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Use of flagellin in immunotherapy of Yersinia pestis

A technology of Yersinia and flagellin, applied in the field of application of flagellin in the immunotherapy of Yersinia pestis, capable of solving problems such as reduced efficacy

Inactive Publication Date: 2016-01-13
WAKE FOREST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although changes in vaccine development from whole pathogens to individual antigens have resulted in safer vaccines, efficacy has decreased significantly

Method used

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  • Use of flagellin in immunotherapy of Yersinia pestis
  • Use of flagellin in immunotherapy of Yersinia pestis
  • Use of flagellin in immunotherapy of Yersinia pestis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1 Cancer antigen and its vaccine

[0122] Effects of flagellin on innate immunity in the mouse lung. A non-surgical intratracheal (i.t.) instillation of 1 μg flagellin was sufficient to induce maximal production of TNFα after approximately 4 hours ( figure 1 ). Cytokine levels in bronchopulmonary lavage fluid returned to baseline levels after 12-24 hours. NOTE: Mutated flagellin that does not bind TLR5 and thus lacks signaling activity does not induce cytokine production. In addition to TNF[alpha], several other cytokines (including IL-6, G-CSF) and chemokines MIP-2 and KC were induced to relatively high levels. An increase in cytokine expression was followed by a transient infiltration of neutrophils (maximum at 12-14 hours). It is important to emphasize that the innate immune response elicited by flagellin does not lead to severe tissue-damaging inflammation. The induced inflammatory response is relatively modest and acute in nature. These findings, toge...

Embodiment 2

[0126] Example 2 Flagellin as an adjuvant to generate antigen-specific breast cancer responses

[0127] In vivo treatment of breast tumors. BALB / c mice were immunized with Fra-1 (an antigen overexpressed in many mammary tumors), flagellin, or an inactive form of flagellin. Mice were boosted once before subcutaneous injection of D2F2 cells, a type of breast cancer tumor. Mice were monitored for tumor growth and tumor volumes were determined. data in figure 2 displayed in . Open circles represent mice administered Fra-1 antigen and an inactive form of flagellin. Solid circles represent mice administered Fra-1 antigen and active form of flagellin. It is evident from the figure that the flagellin+Fra-1 antigen has a significant effect on tumor growth.

[0128] To assess whether flagellin can promote a protective immune response against D2F2 breast cancer cells in a mouse model. The ability of flagellin to promote the protective status of immunity against D2F2 breast cancer...

Embodiment 3

[0139] Example 3 Flagellin is a potent mucosal adjuvant for immunization against lethal respiratory challenge of Yersinia pestis

[0140] method:

[0141] Plasmids and cell cultures. The coding sequence caf1 of the F1 antigen of Yersinia pestis (plasmid containing the entire caf operon, kindly provided by Dr. J.B. Bliska (State University of New York, Stony Brook)) was subcloned into ) in the NdeI and XhoI sites of the pET29a expression vector. 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 that the 21 amino acids corresponding to the signal sequence of F1 were absent.

[0142]Reagents and Antibodies. Purified, Recombinant, His-tagged flagellin. 229 mutated flagellin as well as F1 and F1 / V antigens were purified in the same manner. As by QCL from Cambrex Corporation (East Rutherford, NJ)- As detected by Chromogenic LALTe...

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Abstract

The invention provides a fusion protein comprising a flagellin adjuvant and a Yersinia pestis antigen. Also provided are compositions comprising a flagellin adjuvant and a Yersinia pestis antigen. The invention also discloses methods of making a fusion protein comprising a flagellin adjuvant and a Yersinia pestis antigen. The invention further provides pharmaceutical formulations and methods for inducing an immune response against Yersinia pestis.

Description

[0001] Related application information [0002] This application claims priority to U.S. Provisional Application Serial No. 60 / 636,635, filed December 16, 2004, and U.S. Provisional Application Serial No. 60 / 709,609, filed August 19, 2005, the disclosures of which are incorporated by reference in their entirety This article. [0003] Federal Government Support Statement [0004] This invention was made with Government support under Grant No. P01-AI060642 from the National Institutes of Health. The US Government has certain rights in this invention. field of invention [0005] The present invention relates to flagellin adjuvants, antigens from Yersinia pestis (Yersinia pestis) and fusion proteins thereof for generating an immune response against Yersinia pestis (for example, in response to Yersinia pestis infection use in preventive therapy). Background of the invention [0006] Although the shift in vaccine development from whole pathogens to individual antigens has resu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/00A61K39/02A61K39/102A61K39/385A61K39/116A61K38/00C12P21/04C12N15/09C12N15/00C07H21/04C07K1/00C07K2/00
CPCY02A50/30
Inventor S·B·米策尔A·N·洪科
Owner WAKE FOREST UNIV
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