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-10329339-B2
Publication Date
2019-06-25
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 T cell receptors (TCRs) having antigenic specificity for an HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E6, specifically the E629-38 peptide. The TCRs comprise human variable regions and murine constant regions, and can include related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, and populations of cells. The invention also covers antibodies or antigen binding portions thereof relating to these TCRs and pharmaceutical compositions comprising them.
The invention addresses the problem that HPV 16 infection causes some cancer types, such as uterine cervical cancer, and existing treatments like chemotherapy often result in poor prognosis. There is an unmet need for additional therapies for cancers associated with HPV, especially those expressing HPV 16 E6, an oncoprotein that deregulates cell cycle control and is constitutively expressed in HPV 16-positive cancers but not in normal tissues.
The invention provides highly specific TCRs that recognize HPV 16 E6 peptides presented by MHC class I molecules, particularly HLA-A2, which enables immune responses that specifically target cancer cells, HPV 16-infected cells, or HPV-positive premalignancy cells, minimizing damage to normal tissue. The TCRs' high avidity allows recognition of unmanipulated tumor cells without prior treatments, potentially enabling effective treatment or prevention of multiple forms of HPV 16-associated cancers that are refractory to conventional treatments.
Claims Coverage
The patent claims disclose multiple inventive features related to nucleic acids encoding specific TCR polypeptides, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and methods for detecting and treating conditions associated with HPV 16 E6.
Nucleic acid encoding specific TCR complementarity determining regions (CDRs)
An isolated or purified nucleic acid comprising nucleotide sequences encoding the alpha chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 3, 4, and 5, and the beta chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 6, 7, and 8, including codon-optimized variants.
Recombinant expression vectors comprising TCR-encoding nucleic acids
Recombinant expression vectors comprising the nucleic acid encoding TCR polypeptides with the stated alpha and beta chain CDR sequences, or with the amino acid sequences of SEQ ID NOs: 9 and 10 (variable regions), SEQ ID NOs: 11 and 12 (human alpha and beta chains), or SEQ ID NOs: 17 and 18 (chimeric human variable and murine constant region chains).
Host cells and populations expressing the inventive TCRs
Isolated host cells, including human cells, comprising the recombinant expression vectors encoding the TCRs, and populations of such cells, including clonal populations.
Pharmaceutical compositions
Pharmaceutical compositions comprising a population of cells expressing the inventive TCRs and a pharmaceutically acceptable carrier.
Methods for detecting HPV 16-related conditions
Methods of detecting the presence of cancer, HPV 16 infection, or HPV-positive premalignancy in a mammal by contacting a sample with the host cells expressing the inventive TCRs, forming a complex, and detecting the complex, wherein detection indicates presence of the condition.
Methods for treating or preventing HPV 16-related conditions
Methods of treating or preventing cancer, HPV 16 infection, or HPV-positive premalignancy in a mammal by administering an effective amount of the population of host cells expressing the inventive TCRs.
The claims collectively cover nucleic acids encoding specific TCR CDR sequences targeting HPV 16 E6, vectors and host cells engineered to express such TCRs, pharmaceutical compositions comprising the cells, and methods for detecting and treating HPV 16-associated cancers and conditions.
Stated Advantages
The inventive TCRs specifically target HPV 16 E6-expressing cancer cells and HPV-positive premalignant cells, minimizing damage to normal, non-HPV-infected tissues, thereby reducing toxicity.
They provide the ability to treat or prevent multiple types of HPV 16-associated cancers due to the wide expression of HPV 16 E6 across various cancer types.
The TCRs exhibit high avidity allowing recognition of unmanipulated tumor cells, potentially enabling effective therapy even for cancers resistant to conventional treatments like chemotherapy, surgery, or radiation.
Documented Applications
Detection of cancer, HPV 16 infection, or HPV-positive premalignancy by contacting a sample from a mammal with TCR-expressing host cells or related compositions and detecting specific binding.
Treatment or prevention of cancer, HPV 16 infection, or HPV-positive premalignancy in a mammal by administering host cells expressing the inventive HPV 16 E6-specific TCRs.
Specific application to HPV 16-positive cancers including cancers of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, and penis.
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