Chemical conjugates of Evans Blue derivatives and their use as radiotherapy and imaging agents
Inventors
Chen, Xiaoyuan • Jacobson Weiss, Orit
Assignees
US Department of Health and Human Services
Publication Number
US-10981866-B2
Publication Date
2021-04-20
Expiration Date
2037-10-03
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Abstract
The present invention is directed to a compound of Formula III or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt: Formula III wherein the definitions of R1-R12 and L1-L4 are provided in the disclosure, wherein R13 is a chelating group comprising 177Lu, and wherein R14 is a peptide. The compounds of Formula I may be covalently bonded to a peptide via a linker to provide a compound of Formula III and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.
Core Innovation
The invention relates to chemical conjugates of Evans Blue dye derivatives that are functionalized to act as radiotherapy and imaging agents. Specifically, the inventive compounds are described by Formula III, comprising an Evans Blue derivative covalently bonded to a peptide via linkers, with a chelating group (R13) including radionuclides such as 177Lu and a peptide moiety (R14). These compounds extend the half-life of therapeutic peptides by reversible binding to serum albumin, enabling prolonged circulation and higher accumulation in target tissues such as tumors.
The problem addressed by the invention is the short half-life of pharmaceuticals, especially small molecule drugs and peptides, which limits their effectiveness. Traditional methods to increase half-life, such as PEGylation or fusion with large proteins like albumin or Fc domains, have disadvantages including compromised biological activity and complex synthesis. There is a need for improved drug-albumin conjugates that can extend systemic exposure, reduce renal clearance, and maintain biological function of therapeutic agents.
The invention achieves this by conjugating therapeutic peptides (e.g., somatostatin analogs) to an Evans Blue analog that binds serum albumin. This non-covalent albumin binding increases molecular size and circulation half-life without obscuring therapeutic function. The compounds may be labeled with radionuclides for combined diagnostic imaging and radiotherapy. The extended half-life and targeted tumor accumulation demonstrated improved tumor response and survival in animal models compared to existing agents, offering a novel and effective approach for treating diseases such as cancer and diabetes.
Claims Coverage
The claims cover one independent claim directed to a compound of Formula III with specified structural features and additional claims that elaborated embodiments and methods related to the compound. The main inventive features are extracted as follows.
Compound of Formula III with defined substituents and linkers
A compound of Formula III or its pharmaceutically acceptable derivatives, wherein the compound includes defined substitution patterns (R1-R12) with various possible substituents including hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy groups, and linkers L1-L4 that are alkylene chains substitutable by oxygen or amide bonds, with the chelating group R13 comprising 177Lu, and a peptide moiety R14.
Peptide moiety that targets specific cells or tissues
The peptide R14 is a therapeutic peptide capable of binding to target cells or tissues, such as tumors, including peptides like interferon alpha, GCSF, octreotate, bombesin, RGD, alpha-MSH, CTT1298, or aptamers, exemplified by the cyclic peptide Arg-Gly-Asp-Phe-Lys.
Pharmaceutical compositions including the compound
Pharmaceutical compositions comprising the compound of Formula III together with pharmaceutically acceptable carriers, such as binders, buffers, emulsifiers, lubricants, and preservatives.
Method of treating cancer using the compound
A method of treating cancer by administering to a mammal a therapeutically effective amount of the compound of Formula III, alone or in combination with additional active ingredients including chemotherapeutic agents such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, avastin, trastuzumab, and cetuximab.
The claims principally cover compounds of Formula III with Evans Blue-derived albumin-binding moieties linked to therapeutic peptides and chelators for radionuclides, pharmaceutical compositions containing such compounds, and methods of treating cancer by administering these compounds, highlighting the albumin-binding properties, the peptide targeting, and radionuclide chelating features as key inventive elements.
Stated Advantages
Many small molecules and biologics can be efficiently modified in one step with high yield and purity using the Evans Blue derivative conjugates.
The strong but reversible binding of the Evans Blue moiety to serum albumin allows control over in vivo biodistribution and extends blood circulation half-life.
The relatively small size of the Evans Blue moiety minimizes interference with the biological function of conjugated small molecules or biologics.
Incorporation of a chelator linked to the Evans Blue moiety enables facile addition of radionuclides for dual use as imaging and radiotherapeutic agents.
The compounds provide a versatile system for developing long-acting therapeutic and imaging agents with high efficacy and decreased renal clearance.
Documented Applications
Diagnosis or treatment of cancer by administering therapeutically effective amounts of Evans Blue derivative conjugates with peptides targeting tumor cells, optionally combined with other chemotherapeutic agents.
Radiotherapy using compounds labeled with therapeutic radionuclides (e.g., 90Y, 177Lu) targeting tumors expressing receptors such as somatostatin receptors.
Imaging applications including PET imaging using compounds labeled with positron emitters (e.g., 64Cu, 86Y) to detect tumor localization and receptor expression.
Treatment of diabetes by administering therapeutic peptides conjugated to Evans Blue derivatives to extend half-life and improve therapeutic effects.
Use in veterinary applications for treatment or diagnosis of diseases in non-human mammals including companion and livestock animals.
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