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.

The invention claimed is: 
     
         1 . A method for inducing apoptosis in target cells including the steps of:
 administering to a mammalian host an effective amount of a vaccine, which induces agonist antibodies to at least one death receptor;   inducing agonist antibodies to the at least one death receptor; and   inducing apoptosis in target cells expressing the at least one death receptor through the agonistic action of said agonist antibodies.   
     
     
         2 . The method of  claim 1  further including the step of administering the vaccine prophylactically to prevent the initiation of target cell populations in the body. 
     
     
         3 . The method of  claim 2  wherein said target cell populations include tumor cells. 
     
     
         4 . The method of  claim 3  wherein said tumor cells are metastases of a primary tumor. 
     
     
         5 . The method of  claim 1  further including the step of administering the vaccine therapeutically to reduce or eliminate existing target cell populations in the body. 
     
     
         6 . The method of  claim 5  wherein said target cell populations include tumor cells. 
     
     
         7 . The method of  claim 1 , further including the step of counteracting immunosuppression by administering agents that counteract immunosuppressive influences. 
     
     
         8 . The method of  claim 7  wherein said counteracting step is further defined as downregulating the suppressive effects of suppressive regulatory T cells. 
     
     
         9 . The method of  claim 8  wherein said counteracting step is further defined as administering antibodies to CD25. 
     
     
         10 . The method of  claim 1  further including the step of eliminating target cells through cell mediated cytotoxicity induced by the binding of said antagonist antibodies. 
     
     
         11 . The method of  claim 1  further including the step of breaking tolerance to a death receptor. 
     
     
         12 . The method of  claim 11  wherein said step of breaking tolerance includes administering at least one polynucleotide encoding at least one adjuvant peptide. 
     
     
         13 . The method of  claim 12  wherein the at least one polynucleotide encodes tetanus toxin fragment C domain 1 (td1). 
     
     
         14 . The method of  claim 12  wherein the at least one polynucleotide encodes tetanus toxin fragment p30. 
     
     
         15 . The method of  claim 11  wherein said step of breaking tolerance to a death receptor further includes the step of administering an immunostimulatory cytokine. 
     
     
         16 . The method of  claim 15  wherein said step of administering an immunostimulatory cytokine is further defined as administering GM-CSF. 
     
     
         17 . The method of  claim 16  wherein said administration of GM-CSF is further defined as administering soluble GM-CSF. 
     
     
         18 . The method of  claim 16  wherein said administration of GM-CSF is further defined as administering an expression vector comprising a polynucleotide encoding GM-CSF. 
     
     
         19 . The method of  claim 1  wherein said at least one death receptor is DR5 
     
     
         20 . The method of  claim 1  wherein said at least one death receptor is DR4. 
     
     
         21 . The method of  claim 1  wherein said mammalian subject is human. 
     
     
         22 . A diagnostic test to determine whether a mammalian subject is sufficiently immunocompetent to permit breaking of tolerance to a self-antigen including the steps of:
 administering an effective amount of a vaccine which induces antibodies to at least one death receptor in an immunocompetent subject;   determining whether antibodies to the at least one death receptor are produced; and   recognizing subject producing said antibodies as sufficiently immunocompetent to permit breaking of tolerance to a self antigen.   
     
     
         23 . The diagnostic test of  claim 22  wherein said vaccine is the vaccine of  claim 1 . 
     
     
         24 . The diagnostic test of  claim 22  wherein said vaccine induces antibodies of a type selected from the group of death receptor binding antibodies including antagonist antibodies, agonist antibodies, antibodies without signaling function, or a combination thereof. 
     
     
         25 . The diagnostic test of  claim 22  wherein said mammalian subject is human.