Tumor-specific delivery of therapeutic agents via liposomase
Clostridium novyi is an obligate anaerobe that can infect hypoxic regions within experimental tumors. We found that mice bearing large, established tumors were often cured when treated with C. novyi plus a single dose of liposomal doxorubicin. The secreted factor responsible for this phenomenon was identified and, surprisingly, proved to be a member of the lipase family. The gene encoding this protein, called liposomase, has the potential to be incorporated into diverse therapeutic methods to deliver specifically a variety of chemotherapeutic agents to tumors.
1. A composition comprising:
a first agent which is a vector encoding toxin-defective Clostridium novyi liposomase according to SEQ ID NO: 1 or according to SEQ ID NO: 1 with a substitution mutation in the GXSXG lipase motif at residues 160-164; and
a second agent which is a liposome comprising an anti-tumor drug or biological agent, whereby the tumor regresses or its growth is slowed or arrested.
2. The composition of claim 1 wherein the anti-tumor drug or biological agent is doxorubicin.
3. The composition of claim 1 wherein the anti-tumor drug or biological agent is irinotecan.
4. The composition of claim 1 wherein the anti-tumor drug or biological agent is an antibody.
5. The composition of claim 1 wherein the anti-tumor drug or biological agent is a polynucleotide.
6. The composition of claim 1 wherein the anti-tumor drug or biological agent is a polynucleotide in a viral vector.
7. The composition of claim 1 wherein the anti-tumor drug or biological agent is a polynucleotide in a non-viral vector.
8. The composition of claim 1 wherein the vector is a viral vector.
9. The composition of claim 1 wherein the vector is a non-viral vector.
10. The composition of claim 1 wherein the anti-tumor drug or biological agent is a topoisomerase inhibitor.
11. The composition of claim 1 wherein the anti-tumor drug or biological agent is a DNA synthesis inhibitor.
12. A kit comprising:
a first agent which is a vector encoding toxin-defective Clostridium novyi liposomase according to SEQ ID NO: 1 or according to SEQ ID NO: 1 with a substitution mutation in the GXSXG lipase motif at residues 160-164; and
a second agent which is a liposome comprising an anti-tumor drug or biological agent, whereby the tumor regresses or its growth is slowed or arrested.
13. The kit of claim 12 wherein the anti-tumor drug or biological agent is doxorubicin.
14. The kit of claim 12 wherein the anti-tumor drug or biological agent is irinotecan.
15. The kit of claim 12 wherein the anti-tumor drug or biological agent is an antibody.
16. The kit of claim 12 wherein the anti-tumor drug or biological agent is a polynucleotide.
17. The kit of claim 12 wherein the anti-tumor drug or biological agent is a polynucleotide in a viral vector.
18. The kit of claim 12 wherein the anti-tumor drug or biological agent is a polynucleotide in a non-viral vector.
19. The kit of claim 12 wherein the vector is a viral vector.
20. The kit of claim 12 wherein the vector is a non-viral vector.
21. The kit of claim 12 wherein the anti-tumor drug or biological agent is a topoisomerase inhibitor.
22. The kit of claim 12 wherein the anti-tumor drug or biological agent is a DNA synthesis inhibitor.