CROSS-REFERENCE TO RELATED APPLICATION

[001] This application claims the benefit of, and priority to, U.S. Provisional Application No. 63/288,411, filed on December 10, 2021, the content of which is hereby incorporated by reference in its entirety.

BACKGROUND

[002] The National Cancer Institute has estimated that in the United States, 1 in 3 people will develop cancer during their lifetime. Moreover, approximately 50% to 60% of individuals contracting cancer will eventually succumb to the disease. Despite advances in cancer therapy, existing therapeutic modalities still fail to adequately control or cure many cancers, and those therapeutic modalities that are available often contribute to and/or fail to prevent secondary conditions, in particular those secondary conditions associated with late-stage cancer, that may endanger the patient. These secondary conditions include, for example, sepsis/septicemia, pneumonia, and fungal infection, as well as immunoparalysis resulting from one or more of these secondary conditions. In addition, many of the available therapeutic modalities for treating cancer (e.g., radiation and chemotherapy) are myeloablative, which imparts dose-limiting toxicities and renders the patient vulnerable to secondary clinical conditions, such as bacterial, viral, and fungal infections, which can compromise treatment outcomes.

[003] Current therapeutic modalities to treat or prevent secondary conditions associated with late-stage cancer (e.g., sepsis, pneumonia, and/or fungal infection), including antibiotic, antiviral, and antifungal drugs, may not be sufficient to provide desired treatment outcomes (e.g., resolution of the condition), which may result in death of the patient in need of treatment. Further, current therapeutic modalities may also be insufficient to treat or prevent the secondary conditions associated with cancer therapy, as described above. There is thus an unmet need for novel therapeutic strategies and methods for addressing these conditions, in particular when they are associated with late-stage cancer.

SUMMARY

[004] The present disclosure provides methods of treating or preventing various conditions, diseases, or disorders (e.g., cancer, sepsis/septicemia, pneumonia, fungal infection, immunoparalysis, COVID- 19, and myeloablation) in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effective amount of a soluble 0- glucan, wherein administering the soluble 0-glucan induces trained immunity in the subject, thereby treating or preventing the condition, disease, or disorder. In some embodiments, the condition, disease or disorder is a cancer described herein. In some embodiments, the condition, disease, or disorder is associated with a cancer described herein (e.g., sepsis/septicemia, pneumonia, fungal infection, immunoparalysis) and/or the treatment of cancer (e.g., administration of a chemotherapeutic agent and/or radiation therapy). In some embodiments, the condition, disease, or disorder is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection and/or COVID- 19.

[005] In one aspect, the disclosure provides a method of treating sepsis and/or septicemia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons (kDa) to about 400 kDa. In another aspect, the present disclosure provides a method of treating pneumonia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons. In another aspect, the present disclosure provides a method of treating immunoparalysis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject, wherein the soluble p- glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons. In another aspect, the present disclosure provides a method of treating a fungal infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[006] In another aspect, the present disclosure provides a method of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or COVID- 19 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject.

[007] In another aspect, the present disclosure provides a method of enhancing myelopoiesis in a subject to be administered a myeloablative therapy, the method comprising administering to the subject prior to the administration of the myeloablative therapy a therapeutically effective amount of a soluble p-glucan. wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[008] In another aspect, the present disclosure provides a method of enhancing myelopoiesis in a subject that has been administered a myeloablative therapy, the method comprising (i) contacting a plurality of hematopoietic stem cells (HSC) and/or a plurality of myeloid progenitor cells from a donor with a therapeutically effective amount of soluble P-glucan, and (ii) administering to the subject a therapeutically effective amount of the plurality of HSCs and/or the plurality of myeloid progenitor cells.

[009] In another aspect, the present disclosure provides a method of inducing trained immunity in a subject with cancer, the method consisting of administering to the subject a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the therapeutically effective amount of soluble P-glucan is administered to the subject at least about one day prior to a first administration of a cancer immunotherapy.

BRIEF DESCRIPTION OF THE FIGURES

[010] FIG. 1 is a heat map showing increased gene expression of glycolysis markers (e.g., 1 - ADPGK, 2 - ALDH1A1, 3 - ALDH2, 4 - ALDOA, 5 - BPGM, 6 - ENO1, 7 - ENO2, 8 - GAPDH, 9 - GPI, 10 - HK1, 11 - HK2, 12 - HK3, 13 - HKDC1, 14 - LDHA, 15 - PCK2, 16 - PFKL, 17 - PFKM, 18 - PGAM1, 19 - PGK1, 20 - PKM, 21 - TPI1) in healthy human volunteer (HHV) subjects three hours post-treatment with Imprime PGG. Each genetic marker is represented by a number, and the genetic markers are numbered in ascending order from the top to the bottom of the heat map.

[Oil] FIG. 2 is a heat map showing increased gene expression of PI3K-AKT-mT0R pathway markers (e g., 1 - AKT1, 2 - AKT1S1, 3 - AKT2, 4 - ATG13, 5 - BNIP3, 6 - BRAF, 7 - CAB39, 8 - CAB39L, 9 - CCNE1, 10 - CDK2, 11 -CLIP1, 12 - CYCS, 13 - DDIT4, 14 - DEPTOR, 15 - EEF2, 16 - EIF4A1, 17 - EIF4B, 18 - EIF4E, 19 - EIF4E2, 20 - EIF4EBP1, 21 - FBXW11, 22 - HRAS, 23 - IKBKB, 24 - IRS1, 25 - MAP2K1, 26 - MAP2K2, 27 - MAPK1, 28 - MAPK3, 29 - MAPKAP1, 30 - MLST8, 31 - MTOR, 32 - NRAS, 33 - PDCD4, 34 - PDPK1, 35 - PIK3CA, 36 - PIK3CB, 37 - PIK3R1, 38 - PIK3R2, 39 - PIK3R3, 40 -PIK3R5, 41 - PLD1, 42 - PLD2, 43 - PML, 44 - P0LDIP3, 45 - PRKCA, 46 - PRKCB, 47 - PRR5, 48 - PXN, 49 - RAC1, 50 - RAFI, 51 - RB1CC1, 52 - RHEB, 53 - RHOA, 54 - RICTOR, 55 - RPS6, 56 - RPS6KA1, 57 - RPS6KA2, 58 - RPS6KB1, 59 - RPTOR, 60 - RRAGA, 61 - RRAGB, 62 - RRAGC, 63 - RRAGD, 64 - RRN3, 65 - SGK1, 66 - SREBF1, 67 - STK11, 68 - TNF, 69 - TSC1, 70 - TSC2, 71 - ULK1, 72 - ULK2, 73 - ULK3, 74 - VEGFA, 75 - YWHAB, 76 - YWHAE, 77 - YWHAG, 78 - YWHAH, 79 - YWHAQ, 80 - YWHAZ, 81 - YY1) in HHV subjects three hours posttreatment with Imprime PGG. Each genetic marker is represented by a number, and the genetic markers are numbered in ascending order from the top to the bottom of the heat map.

[012] FIG. 3 is a heat map showing increased gene expression of IL- 1 pathway markers (e.g., 1 - CASP1, 2 - GBP5, 3 - IL18, 4 - IL1B, 5 - IL1R1, 6 - IRAKI, 7 - NFKB1, 8 - NFKBIB, 9 - NFKBIZ, 10 - P2RX7, 11 - PANXI, 12 - TAB1, 13 - TAB2) in HHV subjects three hours post treatment with Imprime PGG. Each genetic marker is represented by a number, and the genetic markers are numbered in ascending order from the top to the bottom of the heat map.

[013] FIG. 4 is a histogram showing an increase in the activation of various transcription factors in human monocytes treated for 12 hours with low binder serum, Imprime PGG 25 pg/mL, and supplemental anti-0-glucan antibody (ABA; 100 pg/mL) compared to monocytes treated for 12 hours with low binder serum and 25 pg/mL Imprime PGG without supplemental ABA.

[014] FIG. 5 is a plot showing an increase in H3K4Me3 on IL-1B in a healthy human volunteer subject seven days post-administration of Imprime PGG, as compared to pre-dose levels.

DETAILED DESCRIPTION

[015] As generally described herein, the present disclosure provides methods of treating or preventing conditions, diseases, or disorders including, but not limited to, cancer, sepsis/septicemia, pneumonia, fungal infection, immunoparalysis, COVID- 19, and myeloablation in a subject by administering to the subject a therapeutically effective amount of a soluble 0-glucan. Administering a soluble 0-glucan described herein to the subject induces trained immunity, thereby treating or preventing the condition, disease, or disorder. Definitions

[016] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[017] Unless defined otherwise, 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 invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[018] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[019] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[020] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein. [021] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.

[022] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[023] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[024] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. [025] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[026] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[027] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention. [028] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[029] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[030] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[031] As used herein, “carrier” refers to a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent such a soluble P-glucan, or a pharmaceutically acceptable salt thereof, from one organ, or portion of the body, to another organ, or portion of the body. [032] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[033] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[034] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewable s.

[035] As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti -cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). A soluble -glucan, or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[036] The terms “disease,” “disorder,” and “condition” are used interchangeably herein. [037] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder, or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).

[038] In general, an “effective amount” or “therapeutically effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a condition, disease, or disorder described herein (e.g., cancer, sepsis/septicemia, pneumonia, fungal infection, immunoparalysis, COVID-19, and/or myeloablation). As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure (e.g., a soluble -glucan described herein) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject

[039] As used herein, the term “immunoparalysis” refers to a state of immunosuppression. For example, in some embodiments, the immune system becomes desensitized to an antigen, e.g., an antigen associated with an infection, e.g., lipopolysaccharide. In some embodiments, immunoparalysis may be mediated by epigenetic changes, e.g., in monocytes. In some embodiments, immunoparalysis occurs as a result of an infection, e.g., sepsis and/or septicemia. [040] As used herein, the term “late-stage cancer” refers to a stage II cancer, stage III cancer, and/or stage IV cancer, or to any cancer that has metastasized. It will be appreciated that the “late-stage” nature of the cancer disease states can be determined by a physician.

[041] As used herein, the term “myelopoiesis” refers to the production of myeloid cells (i.e., cells of the myeloid lineage, e.g., myeloid progenitor cells, granulocytes, monocytes, macrophages, and dendritic cells).

[042] As used herein, the term “hematopoiesis” refers to the formation of cellular components of the blood, derived from hematopoietic stem cells. These stem cells reside in the medulla of the bone marrow and have the unique ability to give rise to all the different mature blood cell types.

[043] As used herein, the term “myeloablative therapy” refers to a therapy that kills or reduces activity or viability of myeloid cells in the bone marrow of a subject. As used herein, myeloablative therapies are not limited to therapies that kill all myeloid cells in the bone marrow of a subject; myeloablative therapies may also refer to therapies that kill or reduce viability/activity of a portion of the myeloid cells in the bone marrow of a subject. For example, in some embodiments, a myeloablative therapy is a low dose of radiation and/or a low dose of chemotherapy. In some embodiments, a myeloablative therapy may comprise a combination of different therapies which are myeloablative individually and/or in combination, e.g., a combination of radiation and a chemotherapeutic agent. [044] As used herein, the term “trained immunity” refers to a state of secondary enhanced responsiveness, including increased cytokine excretion mediated by metabolic and epigenetic alterations, to re-stimulation after a primary stimulation of myeloid cells and/or their progenitors and stem cells in the bone marrow, spleen and blood. Trained immunity (also called innate immune memory) is also characterized by increased responsiveness (e.g., high cytokine production) after re-stimulation with a secondary stimulus of myeloid innate immune cells, being induced by a primary stimulation of these cells or their progenitors and stem cells in the bone marrow and spleen, and mediated by epigenetic, metabolic and transcriptional alterations. The skilled practitioner will appreciate that the re -stimulation need not be of the same type as the primary stimulation. Induction of trained immunity can be used to enhance treatment of, e.g., an infection or cancer.

P-glucans

[045] P-glucans are polymers of glucose that may be derived from a variety of microbiological and plant sources including, but not limited to, yeast, bacteria, algae, seaweed, mushroom, oats, and barley. Yeast P-glucans have immunomodulatory properties. Yeast P-glucans can occur in various forms including, but not limited to, intact yeast, zymosan, purified whole glucan particles, solubilized zymosan polysaccharide, or highly-purified soluble P-glucans of different molecular weights. Structurally, yeast p-glucans may be composed of glucose monomers organized as a p-(l,3)-linked glucopyranose backbone with periodic p~( 1,3) glucopyranose branches linked to the backbone via p~( 1,6) glycosidic linkages. The different forms of yeast p- glucans may exhibit differing properties (e.g., physicochemical and biochemical properties). The mechanism by which yeast p-glucans exert their immunomodulatory effects can be influenced by the structural differences between different forms of the P-glucans including, but not limited to, its particulate or soluble nature, tertiary conformation, length of the main chain, length of the side chain, and frequency of the side chains. The immune stimulating functions of yeast P-glucans are also dependent upon the receptors engaged in different cell types in different species, which again, can be dependent on the structural properties of the P-glucans.

[046] In general, P-glucan immunotherapies can include administering to a subject any suitable form of p-glucan or any combination of two or more forms of p-glucan. Suitable p-glucans and the preparation of suitable P-glucans from their natural sources are described in, for example, U.S. Patent No. 9,610,303, which is incorporated herein by reference in its entirety. In some cases, the p-glucan is derived from a yeast such as, for example, Saccharomyces cerevisiae. (see below). P-glucan is a PAMP (pathogen-associated molecular pattern) capable of triggering innate immune cell function leading to a cascade of immune activation and enhanced anti-tumor killing.

[047] In some embodiments, the P-glucan is a soluble P-glucan.

[048] In some embodiments, the average molecular weight of the soluble p-glucan is about 50 to about 500 kDa, about 75 to about 500 kDa, about 100 to about 500 kDa, about 125 to about 500 kDa, about 150 to about 500 kDa, about 175 to about 500 kDa, about 200 to about 500 kDa, about 225 to about 500 kDa, about 250 to about 500 kDa, about 275 to about 500 kDa, about 300 to about 500 kDa, about 325 to about 500 kDa, about 350 to about 500 kDa, about 375 to about 500 kDa, about 400 to about 500 kDa, about 425 to about 500 kDa, about 450 to about 500 kDa, about 475 to about 500 kDa, about 50 to about 475 kDa, about 50 to about 450 kDa, about 50 to about 425 kDa, about 50 to about 400 kDa, about 50 to about 375 kDa, about 50 to about 350 kDa, about 50 to about 325 kDa, about 50 to about 300 kDa, about 50 to about 275 kDa, about 50 to about 250 kDa, about 50 to about 225 kDa, about 50 to about 200 kDa, about 50 to about 175 kDa, about 50 to about 150 kDa, about 50 to about 125 kDa, about 50 to about 100 kDa, about 50 to about 75 kDa, about 75 to about 475 kDa, about 100 to about 450 kDa, about 125 to about 425 kDa, about 150 to about 400 kDa, about 175 to about 375 kDa, about 200 to about 350 kDa, about 225 to about 325 kDa, about 250 to about 300 kDa, about 100 to about 200 kDa, about 105 to about 200 kDa, about 110 to about 200 kDa, about 115 to about 200 kDa, about 120 to about 200 kDa, about 125 to about 200 kDa, about 130 to about 200 kDa, about 135 to about 200 kDa, about 140 to about 200 kDa, about 145 to about 200 kDa, about 150 to about 200 kDa, about 155 to about 200 kDa, about 160 to about 200 kDa, about 165 to about 200 kDa, about 170 to about 200 kDa, about 175 to about 200 kDa, about 180 to about 200 kDa, about 185 to about 200 kDa, about 190 to about 200 kDa, about 195 to about 200 kDa, about 100 to about 195 kDa, about 100 to about 190 kDa, about 100 to about 185 kDa, about 100 to about 180 kDa, about 100 to about 175 kDa, about 100 to about 170 kDa, about 100 to about 165 kDa, about 100 to about 160 kDa, about 100 to about 155 kDa, about 100 to about 150 kDa, about 100 to about 145 kDa, about 100 to about 140 kDa, about 100 to about 135 kDa, about 100 to about 130 kDa, about 100 to about 125 kDa, about 100 to about 120 kDa, about 100 to about 115 kDa, about 100 to about 110 kDa, about 100 to about 105 kDa, about 105 to about 195 kDa, about 110 to about 190 kDa, about 115 to about 185 kDa, about 120 to about 180 kDa, about 125 to about 175 kDa, about 130 to about 170 kDa, about 135 to about 165 kDa, about 140 to about 160 kDa, about 135 to about 155 kDa, or about 140 to about 150 kDa. In some embodiments, the average molecular weight of the soluble p-glucan is about 50 to about 500 kDa. In certain embodiments, the soluble - glucan has an average molecular weight of about 110 to about 175 kDa.

[049] In some embodiments, the soluble 0-glucan has an average molecular weight of about 110 to about 175 kDa, about 115 to about 175 kDa, about 120 to about 175 kDa, about 125 to about 175 kDa, about 130 to about 175 kDa, about 135 to about 175 kDa, about 140 to about 175 kDa, about 145 to about 175 kDa, about 150 to about 175 kDa, about 155 to about 175 kDa, about 160 to about 175 kDa, about 165 to about 175 kDa, about 170 to about 175 kDa, about 110 to about 170 kDa, about 110 to about 165 kDa, about 110 to about 160 kDa, about 110 to about 155 kDa, about 110 to about 150 kDa, about 110 to about 145 kDa, about 110 to about 140 kDa, about 110 to about 135 kDa, about 110 to about 130 kDa, about 110 to about 125 kDa, about 110 to about 120 kDa, about 110 to about 115 kDa, about 115 to about 170 kDa, about 120 to about 165 kDa, about 125 to about 160 kDa, about 130 to about 155 kDa, about 135 to about 150 kDa, or about 140 to about 145 kDa.

[050] In some embodiments, the soluble p-glucan has an average molecular weight of about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, about 150 kDa, about

160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa, about 210 kDa, about

220 kDa, about 230 kDa, about 240 kDa, about 250 kDa, about 260 kDa, about 270 kDa, about

280 kDa, about 290 kDa, about 300 kDa, about 310 kDa, about 320 kDa, about 330 kDa, about

340 kDa, about 350 kDa, about 360 kDa, about 370 kDa, about 380 kDa, about 390 kDa, about

400 kDa, about 410 kDa, about 420 kDa, about 430 kDa, about 440 kDa, about 450 kDa, about

460 kDa, about 470 kDa, about 480 kDa, about 490 kDa, or about 500 kDa.

[051] In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kDa, about 115 kDa, about 120 kDa, about 125 kDa, about 130 kDa, about 135 kDa, about 140 kDa, about 145 kDa, about 150 kDa, about 155 kDa, about 160 kDa, about 165 kDa, about 170 kDa, or about 175 kDa.

[052] In some embodiments, the soluble p-glucan has an average molecular weight of at least about 110 kDa, at least about 115 kDa, at least about 120 kDa, at least about 125 kDa, at least about 130 kDa, at least about 135 kDa, at least about 140 kDa, at least about 145 kDa, at least about 150 kDa, at least about 155 kDa, at least about 160 kDa, at least about 165 kDa, at least about 170 kDa, or at least about 175 kDa.

[053] In some embodiments, the aqueous solubility of the soluble p-glucan is at least 10 mg/mL, at least 20 mg/mL, at least 30 mg/mL, at least 40 mg/mL, at least 50 mg/mL, at least 60 mg/mL, at least 70 mg/mL, at last 80 mg/mL, at least 90 mg/mL, or at least 100 mg/mL.

Imprime PGG

[054] In certain cases, the p-glucan may be or be derived from P(l,6)-[poly-(l,3)-D- glucopyranosyl]-poly-P(l,3)-D-glucopyranose, which may also be referred to herein as PGG (IMPRIME PGG, Biothera, Eagan, MN) or Odetiglucan, a highly purified and well characterized form of soluble yeast-derived P-glucan.

[055] In some embodiments, Imprime PGG has an average molecular weight of about 110 to about 175 kDa, about 115 to about 175 kDa, about 120 to about 175 kDa, about 125 to about 175 kDa, about 130 to about 175 kDa, about 135 to about 175 kDa, about 140 to about 175 kDa, about 145 to about 175 kDa, about 150 to about 175 kDa, about 155 to about 175 kDa, about 160 to about 175 kDa, about 165 to about 175 kDa, about 170 to about 175 kDa, about 110 to about 170 kDa, about 110 to about 165 kDa, about 110 to about 160 kDa, about 110 to about 155 kDa, about 110 to about 150 kDa, about 110 to about 145 kDa, about 110 to about 140 kDa, about 110 to about 135 kDa, about 110 to about 130 kDa, about 110 to about 125 kDa, about 110 to about 120 kDa, about 110 to about 115 kDa, about 115 to about 170 kDa, about 120 to about 165 kDa, about 125 to about 160 kDa, about 130 to about 155 kDa, about 135 to about 150 kDa, or about 140 to about 145 kDa. In some embodiments, Imprime PGG has an average molecular weight of about 110 to about 175 kDa.

[056] In some embodiments, Imprime PGG has an average molecular weight of about 110 kDa, about 115 kDa, about 120 kDa, about 125 kDa, about 130 kDa, about 135 kDa, about 140 kDa, about 145 kDa, about 150 kDa, about 155 kDa, about 160 kDa, about 165 kDa, about 170 kDa, or about 175 kDa.

[057] In certain embodiments, Imprime PGG has an average molecular weight of about 110 kDa to about 175 kDa and an aqueous solubility of at least 100 mg/mL.

[058] A process for producing Imprime PGG is disclosed in US Patent No. 9,610,303, the contents of which are incorporated herein by reference in their entirety. In certain pharmaceutical compositions and methods of treatment disclosed herein, the soluble p-glucan is Imprime PGG.

Pharmaceutical Compositions

[059] The disclosure provides pharmaceutical compositions, which comprise a therapeutically effective amount of one or more of the soluble -glucans as described herein, formulated together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[060] Pharmaceutical compositions containing a soluble P-glucan disclosed herein can be presented in a unit dosage form and can be prepared by any suitable method. A pharmaceutical composition should be formulated to be compatible with its intended route of administration. The pharmaceutical compositions may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form will depend upon the intended mode of administration and therapeutic application.

[061] Although the pharmaceutical compositions described herein are preferably formulated for administration intravenously, such compositions can be administered by other parenteral modes (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and infrastemal injection and infusion.

[062] The pharmaceutical compositions described herein can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration. Sterile injectable solutions can be prepared by incorporating an agent described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating an agent described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying that yield a powder of an agent described herein plus any additional desired ingredient from a previously sterile -filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[063] Depending upon the mode of administration, for example, by parenteral administration, it may be desirable to produce a pharmaceutical formulation that is sterile. Sterilization can be accomplished by any suitable method, e.g., filtration through sterile filtration membranes.

Where the composition is lyophilized, filter sterilization can be conducted prior to or following lyophilization and reconstitution.

[064] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[065] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a 0- glucan, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[066] Regardless of the route of administration selected, the soluble 0-glucans of the present disclosure, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art. [067] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient (e.g., a soluble 0- glucan described herein) which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [068] The selected dosage level will depend upon a variety of factors including the activity of the particular 0-glucan of the present disclosure employed, or the ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular 0-glucan being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular 0- glucan employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[069] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the soluble 0-glucans of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[070] In general, a suitable daily dose of a soluble 0-glucan of the disclosure will be that amount of the soluble 0-glucan which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. When the soluble 0-glucans described herein are co-administered with another agent, the effective amount may be less than when the agent is used alone.

[071] If desired, the effective daily dose of the soluble 0-glucan may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

[072] The disclosure further provides a unit dosage form (e.g., a solution for intravenous administration) comprising a soluble 0-glucan described herein in a therapeutically effective amount for the treatment of a condition, disease, or disorder described herein. In certain embodiments, the soluble 0-glucan is Imprime PGG.

[073] In some embodiments, the soluble 0-glucan is formulated as an aqueous solution. In some embodiments, the concentration of soluble 0-glucan in the aqueous solution is about 1 to about 10 mg/mL, about 2 to about 10 mg/mL, about 3 to about 10 mg/mL, about 4 to about 10 mg/mL, about 5 to about 10 mg/mL, about 6 to about 10 mg/mL, about 7 to about 10 mg/mL, about 8 to about 10 mg/mL, about 9 to about 10 mg/mL, about 1 to about 9 mg/mL, about 1 to about 8 mg/mL, about 1 to about 7 mg/mL, about 1 to about 6 mg/mL, about 1 to about 5 mg/mL, about 1 to about 4 mg/mL, about 1 to about 3 mg/mL, about 1 to about 2 mg/mL, about 0.2 to about 2 mg/mL, about 0.4 to about 2 mg/mL, about 0.6 to about 2 mg/mL, about 0.8 to about 2 mg/mL, about 1 to about 2 mg/mL, about 1.2 to about 2 mg/mL, about 1.4 to about 2 mg/mL, about 1.6 to about 2 mg/mL, about 1.8 to about 2 mg/mL, about 0.2 to about 1.8 mg/mL, about 0.2 to about 1.6 mg/mL, about 0.2 to about 1.4 mg/mL, about 0.2 to about 1.2 mg/mL, about 0.2 to about 1 mg/mL, about 0.2 to about 0.8 mg/mL, about 0.2 to about 0.6 mg/mL, about 0.2 to about 0.4 mg/mL, or about 0.5 to about 1.5 mg/mL.

[074] In some embodiments, the concentration of soluble P-glucan in the solution is about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 mg/mL.

[075] In some embodiments, the pH of the solution is about 5.9 to about 6.9, about 6.0 to about 6.9, about 6.1 to about 6.9, about 6.2 to about 6.9, about 6.3 to about 6.9, about 6.4 to about 6.9, about 6.5 to about 6.9, about 6.6 to about 6.9, about 6.7 to about 6.9, about 6.8 to about 6.9, about 6.0 to about 6.8, about 6.1 to about 6.7 about 6.2 to about 6.6, about 6.3 to about 6.5, about 5.95 to about 6.85, about 6.05 to about 6.75, about 6.15 to about 6.65, about 6.25 to about 6.55, or about 6.35 to about 6.55.

[076] In some embodiments, the pH of the solution is about 5.95, about 6.0, about 6.05, about 6.1, about 6.15, about 6.2, about 6.25, about 6.3, about 6.35, about 6.4, about 6.45, about 6.5, about 6.55, about 6.6, about 6.75, about 6.7, or about 6.75.

[077] In some embodiments, the osmolality of the solution is about 260 to about 320 mOsmol/kg, about 265 to about 320 mOsmol/kg, about 270 to about 320 mOsmol/kg, about 275 to about 320 mOsmol/kg, about 280 to about 320 mOsmol/kg, about 285 to about 320 mOsmol/kg, about 290 to about 320 mOsmol/kg, about 295 to about 320 mOsmol/kg, about 300 to about 320 mOsmol/kg, about 305 to about 320 mOsmol/kg, about 310 to about 320 mOsmol/kg, about 315 to about 320 mOsmol/kg, about 260 to about 315 mOsmol/kg, about 260 to about 310 mOsmol/kg, about 260 to about 305 mOsmol/kg, about 260 to about 300 mOsmol/kg, about 260 to about 295 mOsmol/kg, about 260 to about 290 mOsmol/kg, about 260 to about 285 mOsmol/kg, about 260 to about 280 mOsmol/kg, about 260 to about 275 mOsmol/kg, about 260 to about 270 mOsmol/kg, about 260 to about 265 mOsmol/kg, about 265 to about 315 mOsmol/kg, about 270 to about 310 mOsmol/kg, about 275 to about 305 mOsmol/kg, about 280 to about 300 mOsmol/kg, or about 285 to about 295 mOsmol/kg.

[078] In some embodiments, the osmolality of the solution is about 260 mOsmol/kg, about 265 mOsmol/kg, about 270 mOsmol/kg, about 275 mOsmol/kg, about 280 mOsmol/kg, about 285 mOsmol/kg, about 290 mOsmol/kg, about 295 mOsmol/kg, about 300 mOsmol/kg, about 305 mOsmol/kg, about 310 mOsmol/kg, about 315 mOsmol/kg, or about 320 mOsmol/kg.

Methods of Treatment

[079] Disclosed herein are methods of treating and/or preventing various conditions in a subject in need thereof comprising or consisting of administering a therapeutically effective amount of a soluble P-glucan described herein or a pharmaceutical composition described herein. Said conditions, diseases, or disorders, include, but are not limited to, cancer, sepsis/septicemia, pneumonia, fungal infection, immunoparalysis, COVID- 19, and myeloablation.

Cancer

[080] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods generally comprise administering to the subject a therapeutically effective amount of a soluble P-glucan.

[081] As used throughout this disclosure, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including, solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including B -acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and/or multiple myeloma. In some further instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma. [082] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumors found in mammals, including leukemia, lymphoma, carcinomas, and sarcomas.

[083] Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget' s Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

[084] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairycell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[085] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma. [086] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infdtrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatinifomi carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signetring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

[087] For example, certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of a cancer. In some embodiments, the methods described herein may be used to treat a cancer by decreasing or eliminating a symptom of a cancer. In some embodiments, the P-glucans and/or pharmaceutical compositions disclosed herein may be used as a single agent in a composition or in combination with another agent in a composition to treat a cancer described herein.

[088] In various embodiments, provided herein are methods of inducing trained immunity in a subject with a cancer, the methods generally comprise administering to the subject a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient.

[089] In various embodiments, provided herein are methods of inducing trained immunity in a subject with cancer, the methods consisting of administering to the subject a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient.

[090] In some embodiments, the therapeutically effective amount of soluble p-glucan is administered to the subject at least about one day prior to a first administration of a cancer immunotherapy.

[091] In various embodiments, provided herein are methods of inducing trained immunity in a subject with cancer, the methods comprising administering to the subject a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the therapeutically effective amount of soluble P-glucan is administered to the subject at least about one day prior to a first administration of a cancer immunotherapy.

[092] In various embodiments, provided herein are methods of inducing trained immunity in a subject with cancer, the methods consisting of administering to the subject a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the therapeutically effective amount of soluble p-glucan is administered to the subject at least about one day prior to a first administration of a cancer immunotherapy. [093] In some embodiments, the soluble p-glucan is a soluble P-glucan described herein. In some embodiments, the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[094] In some embodiments, the composition for use in cancer immunotherapy comprises a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is selected from the group consisting of a PD-1 (programmed cell death protein 1) antagonist, a PD-L1 (programmed cell death protein ligand 1) antagonist, a PD-L2 antagonist, a CD27 (cluster of differentiation 27) antagonist, a CD28 antagonist, a CD70 antagonist, a CD80 antagonist, a CD86 antagonist, a CD 137 antagonist, a CD276 antagonist, a KIRs (killer-cell immunoglobulin-like receptors) antagonist, a LAG3 (lymphocyte-activation gene 3) antagonist, a TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) antagonist, a GITR (glucocorticoid-induced TNFR- related protein) antagonist, a GITRL (GITR ligand) antagonist, a 4-1BBL (4- IBB ligand) antagonist, a CTLA-4 (cytotoxic T lymphocyte associated antigen 4) antagonist, an A2AR (adenosine A2A receptor) antagonist, a VTCN1 (V-set domain-containing T-cell activation inhibitor 1) antagonist, a BTLA (B- and T-lymphocyte attenuator) antagonist, an IDO (Indoleamine 2,3 -dioxygenase) antagonist, a TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) antagonist, a VISTA (V-domain Ig suppressor of T cell activation) antagonist, a KLRA antagonist, and a combination thereof.

[095] In some embodiments, the checkpoint inhibitor is selected from the group consisting of ipilimumab, tremilimumab, nivolumab, pembrolizumab, pidilizumab, lambrolizumab, BMS- 936559, atezolizumab, and AMP-224, AMP224, AUNP12, BGB108, MCLA134, MEDI0680, PDR001, REGN2810, SHR1210, STIA110X, STIA1110, TSR042, MPDL3280A, MEDI-4736, MSB0010718C, ALN-PDL, BGBA317, KD033, KY1003, STIA100X, STIA1010, STIA1011, STIA1012, STIA101, BMS-663513, and PF-05082566.

[096] In certain embodiments, the checkpoint inhibitor comprises an anti -PD-1 antibody or antigen -binding fragment or derivative thereof. In certain embodiment, the anti -PD-1 antibody is pembrolizumab.

[097] In some embodiments, the therapeutically effective amount of soluble P-glucan is administered about 1 hour, about 2 hours, about 3 hour, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks prior to the first administration of the composition for use in cancer immunotherapy. In some embodiments, the therapeutically effective amount of soluble p-glucan is administered about 7 days prior to the first administration of the composition for use in cancer immunotherapy.

[098] In some embodiments, the subject’s cancer has not metastasized at the time of the first administration of the composition for use in cancer immunotherapy. In some embodiments, administration of the therapeutically effective amount of soluble p-glucan to the subject prior to the first administration of the composition for use in cancer immunotherapy decreases the amount of metastatic seeding in the subject below that of a control subject receiving a placebo prior to the first administration of the composition for use in cancer immunotherapy. In some embodiments, administration of the therapeutically effective amount of soluble P-glucan to the subject prior to the first administration of the composition for use in cancer immunotherapy decreases the amount of metastatic seeding in the subject below that of a subject not receiving the therapeutically effective amount of soluble P-glucan prior to the first administration of the composition for use in cancer immunotherapy.

[099] In some embodiments, the subject has not previously received a cancer immunotherapy. In some embodiments, the subject has not received a cancer immunotherapy about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 18 months, about 2 years, or about 5 years prior to being administered the therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient.

Sepsis/Septicemia, Pneumonia, Immunoparalysis, Fungal Infections, and COVID-19

[100] In various embodiments, provided herein are methods of treating and/or preventing sepsis and/or septicemia in a subject in need thereof, the methods generally comprising administering a therapeutically effective amount of a soluble P-glucan to the subject.

[101] In various embodiments, provided herein are methods of treating and/or preventing sepsis and/or septicemia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject. [102] In various embodiments, provided herein are methods of treating and/or preventing sepsis and/or septicemia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble p-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject.

[103] In some embodiments, the soluble -glucan is a soluble p-glucan described herein. In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[104] In various embodiments, provided herein are methods of treating sepsis and/or septicemia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[105] In various embodiments, provided herein are methods of treating sepsis and/or septicemia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[106] In some embodiments, provided herein are methods of treating sepsis and/or septicemia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble p-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[107] In some embodiments, a subject described herein in need of treatment or prevention of sepsis and/or septicemia has a cancer described herein. In some embodiments, the cancer is latestage cancer.

[108] In some embodiments, the methods of the disclosure comprise a step of identifying a subject in need of treatment with soluble P-glucan or a composition (e.g., a pharmaceutical composition) comprising soluble P-glucan.

[109] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject in need of treatment for sepsis. For example, in some embodiments, the methods comprise selecting a subject that has sepsis or that has been diagnosed with sepsis.

[HO] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for sepsis, wherein the subject is at risk for sepsis. In some embodiments, the subject at risk for sepsis has an infection. In some embodiments, the subject at risk for sepsis has cancer. In some embodiments, the subject at risk for sepsis has late-stage cancer. In some embodiments, the subject at risk for sepsis has lung cancer. In some embodiments, the subject at risk for sepsis has diabetes. In some embodiments, the subject at risk for sepsis has pneumonia. In some embodiments, the subject at risk of sepsis has bacteremia. In some embodiments, the subject at risk of sepsis has a chronic kidney or liver disease. In some embodiments, the subject at risk of sepsis has an invasive device, e.g., a catheter. In some embodiments, the subject at risk of sepsis has a catheter-associated infection, e.g., a catheter-associated urinary tract infection. In some embodiments, the subject at risk of sepsis has been intubated. In some embodiments, the subject at risk of sepsis has a wound or a bum. In some embodiments, the subject at risk for sepsis is a human that is 65 years or older. In some embodiments, the subject at risk for sepsis is an infant or a neonate. In some embodiments, the subject at risk for sepsis is in a high-risk environment, e.g., a long-term care facility or an intensive care unit. In some embodiments, the subject at risk for sepsis is immunocompromised. In some embodiments, the subject at risk for sepsis has not been vaccinated against certain infective agents, e.g., influenza or pneumococcus bacteria.

[Hl] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for sepsis, wherein the subject is exhibiting symptoms or signs of sepsis. For example, in some embodiments, the subject has experienced or is experiencing a change in mental status. In some embodiments, the subject has experienced or is experiencing labored breathing or abnormally rapid breathing. In some embodiments, the subject has experienced or is experiencing a drop in systolic blood pressure. In some embodiments, the subject’s systolic blood pressure is less than or equal to about 100 mmHg. In some embodiments, the subject is experiencing or has experienced nausea, vomiting, and/or diarrhea. In some embodiments, is in severe pain. In some embodiments, the subject has a fever and/or chills.

[112] In some embodiments, the methods of the disclose comprise a step of identifying or selecting a subject to be administered treatment for sepsis, wherein the subject is in septic shock or is exhibiting signs of septic shock. For example, in some embodiments, the subject’s systolic blood pressure is less than or equal to about 65 mmHg. In some embodiments, the subject has a high level of lactic acid in their blood. [113] In some embodiments of any of the foregoing methods, the subject having sepsis or at risk of sepsis has not been exposed to radiation, e.g., radiation therapy.

[114] In some embodiments, the subject having sepsis or at risk of sepsis has an infection. In some embodiments, the infection comprises an infection with Streptococcus agalactaie, Escherichia coli, Klebsiella (spp.), Enterobacter (spp.), Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus (spp.), Enterococcus (spp.), Haemophilus influenzae, Legionella (spp.), Chlamydia pnemoniae, Bacteroides fragilis, Candida (spp.), Clostridium (spp.), Listeria monocytogenes, or Rickettsia.

[115] In various embodiments, provided herein are methods of treating and/or preventing pneumonia, the method comprising administering a therapeutically effective amount of a soluble -glucan to the subject. In some embodiments, provided herein are methods of treating and/or preventing pneumonia, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject.

[116] In various embodiments, provided herein are methods of treating and/or preventing pneumonia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble p-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject.

[117] In some embodiments, the soluble p-glucan is a soluble p-glucan described herein. In some embodiments, the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[118] In various embodiments, provided herein are methods of treating pneumonia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[119] In various embodiments, provided herein are methods of treating pneumonia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[120] In some embodiments, provided herein are methods of treating pneumonia in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject, wherein the soluble 0-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[121] In some embodiments, a subject described herein in need of treatment or prevention of pneumonia has a cancer described herein. In some embodiments, the cancer is late-stage cancer.

[122] In some embodiments, the pneumonia is a result, at least in part, of an infection by a bacteria or virus selected from the group consisting of Nocardia (spp.), Rhodococcus equi, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Acinetohacter haumannii-complex, Alcaligenes/Achromohacter (spp.), Burkholderia (spp.), Citrohacter (spp.), Enterohacter cloacaea, Escherichia coli, Klebsiella pneumonia, Moraxella catarrhalis, Neisseria meningitides, Hemophilus influenza, Proteus (spp.), Pseudomonas (spp.), Stenotrophomonas maltophilia, Serretia marcescensa, Chlamydophyla pneumoniae, Legionella (spp.), and Mycoplasma pneumoniae.

[123] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for pneumonia, and administering to the subject a therapeutically effective amount of soluble P-glucan. In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for pneumonia, wherein the subject has pneumonia or has been diagnosed with pneumonia, and administering to the subject a therapeutically effective amount of soluble - glucan.

[124] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for pneumonia, wherein the subject is at risk for developing pneumonia, and administering to the subject a therapeutically effective amount of soluble 0-glucan. In some embodiments, the subject at risk of developing pneumonia is immunocompromised. In some embodiments, the subject is immunosuppressed. In some embodiments, the subject has HIV or AIDS. In some embodiments, the subject has received an organ transplant. In some embodiments, the subject has received chemotherapy and/or steroids. In some embodiments, the subject is intubated. In some embodiments, the subject is a human that is 2 years or younger. In some embodiments, the subject is a human that is 65 years or older. In some embodiments, the subject is hospitalized. In some embodiments, the subject is in an intensive care unit. In some embodiments, the subject is in a long-term care facility. In some embodiments, the subject is a smoker. In some embodiments, the subject has aspirated food or drink. In some embodiments, the subject is prone to aspirating food or drink.

[125] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for pneumonia, wherein the subject is exhibiting signs or symptoms of pneumonia, and administering to the subject a therapeutically effective amount of soluble p-glucan. In some embodiments, the subject exhibiting signs or symptoms of pneumonia is experiencing chest pain, which may be worse with deep breathing. In some embodiments, the subject has a cough, optionally wherein the cough produces phlegm. In some embodiments, the subject has fatigue. In some embodiments, the subject has a fever and/or chills. In some embodiments, the subject is sweating. In some embodiments, the subject has a lower-than-normal body temperature. In some embodiments, the subject has nausea, vomiting, and/or diarrhea. In some embodiments, the subject is experiencing shortness of breath. In some embodiments, the subject is breathing rapidly. In some embodiments, the subject has experienced or is experiencing confusion. In some embodiments, the subject has recently had an illness, e.g., influenza.

[126] In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject.

[127] In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble p-glucan to the subject.

[128] In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject.

[129] In some embodiments, the soluble P-glucan is a soluble P-glucan described herein. In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[130] In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject, wherein the soluble p- glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons. [131] In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble 0-glucan to the subject, wherein the soluble 0- glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons. In various embodiments, provided herein are methods of treating or preventing immunoparalysis in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble 0-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject, wherein the soluble 0-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[132] In some embodiments, a subject described herein in need of treatment or prevention of immunoparalysis has a cancer described herein. In some embodiments, the cancer is late-stage cancer. In some embodiments, a subject described herein in need of treatment or prevention of immunoparalysis has sepsis and/or septicemia.

[133] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for immunoparalysis, and administering to the subject a therapeutically effective amount of soluble 0-glucan.

[134] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for immunoparalysis, wherein the subject is exhibiting a sign or symptom of immunoparalysis, and administering to the subject a therapeutically effective amount of soluble 0-glucan. In some embodiments, the subject has prolonged sepsis. In some embodiments, the subject has severe sepsis. In some embodiments, the subject has sepsis and has impaired immune function. In some embodiments, the subject has prolonged sepsis. In some embodiments, the subject has a monocyte HLA-DR %-positivity level of about 30% or less. In some embodiments, a whole blood sample of the subject has a reduced ability to produce pro-inflammatory cytokines (e.g., TNFa) in response to stimulation with LPS ex vivo, as compared an appropriate control, e.g., a whole blood sample from a healthy subject. In particular embodiments, the whole blood sample from the subject has an ex vivo LPS-induced TNFa response of less than about 200 pg/mL after about 4 hours of incubation at about 37 °C.

[135] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for immunoparalysis, wherein the subject is at risk for developing immunoparalysis, and administering to the subject a therapeutically effective amount of soluble P-glucan. In some embodiments, the subject at risk of developing immunoparalysis has sepsis, has been diagnosed with sepsis, or is at risk of developing sepsis. In some embodiments, the subject has experienced septic shock. In some embodiments, the subject has prolonged sepsis.

[136] In various embodiments, provided herein are methods of treating or preventing a fungal infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject.

[137] In various embodiments, provided herein are methods of treating or preventing a fungal infection in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject.

[138] In various embodiments, provided herein are methods of treating or preventing a fungal infection in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject

[139] In some embodiments, the soluble P-glucan is a soluble P-glucan described herein. In some embodiments, the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[140] In various embodiments, provided here are methods of treating or preventing a fungal infection in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[141] In various embodiments, provided here are methods of treating or preventing a fungal infection in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[142] In various embodiments, provided here are methods of treating or preventing a fungal infection in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[143] In some embodiments, the fungal infection comprises an infection with a species of fungus from a genus selected from the group consisting of Aspergillus, Candida, Cryptococcus, Scedosporium, Fusarium, and Trichosporon. In certain embodiments, the fungal infection comprises an infection with a species of fungus from the class Zygomycetes .

[144] In certain embodiments, the fungal infection comprises an infection with a species of fungus selected from the group consisting of Aspergillus fumigatus, Aspergillus flavus, Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Scedosporium apiospermu, Scedosporium prolificans, Trichosporon asahii, and Trichosporon beigelii,

[145] In some embodiments, a subject described herein in need of treatment or prevention of a fungal infection has a cancer described herein. In some embodiments, the cancer is late-stage cancer.

[146] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for a fungal infection, and administering to the subject a therapeutically effective amount of soluble P-glucan. In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for a fungal infection, wherein the subject has a fungal infection or has been diagnosed with a fungal infection, and administering to the subject a therapeutically effective amount of soluble P-glucan. In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for a fungal infection, wherein the subject is exhibiting a sign or symptom of a fungal infection, and administering to the subject a therapeutically effective amount of soluble p-glucan.

[147] In some embodiments, the methods of the disclosure comprise a step of identifying or selecting a subject to be administered a treatment for a fungal infection, wherein the subject is at risk of developing a fungal infection, and administering to the subject a therapeutically effective amount of soluble P-glucan. In some embodiments, the subject at risk of developing a fungal infection is immunocompromised or immunosuppressed. In some embodiments, the subject has a catheter. In some embodiments, the subject has been treated with broad-spectrum antibiotics. In some embodiments, the subject has neutropenia. In some embodiments, the subject has HIV or AIDS. In some embodiments, the subject is an organ transplant recipient. In some embodiments, the subject has cancer.

[148] In various embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or COVID- 19 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble p-glucan to the subject.

[149] In various embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or COVID- 19 in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject.

[150] In some embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or CO VID-19 in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable diluent, carrier, or excipient to the subject

[151] In some embodiments, the soluble p-glucan is a soluble p-glucan described herein. In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[152] In various embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or COVID- 19 in a subject in need thereof, the method comprising administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[153] In various embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or COVID- 19 in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan to the subject, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[154] In some embodiments, provided herein are methods of treating a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or CO VID-19 in a subject in need thereof, the method consisting of administering a therapeutically effective amount of a soluble P-glucan and a pharmaceutically acceptable carrier, diluent, or excipient to the subject, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

Myelopoiesis [155] In some embodiments, provided herein are methods of enhancing myelopoiesis in a subject to be administered a myeloablative therapy, the method generally comprising administering to the subject prior to the administration of the myeloablative therapy a therapeutically effective amount of a soluble p-glucan.

[156] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject to be administered a myeloablative therapy, the method consisting of administering to the subject prior to the administration of the myeloablative therapy a therapeutically effective amount of a soluble p-glucan.

[157] In some embodiments, the soluble P-glucan is a soluble P-glucan described herein. In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[158] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject to be administered a myeloablative therapy, the method comprising administering to the subject prior to the administration of the myeloablative therapy a therapeutically effective amount of a soluble P-glucan, wherein the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[159] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject to be administered a myeloablative therapy, the method consisting of administering to the subject prior to the administration of the myeloablative therapy a therapeutically effective amount of a soluble p-glucan, wherein the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[160] In some embodiments, a subject described herein in need of treatment prior to administration of myeloablative therapy has a cancer described herein. In some embodiments, the cancer is late -stage cancer.

[161] In some embodiments, the subject described herein in need of treatment prior to administration of myeloablative therapy is to receive an organ and/or tissue transplant. In some embodiments, the organ and/or tissue is selected from the group consisting of liver, kidney, pancreas, heart, lung, intestine, cornea, middle ear, skin, bone, bone marrow, heart valve, and connective tissue. In certain embodiments, the subject described herein in need of treatment prior to administration of myeloablative therapy is to receive an organ transplant

[162] In some embodiments, the myeloablative therapy is selected from the group consisting of radiation, total body radiation, total lymphoid radiation, cyclophosphamide, busulfan, carmustine, cytarabine, 6-thioguanine, melphalan, etoposide, thiotepa, fludarabin, and a combination of any of the foregoing.

[163] In some embodiments, the myeloablative therapy comprises a low dose of chemotherapy and/or a low dose of radiation.

[164] In some embodiments, the myeloablative therapy does not comprise administration of an immunoglobulin .

[165] In some embodiments, administration of the myeloablative therapy ablates a fraction of the subject’s bone marrow myeloid cells. In some embodiments, administration of the myeloablative therapy ablates a majority of the subject’s myeloid cells. In some embodiments, the myeloablative therapy ablates about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the subject’s myeloid cells.

[166] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject that has been administered a myeloablative therapy, the methods comprising (i) contacting a plurality of hematopoietic stem cells (HSC) and/or a plurality of myeloid progenitor cells from a donor with a therapeutically effective amount of soluble p-glucan, and (ii) administering to the subject a therapeutically effective amount of the plurality of HSCs and/or the plurality of myeloid progenitor cells.

[167] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject that has been administered a myeloablative therapy, the methods consisting of (i) contacting a plurality of hematopoietic stem cells (HSC) and/or a plurality of myeloid progenitor cells from a donor with a therapeutically effective amount of soluble P-glucan, and (ii) administering to the subject a therapeutically effective amount of the plurality of HSCs and/or the plurality of myeloid progenitor cells.

[168] In various embodiments, provided herein are methods of enhancing myelopoiesis in a subject that has been administered a myeloablative therapy, the methods consisting of (i) contacting a plurality of hematopoietic stem cells (HSC) and/or a plurality of myeloid progenitor cells from a donor with a therapeutically effective amount of soluble P-glucan, and (ii) administering to the subject a composition comprising a therapeutically effective amount of the plurality of HSCs and/or the plurality of myeloid progenitor cells.

[169] In some embodiments, in step (i), contacting the plurality of HSCs and/or the plurality of myeloid progenitor cells with the therapeutically effective amount of soluble P-glucan occurs ex vivo.

[170] In some embodiments, in step (i), contacting the plurality of HSCs and/or the plurality of myeloid progenitor cells with the therapeutically effective amount of soluble p-glucan occurs in vivo in the donor, and the contacted plurality of HSCs and/or the contacted myeloid progenitor cells are subsequently removed from the donor. In some embodiments, the donor is administered the therapeutically effective amount of soluble P-glucan about 1 hour, about 2 hours, about 3 hour, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about

11 days, about 12 days, about 13 days, about 14 days, about 3 weeks, about 4 weeks, about 6 weeks, or about 8 weeks prior to the removal of the plurality of HSCs and/or myeloid progenitor cells.

[171] In some embodiments, the soluble P-glucan is a soluble P-glucan described herein. In some embodiments, the soluble P-glucan has an average molecular weight of about 110 kilodaltons to about 400 kilodaltons.

[172] In some embodiments, the myeloablative therapy is selected from the group consisting of radiation, total body radiation, total lymphoid radiation, cyclophosphamide, busulfan, carmustine, cytarabine, 6-thioguanine, melphalan, etoposide, thiotepa, fludarabin, and a combination of any of the foregoing.

[173] In some embodiments, the myeloablative therapy comprises a low dose of chemotherapy and/or a low dose of radiation.

[174] In some embodiments, the myeloablative therapy does not comprise administration of an immunoglobulin .

[175] In some embodiments, administration of the myeloablative therapy ablates a fraction of the myeloid cells in the bone marrow of the subject. In some embodiments, administration of the myeloablative therapy ablates a fraction of the subject’s bone marrow cells. In some embodiments, the myeloablative therapy ablates about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of the myeloid cells in the bone marrow of the subject.

[176] In some embodiments, for any of the methods described herein, the soluble P-glucan has an average molecular weight of about 175 kilodaltons to about 400 kilodaltons. In certain embodiments, the soluble p-glucan has an average molecular weight of about 110 kilodaltons to about 175 kilodaltons.

[177] In some embodiments, the soluble p-glucan is isolated from yeast. In certain embodiments, the soluble p-glucan is isolated from .S', cerevisiae.

[178] In some embodiments, the soluble p-glucan comprises soluble p-1,3/1,6 glucan. In certain embodiments, the soluble P-glucan comprises P(l,6)-[poly-(l,3)-D-glucopyranosyl]-poly- P(l,3)-D-glucopyranose (Imprime PGG).

[179] In certain embodiments, the soluble P-glucan is administered intravenously.

[180] In some embodiments, the soluble P-glucan is administered in a dose of about 10 to about 100 mg, about 20 to about 100 mg, about 30 to about 100 mg, about 40 to about 100 mg, about 50 to about 100 mg, about 60 to about 100 mg, about 70 to about 100 mg, about 80 to about 100 mg, about 90 to about 100 mg, about 10 to about 90 mg, about 10 to about 80 mg, about 10 to about 70 mg, about 10 to about 60 mg, about 10 to about 50 mg, about 10 to about 40 mg, about 10 to about 30 mg, about 10 to about 20 mg, about 10 to about 40 mg, about 12 to about 40 mg, about 14 to about 40 mg, about 16 to about 40 mg, about 18 to about 40 mg, about 20 to about 40 mg, about 22 to about 40 mg, about 24 to about 40 mg, about 26 to about 40 mg, about 28 to about 40 mg, about 30 to about 40 mg, about 32 to about 40 mg, about 34 to about 40 mg, about 36 to about 40 mg, about 38 to about 40 mg, about 10 to about 20 mg, about 12 to about 20 mg, about 14 to about 20 mg, about 16 to about 20 mg, about 18 to about 20 mg, about 20 to about 30 mg, about 22 to about 30 mg, about 24 to about 30 mg, about 26 to about 30 mg, or about 28 to about 30 mg.

[181] In some embodiments, the soluble p-glucan is administered in a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

[182] In some embodiments, the soluble P-glucan is administered in a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg. In certain embodiments, the soluble P-glucan is administered in a dose of about 4 mg/kg.

[183] In certain embodiments, the soluble p-glucan is administered at a dose of about 20 mg. In certain embodiments, the soluble p-glucan is administered at a concentration of about 1.0 mg/mL.

[184] In some embodiments, the serum level of IL-ip in the subject increases following administration of the therapeutically effective amount of the soluble p-glucan. In some embodiments, the increase in serum level IL- 1 p is measured about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days after administration of the therapeutically effective amount of the soluble P-glucan to the subject. In certain embodiments, the increase in serum level IL- 1 p is measured about 7 days after administration of the therapeutically effective amount of the soluble P-glucan to the subject.

[185] In some embodiments, expression of one or more genes in the PI3K-AKT-mTOR pathway in the subject’s monocytes is increased following administration of the therapeutically effective amount of the soluble P-glucan. In some embodiments, the increase in expression of one or more genes in the PI3K-AKT-mTOR pathway in the subject’s monocytes is measured about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 3 weeks, or about 1 month after administration of the effective amount of the soluble p-glucan to the subject. In certain embodiments, the increase in expression of one or more genes in the PI3K-AKT-mTOR pathway in the subject’s monocytes is measured about 3 hours after administration of the effective amount of the soluble P-glucan to the subject.

[186] In some embodiments, the therapeutically effective amount of the soluble P-glucan does not comprise particulate (i.e., insoluble) P-glucan. In some embodiments, the soluble P-glucan comprises P-glucan material that is at least about 95% soluble. In some embodiments, the soluble P-glucan comprises P-glucan material that is at least about 99% soluble.

[187] In some embodiments, prior to administration of the therapeutically effective amount of the soluble P-glucan, the subject or the donor is screened to determine the level of serum anti-P- glucan antibody (ABA) in the subject or the donor. In some embodiments, subjects or donors having at least some threshold of serum ABA level (e.g., any of the serum ABA levels described herein, e.g., 20 pg/mL) may be selected for treatment with 0-glucan. In some embodiments, the subject or the donor may be administered a substance, composition, or treatment which increases their level of serum ABA prior to, or simultaneously with, administration of the 0-glucan. Such a treatment may enhance the potency or efficacy of the 0-glucan administration. In some embodiments, said treatment comprises administration of an intravenous immunoglobulin therapy.

[188] In some embodiments, the serum ABA in the subject is at least about 10 pg/mL, about 15 pg/mL, about 20 pg/mL, about 25 pg/mL, about 30 pg/mL, about 35 pg/mL, about 40 pg/mL, about 45 pg/mL, about 50 pg/mL, about 55 pg/mL, about 60 pg/mL, about 65 pg/mL , about 70 pg/mL, about 75 pg/mL, or about 80 pg/mL, about 85 pg/mL, about 90 pg/mL, about 95 pg/mL, about 100 pg/mL, about 105 pg/mL, about 110 pg/mL, about 115 pg/mL, about 120 pg/mL, about 125 pg/mL, about 130 pg/mL, about 135 pg/mL, about 140 pg/mL, about 145 pg/mL, or about 150 pg/mL. In certain embodiments, the level of serum ABA in the subject or the donor is at least about 20 pg/mL.

[189] In some embodiments, the donor or the subject is administered an intravenous immunoglobulin therapy. In some embodiments, administration of the intravenous immunoglobulin therapy increases the level of serum ABA in the donor or the subject.

[190] In some embodiments, the therapeutically effective amount of the soluble 0-glucan is administered systemically.

[191] In some embodiments, the subject is a human.

[192] It is to be understood that administering a therapeutically effective amount of a soluble 0- glucan, as described herein, may be accomplished by administration of a composition (e.g., a pharmaceutical composition) comprising the soluble 0-glucan, as described herein.

EXAMPLES

[193] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Example 1. Assay to determine the expression of genetic markers associated with glycolysis, the PI3K-AKT-mTOR pathway, and the IL-ip pathway in HHV subjects administered Imprime PGG.

[194] Whole blood was collected from healthy human volunteer (HHV) subjects prior to, 3 hours after, and 1 week after infusion of 4 mg/kg Imprime PGG. Volunteers had varying levels of immunoglobulin G anti-0-glucan antibodies (IgG ABA), as determined by enzyme-linked immunosorbent assay (ELISA). Blood was collected into PAXgene blood RNA tubes (BD Biosciences, Franklin Lakes, NJ), and isolated with RNeasy mini kit (Qiagen, Hilden, Germany) according to manufacturer instructions. RNA-seq was performed by Genuity Sciences using standard methods (Ireland, UK). STAR (v2.4.3a) was used for alignment of FASTQ files, and transcript abundance quantified with RSEM (v 1.3.0). Levels of genetic markers associated with glycolysis, the PI3K-AKT-mT0R pathway, and the IL-1B pathway were assessed.

[195] Greater expression of glycolysis markers was observed in subjects having higher ABA levels as compared to subjects having lower ABA levels (FIG. 1). A similar trend was observed in the PI3K-AKT-mT0R pathway (FIG. 2) and the IL- 10 pathway (FIG. 3). The results suggest that Imprime PGG more effectively stimulates glycolysis, the PI3K-AKT-mT0R pathway, and the IL-10 pathway in subjects with higher ABA levels compared to subjects with lower ABA levels.

Example 2. Assay to determine the level of transcription factors in monocytes treated with Imprime PGG or Imprime PGG + IgG ABA.

[196] Monocytes were isolated from whole blood using EasySep Human Monocyte Isolation Kit according to manufacturer instructions (Cat # 19359, StemCell Technologies, Vancouver, BC). Isolated cells were treated with Imprime PGG (25 pg/ml) or Imprime and anti-0-glucan IgG (100 pg/ml), each in the presence of 50% serum, for 12 hours. Nuclear extracts were prepared from isolated monocytes using a Nuclear Extraction kit (SK-0001, Signosis, Inc., Santa Clara, CA), and activation of a panel of transcription factors was measured using a biotinylated probe-based array (TF Activation Profiling Plate Array II, FA- 1002, Signosis, Inc., Santa Clara, CA) according to manufacturer instructions.

[197] A greater increase in expression of transcription factors was observed in monocytes treated with Imprime PGG + IgG ABA as compared to monocytes treated with Imprime PGG alone (FIG. 4). In particular, increased expression of hypoxia-inducible factor (HIF) was observed. The results suggest that treating monocytes with ABA in addition to Imprime PGG more effectively stimulates the production of transcription factors compared to treatment with Imprime PGG alone.

Example 3. Epigenetic assay using H3K4Me3 to determine levels of transcription at IL-1B in subjects treated with Imprime PGG.

[198] Peripheral Blood Mononuclear Cells (PBMCs) were isolated from healthy volunteers prior to and 1 week after infusion of 4 mg/kg Imprime PGG (Bose et al, J Immunol, 2019). Chromatin isolation, H3K4 immunoprecipitation, library generation, sequencing, and data analysis was performed by Active Motif (Carlsbad, CA). The UCSC genome browser (https://genome.ucsc.edu/) was used to visualize H3K4Me3 signals at genes of interest.

[199] In a subject with ABA levels of 177.9 pg/mL, a greater level of H3K4Me3 on IL-1B was observed 7 days after treatment with Imprime PGG compared to H3K4Me3 levels before treatment (FIG. 5), suggesting that treating subjects with high levels of ABA stimulates the IL- 1B pathway in said subjects.

INCORPORATION BY REFERENCE

[200] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

EQUIVALENTS

[201] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.