Treatment of metastatic tumors
Inventors
O'Neill, Alison • Jacoby, Douglas B. • Sentissi, Abdellah • Kesavan, Kamala • EGAN, E. MICHAEL
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9603952-B2
Publication Date
2017-03-28
Expiration Date
Abstract
The present invention is directed to methods and methods for the treatment, inhibition and/or reduction, and detection of metastatic tumors. In some embodiments, the inventive methods include systemic (e.g., intravenous) administration of a chlorotoxin agent that may or may not be labeled. In some embodiments, the inventive methods allow treatment, inhibition and/or reduction, and detection of metastases in the brain. In some embodiments, neovascularization is inhibited and/or newly formed vessels are caused to regress.
Core Innovation
The invention provides chlorotoxin-based agents, including labeled or unlabeled forms, for treating, inhibiting/reducing, and detecting metastatic tumors, particularly brain metastases. A subject having a primary tumor and at least one metastasis located in the brain is administered a chlorotoxin agent that systemically localizes to the brain metastases after systemic administration. The chlorotoxin agent selectively targets metastatic cancer cells over normal cells and localizes to the at least one brain metastasis.
The disclosed approach is supported by anti-angiogenic mechanisms, including inhibition of neovascularization and regression of newly formed vessels/neovasculature. Documented results include imaging/biopsy binding of biotinylated chlorotoxin (TM-601) to melanoma metastases in brain and lung. The disclosure further reports phase I imaging/safety data for intravenously administered 131I-TM-601 showing tumor-specific localization across multiple tumor types, and improved MRI imaging in glioma.
Additional documented evidence includes results from a mouse CNV model showing decreased choroidal neovascularization. The disclosure reports TM-601 localization and apoptosis in neovasculature, including colocalization to Annexin A2 and association with apoptotic cell death (e.g., TUNEL). PEGylated chlorotoxin (e.g., TM-601-PEG) is also disclosed, including extension of half-life and associated anti-angiogenic effects with less frequent dosing, while maintaining tumor/neovasculature targeting.
Claims Coverage
Independent claim clm-00001 covers a systemically administered chlorotoxin agent that comprises a chlorotoxin peptide with at least 90% sequence identity to SEQ ID NO:1 and selectively targets metastatic cancer cells over normal cells while localizing to brain metastases after systemic administration. The independent claim is supported by dependent claims that refine peptide sequence identity, administration route/format, dosage and dosing schedules, payload types and attachment formats, and additional biological effects such as regression of metastasis-associated neovasculature.
Systemic chlorotoxin administration for brain metastases localization
Systemically administering an effective amount of a chlorotoxin agent to a subject suffering from a primary tumor and at least one metastasis located in the brain, where the chlorotoxin agent localizes to the at least one brain metastasis upon being systemically administered.
Chlorotoxin peptide with at least 90% sequence identity to SEQ ID NO:1
The chlorotoxin agent comprises a chlorotoxin peptide whose amino acid sequence is at least 90% identical to that set forth in SEQ ID NO:1.
Selective targeting of metastatic cancer cells over normal cells
The chlorotoxin agent is characterized in that it selectively targets metastatic cancer cells over normal cells.
The claim set centers on systemic administration of a chlorotoxin agent comprising a peptide at least 90% identical to SEQ ID NO:1 that selectively targets metastatic cancer cells and localizes to brain metastases, with dependent claims further defining administration format, dosage and dosing schedules, optional payload and labeling formats, and anti-angiogenic neovasculature regression effects.
Stated Advantages
Selectively targets metastatic cancer cells over normal cells.
Localizes to brain metastases upon systemic administration.
Inhibits/reduces and regresses neovascularization/neovasculature associated with metastases.
Enables detection/imaging of tumors, including tumor-specific localization imaging and improved MRI imaging in glioma.
Extends half-life for PEGylated chlorotoxin and supports anti-angiogenic effects with less frequent dosing.
Documented Applications
Treating metastatic tumors in a subject with a primary tumor and at least one brain metastasis via systemic administration of a chlorotoxin agent.
Inhibiting/reducing neovascularization/neovasculature, including regression of neovascular structures associated with metastases.
Detecting and imaging metastatic disease, including tumor-specific localization imaging using intravenously administered 131I-TM-601 and improved MRI imaging in glioma.
Evaluating and supporting anti-angiogenic effects in a mouse CNV model, including TM-601 localization and apoptosis in neovasculature with colocalization to Annexin A2.
Interested in licensing this patent?