Photosensitizing antibody-fluorophore conjugates
Inventors
Kobayashi, Hisataka • Choyke, Peter
Assignees
US Department of Health and Human Services
Publication Number
US-11364297-B2
Publication Date
2022-06-21
Expiration Date
2031-07-11
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Abstract
The present disclosure relates to compositions and methods of killing cells. In particular examples, the method includes contacting a cell having a cell surface protein with a therapeutically effective amount of an antibody-IR700 molecule, wherein the antibody specifically binds to the cell surface protein, such as a tumor-specific antigen on the surface of a tumor cell. The cell is subsequently irradiated, such as at a wavelength of 660 to 740 nm at a dose of at least 1 J cm−2. The cell is also contacted with one or more therapeutic agents (such as an anti-cancer agent), for example about 0 to 8 hours after irradiating the cell, thereby killing the cell. Also provided are methods of imaging cell killing in real time, using fluorescence lifetime imaging. Also provided are wearable devices that include an article of clothing, jewelry, or covering; and an NIR LED incorporated into the article, which can be used with the disclosed methods.
Core Innovation
The invention disclosed herein relates to compositions and methods for killing cells, specifically leveraging antibody-IR700 conjugates that bind to cell surface proteins such as tumor-specific antigens. The method involves contacting target cells with a therapeutically effective amount of an antibody-IR700 molecule, irradiating the cells with near-infrared (NIR) light at wavelengths between 660 to 740 nm and doses of at least 1 J cm−2, and optionally contacting the cells with additional therapeutic agents (e.g., anti-cancer agents) within about 8 hours after irradiation, thereby selectively killing the target cells.
The problem addressed relates to the limitations of existing cancer therapies such as surgery, radiation, chemotherapy, and conventional photodynamic therapy (PDT). These conventional methods often cause significant damage to non-cancerous cells due to non-selectivity of treatments or photosensitizers. Existing monoclonal antibody therapies require high doses and have side effects tied to biodistribution and catabolism. Conventional PDT suffers from non-targeted photosensitizers that accumulate in normal tissues, causing serious side effects. There is a need for targeted cancer therapies that effectively kill tumor cells while sparing normal cells.
The invention overcomes these problems by introducing antibody-IR700 conjugates that specifically bind to target cell surface proteins and become activated only upon irradiation with NIR light, leading to rapid and selective necrotic cell death of the target cells. The phototoxic effect is primarily dependent on the membrane binding of the conjugate rather than internalization or reactive oxygen species generation. The method also permits real-time imaging of cell killing using fluorescence lifetime imaging (FLT) and introduces wearable NIR LED devices incorporated into articles of clothing or jewelry to allow prolonged treatment of circulating tumor cells in the blood or lymph.
Claims Coverage
The patent contains two independent claims relating to a phototoxic pharmaceutical composition comprising an IR700 conjugate with pertuzumab or fragments thereof, and a combination therapy including this conjugate and additional therapeutic agents. The main inventive features are extracted as follows.
Phototoxic conjugate comprising an IR700 molecule conjugated to pertuzumab or antigen binding fragments
A pharmaceutical composition containing a phototoxic conjugate of IR700 dye covalently linked to pertuzumab antibody or its antigen binding fragments (e.g., Fab, Fab', F(ab')2, scFv, dsFv) specifically binding to a cell surface protein on target cells such as tumor cells, formulated with a pharmaceutically acceptable carrier.
Combination therapy with phototoxic conjugate and additional therapeutic agents
A combination comprising (1) the phototoxic composition containing pertuzumab-IR700 conjugate and (2) a separate pharmaceutical composition containing additional therapeutic agents such as anti-cancer or anti-neoplastic agents, including radiotherapeutic agents, chemotherapeutic agents, antibiotics, alkylating agents, antioxidants, kinase inhibitors, microtubule binding agents, DNA intercalators, DNA synthesis inhibitors, antibodies, enzyme inhibitors, or gene regulators. Specific examples of additional agents include paclitaxel, docetaxel, vinblastine, daunorubicin, cisplatin, methotrexate, tamoxifen, imatinib, interleukin-2 and anti-CTLA4 antibodies.
The independent claims cover a pharmaceutical phototoxic composition that comprises an IR700 conjugate of the antibody pertuzumab or its antigen binding fragments, alone or in combination with a separate pharmaceutical composition comprising additional cancer therapeutic agents. The inventive features focus on the specific antibody-IR700 conjugate and its use in combination therapies with detailed lists of potential second agents.
Stated Advantages
The disclosed antibody-IR700 conjugates are highly selective, killing target cells specifically bound by the antibody without significant damage to non-target cells, thereby minimizing side effects.
The method allows deeper tissue penetration due to use of near-infrared light, enabling eradication of tumors with a single irradiation dose.
Fluorescence induced by the conjugate enables non-invasive real-time guidance of photoimmunotherapy and monitoring of therapeutic outcomes.
The photosensitizer is only active where intense light is applied, reducing off-target phototoxicity compared to conventional photosensitizers.
The phototoxic effect is rapid and necrotic, not requiring internalization or relying heavily on reactive oxygen species, enabling efficient cell killing.
Wearable devices incorporating NIR LEDs permit prolonged therapy targeting circulating tumor cells or lymphatic cancer cells.
Combining photoimmunotherapy with one or more additional therapeutic agents enhances treatment effectiveness by increasing delivery and tumor penetration of nano-sized agents.
Documented Applications
Treatment of cancers including solid tumors such as breast, ovarian, lung, colorectal, prostate, pancreatic, and skin cancers, and hematological cancers such as leukemias and lymphomas.
Selective killing of tumor cells expressing cell surface proteins such as HER1, HER2, and PSMA using antibody-IR700 conjugates followed by irradiation with NIR light.
Use of photoimmunotherapy in combination with chemotherapeutic or anti-neoplastic agents to potentiate therapeutic effects and enhance delivery of nano-sized agents to tumors.
Real-time imaging and monitoring of cell killing during therapy using fluorescence lifetime imaging techniques.
Therapeutic treatment of metastatic tumors and circulating tumor cells through devices incorporating wearable NIR LEDs for prolonged irradiation.
Applications in surgical procedures including tumor margin visualization during resections and endoscopic treatments.
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