Methods and compositions for the treatment and prevention of cancer
Inventors
Arya, Bira • Longo, Dan • Espinoza, Igor
Assignees
US Department of Health and Human Services
Publication Number
US-8258278-B2
Publication Date
2012-09-04
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 methods and compositions for the treatment and prevention of cancer by rendering weakly or non-immunogenic tumor-associated embryonic antigens immunogenic. This is achieved by linking such antigens, for example the oncofetal antigen immature laminin receptor protein (OFA-iLRP), to chemoattractant ligands such as proinflammatory chemokines MIP3α/CCL20 or β-defensin mDF2β. The fused molecules target immature dendritic cells (iDCs) through chemokine receptors, facilitating uptake, processing, and presentation of antigens to the immune system, inducing therapeutic antitumor immunity against a variety of tumors.
The problem addressed is that tumor-associated antigens (TAAs), including OFA-iLRP, are typically poorly immunogenic, limiting the efficacy of cancer immunotherapy. Moreover, existing vaccines such as idiotypic (Id) vaccines for B cell malignancies require individual tailoring, have unpredictable T cell epitopes, and can be suppressed by tumor derived factors. The invention overcomes these limitations by providing broadly applicable cancer vaccines that do not require individual customization and utilize chemoattractant-mediated targeting to enhance immunogenicity.
Claims Coverage
The patent discloses four independent claims covering nucleic acid molecules encoding fusion proteins of chemoattractant ligands and tumor-associated embryonic antigen OFA-iLRP, vectors, immunogenic compositions, and kits.
Nucleic acid encoding β-defensin DF2β and OFA-iLRP
A nucleic acid molecule comprising the sequence set forth in SEQ ID NO: 1 that encodes a fusion of β-defensin DF2β and OFA-iLRP.
Nucleic acid encoding MIP3α/CCL20 and OFA-iLRP
A nucleic acid molecule comprising the sequence set forth in SEQ ID NO: 3 that encodes a fusion of MIP3α/CCL20 and OFA-iLRP.
Nucleic acid molecule encoding EP2C and OFA-iLRP
A nucleic acid molecule comprising the sequence set forth in SEQ ID NO: 5 encoding a fusion of EP2C and OFA-iLRP.
Nucleic acid molecule encoding C-terminal fragment of mycobacterial HSP 70 and OFA-iLRP
A nucleic acid molecule comprising the sequence set forth in SEQ ID NO: 7 encoding a fusion of the C-terminal fragment of mycobacterial HSP 70 and OFA-iLRP.
The claims collectively cover nucleic acid molecules encoding fusion proteins of various chemoattractant ligands to the tumor-associated antigen OFA-iLRP, vectors containing these nucleic acids, immunogenic compositions comprising these molecules, and kits including the compositions with usage instructions.
Stated Advantages
The invention elicits potent tumor-specific CD8+ cytolytic T cell responses through CCR6-mediated targeting of immature dendritic cells, leading to effective immunotherapy and prevention of diverse cancers.
The vaccine avoids the need for individual patient-specific formulations, providing a broadly applicable cancer immunotherapy approach.
The fusion constructs induce durable protective immune responses and long-lasting antitumor memory against tumor challenges in vivo.
Documented Applications
Treatment and prevention of cancers including hematological malignancies, breast, renal, lung, and ovarian cancers using nucleic acid molecules or polypeptides encoding fusion proteins of tumor-associated embryonic antigens and chemoattractant ligands.
Use as cancer vaccines comprising nucleic acid molecules or polypeptides of the invention formulated with adjuvants for therapeutic or prophylactic immunization.
Gene therapy applications involving delivery of vectors encoding fusion molecules for induction of antitumor immunity.
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