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-9822162-B2
Publication Date
2017-11-21
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 human papillomavirus (HPV) 16 E6, particularly an HLA-A2-restricted epitope E629-38. These TCRs comprise human variable regions and murine constant regions or can be fully human. They are capable of binding HPV 16 E6 in a major histocompatibility complex (MHC) class I-dependent manner, enabling specific immune recognition of HPV 16-infected or HPV-positive cancer cells.
This technology includes not only the TCRs themselves but also related polypeptides, proteins, nucleic acids encoding these TCRs, recombinant expression vectors, host cells expressing the TCRs, antibodies that bind to the TCR or portions thereof, and pharmaceutical compositions containing these materials. Methods for detecting HPV 16 infection, HPV-positive premalignancy, or cancer via the binding of these TCRs to target cells, as well as methods for treating or preventing these conditions by administering the inventive materials, are also encompassed.
The problem addressed is the unmet need for additional treatments for cancers caused by HPV infection, such as uterine cervical cancer, which has a poor prognosis despite existing therapies like chemotherapy. Because HPV 16 E6 is uniquely expressed in HPV-positive cancers and not in normal human tissues, targeting this antigen with specific TCRs can enhance immune-mediated destruction of cancer cells while minimizing toxicity to normal cells. The invention thereby aims to provide more effective and safer immunotherapy options for HPV 16-associated cancers.
Claims Coverage
The patent claims cover multiple inventive features related to TCRs specific for HPV 16 E6, isolated polypeptides and proteins including functional portions, nucleic acids encoding these TCRs, recombinant expression vectors, host cells, methods of detection, and methods of treatment using these materials.
TCRs with human variable and murine constant regions specific for HPV 16 E6
T cell receptors having antigenic specificity for HPV 16 E6 comprising human variable regions with specific complementarity determining regions (CDRs) (SEQ ID NOs: 3-8) and murine constant regions (SEQ ID NOs: 15 and 16), including alpha and beta chain configurations.
Isolated or purified TCRs and polypeptides with defined antigen specificity
Isolated or purified TCRs and polypeptides including functional portions containing the CDR sequences (SEQ ID NOs: 3-8), variable regions (SEQ ID NOs: 9 and 10), and combinations thereof with human or murine constant regions (SEQ ID NOs: 11-14, 17-18).
Proteins comprising TCR polypeptides and fusion/recombinant antibodies
Proteins that include the polypeptides described, which may be assembled as alpha and beta chains of TCRs, fusion proteins, or recombinant antibodies incorporating inventive polypeptides.
Nucleic acids and recombinant expression vectors encoding the inventive TCRs
Nucleic acid molecules encoding the TCRs including sequences defined by SEQ ID NOs: 19-28, 31-36, including codon-optimized sequences, and recombinant expression vectors (e.g., MSGV1 vectors containing SEQ ID NOs: 29 or 30).
Host cells and populations expressing the inventive TCRs
Isolated host cells, preferably human T cells, transduced with recombinant expression vectors encoding the inventive TCRs, as well as cell populations comprising such host cells.
Methods for detection and treatment of HPV-related conditions
Methods for detecting cancer, HPV 16 infection, or HPV-positive premalignancy by contacting a sample with the inventive TCR materials and detecting complexes, and methods for treating or preventing these conditions by administering host cells expressing the inventive TCRs or related compositions.
The claims collectively cover compositions of matter consisting of TCRs specific for HPV 16 E6 with defined variable and constant regions, nucleic acids and expression vectors encoding them, host cells expressing these TCRs, antibodies binding to TCR portions, and methods for detecting and treating HPV 16-associated cancers and premalignancies using these inventive materials.
Stated Advantages
The inventive TCRs target HPV 16 E6, which is expressed only in HPV 16-infected or HPV-positive cancer cells, thereby minimizing toxicity to normal tissues.
They enable destruction of multiple types of HPV 16-associated cancers by recognizing a common viral oncoprotein expressed in various malignancies.
They can potentially treat HPV-positive cancers that are refractory to conventional treatments such as chemotherapy, surgery, or radiation.
The TCRs provide highly avid recognition of HPV 16 E6, allowing recognition of unmanipulated tumor cells without requiring external modifications like interferon-gamma treatment or peptide pulsing.
Documented Applications
Therapeutic treatment or prevention of cancer, HPV 16 infection, or HPV-positive premalignancy in mammals, including humans, by administration of TCRs, host cells expressing the TCRs, or related pharmaceutical compositions.
Detection methods for the presence of cancer, HPV 16 infection, or HPV-positive premalignancy by contacting biological samples with the inventive TCRs or related materials and detecting complexes formed.
Adoptive cell transfer therapy using autologous T cells transduced with recombinant vectors encoding the inventive TCRs for treating recurrent/refractory or metastatic HPV 16-positive cancers.
Use in cancers of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, penis, and other HPV 16-positive malignancies.
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