Surface expression of enzyme in gene directed prodrug therapy
First Claim
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1. A product comprising two components for use in association with one another comprising:
- (a) a vector comprising a eukaryotic promoter operably linked to a gene, said gene comprising a nucleic acid sequence encoding a bacterial carboxypeptidase G which has been altered at one or more glycosylation sites to prevent glycosylation at said site or sites together with a signal sequence, wherein upon expression of said gene in a eukaryotic tumor cell said signal sequence directs and tethers said bacterial carboxypeptidase to the plasma membrane of said tumor cell; and
(b) a prodrug which can be converted into an active drug by said bacterial carboxypeptidase G.
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Abstract
The invention provides a two component system for use in association with one another comprising:
(a) a vector capable of expressing an enzyme at the surface of a cell; and
(b) a prodrug which can be converted into an active drug by said enzyme, useful in the treatment of tumours.
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Citations
23 Claims
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1. A product comprising two components for use in association with one another comprising:
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(a) a vector comprising a eukaryotic promoter operably linked to a gene, said gene comprising a nucleic acid sequence encoding a bacterial carboxypeptidase G which has been altered at one or more glycosylation sites to prevent glycosylation at said site or sites together with a signal sequence, wherein upon expression of said gene in a eukaryotic tumor cell said signal sequence directs and tethers said bacterial carboxypeptidase to the plasma membrane of said tumor cell; and (b) a prodrug which can be converted into an active drug by said bacterial carboxypeptidase G. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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- 9. A bacterial carboxypeptidase G which comprises a substitution, deletion or insertion at one or more glycosylation sites so as to prevent glycosylation at said site while retaining carboxypeptidase activity.
- 16. A method of treating a tumor in a patient in need of treatment which method comprises administering to said patient an effective amount of a vector comprising a eukaryotic promoter operably linked to a gene, said gene comprising a nucleic acid sequence encoding a bacterial carboxypeptidase G which has been altered at one or more glycosylation sites to prevent glycosylation at said site or sites, together with a signal sequence, wherein upon expression of said gene in a eukaryotic tumor cell said signal sequence directs and tethers said bacterial carboxypeptidase G to the plasma membrane of said tumor cell, and, a prodrug which can be converted into an active drug by said bacterial carboxypeptidase G to provide a tumoricidal effect on said tumor.
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19. A method of treating a breast tumor in a patient in need of treatment which method comprises administering to said patient an effective amount of a vector comprising a eukaryotic promoter operably linked to a gene, said gene comprising a nucleic acid sequence encoding a bacterial carboxypeptidase G which has been altered at one or more glycosylation sites to prevent glycosylation at said site or sites, together with a signal sequence, wherein upon expression of said gene in a eukaryotic tumor cell said signal sequence directs and tethers said bacterial carboxypeptidase G to the plasma membrane of said tumor cell, and, a nitrogen mustard prodrug which can be converted into an active drug by said bacterial carboxypeptidase G, said active drug having a tumoricidal effect on said breast tumor.
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20. In a method of treatment of a tumor cell by gene-directed enzyme-prodrug therapy by delivering to a patient in need of treatment a gene which is expressed in the tumor to provide a gene product, and a prodrug which is converted to an active drug by said gene product, the improvement comprising expressing a gene which encodes a gene product comprising a bacterial carboxypeptidase G which has been altered at one or more glycosylation sites to prevent glycosylation at said site or sites, which gene product is transported to and tethered to the plasma membrane of the tumor cell and said active drug provides a tumoricidal effect on said tumor cell.
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23. A vector comprising a eukaryotic promoter operably linked to a gene, said gene comprising a nucleic acid sequence encoding a bacterial carboxypeptidase G together with a signal sequence, wherein upon expression of said gene in a eukaryotic tumor cell said signal sequence directs and tethers said bacterial carboxypeptidase G to the plasma membrane of said tumor cell.
Specification