Thymidylate kinase fusions and uses thereof
AssigneeUniversity Health Network
InventorsJeffrey A. Medin, Sean Devine
Life of this patent
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Abstract
The application relates to a composition comprising: a stably integrating delivery vector; a modified mammalian thymidylate kinase (tmpk) wherein the modified mammalian tmpk increases phosphorylation of a prodrug relative to phosophorylation of the prodrug by wild-type human tmpk; and a detection cassette fused to tmpk. The application also relates to use of these compositions in methods of treatment of diseases such as graft versus host disease and cancer.
Claims17
A composition comprising:
- a stably integrating delivery vector;
- a modified human thymidylate kinase (tmpk) polynucleotide that encodes a modified human tmpk polypeptide that increases phosphorylation of AZT relative to phosphorylation of AZT by wild type human tmpk polypeptide;
- a detection cassette polynucleotide that encodes a detection cassette polypeptide that is cell surface expressed, wherein the detection cassette polynucleotide is fused to the modified human tmpk polynucleotide and the detection cassette polypeptide is fused to the modified human tmpk polypeptide;
- and
- a therapeutic polynucleotide cassette,
- wherein the modified human tmpk polypeptide comprises a modification selected from (a) a F to Y mutation at amino acid position 105 of SEQ ID NO:
- 11, (b) a R to G point mutation at amino acid position 16 of SEQ ID NO:
- 12, or (c) a R to A mutation at amino acid position 200 of SEQ ID NO:
- 16.
An isolated polynucleotide encoding an isolated polypeptide comprising:
- a modified human thymidylate kinase (tmpk) polypeptide that increases phosphorylation of AZT relative to phosphorylation of AZT by wild type human tmpk polypeptide;
- and
- a detection cassette polypeptide fused to the modified human tmpk polypeptide,
- wherein the detection cassette polypeptide is a cell surface expressed detection cassette polypeptide,
- the modified human tmpk polypeptide comprises a modification encoding selected from (a) a F to Y mutation at amino acid position 105 of SEQ ID NO:
- 11, (b) a R to G point mutation at amino acid position 16 of SEQ ID NO:
- 12, or (c) a R to A mutation at amino acid position 200 of SEQ ID NO:
- 16 and the detection cassette polypeptide fused to the modified human tmpk polypeptide is a tmpk/detection cassette fusion polypeptide.
An isolated cell that expresses a modified tmpk/detection cassette fusion polynucleotide comprising:
- a stably integrating delivery vector;
- a modified human thymidylate kinase (tmpk) polynucleotide that encodes a modified human tmpk polypeptide that increases phosphorylation of AZT relative to phosphorylation of AZT by wild type human tmpk polypeptide;
- a detection cassette polynucleotide that encodes a detection cassette polypeptide that is cell surface expressed, wherein the detection cassette polynucleotide is fused to the modified human tmpk polynucleotide and the detection cassette polypeptide is fused to the modified human tmpk polypeptide;
- and
- a therapeutic polynucleotide cassette,
- wherein the modified human tmpk polypeptide comprises a modification selected from (a) a F to Y mutation at amino acid position 105 of SEQ ID NO:
- 11, (b) a R to G point mutation at amino acid position 16 of SEQ ID NO:
- 12, or (c) a R to A mutation at amino acid position 200 of SEQ ID NO:
- 16.
Dependencies are inferred from the claim text.