Immunogenic POTE peptides and methods of use
Inventors
Berzofsky, Jay A. • Huang, Yi-Hsiang • Terabe, Masaki • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-9394352-B2
Publication Date
2016-07-19
Expiration Date
2031-03-08
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Abstract
POTE has recently been identified as a tumor antigen expressed in a variety of human cancers, including colon, ovarian, breast, prostate, lung and pancreatic cancer. Described herein are immunogenic POTE polypeptides, including modified POTE polypeptides, that bind MHC class I molecules. The immunogenic POTE polypeptides are capable of inducing an immune response against POTE-expressing tumor cells. Thus, provided herein is a method of eliciting an immune response in a subject, such as a subject having a type of cancer that expresses POTE.
Core Innovation
POTE has been identified as a tumor antigen expressed in a variety of human cancers such as colon, ovarian, breast, prostate, lung, and pancreatic cancer. The invention discloses immunogenic POTE polypeptides, including modified versions, that bind MHC class I molecules and are capable of inducing an immune response against tumor cells expressing POTE. Methods for eliciting this immune response in subjects, particularly those with cancers expressing POTE, are provided.
The invention addresses the problem that current cancer treatments like radiotherapy or chemotherapy often affect normal cells and have limiting side effects, and that treatments for advanced, recurrent, or metastatic cancer are mostly palliative. Since CD8+ cytotoxic T lymphocytes (CTLs) can specifically kill tumor cells presenting tumor-associated antigens via MHC class I molecules, the development of cancer immunotherapy targeting such epitopes is promising. However, natural CTL epitopes may not be optimal due to tolerance. Therefore, the invention utilizes epitope enhancement by modifying amino acid sequences to improve peptide binding affinity to MHC molecules and induce stronger immune responses.
The background section elaborates that POTE is a cancer-testis antigen expressed in limited normal tissues but in various cancers, making it a suitable immunotherapy target. The disclosed immunogenic POTE polypeptides comprise short sequences (no more than 10 consecutive amino acids) derived from POTE, with modifications to enhance MHC binding and immunogenicity. Fusion proteins, nucleic acid vectors encoding these peptides, and administration methods are provided to induce anti-tumor immunity. The invention thus offers potential systemic immunotherapeutic approaches with specificity and reduced toxicity for treating cancers expressing POTE.
Claims Coverage
The patent contains multiple inventive features focused on isolated nucleic acid molecules encoding immunogenic POTE polypeptides, their modifications, fusion proteins, compositions, vectors, and methods of eliciting immune responses.
Isolated nucleic acid molecules encoding immunogenic POTE polypeptides
Isolated nucleic acid molecules encode polypeptides comprising no more than 10 consecutive amino acids of the human POTE sequence set forth as SEQ ID NO: 20, including specific embodiments of 9-mer peptides corresponding to amino acids 222-230, 252-260, 272-280, 323-331, and 553-561 with defined allowable substitutions (X positions). These polypeptides can be the unmodified sequences or modified variants with amino acid substitutions to alter binding affinity to MHC class I molecules.
Nucleic acids encoding fusion proteins comprising immunogenic POTE polypeptides and heterologous polypeptides
Isolated nucleic acid molecules encode fusion proteins that comprise an immunogenic POTE polypeptide (no more than 10 amino acids) joined to a heterologous polypeptide sequence, including tags or proteins that enhance immunogenicity.
Compositions comprising isolated nucleic acid molecules or vectors with carriers
Pharmaceutical compositions comprising the isolated nucleic acid molecules or vectors encoding immunogenic POTE polypeptides together with pharmaceutically acceptable carriers are disclosed for therapeutic administration.
Vectors comprising nucleic acids encoding immunogenic POTE polypeptides
Vectors (e.g., plasmids, viral vectors) containing nucleic acid molecules encoding immunogenic POTE polypeptides are provided, suitable for expression in host cells and use in immunization.
Methods of eliciting immune responses by administration of nucleic acids encoding immunogenic POTE polypeptides
Methods entail selecting a subject in need of treatment, administering a therapeutically effective amount of nucleic acid molecules encoding immunogenic POTE polypeptides to elicit an immune response. This includes subjects with cancers such as colon, ovarian, breast, prostate, lung or pancreatic cancer expressing POTE.
The claims cover isolated nucleic acid molecules encoding specified immunogenic POTE peptides including modified sequences, nucleic acids encoding fusion proteins, pharmaceutical compositions, vectors, and methods for eliciting immune responses in subjects, especially those with POTE-expressing cancers, thereby providing molecular and therapeutic tools for cancer immunotherapy targeting POTE antigens.
Stated Advantages
The immunogenic POTE polypeptides can induce a measurable cytotoxic T lymphocyte (CTL) response leading to specific killing of tumor cells expressing POTE.
Modified POTE epitopes with enhanced binding affinity to MHC class I molecules can overcome immune tolerance and induce a stronger immune response.
The approach provides a specific and systemic immunotherapy for advanced, recurrent, or metastatic cancers expressing POTE, which may have fewer toxic side effects compared to chemotherapy or radiotherapy.
Using peptide modifications enhances vaccine efficacy, such as improved peptide stability and immunogenicity, allowing effective targeting of a broad population expressing HLA-A2.
Documented Applications
Therapeutic cancer vaccine development targeting a variety of human cancers expressing POTE, including colon, ovarian, breast, prostate, lung, and pancreatic cancers.
Immunotherapy methods to elicit CTL responses in subjects diagnosed with POTE-expressing cancers.
Use of nucleic acid vectors and immunogenic polypeptides in pharmaceutical compositions for cancer treatment.
Adoptive immunotherapy using antigen presenting cells pulsed with immunogenic POTE polypeptides or sensitized lymphocytes to induce anti-tumor responses.
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