Vaccine targeting cellular death receptor DR5
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.
1. A vaccine for inducing agonist antibodies in a mammalian subject against the cellular death receptor DR5 expressed by target cells of the mammalian subject, said vaccine comprising an effective amount of a naked DNA expression vector including an isolated nucleic acid sequence encoding an antigenic fusion polypeptide consisting of the extracellular (ec) domain of DR5 fused to the transmembrane (tm) domain of DR5, and a nontoxic fragment of tetanus toxin fused to said tm domain,
wherein said ec and tm domains are selected from the group consisting of the ec and tm domains of murine DR5 and the ec and tm domains of human DR5, and said nontoxic fragment of tetanus toxin consists of toxin fragment C domain 1 (td1),
wherein said expression vector induces the expression of said antigenic fusion polypeptide in the mammalian subject,
wherein said agonist antibodies induced in response to said vaccine agonize DR5 expressed by the target cells of the mammalian subject, to trigger apoptosis in the target cells, and
said vaccine further including an effective amount of granulocyte macrophage colony stimulating factor (GM-CSF) as an adjuvant.
2. The vaccine of claim 1 , wherein the mammalian subject is human.
3. The vaccine of claim 1 , wherein the target cells are tumor cells.
4. The vaccine of claim 3 , wherein the tumor cells are solid tumor cells.
5. The vaccine of claim 4 wherein the solid tumor cells are mammary tumor cells.
6. The vaccine of claim 4 wherein the solid tumor cells are selected from the group consisting of colorectal, ovarian, breast, non-small cell lung, prostate, pancreatic, head and neck, and skin cancers.
7. The vaccine of claim 3 wherein the tumor cells are hematopoietic tumor cells.
8. The vaccine of claim 1 , wherein said GM-CSF is delivered to the mammalian subject as an expression vector comprising a polynucleotide encoding GM-CSF, said expression vector being suitable for expression of said polynucleotide in the mammalian subject.
9. The vaccine of claim 1 , wherein said GM-CSF is delivered to the mammalian subject as GM-CSF protein.
10. The vaccine according to claim 1 , wherein said ec domain of murine DR5 consists of a polypeptide consisting of SEQ ID NO: 2, said tm domain consists of a polypeptide consisting of SEQ ID NO: 4, said ec domain of human DR5 consists of a polypeptide consisting of SEQ ID NO: 6, and said tm domain of human DR5 consists of a polypeptide consisting of SEQ ID NO: 8.