Flagellin-based adjuvants and vaccines

Inventors

Sotomayor, Eduardo M.Suarez, Ildefonso

Assignees

University of South Florida

Publication Number

US-7404963-B2

Publication Date

2008-07-29

Expiration Date

2025-10-03

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Abstract

The present invention provides adjuvants, vaccines and related methods that are useful in eliciting immune responses, particularly immune responses against tumor antigens. We discovered that flagellin is capable of inhibiting tolerance when it is administered in conjunction with a tolerogenic antigen. This effect is likely mediated by the ability of flagellin to induce IL-12 while keeping IL-10 levels low. Furthermore, flagellin can be provided in an extended-releasing manner by using a flagellin-expressing cell. Preferably, the flagellin-expressing cell is treated such that it is no longer capable of replicating, yet retaining the ability to express flagellin, such as by lethal irradiation.

Core Innovation

The invention provides adjuvants, vaccines, and methods that enhance immune responses, particularly against tumor antigens. Flagellin, a bacterial protein, has been discovered to inhibit tolerance when administered with a tolerogenic antigen. This effect is attributed to flagellin's ability to induce IL-12 while maintaining low IL-10 levels, tipping the balance toward immune activation rather than tolerance.

Flagellin can be delivered through a flagellin-expressing eukaryotic cell, advantageously providing an extended release. The flagellin-expressing cell is preferably lethally irradiated to prevent replication but retains the ability to express flagellin for a period of time. The composition may include the flagellin-expressing cell alone or combined with a tumor-associated antigen, which may also be a lethally irradiated tumor cell.

The background problem being addressed arises from the inability of tumor-associated antigens to provoke an adequate immune response, as antigen-presenting cells do not sufficiently mature and thus fail to activate T cells, leading to tolerance. This invention resolves this by using flagellin to activate APCs and inhibit tolerance, thus promoting effective immune responses against tumor antigens.

Claims Coverage

There are three main inventive features covered by the independent claims of the patent.

Compositions comprising lethally irradiated flagellin-expressing eukaryotic cells

The inventive feature covers compositions that include a flagellin-expressing eukaryotic cell, wherein the cell has been lethally irradiated. The composition may optionally include a tumor-associated antigen.

Method of preparing an adjuvant by lethally irradiating a flagellin-expressing eukaryotic cell

This inventive feature pertains to methods for preparing an adjuvant by subjecting a flagellin-expressing eukaryotic cell to lethal irradiation, so that the cell is incapable of replicating but maintains its ability to express flagellin.

Method for inducing IL-12 in a subject using a lethally irradiated flagellin-expressing cell

This inventive feature covers methods for inducing IL-12 production in a subject by administration of a lethally irradiated flagellin-expressing eukaryotic cell.

The patent claims focus on the composition of lethally irradiated flagellin-expressing eukaryotic cells, their use as adjuvants and in vaccine formulations, and methods for inducing IL-12 through their administration.

Stated Advantages

Flagellin inhibits immune tolerance when administered with a tolerogenic antigen, likely by inducing IL-12 while keeping IL-10 levels low.

The use of a flagellin-expressing cell allows for extended release of flagellin, providing prolonged stimulation of the immune system.

Lethally irradiating the flagellin-expressing cell prevents it from replicating while retaining flagellin expression, enhancing safety while maintaining function.

Using flagellin-expressing cells that lack MHC class I and/or II reduces the chance of unwanted immune responses against the cell itself.

Documented Applications

Eliciting immune responses against tumor antigens using adjuvants or vaccines containing flagellin-expressing cells.

Preparation of an adjuvant for enhancing an immune response to an antigen, especially tumor-associated antigens.

Preparation of a vaccine against tumors by combining lethally irradiated flagellin-expressing cells with a tumor-associated antigen.

Treatment of a tumor in a subject by administering both an antigen associated with the tumor and a flagellin-expressing cell adjuvant.

Inducing the production of IL-12 in a subject by administering a flagellin-expressing cell.

Inhibiting tolerance to a tumor in a subject by administering a tumor-associated antigen and a flagellin-expressing cell.

Screening for candidate compounds that inhibit immune tolerance by measuring IL-12 and IL-10 induction in antigen-presenting cells.

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