Photosensitizing antibody-fluorophore conjugates
Inventors
Kobayashi, Hisataka • Choyke, Peter
Assignees
US Department of Health and Human Services
Publication Number
US-10537641-B2
Publication Date
2020-01-21
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 relates to antibody-IR700 conjugates and methods of their use for killing cells that specifically bind to the antibody following irradiation with near infrared (NIR) light. In particular, the antibody-IR700 molecule specifically binds to a cell surface protein, such as a tumor-specific antigen on tumor cells. The method includes contacting the cell with a therapeutically effective amount of the antibody-IR700 molecule, irradiating the cell at a wavelength of 660 to 740 nm at a dose of at least 1 J cm−2, and optionally contacting the cell with one or more therapeutic agents, such as anti-cancer agents, thereby killing the target cells.
The problem addressed is the need for cancer therapies that selectively kill tumor cells with minimal harm to non-cancerous cells. Conventional cancer therapies including surgery, radiation and chemotherapy have side effects that damage healthy cells. Existing photodynamic therapy (PDT) lacks tumor selectivity, causing serious side effects. Monoclonal antibody therapies, while more targeted, require multiple doses and have limitations due to biodistribution and catabolism of antibody conjugates.
The disclosed antibody-IR700 conjugates overcome these limitations by combining the targeting specificity of monoclonal antibodies with the phototoxic action of IR700 photosensitizer activated by NIR light. The phototoxicity depends primarily on binding of the conjugate to the cell membrane rather than internalization. Upon irradiation, rapid necrotic cell death is induced specifically in antibody-bound cells, sparing non-target cells. This selective activation reduces off-target toxicity and permits simultaneous imaging and therapy. Additionally, therapeutic agents can be delivered during an enhanced permeability window following irradiation, improving treatment efficacy.
Claims Coverage
The patent includes two independent claims covering phototoxic pharmaceutical compositions comprising antibody-IR700 conjugates targeting HER1 and combinations of such compositions with additional therapeutic agents.
phototoxic pharmaceutical composition targeting HER1
A pharmaceutical composition comprising a phototoxic conjugate formed by conjugating IR700 to an antibody that binds HER1, wherein the conjugate exhibits phototoxicity to kill HER1-expressing tumor cells, and a pharmaceutical carrier.
combination therapy comprising antibody-IR700 conjugate and additional therapeutic agent
A combination including a first pharmaceutical composition comprising an IR700-antibody conjugate targeting HER1 with phototoxic activity and a second pharmaceutical composition comprising an additional therapeutic agent, wherein each composition optionally includes a pharmaceutically acceptable carrier. The therapeutic agent can be an anti-cancer or anti-neoplastic agent including but not limited to chemotherapeutic agents, kinase inhibitors, antibodies, microtubule binding agents, DNA synthesis or transcription inhibitors, and immune modulators.
The claims cover compositions of antibody-IR700 conjugates targeting HER1 for phototoxic treatment of tumors, and combinations of such compositions with various additional therapeutic agents to enhance anti-tumor effects.
Stated Advantages
The methods selectively kill tumor cells while sparing non-target normal cells, minimizing off-target effects.
The therapy can be activated specifically where NIR light is applied, reducing systemic toxicity of photosensitizers.
The conjugates emit diagnostic fluorescence permitting simultaneous imaging to guide and monitor therapy in real-time.
The window of enhanced permeability following irradiation improves delivery and effectiveness of additional therapeutic agents.
The modality can be adapted for repeated treatments without cumulative toxicities seen in ionizing radiation.
Wearable NIR LED devices allow long-term treatment of circulating tumor cells in blood or lymph with minimal patient interference.
Documented Applications
Targeted treatment of solid tumors expressing cell surface proteins such as HER1, HER2, or PSMA through administration of antibody-IR700 conjugates followed by NIR irradiation.
Treatment of circulating tumor cells, including leukemias and metastatic cells, by administering antibody-IR700 conjugates and using wearable NIR LED devices to irradiate superficial blood vessels.
Combination therapies with additional anti-cancer agents (chemotherapeutics, kinase inhibitors, antibodies, immune modulators) administered during enhanced permeability post-PIT.
Real-time monitoring of tumor cell death and treatment efficacy via fluorescence lifetime imaging post irradiation.
Use during surgical or endoscopic procedures to visualize tumor margins and ensure complete resection by applying antibody-IR700 conjugates and NIR light.
Therapeutic treatment of tumor metastases, such as lung metastases, by intravenous administration of antibody-IR700 conjugates and localized NIR irradiation.
Use of antibody-IR700 conjugates targeting various tumor-specific proteins to treat multiple cancer types including adenocarcinoma, sarcomas, leukemias, lymphomas and other solid and liquid tumors.
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