Near infrared photoimmunotherapy (NIR-PIT) of suppressor cells to treat cancer
Inventors
Kobayashi, Hisataka • Choyke, Peter • Sato, Kazuhide • Sato, Noriko
Assignees
US Department of Health and Human Services
Publication Number
US-11013803-B2
Publication Date
2021-05-25
Expiration Date
2036-08-02
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Abstract
It is shown that CD25-targeted near-infrared photo-immunotherapy causes a unique, rapid and spatially selective depletion of Tregs leading to regression of the treated tumor and inducing systemic immunologic responses in untreated tumors. Based on these observations, provided are compositions and methods of killing immune suppressor cells, for example to treat cancer. Reducing the number of suppressor cells in a subject can remove suppression of effector T cells, for example, to treat cancer using the subject's own immune system. In particular examples, the method includes contacting suppressor cells having a suppressor cell surface protein with an antibody-IR700 molecule, wherein the antibody specifically binds to the suppressor cell surface protein, and in some examples the antibody does not have a functional Fc region. The cell is subsequently irradiated, such as at a wavelength of 660 to 740 nm, for example at a dose of at least 4 J cm−2.
Core Innovation
The invention provides methods and compositions for selectively killing suppressor immune cells, such as regulatory T cells (Tregs), within the tumor microenvironment using near-infrared photoimmunotherapy (NIR-PIT). The core of the method involves the administration of antibody-IR700 conjugates, where the antibody specifically binds a suppressor cell surface protein and typically lacks a functional Fc region. Following systemic or local administration, the suppressor cells bound to these antibody-IR700 molecules are exposed to near-infrared light at a wavelength between 660 to 740 nm, causing rapid and selective depletion of the suppressor cells in the irradiated area.
The depletion of suppressor cells, such as CD4+CD25+Foxp3+ Tregs, localizes within the tumor microenvironment, leading to the activation of anti-tumor effector immune cells like CD8 T cells and natural killer (NK) cells. This local immune activation results in regression of the treated tumor and induces systemic immunologic responses, including regression of distant, non-irradiated tumors. In some examples, the antibody lacks a functional Fc region to avoid systemic immune-mediated toxicity such as antibody-dependent cell-mediated cytotoxicity (ADCC) and to enhance spatial selectivity during NIR activation.
The problem addressed by this invention arises from the limitations of existing cancer immunotherapies that systemically block immunosuppressive regulatory mechanisms, often causing life-threatening autoimmune side effects. Current methods to deplete Tregs systemically inadvertently reduce anti-tumor effector cells and are not spatially selective, leading to adverse systemic effects. Therefore, there is a need for a method that allows selective, local depletion of tumor-infiltrating suppressor cells to enhance anti-cancer immune response while avoiding systemic immune-related toxicity.
Claims Coverage
The patent includes 15 claims with one independent claim covering a method of treating cancer using antibody-IR700 conjugates with selective binding and NIR irradiation. The inventive features mainly concern the targeting of suppressor cells in tumors, antibody characteristics, irradiation parameters, and therapeutic outcomes.
Selective targeting and killing of suppressor cells in tumors using antibody-IR700 molecules without functional Fc regions
A method of treating cancer comprising administering antibody-IR700 molecules that specifically bind suppressor cell surface proteins on suppressor cells within a tumor or lesion, wherein the antibody does not have a functional Fc region to avoid systemic effects.
Irradiation parameters inducing local and systemic anti-tumor effects
Irradiating the tumor or lesion at a wavelength of 660 to 740 nm and at a dose of at least 4 J/cm2, resulting in depletion of suppressor cells locally and killing of cancer cells in distant non-irradiated tumor areas.
Range of suppressor cells and surface proteins targeted
Suppressor cells targeted include Tregs (e.g., CD4+CD25+Foxp3+), type II NKT cells, M2 macrophages, tumor infiltrating fibroblasts, myeloid-derived suppressor cells, each recognized via specific surface proteins such as CD25, CD4, CXCR4, CCR4, CTLA4, GITR, OX40, FR4, CD16, CD56, CD8, CD122, CD23, CD163, CD206, CD11b, Gr-1, CD14, IL-4Ra, IL-1Ra, IL-1 decoy receptor, FAP, CD103, CXCR2, CD33, and CD66b.
Use of antibody fragments and combinations of antibody-IR700 molecules
The antibody in the conjugate can be Fab' and/or F(ab')2 fragments lacking functional Fc regions. The method includes use of at least two different antibody-IR700 molecules targeting either different epitopes of the same suppressor cell protein or different suppressor cell surface proteins.
Treatment of cancers and therapeutic outcomes
The method is applicable to cancers of multiple organs including breast, liver, colon, ovary, prostate, pancreas, brain, cervix, bone, skin, head and neck, blood, and lung, resulting in tumor size reduction, increased survival time, and treating metastatic cancer.
Use of wearable devices for irradiation
Irradiation can be delivered by a device worn by the subject containing near-infrared (NIR) light-emitting diodes (LEDs) to irradiate blood or tumor areas, providing targeted activation of the antibody-IR700 molecules.
The claims define a cancer treatment method using antibody-IR700 conjugates lacking functional Fc regions to selectively kill suppressor cells within tumors upon near-infrared light irradiation, leading to local depletion of suppressor cells and systemic anti-tumor effects, including at distant sites. The claims recite ranges of suppressor cells targeted, specific antibody fragments used, irradiation parameters, disease targets, and devices for irradiation, supporting a novel and spatially selective immunotherapeutic approach.
Stated Advantages
Selective and localized depletion of tumor-infiltrating regulatory T cells and other suppressor cells, avoiding systemic autoimmune side effects caused by systemic immunotherapies.
Rapid activation of anti-tumor immune effector cells such as CD8 T cells and NK cells within tumors, leading to effective tumor regression locally and at distant metastatic sites.
Minimized damage to non-target immune cells because killing only occurs where antibody-IR700 molecules are bound and NIR light is applied.
Potential applicability to a broad range of cancers due to the common presence of CD25-expressing suppressor cells in many tumor types.
Capability to be combined with other cancer therapies or immune modulatory approaches to enhance treatment efficacy.
Documented Applications
Treating a tumor or cancer by selectively killing suppressor immune cells within the tumor microenvironment using antibody-IR700 conjugates and NIR irradiation.
Inducing regression and reduction in tumor volume, size, and weight, including metastatic tumors, locally and at distant sites.
Activation of systemic anti-tumor immunity after localized NIR-PIT treatment of primary tumors.
Use in multiple cancer types such as lung, colon, prostate, breast, liver, ovarian, pancreatic, brain, cervix, bone, skin, and blood cancers.
Treatment of circulating suppressor cells via wearable NIR LED devices to irradiate blood and lymph in subjects.
Combination with other therapies including chemotherapeutic agents, biologics, radiation therapy, and additional antibody-IR700 conjugates targeting tumors or other cells.
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