Anti-human papillomavirus 16 E6 T cell receptors
Inventors
Hinrichs, Christian S. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-10913785-B2
Publication Date
2021-02-09
Expiration Date
2034-07-14
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Abstract
Disclosed is a T cell receptor (TCR) having antigenic specificity for an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E6, E629-38. 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.
Core Innovation
The invention provides a T cell receptor (TCR) having antigenic specificity for an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E6, specifically HPV 16 E629-38. The invention includes isolated or purified TCRs comprising particular amino acid sequences, related polypeptides and proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions relating to these TCRs.
The problem solved by the invention is the unmet need for additional treatments for cancer, particularly HPV-associated cancers, due to poor prognosis despite advances such as chemotherapy. HPV 16 is the subtype most commonly associated with malignancy, believed to cause cancer through the oncoprotein E6 which deregulates cell cycle control and is constitutively expressed in cancer cells but not in normal, uninfected tissues.
The inventive TCRs are capable of recognizing HPV 16 E6 in a major histocompatibility complex (MHC) class I-dependent manner, specifically in context of HLA-A2 molecules. The invention provides methods of detecting the presence of cancer, HPV 16 infection, or HPV-positive premalignancy by contacting samples with the inventive TCRs or related materials and detecting complexes formed. Methods for treating or preventing such conditions include administering the inventive TCRs, nucleic acids encoding them, recombinant expression vectors, or host cells expressing these receptors in an effective amount.
Claims Coverage
The patent claims include 14 inventive features covering nucleic acids encoding TCRs, recombinant vectors, host cells, and related embodiments. The main inventive features relate to isolated nucleic acids encoding TCRs specific for HPV 16 E6, with specified amino acid sequences, vector constructs, and pharmaceutical compositions.
Nucleic acid encoding TCR with antigenic specificity for HPV 16 E6
An isolated or purified nucleic acid comprising a nucleotide sequence encoding a TCR having antigenic specificity for HPV 16 E6 and comprising the amino acid sequences of SEQ ID NOs: 9 and 10.
TCR specificity for HPV 16 E629-38 epitope
The TCR encoded by the nucleic acid has antigenic specificity for the HPV 16 E629-38 peptide comprising the amino acid sequence of SEQ ID NO: 2.
TCR variants with murine or chimeric constant regions
The TCR encoded can comprise murine constant regions (SEQ ID NOs: 15 and 16) or chimeric hybrid chains comprising human variable regions and murine constant regions (SEQ ID NOs: 17 and 18).
Encoding antigen-binding protein comprising specified CDR sequences
Nucleic acids encoding an antigen-binding protein comprising first and second polypeptide chains with the complementarity determining regions (CDRs) of the alpha and beta chains specified by SEQ ID NOs: 3 to 8.
Recombinant expression vector comprising nucleotide sequences encoding inventive TCRs
Vector constructs comprising the nucleic acids encoding TCRs with the specified sequences including codon-optimized versions.
Host cells comprising recombinant expression vectors
Isolated host cells, preferably human, containing the recombinant expression vectors that encode the inventive TCRs.
Populations of cells and pharmaceutical compositions
Populations comprising at least one host cell with the expression vector, and pharmaceutical compositions comprising such cell populations and pharmaceutically acceptable carriers.
Fusion proteins and recombinant antibodies
Nucleic acids encoding fusion proteins or recombinant antibodies comprising the TCR sequences or portions thereof.
The claims broadly cover isolated nucleic acids encoding TCRs specific for HPV 16 E6, their variants including chimeric forms, recombinant expression vectors, host cells expressing these TCRs, related populations of cells, pharmaceutical compositions, and certain protein embodiments such as fusion proteins and recombinant antibodies, providing comprehensive protection of the molecular and cellular components involved in HPV 16 E6-specific TCR therapy.
Stated Advantages
The inventive TCRs can destroy cells of multiple types of HPV 16-associated cancers due to recognition of the HPV 16 E6 oncoprotein expressed in various malignancies.
The TCRs specifically target cancer cells, HPV 16-infected cells, or HPV-positive premalignant cells while minimizing or eliminating destruction of normal cells, thereby reducing toxicity.
The TCRs may successfully treat or prevent HPV-positive cancers that do not respond to other treatments such as chemotherapy, surgery, or radiation.
The inventive TCRs provide highly avid recognition of HPV 16 E6, enabling recognition of unmanipulated tumor cells without requiring artificial enhancement or manipulation.
Documented Applications
Use of TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, or cells expressing these TCRs in methods of detecting HPV 16 infection, HPV-positive premalignancy, or cancer in mammals.
Methods of treating or preventing cancer, HPV 16 infection, or HPV-positive premalignancy in a mammal by administering effective amounts of the inventive TCRs or related materials, including transduced autologous T cells.
Treatment of patients with recurrent, refractory, or metastatic HPV 16-positive cancers using autologous T cells transduced to express anti-HPV 16 E629-38 TCRs comprising amino acid sequences SEQ ID NOs: 17 and 18.
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