WO2025189143A1

WO2025189143A1 - Compositions and methods of their use

Info

Publication number: WO2025189143A1
Application number: PCT/US2025/019002
Authority: WO
Inventors: Shenda M. Baker; William P. Wiesmann
Original assignee: Synedgen Inc
Current assignee: Synedgen Inc
Priority date: 2024-03-08
Filing date: 2025-03-07
Publication date: 2025-09-12
Anticipated expiration: 2026-09-08
Also published as: WO2025189143A8

Abstract

Provided herein are methods of treating a disease or disorder (e.g., a disease or disorder of the gastrointestinal tract), or a symptom or a complication thereof, in a subject in need thereof (e.g., in a subject identified as being exposed to radiation), comprising administering to the subject a combination of a polyglucosamine-arginine (PAAG) of the Formula (I) and an additional agent.

Description

COMPOSITIONS AND METHODS OF THEIR USE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application 63/563,307, filed on March 8, 2024, U.S. Provisional Application 63/563,310, filed on March 8, 2024, U.S. Provisional Application 63/724,885, filed on November 25, 2024, and U.S. Provisional Application No. 63/724,891, filed on November 25, 2024, each of which is incorporated by reference herein in its entirety and for all purposes.

STATEMENT OF GOVERNMENT RIGHTS

This invention was made with government support under contract numbers W81XWH2210869 and W81XWH1910165 issued by the Department of Defense. The government has certain rights in the invention.

BACKGROUND

Exposure to radiation (e.g., radiation therapy, radiological or nuclear attacks or associated accidents) will evoke invariably significant damage to selective tissues of vital organ systems of the body, including the blood-forming and gastrointestinal and other organ systems. Following irradiation, acute lymphohematopoietic tissue damage rapidly manifests as evidenced by rapid changes in clinically relevant blood parameters, namely by fast, timedependent decreases in blood cell concentrations (specifically lymphocytes, granulocytes, and thrombocytes/platelets). Acute gastrointestinal tissue damage also rapidly manifests post irradiation. Thus, there is a need for compounds, compositions, and methods of use thereof, for mitigating effects of radiation exposures, particularly effects associated with acute radiation syndrome (ARS), including hematopoietic acute radiation syndrome (H-ARS) and gastrointestinal acute radiation syndrome, (GLARS).

Many existing therapies for treating diseases and disorders of the gastrointestinal tract (e.g., immunomodulators) are administered parenterally and designed to address specific immune and inflammatory pathways to reduce inflammation. The therapeutic rationale is to reduce inflammation in order to reduce a driver of mucosal damage. However, such therapies are systemic and do not directly address local symptoms or complications, such as repairing GI tissue damage. Many existing therapies also have significant side effects (e.g., black box warnings). Patients are highly refractory to these therapies. Thus, there is a need for compounds, compositions, and methods of use thereof, for synergistically treating both systemic symptoms (e.g., systemic inflammation) and local symptoms (e.g., local inflammation, restoration of GI tissue regeneration, barrier function, and reduced bacterial translocation) in order to effectively treat diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, Crohn’s disease, and ulcerative colitis.

The combination of compounds, compositions, and methods of use thereof are directed toward these needs.

SUMMARY

Disclosed herein, in some embodiments, are methods of treating a disease or disorder (e.g., a disease or disorder of the gastrointestinal tract), or a symptom or a complication thereof, in a subject in need thereof (e.g., in a subject identified as being exposed to radiation), comprising administering to the subject a combination of a polyglucosamine- arginine (PAAG) of the Formula (I) and an additional agent.

In an aspect, provided is a method of treating a disease or disorder, or a symptom or a complication thereof, in a subject identified as being exposed to radiation, comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

Formula (I) wherein: n is an integer between 20 and 6000; and each R¹ is independently selected for each occurrence from hydrogen, acetyl, wherein at least about 25% of R¹ substituents are H, and at least about 2% of

R¹ substituents and (b) a hematopoietic agent.

In some embodiments, the disease or disorder is acute radiation syndrome.

In some embodiments, the hematopoietic agent is a leukocyte growth factor.

In some embodiments, the leukocyte growth factor is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony- Stimulating Factor, and Erythropoietin.

In some embodiments, the leukocyte growth factor is selected from the group consisting of pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

In some embodiments, the hematopoietic agent is a thrombopoietin receptor agonist.

In some embodiments, the thrombopoietin receptor agonist is selected from the group consisting of romiplostim and eltrombopag.

In some embodiments, the hematopoietic agent is selected from the group consisting of Granulocyte Colony- Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Erythropoietin, romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

In some embodiments, the hematopoietic agent is selected from the group consisting of Granulocyte Colony- Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, and Erythropoietin.

In some embodiments, the hematopoietic agent is selected from the group consisting of romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

In some embodiments, the hematopoietic agent is selected from the group consisting of romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim. In some embodiments, the hematopoietic agent is selected from the group consisting of romiplostim, pegfilgrastim, filgrastim, and sargramostim.

In some embodiments, the hematopoietic agent is administered parenterally.

In some embodiments, the PAAG is administered orally.

In some embodiments, the PAAG and the hematopoietic agent are administered substantially simultaneously.

In some embodiments, the PAAG is administered prior to the hematopoietic agent.

In some embodiments, the hematopoietic agent is administered prior to the PAAG.

In some embodiments, the subject has cancer. In some embodiments, the subject is or has undergone a cancer treatment. In some embodiments, the cancer treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, surgery, and combinations thereof. In some embodiments, the subject has hematopoietic acute radiation syndrome (H-ARS) or gastrointestinal acute radiation syndrome (GI-ARS), or a combination thereof.

In an aspect, provided is a method of treating a disease or disorder of the gastrointestinal tract, or a symptom or a complication thereof, in a subject in need thereof, comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

R¹ substituents and (b) a an additional agent selected from the group consisting of steroid, TNF inhibitor, a407 integrin inhibitor, IL-12 and/or IL-23 inhibitor, SIP receptor modulator, JAK inhibitor, TYK2 inhibitor, RIP IK inhibitor, IL-6R antagonist, and LANCL2 agonist.

In some embodiments, the steroid is an aminosalicylate or a corticosteroid.

In some embodiments, the aminosalicylate is selected from the group consisting of 4- aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, and budesonide.

In some embodiments, the corticosteroid is selected from the group consisting of hydrocortisone, methylprednisone, and prednisone.

In some embodiments, the steroid is selected from the group consisting of 4- aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, budesonide, hydrocortisone, methylprednisone, and prednisone.

In some embodiments, the TNF inhibitor is selected from the group consisting of adalimumab, infliximab, golimumab, certrolizumab, and etanercept.

In some embodiments, the a4P7 integrin inhibitor is selected from the group consisting of vedolizumab, natalizumab, etrolizumab, abrilumab, carotegrast methyl, zaurategrast, TR-14035, and R411.

In some embodiments, the IL- 12 and/or IL-23 inhibitor is selected from the group consisting of ustekinumab, risankizumab, guselkumab, mirikizumab, and brazikumab.

In some embodiments, the SIP receptor modulator is selected from the group consisting of fingolimod, etrasimod, KRP-203, siponimod, CS-0777, ponesimod, ozanimod, ceralifimod, GSK2018682, MT-1303, SEW2871, AUY954, and JTE-013.

In some embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib, baricitinib, deucravacitinib, ruxolitinib, ritlecitinib, abrocitinib, delgocitinib, fedratinib, filgotinib, momelotinib, pacritinib, upadacitinib, LS104, ON044580, NVP- BBT594, and NVP-CHZ868. In some embodiments, the TYK2 inhibitor is selected from the group consisting of deucravacitinib, ropsacitinib, and brepocitinib.

In some embodiments, the RIPK1 inhibitor is selected from the group consisting of GSK2982772, SAR443060, and necrostatin-ls.

In some embodiments, the IL-6R antagonist is selected from the group consisting of olamkicept, tocilizumab, and sarilumab.

In some embodiments, the LANCL2 agonist is omilancor.

In some embodiments, the disease or disorder of the gastrointestinal tract is a condition of the gut, inflammatory bowel disease, irritable bowel syndrome, Crohn's Disease, stomach ulcer, ulcerative colitis, neonatal necrotizing enterocolitis, gastroesophageal reflux disease, gastroparesis, constipation, functional bloating, gastritis, lactose intolerance, visceral hyperalgesia, colic, pouchitis, diverticulitis, or diarrhea.

In some embodiments, the disease or disorder of the gastrointestinal tract is inflammatory bowel disease. In some embodiments, the disease or disorder of the gastrointestinal tract is Crohn’s disease. In some embodiments, the disease or disorder of the gastrointestinal tract is ulcerative colitis.

In some embodiments, the additional agent is administered parenterally.

In some embodiments, the additional agent is administered orally.

In some embodiments, the PAAG is administered orally.

In some embodiments, the PAAG and the additional agent are administered substantially simultaneously.

In some embodiments, the PAAG is administered prior to the additional agent.

In some embodiments, the additional agent is administered prior to the PAAG.

In some embodiments, at least about 5% of R¹ is acetyl. In some embodiments, at least about 10% of R¹ is acetyl. In some embodiments, at least about 20% of R¹ is

In some embodiments, between about 25% to about 40% of R¹ is

In some embodiments, less than about 5% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 5% of the PAAG has a molecular weight greater than about 250 kDa. In some embodiments, the weight average molecular weight (M_w) of the PAAG is between about 30 to about 70 kDa. In some embodiments, the number average molecular weight (M_n) of the PAAG is between about 20 to about 60 kDa.

In some embodiments, the % arginine functionalization of the PAAG is between 25 and 40%. In some embodiments, the % arginine functionalization of the PAAG is between 25 and 35%. In some embodiments, the % arginine functionalization of the PAAG is between 30 and 40%.

DETAILED DESCRIPTION

The present disclosure features methods of treating a disease or disorder (e.g., a disease or disorder of the gastrointestinal tract), or a symptom or a complication thereof, in a subject in need thereof (e.g., in a subject identified as being exposed to radiation), comprising administering to the subject a combination of a polyglucosamine-arginine (PAAG) of the Formula (I) and an additional agent.

Methods

Disease, disorder, and condition are used interchangeably herein.

As used herein, the terms “a,” “an,” and “the” refer to one or to more than one, unless context indicates otherwise. Similarly, the term “or” is intended to include “and”, unless context indicates otherwise.

As used herein, “about” all generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10% , and more typically, within 5% of a gi ven value or range of values. As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal.

As used herein, the term “treat” or “treatment” is defined as the application or administration of a composition or compound (e.g., a combination of a polyglucosamine- arginine (PAAG) of the Formula (I) and an additional agent) to a subject (e.g., a patient) or application or administration of the composition or compound to an isolated tissue from a subject (e.g., a patient) with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve and/or affect a disease or disorder described herein (e.g., a disease or disorder of the gastrointestinal tract), or a symptom or a complication thereof.

As used herein, an amount of a composition or compound (e.g., a combination of a polyglucosamine-arginine (PAAG) of the Formula (I) and an additional agent) effective to treat a disease or disorder described herein, or a “therapeutically effective amount,” refers to an amount of the composition or compound which is sufficient or effective to elicit a desired therapeutic response, such as providing a therapeutic benefit in the treatment of a disease or disorder (e.g., a disease or disorder of the gastrointestinal tract), or a symptom or a complication thereof.

Disclosed herein, in some embodiments, are methods of treating a disease, or a symptom or a complication thereof, in a subject in need thereof (e.g., a subject identified as being exposed to radiation), comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

Formula (I) wherein: n is an integer between 20 and 6000; and each R¹ is independently selected for each occurrence from hydrogen, acetyl,

wherein at least about 25% of R¹ substituents are H, and at least about 2% of

R¹ substituents and (b) a hematopoietic agent.

In some embodiments, the PAAG is administered orally (e.g., as a dry product (e.g., capsule or tablet) or as an aqueous solution).

In some embodiments, the hematopoietic agent is administered parenterally.

In an embodiment, the PAAG and the hematopoietic agent are administered substantially simultaneously (e.g., two unit dosages administered at the same time, or a combined unit dosage of the PAAG and the hematopoietic agent). In some embodiment, the PAAG and the hematopoietic agent are delivered in separate unit dosages. The PAAG and the hematopoietic agent can be administered in any order. In some embodiments, the PAAG is administered prior to the hematopoietic agent. In some embodiments, the hematopoietic agent is administered prior to the PAAG. In some embodiments, the PAAG and the hematopoietic agent delivered in combined unit dosages.

Disclosed herein, in some embodiments, are methods of treating a disease or disorder of the gastrointestinal tract, or a symptom or a complication thereof, in a subject in need thereof, comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

R¹ substituents and (b) a an additional agent selected from the group consisting of steroid, TNF inhibitor, a4p7 integrin inhibitor, IL- 12 and/or IL-23 inhibitor, SIP receptor modulator, JAK inhibitor, TYK2 inhibitor, RIP IK inhibitor, IL-6R antagonist, and LANCL2 agonist.

In some embodiments, the PAAG is administered orally (e.g., as a dry product (e.g., capsule or tablet) or as an aqueous solution). In some embodiments, the additional agent is administered parenterally. In some embodiments, the additional agent is administered orally.

In an embodiment, the PAAG and the additional agent are administered substantially simultaneously (e.g., two unit dosages administered at the same time, or a combined unit dosage of the PAAG and the additional agent). In some embodiment, the PAAG and the additional agent are delivered in separate unit dosages. The PAAG and the additional agent can be administered in any order. In some embodiments, the PAAG is administered prior to the additional agent. In some embodiments, the additional agent is administered prior to the PAAG. In some embodiments, the PAAG and the additional agent are delivered in combined unit dosages.

Diseases and Disorders

Radiation

Disclosed herein, in some embodiments, are methods of treating a disease or disorder, or a symptom or a complication thereof, in a subject in need thereof (e.g., a subject identified as being exposed to radiation). In some embodiments, the disease or disorder is acute radiation syndrome. In some embodiments, the disease or disorder of the gastrointestinal tract is a result of fractionated radiation.

In some embodiments, the subject is a subject identified as being exposed to radiation (e.g., radiation related to the treatment of cancer). In some embodiments, the subject has cancer.

In some embodiments, the subject is or has undergone a cancer treatment. In some embodiments, the cancer treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, surgery, and combinations thereof. In some embodiments, the cancer treatment is radiation therapy. In some embodiments, the subject has been exposed to a radiological agent. In some embodiments, the subject has radiological injury. In some embodiments, the subject has acute radiation syndrome. In some embodiments, the subject has delayed effects of acute radiation syndrome. In some embodiments, the subject has hematopoietic acute radiation syndrome (H-ARS) or gastrointestinal acute radiation syndrome (GI-ARS), or a combination thereof.

Disclosed herein, in some embodiments, are methods for treating diseases or disorders of the gastrointestinal tract. In some embodiments, the disease or disorder of the gastrointestinal tract is a condition of the gut, inflammatory bowel disease, irritable bowel syndrome, Crohn's Disease, stomach ulcer, ulcerative colitis, neonatal necrotizing enterocolitis, gastroesophageal reflux disease, gastroparesis, constipation, functional bloating, gastritis, lactose intolerance, visceral hyperalgesia, colic, pouchitis, diverticulitis, or diarrhea. In some embodiments, the disease or disorder of the gastrointestinal tract is a condition of the gut. In some embodiments, the disease or disorder of the gastrointestinal tract is inflammatory bowel disease. In some embodiments, the disease or disorder of the gastrointestinal tract is irritable bowel syndrome. In some embodiments, the disease or disorder of the gastrointestinal tract is Crohn's Disease. In some embodiments, the disease or disorder of the gastrointestinal tract is stomach ulcer. In some embodiments, the disease or disorder of the gastrointestinal tract is ulcerative colitis. In some embodiments, the disease or disorder of the gastrointestinal tract is neonatal necrotizing enterocolitis. In some embodiments, the disease or disorder of the gastrointestinal tract is gastroesophageal reflux disease. In some embodiments, the disease or disorder of the gastrointestinal tract is gastroparesis. In some embodiments, the disease or disorder of the gastrointestinal tract is constipation. In some embodiments, the disease or disorder of the gastrointestinal tract is functional bloating. In some embodiments, the disease or disorder of the gastrointestinal tract is gastritis. In some embodiments, the disease or disorder of the gastrointestinal tract is lactose intolerance. In some embodiments, the disease or disorder of the gastrointestinal tract is visceral hyperalgesia. In some embodiments, the disease or disorder of the gastrointestinal tract is colic. In some embodiments, the disease or disorder of the gastrointestinal tract is pouchitis. In some embodiments, the disease or disorder of the gastrointestinal tract is diverticulitis. In some embodiments, the disease or disorder of the gastrointestinal tract is diarrhea.

Gastritis

In some embodiments, the methods described herein have partial or complete alleviation, amelioration, relief, inhibition, delaying onset, reducing severity or incidence of of gastritis. Gastritis refers to irritation from excessive alcohol use, chronic vomiting, stress, or use of certain medications (e.g., aspirin or NSAIDs).

Diverticulitis

In some embodiments, the methods described herein have partial or complete alleviation, amelioration, relief, inhibition, delaying onset, reducing severity or incidence of symptoms of diverticulitis. Diverticulitis occurs when pouches (diverticula) form in the wall of the colon and become inflamed or infected (e.g., from bacterial growth in the diverticula).

Pouchitis

In some embodiments, the methods described herein have partial or complete alleviation, amelioration, relief, inhibition, delaying onset, reducing severity or incidence of symptoms of pouchitis. Pouchitis refers to inflammation of the ileal pouch (an artificial rectum surgically created out of ileal gut tissue in subjects who have undergone a colectomy), which is created in the management of subjects with ulcerative colitis, indeterminate colitis, FAP, or colitides.

Compounds and Compositions

Soluble polyglucosamines and polyglucosamines derivatives

Soluble polyglucosamine or a derivatized polyglucosamine, such as polyglucosamine- arginine compounds (PAAGs), are described herein.

Polyglucosamines can be derived from chitin or chitosan. Chitosan is an insoluble polymer derived from the deacetylation of chitin, which is a polymer of N- acetylglucosamine, that is the main component of the exoskeletons of crustaceans (e.g., shrimp, crab, lobster). Chitosan is generally a P 1 — >4) poly glucosamine that is less than 50% acetylated while chitin is generally considered to be more than 50% acetylated. Polyglucosamines are also found in various fungi and arthropods. Synthetic sources and alternate sources of 1— >4) polyglucosamines may serve as the starting material for polyglucosamine derivatives. Polyglucosamines, as opposed to polyacetylglucosamines, are defined herein to be less than 50% acetylated. If greater than 50% of the amino groups are acetylated, the polymer is considered a polyacetylglucosamine.

A soluble polyglucos amine described herein refers to a neutral pH, water soluble polyglucosamine or poly glucosamine that is not derivatized (e.g., intentionally or unintentionally) on the hydroxyl or amine moieties other than with acetyl groups. A soluble polyglucosamine is comprised of glucosamine and acetylglucosamine monomers. Generally, a water soluble polyglucosamine (at neutral pH) has a molecular weight of less than or equal to about 5,000 kDa and a degree of deacetylation equal to or greater than 80%.

A polyglucosamine derivative described herein is generated by functionalizing the free hydroxyl or amine groups with positively charged or neutral moieties. The percent of functionalization is defined as the total percent of monomers on the poly glucosamine backbone that have been functionalized with a positively charged or neutral moiety. The degrees of deacetylation and functionalization impart a specific charge density to the functionalized polyglucosamine derivative. The resulting charge density affects solubility and effectiveness of treatment. Thus, in accordance with the present invention, the degree of deacetylation, the functionalization and the molecular weight must be optimized for optimal efficacy. The poly glucosamine derivatives described herein have a number of properties which are advantageous, including solubility at physiologic (neutral) pH. In some embodiments, the polyglucosamine derivative is soluble up to a pH of 10.

Polyglucosamines with any degree of deacetylation (DDA) greater than 50% are used in the present invention, with functionalization between 2% and 50% of the total monomers on the polyglucosamine backbone. The degree of deacetylation determines the relative content of free amino groups to total monomers in the polyglucosamine polymer. Methods that can he used for determination of the degree of deacetylation of polyglucosamine include, e.g., ninhydrin test, linear potentiometric titration, near-infrared spectroscopy, nuclear magnetic resonance spectroscopy, hydrogen bromide titrimetry, infrared spectroscopy, quantitative elemental analysis, and first derivative UV- spectrophotometry. Preferably, the degree of deacetylation of a soluble polyglucosamine or a derivatized polyglucosamine described herein is determined by quantitative infrared spectroscopy.

Percent functionalization by active derivitization of the amines is determined relative to the total number of monomers on the polyglucosamine polymer. Preferably, the percent functionalization of a derivatized polyglucosamine described herein is determined by H- NMR or quantitative elemental analysis. The degrees of deacetylation and functionalization impart a specific charge density to the functionalized poly glucosamine derivative. The resulting charge density affects solubility, and strength of interaction with tissue, glycocalyx, biofilm components and bacterial membranes. The molecular weight is also an important factor in a derivatized polyglucosamine’s mucoadhesivity and biofilm disrupting capability. Thus, in accordance with the present invention, these properties must be optimized for optimal efficacy. Exemplary polyglucosamine derivatives are described in U.S.P.N. 8,119,780, which is incorporated herein by reference in its entirety.

The polyglucosamine derivatives described herein have a range of polydispersity index (PDI) between about 1.0 to about 2.5. As used herein, the polydispersity index (PDI), is a measure of the distribution of molecular weights in a given polymer sample. The PDI calculated is the weight averaged molecular weight divided by the number averaged molecular weight. This calculation indicates the distribution of individual molecular weights in a batch of polymers. The PDI has a value always greater than 1, but as the polymer chains approach uniform chain length, the PDI approaches unity (1). The PDI of a polymer derived from a natural source depends on the natural source (e.g. chitin or chitosan from crab vs. shrimp vs. fungi vs. yeast) and can be affected by a variety of reaction, production, processing, handling, storage and purifying conditions. Methods to determine the polydispersity include, e.g., gel permeation chromatography (also known as size exclusion chromatography); light scattering measurements; and direct calculation from MALDI or from electrospray mass spectrometry. HPLC and multi angle light scattering methods are used to determine the molecular mass and PDI of a soluble poly glucosamine or a derivatized polyglucosamine. Size exclusion chromatography and multi-angle light scattering (SEC- MALS) are often used for determination of molecular weight(s) and mass distributions of PAAG, but many other techniques for determining molecular mass distributions and average molecular mass (weight averaged molecular weight or number averaged molecular weight) can be used and easily correlated to SEC-MALS. The use of MALS instrument allows for the absolute determination of molar mass of a molecule and the distribution of molecules.

Integrated with MALS is an RI detector that captures the polymer concentration at each mass. From absolute molar mass and concentration with appropriate index of refraction information, software is available to apply calculations to determine the weight average M_w and the number average M_n. Other types of molecular weights (i.e. M_z) can be calculated from these measurements or measured by other techniques known to one skilled in the art.

Functionalized polyglucosamine derivatives include, but are not limited, to the following:

(A) Polyglucos amine- arginine (PAAG) compounds;

(B) Polyglucosamine-natural amino acid derivative compounds;

(C) Polyglucosamine-unnatural amino acid compounds;

(D) Polyglucos amine- acid amine compounds;

(E) Polyglucosamine-guanidine compounds; and

(F) Neutral polyglucosamine derivative compounds.

(A) Polyglucosamine-arginine (PAAG) compounds

Disclosed herein, in some embodiments, are methods that use polyglucosamine- arginine (PAAG) compounds of the Formula (I), where the arginine is bound through a peptide (amide) bond via its carbonyl to the primary amine on the glucosamines of polyglucosamine:

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: n is an integer between 20 and 6000; and

R¹ is independently selected for each occurrence from the group consisting of hydrogen, acetyl, wherein at least 25% of R¹ is hydrogen, and at least 2% of R¹ substituents are optionally wherein one or more of R¹ is replaced by a sugar (e.g., a naturally occurring or modified sugar) or an a-hydroxy acid.

Sugars can be monosaccharides, disaccharides or polysaccharides such as glucose, mannose, lactose, maltose, celluhiose, sucrose, amylose, glycogen, cellulose, gluconate, or pyruvate. Sugars can be covalently attached via a spacer or via the carboxylic acid, ketone or aldehyde group of the terminal sugar. Examples of -hydroxy acids include glycolic acid, lactic acid, and citric acid. In some preferred embodiments, the neutral polyglucosamine derivative is polyglucosamine-lactobionic acid compound or polyglucosamine-glycolic acid compound. Exemplary salts and coderivatives include those known in the art, for example, those described in US 8,119,780, the contents of which is incorporated by reference in its entirety. In some embodiments, between about 5% to about 10% of R¹ is acetyl. In some embodiments, between about 10% to about 15% of R¹ is acetyl. In some embodiments, at least about 5% (e.g., at least about 5.5%, at least about 6%, at least about 6.5%, at least about 7%, at least about 7.5%, at least about 8%, at least about 8.5%, at least about 8.5%, at least about 9%, at least about 9.5%, or at least about 10%) of R¹ is acetyl. In some embodiments, at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%) of R¹ is acetyl.

In some embodiments, between about 5% to about 10% of R¹ sugar e.g., a naturally occurring or modified sugar) or a-hydroxy acid. In some embodiments, between about 10% to about 15% of R¹ is sugar (e.g., a naturally occurring or modified sugar) or a-hydroxy acid. In some embodiments, at least about 5% (e.g., at least about 5.5%, at least about 6%, at least about 6.5%, at least about 7%, at least about 7.5%, at least about 8%, at least about 8.5%, at least about 8.5%, at least about 9%, at least about 9.5%, or at least about 10%) of R¹ is sugar (e.g., a naturally occurring or modified sugar) or a-hydroxy acid. In some embodiments, at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, or at least about 15%) of R¹ is sugar (e.g., a naturally occurring or modified sugar) or a-hydroxy acid.

In some embodiments, between about 25% to about 40% of R¹ is

In some embodiments, at least about 20% (e.g., at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, or at least about 40%) of R¹ is

In some embodiments, less than about 5% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 6% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 7% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 8% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 9% of the PAAG has a molecular weight of less than about 5 kDa. In some embodiments, less than about 10% of the PAAG has a molecular weight of less than about 5 kDa.

In some embodiments, less than about 5% of the PAAG has a molecular weight greater than about 250 kDa. In some embodiments, less than about 6% of the PAAG has a molecular weight of greater than about 250 kDa. In some embodiments, less than about 7% of the PAAG has a molecular weight of greater than about 250 kDa. In some embodiments, less than about 8% of the PAAG has a molecular weight of greater than about 250 kDa. In some embodiments, less than about 9% of the PAAG has a molecular weight of greater than about 250 kDa. In some embodiments, less than about 10% of the PAAG has a molecular weight of greater than about 250 kDa.

In some embodiments, less than about 5% of the PAAG has a molecular weight greater than about 200 kDa. In some embodiments, less than about 6% of the PAAG has a molecular weight of greater than about 200 kDa. In some embodiments, less than about 7% of the PAAG has a molecular weight of greater than about 200 kDa. In some embodiments, less than about 8% of the PAAG has a molecular weight of greater than about 200 kDa. In some embodiments, less than about 9% of the PAAG has a molecular weight of greater than about 200 kDa. In some embodiments, less than about 10% of the PAAG has a molecular weight of greater than about 200 kDa.

In some embodiments, the weight average molecular weight (M_w) of the PAAG is about 30 to about 70 kDa (e.g., about 30 to about 65 kDa, about 30 to about 60 kDa, about 30 to about 55 kDa, about 30 to about 50 kDa, about 30 to about 45 kDa, about 30 to about 40 kDa, about 35 to about 70 kDa, about 35 to about 70 kDa, about 40 to about 70 kDa, or about 45 to about 70 kDa).

In some embodiments, the number average molecular weight (M_n) of the PAAG is about 20 to about 60 kDa (e.g., about 20 to about 55 kDa, about 20 to about 50 kDa, about 20 to about 45 kDa, about 20 to about 40 kDa, about 20 to about 35 kDa, about 20 to about 30 kDa, about 25 to about 60 kDa, about 30 to about 60 kDa, about 35 to about 60 kDa, about 40 to about 60 kDa, about 45 to about 60 kDa, or about 50 to about 60 kDa).

In some embodiments, the % arginine functionalization of the PAAG is about 25% to about 40% (e.g., about 25% to about 35%, about 25% to about 30%, about 30% to about 40%, or about 35% to about 40%).

(B) Polyglucosamine-natural amino acid derivative compounds

In some embodiments, the present disclosure is directed to polyglucosamine-natural amino acid derivative compounds, wherein the natural amino acid may be histidine or lysine. The amino is bound through a peptide (amide) bond via its carbonyl to the primary amine on the glucosamines of polyglucosamine: wherein each R¹ is independently selected from hydrogen, acetyl, and a group of the following formula: or a racemic mixture thereof, wherein at least 25% of R¹ substituents are H, at least 1% are acetyl, and at least 2% are a group of the formula shown above; or a group of the following formula: or a racemic mixture thereof, wherein at least 25% of R¹ substituents are H, at least

1% are acetyl, and at least 2% are a group of the formula shown above.

(C) Poly glucosamine -unnatural amino acid compounds In some embodiments, the present disclosure is directed to polyglucosamine-unnatural amino acid compounds, where the unnatural amino acid is bound through a peptide (amide) bond via its carbonyl to the primary amine on the glucosamines of polyglucosamine: wherein each R¹ is independently selected from hydrogen, acetyl, and a group of the following formula: wherein R³ is an unnatural amino acid side chain, and wherein at least 25% of R¹ substituents are H, at least 1% are acetyl, and at least 2% are a group of the formula shown above. Unnatural amino acids are those with side chains not normally found in biological systems, such as ornithine (2,5-diaminopentanoic acid). Any unnatural amino acid may be used in accordance with the invention. In some embodiments, the unnatural amino acids coupled to polyglucosamine have the following formulae:

(D) Polyglucosamine-acid amine compounds

In some embodiments, the present disclosure is directed to polyglucosamine-acid amine compounds, or their guanidylated counterparts. The acid amine is bound through a peptide (amide) bond via its carbonyl to the primary amine on the glucosamines of polyglucosamine: wherein each R¹ is independently selected from hydrogen, acetyl, and a group of the following formula: wherein R³ is selected from amino, guanidino, and Ci-Ce alkyl substituted with an amino or a guanidino group, wherein at least 25% of R¹ substituents are H, at least 1% are acetyl, and at least 2% are a group of the formula shown above

In some embodiments, R¹ is selected from one of the following: (E) Poly glucosamine- guanidine compounds

In some embodiments, the present disclosure is directed to polyglucosamine- guanidine compounds: wherein each R¹ is independently selected from hydrogen, acetyl, and a group in which R¹, together with the nitrogen to which it is attached, forms a guanidine moiety; wherein at least 25% of R¹ substituents are H, at least 1% are acetyl, and at least 2% form a guanidine moiety together with the nitrogen to which it is attached.

(F) Neutral poly glucosamine derivative compounds

In some embodiments, the present disclosure is directed to neutral polyglucosamine derivative compounds. Exemplary neutral polyglucosamine derivative compounds include those where one or more amine nitrogens of the polyglucosamine have been covalently attached to a neutral moiety such as a sugar: wherein each R¹ is independently selected from hydrogen, acetyl, and a sugar (e.g., a naturally occurring or modified sugar) or an a-hydroxy acid. Sugars can be monosaccharides, disaccharides or polysaccharides such as glucose, mannose, lactose, maltose, cellubiose, sucrose, amylose, glycogen, cellulose, gluconate, or pyruvate. Sugars can be covalently attached via a spacer or via the carboxylic acid, ketone or aldehyde group of the terminal sugar. Examples of -hydroxy acids include glycolic acid, lactic acid, and citric acid. In some preferred embodiments, the neutral polyglucosamine derivative is polyglucosamine- lactobionic acid compound or polyglucosamine-glycolic acid compound. Exemplary salts and coderivatives include those known in the art, for example, those described in US 8,1 19,780, the contents of which is incorporated by reference in its entirety.

Hematopoietic agent

Disclosed herein, in some embodiments, are methods that use hematopoietic agents. A hematopoietic agent is an agent (e.g., compound, antibody, protein, cell, or other molecule) that modulates hematopoiesis. In some embodiments, the hematopoietic agent is a leukocyte growth factor or a thrombopoietin receptor agonist. In some embodiments, the hematopoietic agent is a leukocyte growth factor. In some embodiments, the hematopoietic agent is a thrombopoietin receptor agonist.

Exemplary leukocyte growth factors include, but are not limited to, Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Erythropoietin, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim. Exemplary thrombopoietin receptor agonists include, but are not limited to, romiplostim and eltrombopag.

In some embodiments, the hematopoietic agent is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Erythropoietin, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, efbemalenograstim, romiplostim, and eltrombopag. In some embodiments, the hematopoietic agent is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Erythropoietin, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim. In some embodiments, the hematopoietic agent is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, and Erythropoietin. In some embodiments, the hematopoietic agent is selected from the group consisting of pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim. In some embodiments, the hematopoietic agent is selected from the group consisting of romiplostim and eltrombopag.

In some embodiments, the hematopoietic agent is Granulocyte Colony-Stimulating Factor. In some embodiments, the hematopoietic agent is Granulocyte Macrophage Colony- Stimulating Factor. In some embodiments, the hematopoietic agent is pegfilgrastim. Pegfilgrastim is also known as NEULASTA®. In some embodiments, the hematopoietic agent is Erythropoietin. In some embodiments, the hematopoietic agent is filgrastim. Filgrastim is also known as NEUPOGEN®. In some embodiments, the hematopoietic agent is sargramostim. Sargramostim is also known as LEUKINE®. In some embodiments, the hematopoietic agent is eflapegrastim. Eflapegrastim is also known as ROLVEDON®. In some embodiments, the hematopoietic agent is efbemalenograstim. Efbemalenograstim is also known as RYZNEUTA®. In some embodiments, the hematopoietic agent is romiplostim. Romiplostim is also known as NPLATE®. In some embodiments, the hematopoietic agent is eltrombopag. Eltrombopag is also known as PROMACTA®.

Additional agents

Disclosed herein, in some embodiments, are methods that use additional agents selected from the group consisting of steroid, TNF inhibitor, a4P7 integrin inhibitor, IL- 12 and/or IL-23 inhibitor, SIP receptor modulator, JAK inhibitor, TYK2 inhibitor, RIP1K inhibitor, IL-6R antagonist, and LANCL2 agonist. In some embodiments, the additional agent is a steroid. In some embodiments, the additional agent is a TNF inhibitor. In some embodiments, the additional agent is a TNF inhibitor. In some embodiments, the additional agent is an a4p7 integrin inhibitor. In some embodiments, the additional agent is an IL- 12 and/or IL-23 inhibitor. In some embodiments, the additional agent is a SIP receptor modulator. In some embodiments, the additional agent is a JAK inhibitor. In some embodiments, the additional agent is a TYK2 inhibitor. In some embodiments, the additional agent is a RIP IK inhibitor. In some embodiments, the additional agent is an IL-6R antagonist. In some embodiments, the additional agent is a LANCL2 agonist.

In some embodiments, the steroid is an aminosalicylate or a corticosteroid. In some embodiments, the steroid is an aminosalicylate. In some embodiments, the steroid is a corticosteroid. In some embodiments, the aminosalicylate is selected from the group consisting of 4-aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, and budesonide. In some embodiments, the aminosalicylate is 4-aminosalicylic acid. In some embodiments, the aminosalicylate is balsalazide. In some embodiments, the aminosalicylate is mesalamine. In some embodiments, the aminosalicylate is olsalazine. In some embodiments, the aminosalicylate is sulfasalazine. In some embodiments, the aminosalicylate is budesonide. In some embodiments, the corticosteroid is selected from the group consisting of hydrocortisone, methylprednisone, and prednisone. In some embodiments, the corticosteroid is hydrocortisone. In some embodiments, the corticosteroid is methylprednisone. In some embodiments, the corticosteroid is prednisone. In some embodiments, the steroid is selected from the group consisting of 4-aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, budesonide, hydrocortisone, methylprednisone, and prednisone.

In some embodiments, the TNF inhibitor is selected from the group consisting of adalimumab, infliximab, golimumab, certrolizumab, and etanercept. In some embodiments, the TNF inhibitor is adalimumab. Adalimumab is also known as HUMIRA®. In some embodiments, the TNF inhibitor is infliximab. Infliximab is also known as REMICADE®. In some embodiments, the TNF inhibitor is golimumab. Golimumab is also known as SIMPONI®. In some embodiments, the TNF inhibitor is certrolizumab. Certrolizumab is also known as CIMZIA®. In some embodiments, the TNF inhibitor is etanercept. Etanercept is also known as ENBREL®.

In some embodiments, the a4p7 integrin inhibitor is selected from the group consisting of vedolizumab, natalizumab, etrolizumab, abrilumab, carotegrast methyl, zaurategrast, TR-14035, and R41 1. In some embodiments, the a4p7 integrin inhibitor is vedolizumab. Vedolizumab is also known as ENTYVIO®. In some embodiments, the a4p7 integrin inhibitor is natalizumab. Natalizumab is also known as TYSABRI®. In some embodiments, the a4p7 integrin inhibitor is etrolizumab. Etrolizumab is also known as rhuMAb Beta7. In some embodiments, the a4P7 integrin inhibitor is abrilumab. Abrilumab is also known as AMG 181. In some embodiments, the a4p7 integrin inhibitor is carotegrast methyl. Carotegrast methyl is also known as CAROGRA®. In some embodiments, the a4p7 integrin inhibitor is zaurategrast. Zaurategrast is also known as CDP323. Zaurategrast has the structure of:

In some embodiments, the a4p7 integrin inhibitor is TR-14035. TR-14035 has the structure of:

In some embodiments, the a4p7 integrin inhibitor is R411. R411 is also known as R-411.

Valategrast is R411 free base and has the structure of:

In some embodiments, the IL- 12 and/or IL-23 inhibitor is selected from the group consisting of ustekinumab, risankizumab, guselkumab, mirikizumab, and brazikumab. In some embodiments, the IL-12 and/or IL-23 inhibitor is ustekinumab. Ustekinumab is also known as STELARA®. In some embodiments, the IL- 12 and/or IL-23 inhibitor is risankizumab. Risankizumab is also known as SKYRIZI®. In some embodiments, the IL- 12 and/or IL-23 inhibitor is guselkumab. Guselkumab is also known as TREMFYA®. In some embodiments, the IL- 12 and/or IL-23 inhibitor is mirikizumab. Mirikizumab is also known as OMVOH™. In some embodiments, the IL-12 and/or IL-23 inhibitor is brazikumab. Brazikumab is also known as MEDI2070.

In some embodiments, the SIP receptor modulator is selected from the group consisting of fingolimod, etrasimod, KRP-203, siponimod, CS-0777, ponesimod, ozanimod, ceralifimod, GSK2018682, MT-1303, SEW2871, AUY954, and JTE-013. In some embodiments, the SIP receptor modulator is fingolimod. Fingolimod is also known as GILENYA®. In some embodiments, the SIP receptor modulator is etrasimod. Etrasimod is also known as VELSIPITY™. In some embodiments, the SIP receptor modulator is KRP- 203. KRP-203 is also known as mocravimod hydrochloride. KRP-203 has the structure of:

In some embodiments, the S IP receptor modulator is siponimod. Siponimod is also known as BAF-312 and MAYZENT®. Siponimod has the structure of:

In some embodiments, the SIP receptor modulator is CS-0777. CS-0777 has the structure of:

In some embodiments, the S IP receptor modulator is ponesimod. Ponesimod is also known as PONVORY®. Ponesimod has the structure of: In some embodiments, the S IP receptor modulator is ozanimod. Ozanimod is also known as

RPC-1063 and ZEPOSIA®. Ozanimod has the structure of:

In some embodiments, the S IP receptor modulator is ceralifimod. Ceralifimod has the structure of:

In some embodiments, the S IP receptor modulator is GSK2018682. GSK2018682 has the structure of:

In some embodiments, the SIP receptor modulator is MT-1303. In some embodiments, the SIP receptor modulator is MT-1303 hydrochloride. MT-1303 is also known as amiselimod. MT-1303 has the structure of:

In some embodiments, the SIP receptor modulator is SEW2871. SEW2871 has the structure of:

In some embodiments, the S IP receptor modulator is AUY954. AUY954 has the structure of:

In some embodiments, the S IP receptor modulator is ITE-013. JTE-013 has the structure of: In some embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib, baricitinib, deucravacitinib, ruxolitinib, ritlecitinib, abrocitinib, delgocitinib, fedratinib, filgotinib, momelotinib, pacritinib, upadacitinib, LS104, ON044580, NVP- BBT594, and NVP-CHZ868. In some embodiments, the JAK inhibitor is tofacitinib. Tofacitinib is also known as XELJANZ®. Tofacitinib has the structure of:

In some embodiments, the JAK inhibitor is baricitinib. Baricitinib is also known as

OLUMIANT®. Baricitinib has the structure of: In some embodiments, the JAK inhibitor is deucravacitinib. Deucravacitinib is also known as SOTYKYTU®. Deucravacitinib has the structure of:

In some embodiments, the JAK inhibitor is ruxolitinib. Ruxolitinib is also known as

JAKAFI®. Ruxolitinib has the structure of:

In some embodiments, the JAK inhibitor is ritlecitinib. Ritlecitinib is also known as

LfTFULO®. Ritlecitinib has the structure of: In some embodiments, the JAK inhibitor is abrocitinib. Abrocitinib is also known as

CIBINQO®. Abrocitinib has the structure of:

In some embodiments, the JAK inhibitor is delgocitinib. Delgocitinib is also known as

CORECTIM®. Delgocitinib has the structure of:

In some embodiments, the JAK inhibitor is fedratinib. Fedratinib is also known as

INREBIC®. Fedratinib has the structure of:

In some embodiments, the JAK inhibitor is filgotinib. Filgotinib is also known as

JYSELECA®. Filgotinib has the structure of: In some embodiments, the JAK inhibitor is momelotinib. Momelotinib has the structure of:

In some embodiments, the JAK inhibitor is pacritinib. Pacritinib is also known as VONJO®.

Pacritinib has the structure of: In some embodiments, the IAK inhibitor is upadacitinib. Upadacitinib is also known as RINVOQ®. Upadacitinib has the structure of:

In some embodiments, the JAK inhibitor is LSI 04 LS104 has the structure of:

In some embodiments, the JAK inhibitor is ON044580. ON044580 has the structure of:

In some embodiments, the JAK inhibitor is NVP-BBT594. NVP-BBT594 is also known as

BBT594. NVP-BBT594 has the structure of:

In some embodiments, the JAK inhibitor is NVP-CHZ868. NVP-CHZ868 has the structure of:

In some embodiments, the TYK2 inhibitor is selected from the group consisting of deucravacitinib, ropsacitinib, and brepocitinib. In some embodiments, the TYK2 inhibitor is deucravacitinib. Deucravacitinib is also known as SOTYKTU®. Deucravacitinib has the structure of:

In some embodiments, the TYK2 inhibitor is ropsacitinib. Ropsacitinib is also known as PF- 06826647. Ropsacitinib has the structure of: In some embodiments, the TYK2 inhibitor is brepocitinib. Brepocitinib has the structure of: In some embodiments, the RIPK1 inhibitor is selected from the group consisting of GSK2982772, SAR443060, and necrostatin-ls. In some embodiments, the RIPK1 inhibitor is GSK2982772. GSK2982772 has the structure of:

In some embodiments, the RIPK1 inhibitor is SAR443060. SAR443060 is also known as DNL747. In some embodiments, the RIPK1 inhibitor is necrostatin-ls. Necrostatin- ls is also known as Nec-lS. Necrostatin-ls has the structure of:

In some embodiments, the IL-6R antagonist is selected from the group consisting of olamkicept, tocilizumab, and sarilumab. In some embodiments, the IL-6R antagonist is olamkicept. In some embodiments, the IL-6R antagonist is tocilizumab. Tocilizumab is also known as ACTEMRA®. In some embodiments, the IL-6R antagonist is sarilumab. Sarilumab is also known an KEVZARA®.

In some embodiments, the LANCL2 agonist is omilancor. Omilancor is also known as

BT-11. Omilancor has the structure of:

Compositions and Dosage Forms

The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

In some embodiments, the composition described herein is configured as a solid dosage formulation. For example, the composition can be a dry powder that is used in a capsule or tablet (e.g., compressed with cellulose). In some embodiments, the composition is a dry powder dissolved in water. In some embodiments, the compositions are configured for controlled release or timed release, e.g., in a gel capsule, in the gastrointestinal tract.

In some embodiments, the compositions are oven-dried, freeze-dried, or spray-dried.

Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. In some embodiments, the compositions described herein is configured as a liquid formulation (e.g., aqueous formulation, e.g., aqueous formulation without stabilizer).

Liquid forms suitable for rectal administration, such as enemas, may include suitable aqueous or nonaqueous vehicles comprising buffers, suspending and dispensing agents, colorants, and the like. Exemplary excipients for enema formulations comprise sodium chloride, sodium bicarbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, glycerin, docusate, mineral oil, ethanol, propylene glycol, and polyethylene glycol. Solid forms for rectal administration includes suppositories, which can prepared to melt or dissolve when inserted into the rectum. Exemplary excipients for suppository formulations include cocoa butter, propylene glycol, polyethylene glycol, and agar.

Due to its efficacy, supportive care may well be the most effective radiation mitigator currently available. Supportive care in large animals includes (a) intravenous fluid/electrolyte support, (b) a stepwise algorithm for introduction of broad- spectrum antibiotic treatment in response to specific clinical signs and symptoms, and (c) transfusion support with irradiated blood products.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Co-administration of hematopoietic agent and PAAG in animal model. Animal model

In order to test for efficacy in addressing radiation-induced injuries, an animal model will be used to adequately reproduce anticipated human responses. Animal model (e.g., porcine) will be exposed to radiation and treated with a combination of a hematopoietic agent (e.g., filgrastim (NEUPOGEN®), pegfilgrastim (NEULASTA®), romiplostim (NPLATE®), or sargramostim (LEUKINE®)) and PAAG.

Example 2. Characterization of PAAG

During manufacturing the size of PAAG is controlled through the depolymerization process to yield a final weight- averaged molecular weight (M_w) range of about 20-70 kDa. To assure control of the process and minimize the influence of very small or large molecules on M_w, the molecular distribution is restricted defining cutoffs (M5 and M95) with no more than 5% of molecules having a molar mass M5 of =10kDa and no more than 5% of the total molecules having a molar mass above M95 of =200kDa.

The molecular weight (M_w) of available poly (acetyl) glucosamine ranges from 10- 8,000 kDa. The range of the starting material may be between lOO-lOOOkDa. During manufacturing the size of PAAG is controlled through the depolymerization process to yield a final weight-averaged molecular weight (M_w) range. To assure control of the process and minimize the influence of very small or large molecules on M_w, the molecular distribution is restricted defining cutoffs (M5 and M95) with no more than 5% of molecules having a molar mass M5 of = lOkDa and no more than 5% of the total molecules having a molar mass above M95 of = 200kDa.

PAAG is defined by having a particular distribution of mass. By defining the molar mass cut off for which no more than 5% of the total mass can be found on both the low and the high end, the bulk of the molecular distribution is confined to a narrow band. By defining a M_w (or M_n), the bulk of the distribution is defined between the M5 and M95 limits. By defining a PDI, a relative ratio of M„ and M_w are calculated, but the shape of the curve is indefinite, and molar mass extremes are not defined. Stability of the distribution of the molecular distribution allows for some variation over time, but still maintains the specifications for activity. Accumulation of low molecular weight molecules indicates rapid hydrolysis is occurring and would be reflected in a lower M5; and increased higher molecular weight suggests aggregation could be occurring, reflected in a higher M95. Defining these areas allows for product and storage design to enhance shelf life.

Claims

1. A method of treating a disease or disorder, or a symptom or a complication thereof, in a subject identified as being exposed to radiation, comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

R¹ substituents

(b) a hematopoietic agent. 2. The method of claim 1 , wherein the disease or disorder is acute radiation syndrome

(ARS). The method of claim 1 or 2, wherein the hematopoietic agent is a leukocyte growth factor.

4. The method of claim 3, wherein the leukocyte growth factor is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, and Erythropoietin.

5. The method of claim 3, wherein the leukocyte growth factor is selected from the group consisting of pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

6. The method of claim 1 or 2, wherein the hematopoietic agent is a thrombopoietin receptor agonist.

7. The method of claim 6, wherein the thrombopoietin receptor agonist is selected from the group consisting of romiplostim and eltrombopag.

8. The method of claim 1 or 2, wherein the hematopoietic agent is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony-Stimulating Factor, Erythropoietin, romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

9. The method of claim 1 or 2, wherein the hematopoietic agent is selected from the group consisting of Granulocyte Colony-Stimulating Factor, Granulocyte Macrophage Colony- Stimulating Factor, and Erythropoietin.

10. The method of claim 1 or 2, wherein the hematopoietic agent is selected from the group consisting of romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

11. The method of claim 1 or 2, wherein the hematopoietic agent is selected from the group consisting of romiplostim, eltrombopag, pegfilgrastim, filgrastim, sargramostim, eflapegrastim, and efbemalenograstim.

12. The method of claim 1 or 2, wherein the hematopoietic agent is selected from the group consisting of romiplostim, pegfilgrastim, filgrastim, and sargramostim.

13. The method of any one of claims 1-12, wherein the hematopoietic agent is administered parenterally.

14. The method of any one of claims 1-13, wherein the PAAG is administered orally.

15. The method of any one of claims 1-14, wherein the PAAG and the hematopoietic agent are administered substantially simultaneously.

16. The method of any one of claims 1-14, wherein the PAAG is administered prior to the hematopoietic agent.

17. The method of any one of claims 1-14, wherein the hematopoietic agent is administered prior to the PAAG.

18. The method of any one of claims 1-17, wherein the subject has cancer.

19. The method of any one of claims 1-18, wherein the subject is or has undergone a cancer treatment.

20. The method of claim 19, wherein the cancer treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, surgery, and combinations thereof.

21. The method of any one of claims 1-20, wherein the subject hematopoietic acute radiation syndrome (H-ARS) or gastrointestinal acute radiation syndrome (GI-ARS), or a combination thereof.

22. A method of treating a disease or disorder of the gastrointestinal tract, or a symptom or a complication thereof, in a subject in need thereof, comprising administering to the subject:

(a) a polyglucosamine-arginine (PAAG) of the Formula (I):

Formula (I) wherein: n is an integer between 20 and 6000; and each R¹ is independently selected for each occurrence from hydrogen, acetyl, wherein at least about 25% of R¹ substituents are H, and at least about 2% of R¹ substituents and (b) an additional agent selected from the group consisting of steroid, TNF inhibitor, a407 integrin inhibitor, IL- 12 and/or IL-23 inhibitor, S IP receptor modulator, JAK inhibitor, TYK2 inhibitor, RIP IK inhibitor, IL-6R antagonist, and LANCL2 agonist. 23. The method of claim 22, wherein the steroid is an aminosalicylate or a corticosteroid.

24. The method of claim 23, wherein the aminosalicylate is selected from the group consisting of 4-aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, and budesonide.

25. The method of claim 23, wherein the corticosteroid is selected from the group consisting of hydrocortisone, methylprednisone, and prednisone.

26. The method of claim 22, wherein the steroid is selected from the group consisting of 4-aminosalicylic acid, balsalazide, mesalamine, olsalazine, sulfasalazine, budesonide, hydrocortisone, methylprednisone, and prednisone.

27. The method of claim 22, wherein the TNF inhibitor is selected from the group consisting of adalimumab, infliximab, golimumab, certrolizumab, and etanercept.

28. The method of claim 22, wherein the a4p7 integrin inhibitor is selected from the group consisting of vedolizumab, natalizumab, etrolizumab, abrilumab, carotegrast methyl, zaurategrast, TR- 14035, and R411.

29. The method of claim 22, wherein the IL- 12 and/or IL-23 inhibitor is selected from the group consisting of ustekinumab, risankizumab, guselkumab, mirikizumab, and brazikumab.

30. The method of claim 22, wherein the SIP receptor modulator is selected from the group consisting of fingolimod, etrasimod, KRP-203, siponimod, CS-0777, ponesimod, ozanimod, ceralifimod, GSK2018682, MT-1303, SEW2871, AUY954, and JTE-013.

31. The method of claim 22, wherein the JAK inhibitor is selected from the group consisting of tofacitinib, baricitinib, deucravacitinib, ruxolitinib, ritlecitinib, abrocitinib, delgocitinib, fedratinib, filgotinib, momelotinib, pacritinib, upadacitinib, LS104, ON044580, NVP-BBT594, and NVP-CHZ868.

32. The method of claim 22, wherein the TYK2 inhibitor is selected from the group consisting of deucravacitinib, ropsacitinib, and brepocitinib.

33. The method of claim 22, wherein the RIPK1 inhibitor is selected from the group consisting of GSK2982772, SAR443060, and necrostatin-l s.

34. The method of claim 22, wherein the IL-6R antagonist is selected from the group consisting of olamkicept, tocilizumab, and sarilumab.

35. The method of claim 22, wherein the LANCL2 agonist is omilancor.

36. The method of any one of claims 22-35, wherein the disease or disorder of the gastrointestinal tract is a condition of the gut, inflammatory bowel disease, irritable bowel syndrome, Crohn's Disease, stomach ulcer, ulcerative colitis, neonatal necrotizing enterocolitis, gastroesophageal reflux disease, gastroparesis, constipation, functional bloating, gastritis, lactose intolerance, visceral hyperalgesia, colic, pouchitis, diverticulitis, or diarrhea.

37. The method of any one of claims 22-36, wherein the disease or disorder of the gastrointestinal tract is inflammatory bowel disease.

38. The method of any one of claims 22-36, wherein the disease or disorder of the gastrointestinal tract is Crohn’s disease.

39. The method of any one of claims 22-36, wherein the disease or disorder of the gastrointestinal tract is ulcerative colitis.

40. The method of any one of claims 22-39, wherein the additional agent is administered parenterally.

41. The method of any one of claims 22-40, wherein the additional agent is administered orally.

42. The method of any one of claims 22-41 , wherein the PAAG is administered orally.

43. The method of any one of claims 22-42, wherein the PAAG and the additional agent are administered substantially simultaneously.

44. The method of any one of claims 22-42, wherein the PAAG is administered prior to the additional agent.

45. The method of any one of claims 18-42, wherein the additional agent is administered prior to the PAAG.

46. The method of any one of claims 1-45, wherein at least about 5% of R¹ is acetyl.

47. The method of any one of claims 1-46, wherein at least about 10% of R¹ is acetyl.

48. The method of any one of claims 1-47, wherein at least about 20% of R¹ is The method of any one of claims 1-44, wherein between about 25% to about 40% of R¹ is

49. The method of any one of claims 1-48, wherein less than about 5% of the PAAG has a molecular weight of less than about 5 kDa. 50. The method of any one of claims 1-49, wherein less than about 5% of the PAAG has a molecular weight greater than about 250 kDa.

51. The method of any one of claims 1 -50, wherein the weight average molecular weight (M_w) of the PAAG is between about 30 to about 70 kDa.

52. The method of any one of claims 1-50, wherein the number average molecular weight (M_n) of the PAAG is between about 20 to about 60 kDa.

53. The method of any one of claims 1-52, wherein the % arginine functionalization of the PAAG is between 25 and 40%.

54. The method of any one of claims 1-53, wherein the % arginine functionalization of the PAAG is between 25 and 35%. 55. The method of any one of claims 1-53, wherein the % arginine functionalization of the PAAG is between 30 and 40%.