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Use of Flagellin in Tumor Immunotherapy

a tumor immunotherapy and flagellin technology, applied in the field of flagellin adjuvants, can solve the problems of limiting the effectiveness of a potentially efficacious vaccination strategy, not being the case with mutated forms of these antigens, and limited positive clinical results to a relatively small subset of patients, so as to induce an immune response

Inactive Publication Date: 2008-09-11
WAKE FOREST UNIV HEALTH SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention is a fusion protein that combines a flagellin adjuvant and a tumor antigen. This fusion protein can be used as a vaccine to induce an immune response to the tumor antigen and treat tumors in mammals, including humans. The invention also includes a nucleic acid encoding the fusion protein and a vector for its expression. The technical effects of the invention include improved immunogenicity and efficacy of tumor vaccines."

Problems solved by technology

Although a number of these studies have revealed instances of enhanced immune reactivity, for example, T cell proliferation or cytotoxic T cell activity, positive clinical results have been limited to a relatively small subset of patients.
However, this may not be the case with mutated forms of these antigens.
Finally, the over-production of transforming growth factor β (TGF-β) by tumor cells may limit the effectiveness of a potentially efficacious vaccination strategy.
Although individual cytokines possess some adjuvant activity, their effectiveness may be limited by the scope of their individual biologic activities.

Method used

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  • Use of Flagellin in Tumor Immunotherapy
  • Use of Flagellin in Tumor Immunotherapy
  • Use of Flagellin in Tumor Immunotherapy

Examples

Experimental program
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Effect test

example 1

Cancer Antigens and Vaccines Thereof

[0130]Effect of flagellin on innate immunity in the mouse lung. Non-surgical intratracheal (i.t.) instillation of 1 μg of flagellin is sufficient to induce maximal production of TNFα after approximately 4 hr (FIG. 1). By 12-24 hr, cytokine levels in broncheoalveolar lavage fluid return to baseline levels. Note that a mutant flagellin that does not bind to TLR5 and thus lacks signaling activity, did not induce cytokine production. In addition to TNFα, several other cytokines including IL-6, G-CSF, and the chemokines, MIP-2 and KC were induced to relatively high levels. The increase in cytokine expression is followed by the transient infiltration of neutrophils (maximal at 12-24 hr). It is important to emphasize that the innate immune response initiated by flagellin does not result in severe tissue damaging inflammation. The induced inflammatory response is relatively moderate and acute in nature. These findings, in conjunction with those of other i...

example 2

Flagellin as an Adjuvant to Produce an Antigen-Specific Breast Cancer Response

[0132]Treatment of breast tumor in vivo. BALB / c mice were immunized with the Fra-1 antigen, an antigen that is over-expressed by many breast tumors, and either flagellin or an inactive form of flagellin. The mice were boosted once prior to subcutaneous injection of D2F2 cells, a breast cancer tumor. The mice were monitored for the growth of tumors and the tumor volumes were determined. Data are shown in FIG. 2. The open circles represent the mice given the Fra-1 antigen and the inactive form of flagellin. The closed circles represent the mice given Fra-1 antigen and the active form of flagellin. As can readily be seen, flagellin+Fra-1 antigen had a significant effect on the growth of the tumor.

[0133]Evaluation of whether flagellin can promote a protective immune response against D2F2 breast cancer cells in a mouse model. The ability of flagellin to promote a protective state of immunity against D2F2 breast...

example 3

Flagellin is an Effective Mucosal Adjuvant for Immunization Against Lethal Respiratory Challenge with Yersinia pestis

Methods:

[0144]Plasmids and cell culture. The coding sequence for the F1 antigen of Yersinia pestis, caf1, (plasmid containing the entire caf operon kindly provided by Dr. J. B. Bliska, State University of New York, Stony Brook) was subcloned into the NdeI and XhoI sites of the pET29a expression vector from Novagen (EMD Biosciences, Inc., Madison, Wis.). The recombinant F1 / V fusion construct (Heat et al. (1998) Vaccine 16:1131-1137) (provided by Drs. G. Andrews and P. Worsham, USAMRIID) was sequenced and subcloned into pET16b. Sequencing revealed the absence of 21 amino acids corresponding to the signal sequence of F1.

[0145]Reagents and antibodies. Purified, recombinant His-tagged flagellin from Salmonella enteritidis was prepared as described previously (Honko and Mizel (2004) Infect. Immun. 72:6676-6679; McDermott et al. (2000) Infect. Immun. 68:5525-5529). The 229 ...

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Abstract

The invention provides a fusion protein comprising a flagellin adjuvant and a tumor antigen. Also provided are compositions comprising a flagellin adjuvant and a tumor antigen. The invention further provides pharmaceutical formulations and methods for inducing an immune response against a tumor antigen and methods of treating a tumor in a subject.

Description

RELATED APPLICATION INFORMATION[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 636,635, filed 16 Dec. 2004, and U.S. Provisional Application Ser. No. 60 / 709,609, filed 19 Aug. 2005; the disclosures of which are incorporated herein by reference in their entireties.STATEMENT OF FEDERAL SUPPORT[0002]This invention was made with government support under grant numbers R01-A1051319 and T32-AI007401 from the National Institutes of Health. The United States government has certain rights to this invention.FIELD OF THE INVENTION[0003]The present invention concerns the use of a flagellin adjuvant, tumor antigens and fusion proteins thereof to produce an immune response against tumors (e.g., in prophylactic or therapeutic methods).BACKGROUND OF THE INVENTION[0004]Currently accepted treatments for breast cancer include surgery, chemotherapy, and radiation therapy. Immunotherapy represents a relatively new approach for which there has been a surge of interest...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/02C07K14/00C07H21/00C12N15/00A61P35/04C12N1/00C12P21/04
CPCA61K39/0011A61K2039/55594A61K2039/6068C07K2319/00A61K39/0291A61K2039/575Y10S530/825Y10S530/806A61K2039/543A61K2300/00A61K39/025A61P31/04A61P35/00A61P35/04A61P37/04Y02A50/30
Inventor MIZEL, STEVEN B.
Owner WAKE FOREST UNIV HEALTH SCI INC
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