Immune response modulator / immunotherapy combination systems and methods

Abstract

A system for treating a disease susceptible to excessive activation of a subject's immune system is described and discussed. The system includes an immunotherapeutic agent capable of treating the disease by modulating the activity of the subject's immune system, and an immune response modifier composition including 3-bromopyruvic acid (3-BP) and salts thereof, at least one sugar for stabilizing 3-BP by substantially preventing 3-BP from hydrolyzing, and a biological buffer present in an amount sufficient to at least partially deoxidize and neutralize metabolic byproducts of 3-BP.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 359,674, filed July 8, 2022, which is incorporated herein by reference in its entirety.

[0002] [Sequence table] This application contains a Sequence Listing in ST.26 XML format named 2553-052.PCT SEQ Listing.xml, which is incorporated herein by reference and is 14KB in size, created July 10, 2023. The sequences contained in the Sequence Listing can be found throughout the application as originally filed. [Background technology]

[0003] The immune system is a large collection of organs, specialized cells, and substances that help defend the body against infections, pathogens, and various other diseases. The immune system tracks various substances normally found in the body to prevent them from triggering specialized immune cells that target the body's tissues. However, substances that the immune system does not recognize can generate signals that cause the immune system to attack them. For example, pathogens have surface proteins that are not recognized by immune system proteins found in the human body. The immune system sees these as "foreign," and activated immune cells attack the pathogen, triggering an immune response that can destroy the foreign substance and anything associated with it.

[0004] Although the following detailed description contains many details for the purposes of illustration, those skilled in the art will understand that many variations and modifications to the following details are possible and are considered to be included herein. Accordingly, the following embodiments are described without loss of generality and without imposing limitations on any claims set forth herein. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Furthermore, the same reference numerals appearing in different drawings refer to the same elements. Numbers shown in flowcharts and processes are provided for clarity in describing steps and operations and do not necessarily indicate a particular order or sequence.

[0005] Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided, such as example layouts, distances, and example networks, to provide a thorough understanding of various embodiments. However, those skilled in the relevant art will recognize that such detailed embodiments do not limit the overall concepts described herein, but are merely representative thereof. Those skilled in the relevant art will also recognize that the technology can be practiced without one or more of the specific details, or with other methods, components, layouts, etc. In other cases, well-known structures, materials, or operations may not be shown or described in detail to avoid obscuring aspects of the disclosure.

[0006] As used in this application, words such as "comprises," "comprising," "containing," and "having" can have the meaning ascribed to them under U.S. patent law and can mean "includes," "including," and the like, and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed terms and include only the components, structures, steps, etc. specifically recited in conjunction with such term and those in conjunction with U.S. patent law. The terms "consisting essentially of" or "consists essentially of" have the meaning ascribed to them generally under U.S. patent law. Notably, such terms are generally closed terms, except that they may include additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item with which such term is used. For example, trace elements that are present in a composition but do not affect the properties or characteristics of the composition may be permitted, if present under the term "consisting essentially of," even if they are not explicitly mentioned in the list of items enumerated after such term. When open-ended terms such as "comprising" or "including" are used herein, it is understood that the words "consisting essentially of" should be directly supported as well as the words "consisting of," as if explicitly recited, and vice versa.

[0007] As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, attribute, state, structure, item, or result. For example, a "substantially" enclosed object means that the object is completely enclosed or nearly completely enclosed. The exact degree of acceptable deviation from absolute completeness may vary, depending on the specific situation. However, generally, near completion will result in the same overall result as if absolute and complete completion had been achieved. The use of "substantially" is equally applicable when used in a negative sense to indicate the complete or nearly complete absence of an action, characteristic, attribute, state, structure, item, or result. For example, a composition "substantially free" of particles will exhibit the same effect as if the particles were completely absent, either because of the complete absence or nearly complete absence of particles. In other words, a composition "substantially free" of a component or element may actually contain the item, so long as there is no measurable effect of the item.

[0008] As used herein, the term "about" is used to provide flexibility for a given term, metric, value, range endpoint, etc. The degree of flexibility for a particular variable can be readily determined by one of ordinary skill in the art. However, unless otherwise specified, the term "about" generally provides flexibility of less than 0.01%. When the term "about" is used in conjunction with a specific numerical value herein, it should be understood that support for the exact numerical value stated apart from the term "about" is also provided.

[0009] As used herein, a plurality of ingredients, conditions, and / or compositional components may be provided in a common list for convenience. However, such lists should be construed as though each member of the list were individually identified as a separate and unique member. Accordingly, the individual members of such lists should not be construed as de facto equivalents of any other members of the same list merely by virtue of being presented in a common group, unless expressly indicated to the contrary.

[0010] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range formats are used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values expressly recited as the limits of the range, but also all individual numerical values or subranges subsumed within that range, as if each numerical value and subrange were expressly recited. As an example, a numerical range of "about 1 to about 5" should be interpreted not only to include the explicitly recited values of about 1 to about 5, but also to include each individual value and subrange within the stated range. Thus, this numerical range includes individual values such as 2, 3, and 4, and subranges such as 1 to 3, 2 to 4, and 3 to 5, as well as 1, 1.5, 2, 2.3, 3, 3.8, 4, 4.6, 5, and 5.1, individually. This same principle applies to ranges reciting only a single numerical value as the minimum or maximum value. Furthermore, this interpretation should apply regardless of the width or characteristics of the range described.

[0011] References throughout this specification to an "example" mean that the particular feature, structure, or characteristic described in connection with that example is included in at least one embodiment. Thus, the appearances of the phrase "example" or "embodiment" in various places throughout this specification do not necessarily all refer to the same example or embodiment.

[0012] Terms such as "first," "second," "third," and "fourth" in the specification and claims, when present, are used to distinguish between similar elements and not necessarily to describe a particular order or chronology. It should be understood that terms so used are interchangeable under appropriate circumstances, such that the embodiments described herein can, for example, operate in orders other than those illustrated or otherwise described herein. Similarly, when a method is described herein as including a series of steps, the order of such steps presented herein is not necessarily the only order in which such steps can be performed; certain of the described steps can be omitted and / or certain other steps not described herein can be added to the method.

[0013] The formulations of the present invention can include pharmaceutically acceptable carriers and other ingredients as determined by the specific needs of a particular dosage formulation. Such ingredients are well known to those skilled in the art. See, for example, Gennaro, A. Remington, The Science and Practice of Pharmacy, 19th Edition (1995), which is incorporated by reference in its entirety.

[0014] As used herein, "administration" and "administering" refer to the method by which a composition is presented to a subject. Administration can be achieved by various art-known routes, such as enteral, parenteral, transdermal, and the like, optionally including a combination thereof. Thus, enteral administration can be achieved by drinking, swallowing, chewing, or inhaling an oral dosage form containing the active agent or other compound to be delivered. Parenteral administration can be achieved by injecting a drug composition intravenously, intraarterially, intramuscularly, intrathecally, subcutaneously, etc. Transdermal administration can be achieved by applying, pasting, rolling, adhering, injecting, applying pressure, rubbing, etc., a transdermal formulation to the skin surface. These and additional administration methods are well known in the art.

[0015] As used herein, the terms "subject" and "subject" may be used interchangeably where the context allows, and refer to a mammal that can benefit from the administration of a pharmaceutical composition or method of the present invention. Examples of subjects include humans and other animals, such as horses, pigs, cows, sheep, goats, dogs (felines), cats (canines), rabbits, rodents, primates, and aquatic mammals. In one embodiment, subject can refer to a human.

[0016] As used herein, a "cellular energy inhibitor" refers to an agent or substance that has a measurable, specific, or selected physiological activity when administered to a subject in a significant or effective amount. It should be understood that the term "drug" is expressly encompassed by this definition, as many drugs and prodrugs are known to have specific physiological activities. These terms are well known in the pharmaceutical and medical fields. Furthermore, when these terms are used, or when a particular active agent is specifically identified by name or category, it is understood that such reference is intended to include the active agent itself, as well as compounds significantly related thereto, including, but not limited to, pharmaceutically acceptable salts, or prodrugs, active metabolites, isomers, and the like. Terms such as "cellular energy inhibitors," "glycolysis inhibitors," and "mitochondrial inhibitors" are considered to be active agents.

[0017] As used herein, the terms "inhibit," "inhibiting," or any other derivative thereof, refer to the process of holding back, suppressing, or restraining so as to block, prevent, limit, or reduce the rate of an action or function. Use of this term should not be misconstrued to mean only absolute prevention, but can refer to all minor and incremental measures that limit or reduce a function through complete and absolute prevention of the function.

[0018] As used herein, a "cellular energy inhibitor" refers to a compound that inhibits ATP production in a cell. In some embodiments, the cellular energy inhibitor can inhibit glycolysis, oxidative phosphorylation, or both glycolysis and oxidative phosphorylation in a cell.

[0019] As used herein, "glycolytic inhibitor" refers to a compound that inhibits, reduces, or stops glycolysis in a cell.

[0020] As used herein, "mitochondrial inhibitor" refers to a compound that inhibits, reduces, or stops mitochondrial ATP production in a cell.

[0021] As used herein, "carrier" or "pharmaceutically acceptable carrier" refers to a substance that can be combined with a drug to achieve a particular dosage formulation for delivery to a subject. In some examples, a carrier may or may not enhance drug delivery. As a general rule, a carrier will not react with a drug in a manner that substantially degrades or otherwise adversely affects the drug, although some carriers may react with a drug such that the drug cannot exert its therapeutic effect until it is released from the carrier. Additionally, the carrier, or at least a portion thereof, must be physiologically suitable for administration to a subject along with the drug.

[0022] The term "excipient," as used herein, includes any substance used as a carrier for an active agent in, for example, a liquid formulation, e.g., any substance added to an active agent and / or solid formulation to improve its handling characteristics, enable the resulting composition to be formed into a suitable storage form, facilitate dissolution in liquid, etc. Excipients include, by way of example and not limitation, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, dyes, and any other substance other than an active ingredient conventionally used in the preparation of liquid or solid formulations.

[0023] The terms "reaction" and "reacting" include any form of chemical change that occurs in a formulation component as a result of contact with another formulation component, including a reaction that activates one or more molecules or components (e.g., the conversion of an activator precursor to an activator), a reaction that degrades at least one component, etc.

[0024] As used herein, "admixed" means that at least two components of the composition may be partially or completely mixed, dispersed, suspended, dissolved, or emulsified with one another. In some cases, at least a portion of the drug may be mixed with at least one carrier substance.

[0025] An initial overview of embodiments is provided below, followed by a more detailed description of specific embodiments. This initial summary is intended to help the reader more quickly understand the disclosure, but is not intended to identify key or essential technical features, nor is it intended to limit the scope of the claimed subject matter. DETAILED DESCRIPTION OF THE INVENTION

[0026] The immune system is a large collection of organs, specialized cells, and substances that help defend the body against infections, pathogens, and various other diseases. The immune system tracks various substances normally found in the body to prevent them from triggering specialized immune cells that target the body's tissues. However, substances that the immune system does not recognize can generate signals that cause the immune system to attack them. For example, pathogens have surface proteins that are not recognized by immune system proteins found in the human body. The immune system sees these as "foreign," and activated immune cells attack the pathogen, triggering an immune response that can destroy the foreign substance and anything associated with it.

[0027] However, because cancer is an abnormality of normal cells that the immune system does not recognize as foreign, the immune system can have difficulty targeting cancer cells. This lack of recognition, or reduced recognition, inhibits the immune system's ability to fight cancer on its own. Immunotherapy is a very common category of treatment that harnesses the body's own immune system to fight cancer. However, stimulating a subject's immune system to fight cancer can be dangerous, often leading to serious conditions such as autoimmune disease, tissue damage, and even death. In such cases, the immune system becomes overactive and begins to attack normal cells and tissues within the body.

[0028] One mechanism that plays a key role in an overactive immune system and the damage it subsequently causes involves the signaling pathways that immune cells use to coordinate their response to foreign invaders. Cells involved in the body's immune response coordinate their attack by releasing proteins that function as chemical messengers. Cytokines are a type of protein used as chemical messages and are therefore an essential part of the body's immune response. Cytokines are often crucial for various immunotherapeutic treatments against cancer and other pathogenic attacks, diseases, and illnesses. Cytokines trigger symptoms such as fever, inflammation, runny nose, and body aches often associated with influenza.

[0029] However, during immunotherapy treatments, cytokine production can easily become uncontrollable. Essentially, immune cells release cytokines, which in turn instruct the immune system to produce more immune cells, which then release even more inflammatory cytokines. A subset of cytokines, known as chemokines, is crucial for recruiting cells to sites of inflammation and help fight pathogens, but this process can have deleterious effects overall. Cytokine production can enter a positive feedback loop, thus creating a so-called "cytokine storm," a situation in which excessive cytokine production triggers an immune response that induces increased cytokine production, which can damage organs, particularly the lungs and kidneys, and even lead to death. Therefore, stimulating the body's immune system to fight cancer can lead to excessive activation of cytokine signaling pathways, which, at least in the short term, is far more dangerous than the cancer itself.

[0030] In one example, the present disclosure provides systems and methods for treating cancer or other diseases with a combination of immunotherapy, which enhances immune system activity, and an immune response modifier (i.e., energy inhibitor). In some examples, the immune response modifier can function to eliminate or otherwise calm overactivated immune cells. The immune response modifier functions to inhibit energy production in immune cells that have become overactivated as a result of a treatment, such as immunotherapy. Examples can include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. Such molecules can function to inhibit cellular energy production in overactivated immune cells, thereby limiting the ability of such cells to produce additional cytokines.

[0031] In another embodiment, the present disclosure provides systems and methods for treating diseases with a therapy that produces harmful amounts of cytokines in combination with an immune response modulator (i.e., energy inhibitor) to reduce cytokine release. The immune response modulator functions to inhibit energy production in immune cells that are releasing harmful levels of cytokines. Examples can include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. Such molecules function to inhibit cellular energy production in cytokine-releasing cells, thereby limiting the ability of such cells to produce additional cytokines. Note that while the present disclosure refers to cytokines and cytokine hyperactivation, this is not intended to limit the scope of the disclosure.

[0032] A variety of conditions treatable using immunotherapy that would benefit from combination with an immune response modifier according to the present disclosure are contemplated, including, but not limited to, viral or other pathogenic diseases, immunodeficiencies, hypersensitivity reactions, autoimmune diseases, tissue and organ transplants, cancer, inflammatory diseases, and vaccination reactions, among others. Specific non-limiting examples include myasthenia gravis, vasculitis, X-linked agammaglobulinemia, transient hypogammaglobulinemia of infancy, common variable immunodeficiency, severe combined immunodeficiency, selective immunoglobulin deficiency, interstitial pneumonia in acquired immunodeficiency states, hyper-IgM syndrome, lupus and lupus-like syndromes, recurrent viral infections in immunodeficiency syndromes, chronic mucocutaneous candidiasis, primary tuberculosis with immunodeficiency, Wiskott-Aldrich syndrome, chronic active hepatitis, coccidioidomycosis, Behcet's disease, aphthous stomatitis, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, autoimmune lymphoproliferative syndrome, idiopathic CD4+ lymphopenia, complement system deficiencies, among others. deficiencies), Chagas disease, lepromatous leprosy, HIV / AIDS, cryptococcal meningitis, septic shock, inflammatory bowel disease, ischemia-reperfusion injury, adult respiratory distress syndrome, osteoporosis, polyarteritis nodosa, glomerulonephritis, chronic granulomatous disease, bone marrow recovery after bone marrow transplantation, primary neutropenia, myelodysplastic syndrome, myeloproliferative disorders, aplastic anemia, and neutropenia associated with Felty's syndrome.

[0033] Additionally, various cancers treatable using immunotherapy that would benefit from combination with an immune response modulator according to the present disclosure are contemplated, including, but not limited to, bladder cancer, born cancer, breast cancer, cervical cancer, colon cancer, keratoacanthoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, and the like, including combinations of such cancers.

[0034] When white blood cells become overactivated, for example, ATP production increases dramatically. If white blood cells become overactivated and begin to damage non-infected tissues in a subject, sepsis and / or other harmful processes can occur, often resulting in significant damage / illness to the subject. By downregulating and / or killing these overactivated immune cells, immune response modulators can further mitigate potential harmful systemic effects.

[0035] One specific, non-limiting example of an immune response modulator that is a useful cellular energy inhibitor is 3-bromopyruvate (3-BP). 3-BP is a small molecule with a chemical structure similar enough to lactate that it enters overactivated cells through an upregulated lactate transport system. 3-BP has little effect on normal cells, because such cells contain few lactate transporters when functioning normally. Once inside overactivated immune cells, 3-BP's highly reactive nature impairs glycolysis and oxidative phosphorylation, thereby significantly reducing ATP production. This reduction in ATP production subsequently leads to the death of overactivated immune cells and the eventual cessation of the effects of overactivation, such as cytokine storms.

[0036] Immunotherapy is a type of treatment that improves the immune system's ability to eliminate a given disease or illness. There are several types of immunotherapy, each of which helps the immune system in a different way. The following describes immunotherapy used to treat cancer, but it should be understood that the scope of the present invention also extends to immunotherapy used to treat other diseases or illnesses.

[0037] Cancer immunotherapy thus improves the immune system's ability to detect and / or eliminate cancer. Below are some non-limiting selections of cancer immunotherapies: As stated above, immunotherapy is defined as a treatment that utilizes a person's own immune system to detect and / or eliminate cancer. In other words, immunotherapy can boost or change how the immune system functions so that it can find and attack cancer cells.

[0038] One common type of immunotherapy used in cancer treatment stimulates the immune system to become more active, making it easier and more effective at finding and eradicating cancer cells. Another common type of immunotherapy uses immune system components produced in vitro in the laboratory to boost the immune system to a level where it can more effectively find and eradicate cancer cells.

[0039] Adoptive Cell Therapy Adoptive cell therapy is an example of a treatment that increases the number and / or effectiveness of immune cells, often T cells, thereby improving the immune response to cancer. There are at least four major types of adoptive cell therapy:

[0040] Chimeric Antigen Receptor (CAR) T-Cell Therapy—The immune system recognizes foreign substances in the body by identifying antigens on their surface. T cells possess immune receptors that specifically bind to foreign antigens, activating other immune system components to initiate processes that degrade or otherwise eliminate the foreign substance associated with the foreign antigen. Antigens expressed by cancer cells may not be sufficiently foreign to bind to immune receptors, and T cells often fail to mount an immune response against them. In CAR T therapy, T cells are harvested from either the patient or a donor and engineered to express a CAR that closely matches the antigen expressed by the targeted cancer. The CAR T cells are expanded and reinfused into the patient, enhancing the T cells' ability to recognize cancer cells as foreign. Examples of cancers treated with CAR T therapy include, but are not limited to, leukemia, lymphoma, and multiple myeloma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, and B-cell acute lymphoblastic leukemia (ALL). Non-limiting examples of specific CAR T cell therapies include axicabtagene siloreucel, brexcabtagene autorucel, siltacabtagene autorucel, idecabtagene bicrueucel, lisocabtagene maraleucel, and tisagenlecleucel.

[0041] Like many other cancer immunotherapies, CAR-T cell therapy can cause side effects, some of which can be severe. For example, increasing the number and activity of a subject's T cells increases the production of cytokines, which are used as signals by T cells. Cytokine release syndrome (CRS) is a potentially serious condition that occurs when cytokine signaling pathways become overactivated, resulting in a continuous increase in cytokine release, further stimulating a mounting immune response. Cases of CRS range from mild to life-threatening.

[0042] Chimeric antigen receptor (CAR) natural killer (NK) cell therapy - NK cells are immune system cells that identify and kill abnormal cells, including some cancer cells. Similar to CAR-T cell therapy, CAR-NK cell therapy is used to enhance the ability of NK cells to detect specific cancers, thereby enabling them to detect cancer cells as foreign.

[0043] Tumor-infiltrating lymphocyte (TIL) therapy - TIL therapy involves taking T cells from a portion of a patient's cancerous tumor; the T cells recognize the cancer but are too few in number to be effective. These cells recognize cancer cells as foreign, but are generally too few in number to fight tumors. In TIL therapy, the T cells are expanded in vitro and then reintroduced back into the subject.

[0044] Endogenous T cell (ETC) therapy - In ETC therapy, T cells are extracted from the subject's blood, from which specific cancer-recognizing T cells are selected based on various biomarker profiles, and these selected T cells are then significantly expanded in number and reintroduced into the subject.

[0045] Cancer vaccines Cancer vaccines represent another form of cancer immunotherapy that is used to stimulate the immune system to recognize and fight specific types of cancer cells. Cancer vaccines often contain one of the following: a) cancer cells taken from a subject's tumor, b) proteins designed to bind to cancer cells to enhance recognition by the immune system, RNA vaccines that use the subject's cellular machinery to produce cancer-associated antigens that stimulate the immune system against cancer cells, or d) proteins specific to the subject's tumor.

[0046] Cytokine therapy Expanding on this discussion, cytokines are small proteins that cannot cross the cellular lipid bilayer and typically bind to cytokine receptors on the surface of target cells. Acting through these cell surface receptors, cytokines play a critical role in the immune system by modulating immune responses and regulating the maturation, growth, and responsiveness of specific cell populations. Furthermore, cytokines can enhance or suppress the actions of other cytokines in response to infection, inflammation, trauma, sepsis, and cancer. The cellular effects of cytokines depend on the specific cytokine, its extracellular abundance, the presence and abundance of complementary receptors on the cell surface, and the downstream signals activated by receptor binding.

[0047] Chemokines are a specific type of cytokine that influences immune cells to migrate toward targets. There are various types of chemokines, including interleukins, interferons, tumor necrosis factors, and growth factors.

[0048] Interleukins - Interleukins are a group of cytokines that act as chemical signals between white blood cells. Interleukin-2 (IL-2) helps immune system cells grow and divide more quickly. One version of IL-2 is used to treat advanced kidney cancer and metastatic melanoma. IL-2 can be used as a single-drug treatment for these cancers or may be combined with chemotherapy or with other cytokines such as interferon-α. Other interleukins, such as IL-7, IL-12, and IL-21, are also being studied for use in cancer, both as adjuvants and as single agents.

[0049] Interferon - Interferon (IFN) is a protein that promotes the body's resistance to infection and cancer. Various types of (IFN) include IFN-α, IFN-β, and IFN-γ. IFN-α is currently used to treat cancer by enhancing the ability of certain immune cells to attack cancer cells. This may directly slow the growth of cancer cells, as well as the blood vessels needed for tumor growth. Cytokine therapy relies on interferons and interleukins to trigger an immune response in the subject's body. For example, IL-2 is used to treat kidney cancer and melanoma that has spread to other parts of the body. IFN-α is currently used to treat melanoma, kidney cancer, and certain leukemias and lymphomas.

[0050] However, cytokine therapy can cause side effects and has been associated with a variety of conditions and diseases, including schizophrenia, major depression, and Alzheimer's disease. T regulatory cells and associated cytokines have also been implicated in and may be involved in the process of tumor immune evasion, potentially functionally inhibiting the immune response against tumors.

[0051] The overproduction of cytokines can further lead to a cytokine storm. The severity of the cytokine storm is greater in individuals with healthy immune systems due to their ability to generate a stronger immune response, resulting in higher cytokine levels compared to individuals with weakened immune systems. During the COVID-19 pandemic, it is believed that the cytokine storm may have contributed to lung tissue damage and coagulation dysfunction, among other things.

[0052] Monoclonal antibodies Antibodies are highly variable proteins that circulate through the bloodstream, bind to foreign antigens, and signal immune cells to attack them. Monoclonal antibodies (mAbs) are antibodies produced by cloned white blood cells. Such mAbs generally have monovalent affinity, meaning they bind to the same substate, or epitope, of the antigen recognized by the antibody. Monoclonal antibodies bind to specific proteins on the surface of cancer cells or immune cells, either 1) marking the cancer as a target for the immune system or 2) enhancing the ability of immune cells to fight cancer.

[0053] mAb therapy for cancer involves the use of mAbs that bind only to cancer cell-specific antigens and induce an immune response against targeted cancer cells. Such mAbs can be modified to deliver toxins, radioisotopes, cytokines, or other active conjugates. Examples of mAbs approved by the FDA for cancer treatment include alemtuzumab, bevacizumab, cetuximab, dostarlimab, gemtuzumab ozogamicin, ipilimumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, ranibizumab, rituximab, and trastuzumab.

[0054] Conjugated Monoclonal Antibodies In conjugated mAb therapy, mAbs are coupled with chemotherapy drugs or radioactive particles. These mAbs are used as homing devices to deliver one of these agents directly to cancer cells. The mAb circulates throughout the body until it finds and binds to the target antigen, thereby delivering the toxic agent specifically to the target cells and reducing damage to healthy cells in other parts of the body. Conjugated mAbs are also sometimes called tagged, labeled, or loaded antibodies.

[0055] Bispecific monoclonal antibodies These drugs are made up of two different mAb parts, meaning they can bind to two different proteins at the same time. An example is blinatumomab (Blincyto), which is used to treat certain types of leukemia. One part of blinatumomab binds to the CD19 protein, which is found on some leukemia and lymphoma cells. Another part binds to CD3, a protein found on immune cells called T cells. By binding to both of these proteins, the drug brings cancer cells and immune cells together, which is thought to prompt the immune system to attack the cancer cells.

[0056] Immune checkpoint inhibitors and their side effects As we have discussed, one important role of the immune system is its ability to detect and signal the presence of foreign substances (e.g., pathogens and cancer cells). This allows the immune system to attack what is foreign while leaving normal cells alone. One mechanism that facilitates this recognition process is through "checkpoint" proteins on immune cells. Checkpoints function as molecular switches that must be activated (or inactivated) to mount an immune response. However, some cancer cells have the ability to bypass these checkpoints and avoid triggering an immune response.

[0057] Immune checkpoint therapy targets immune checkpoints, which are key regulators of the immune system. When stimulated, these checkpoint proteins can dampen the immune response to immune stimulation, which is how some cancers protect themselves from attack. Checkpoint therapy can restore immune system function by blocking inhibitory checkpoints. Thus, immune checkpoint therapy helps cancer-fighting T cells mount a longer-lasting response against cancer.

[0058] Drugs that target various checkpoint proteins are currently used to treat several types of cancer. The monoclonal antibodies mentioned above are one class of drugs that can be used to target these checkpoint proteins. The following non-limiting examples describe some of these drugs.

[0059] PD-1 and PD-L1 inhibitors PD-1 is a checkpoint protein on T cells that normally acts as an inhibitory control, helping to prevent T cells from indiscriminately attacking other cells in the body. PD-1 does this by binding to PD-L1, a protein expressed on normal cells (and some cancer cells). When PD-1 binds to PD-L1, it sends a "normal" signal to the T cell, preventing the T cell from attacking that cell. Some cancer cells overexpress PD-L1 and therefore appear normal to T cells. Monoclonal antibodies targeting either PD-1 or PD-L1 can block this binding and enhance the immune response against cancer cells.

[0060] Both PD-1 and PD-L1 inhibitors have been shown to be useful in treating many different types of cancer. Examples of drugs that target PD-1 include pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo). Examples of drugs that target PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0061] CTLA-4 inhibitors CTLA-4 is another checkpoint protein on some T cells, which acts as a kind of "off switch" that helps keep the immune system in check. Ipilimumab (Yervoy) is a monoclonal antibody that binds to CTLA-4 and removes this inhibitory check, boosting the immune response against cancer. This drug is typically used with a PD-1 inhibitor, such as nivolumab. It can be used to treat melanoma of the skin and several other types of cancer.

[0062] LAG-3 inhibitors LAG-3 is another checkpoint protein on certain immune cells that normally acts as a kind of "off switch" that helps keep the immune system in check. Relatlimab is a monoclonal antibody that binds to LAG-3 and removes this inhibitory control, boosting the immune response against cancer. This drug is given along with the PD-1 inhibitor nivolumab (in a combination known as Opdualag). It can be used to treat melanoma of the skin and is being studied for use in several other types of cancer.

[0063] By targeting checkpoint proteins, these and similar drugs remove one of the body's immune system's safeguards. Sometimes, the immune system responds by attacking other parts of the body, which can lead to serious or life-threatening problems in the lungs, intestines, liver, hormone-producing glands, kidneys, or other organs. This process, in which the immune system attacks the body's organs and tissues, is known as an autoimmune response. By using immune response modulators (e.g., 3-bromopyruvate, as disclosed herein) that remove such checkpoints, overactive immune cells are eliminated before an autoimmune response can occur. Furthermore, it should be noted that autoimmune responses can also occur with other immunotherapies, and therefore, the prevention or reduction of autoimmune responses associated with other immunotherapies is considered within the scope of the present invention.

[0064] immunomodulators Immunomodulators are a group of drugs that primarily target pathways to treat multiple myeloma and some other cancers. They work in a variety of ways, including directly affecting the immune system by decreasing some proteins and increasing others.

[0065] Immune response regulator / cellular energy inhibitor Generally, there are two energy (ATP)-producing factories within cells: glycolysis and mitochondrial oxidative phosphorylation. In normal cells, approximately 5% of total cellular energy (ATP) production comes from glycolysis, and approximately 95% comes from mitochondria. In overactivated immune cells, energy production through glycolysis can be significantly increased (up to 60%). This dramatic increase in glycolysis results in a significant increase in lactate production.

[0066] Examples of cellular energy inhibitors include lactate, iodoacetate, pyruvate, and halopyruvates, including their salts and acids. In one specific example, a presently disclosed cellular energy inhibitor (immune response modulator) is 3-bromopyruvate (3-BP) (a lactic acid analog).

[0067] As mentioned above, 3-BP is a small molecule with a chemical structure sufficiently similar to lactate that it can enter overactivated cells through an upregulated lactate transport system. 3BP has little effect on normal cells, because such cells contain few lactate transporters when functioning normally. Once inside overactivated immune cells, 3-BP's highly reactive nature impairs glycolysis and oxidative phosphorylation, thereby significantly reducing ATP production. This reduction in ATP production subsequently leads to the death of overactivated immune cells and the eventual cessation of the effects of overactivation, such as cytokine storms.

[0068] In addition to functioning as an immune response regulator, 3-halopyruvates, such as 3-BP, can function as immunotherapeutic agents. This dual function allows 3-BP to act as an immune response regulator and additional immunotherapy for the effects of an overactive immune system.

[0069] In one embodiment, 3-BP exerts its immunotherapeutic effect against the PD-1 / PD-L1 immune checkpoint (discussed above) by inhibiting the binding of PD-1 to PD-L1. Without wishing to be bound by any scientific theory, 3-BP binds to PD-1 with sufficiently high affinity to prevent PD-1 from binding to PD-L1. As discussed above, PD-1 / PD-L1 binding produces an inhibitory effect by signaling T cells not to attack cells because they are "self" as opposed to "foreign invaders." Thus, 3-BP binding to PD-1 removes this inhibitory control, allowing T cells to recognize and attack cancer cells as foreign.

[0070] Furthermore, 3-BP has a direct therapeutic effect on cancer cells due to its ability to inhibit energy production within the cells. Once energy production is inhibited, the cells begin to die and release their contents into the tissue, which triggers a local immune response and results in increased immune recognition of the remaining cancer cells.

[0071] In one specific embodiment, the cellular energy inhibitor can be a molecule according to Formula I: [ka]

[0072] A variety of specific molecules are contemplated, where, for example, X may be, but is not limited to, nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, amine oxide, etc. Additionally, R may be, but is not limited to, OR', N(R")2, C(O)R'", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, alkali metal, etc., where R' represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R'", R" represents H, C1-C6 alkyl, or C6-C12 aryl, and R'" represents H, C1-C20 alkyl, or C6-C12 aryl.

[0073] In some embodiments, the cellular energy inhibitor composition can include various excipients, activators, prodrugs, metabolites, buffers, etc., such as, for example, one or more sugars, polyhydric alcohols, etc., glycolytic inhibitors, biological buffers, etc. In some embodiments, the cellular energy inhibitor molecule can be formulated in the composition with at least one sugar that can stabilize the cellular energy inhibitor by substantially preventing the cellular energy inhibitor from hydrolysis.

[0074] In one embodiment, R in formula (I) can be OH, and X in formula (I) can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, amine oxide, etc. Additionally, X can be a halide, such as fluoride, bromide, chloride, iodide, etc. In one embodiment, X can be a sulfonate, such as triflate, mesylate, tosylate, etc. In another embodiment, X can be an amine oxide. In yet another embodiment, the amine oxide can be dimethylamine oxide.

[0075] In another example, the cellular energy inhibitor may be a 3-halopyruvate, such as 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof. A general structure showing the halide at the 3-position is represented by Formula II: [ka]

[0076] In a further non-limiting example, the cellular energy inhibitor can have a bromine at the 3-position, as shown in Formula III. [ka]

[0077] In one further non-limiting example, the cellular energy inhibitor can be 3-bromopyruvate (3-BP), as shown in Formula IV. [ka]

[0078] In another non-limiting example, the cellular energy inhibitor can be 3-bromopyruvic acid, as shown in Formula V: [ka]

[0079] It should be noted that 3-bromopyruvate or 3-bromopyruvic acid may be referred to herein as "3-BP," and the two molecules may be used interchangeably unless the context clearly dictates otherwise.

[0080] In some embodiments, the cellular energy inhibitor may be formulated in a composition with at least one sugar, which can stabilize the cellular energy inhibitor by substantially preventing hydrolysis of the cellular energy inhibitor. In some embodiments, a composition may include, for example, 3-BP as the cellular energy inhibitor and at least one sugar, at least two sugars, at least three sugars, etc. In one embodiment, the sugar may include a monosaccharide, a disaccharide, an oligosaccharide, or a combination thereof. Non-limiting examples of monosaccharides may include glucose, fructose, galactose, etc. Non-limiting examples of disaccharides may include sucrose, lactose, maltose, etc. It is noted that for purposes of this disclosure, the term "sugar" may also include oligosaccharides, polysaccharides, polyols, polyhydric alcohols, and similar molecules that function to stabilize 3-BP.

[0081] Sugars can include 3-carbon sugars, 4-carbon sugars, 5-carbon sugars, 6-carbon sugars, 7-carbon sugars, etc., including combinations thereof. In one aspect, the sugars can be trioses, tetraoses, pentoses, hexoses, heptoses, etc., including combinations thereof, provided that the sugars are not involved in energy metabolism to the extent that they produce energy (i.e., non-metabolizable sugars).

[0082] In one embodiment, the sugar may be gluconic acid. In another embodiment, the sugar may be glucuronic acid. At least one of the sugars may be a pentose. In one embodiment, at least two of the sugars may be pentoses. The pentoses may be independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, and the like, including combinations thereof. In one embodiment, at least one of the sugars may be glycerol. In another embodiment, the sugars may be glycerol, inositol, and sorbitol. Other non-limiting examples of sugars may include ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetriitol, and polyglycitol, including combinations thereof. In one embodiment, the sugar may include glycerol, inositol, sorbitol, mannitol, or any combination thereof. In another embodiment, the sugar can include glycerol, inositol, sorbitol, or any combination thereof. In yet another embodiment, the inositol can be myo-inositol. In other embodiments, the sugar can be a polyhydric alcohol.

[0083] The sugars described herein may be in any isomeric form. In one embodiment, the compositions described herein may include a form of the sugar that has a lower biological activity than its isomer. In some cases, the sugar with a lower biological activity may be an L-enantiomer sugar. However, if a D-enantiomer sugar is known to have a lower biological activity than its L-enantiomer, the D-enantiomer can be used. In one embodiment, such sugars can function as glycolysis inhibitors.

[0084] In one embodiment, the composition may comprise one or more sugars in the range of about 0.5% to about 50.0% by weight, or about 1.0% to about 25.5% by weight. In yet another embodiment, the composition may comprise one or more sugars in the range of about 0.2% to about 75.0% by weight, or about 0.5% to about 50.0% by weight. In further embodiments, the composition may comprise one or more sugars in the range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

[0085] In some examples, the composition may contain glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight. In other examples, the composition may contain inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight. In further examples, the composition may contain sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight. In still further examples, the composition may contain mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight. Additionally, each sugar may be added to the formulation or composition in a volumetric amount up to the sugar's maximum solubility. Note also that the weight percentages of the ingredients listed above do not include water or other liquid carriers. Additionally, each sugar may be added to the formulation or composition in a volumetric amount up to the sugar's maximum solubility.

[0086] Generally, 3-BP can be formulated into any type of dosage form that can be delivered to a subject. Such dosage forms can be enteral, parenteral, transdermal, etc. Enteral dosage forms can be sustained-release or immediate-release and can include, but are not limited to, tablets, troches, capsules, caplets, encapsulated pellets, encapsulated granules, encapsulated powders, gelatin capsules, liquids, syrups, elixirs, suspensions, sprays, aerosols, powders, etc., including combinations thereof. Non-limiting examples of transdermal dosage forms include lotions, gels, creams, pastes, ointments, liquid sprays, liquid drops, powder sprays, wipes, emulsions, aerosols, transmucosal tablets, adhesive devices, adhesive matrix transdermal patches, liquid reservoir transdermal patches, microneedle devices, magnetic devices, etc. Non-limiting examples of parenteral dosage forms include intravenous, subcutaneous, etc.

[0087] In some embodiments, the 3-BP composition can include a biological buffer present in an amount sufficient to at least partially deoxidize the cellular energy inhibitor and neutralize metabolic byproducts of the cellular energy inhibitor. Non-limiting examples of biological buffers can include citrate buffer, phosphate buffer, acetate buffer, and the like, including combinations thereof. In one specific embodiment, the biological buffer can be a citrate buffer, such as, but not limited to, sodium citrate. In another specific embodiment, the biological buffer can be a phosphate buffer, such as, but not limited to, sodium phosphate. In one specific embodiment, the biological buffer can be an acetate buffer, such as, but not limited to, sodium acetate. In yet other embodiments, the biological buffer can include at least two biological buffers, such as, but not limited to, a citrate buffer and an acetate buffer, a citrate buffer and a phosphate buffer, an acetate buffer and a phosphate buffer, or a citrate buffer, a phosphate buffer and an acetate buffer.

[0088] In some examples, the composition may include a biological buffer at a concentration of about 0.1 mM to about 200 mM. In one embodiment, the composition may include a biological buffer at a concentration of about 1 mM to about 20 mM. In some examples, the composition may include a biological buffer in a range of about 0.1% to about 15% by weight, or about 2.0% to about 8.0% by weight. Furthermore, the biological buffer is capable of maintaining a physiological pH of 4.0 to 8.5. In one embodiment, the biological buffer is capable of maintaining a physiological pH of 5.5 to 8.0. In another embodiment, the biological buffer is capable of maintaining a physiological pH of 6.8 to 7.8. In yet another embodiment, the biological buffer is capable of maintaining a physiological pH of 7.3 to 7.6. It should also be noted that the weight percentages of the components listed above do not include water or other liquid carriers.

[0089] In some embodiments, the 3-BP formulations of the present invention may include, but are not limited to, antifungals, antibiotics, glycolytic inhibitors, mitochondrial inhibitors, sugars, and biological buffers. Examples of such agents include, but are not limited to, amphotericin B, efrapeptin, doxorubicin, (2-DG), analogs of 2-DG, d-lactic acid, dichloroacetic acid (or the salt form of dichloroacetate), oligomycin, analogs of oligomycin, glycerol, inositol, sorbitol, glycol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitate, succinate, fumarate, malate, dilute saline solutions having various concentrations of NaCl, and water. In addition to the sodium ions associated with these biological buffers, calcium and potassium cations may also be associated with the biological buffers. Various active agents of the composition may include cellular energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halo monocarboxylate compounds, antifungal agents, antibiotic agents, etc. In the various dosage forms described above, any of the above ingredients may be included with 3-BP, any of the excipients, or in a separate container.

[0090] In addition to the above components, the 3-BP compositions described herein may further comprise a halogenated monocarboxylate compound separate from the cellular energy inhibitor. If the halogenated monocarboxylate compound can act to inhibit glycolysis and / or mitochondrial function, the halogenated monocarboxylate can be considered a second cellular energy inhibitor. In one embodiment, the halogenated monocarboxylate compound may be a two-carbon halogenated monocarboxylate compound. The two-carbon halogenated monocarboxylate compound may be selected from, but is not limited to, 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and the like, including combinations thereof. In one embodiment, the two-carbon halogenated monocarboxylate compound may be 2-bromoacetate. In one example, the composition may comprise the two-carbon halogenated monocarboxylate compound at a concentration of about 0.01 mM to about 5.0 mM. In another example, the composition may include a monocarboxylate compound halogenated at the 2-carbon position at a concentration of about 0.1 mM to about 0.5 mM.

[0091] Furthermore, the halogenated monocarboxylate compound may be a monocarboxylate compound having a halogenated carbon at the 3-position. In one embodiment, the monocarboxylate compound having a halogenated carbon at the 3-position may be selected from, but is not limited to, 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, and the like, including combinations thereof. In another example, the composition may include a monocarboxylate compound having a halogenated carbon at the 3-position at a concentration of about 0.5 mM to about 250 mM. In one embodiment, the composition may include a monocarboxylate compound having a halogenated carbon at the 3-position at a concentration of about 10 mM to about 50 mM.

[0092] In some embodiments, the 3-BP formulations described herein may further comprise a mitochondrial inhibitor in addition to a cellular energy inhibitor. The mitochondrial inhibitor may be selected from, but is not limited to, oligomycin, efrapeptin, aurovertin, and the like, including combinations thereof. In another embodiment, the composition may comprise the mitochondrial inhibitor at a concentration of about 0.001 mM to about 5.0 mM. In one embodiment, the composition may comprise the mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM.

[0093] In some examples, the 3-BP compositions described herein may further comprise an antifungal and / or antibacterial agent. In one embodiment, the composition may comprise an antifungal and / or antibacterial agent individually at a concentration of about 0.01 mM to about 5.0 mM. In another embodiment, the composition may comprise an antifungal and / or antibacterial agent individually at a concentration of about 0.05 mM to about 0.5 mM.

[0094] In some embodiments, the 3-BP formulation can include a glycolysis inhibitor. Many suitable glycolysis inhibitors are contemplated, but a non-limiting list can include 2-DG, lonidamine, imatinib, oxythiamine, 6-aminonicotinamide, genistein, 5-thioglucose (5-TG), mannoheptulose, α-chlorohydrin, ornidazole, oxalate, glufosfamide, and the like, including combinations thereof. The 3-BP formulation can include any effective amount of a glycolysis inhibitor.

[0095] In addition to the concentrations described above, the compositions may have various ratios of the components described herein. In one embodiment, the cellular energy inhibitor and biological buffer may be present in a ratio ranging from 1:1 to 1:5 in mM. In another embodiment, the cellular energy inhibitor and glycolytic inhibitor may be present in a ratio ranging from 5:1 to 1:1 in mM. In yet another embodiment, the cellular energy inhibitor and at least one sugar may be present in a ratio ranging from 1:1 to 1:5 in mM. In yet another embodiment, the cellular energy inhibitor and 2-carbon halogenated monocarboxylate compound may be present in a ratio ranging from 20:1 to 4:1 in mM. In yet another embodiment, the cellular energy inhibitor and mitochondrial inhibitor may be present in a ratio ranging from 20:1 to 40:1 in mM.

[0096] In some examples, the 3-BP compositions described herein can further comprise a hexokinase inhibitor. The hexokinase inhibitor can be any molecule that inhibits hexokinase 1, hexokinase 2, and / or their isozymes (collectively referred to herein as "hexokinases"). As used herein, "hexokinase 1" or "hexokinase 1 isozyme" refers to any isoform of hexokinase 1 and naturally known variants thereof, including those provided in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, as follows: [Table 1] [Table 2] [Table 3] [Table 4]

[0097] As used herein, "hexokinase 2" or "hexokinase 2 isozyme" refers to any isoform of hexokinase 2 and its naturally occurring variants, including those provided in SEQ ID NO: 5, as follows: [Table 5]

[0098] As mentioned above, the primary source of ATP production occurs in the mitochondria of normal cells. However, in cancer cells, ATP production through glycolysis is significantly upregulated. One reason for this upregulation is that hexokinase molecules bind to and complex with the mitochondrial voltage-dependent anion channel (VDAC) in ATP synthasomes, forming so-called "ATP synthasome megacomplexes." The formation of these ATP synthasome megacomplexes allows cancer cells to become immortal and continuously use the cellular energy production process for cancer growth. Therefore, hexokinase inhibitors can either block hexokinase binding to the VDAC or displace hexokinase molecules from the VDAC of already formed ATP synthasome megacomplexes.

[0099] In one example, the hexokinase inhibitor may be up to 25 amino acid units from the N-terminal region of hexokinase 2 isozyme or hexokinase 1 isozyme. In another example, the hexokinase inhibitor may be an amino acid sequence of 5 to 20 amino acid units, wherein the 5 to 20 amino acid sequence is present in the first 25 amino acid unit region starting from the N-terminus of hexokinase 1 isozyme or hexokinase 2 isozyme. In one example, the 5 to 20 amino acid sequence may be any 5 to 20 amino acid sequence present in the first 25 amino acid unit region of the N-terminus of hexokinase 11 or hexokinase 2. Such amino acid sequences can displace hexokinase bound to cells or competitively bind to voltage-dependent anion channels (VDACs) to prevent initial hexokinase binding.

[0100] In other examples, the hexokinase inhibitor can include an antibody against a portion of HK1 or HK2, such as the N-terminal region of the HK1 or HK2 molecule. In one specific example, the hexokinase inhibitor can be an amino acid sequence such as SEQ ID NO: 6, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 1), which has the sequence: [Table 6]

[0101] In another example, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 7, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 2), which has the sequence: [Table 7]

[0102] In yet another embodiment, the hexokinase inhibitor may have an amino acid sequence such as SEQ ID NO: 8, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 3), which has the sequence: [Table 8]

[0103] In yet another embodiment, the hexokinase inhibitor may have an amino acid sequence such as SEQ ID NO: 9, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 4), which has the sequence: [Table 9]

[0104] In yet another embodiment, the hexokinase inhibitor may have an amino acid sequence such as SEQ ID NO: 10, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 2, which has the sequence: [Table 10]

[0105] Additional hexokinase inhibitors may be those disclosed in U.S. Patent No. 5,854,067 (Newgard et al., issued December 29, 1998) and / or U.S. Patent No. 5,891,717 (Newgard et al., issued April 6, 1999), both of which are incorporated by reference in their entireties. Additional hexokinase inhibitors that can be used in the present formulations include those disclosed in U.S. Patent Nos. 6,670,330; 6,218,435; 5,824,665; 5,652,273; and 5,643,883; and U.S. Patent Application Publication Nos. 20030072814; 20020077300; and 20020035071, the entire texts of which are each incorporated by reference herein.

[0106] In some embodiments, the 3-BP compositions described herein can further comprise various ingredients, as listed below. In the various dosage forms described above in Figures 4-7, any of these various ingredients can be mixed with 3-BP, provided they do not react with 3-BP, or they can be present in a separate layer or any of the layers described above, provided they are reactively isolated in the reservoir form.

[0107] In one embodiment, the composition can promote cancer cell starvation by including an amino acid with lower biological activity than its isomer. In one aspect, the amino acid with lower biological activity can be a D-amino acid. However, if the L-amino acid has lower biological activity than the D-isomer, the L-amino acid can also be used.

[0108] In one embodiment, the composition may include a DNA replication inhibitor, a DNA binding inhibitor, and / or a DNA transcription inhibitor. In another embodiment, the composition may include an inhibitor of cell cycle, growth, and / or proliferation. In yet another embodiment, the composition may include an inhibitor of a signal transduction pathway. In yet another embodiment, the composition may include an inhibitor of angiogenesis. In yet another embodiment, the composition may include small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA. In yet another embodiment, the composition may include a dietary supplement containing vitamin C; vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, goji berry, mango, pomegranate, L-carnitine, selenium, or the like.

[0109] Thus, therapeutic systems are contemplated, including immunotherapy treatment systems comprising an immunotherapy and an immune response modifier composition. Such therapeutic systems may be delivered to a subject separately or mixed together in a single delivery composition or multiple delivery compositions. In some examples, the immunotherapy component is delivered first, followed by the immune response modifier at any of a variety of times after the immunotherapy, which may vary from therapy to therapy. For example, administration of the immune response modifier can occur minutes, hours, days, or even weeks after administration of the immunotherapy component. In other examples, the immune response modifier is delivered first, followed by the immunotherapy component at any of a variety of times after the immune response modifier, which may vary from therapy to therapy. For example, administration of the immunotherapy component can occur minutes, hours, days, or even weeks after administration of the immune response modifier.

[0110] For example, an immunotherapy treatment system can include an immune response modifier composition and an adoptive cell therapy component, such as, for example, chimeric antigen receptor (CAR) T cell therapy, chimeric antigen receptor (CAR) natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy.

[0111] In another example, therapeutic systems are contemplated, including immunotherapy treatment systems, including various cancer vaccines and immune response modifier compositions, which may be delivered to a subject separately or mixed together in a single delivery composition or multiple delivery compositions.

[0112] In some embodiments, the immunotherapy component is delivered first, followed by the immune response modifier, at a different time after the immunotherapy, which may vary depending on the therapy. For example, the immune response modifier may be administered minutes, hours, days, or even weeks after the cancer vaccine component. In other embodiments, the immune response modifier is delivered first, followed by the cancer vaccine component, at a different time after the immune response modifier, which may vary depending on the therapy. For example, the cancer vaccine component may be administered minutes, hours, days, or even weeks after the immune response modifier. Immune response modifiers may include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. One specific example of an immune response modifier is 3-BP.

[0113] In another example, a therapeutic system is contemplated, including an immunotherapy treatment system comprising a cytokine therapy component and an immune response modifier composition. Such therapeutic systems can be delivered to a subject separately or mixed together in a single delivery composition or multiple delivery compositions. In some examples, the cytokine therapy component is delivered first, followed by the immune response modifier at various times after the cytokine therapy component, which can vary from therapy to therapy. For example, administration of the immune response modifier can occur minutes, hours, days, or even weeks after administration of the cytokine therapy component. In other examples, the immune response modifier is delivered first, followed by the cytokine therapy component at various times after the immune response modifier, which can vary from therapy to therapy. For example, administration of the cytokine therapy component can occur minutes, hours, days, or even weeks after administration of the immune response modifier. Immune response modifiers include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. One specific example of an immune response modifier is 3-BP.

[0114] In another example, a therapeutic system is contemplated, including an immunotherapy treatment system comprising a monoclonal antibody (mAb) component and an immune response modifier composition. Such therapeutic systems can be delivered to a subject separately or mixed together in a single delivery composition or multiple delivery compositions. In some examples, the mAb component is delivered first, followed by the immune response modifier at various times after the mAb component, which can vary from therapy to therapy. For example, administration of the immune response modifier can occur minutes, hours, days, or even weeks after administration of the mAb component. In other examples, the immune response modifier is delivered first, followed by the mAb component at various times after the immune response modifier, which can vary from therapy to therapy. For example, administration of the mAb component can occur minutes, hours, days, or even weeks after administration of the immune response modifier. The mAb component can include, but is not limited to, mAb compositions such as alemtuzumab, bevacizumab, cetuximab, dostarlimab, gemtuzumab ozogamicin, ipilimumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, ranibizumab, rituximab, and trastuzumab. Furthermore, the mAb component can be a conjugated mAb and / or a bispecific mAb therapy. The immune response modifier can include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. One specific example of an immune response modifier is 3-BP.

[0115] In another example, a therapeutic system is contemplated, including an immunotherapy treatment system comprising an immune checkpoint modulator component and an immune response modulator composition. Such therapeutic systems may be delivered to a subject separately or mixed together in a single delivery composition or multiple delivery compositions. In some examples, the immune checkpoint modulator component is delivered first, followed by delivery of the immune response modulator at various times after the immune checkpoint modulator component, which may vary from therapy to therapy. For example, administration of the immune response modulator can occur minutes, hours, days, or even weeks after administration of the immune checkpoint modulator component. In other examples, the immune response modulator is delivered first, followed by delivery of the immune checkpoint modulator component at various times after the immune response modulator, which may vary from therapy to therapy. For example, administration of the immune checkpoint modulator component can occur minutes, hours, days, or even weeks after administration of the immune response modulator.

[0116] Non-limiting examples of immune checkpoint regulator components include PD-1 and PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, etc. Specific immune checkpoint regulator components targeting PD-1 include pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), while examples targeting PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). Furthermore, examples of immune checkpoint regulator components targeting CTLA-4 and LAG-3 inhibitors include ipilimumab (Yervoy) and leratolimab, respectively. Immune response regulators can include lactate, iodoacetate, pyruvate, and various halopyruvates, including their salts and acids. One specific example of an immune response regulator is 3-BP.

[0117] [Embodiment] (1) A system for treating a disease susceptible to excessive activation of a subject's immune system, comprising: immunotherapeutic drugs that can treat diseases by modulating the activity of the subject's immune system; 1. An immune response modifier composition comprising: 3-bromopyruvic acid (3-BP) and its salts, at least one sugar to stabilize the 3-BP by substantially preventing the 3-BP from hydrolyzing; a biological buffer present in an amount sufficient to at least partially deacidify and neutralize metabolic by-products of said 3-BP; an immune response modifier composition comprising: Including, the system. (2) The system of embodiment 1, wherein the immunotherapeutic agent is capable of treating an immune deficiency, a hypersensitivity reaction, an autoimmune disease, a pathogenic infection, a tissue or organ transplant, a cancer, an inflammatory disease, an infectious disease, a vaccination reaction, or a combination thereof. (3) The system of embodiment 2, wherein the immunotherapeutic drug is capable of treating cancer. (4) The system of embodiment 1, wherein the at least one sugar is a member selected from the group consisting of gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetritoitol, polyglycitol, and combinations thereof. (5) The system of embodiment 1, wherein the immune response modifier composition further comprises a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

[0118] (6) The system of embodiment 1, wherein the immune response modifier composition further comprises a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, sorbitol, or a combination thereof. (7) The system of embodiment 1, wherein the immune response modifier composition further comprises at least one sugar selected from glycerol, inositol, and sorbitol. (8) The system of embodiment 1, wherein the immune response regulator composition further comprises d-lactic acid and epinephrine. (9) The system of embodiment 1, wherein the immune response regulator composition further comprises a glycolysis inhibitor. (10) The system described in embodiment 9, wherein the glycolysis inhibitor is 2-deoxyglucose.

[0119] (11) The system according to embodiment 10, wherein the 2-deoxyglucose is at a concentration of about 1 mM to about 5 mM. (12) The system of embodiment 1, wherein the biological buffer is selected from a citrate buffer, a phosphate buffer, and an acetate buffer. (13) The system of embodiment 1, wherein the biological buffer is a citrate buffer. (14) The immune response modifier composition may comprise an immune system modulator and / or immune system booster, including phospholipids; liposomes; nanoparticles; brown rice extract, muramyl dipeptide including analogs, mushroom extract, bioflavonoids, vitamin D3 binding protein-derived macrophage-activating factor (GcMAF), Nagalase inhibitors, threonine linked to N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and and / or proliferation inhibitors; inhibitors of signal transduction pathways; inhibitors of angiogenesis; small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; dietary supplements containing vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, goji berry, mango, pomegranate, L-carnitine, and selenium; amino acids that have lower biological activity than their isomers; and mixtures thereof. (15) The system of embodiment 1, wherein the immune response modifier composition further comprises a hexokinase inhibitor.

[0120] (16) A method for treating a disease susceptible to excessive activation of a subject's immune system, comprising: administering to the subject an immunotherapeutic agent capable of increasing the activity of the immune system to treat the disease; delivering an immune response modifier composition to the subject to eliminate or otherwise calm overly activated immune cells, wherein the immune response modifier comprises: 3-bromopyruvic acid (3-BP) and its salts, at least one sugar to stabilize the 3-BP by substantially preventing the 3-BP from hydrolyzing; a biological buffer present in an amount sufficient to at least partially deacidify and neutralize metabolic by-products of said 3-BP; and A method comprising: (17) The system of embodiment 16, wherein the disease is an immunodeficiency, a hypersensitivity reaction, an autoimmune disease, a pathogenic infection, a tissue or organ transplant, a cancer, an inflammatory disease, an infectious disease, a vaccination reaction, or a combination thereof. (18) The method of embodiment 17, wherein the disease is cancer. (19) The method of embodiment 16, further comprising determining excessive activation of the subject's immune system prior to administering the immune response modifier. (20) The method of embodiment 16, wherein the excessive activation of the subject's immune system further comprises the production of harmful amounts of cytokines.

[0121] 21. The method of claim 20, further comprising administering the immune response modifier to reduce the harmful amount of cytokines. (22) The method of embodiment 21, wherein delivery of the immune response modifier composition inhibits cellular energy production in overactivated immune cells, thereby limiting the ability of the overactivated immune cells to produce additional cytokines.

Claims

1. 1. A system for treating a disease susceptible to overactivation of a subject's immune system, comprising: immunotherapeutic drugs that can treat diseases by modulating the activity of the subject's immune system; 1. An immune response modifier composition comprising: 3-bromopyruvic acid (3-BP) and its salts, at least one sugar to stabilize the 3-BP by substantially preventing the 3-BP from hydrolyzing; a biological buffer present in an amount sufficient to at least partially deacidify and neutralize metabolic by-products of said 3-BP; an immune response modifier composition comprising: Including, the system.

2. 10. The system of claim 1, wherein the immunotherapeutic agent is capable of treating an immune deficiency, a hypersensitivity reaction, an autoimmune disease, a pathogenic infection, a tissue or organ transplant, cancer, an inflammatory disease, an infectious disease, a vaccination reaction, or a combination thereof.

3. The system of claim 2 , wherein the immunotherapeutic drug is capable of treating cancer.

4. 2. The system of claim 1, wherein the at least one sugar is a member selected from the group consisting of gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetritoitol, polyglycitol, and combinations thereof.

5. 10. The system of claim 1, wherein the immune response modifier composition further comprises a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

6. 10. The system of claim 1, wherein the immune response modifier composition further comprises a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, or combinations thereof.

7. 10. The system of claim 1, wherein the immune response modifier composition further comprises at least one sugar selected from glycerol, inositol, and sorbitol.

8. The system of claim 1, wherein the immune response modifier composition further comprises d-lactic acid and epinephrine.

9. The system of claim 1 , wherein the immune response modifier composition further comprises a glycolysis inhibitor.

10. The system of claim 9, wherein the glycolysis inhibitor is 2-deoxyglucose.

11. The system of claim 10, wherein the 2-deoxyglucose is at a concentration of about 1 mM to about 5 mM.

12. 10. The system of claim 1, wherein the biological buffer is selected from a citrate buffer, a phosphate buffer, and an acetate buffer.

13. The system of claim 1 , wherein the biological buffer is a citrate buffer.

14. The immune response modifier composition may be selected from the group consisting of phospholipids, liposomes, nanoparticles, immune system modulators and / or immune system boosters including brown rice extract, muramyl dipeptide including analogs, mushroom extract, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine linked to N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and 10. The system of claim 1, further comprising at least one additive selected from the group consisting of inhibitors of cell proliferation and / or proliferation; inhibitors of signal transduction pathways; inhibitors of angiogenesis; small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; dietary supplements containing vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, goji berry, mango, pomegranate, L-carnitine, and selenium; amino acids that have lower biological activity than their isomers; and mixtures thereof.

15. The system of claim 1 , wherein the immune response modifier composition further comprises a hexokinase inhibitor.

16. 1. A method for treating a disease susceptible to overactivation of a subject's immune system, comprising: administering to the subject an immunotherapeutic agent capable of increasing the activity of the immune system to treat the disease; delivering an immune response modifier composition to the subject to eliminate or otherwise calm overly activated immune cells, wherein the immune response modifier comprises: 3-bromopyruvic acid (3-BP) and its salts, at least one sugar to stabilize the 3-BP by substantially preventing the 3-BP from hydrolyzing; a biological buffer present in an amount sufficient to at least partially deacidify and neutralize metabolic by-products of said 3-BP; and A method comprising:

17. 17. The method of claim 16, wherein the disease is an immunodeficiency, a hypersensitivity reaction, an autoimmune disease, a pathogenic infection, a tissue or organ transplant, cancer, an inflammatory disease, an infectious disease, a vaccination reaction, or a combination thereof.

18. 18. The method of claim 17, wherein the disease is cancer.

19. 17. The method of claim 16, further comprising determining excessive activation of the subject's immune system prior to administering the immune response modifier.

20. 17. The method of claim 16, wherein the excessive activation of the subject's immune system further comprises the production of harmful amounts of cytokines.

21. 21. The method of claim 20, further comprising administering said immune response modifier to reduce said harmful amount of cytokines.

22. 22. The method of claim 21, wherein delivery of the immune response modifier composition inhibits cellular energy production in overactivated immune cells, thereby limiting the ability of the overactivated immune cells to produce additional cytokines.

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