Chlorotoxin polypeptides and conjugates and uses thereof
Inventors
Sentissi, Abdellah • Jacoby, Douglas B.
Assignees
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Publication Number
US-9637526-B2
Publication Date
2017-05-02
Expiration Date
Abstract
Reduced lysine chlorotoxin polypeptides that may be used to generate single species conjugates of chlorotoxin. Conjugates comprising such chlorotoxin polypeptides and pharmaceutical compositions thereof. Methods of using such compositions and/or conjugates.
Core Innovation
The invention provides reduced-lysine chlorotoxin polypeptides and chlorotoxin conjugates. It addresses issues arising from wild-type chlorotoxin being a mixture due to multiple lysine conjugation sites and defines chlorotoxin concepts such as reduced lysine and monolysine to control the number of lysine residues available for conjugation. The modified chlorotoxin peptides comprise at least 90% sequence identity with SEQ ID NO: 1 and comprise a single lysine residue.
Conjugates are formed by covalently coupling the modified chlorotoxin peptide having a single lysine residue to an imaging agent or a detectable agent. The document describes covalent and indirect conjugation with linkers, including cleavable and non-cleavable linkers, and uses available lysine or termini for coupling.
The conjugates expand payload options while retaining chlorotoxin-based binding. The document describes therapeutic agent options including cytotoxics, drug-resistance-associated agents, nucleic acids/RNAi, photosensitizers, radiosensitizers, superantigens, anti-angiogenic agents, and prodrug-activating enzymes, as well as detectable imaging labels including radioisotopes/paramagnetic ions, fluorescent dyes, enzymes, and nanoparticles. The document also includes pharmaceutical compositions, delivery/administration, and disease/indication coverage for tumor therapy/diagnosis and anti-angiogenic uses such as macular degeneration.
Claims Coverage
The independent claims are clm-00001 and clm-00002. Both claims share the core chlorotoxin conjugate structure that includes a modified chlorotoxin peptide with at least 90% sequence identity to SEQ ID NO: 1, a single lysine residue, and covalent coupling to an imaging or detectable agent, differing in the end use.
Chlorotoxin imaging with single-lysine modified peptide conjugate
An imaging method comprising contacting tissue imagable by chlorotoxin with a chlorotoxin conjugate to image the tissue, wherein the chlorotoxin conjugate comprises a modified chlorotoxin peptide having at least 90% sequence identity with SEQ ID NO: 1, and wherein the modified chlorotoxin peptide comprises a single lysine residue and is covalently coupled to an imaging agent.
Cancer detection with single-lysine modified peptide conjugate
A cancer-detection method comprising contacting cancer tissue detectable by chlorotoxin with a chlorotoxin conjugate to detect the cancer tissue, wherein the chlorotoxin conjugate comprises a modified chlorotoxin peptide having at least 90% sequence identity with SEQ ID NO: 1, and wherein the modified chlorotoxin peptide comprises a single lysine residue and is covalently coupled to a detectable agent.
Across clm-00001 and clm-00002, the claims cover imaging or detecting chlorotoxin-detectable tissue using a chlorotoxin conjugate built from a modified chlorotoxin peptide (≥90% identity to SEQ ID NO: 1) containing a single lysine residue, with covalent coupling to an imaging agent or detectable agent.
Stated Advantages
Expands payload options while retaining chlorotoxin-based binding.
Documented Applications
Tumor therapy/diagnosis using chlorotoxin conjugates and imaging/detection of tumor tissue.
Anti-angiogenic use, including macular degeneration (wet macular degeneration and neovasculature).
In vivo uptake imaging and in vivo breast cancer tumor model with paclitaxel-chlorotoxin conjugates.
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