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-8871902-B2
Publication Date
2014-10-28
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 recently been identified as a tumor antigen expressed in a variety of human cancers, including colon, ovarian, breast, prostate, lung and pancreatic cancer. The invention provides immunogenic POTE polypeptides, including modified POTE polypeptides, that bind MHC class I molecules and are capable of inducing an immune response against POTE-expressing tumor cells. Methods of eliciting an immune response in a subject, such as a subject having a type of cancer that expresses POTE, by administering these polypeptides or nucleic acid molecules encoding them are disclosed.
The background describes that breast and prostate cancers are frequently diagnosed malignancies frequently not curatively resectable except if early detected. Existing treatments like radiotherapy or chemotherapy cause side effects due to effects on normal cells and only provide palliative care for recurrent or metastatic cancers. There is a need for novel systemic therapies for advanced cancers. Cancer immunotherapy, particularly induction of cytotoxic T lymphocytes (CTLs) against tumor-associated antigens via MHC class I presentation, offers specificity and reduced toxicity.
The invention solves the problem of identifying and enhancing tumor-specific CD8+ T cell epitopes from POTE that are capable of binding MHC class I molecules like HLA-A2 to induce CTL responses that target tumor cells. Because natural CTL epitopes may be suboptimal due to immune tolerance or low affinity, the disclosed immunogenic POTE polypeptides include modified peptides with amino acid substitutions to increase binding affinity and immunogenicity. These enhanced epitopes enable more effective anti-tumor immune responses.
Claims Coverage
The claims include multiple independent claims focusing on isolated immunogenic POTE polypeptides comprising no more than 10 consecutive amino acids of human POTE with specified amino acid substitutions, fusion proteins including such polypeptides, compositions thereof, and methods of eliciting immune responses by administering these polypeptides.
Isolated immunogenic POTE polypeptides with specified amino acid substitutions
Isolated polypeptides comprising no more than 10 consecutive amino acids of human POTE (SEQ ID NO: 20) with defined variable amino acid positions (X1 to X11), wherein the polypeptide comprises specific amino acid ranges, e.g., amino acids 252-260, 323-331, or 553-561, and includes substitutions to alter MHC class I binding affinity.
Isolated immunogenic POTE polypeptides of 9 or 10 amino acids in length with specified substitutions
Isolated polypeptides of 9 or 10 residues derived from defined regions of human POTE (SEQ ID NO: 20) with substitutions altering binding affinity to MHC class I molecules, such as specific sequences SEQ ID NOs: 7-11, 12-15, and 16-19 representing modified POTE peptides.
Fusion proteins comprising immunogenic POTE polypeptides and heterologous sequences
Fusion proteins including an isolated immunogenic POTE polypeptide as described and a heterologous polypeptide sequence, which may include tags or proteins that enhance immune response.
Compositions including immunogenic POTE polypeptides and pharmaceutically acceptable carriers
Pharmaceutical compositions comprising the isolated immunogenic POTE polypeptides and suitable carriers for administration.
Methods of eliciting immune responses by administering immunogenic POTE polypeptides
Methods involving selecting a subject in need of treatment and administering a therapeutically effective amount of at least one immunogenic POTE polypeptide or composition thereof to elicit an immune response, particularly for treating cancers expressing POTE such as colon, ovarian, breast, prostate, lung, or pancreatic cancer.
The independent claims cover isolated immunogenic POTE polypeptides with defined amino acid substitutions to enhance MHC class I binding, fusion proteins comprising such polypeptides, pharmaceutical compositions thereof, and therapeutic methods of eliciting immune responses in subjects, particularly for cancer treatment. The inventive features focus on sequence modifications, delivery formats, and therapeutic applications to improve immunogenicity and therapeutic efficacy.
Stated Advantages
The immunogenic POTE polypeptides can induce specific CTL responses against POTE-expressing cancer cells with enhanced binding affinity to MHC class I molecules (e.g., HLA-A2).
Modified peptides with amino acid substitutions show improved immunogenicity and cross-reactivity with wild-type peptides, potentially overcoming immune tolerance to self-antigens.
Combination of multiple enhanced POTE epitopes can provide a broader vaccine strategy to avoid immune-escape variants and target a large population of HLA-A2+ individuals.
Documented Applications
Immunotherapy of cancers expressing POTE, including colon, ovarian, breast, prostate, lung, and pancreatic cancer.
Use as cancer vaccines to elicit anti-tumor CTL responses by administering immunogenic POTE polypeptides or nucleic acid molecules encoding them to subjects diagnosed with POTE-expressing tumors.
Use of fusion proteins and compositions for stimulating specific immune responses in subjects with POTE-positive tumors.
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