Reprogramming urokinase into an antibody-recruiting anticancer agent
Inventors
Spiegel, David A. • Jakobsche, Charles E.
Assignees
Publication Number
US-12312621-B2
Publication Date
2025-05-27
Expiration Date
2032-11-07
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Abstract
The present invention relates to chimeric (preferably, bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds preferably covalently bind to the urokinase receptor and recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC) against a large number and variety of cancers, thus providing cancer cell death and/or an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.
Core Innovation
The invention provides chimeric, preferably bifunctional, compounds and associated pharmaceutical compositions for the treatment of cancer, particularly metastatic cancers, by targeting cancer cells that overexpress surface urokinase-type plasminogen activator receptor (uPAR). These compounds are designed to covalently bind to urokinase-type plasminogen activator (uPA) present on the cancer cell surface, converting uPA into a catalytically inactive, antibody-recruiting molecule that maintains its receptor-binding function.
The compounds employ a dual-function approach. They contain a moiety that binds uPA’s active site and simultaneously present an antibody-binding hapten, such as dinitrophenyl (DNP) or fluorescein, via a linker. Upon complexation with uPA and localization to cancer cell surfaces (via uPAR), these bifunctional constructs recruit endogenous antibodies. The recruited antibodies are then able to mediate selective immune destruction of cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC).
The problem addressed is the challenge of treating advanced-stage, invasive, and metastatic cancers, which are difficult to manage due to aggressive cell migration and metastasis often facilitated by the uPA-uPAR system. Conventional therapies lack selectivity or efficacy against such cancers. The invention exploits the selective overexpression of uPA/uPAR on invasive cancer cells, using them both as markers and as conduits for targeted immune-mediated therapy, thus representing a novel synthetic immunology strategy to redirect natural immune effector mechanisms against uPAR-expressing human cancer cells.
Claims Coverage
The patent claims coverage is centered on a method of treating cancer by administering a pharmaceutical composition containing a specific chimeric compound with defined structural and functional features. There is one independent claim, with several dependent claims specifying preferred embodiments.
Method of cancer treatment using bifunctional urokinase-based antibody-recruiting compounds
This feature involves administering to a patient in need an effective amount of a composition in pharmaceutical dosage form comprising an anti-cancer effective amount of a compound defined by a specific chemical formula. The compound consists of: - A moiety that covalently or non-covalently (preferably covalently) binds the active site of urokinase-type plasminogen activator (uPA) present on cancer cells. - An antibody binding moiety comprising a hapten that is capable of binding to an antibody already present in the patient or subject. - At least one linker (L1 and/or L2) to chemically link the binding moiety and the antibody binding moiety, optionally connected by a connector group (CT). - The overall construct may further include defined variations and pharmaceutically acceptable salt, solvate, or polymorph thereof.
In summary, the core inventive feature is the method of treating cancer by using specifically structured, bifunctional chimeric compounds that bind to cancer cell surface uPA and recruit endogenous antibodies for selective immune-mediated cancer cell destruction.
Stated Advantages
Compounds selectively target cancer cells that overexpress uPA/uPAR with minimal impact on healthy tissues due to low expression of these markers outside malignant cells.
Bifunctional constructs recruit endogenous antibodies, enabling the patient’s own immune system to mediate targeted destruction of cancer cells via antibody-dependent phagocytosis and cytotoxicity.
Modifying an endogenous human protein (uPA) minimizes the risk of anaphylactoid or immunological side effects typical of non-native protein therapeutics.
The approach exploits a natural, high-affinity protein-protein interaction and has potential efficacy across a wide variety of invasive cancer types, due to broadly upregulated uPAR.
Use of already existing anti-hapten antibodies (such as anti-DNP) in most humans eliminates the need for pre-vaccination or immunization.
Documented Applications
Treatment of cancer, especially metastatic cancer, in humans or other mammals through administration of the disclosed bifunctional chimeric compounds.
Reducing likelihood or inhibiting spread or metastasis for any cancer, particularly cancers of bone, lymph nodes, bladder, vas deferens, kidneys, liver, lungs, pancreas, brain, prostate, and ovaries.
Cancer types explicitly listed for treatment include: prostate, stomach, colon, rectal, liver, pancreatic, lung, breast, cervical, uterine, ovarian, testicular, bladder, renal, brain/CNS, head and neck, throat, Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing’s sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms’ tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, esophagus, larynx, kidney cancer, and lymphoma.
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