Photosensitizing antibody-fluorophore conjugates
Inventors
Kobayashi, Hisataka • Choyke, Peter • Bernardo, Marcelino
Assignees
US Department of Health and Human Services
Publication Number
US-9358306-B2
Publication Date
2016-06-07
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 relates to antibody-IR700 conjugates and methods of their use to selectively kill cells that specifically bind to the antibody following irradiation with near infrared (NIR) light. The method includes contacting a target cell expressing a cell surface protein, such as a tumor-specific antigen, with a therapeutically effective amount of an antibody-IR700 molecule. Upon irradiation at a wavelength of 660 to 740 nm, the target cells bound by the antibody-IR700 are killed with high specificity, sparing non-target cells such as normal healthy cells.
The problem being solved is the need for cancer therapies that effectively kill tumor cells while minimizing harm to non-cancerous cells. Conventional cancer therapies like surgery, radiation, and chemotherapy tend to have dose-limiting toxicity due to non-selectivity. Moreover, traditional photodynamic therapy (PDT) uses non-targeted photosensitizers absorbed by normal tissues, causing serious side effects. The invention addresses these limitations by employing antibody-IR700 conjugates that activate cytotoxicity only upon specific binding to target cells and under NIR irradiation, offering tumor selectivity and reduced side effects.
Claims Coverage
The patent contains one independent claim encompassing a method for treating tumors using antibody-IR700 conjugates with specific irradiation and therapeutic agent administration. The claim's main inventive features focus on targeted antibody conjugates, irradiation parameters, combinatory treatment, and devices for irradiation.
Method of treating tumors using antibody-IR700 molecules
Administering one or more antibody-IR700 molecules that specifically bind to a cell surface protein on tumor cells to the subject, followed by irradiation of the tumor at 660 to 740 nm wavelength and at a dose of at least 1 J/cm2, thereby treating the tumor.
Combining antibody-IR700 treatment with therapeutic agents
Administering one or more therapeutic agents to the subject alongside antibody-IR700 molecules and irradiation, which can be administered prior to, during, or after the antibody-IR700 administration and irradiation, enhancing cancer treatment.
Targeting tumor-specific proteins with antibody-IR700 molecules
Using antibodies that specifically bind to tumor-specific proteins such as HER1, HER2, HER3, HER4, CD antigens, melanoma-associated antigens, carcinoembryonic antigen, or others, which enables selective targeting of tumor cells.
Use of multiple antibody-IR700 molecules for targeting
Using at least two different antibody-IR700 molecules where the first antibody targets a first antigen and the second antibody targets a different epitope of the first antigen or a different antigen, allowing broader or more precise tumor cell targeting.
Irradiation using devices worn by subjects for circulating tumors
Irradiating circulating tumor cells in blood by using a wearable device incorporating near infrared (NIR) light-emitting diodes (LEDs), facilitating treatment of circulating tumor cells.
Selecting subjects based on tumor expression
Selecting a subject who has a tumor expressing a cell surface protein that can specifically bind to the antibody-IR700 molecule prior to treatment, improving therapeutic specificity and effectiveness.
Low-dose detection and monitoring of tumors
Contacting tumors with less than therapeutic doses of antibody-IR700 molecules and irradiating at low doses (at least 0.001 J/cm2) to permit detection or imaging of the tumor without inducing cell killing.
Use of tumor irradiation at specific NIR wavelengths
Irradiating tumors specifically at or around 680 nm to activate the antibody-IR700 conjugate selective phototoxic effects.
Administration of various therapeutic agents in combination
Employing a broad range of therapeutic agents including anti-cancer agents, chemotherapeutics, radiotherapeutic agents, antibiotics, alkylating agents, kinase inhibitors, microtubule binding agents, DNA synthesis inhibitors, and immunomodulatory agents alongside antibody-IR700 therapies.
The claims cover a highly targeted tumor treatment method using antibody-IR700 conjugates that bind tumor-specific proteins, activated by precise NIR irradiation, combined with therapeutic agents for enhanced efficacy. The claims also encompass the use of combinations of antibody-IR700 molecules, wearable LED devices for circulating tumor cells, subject selection strategies, tumor detection via low-dose methods, and broad therapeutic combinations, illustrating a comprehensive approach to targeted phototherapy.
Stated Advantages
High target specificity enabling selective killing of tumor cells while sparing normal cells, minimizing side effects of cancer therapies.
Use of near infrared (NIR) light allowing deep tissue penetration and activation only at targeted sites, reducing off-target damage.
Ability to monitor therapy in real-time through fluorescence and fluorescence lifetime imaging for immediate assessment of cell killing.
Enhanced delivery and effectiveness of additional therapeutic agents due to increased tumor permeability after photoimmunotherapy.
Wearable NIR LED devices allow long-term, continuous treatment of circulating tumor cells in blood or lymph, increasing therapeutic reach.
Repeated photoimmunotherapy can control tumor regrowth and extend survival without cumulative toxicity associated with ionizing radiation.
Documented Applications
Treatment of solid tumors including breast, lung, colon, ovary, prostate, pancreas, brain, cervix, bone, skin cancers, and metastatic or circulating tumor cells.
Treatment of liquid tumors such as leukemias, lymphomas, and other blood cancers by targeting circulating tumor cells using wearable NIR LED devices.
Combination cancer therapy with chemotherapy, radiation, and immunotherapy agents to improve tumor control and survival outcomes.
Real-time intraoperative imaging and therapy to precisely identify and eradicate tumor margins during surgery or endoscopy.
Therapy of transplant rejection by targeting cells expressing specific surface proteins such as CD25.
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