Stimulation of cell-mediated immune responses by targeted particulate genetic immunization

Abstract

The present invention relates to various methods of genetic immunization for the purpose of providing antigen-specific immunity in a mammalian host, including a human host. The invention is based on the ability to direct particulate polynucleotides which express an antigenic protein or protein fragment to the cytoplasm of host target cells, such as antigen presenting cells. A directed delivery of such particulate polynucleotides to the cytoplasm of antigen presenting cells will stimulate antigen-specific CTL production, thus promoting destruction of affected cells such as neoplastic cells and virally infected cells.

Description

1. INTRODUCTION[0001] Genetic immunization for the purpose of stimulating antigen-specific immunity in a mammalian host, including a human host, is at the core of the present disclosure. This specification discloses delivery of particulate polynucleotides to the cytoplasm of host target cells, such as antigen presenting cells. These particulate polynucleotides encode an antigenic protein or antigenic protein fragment which accesses the cytoplasm of the target cell. Expression of the antigen gene results in antigen-specific immune responses, including but not limited to, the induction of antigen-specific cytotoxic T-lymphocytes (CTLs). Cytosolic access of the antigen allows membrane presentation of the antigenic peptide through the endogenous MHC class I pathway. Membrane presentation via the endogenous MHC class I pathway stimulates the induction of antigen-specific CTLs. Induced antigen-specific CTLs then target and destroy antigen-expressing affected host cells such as neoplastic ...

AI Technical Summary

Benefits of technology

[0028] In another especially preferred embodiment of the present invention, subcutaneous injection for direct targeting to an APC involves delivery of a particulate polynucleotide encoding a tumor rejection antigen (TRA) or biologically active fragment thereof. Directed delivery of a TRA particulate polynucleotide in this manner will maximize entry of tumor specific antigenic peptides into the class I pathway as well as avoiding substantial particulate translocation within non-APC cells.

[0029] In another especially preferred embodiment of the present invention, subcutaneous injection for direct targeting to an APC involves delivery of a particulate polynucleotide encoding a viral antigen or biologically active fragment thereof. Directed delivery of a viral antigen encoding particulate polynucleotide in this manner will maximize entry of viral specific antigenic peptides into the class I pathway as well as avoiding substantial particulate translocation within non-APC cells.

Problems solved by technology

Attempts to induce antigen-specific CTL responses in vivo by immunization with killed tumor cells, killed virus-infected cells, or component proteins have generally been unsuccessful, presumably because proteins in the extracellular fluids cannot enter the cytosol and access the MHC class I presentation pathway.

Tang, et al. does not disclose genetic immunization targeting the cell-mediated immune pathway.

The studies do not disclose targeting of genetic material to APCs for genetic immunization.

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