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-11697676-B2
Publication Date
2023-07-11
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) with antigenic specificity for the HLA-A2-restricted epitope of human papillomavirus (HPV) 16 E6, specifically the E629-38 peptide sequence TIHDIILECV (SEQ ID NO: 2). The TCR comprises a human variable region paired with a murine constant region, with isolated or purified examples provided, including specific amino acid sequences (SEQ ID NOs: 3-8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, and antibodies or antigen binding portions thereof are also disclosed. Methods use these components to detect and treat or prevent conditions such as cancer, HPV 16 infection, and HPV-positive premalignancy.
The problem being solved is that HPV infection, particularly HPV 16, is a primary cause of several cancers including uterine cervical cancer and others. Current treatment modalities like chemotherapy may yield poor prognosis in many HPV-associated cancers. There exists an unmet need for additional, effective treatments that can specifically target HPV 16-associated malignancies.
The invention addresses this need by providing TCRs that target HPV 16 E6 antigens presented in the context of HLA-A2 molecules, enabling specific immune recognition and destruction of HPV 16-positive cancer cells. The inventive TCRs selectively recognize HPV 16 E6, which is expressed exclusively on cancerous, HPV-infected, or HPV-positive premalignant cells, but not on normal tissues, thereby facilitating targeted therapy with minimized toxicity.
Claims Coverage
The patent includes several independent claims focusing on methods of treating or preventing conditions using populations of cells expressing TCRs specific for HPV 16 E6 with defined complementarity determining regions (CDRs).
Use of cell populations expressing TCRs with HPV 16 E6-specific CDRs for treatment or prevention
A method involving administering a population of host cells expressing TCRs that have the defined alpha chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 3, 4, and 5 respectively, and beta chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 6, 7, and 8 respectively, to treat or prevent cancer, HPV 16 infection, or HPV-positive premalignancy in a mammal.
Application to HPV 16-positive cancers
The method applies to treating or preventing HPV 16-positive cancers among various cancer types specified, such as uterine cervical cancer, oropharynx cancer, anal cancer, and others listed.
Use of allogeneic or autologous populations of cells
The population of cells administered can be either allogeneic or autologous to the mammal receiving treatment.
Inclusion of TCRs with murine constant regions
The TCRs may comprise murine constant regions combined with human variable regions, forming chimeric receptors.
Use of specific TCR amino acid sequence combinations
TCRs comprising any of the specified amino acid sequence pairs from SEQ ID NOs: 9 and 10; 13 and 14; 11 and 12; 15 and 16; or 17 and 18 are claimed for use in treatment methods.
Population characteristics of cells
Methods include administering populations of cells that are substantially homogeneous populations expressing the specified TCRs.
Use of human T cell populations
The population of cells administered in the methods can be human T cells.
Formulations for administration
Administration can be via pharmaceutical compositions comprising the population of cells and pharmaceutically acceptable carriers.
The independent claims cover methods of treating or preventing cancer, HPV 16 infection, or HPV-positive premalignancy in mammals using populations of host cells, particularly T cells, that express TCRs with defined HPV 16 E6-specific CDR sequences. These TCRs may be chimeric with murine constant regions and human variable regions, and the treatments can be performed with autologous or allogeneic cells, formulated in pharmaceutical compositions.
Stated Advantages
Ability to destroy cells of multiple types of HPV 16-associated cancer due to expression of HPV 16 E6 in various cancers.
Selective targeting of cancerous and HPV-infected cells while sparing normal cells, reducing toxicity.
Potential to treat or prevent HPV-positive cancers unresponsive to conventional treatments like chemotherapy, surgery, or radiation.
Highly avid recognition of HPV 16 E6 enabling recognition of unmanipulated tumor cells without prior treatment or manipulation.
Documented Applications
Methods for detecting the presence of cancer, HPV 16 infection, or HPV-positive premalignancy in mammals using the inventive TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, antibodies, or pharmaceutical compositions.
Methods for treating or preventing cancer, HPV 16 infection, or HPV-positive premalignancy in mammals by administering populations of cells expressing the inventive TCRs or related pharmaceutical compositions.
Specific treatment of a broad range of cancers, particularly HPV 16-positive cancers including cancer of the uterine cervix, oropharynx, anus, anal canal, anorectum, vagina, vulva, and penis.
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