR2 amino acid sequence of SEQ ID NO: 7, and the beta chain CDR3 amino acid sequence of SEQ ID NO: 8.
6. The TCR of claim 5 comprising the amino acid sequences of SEQ ID NOs: 9 and 10.
7. The TCR of claim 5 comprising the amino acid sequences of SEQ ID NOs: 13 and 14.
8. The TCR of claim 5 comprising the amino acid sequences of SEQ ID NOs: 11 and 12.
9. An isolated or purified polypeptide comprising a functional portion of the TCR of claim 1 , wherein the functional portion comprises the alpha chain CDR1 amino acid sequence of SEQ ID NO: 3, the alpha chain CDR2 amino acid sequence of SEQ ID NO: 4, the alpha chain CDR3 amino acid sequence of SEQ ID NO: 5, the beta chain CDR1 amino acid sequence of SEQ ID NO: 6, the beta chain CDR2 amino acid sequence of SEQ ID NO: 7, and the beta chain CDR3 amino acid sequence of SEQ ID NO: 8.
10. The isolated or purified polypeptide of claim 9 , comprising the amino acid sequences of (a) SEQ ID NO: 9, (b) SEQ ID NO: 10, or (c) SEQ ID NOs: 9 and 10.
11. The isolated or purified polypeptide of claim 9 , comprising the amino acid sequence(s) of (a) SEQ ID NO: 11, (b) SEQ ID NO: 12, or (c) SEQ ID NOs: 11 and 12.
12. The polypeptide of claim 9 , comprising the amino acid sequence(s) of (a) SEQ ID NO: 17, (b) SEQ ID NO: 18, or (c) SEQ ID NOs: 17 and 18.
13. An isolated or purified protein comprising the polypeptide of claim 9 .
14. A protein comprising at least one of the polypeptides of claim 12 .
15. An isolated or purified protein comprising a first polypeptide chain comprising the alpha chain CDR1 amino acid sequence of SEQ ID NO: 3, the alpha chain CDR2 amino acid sequence of SEQ ID NO: 4, the alpha chain CDR3 amino acid sequence of SEQ ID NO: 5 and a second polypeptide chain comprising the beta chain CDR1 amino acid sequence of SEQ ID NO: 6, the beta chain CDR2 amino acid sequence of SEQ ID NO: 7, and the beta chain CDR3 amino acid sequence of SEQ ID NO: 8.
16. The isolated or purified protein according to claim 15 , comprising a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 9 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 10.
17. The isolated or purified protein of claim 15 , comprising a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 11 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 12.
18. The protein of claim 15 , comprising a first polypeptide chain comprising the amino acid sequence of SEQ ID NO: 17 and a second polypeptide chain comprising the amino acid sequence of SEQ ID NO: 18.
19. The protein of claim 13 , wherein the protein is a fusion protein.
20. The protein of claim 13 , wherein the protein is a recombinant antibody.
21. An isolated or purified nucleic acid comprising a nucleotide sequence encoding the TCR according to claim 5 .
22. A nucleic acid comprising a nucleotide sequence encoding the TCR according to claim 1 .
23. The nucleic acid according to claim 21 , comprising the nucleotide sequences of (a) SEQ ID NOs: 31-36 or (b) SEQ ID NOs: 19 and 20.
24. The nucleic acid according to claim 23 , further comprising the nucleotide sequences of (a) SEQ ID NOs: 23 and 24 or (b) SEQ ID NOs: 25 and 26.
25. The nucleic acid according to claim 21 , comprising the nucleotide sequences of (a) SEQ ID NOs: 21 and 22 or (b) SEQ ID NOs: 27 and 28.
26. The nucleic acid according to claim 21 , wherein the nucleotide sequence is codon-optimized.
27. The nucleic acid according to claim 26 , comprising the nucleotide sequences of SEQ ID NOs: 38 and 39.
28. A recombinant expression vector comprising the nucleic acid according to claim 21 .
29. The recombinant expression vector according to claim 28 comprising the nucleotide sequence of SEQ ID NO: 29 or SEQ ID NO: 30.
30. An isolated host cell comprising the recombinant expression vector of claim 28 .
31. The host cell according to claim 30 , wherein the cell is human.
32. A population of cells comprising at least one host cell of claim 30 .
33. A pharmaceutical composition comprising the TCR population of cells according to claim 32 , and a pharmaceutically acceptable carrier.
34. A method of detecting the presence of a condition in a mammal, comprising:
(a) contacting a sample comprising one or more cells from the mammal with the TCR according to claim 5 , thereby forming a complex, and
(b) detecting the complex, wherein detection of the complex is indicative of the presence of the condition in the mammal, wherein the condition is cancer, HPV 16 infection, or HPV-positive premalignancy.
35. The method of claim 34 , wherein the condition is cancer of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, or penis.
36. The method of claim 34 , wherein the condition is an HPV 16-positive cancer.
37. A method of treating or preventing a condition in a mammal, comprising administering the population of cells of claim 32 to the mammal in an amount effective to treat or prevent the condition in the mammal, wherein the condition is cancer, HPV 16 infection, or HPV-positive premalignancy.
38. The method of claim 37 , wherein the condition is cancer of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, or penis.
39. The method of claim 37 , wherein the condition is an HPV 16-positive cancer.