Photosensitizing antibody-fluorophore conjugates
Inventors
Kobayashi, Hisataka • Choyke, Peter
Assignees
US Department of Health and Human Services
Publication Number
US-11364298-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 vitro or in vivo. 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. In particular examples the antibody recognizes 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, thereby killing the cell. 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 provides compositions and methods for killing cells in vitro or in vivo using antibody-IR700 molecules. These molecules consist of an antibody that specifically binds to a cell surface protein conjugated to the IR700 near-infrared (NIR) photosensitizer. Upon binding to target cells expressing the specific cell surface protein, the cells are irradiated with NIR light (660 to 740 nm) at a dose of at least 1 J cm−2, resulting in selective cell killing. The method is specific to target cells such as tumor cells, with minimal killing of non-target cells, including normal cells.
The problem addressed is the need for effective cancer therapies that selectively kill tumor cells while sparing normal cells, thereby minimizing side effects. Conventional therapies, including surgery, radiation, chemotherapy, and conventional photodynamic therapy (PDT), suffer from limitations such as non-specific toxicity and damage to normal tissues. Existing monoclonal antibody therapies rely on mechanisms like ADCC, CDC, and receptor blockade but require high doses and have limitations related to biodistribution and toxicity. Conventional PDT is hindered by lack of selectivity as photosensitizers accumulate in normal tissues, causing side effects despite the safety of NIR light itself.
This invention overcomes these issues by using antibody-IR700 conjugates that bind specifically to cell surface proteins unique or overexpressed on tumor cells, such as HER1, HER2, or PSMA. Activation and phototoxic effects occur only when the conjugate is bound to the cell membrane and irradiated with NIR light, inducing rapid necrotic cell death primarily through physical membrane damage rather than reactive oxygen species production. The approach enables highly selective photodynamic therapy with minimal off-target effects, deeper tissue penetration of activating light, and the ability to monitor therapy through fluorescence from the conjugate. Wearable devices incorporating NIR LEDs allow extended treatment of circulating tumor cells or superficial tumors.
Claims Coverage
The patent claims cover pharmaceutical compositions and combinations involving antibody-IR700 conjugates targeting CD25, as well as their combinations with additional therapeutic agents, with key inventive features focused on antibody identity, conjugate composition, and therapeutic combinations.
Phototoxic conjugates comprising IR700 conjugated to anti-CD25 antibodies
A phototoxic pharmaceutical composition comprising an IR700 molecule conjugated to an antibody that binds to a cell surface protein on a cell, wherein the antibody is an anti-CD25 antibody or an antigen binding fragment thereof, including daclizumab or basiliximab.
Pharmaceutical compositions with pharmaceutically acceptable carriers
The antibody-IR700 conjugates are formulated with pharmaceutically acceptable carriers suitable for therapeutic use.
Combinations of phototoxic conjugates with additional therapeutic agents
Therapeutic combinations comprising a phototoxic conjugate as above and a second pharmaceutical composition containing an additional therapeutic agent, including anti-cancer or anti-neoplastic agents such as radiotherapeutics, chemotherapeutics, antibiotics, alkylating agents, antioxidants, or kinase inhibitors.
Formulation of antibody fragments as conjugates
Antigen binding fragments include Fab, Fab′, F(ab′)2, single chain Fv (scFv), or disulfide stabilized Fv (dsFv) are included in the antibody-IR700 conjugates.
The claims define compositions of antibody-IR700 conjugates targeting CD25 and their pharmaceutical formulations, alone or in combination with a broad range of therapeutic agents, highlighting antibodies daclizumab and basiliximab, and include antigen binding fragments, covering both standalone and combination treatments.
Stated Advantages
Highly selective killing of target cells expressing specific surface proteins while sparing non-target normal cells.
Activation of phototoxicity only upon binding to the target cell membrane and irradiation with NIR light, minimizing off-target toxicity.
Improved tissue penetration of NIR excitation light (660-740 nm), allowing effective treatment of deeper tumors or circulating tumor cells.
Capability to non-invasively monitor therapy through fluorescence of the antibody-IR700 conjugate.
Potential for repeated dosing and lack of cumulative toxicity unlike ionizing radiation, enabling long-term management of tumors.
Wearable devices incorporating NIR LEDs permit prolonged treatment of tumor cells located in superficial blood vessels or lymphatic circulation.
Documented Applications
Treatment of cancer by selectively killing tumor cells expressing specific cell surface proteins such as HER1, HER2, PSMA, or CD25 using antibody-IR700 conjugates activated by NIR light.
Treatment of solid tumors, including breast, lung, prostate, ovarian, colon, and others, as well as hematologic malignancies like leukemias and lymphomas.
Use in combination with other cancer therapies like chemotherapy, radiation, immunosuppressants, or cytokines.
Use with wearable NIR LED devices for treatment of circulating tumor cells or superficial skin tumors, allowing long-term therapy.
Monitoring tumor size and therapeutic response during or after treatment using fluorescence from antibody-IR700 conjugates.
Photoimmunotherapy during surgical procedures such as endoscopy to visualize tumor margins and ensure complete tumor resection.
Treatment of transplant rejection by targeting cells expressing CD25 with specific antibody-IR700 conjugates.
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