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-11434272-B2
Publication Date
2022-09-06
Expiration Date
2035-05-29
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E7, specifically the E711-19 epitope. The disclosed TCRs include those with human variable regions and murine constant regions, functional variants, related polypeptides and proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions. Methods are also provided for detecting the presence of conditions such as cancer, HPV 16 infection, or HPV-positive premalignancy in mammals, as well as methods for treating or preventing these conditions by administering the inventive TCRs, nucleic acids, vectors, or host cells.
The problem addressed by the invention arises from the poor prognosis associated with many HPV-associated cancers despite advances in treatments such as chemotherapy. HPV 16, a subtype most commonly associated with malignancy, expresses the oncoprotein E7, which contributes to cancer cell growth. There is an unmet need for additional treatments targeting HPV-associated cancers that are more effective and minimize toxicity by targeting only cancer cells.
The inventive TCRs exhibit antigenic specificity for HPV 16 E7 peptides in an MHC class I-dependent manner, preferably restricted by HLA-A2 molecules. These TCRs enable recognition and destruction of HPV 16-infected cancer cells while sparing normal tissues. The invention includes modified TCRs with enhanced recognition properties, such as chimeric TCRs with human variable and murine constant regions, cysteine substitutions in the constant region, and hydrophobic amino acid substitutions in the transmembrane domain, which improve TCR expression and function. The TCRs can be expressed in host cells for adoptive cell transfer therapy.
Claims Coverage
The patent claims cover multiple inventive features related to methods of treating or preventing HPV 16-related conditions using populations of host cells expressing TCRs with specific amino acid sequences and characteristics.
Use of T cell receptors with specific amino acid sequences to treat HPV 16-related conditions
The population of host cells comprises recombinant expression vectors encoding T cell receptors having antigenic specificity for HPV 16 E7 and comprising the amino acid sequences of SEQ ID NOs: 3-8. These TCRs are used to treat or prevent cancer, HPV 16 infection, or HPV-positive premalignancy in mammals, including allogeneic or autologous cells.
Incorporation of human variable regions with murine or human constant regions in TCRs
The TCRs can comprise either (i) a human variable region and a murine constant region or (ii) a fully human constant region, potentially enhancing TCR specificity or function.
Specificity for HPV 16 E711-19 epitope
The TCRs have antigenic specificity for the HPV 16 E711-19 peptide sequence (SEQ ID NO: 2), enabling targeted immune response.
TCRs with defined amino acid sequences in variable and constant regions
The TCRs comprise specific amino acid sequences, including SEQ ID NOs: 9 and 10 (variable regions), with defined residues at position 2, and substituted constant regions as per SEQ ID NOs: 16 and 18 with variable amino acid substitutions to improve function.
TCRs incorporating specific amino acid sequence variants in constant regions
The TCRs include amino acid sequences from specified SEQ ID NOs: 14, 15, 17, 19, 21, 23, 24, and 25 in variable combinations, including full-length alpha and beta chains with human or murine constant regions and modified residues.
Use of polypeptides comprising specific amino acid sequences
Methods include administering recombinant expression vectors encoding polypeptides with defined sequences (e.g., SEQ ID NOs: 3-8, 9-10, 12-13, 20-22, 26-27), allowing for flexibility in the polypeptide form used for treatment.
Recombinant expression vectors with beta chain positioned 5' of alpha chain
Vectors encoding alpha and beta chains with the beta chain positioned 5' of the alpha chain, including vectors SEQ ID NOs: 37, 38, 39, or 40, provide improved TCR expression and function.
Use of human host cells, pharmaceutical compositions, and specific cancer indications
The methods administer human host cells expressing the inventive TCRs, optionally as pharmaceutical compositions with carriers, to treat cancers of specific anatomical regions (uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, penis) and HPV 16-positive cancers.
The claims cover methods of treating or preventing HPV 16-related diseases using host cells expressing TCRs with defined amino acid sequences and structural modifications, recombinant vectors optimized for expression, and compositions suitable for administration to humans. The inventive features include antigen specificity, chimeric receptor constructs, sequence modifications enhancing stability and function, and preferred vector designs.
Stated Advantages
The inventive TCRs enable the destruction of multiple types of HPV 16-associated cancer cells due to targeting a conserved HPV 16 E7 antigen expressed in diverse tumors.
Because HPV 16 E7 is expressed only in cancer cells, the TCRs minimize or eliminate destruction of normal cells, thereby reducing toxicity.
The TCRs allow treatment or prevention of HPV-positive cancers that are resistant to other treatments such as chemotherapy, surgery, or radiation.
Highly avid recognition of HPV 16 E7 by the TCRs provides the ability to recognize unmanipulated tumor cells without prior treatment or manipulation.
Structural modifications to the TCRs, such as cysteine substitutions and hydrophobic amino acid substitutions, enhance target recognition, expression, and anti-tumor activity.
Documented Applications
Treatment or prevention of cancer, HPV 16 infection, or HPV-positive premalignancy in mammals by administering host cells expressing the inventive TCRs or related compositions.
Detection of cancer, HPV 16 infection, or HPV-positive premalignancy by contacting a sample with the inventive TCRs or antibodies and detecting complexes formed.
Adoptive cell transfer therapies using peripheral blood lymphocytes or T cells transduced with recombinant vectors encoding the inventive TCRs to target HPV 16-positive tumors.
Treatment of cancers of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, and penis, as well as other HPV 16-positive cancers.
Interested in licensing this patent?