Filipil compositions and methods for treating cancer
Inventors
Libutti, Steven K. • Kwon, Mjung • Tandle, Anita
Assignees
US Department of Health and Human Services
Publication Number
US-8501912-B2
Publication Date
2013-08-06
Expiration Date
2028-12-08
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Abstract
A purified DOC1 polypeptide comprising a fragment of SEQ ID NO: 1 is provided, wherein the DOC1 polypeptide is not the full-length DOC1 polypeptide sequence. A method of inhibiting angiogenesis in a subject is provided comprising administering to a subject a nucleic acid encoding a DOC1 polypeptide, whereby a cell in the subject produces the DOC1 polypeptide, thus inhibiting angiogenesis. A method of inhibiting tumor growth in a subject is provided comprising administering to a subject a nucleic acid encoding a DOC1 polypeptide, whereby a cell in the subject produces the DOC1 polypeptide, thus inhibiting tumor growth.
Core Innovation
The invention relates to purified polypeptides of FILIP1L (also known as DOC1, filamin A interacting protein 1-like) comprising fragments of the full-length DOC1 sequence (SEQ ID NO:1) but not the full sequence itself. These fragments retain functional activity, including anti-angiogenic, apoptotic, anti-proliferative, and anti-migration activities, which are characteristic of the native DOC1 protein. The invention also encompasses methods of inhibiting angiogenesis and tumor growth in subjects by administering nucleic acids encoding these DOC1 polypeptides, resulting in cellular production of the polypeptides to bring about therapeutic effects.
The background of the invention reveals that angiogenesis is essential for tumor growth, invasion, and metastasis, making inhibition of tumor angiogenesis a crucial target in cancer therapy. Although DOC1 gene expression is downregulated in various cancers and modulated by known angiogenesis inhibitors, the function of DOC1 remained unknown prior to this invention. The invention addresses this unmet need by elucidating the anti-angiogenic and anti-tumor activities of DOC1 fragments and providing compositions and methods that leverage these functional properties to treat cancer.
Specifically, the invention identifies and characterizes functional fragments of DOC1 polypeptides that inhibit endothelial and tumor cell proliferation and migration, and induce apoptosis. The invention also provides fusion proteins comprising these fragments linked to targeting molecules that direct the activity to specific cells or tissues, such as tumor vasculature, for improved efficacy. Compositions including nucleic acids encoding these polypeptides, vectors for delivery, and antibodies recognizing DOC1 or its fragments are also disclosed to support therapeutic application and diagnostic methods.
Claims Coverage
The patent includes multiple independent claims focusing on purified polypeptides comprising specific DOC1 fragments and their use in inhibiting angiogenesis and tumor growth.
Purified DOC1 polypeptides comprising specified functional fragments
Polypeptides consisting of DOC1 fragments from SEQ ID NO:1 selected from specific amino acid ranges such as 1-790, 1-650, 1-512, 127-512, and others, that retain biological activity are disclosed.
Polypeptides with high sequence identity that inhibit tumor growth
Polypeptides having at least about 95% sequence identity to the specified DOC1 fragments exhibiting tumor growth inhibition.
Fusion polypeptides with targeting moieties and DOC1 fragments
Purified polypeptides comprising DOC1 fragments flanked by groups such as H, acyl, targeting sequences or molecules to enhance selectivity and delivery.
Methods of inhibiting angiogenesis with DOC1 fragments
Administering therapeutically effective amounts of purified DOC1 polypeptides or fusion proteins to endothelial cells in a subject to inhibit angiogenesis.
Methods of inhibiting tumor growth with DOC1 fragments
Administering therapeutically effective amounts of purified DOC1 polypeptides or fusion proteins to tumor cells in a subject to inhibit tumor growth.
The claims collectively cover purified functional fragments of DOC1 polypeptides, methods for their use in inhibiting angiogenesis and tumor growth, and compositions that include fusion proteins with targeting molecules, demonstrating a comprehensive protection of the invention's therapeutic applications and molecular constructs.
Stated Advantages
Inhibition of cell proliferation and migration in endothelial and tumor cells.
Induction of apoptosis in endothelial and tumor cells.
Potent anti-tumor activity demonstrated in vivo.
Targeted delivery to tumor vasculature leading to selective tumor growth inhibition.
Compositions and methods enable modulation of DOC1 activity for therapeutic benefit in cancer treatment.
Documented Applications
Treatment of cancer by inhibiting tumor growth and angiogenesis using DOC1 polypeptides or nucleic acids encoding them.
Inhibition of endothelial and tumor cell proliferation, migration, and induction of apoptosis.
Use in diagnostic and prognostic methods for cancer by measuring DOC1 expression levels.
Delivery of DOC1 polypeptides or encoding nucleic acids locally or systemically for therapeutic purposes.
Combination therapies involving DOC1 polypeptides and other anti-cancer agents.
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