FILIP1L nucleic acid fragments
Inventors
Libutti, Steven K. • Kwon, Mijung • Tandle, Anita
Assignees
US Department of Health and Human Services
Publication Number
US-9279009-B2
Publication Date
2016-03-08
Expiration Date
2028-12-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 DOC1 polypeptides comprising fragments of the full-length DOC1 (also known as FILIP1L) protein sequences as specified by SEQ ID NO:1 and related variants. These DOC1 polypeptides are not the full-length protein but include various functional fragments that retain at least one native DOC1 function, such as anti-angiogenic activity, anti-proliferative activity, apoptotic activity, and anti-migration activity. The invention also encompasses nucleic acids encoding these DOC1 polypeptides or fragments, methods of administering these nucleic acids or polypeptides to subjects, and vectors and host cells containing such nucleic acids.
The problem addressed by the invention is the need for effective agents that inhibit angiogenesis, tumor growth, and cancer progression. Angiogenesis facilitates tumor growth and metastasis, and therefore, the inhibition of tumor angiogenesis is a critical therapeutic target. Prior to this invention, DOC1 was known to be downregulated in certain cancers and modulated by angiogenesis inhibitors, but its function was unknown. This invention identifies functional DOC1 fragments and polypeptides that inhibit endothelial cell proliferation, induce apoptosis, inhibit cell migration, and suppress tumor growth, thus providing novel therapeutic agents targeting angiogenesis and cancer.
Claims Coverage
The patent includes several independent claims directed to nucleic acids encoding DOC1 polypeptide fragments, vectors and host cells containing such nucleic acids, and fusion proteins incorporating targeting sequences.
Nucleic acid encoding specific DOC1 polypeptide fragments
A nucleic acid encoding a polypeptide consisting of a fragment of SEQ ID NO:1 selected from specified amino acid ranges such as 1-790, 1-650, 1-512, 1-369, 65-893, 127-369, 127-442, 127-512, 127-580, 127-650, 127-720, 127-790, 127-893, 190-893, 310-893, and 369-893, or a polypeptide with at least 95% identity to these sequences.
Vectors and host cells comprising the nucleic acids
Vectors comprising the nucleic acids encoding the DOC1 fragments and host cells containing these vectors for expression of functional DOC1 polypeptides.
Fusion proteins with targeting amino acid sequences flanking DOC1 fragments
Nucleic acids encoding a polypeptide consisting of a fragment of SEQ ID NO:1 flanked at the N-terminus (R1) or C-terminus (R2) by H or a targeting amino acid sequence, where the fragment is selected from the specified amino acid groups, enabling targeted delivery.
Use of RGD-4C targeting fusion constructs
DOC1 polypeptide fragments flanked by the RGD-4C targeting sequence (CDCRGDCFC, SEQ ID NO:14) to target tumor vasculature and inhibit angiogenesis or tumor growth.
The claims define compositions including nucleic acids encoding specific functional DOC1 protein fragments, their use in vectors and host cells, and fusion constructs incorporating targeting sequences to inhibit angiogenesis and tumor growth via expression of DOC1 fragments.
Stated Advantages
The DOC1 polypeptides and fragments provide agents capable of inhibiting endothelial cell proliferation, increasing apoptosis, inhibiting cell migration, and reducing tumor growth.
Certain DOC1 fragments are more potent than the full-length protein in mediating anti-proliferative activity.
Targeted delivery of DOC1 fragments to tumor vasculature using fusion proteins or viral vectors effectively inhibits tumor growth in vivo.
Documented Applications
Treatment of cancer by inhibiting angiogenesis and tumor growth through administration of nucleic acids encoding DOC1 polypeptides or the polypeptides themselves.
Inhibition of cell migration including migration of endothelial cells, cancer cells, prostate cancer cells (DU145), and immune system cells to address metastasis and inflammatory diseases.
Increasing apoptosis in endothelial cells, cancer cells, and disease-causing cells.
Use as cancer diagnostics by measuring DOC1 expression levels to diagnose, classify cancer, and determine cancer stage.
Screening for modulators of DOC1 expression with potential therapeutic implications.
Research tools for studying tissue distribution and efficacy of anti-cancer treatments involving DOC1.
Interested in licensing this patent?