Soluble HER2 and HER3 splice variant proteins, splice-switching oligonucleotides, and their use in the treatment of disease
First Claim
1. An isolated, soluble, human epidermal growth factor receptor-2 (HER2) protein lacking the region encoded by exon 15 of the full-length mRNA transcript of the HER2 gene, and truncated, at its C terminus, in the region encoded by exon 16 of the HER2 transcript.
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Abstract
Soluble epidermal growth factor receptors 2 and 3 (HER2 and HER3) splice variant proteins with HER2 and HER3 antagonist activity and anti-proliferative properties, as well as the corresponding nucleic acids, are provided for treatment of proliferative diseases, in particular cancer. Also provided are compositions and methods for inducing expression of these splice variants, including splice switching oligonucleotides that modulate splicing of pre-mRNA that codes for these receptors.
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Citations
20 Claims
- 1. An isolated, soluble, human epidermal growth factor receptor-2 (HER2) protein lacking the region encoded by exon 15 of the full-length mRNA transcript of the HER2 gene, and truncated, at its C terminus, in the region encoded by exon 16 of the HER2 transcript.
- 4. An isolated nucleic acid encoding human epidermal growth factor receptor-2 (HER2) protein, but lacking exon 15 of the normal (HER2) transcript, with exon 14 joined directly to exon 16, and containing a stop codon within exon 16.
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6. A method of treating a female subject having an ovarian or breast cancer characterized by overexpression of human epidermal growth factor receptor-2 (HER2), comprising
administering to the subject, a pharmaceutically effective amount of a soluble, human epidermal growth factor receptor-2 (HER2) protein lacking the region encoded by exon 15 of the full-length mRNA transcript of the HER2 gene, and truncated, at its C terminus, in the region encoded by exon 16 of the HER2 transcript, and continuing said administering, at periodic intervals, until a defined end point in the status of the cancer is obtained.
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9. A splice-switching oligonucleotide compound comprising
an oligonucleotide containing between 12-30 bases and at least 12 contiguous bases complementary to an exon-15 acceptor or donor splice site region contained within SEQ ID. NO: - 15 of the full-length mRNA transcript of human epidermal growth factor receptor-2 (HER2) protein.
- View Dependent Claims (10, 11, 12, 13, 14)
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15. A method of treating a female subject having an ovarian or breast cancer characterized by overexpression of human epidermal growth factor receptor-2 (HER2), comprising
administering to the subject, a pharmaceutically effective amount of a compound comprising an oligonucleotide containing between 12-30 bases and at least 12 contiguous bases complementary to an exon-14 acceptor or donor splice site region contained within SEQ ID. NO: - 15 of the full-length mRNA transcript of human epidermal growth factor receptor-2 (HER2) protein, and
continuing said administering, at periodic intervals, until a defined end point in the status of the cancer is obtained. - View Dependent Claims (16, 17, 18, 19, 20)
- 15 of the full-length mRNA transcript of human epidermal growth factor receptor-2 (HER2) protein, and
Specification