Methods and compositions for the treatment and prevention of cancer
Inventors
Arya, Bira • Longo, Dan • Espinoza-Delgardo, Igor
Assignees
US Department of Health and Human Services
Publication Number
US-10077296-B2
Publication Date
2018-09-18
Expiration Date
2027-09-03
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Abstract
The instant invention provides compositions for the treatment of cancer. Specifically, the invention provides polypeptides and nucleic acid molecules comprising tumor-associated embryonic antigens, e.g., OFA-iLRP, and chemoattractant ligands, e.g., a proinflammatory chemokine such as MIP3α/CCL20 or β-defensin mDF2β. The invention further provides cancer vaccines and methods for treating subjects having, or at risk of developing, cancer.
Core Innovation
The invention provides compositions for the treatment and prevention of cancer by rendering weakly or non-immunogenic self tumor-associated embryonic antigens, such as OFA-iLRP, immunogenic. This is achieved by linking these tumor antigens to chemoattractant ligands, specifically proinflammatory chemokines like MIP3α/CCL20 or β-defensin mDF2β, which target immature dendritic cells (iDCs) through chemokine receptors differentially expressed on antigen-presenting cells.
The problem being solved is that tumor-associated antigens (TAAs), including idiotypic antibodies in B cell malignancies, are often poorly immunogenic, have limited repertoire for immunotherapy, and may require individually tailored vaccines for each patient, limiting their broader applicability. OFA-iLRP is a highly conserved tumor antigen expressed in various human tumors but is non-antigenic alone, thus necessitating a strategy to make it effective in cancer treatment.
The inventive strategy discovered involves fusing tumor-associated embryonic antigens to chemoattractant ligands to facilitate their delivery and uptake by immature dendritic cells, enhancing antigen processing and presentation to the immune system. This method elicits therapeutic antitumor immunity and provides methods, nucleic acid molecules, polypeptides, vaccines, and kits useful for treating or preventing cancers expressing OFA-iLRP, including hematological and solid tumors such as breast, renal, lung, and ovarian cancers.
Claims Coverage
The independent claims focus on polypeptides comprising tumor-associated embryonic antigens fused with chemoattractant ligands, cancer vaccines comprising these polypeptides, and kits including such vaccines and instructions for use. There are three main inventive features related to the fusion polypeptides, their composition, and their application in vaccines and kits.
Polypeptides comprising tumor-associated embryonic antigen OFA-iLRP fused with β-defensin DF2β
A polypeptide comprising OFA-iLRP translationally fused with a CCR6-targeting chemoattractant ligand, specifically β-defensin DF2β, where the polypeptide comprises SEQ ID Nos: 2 or 20.
Polypeptides comprising tumor-associated embryonic antigen OFA-iLRP fused with MIP3α/CCL20
A polypeptide comprising OFA-iLRP fused with the chemoattractant ligand MIP3α/CCL20, including polypeptides comprising amino acid sequences of SEQ ID NOs: 4, 12, 18, 22, 24, or 30.
Cancer vaccines and kits comprising fusion polypeptides
A cancer vaccine comprising the fusion polypeptide of OFA-iLRP with β-defensin DF2β, and kits comprising such vaccines with instructions for use.
The claims cover compositions of fusion polypeptides combining tumor-associated embryonic antigen OFA-iLRP with specific chemoattractant ligands targeting CCR6, formulations of these polypeptides as cancer vaccines, and kits including these vaccines and usage instructions, demonstrating an inventive integration of antigen targeting with immune activation for cancer therapy.
Stated Advantages
Ability to render weakly or non-immunogenic tumor antigens immunogenic through fusion with chemoattractant ligands.
Broad applicability in treating various cancers without individual tailoring of vaccines, unlike idiotypic vaccines.
Induction of potent antitumor immunity including robust CD8+ cytolytic T cell and Th1 helper CD4+ T cell responses.
Targeting of immature dendritic cells via CCR6 improves antigen uptake, processing, and presentation to MHC class I molecules, leading to effective cross-presentation.
Induction of long-lasting protective immune memory against tumors expressing OFA-iLRP.
Documented Applications
Treatment and prevention of cancers, including hematological malignancies and solid tumors such as breast, renal, lung, and ovarian cancer.
Use as cancer vaccines comprising nucleic acid molecules or polypeptides encoding fusion proteins to immunize subjects at risk or suffering from cancer.
Therapeutic administration to subjects with established cancers to elicit tumor-specific immunity leading to tumor eradication or growth suppression.
In vitro and in vivo induction of antigen-specific CD8+ cytolytic T cell responses targeting tumor cells expressing OFA-iLRP.
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