Methods and compositions for promoting Anti-tumor immunity and enchancing the immune function

Abstract

Various methods and compositions for the activating or augmenting an immune response, and for augmenting an antibody production are presented herein. Also presented herein are methods of augmenting an immune response to a vaccine. Also presented herein are methods of preventing or delaying age-related decline in physical strength or exercise tolerance. Further presented herein are methods and compositions for improving wound healing. Yet further presented herein are methods for inhibiting growth of a tumor.

Description

METHODS AND COMPOSITIONS FOR PROMOTING ANTI-TUMOR IMMUNITYAND ENCHANCING THE IMMUNE FUNCTIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 627,347, filed January 31, 2024, the disclosure of which is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under R35 GM147119 and CA245822 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION

[0003] Various aspects of the present invention relate to methods and compositions for the activating or augmenting an immune response, and methods for augmenting an antibody production. Some aspects of the present invention relate to methods of augmenting an immune response to a vaccine. Some aspects of the present invention relate to methods of preventing or delaying age-related decline in physical strength or exercise tolerance. Further aspects of the present invention relate to methods and compositions for improving wound healing. Yet further aspects of the present invention relate to methods of inhibiting growth of a tumor.BACKGROUND

[0004] An increased incidence of infections and cancers with age are two major contributors of age-related morbidity, mortality, and decreased healthspan. The higher risks of cancers and infections with age are in part due to decreased immune function and surveillance, both of which decline with age.

[0005] Most cases of pancreatic ductal adenocarcinoma (PDAC) are diagnosed after the age of 65. These cancer diagnoses are coincident with the age in which our body's immune system begins to decline. Consistent with these observations, PDAC is highly refractory to immunotherapy as well as all other current standards of care.

[0006] PDAC has a 5-year survival rate of 9%. No new targets for this disease have been discovered in the last 5 years. There is an urgent need for new therapeutics for this disease. Pancreatic cancers are amongst the most hypoxic of cancers, with oxygen tensions as low as 0.1% (for comparison, the ambient oxygen tension is 21%).

[0007] As such, there is an unmet need for novel therapeutics for the treatment of cancers, such as pancreatic cancer, or enchancement of the immune function to reduce infections especially in aged populations.SUMMARY OF THE INVENTION

[0008] In one aspect, provided herein is a method of activating or augmenting an immune response in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), or a compound of Formula (I):R2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andOR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the subject has cancer and the activated or augmented immune response is against said cancer. In some embodiments, the subject has pancreatic cancer.

[0010] In some embodiments, the subject is receiving immune checkpoint blockade or other immuno-oncology agents, including cell-based therapies.

[0011] In some embodiments, the subject has an infection and the activated or augmented immune response is against said infection. In some embodiments, the infection is selected fromthe group consisting of a viral infection, a bacterial infection, a fungal infection, and a parasitic infection. In some embodiments, the infection is a chronic bacterial, fungal, viral, or parasitic infection. In some embodiments, the subject has sepsis.

[0012] In another aspect, provided herein is a method of augmenting an immune response to a vaccine in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), a compound of Formulwherein:Ri is selected from the group consistingR.2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andR4 is selected from the group consisting of H and, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered together with the vaccine. In some embodiments, 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof and the vaccine are administered simultaneously in the same composition. In other embodiments, 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof and the vaccine are administered simultaneously in different compositions.

[0014] In some embodiments, 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered before, during, or after the administration of the vaccine.

[0015] In some embodiments, the administration of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof produces an increase of serum immunoglobulin concentrations following immunization.

[0016] In another aspect, provided herein is a method of augmenting an antibody production in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andR4 is selected from the group consisting of H and, or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a method of preventing or delaying age-related decline in physical strength or exercise tolerance in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, and oR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, provided herein is a method of treating muscle weakness, muscular dystrophy, cerebral palsy, neurodegenerative disease, white matter disease, or other neurodegenerative or neuromuscular disorders in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andOR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the neurodegenerative disease is selected from the group condidting of Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS) (Lou Gehrig's disease), and Parkinson’s disease.

[0020] In some embodiments, the muscle weakness is related to aging. In some embodiments, the subject is over 65 years of age.

[0021] In another aspect, provided herein is a method of improving wound healing in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andOR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, provided herein is a method of inhibiting growth of a tumor in a subject in need thereof. This method includes administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andOR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

[0023] In various embodiments of the methods described above, 4-hydroxymandelic acid (4- HMA) or pharmaceutically acceptable salt thereof is administered to the subject. In someembodiments, the 4-HMA is enantioentriched (R)-4-HMA. In some embodiments, the enantioentriched (R)-4-HMA has enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%. In various embodiments, the 4-HMA is enantiopure (R)-4-HMA.

[0024] In various embodiments of the methods described above, 4-hydroxybenzoate (4-HB) or pharmaceutically acceptable salt thereof is administered to the subject.

[0025] In various embodiments of the methods described above, a compound of Formula (I) or pharmaceutically acceptable salt thereof is administered to the subject.

[0026] In some embodiments, Ri is H. In other embodiments,

[0027] In some embodiments, R2 is methyl. In other embodiments, R2 is H.

[0028] In some embodiments, R3 is H. In other embodiments, R3 is methyl.

[0029] In some embodiments, R4 is H. In other embodiments, R4 is

[0030] In some embodiments, the compound of Formula (I) has the structure according toFormula (II):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingR4 is selected from the group consisting of H and

[0031] In some embodiments, the compound of Formula (I) has the structure according to Formula (III):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingR4 is selected from the group consisting of H and.

[0032] In some embodiments, the compound having the structure of Formula (I) is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound having the structure of Formula (I) is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0035] In some embodiments, 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with one or more drugs.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figs. 1A-1C show MNU mutated cell line in aged and 4-HMA treated animals. Fig. 1A shows tumor weight of orthotopic injections comparing WT (HY19636 cell line) and MNU treated cell lines in young (8-week old) and aged (>50 week old) mice, and nude mice (8-week old). Fig. IB shows tumor growth of HY and MNU cells in NSG animals. Fig. 1C shows MNU tumor growth in aged animals treated with metabolite 4-HMA.

[0037] Fig. 2A shows single-cell RNAseq data demonstrating that transcripts for HPDL, which makes 4-HMA, is high in immune cells, specifically B cells that are the precursors of plasma cells that make antibodies. Fig. 2B shows HPDL, which makes 4-HMA, is increased in activated B cells.

[0038] Fig. 3A shows that 4-HMA treatment reduces the size of MNU-driven pancreatic tumors in aged mice. Fig. 3B shows that 4-HMA treatment increases plasma IgG levels in mice.

[0039] Fig. 4 shows that treatment with 4-HMA increases the Rotarod latency (time on the Rotarod) in 1 -year-old, middle-aged mice.

[0040] Fig. 5 shows that treatment with 4-HMA increases normalized 4-paw grip strength in 1- y ear-old, middle-aged mice.DETAILED DESCRIPTION

[0041] An increased incidence of infections and cancers with age are two major contributors of age-related morbidity, mortality, and decreased healthspan. The higher risks of cancers and infections with age are in part due to decreased immune function and surveillance, both of which decline with age. It is believed that 4-HMA or CoQlO precursor headgroup treatment will be useful for promoting immune function and tumor control in aging patients. This might augment existing immune therapies and help to control tumor burden in aged populations. Furthermore, 4- HMA supplementation may help reduce infections in aged populations by promoting enhanced immune activation. This will help with tumor control through antibody dependent cytotoxicity (ADCC) and fighting infections especially in aged populations where tumor and infection incidence is high and immune function is compromised.

[0042] To facilitate an understanding of the principles and features of the various embodiments of the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0043] As used herein, the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ±20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.

[0044] As used herein, the term “alkyl” is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-20 for straight chain, C2-20 for branched chain), and alternatively, about 1-10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, a cycloalkyl ring has from about 3-10 carbon atoms in their ring structure where such rings aremonocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, a cycloalkyl group is a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl group. In some embodiments, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., Ci-4 for straight chain lower alkyls). When used in the context of a divalent alkyl group, it is to be understood that “alkyl” refers to an alkylene group.

[0045] As described herein, in certain embodiments, certain compounds of the disclosure can be indicated to comprise “optionally substituted” moieties. When indicated, in general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0046] As used herein, a substituent, e.g., -B, can be represented as a, where denotes a point of attachment.

[0047] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure.

[0048] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985,p. 1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. By way of an example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable anion selected from F , Cl", Br , I", OH , BF4, CF3SO3", monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO3 , PF 6 , NCh", carboxylate, CeFfSOi , (where e=2-10 and f=2e+l), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxy naphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, oxalate, palmitate, pamoate, pantothenate, poly galacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide. By way of another example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0049] The term “prodrug” as used herein includes a chemical which may be transformed in vivo to a pharmacologically active drug. The term “metabolite” as used herein includes a chemical that a given agent is transformed into in vivo.

[0050] The enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage of the major enantiomer less the percentage of the minor enantiomer. A “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee.

[0051] The term “enantiomerically enriched” or “enantioenriched” as used herein includes compounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and <100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer.

[0052] The term “enantiomerically pure” or “enantiopure” as used herein includes compounds where the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only.

[0053] As used herein, the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human.

[0054] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub- clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0055] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the state, disorder, or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0056] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a state, disorder, or condition or to delay or minimize one or more symptoms associated with the state, disorder, or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0057] It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named. In other words, the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.

[0058] Also, in describing the exemplary embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

[0059] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a composition does not preclude the presence of additional components than those expressly identified.

[0060] The materials described hereinafter as making up the various elements of the present invention are intended to be illustrative and not restrictive. Many suitable materials that would perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the invention. Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention.Compounds of the Disclosure

[0061] In one aspect, provided herein is a compound having the structure of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl, andR4 is selected from the group consisting of H andor pharmaceutically acceptable salt thereof.

[0062] In one embodiment, Ri is H.

[0063] In one embodiment,

[0064] In one embodiment, R2 is methyl.

[0065] In one embodiment, R2 is H.

[0066] In one embodiment, R3 is H.

[0067] In one embodiment, R3 is methyl.

[0068] In one embodiment, R4 is H.

[0069] In one embodiment,

[0070] In one embodiment, the compound of Formula (I) has the structure according toFormula (II):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingR4 is selected from the group consisting of H and

[0071] In one embodiment, the compound of Formula (I) has the structure according to Formula (III):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingOR4 is selected from the group consisting of H andMe.

[0072] In one embodiment, the compound having the structure of Formula (I) is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the compound having the structure of Formula (I) is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.

[0074] In one aspect, the present invention provides 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (also known as 4-hydroxymandelic acid (4-HMA)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0075] In one embodiment, 4-HMA is provided as a racemic mixture of the R- and the S- enantiomers of 4-HMA, depicted below:

[0076] In another embodiment, 4-HMA is provided as an enantioenriched mixture of the R- enantiomer, i.e., (R)-4-HMA. In one embodiment, the (R)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0077] In one embodiment, the (R)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at leastabout 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0078] In another embodiment, 4-HMA is provided as the enantiopure R-enantiomer (R)-4- HMA.

[0079] In another embodiment, 4-HMA is provided as an enantioenriched mixture of the S- enantiomer, i.e., (S)-4-HMA. In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0080] In one embodiment, the (S)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0081] In another embodiment, 4-HMA is provided as the enantiopure S-enantiomer (S)-4- HMA.

[0082] In one aspect, provided herein is 4-hydroxybenzoate (4-HB) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0083] An effective amount of a compound may vary from about 0.001 mg / kg to about 1000 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, and from about 10.0 mg / kg to about 150 mg / kg.

[0084] Compounds of the present disclosure as well as their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof can be administered alone or in a form of a pharmaceutical composition.

[0085] Pharmaceutical compositions can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound(s) described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0086] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0087] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0088] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0089] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0090] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0091] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, propylene glycol monostearate, and polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myij 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0092] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethyl cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol,inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0093] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0094] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0095] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chi orhexi dine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0096] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0097] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0098] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0099] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.

[0100] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0101] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0102] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0103] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition tothe active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0104] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0105] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0106] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0107] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0108] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or di calcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0109] Solid compositions of a similar type can be employed as fdlers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0110] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0111] Dosage forms for topical and / or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0112] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and / or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0113] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oilemulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0114] A pharmaceutical composition can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0115] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid nonionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0116] Pharmaceutical compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent suchas saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0117] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0118] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the invention can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0119] A pharmaceutical composition can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 / 1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are contemplated as being within the scope of this invention.

[0120] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0121] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0122] The compounds and compositions provided herein can be administered by any route, including enteral (e g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0123] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of asubject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0124] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0125] In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect.

[0126] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0127] The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity and are determined to safe and efficacious for such combined administration. For example, a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents).

[0128] The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity in treating or preventing (or both) a disease or disorder associated with aberrant activity (e.g., reduced or abolished activity) of HPDL, treating or preventing (or both) a disease associated with abnormal production of CoQlO (e.g., insufficient CoQlO production), modulating HPDL expression and / or activity, and / or modulating (e.g., increasing) CoQlO production), bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body of a subject. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0129] In some embodiments, the compounds of this invention can be administered in combination with one or more antibiotics, antiviral agents, antigungal agents, and / or antiparasitic agent.

[0130] Suitable antibiotics that can be used in combination with the compounds of this invention include penicillins (such as amoxicillin, ampicillin, azlocillin, dicloxacillin, flucloxacillin, mexlocillin, methicillin, oxacillin, pencillin G, penicillin V, piperacillin, temocillin, or ticarcillin), macrolides (such as azithromycin, clarithromycin, erythromycin, roxithromycin, telithromycin, spiramycin, or fidaxomicin), ansamycins (such as geldanamycin, herbimycin, or rifaximin), carbacephem (such as lorcarbef), carbapnems (such as ertapenem, doripenem, imipenem / cilastatin, or meropenem), cephalosporins (1st generation) (such as cefadroxil, cefazolin, cephradine, cehaparin, or cefalexin), cephalosporins (2nd generation) (such as cefaclor, cefoxitin, cefotetan, cefamandole, cefametazole, cefonicid, loracarbef, cefprozil, or cefuroxime), cephalosporins (3rd generation) (such as cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, moxalactam, ceftriaxone, moxalactam, or ceftriaxone), cephalosporins (4th generation) (such as cefepime), cephalosporins (5th generation) (such as ceftaroline, fosamil, or ceftobiprole), glycopeptides (such as teicoplanin, vancomycin, telavancin, dalbavancin, or oritavancin), lipopeptide (such as daptomycin), monobactams (such as aztreomam), nitrofurans (such as furazolidone or nitrofurantoin), oxazolidinones (such as linezolid, posizolid, radezolid, or torezolid), polypeptides (such as bacitracin, colistin, or polymyxin B), quinolones / fluoroquinolones (such as ciprofloxacin, enoxacin, gatifloxain, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, torovafloxacin, grepafloxacin, sparfloxacin,or temfloxacin), beta-lactams (such as amoxicillin with clavulanate), urinary anti-infectives (such as nitrofurantoin), lincosamides (such as clindamycin or lincomycin), tetracyclines (such as rolitetracycline, demeclocycline, doxycycline, metacycline, minocycline, oxytetracycline, or tetracycline), sulfonamides (such as mafenie, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, fulfamethoxaxole, sulffanilmide, sulfasalaxine, trimethoprim-sulfamethoxazole, or sulfoamidochrysoidine), glycopeptides (such as vancomycin, teicoplanin, telavancin, or ramoplanin), aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, or streptomycin), drugs against mycobacteria (such as clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethioamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, or streptomycin), and others (such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin / dalfopristin, thiamphenicol, tigecycline, tinidazole, or trimetheoprim).

[0131] Suitable antiviral agents that can be used in combination with the compounds of this invention include protease inhibitors (such as atazanavir, darunavir, fosamprenavir, lopinavir, ritonavir, or tipranavir), fusion inhibitors (such as enfuvirtide or the like), nucleoside / nucleotide reverse transcriptase inhibitors (such as abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, or zidovudine), non-nucleoside reverse transcriptase inhibitors (such as doravirine, efavirenz, etravirine, nevirapine, or rilpivirine), entry inhibitors (prevent viral entry into the cell) (such as ibalizumabuiyk, fostemsavir, or lenacapavir), and HIV integrase strand transfer inhibitors (INSTIs) (such as raltegravir, dolutegravir, elvitegravir, dolutegravir + abacavir + lamivudine, elvitegravir + cobicistat + tenofovir + emtricitabine, elvitegravir + cobicistat + tenofovir AF + emtricitabine, dolutegravir + rilpivirine, or bictegravir + tenofovir AF + emtricitabine).

[0132] In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, adefovir, valacyclovir, famciclovir, entecavir, sofosbuvir, tenofovir, velpatasvir, lamivudine, ledipasvir, oseltamivir, zanamivir, valganciclovir, voxilaprevir, ganciclovir, foscarnet, cidofovir, glecapravir, pibrentasvir, amantadine, rimantadine, imiquimod, and interferon.

[0133] Suitable antigungal agents that can be used in combination with the compounds of this invention include polyenes (such as nystatin or amphotericin B), azoles (imidazoles such as clotrimazole, ketoconazole, or miconazole; or triazoles such as fluconazole, isavuconazole,itraconazole, posaconazole, or voriconazole), allylamines (such as terbinafine or the like), or echinocandins (such as anidulafungin, caspofungin, rezafungin, or micafungin).

[0134] Suitable antiparasitic agents that can be used in combination with the compounds of this invention include antiprotozoal agents, anthelmintics, and ectoparasiticides.

[0135] Suitable antiprotozoal agents that can be used in combination with the compounds of this invention include antimalarials (such as chloroquine and its derivatives, artesunate, atovaquone-proguanil, artemether, or lumefantrine), antibabesial agents (such as atovaquone + azithromycin or clindamycin + quinine), anti-toxoplasma agents (such as sulfadiazine + pyrimethamine, trimethoprim +sulfamethoxazole, or pyrimethamine + clindamycin), antiamoebic agents (paromomycin sulfate, metronidazole, or pentamidine), trypanocidal agents (such as benznidazole and the like), antileishmanial agents (such as liposomal amphotericin B or miltefosine), anti trichomoniasis agents (such as metronidazole or the like), and antigiardial agents (such as metronidazole or albendazole).

[0136] Suitable anthelmintics that can be used in combination with the compounds of this invention include anticestodal drugs (such as praziquantel, pyrantel, nitazoxanide, or albendazole), antitrematodal drugs (such as praziquantel or the like), and antinematodal drugs (such as albendazole, mebendazole, or ivermectin).

[0137] Suitable ectoparasiticides that can be used in combination with the compounds of this invention include antiscabietic agents (such as lindane, permethrin, or ivermectin) and pediculicides (such as permethrin or ivermectin).

[0138] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be given in conjunction with antibiotics to elderly patients with infections to augment the immune system’s response to these infections.

[0139] In some embodiments, the elderly patients can be critically ill.

[0140] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a singledose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.Methods of Treatment and Uses

[0141] The present invention also provides methods of using the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), for treating or preventing a disease or disorder.

[0142] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in activating or augmenting an immune response in a subject in need thereof.

[0143] In some embodiments, the subject being treated has cancer and the activated or augmented immune response is against said cancer.

[0144] In some embodiments, the subject has leukemia, breast cancer, prostate cancer, lung cancers, ovarian cancer, pancreatic cancer, hepatocellular cancer, sarcoma, vascular endothelial cancer, central nervous system cancers (e.g., astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma, and glioblastoma), bronchus cancer, larynx cancer, esophagus cancer, colon cancer, colorectal cancer, gastro-intestinal cancer, melanoma, endometrial cancer, renal scancer, bladder cancer, liver cancer, or endocrine cancer (e.g., thyroid cancer). In some embodiments, the subject has pancreatic cancer.

[0145] In some embodiments, the subject is receiving immune checkpoint blockade or other immuno-oncology agents. In some embodiments, the subject is receiving cell-based therapies.

[0146] In some embodiments, the subject has an infection and the activated or augmented immune response is against said infection. The subject can have a viral infection, a bacterial infection, a fungal infection, and a parasitic infection. In some embodiments, the subject has a chronic bacterial, fungal, viral, or parasitic infection. In some embodiments, the subject has sepsis.

[0147] Examplary viral infections include herpes simplex virus (HSV), varicella-zoster virus (VZV), human papillomavirus, influenza, cytomegalovirus (CMV), varicella-zoster virus, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), COVID-19, ebola, or flu.

[0148] Examplary bacterial infections include infections caused by gram positive cocci (MRSA, MSSA, or Streptococci), gram negative bacili (E. coli, P. mirabilis, Klebsiella, Pseudomonas, ESCAPPM), gram-negative cocci (N. gonorrhoeae or N. meningitidis), anaerobes, or atypicals (Mycoplasma).

[0149] Examplary fungal infections include fungal nail infections, ringworm, vaginal candidiasis, Candida infections of the mouth, throat, and esophagus, blastomycosis, valley fever (coccidioidomycosis), C. gattii infection, histoplasmosis, paracoccidioidomycosis, aspergillosis, Candida auris, C. neoformans infection, invasive candidiasis, mucormycosis, pneumocystis pneumonia, talaromycosis (penicilliosis), fungal eye infections, mycetoma, sporotrichosis, fungal meningitis (including healthcare-associated fungal meningitis).

[0150] Examplary parasitic infections include infections caused by various protozoa (malaria, babesiosis, toxoplasmosis, infections caused by amoebas, including granulomatous amebic encephalitis (GAE) and amebiasis, chagas disease (american trypanosomiasis), sleeping sickness (african trypanosomiasis), leishmaniasis, trichomoniasis, and giardia), helminths (enterobiasis, soil-transmitted helminths (STH), schistosomiasis, echinococcosis, and strongyloides), and ectoparasites (lice, scabies, fleas, or mites).

[0151] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be used as a vaccine adjuvant to enhance vaccine efficacy. For example, the compound(s) or pharmaceutical compositions of the present disclosure may be given in combination with the vaccine to patients (e.g., elderly patients or immunocompromised patients) whose responses to vaccination are not as durable as, e g., in young and healthy patients due to immunosenescence.

[0152] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in augmenting an immune response to a vaccine in a subject in need thereof.

[0153] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be used to boost serum immunoglobulin concentrations following immunization.

[0154] The compound or composition can be administered concurrently with, prior to, or subsequent to, administration of a vaccine. The compound or composition can be administered together with the vaccine. The compound or composition and the vaccine can be administered simultaneously in the same composition. The compound or composition and the vaccine can be administered simultaneously in different compositions. Alternatively, the compound or composition can be administered before, during, or after the administration of the vaccine.

[0155] In some embodiments, administration of the compound(s) or pharmaceutical compositions of the present disclosure produces an increase of serum immunoglobulin concentrations following immunization.

[0156] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in augmenting an antibody production in a subject.

[0157] In some embodiments, the administration of the compound(s) or pharmaceutical compositions of the present disclosure may result in enhancing monoclonal antibody production.

[0158] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in preventing or delaying age-related decline in physical strength or exercise tolerance in a subject.

[0159] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating muscle weakness, muscular dystrophy, cerebral palsy, neurodegenerative disease, white matter disease, or other neurodegenerative or neuromuscular disorders in a subject.

[0160] In some embodiments, the neurodegenerative disease is selected from the group condidting of Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS) (Lou Gehrig's disease), and Parkinson’s disease.

[0161] In some embodiments, the muscle weakness is related to aging. In some embodiments, the subject is over 65 years of age.

[0162] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving wound healing in a subject.

[0163] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be useful in inhibiting growth of a tumor in a subject.

[0164] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be administered to a subject a prophylactic. In some embodiment, thecompound(s) or pharmaceutical compositions of the present disclosure may be administered to a subject above a particular age (e.g., above 60, or 65, or 70, or 75 years of age), or who have presented to their physicians or to the hospital with multiple infections.

[0165] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be used to treat autoimmune diseases. In some embodiments, autoimmune diseases are the ones mediated by immune complex formation. In some embodiments, the autoimmune disease is selected from a group consisng of vasculitis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, and systemic lupus erythematosus.

[0166] In some embodiments, the compound(s) or pharmaceutical compositions of the present disclosure may be used to boost mitochondrial function of a cell. In some embodiments, the cell is an immune cell.

[0167] In various embodiments of the methods described above, the subject is a mammal. In some embodiments, the subject is a human.

[0168] In some embodiments, the subject is a pediatric subject 0 to 18 years of age. In some embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler. In some embodiments, treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus.

[0169] In some embodiments, the subject is an adult. In some embodiments, the subject is an elderly adult. In some embodiments, the subject is 65 year old adult or older.

[0170] In some embodiments, when the subject being treated is a child, the child may be treated with the the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), in utero, immediately after birth, or in postpartum days.

[0171] In some embodiments, the method may involve treating a newborn or infant by administering the the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the newborn or infant.

[0172] In some embodiments, the method may involve treating an unborn fetus by administering the the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the pregnant female.EXAMPLES

[0173] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.Example 1. Progression of Pancreatic Cancer in Elderly Mice vs. Younger Mice

[0174] Wild type (HY) and mutated (MNU) cell lines were implanted into the pancreata of young and aged mice (Fig. 1A). In young animals, there was a significant difference in the growth between the HY and MNU cells which was not observed in the aged populations. Furthermore, the growth inhibition of MNU cells in young animals was correlated with an increase in the number of macrophages (F4 / 80+) and granulocytic cells of unknown origin. These data were unexpected as the infiltrating cells were not CD3+ suggesting a potential role for the innate immune system in mediating tumor growth inhibition.

[0175] HY and MNU cells were implanted in the pancreata of nude mice and a significant growth disadvantage for MNU tumors was observed (Fig. 1A). Nude mice lack an adaptive immune system and compensate for this loss by maintaining highly activated NK cell populations. These data suggest that the mutagenized cancer cells can still evade adaptive immunity, yet are susceptible to the innate immune system.

[0176] Next, HY and MNU cells were injected in the pancreata of NSG animals (immune incompetent). No growth inhibition was observed (Fig. IB). Thus, the model system allowed to dissect the role of the innate immune system in controlling tumor burden in aged populations.

[0177] While it has been reported that the adaptive immune system declines with age which may lead to poor tumor control in aged populations, much less work has been done to understand how the innate immune system contributes to anti-tumor immunity especially in regard to aging. Indeed, this is a rapidly growing field of study as NK cells and other innate lymphoid cells (ILC) may have a broader range of anti-cancer properties since they do not require recognition of neoantigens to elicit an anti-tumor response. The advent of immunotherapy has revolutionized cancer treatment yet there are still many patients that do not respond to checkpoint blockade.

[0178] It was assumed that increased mitochondrial activity of immune cells would augment the immune response, and that mitochondrial activity could be increased by metabolite administration. Mitochondrial activity has been shown to decline with age and restoration of mitochondrial function may be beneficial for overall immune function as well as anti-cancerimmunity. Coenzyme Q10 (CoQlO) is a lipophilic, endogenously synthesized antioxidant critical for mitochondrial electron transport chain function. End-organ concentrations of CoQlO decline with age in nearly all organs except the liver.

[0179] A mutagenized (MNU) mouse pancreatic ductal adenocarcinoma (PDAC) cell line was developed that was rejected in young mice, but not in aged mice (>45 weeks old) (Fig. 1C). The MNU model is believed to more accurately reflect the increased mutational burden that is frequently found in tumors from patients that are advanced in age. Most cases of PDAC are diagnosed after the age of 65. These cancer diagnoses are coincident with the age in which the body's immune system begins to decline. Consistent with these observations, PDAC is highly refractory to immunotherapy as well as all other current standards of care. This model system was used to understand how to potentiate anti-tumor immunity in aged populations which is of particular clinical relevance to PDAC. Aged animals were fed with 4-hydroxymandelate (4- HMA), a CoQlO headgroup precursor. A significant tumor reduction in 4-HMA treated animals was observed (Fig. 1C). These results showed that augmenting CoQlO synthesis would augment immune function. Furthermore, tumor growth was not significantly different in NSG animals which lack a functional immune system. These data suggest that innate immune cells found in both young C57 BL6 / J and Nu / Nu mice. Finally, clodronate treatment (used as a means of depleting macrophages and other phagocytic cells) did not restore tumor growth.

[0180] These studies revealed that tumor control was correlated with an influx of granulocytic cells in the TME in 4-HMA treated mice. Indeed, it has been shown that mitochondrial function is critical for NK cell cytokine production in viral infection. It was assumed that the same may be true in the setting of pancreatic cancer. Furthermore, analysis of publicly available single-cell sequencing data revealed that plasma cells express high levels of HPDL transcript. Plasma cells are responsible for antibody production, which requires protein synthesis, which requires abundant ATP and highly functional mitochondria. Without wishing to be bound by theory, these data suggest that 4-HMA augments antibody production in aging plasma cells which cooperate with NK cells to promote an anti-tumor immune response through a process known as antibody-dependent cell cytotoxicity (ADCC).

[0181] While these data revealed immunostimulatory function in the setting of pancreatic cancer, it was postulated that enhancing immune system function through 4-HMA administration will likely be beneficial for a broad range of indications. It was assumed that there will bemultiple applications for 4-HMA in treating immunosenescence, which leads to increased incidences of cancer and infections in the elderly due to defects in immune surveillance.

[0182] Plasma cells have high transcript levels of HPDL, the gene that makes 4-HMA (Fig. 2A; Human Protein atlas). The increase in HPDL transcript in activated B cells, which are the precursors to plasma cells that make antibodies, is statistically significant (Fig. 2B). We contend that 4-HMA supplementation may augment the function of these cells with age. From a biotechnology perspective, 4-HMA supplementation may increase the yield of monoclonal antibody production.Example 2. 4-HMA Treatment Increases Plasma IgG Levels in Mice

[0183] Fig. 3A shows that 4-HMA treatment attenuates the growth of MNU-mutagenized orthotopically implanted PDAC cells in >45-week-old male mice. Fig. 3B shows that 4-HMA treatment of aged male mice significantly increases their levels of serum IgG. This suggests that the mechanism of tumor control is at least partially driven by enhancement of B cell function and that 4-HMA could be used to boost serum immunoglobulin concentrations following immunization (acting as an adjuvant).Example 3. Treatment of Muscle Weakness Using 4-HMA

[0184] 1 year-old mice (equivalent to middle-aged humans) were treated with 4-HMA at 10 mg / kg in the water for 3-4 weeks. Their latency time on the Rotarod (a test of balance, strength, motor coordination, and striatal function) was tested. Middle-aged animals treated with 4-HMA demonstrated increased time on the Rotarod in comparison to a control group that was not treated (Fig. 4). One-year-old, middle-aged mice treated with 4-HMA also demonstrated stable to improved 4-paw grip strength in comparison to untreated mice (Fig. 5).

[0185] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0186] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

WHAT IS CLAIMED IS:

1. A method of activating or augmenting an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4- hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), or a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andOR4 is selected from the group consisting of H and LMe, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the subject has cancer and the activated or augmented immune response is against said cancer.

3. The method of claim 2, wherein the subject has pancreatic cancer.

4. The method of claim 2, wherein the subject is receiving immune checkpoint blockade or other immuno-oncology agents, including cell-based therapies.

5. The method of claim 1, wherein the subject has an infection and the activated or augmented immune response is against said infection.

6. The method of claim 5, wherein the infection is selected from the group consisting of a viral infection, a bacterial infection, a fungal infection, and a parasitic infection.

7. The method of claim 6, wherein the infection is a chronic bacterial, fungal, viral, or parasitic infection.

8. The method of claim 5, wherein the subject has sepsis.

9. A method of augmenting an immune response to a vaccine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4- hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andR4 is selected from the group consisting of H andora pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein 4-hydroxymandelic acid (4-HMA), 4 -hydroxy benzoate (4- HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered together with the vaccine.

11. The method of claim 10, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof and the vaccine are administered simultaneously in the same composition.

12. The method of claim 10, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof and the vaccine are administered simultaneously in different compositions.

13. The method of claim 9, wherein 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4- HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered before, during, or after the administration of the vaccine.

14. The method of claim 9, wherein the administration of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof produces an increase of serum immunoglobulin concentrations following immunization.

15. A method of augmenting an antibody production in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andR4 is selected from the group consisting of H and,ora pharmaceutically acceptable salt thereof.

16. A method of preventing or delaying age-related decline in physical strength or exercise tolerance in a subject in need thereof, comprising administering to the subject atherapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andR4 is selected from the group consisting of H and,ora pharmaceutically acceptable salt thereof.

17. A method of treating muscle weakness, muscular dystrophy, cerebral palsy, neurodegenerative disease, white matter disease, or other neurodegenerative or neuromuscular disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andR4 is selected from the group consisting of H and, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the muscle weakness is related to aging.

19. The method of claim 17, wherein the subject is over 65 years of age.

20. A method of improving wound healing in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andR4 is selected from the group consisting of H and,ora pharmaceutically acceptable salt thereof.

21. A method of inhibiting growth of a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 4-hydroxymandelic acid (4- HMA), 4-hydroxybenzoate (4-HB), a compound of Formula (I):wherein:Ri is selected from the group consistingR2 is selected from the group consisting of H and C1-C3 alkyl;R3 is selected from the group consisting of H and C1-C3 alkyl; andOR4 is selected from the group consisting of H andMe, or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1-21, wherein 4-hydroxymandelic acid (4-HMA) or pharmaceutically acceptable salt thereof is administered to the subject.

23. The method of any one of claims 1-22, wherein the 4-HMA is enantioentriched (R)-4-HMA.

24. The method of claim 23, wherein the enantioenriched (R)-4-HMA has enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

25. The method of any one of claims 1-22, wherein the 4-HMA is enantiopure (R)-4-HMA.

26. The method of any one of claims 1-21, wherein 4-hydroxybenzoate (4-HB) or pharmaceutically acceptable salt thereof is administered to the subject.

27. The method of any one of claims 1-21, wherein a compound of Formula (I) or pharmaceutically acceptable salt thereof is administered to the subject.

28. The method of any one of claims 1-21 or 27, wherein Ri is H.

29. The method of any one of claims 1-21 or 27, wherein30 . The method of any one of claims 1-21 or 27-29, wherein R2 is methyl.31 . The method of any one of claims 1-21 or 27-29, wherein R2 is H.32 . The method of any one of claims 1-21 or 27-31, wherein R3 is H.33 . The method of any one of claims 1-21 or 27-31, wherein R3 is methyl.34 . The method of any one of claims 1-21 or 27-33, wherein R4 is H.35 . The method of any one of claims 1-21 or 27-33, wherein R4 is36 . The method of any one of claims 1-21 or 27, wherein the compound of Formula (I) has the structure according to Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingR4 is selected from the group consisting of H and37 . The method of any one of claims 1-21 or 27, wherein the compound of Formula (I) has the structure according to Formula (III):or a pharmaceutically acceptable salt thereof, wherein:Ri is selected from the group consistingOR.4 is selected from the group consisting of H and38. The method of any one of claims 1-21 or 27, wherein the compound having the structure of Formula (I) is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 1-21 or 27, wherein the compound having the structure of Formula (I) is selected from the group consisting of:, or a pharmaceutically acceptable salt thereof.

40. The method of any one of claims 1-39, wherein the subject is a mammal.

41. The method of claim 40, wherein the subject is a human.

42. The method of claim 40, wherein the subject is a pediatric subject 0 to 18 years of age.

43. The method of claim 40, wherein the subject is an adult.

44. The method of claim 43, wherein the subject is an elderly adult.

45. The method of claim 43, wherein the subject is 65 years or older.

46. The method of any one of claims 1-45, wherein 4-hydroxymandelic acid (4-HMA), 4- hydroxybenzoate (4-HB), a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with one or more drugs.

47. The method of any one of claims 17-19, wherein neurodegenerative disease is selected from the group condi dting of Alzheimer’s disease, Amyotrophic lateral sclerosis, and Parkinson’s disease.

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