Photosensitizing antibody-fluorophore conjugates
Inventors
Kobayashi, Hisataka • Choyke, Peter
Assignees
US Department of Health and Human Services
Publication Number
US-10538590-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 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 antibody-IR700 conjugates and methods for killing target cells, such as tumor cells, by specifically binding an antibody-IR700 molecule to a cell surface protein on the target cell and subsequently irradiating the cell with near infrared (NIR) light, particularly at wavelengths between 660 to 740 nm. The antibody specifically binds to a cell surface protein, often a tumor-specific antigen like HER1, HER2, or PSMA, allowing selective killing of target cells when illuminated with a therapeutically effective dose of NIR light.
The problem addressed by this invention arises from the limitations of conventional cancer therapies and traditional photodynamic therapy (PDT). Conventional therapies such as surgery, radiation, and chemotherapy often cause damage to non-cancerous cells and have side effects due to lack of specificity. Traditional PDT uses photosensitizers that are non-targeted, leading to uptake in normal tissues and resulting in serious side effects. Existing photosensitizers also require intracellular localization for effectiveness and absorb in visible light ranges, limiting tissue penetration and selectivity. Hence, there is a need for therapies that can selectively kill tumor cells with minimal harm to normal cells.
The invention solves this need by conjugating a hydrophilic near infrared dye, IR700, to antibodies that specifically bind cell surface proteins on target cells, enabling target-specific photoimmunotherapy (PIT). The selectivity is derived from the antibody binding specificity and activation of phototoxicity only when bound to the cell membrane upon NIR irradiation. This method effectively kills target cells through membrane damage and necrotic death without widespread damage to normal cells. The IR700 conjugates also emit diagnostic fluorescence for tumor identification and therapy monitoring. Additionally, wearable devices incorporating NIR LEDs are provided for long-term, non-invasive treatment of circulating tumor cells.
Claims Coverage
The claims define a phototoxic pharmaceutical composition comprising an IR700-conjugated antibody targeting specific cell surface proteins, particularly HER1, HER2, or PSMA, and a pharmaceutical carrier. Three main inventive features are present in the independent claims.
Phototoxic conjugate comprising IR700 conjugated to specific antibodies
The composition includes a phototoxic conjugate composed of an IR700 molecule covalently conjugated to an antibody that binds to a cell surface protein. The antibody is specifically selected from Panitumumab, Trastuzumab, and J591, or an antigen binding fragment thereof.
Selective phototoxicity against cells expressing target cell surface proteins
The phototoxic conjugate exhibits the property of phototoxicity that can kill cells expressing the cell surface protein bound by the antibody or antigen binding fragment, enabling selective killing of tumor cells presenting HER1, HER2, or PSMA.
Inclusion of pharmaceutically acceptable carriers and antibody fragments
The pharmaceutical composition includes a pharmaceutical carrier such as physiological saline or water, and encompasses antibody fragments like Fab, Fab′, F(ab)′2, single chain Fv (scFv), or disulfide stabilized Fv (dsFv), which retain binding and phototoxic properties.
The claims focus on compositions that combine IR700 dye conjugated to antibodies specifically targeting HER1, HER2, or PSMA to achieve targeted photoimmunotherapy with phototoxic effects, suitable pharmaceutical carriers, and use of antibody fragments maintaining activity.
Stated Advantages
Selective killing of tumor cells with minimal damage to normal cells due to antibody-targeted delivery and activation only upon NIR irradiation.
Deeper tissue penetration due to use of near infrared light (660-740 nm), enabling effective treatment of tumors in vivo.
Dual function of antibody-IR700 conjugates providing both therapeutic phototoxicity and diagnostic fluorescence for tumor visualization and therapy monitoring.
Wearable devices incorporating NIR LEDs enable prolonged, non-invasive treatment of circulating tumor cells and tumors on or near skin, improving patient convenience and privacy.
Reduced side effects and dose-limiting toxicity compared to conventional cancer therapies and traditional photodynamic therapy due to targeted approach and activation only at illuminated sites.
Capacity for repeated treatments and combination with other therapies such as chemotherapy, radiation, or immunotherapy without cumulative toxicity risks associated with ionizing radiation.
Documented Applications
Treatment of cancer cells expressing tumor-specific proteins such as HER1, HER2, and PSMA using antibody-IR700 conjugates activated by near infrared light to selectively kill tumor cells in vitro and in vivo.
Use in treating various solid tumors including breast, ovarian, lung, colorectal, prostate, and others expressing the target antigens.
Treatment of liquid tumors such as leukemias and lymphomas expressing target antigens like CD20 or CD33.
Reduction and treatment of tumor metastases, including lung metastases, through targeted photoimmunotherapy.
Use in vivo via administration of the antibody-IR700 conjugates followed by irradiation to inhibit tumor growth and increase survival time.
Long term management of circulating tumor cells through wearable devices containing NIR LEDs that expose superficial blood vessels to light activating the conjugates on circulating tumor cells.
Therapeutic monitoring during surgery, such as endoscopic procedures, by utilizing the diagnostic fluorescence of antibody-IR700 conjugates to visualize tumor margins.
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