Vaccines targeting cellular death receptors

Abstract

The invention provides therapeutics and methods to induce a mammalian host, including a human, to produce antibodies, which agonize death receptors and cause the apoptotic death of target cells within the host's body. The therapeutics are vaccine compositions, including genetic vaccines encoding death receptor antigens of the tumor necrosis factor receptor family. Also provided are means and methods for overcoming host immunological tolerance to death receptors. The vaccines are useful against cancer cells and other death receptor bearing target cells within the host, and can be used in both therapeutic and prophylactic settings. The vaccines are also useful for diagnostic testing of the immunocompetence of a host.

Description

GRANT INFORMATION[0001]Research in this application was supported in part by a grant from the Department of Defense DOD W81XWH-07-1-0521, National Institutes of Health (NIH Grant No. NIH CA 76340). The Government has certain rights in the invention.TECHNICAL FIELD[0002]The invention relates to the field of vaccines which induce a host to produce antibodies against self antigens and particularly antigens that agonize death receptors of cells within the body of a host; the vaccines induce apoptosis in target cells and are useful in the treatment of cancer and other chronic diseases in which the apoptosis of target cells is desired.BACKGROUND OF THE INVENTION[0003]There is a pressing need for new regimens to treat existing cancers and prevent their recurrence. A recently developed strategy that shows great promise is the induction of tumor cell apoptosis (programmed cell death) through the triggering of death receptors expressed on tumor cell surfaces.[0004]Cell apoptosis (programmed c...

AI Technical Summary

Benefits of technology

The invention provides new methods for increasing the immunogenicity of a vaccine, which can help to break tolerance and improve its effectiveness. One method involves using a polynucleotide to express a fusion peptide made of a death receptor antigen and an adjuvant peptide. Another method involves fusing the polynucleotide sequence of a self death receptor antigen with axenogeneic death receptor antigen. These methods can be combined with cytokines to further enhance the vaccine's ability to break tolerance. Additionally, the patent describes a method of transiently depleting tolerance-promoting regulatory T cells by administering antibodies to surface markers of those cells. Overall, the invention provides new tools to improve the immunogenicity of vaccines and enhance their ability to break tolerance.

Problems solved by technology

Unfortunately, monoclonal antibody regimes, essentially “passive immunotherapy”, are impractical for the prolonged treatments required for chronic diseases like cancer.

First, clinical monoclonal antibodies are extremely expensive to manufacture.

Second, exogenous antibodies have the possibility of provoking host immune responses to themselves.

Once an immune response against a monoclonal antibody is established, it permanently renders the antibody useless for therapy.

The problems of great expense and anti-antibody response limit or destroy the usefulness of recombinant TRAIL and exogenous anti-TRAIL receptor antibodies in cancer treatment.

Therapeutic treatment cannot be maintained for the prolonged periods needed to eliminate existing tumor, and to render lifelong protection.

The only cost is that of a course of vaccination.

The main roadblock to the development of a therapeutic or prophylactic vaccine against host cell death receptors has been the phenomenon of tolerance, the immune system's safeguard against autoimmune disease.

It is often impossible to define an antigen and immunization protocol that will break tolerance to a self antigen to achieve effective vaccination.

This problem has defeated the development of many vaccines intended to induce immune response against tumor antigens (Wei et al, 2004).

Another roadblock to the development of an agonist anti-death receptor vaccine is the need for a fully competent immune system that can meet the challenge of mounting a response to a self antigen.

Finally, the long lived antibody titers induced by effective vaccinations may bring out side effects of death receptor agonism which are not apparent in short term treatments.

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