Anti-human papillomavirus 16 E7 T cell receptors
Inventors
Hinrichs, Christian S. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-10174098-B2
Publication Date
2019-01-08
Expiration Date
2035-05-29
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Abstract
Disclosed is a synthetic T cell receptor (TCR) having antigenic specificity for an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E7, E711-19. 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 synthetic T cell receptors (TCRs) having antigenic specificity for human papillomavirus (HPV) 16 E7, specifically targeting an HLA-A2-restricted epitope of HPV 16 E7 known as E711-19. The invention further encompasses related polypeptides, proteins, nucleic acids encoding these TCRs, recombinant expression vectors, host cells, and cell populations. Additionally, it includes antibodies or antigen binding portions thereof, pharmaceutical compositions, and methods of detecting, treating, or preventing conditions such as cancer, HPV 16 infection, or HPV-positive premalignancy using these TCR-related materials.
The problem being addressed arises from the poor prognosis associated with cancers caused by HPV infections, such as uterine cervical cancer. Despite advances including chemotherapy, existing treatments may be inadequate, creating a need for new therapies for HPV-associated cancers. The invention aims to provide TCRs with specific antigenic recognition to target HPV 16 E7-expressing cancer cells, which are constitutively expressed in cancer cells but not in normal tissues, thereby enabling improved detection and treatment options.
The inventive TCRs can recognize HPV 16 E7 in an MHC class I-dependent manner, preferably restricted to HLA-A2 molecules. This TCR specificity allows for selective targeting of infected or cancerous cells expressing HPV 16 E7 while minimizing damage to normal cells. The invention also provides functional variants and chimeric TCRs combining human variable regions with murine constant regions, including variants with modifications such as cysteine substitutions and hydrophobic residue substitutions, to enhance expression, stability, or function.
Claims Coverage
The patent includes multiple independent claims primarily covering nucleic acids encoding TCRs with specific antigenic specificity for HPV 16 E7, recombinant expression vectors, host cells, and methods of detection and treatment involving these TCRs.
TCR comprising human variable region and murine constant region with antigenic specificity for HPV 16 E7
A nucleic acid encoding a T cell receptor having a human variable region and a murine constant region, or a functional variant thereof, wherein the TCR specifically recognizes HPV 16 E7 and comprises the amino acid sequences of SEQ ID NOs: 3-8.
TCR comprising human variable region with antigenic specificity for HPV 16 E7
An isolated or purified nucleic acid encoding a TCR having antigenic specificity for HPV 16 E7, comprising the amino acid sequences of SEQ ID NOs: 3-8, with the TCR optionally comprising human constant regions.
TCRs with specific amino acid substitutions enhancing function
Nucleic acids encoding TCR variants with substitutions in constant regions, including cysteine substitutions forming disulfide bonds and modifications in transmembrane regions to hydrophobic residues, enhancing expression and HPV 16 E7 recognition.
Nucleic acids encoding TCR alpha and beta chains with defined CDRs and variable regions
Nucleic acids encoding TCR polypeptides or proteins comprising combinations of alpha and beta chains with specific complementarity determining regions (CDRs) and variable regions, including polypeptides encoded by SEQ ID NOs: 9, 10 (with position 2 Ala or Gly), 12, 13, and functional variants thereof.
Recombinant expression vectors encoding TCRs with beta chain 5' of alpha chain
Recombinant expression vectors comprising nucleotide sequences encoding alpha and beta chains of TCRs, with the beta chain encoding sequence positioned 5′ of the alpha chain, including codon-optimized sequences such as SEQ ID NO: 37 and SEQ ID NO: 38.
Host cells and populations expressing TCRs for use in detection and therapy
Host cells, including human T cells, and cell populations comprising recombinant expression vectors encoding the inventive TCRs, capable of detecting or treating conditions involving HPV 16 infection or HPV 16-associated cancers.
Methods of detecting and treating HPV 16 related conditions using TCR-expressing cells
Methods comprising contacting a sample or mammal with cells expressing the inventive TCRs to detect cancer, HPV infection, or premalignancy, or administering such cells to treat or prevent these conditions, including specific HPV 16-positive cancers such as cervical, oropharynx, anal, vaginal, vulvar, or penile cancers.
The independent claims cover nucleic acids encoding TCRs with specific HPV 16 E7 antigenic specificity, including functional and variant forms; recombinant expression vectors with defined chain orientation; host cells expressing these TCRs; and methods of detection and treatment of HPV 16-related infections and cancers, particularly HPV 16-positive cancers.
Stated Advantages
Ability to destroy cells of multiple HPV 16-associated cancer types by targeting HPV 16 E7 expressed in various cancers.
Selective targeting of cancer cells while sparing normal cells, reducing toxicity.
Potential to treat or prevent HPV-positive cancers that do not respond to other treatments such as chemotherapy, surgery, or radiation.
Highly avid recognition of HPV 16 E7 enabling recognition of unmanipulated tumor cells.
Documented Applications
Use in methods for detecting HPV 16 infection, HPV-positive premalignancy, or cancer by binding to cells expressing HPV 16 E7 to form detectable complexes.
Treatment or prevention of cancers associated with HPV 16 infection, including uterine cervical cancer, oropharyngeal cancer, anal cancer, anal canal cancer, anorectum cancer, vaginal cancer, vulvar cancer, and penile cancer.
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