Treatment of metastatic tumors
Inventors
O'Neill, Alison • Jacoby, Douglas B. • Sentissi, Abdellah • Kesavan, Kamala • EGAN, E. MICHAEL
Assignees
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Publication Number
US-9023595-B2
Publication Date
2015-05-05
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 patent describes chlorotoxin-based agents, including labeled or unlabeled forms, for systemic targeting of metastatic tumors, including brain metastases. The approach includes measuring agent binding in the body at locations other than the primary tumor, where elevated binding relative to normal tissue indicates the presence of one or more metastases.
The document reports that chlorotoxin (TM-601) inhibits new blood vessel formation and induces regression of established neovasculature. Selective localization is described with newly formed endothelial cells, and mechanistic findings include induction of apoptosis with TUNEL-positive signals and colocalization with Annexin A2.
Additional mechanistic data are described for endothelial and glioma-related migration inhibition and inhibition of MMP-2 activity. PEGylation of chlorotoxin (TM-601-PEG) is described to increase chlorotoxin half-life and reduce dosing frequency, and clinical Phase I data are summarized for IV 131I-TM-601 in patients with recurrent/refractory metastatic solid tumors, including tumor-specific uptake in multiple contexts such as CNS.
Claims Coverage
The partial content provides two independent claims. Across both independent claims, the central coverage is a method for detecting one or more metastases by systemically administering a labeled chlorotoxin agent and measuring elevated binding at locations other than the primary tumor, relative to normal tissue.
Systemic administration of a selectively cancer-targeting labeled chlorotoxin agent
Administering to the individual an effective amount of a labeled chlorotoxin agent comprising a chlorotoxin polypeptide having at least 90% overall sequence identity with SEQ ID NO:1, wherein the labeled chlorotoxin agent selectively targets cancer cells over normal cells, and wherein the labeled chlorotoxin agent is administered systemically.
Measuring elevated binding outside the primary tumor to indicate metastases
Measuring binding of the labeled chlorotoxin agent in the individual's body in at least one location other than the location of the at least one primary tumor, wherein an elevated level of binding, relative to normal tissue, indicates the presence of one or more metastases.
Systemic administration of a labeled chlorotoxin agent defined by SEQ ID NO:1
Administering to the individual an effective amount of a labeled chlorotoxin agent comprising a chlorotoxin polypeptide as set forth in SEQ ID NO:1, wherein the labeled chlorotoxin agent is administered systemically.
Measuring elevated binding outside the primary tumor relative to normal tissue
Measuring binding of the labeled chlorotoxin agent in the individual's body in at least one location other than the location of the at least one primary tumor, wherein an elevated level of binding, relative to normal tissue, indicates the presence of one or more metastases.
Both independent claims cover metastasis detection by systemically administering a labeled chlorotoxin agent that selectively targets cancer cells and then measuring its binding at sites other than the primary tumor location; elevated binding relative to normal tissue indicates the presence of one or more metastases. One independent claim additionally requires a chlorotoxin polypeptide with at least 90% overall sequence identity to SEQ ID NO:1, while the other specifies a chlorotoxin polypeptide as set forth in SEQ ID NO:1.
Stated Advantages
Elevated binding outside the primary tumor, relative to normal tissue, indicates the presence of one or more metastases.
In Phase I, tumor-specific uptake is reported, including CNS, for IV 131I-TM-601 in recurrent/refractory metastatic solid tumors.
Some MRI response in glioma patients is reported.
TM-601-PEG increases chlorotoxin half-life and reduces dosing frequency.
Documented Applications
Detecting the presence of one or more metastases by systemically administering a labeled chlorotoxin agent and measuring elevated binding at locations other than the primary tumor.
Targeting and imaging metastatic tumors, including brain metastases, using labeled agents such as 131I for SPECT or gamma camera imaging and associated imaging outcomes such as MRI response in glioma patients.
Anti-angiogenic activity of chlorotoxin (TM-601), including inhibition of new blood vessel formation and regression of established neovasculature.
Clinical Phase I use of IV 131I-TM-601 in patients with recurrent/refractory metastatic solid tumors, reporting tumor-specific uptake including CNS and some MRI response in glioma patients.
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