Composition for treating or sensitizing interferon beta resistant cancer disease comprising cFLIP siRNA
Inventors
Shin, Young Kee • Kim, Tae Eun • HONG, SUNG YOUL • Choi, Jun Young • Kim, Na Young
Assignees
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Publication Number
US-11464832-B2
Publication Date
2022-10-11
Expiration Date
Abstract
The present invention relates to a composition for treating or sensitizing interferon beta resistant cancer disease comprising cFLIP siRNA, and, more specifically, to a pharmaceutical composition for treating interferon beta resistant cancer disease, comprising, as an active ingredient: (a) an siRNA complementarily binding to mRNA of a cFLIP gene; and (b) a human interferon beta variant which comprises glycine-asparagine-isoleucine-treonine-valine sequence (GNITV) at C-terminus in a human natural interferon beta amino acid sequence shown in SEQ ID NO: 1, or has replaced the 27th arginine amino acid with threonine or serine, and to a composition for sensitizing interferon beta resistant cancer cells comprising cFLIP siRNA as an active ingredient. The composition of the present invention can be effectively used to develop an anticancer agent or anticancer adjuvant having a new mechanism to promote apoptosis and effectively sensitize cells for treatment, by lowering an expression level of cFLIP proteins in a cancer showing resistance to interferon beta or a cancer becoming resistant to interferon beta.
Core Innovation
The invention relates to pharmaceutical compositions and methods that treat or sensitize interferon-beta-resistant cancer. The compositions include an siRNA that binds to mRNA of the cFLIP gene in a complementary manner, together with a human interferon-beta mutant comprising a GNITV sequence at the C-terminus and/or a threonine or serine substitution for arginine at the 27th amino acid in a wild-type human interferon-beta amino acid sequence defined by SEQ ID NO: 1.
The interferon-beta mutant further comprises a fusion protein of any one amino acid sequence selected from SEQ ID NO: 18 to SEQ ID NO: 21. The claimed compositions and methods associate the cFLIP-targeting siRNA with the specified IFNβ mutant variant to provide activity in IFNβ-resistant cancer contexts.
The claimed methods include treating interferon-beta-resistant cancer diseases where the cancer is ovarian or gastric cancer. A sensitizing method is directed to sensitizing interferon-beta-resistant cancer cells that are ovarian or gastric cancer cells, with the siRNA limited to any one nucleotide sequence selected from SEQ ID NO: 9 to SEQ ID NO: 13 and the IFNβ mutant limited to any one amino acid sequence selected from SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21.
Claims Coverage
The independent claims cover three main aspects of the invention: a composition combining cFLIP-targeting siRNA and a specified human interferon-beta mutant fusion protein, a treatment method for interferon-beta-resistant ovarian or gastric cancer disease using the composition, and a sensitization method for interferon-beta-resistant ovarian or gastric cancer cells using the composition administered simultaneously or sequentially. Across the claims, the inventive features center on the complementary cFLIP gene mRNA-binding siRNA and the GNITV/27th-position IFNβ mutant, including specified fusion protein sequences, with the siRNA and mutant restricted to enumerated SEQ ID ranges.
cFLIP-mRNA-binding siRNA with complementary binding and specified IFNβ mutant fusion protein
A composition comprising siRNA that binds to mRNA of the cFLIP gene in a complementary manner, and a human interferon-beta mutant comprising a GNITV sequence at the C-terminus or in which threonine or serine is substituted for arginine at the 27th amino acid in a wild-type human interferon-beta amino acid sequence defined by SEQ ID NO: 1, wherein the interferon-beta mutant is a fusion protein comprising any one amino acid sequence selected from SEQ ID NO: 18 to SEQ ID NO: 21.
Treatment of IFNβ-resistant ovarian or gastric cancer using the cFLIP-siRNA/IFNβ mutant composition
A method for treating an interferon-beta-resistant cancer disease, wherein the cancer is ovarian or gastric cancer, comprising administering an effective amount of a composition to a subject in need thereof, where the composition comprises siRNA that binds to mRNA of cFLIP gene in a complementary manner and a human interferon-beta mutant comprising a GNITV sequence at the C-terminus or in which threonine or serine is substituted for arginine at the 27th amino acid, in a wild-type human interferon-beta amino acid sequence defined by SEQ ID NO: 1, wherein the interferon-beta mutant comprises any one amino acid sequence selected from the group consisting of SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21, and wherein the siRNA comprises any one nucleotide sequence selected from the group consisting of SEQ ID NO: 9 to SEQ ID NO: 13.
Sensitization of IFNβ-resistant ovarian or gastric cancer cells by simultaneous or sequential administration
A method for sensitizing interferon-beta-resistant cancer cells, wherein the cells are ovarian or gastric cancer cells, comprising administering to a subject in need thereof an effective amount of a composition comprising siRNA that binds to mRNA of cFLIP gene in a complementary manner, wherein the siRNA comprises any one nucleotide sequence selected from the group consisting of SEQ ID NO: 9 to SEQ ID NO: 13, wherein the composition is administered simultaneously or sequentially with an interferon-beta mutant which comprises any one amino acid sequence selected from the group consisting of SEQ ID NO: 2 to SEQ ID NO: 6 and SEQ ID NO: 18 to SEQ ID NO: 21.
Overall, the claims define a cFLIP-targeting siRNA paired with a specified human interferon-beta mutant, used as a composition, as a treatment method for interferon-beta-resistant ovarian or gastric cancer disease, or as a sensitization method for interferon-beta-resistant ovarian or gastric cancer cells with simultaneous or sequential administration.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating an interferon-beta-resistant cancer disease where the cancer is ovarian or gastric cancer.
Sensitizing interferon-beta-resistant cancer cells where the cells are ovarian or gastric cancer cells.
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