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US 9,173,964 B2Granted
Diphtheria toxin first open reading frame operably linked to an H19 promoter and a diphtheria toxin second open reading frame operably linked to an IGF-II promoter as nucleic acid construct
AssigneeYissum Research Development Company of the Hebrew University of Jerusalem
InventorsAvraham Hochberg, Doron Amit
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Abstract
The present invention relates to the field of cancer treatment, particularly to a novel constructs useful for treating tumors expressing H19 and/or IGF-II. More specifically, the invention provides compositions and methods utilizing a nucleic acid construct enabling expression of a cytotoxic gene product directed by more than one tumor specific promoter.
Claims15
An isolated nucleic acid construct, comprising:
- a) a first open reading frame encoding a diphtheria toxin, the first open reading frame being operably linked to an H19 promoter;
- and
- b) a second open reading frame encoding a diphtheria toxin, the second open reading frame being operably linked to an IGF-II-promoter selected from IGF-II P3 and IGF-II P4 promoter sequences;
- and
- wherein the diphtheria toxin is diphtheria toxin A (DTA) or comprises a sequence that is at least 90% homologous to the sequence set forth in SEQ ID NO:
- 7;
- and
- wherein the nucleic acid sequence of the H19 promoter exhibits H19 promoter activity and is at least 90% homologous to SEQ ID NOS:
- 1 or 2, and the nucleic acid sequence of the IGF-II P4 promoter exhibits IGF-II P4 promoter activity and is at least 90% homologous to SEQ ID NO:
- 9, the nucleic acid sequence of the IGF-II P3 promoter exhibits IGF-II P3 promoter activity and is at least 90% homologous to the sequence selected from SEQ ID NO:
- 8, SEQ ID NO:
- 12, and SEQ ID NO:
- 17.
10 more elements
An isolated nucleic acid construct, comprising:
- a) a first open reading frame encoding a diphtheria toxin, said first open reading frame being operably linked to an IGF-II P3 promoter;
- and
- b) a second open reading frame encoding the diphtheria toxin, said second open reading frame being operably linked to an IGF-II P4 promoter;
- wherein the IGF-II P3-promoter comprises the nucleic acid sequence as set forth in the sequence selected from SEQ ID NO:
- 8, SEQ ID NO:
- 12, and SEQ ID NO:
- 17, or wherein the IGF-II P4-promoter comprises the nucleic acid sequence as set forth in SEQ ID NO:
- 9.
5 more elements
An isolated nucleic acid construct, comprising:
- a first open reading frame encoding a cytotoxic or cytostatic gene product, the first open reading frame being operably linked to a first promoter;
- and
- a second open reading frame encoding the cytotoxic or cytostatic gene product, the second open reading frame being operably linked to a second promoter;
- wherein the first promoter and the second promoter are selected from the group consisting of:
- i) the first promoter being an H19 promoter comprising the nucleic acid sequence as set forth in any one of SEQ ID NOS:
- 1 or 2, and the second promoter being an IGF-II P4 promoter comprising the nucleic acid sequence as set forth in SEQ ID NO:
- 9;
- ii) the first promoter being an H19 promoter comprising the nucleic acid sequence as set forth in any one of SEQ ID NOS:
- 1 or 2, and the second promoter being an IGF-II P3 promoter comprising the nucleic acid sequence as set forth in a sequence selected from SEQ ID NO:
- 8, SEQ ID NO:
- 12, and SEQ ID NO:
- 17;
- and
- iii) the first promoter being an IGF-II P4 promoter comprising the nucleic acid sequence as set forth in SEQ ID NO:
- 9, and the second promoter being an IGF-II P3 promoter comprising the nucleic acid sequence as set forth in the sequence selected from SEQ ID NO:
- 8, SEQ ID NO:
- 12, and SEQ ID NO:
- 17.
15 more elements
An isolated nucleic acid construct comprising:
- a) a first open reading frame encoding a diphtheria toxin, the first open reading frame being operably linked to an H19 promoter;
- and
- b) a second open reading frame encoding a diphtheria toxin, the second open reading frame being operably linked to an IGF-II promoter selected from IGF-II P3 and IGF-II P4 promoter sequences, and
- wherein the nucleic acid sequence of the diphtheria toxin is at least 90% homologous to SEQ ID NO:
- 7, and
- wherein the H19 promoter comprises the nucleic acid sequence as set forth in any one of SEQ ID NOS:
- 1 or 2, and wherein the IGF-II P4 promoter comprises the nucleic acid sequence as set forth in SEQ ID NO:
- 9, or wherein the IGF-II P3 promoter comprises the nucleic acid sequence as set forth in the sequence selected from SEQ ID NO:
- 8, SEQ ID NO:
- 12, and SEQ ID NO:
- 17.
8 more elements
Dependencies are inferred from the claim text.