Sublingual formulations of a peptide derived from chaperonin 60.1 and related methods

Abstract

Described herein are formulations of a peptide derived from Chaperonin 60.1 suitable for sublingual administration. A dissolvable tablet pharmaceutical formulation is designed for sublingual administration of a Chaperonin 60.1-derived peptide. This dissolvable tablet formulation includes a matrix-forming agent, a surfactant, a pH modifier, and a solvent. It may also contain sweeteners, flavor enhancers, or flavoring agents. In addition, a liquid pharmaceutical formulation is designed for sublingual administration of a Chaperonin 60.1-derived peptide. This liquid pharmaceutical formulation includes the peptide, bovine serum albumin, and phosphate-buffered saline. The sublingual formulations achieve rapid systemic delivery comparable to IV administration. These formulations are intended for treating inflammatory conditions through sublingual administration. The formulations can be used for various inflammatory conditions and are adaptable for different administration frequencies and subject types.

Description

PATENT  Attorney Docket No.:  409176‐1182001WO SUBLINGUAL FORMULATIONS OF A PEPTIDE DERIVED FROM CHAPERONIN 60.1 AND RELATED METHODS FIELD OF THE INVENTION

[0001] The embodiments of the present invention relate to formulations of a peptide derived from Chaperonin 60.1; namely stable formulations suitable for delivering a Chaperonin 60.1-derived peptide through sublingual administration. BACKGROUND OF THE INVENTION

[0002] Chaperonin polypeptides are a subgroup of heat shock polypeptides whose role in polypeptide folding is well known. There are two families of chaperonin polypeptide, the chaperonin 60 (approximately 60 kDa) and chaperonin 10 (approximately 10 kDa) families.1Some Chaperonin polypeptides have been shown to have a role in immune regulation. Mycobacterium tuberculosis (M. tuberculosis) produces Chaperonin 60.1 (Cpn60.1), a polypeptide that is named based on its amino acid sequence identity to other known chaperonins. International Patent Application WO 2002 / 0400372disclosed pharmaceutical compositions comprising Cpn60.1 from M. tuberculosis (MtCpn60.1) and its encoding nucleic acid molecules. A variety of therapeutic uses for these molecules is also disclosed, including the treatment and / or prevention of autoimmune disorders, allergic conditions, conditions typified by a Th2-type immune response and conditions associated with eosinophilia.

[0003] International Patent Application, Publication Number WO2009 / 106819A2 disclosed a series of novel peptides derivable from MtCpn60.1 including a peptide (designated as "Peptide 4") having an amino acid sequence: DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD (SEQ ID NO: 1), which exhibited anti- inflammatory activity and was shown to significantly reduce the recruitment of eosinophils in an animal model of allergic airway inflammation. This peptide (also known as IRL201104, PIN201104, and ‘1104) has been reported to have therapeutic efficacy in various diseases and conditions including, but not limited to, allergic airways diseases;3relapsing-remitting conditions, such as allergic inflammatory condition, such as, atopic dermatitis, rhinitis, rheumatoid arthritis, and inflammatory bowel disease;4food allergies and food intolerances;5and eosinophilic esophagitis.6In clinical studies conducted to date, ‘1104 was administered by intravenous (IV) infusion of reconstituted lyophilized powder containing 8 mg of ‘1104, with a reconstituted dose of either 0.8 mg / mL or 2.0 mg / mL strength.

[0004] However, IV administration requires access to a medical facility with trained medical professionals, which is prohibitive to many patients due to the distance or travel to medical facilities. Furthermore, IV administration typically requires a trained medical  1Attorney Docket No.:  409176‐1182001WO professional to set-up an IV infusion, set and determine appropriate dosing / infusion rate, and time required before, during, and after the actual infusion for the preparation, infusion duration, and observation post-infusion. In addition to the risk of infection at the injection site, IV administration is also associated with the risk of systemic infection, potential exposure to IV particulate matter, and exposure to hospital-acquired infections.

[0005] Transmucosal routes, such as intranasal, sublingual and intravaginal delivery, provide attractive alternatives due to their high accessibility and permeability. In addition to reduced concentrations of digestive enzymes, these alternative routes also allow bypassing of first-pass metabolism. All of the above contribute to increased absorption of biological drugs from the mucosal routes. Among these, sublingual administration has emerged as a promising option, characterized by increased patient preference and reduced formulation requirements, such as pH and osmolarity.7

[0006] Sublingual (SL) administration provides a simple and non-invasive alternative and offers numerous advantages over IV infusion (e.g., self-administration by patient in home, superior dosing compliance, no risk of infusion site infection). Sublingual delivery also boasts convenience and rapid absorption, which is particularly beneficial for emergent conditions. However, thick, mucinous fluid secreted by sublingual glands and the tight epithelial layer under the mucus minimize drug absorption, especially for large molecules, which is quite challenging for low solubility peptides such as ‘1104. Other disadvantages for efficient sublingual drug delivery include: (i) small surface area for absorption; (ii) limited dose and volume; (iii) dissolution issues in patients with dry mouth condition; and solution with unpalatable taste.

[0007] Accordingly, there is a need for a formulation of ‘1104 suitable for SL administration. BRIEF SUMMARY OF THE INVENTION

[0008] The embodiments of the present disclosure provide pharmaceutical formulations of Chaperonin 60.1-related peptide molecule suitable for SL administration. Administration of the sublingual pharmaceutical formulations achieve rapid systemic delivery comparable to IV injection. In some embodiments, the relative bioavailability is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99%.

[0009] In some embodiments, the present disclosure provides a dissolvable tablet pharmaceutical formulation designed for sublingual administration of a peptide with a specific sequence. The dissolvable tablet formulation may include a Chaperonin 60.1- related peptide molecule, at least one matrix-forming agent, at least one surfactant, at least one pH modifier, and at least one solvent. The matrix-forming agent in the formulation can  2Attorney Docket No.:  409176‐1182001WO be selected from substances like gelatin, mannitol, glucidex, methocel, dextrose, lactose, galactose, cyclodextrin, or combinations thereof, which may help in forming the structure of the tablet. Surfactants can be present in specific amounts and may have a critical micelle concentration within a certain range. Surfactants in the formulation may include a non-ionic surfactant or an anionic surfactant, which can aid in the dispersion of the tablet components. Non-ionic surfactant may include Tween 80, poloxamer 188, a polyoxyethylene- polyoxypropylene copolymer, or a combination thereof. Anionic surfactant may include sodium lauryl sulfate and / or docusate sodium. The pH modifier may be present in an amount sufficient to maintain a specific pH range and can have a particular pKa value. The pH modifier, which may help maintain the desired pH level of the formulation, may include citric acid, sodium bicarbonate, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, and sodium hydroxide, or combinations thereof. Solvents may be used in the formulation to dissolve the components and aid in the tablet's formation and may include methanol, ethanol, butanol, isopropanol, and water, or combinations thereof.

[0010] The dissolvable tablet formulation may also contain at least one sweetener, at least one flavor enhancer or flavoring agent. Some examples of sweeteners can be sucrose, mannitol, fructose, sucralose, aspartame, acesulfame K and thaumatin, or combinations thereof. Some examples of flavor enhancer or flavoring agent may include glycine, mint, raspberry, licorice, orange, lemon, grapefruit, caramel, cherry, menthol vanilla, grape flavors, or combinations thereof.

[0011] In some embodiments, the dissolvable tablet pharmaceutical formulation includes a peptide having SEQ ID NO: 1, gelatin, mannitol, Tween 80, sucralose, mint, sodium hydroxide, and water. In some embodiments, this dissolvable tablet pharmaceutical formulation further includes glycine.

[0012] In some embodiments, the dissolvable tablet pharmaceutical formulation includes a peptide having SEQ ID NO: 1, mannitol, Glucidex 6, Methocel E15, Tween 80, sucralose, mint; sodium hydroxide, and water.

[0013] The process for preparing the dissolvable tablet formulation may involve mixing the components to form a homogeneous mixture and compressing it into a tablet. The process may include granulating the mixture before compressing, using methods like wet granulation or dry granulation. Mixing the components can be done using various methods, such as dry blending or spray drying, at specific temperatures and pressures. The formulation may also include additional components like disintegrants or binders, with examples such as croscarmellose sodium or acacia. Lubricants, glidants, or preservatives may be included in the formulation, with examples like magnesium stearate or sodium benzoate. The formulation may have specific disintegration and dissolution times when placed under the tongue. The formulation can have a particular hardness and friability,  3Attorney Docket No.:  409176‐1182001WO ensuring it maintains its integrity during handling. The formulation may be available in various forms, such as a compressed tablet or a lozenge, and in different shapes like round or star-shaped. Packaging options for the formulation can include blister packs or bottles, and it may be packaged with a desiccant.

[0014] A kit may include the dissolvable tablet formulation and instructions for use, possibly with a device for administering the tablet.

[0015] In some embodiments, the present disclosure provides a liquid pharmaceutical formulation designed for sublingual administration of a peptide with a specific sequence. The liquid pharmaceutical formulation may include a peptide having SEQ ID NO: 1, bovine serum albumin (BSA), and phosphate-buffered saline (PBS).

[0016] Sublingual delivery of a peptide derived from Chaperonin 60.1 exhibits anti- inflammatory activity that reduces the recruitment or trafficking of cells (including, but not limited to, eosinophils, neutrophils, lymphocytes, and macrophages) for infiltration to the site of inflammation in the human or animal subject relative to a control subject who has not been administered the Chaperonin 60.1-related peptide molecule. In some embodiments, the Chaperonin 60.1-related peptide is administered sublingually to treat or prevent various diseases and conditions including, but not limited to, allergic airways diseases, relapsing- remitting conditions, such as allergic inflammatory condition, atopic dermatitis, rhinitis, rheumatoid arthritis, and inflammatory bowel disease, food allergies and food intolerances, and eosinophilic esophagitis.

[0017] Other implementations are also described and recited herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] For the purpose of illustration, certain embodiments of the present invention are shown in the drawings described below. It should be understood, however, that the invention is not limited to the precise arrangements, dimensions, and instruments shown. In the drawings:

[0019] FIG.1A-B provides bar graphs showing the effect on total number of white blood cells in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.) or vehicle (see FIG.1A); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (see FIG.1B). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. OVA + vehicle, s.l. OVA + vehicle, i.v. were compared to matched treatment groups using ANOVA followed by Bonferroni’s test. **P<0.01 and ***P<0.001.  4Attorney Docket No.:  409176‐1182001WO

[0020] FIG.2A-B provides bar graphs showing the effect on the number of eosinophils in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.) or vehicle (see FIG.2A); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (see FIG.2B). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. OVA + vehicle, s.l. OVA + vehicle, i.v. were compared to matched treatment groups using ANOVA followed by Bonferroni’s test. **P<0.01 and ***P<0.001.

[0021] FIG.3A-B provides bar graphs showing the effect on the number of neutrophils in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.) or vehicle (see FIG.3A); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (see FIG.3B). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. OVA + vehicle, s.l. OVA + vehicle, i.v. were compared to matched treatment groups using ANOVA followed by Bonferroni’s test. ***P<0.001.

[0022] FIG.4A-B provides bar graphs showing the effect on the number of macrophages in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.) or vehicle (see FIG.4A); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (see FIG.4B). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. OVA + vehicle, s.l. OVA + vehicle, i.v. were compared to matched treatment groups using ANOVA followed by Bonferroni’s test. ***P<0.001.

[0023] FIG.5A-B provides bar graphs showing the effect on the number of lymphocytes in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.) or vehicle (see FIG.5A); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, s.l.), ‘1104 (80 μg / kg, i.v.), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (see FIG.5B). BALF was collected 24 hours after the final OVA  5Attorney Docket No.:  409176‐1182001WO challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. OVA + vehicle, s.l. OVA + vehicle, i.v. were compared to matched treatment groups using ANOVA followed by Bonferroni’s test. **P<0.01 and ***P<0.001.

[0024] FIG.6 provides a manufacturing flow diagram of the dispensing and mixing protocol for batches Z6218 / 82 / 1-6.

[0025] FIG.7 provides a manufacturing flow diagram of the dosing, freezing, freeze drying, sacheting protocols for batches Z6218 / 82 / 1-6.

[0026] FIG.8 shows the macroscopic appearance of batches Z6218 / 82 / 1-6 at 0 SH.

[0027] FIG.9 shows the macroscopic appearance of batches Z6218 / 82 / 1-6 at 24 SH 6.

[0028] FIG.10 shows the macroscopic appearance of batches Z6218 / 82 / 1-6 at 48 SH.

[0029] FIGS.11A-L shows the appearance of the finished product in batches Z6218 / 82 / 1-6 at 24 SH and at 48 SH.

[0030] FIG.12 shows an example of a Unit Dispersion from Batch Z6218 / 82 / 124SH.

[0031] FIG.13 shows the macroscopic appearance of gelatin mixes (batches 1-2) and non-gelatin mix (batch 3).

[0032] FIGS.14A-C shows the appearance of the finished product in batch 1 (gelatin based), batch 2 (gelatin based, glycine), and batch 3 (non-gelatin based).

[0033] FIG.15 provides a diagrammatic representation of the protocol for the study comparing ‘1104 (80 μg / kg) administered IV to two SL prototypes: SL1 (gelatin + glycine) and SL2 (non-gelatin).

[0034] FIG.16 provides bar graphs showing the effect on total number of white blood cells in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.16, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.16, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. ***P<0.001.

[0035] FIG.17 provides bar graphs showing the effect on total number of eosinophils in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.17, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg,  6Attorney Docket No.:  409176‐1182001WO SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.17, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0036] FIG.18 provides bar graphs showing the effect on total number of neutrophils in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.18, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.18, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. **P<0.01 and ***P<0.001.

[0037] FIG.19 provides bar graphs showing the effect on total number of lymphocytes in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.19, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.19, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0038] FIG.20 provides bar graphs showing the effect on total number of macrophages in bronchoalveolar lavage fluid (BALF) of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.20, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.20, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8.  7Attorney Docket No.:  409176‐1182001WO Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. ***P<0.001.

[0039] FIG.21 provides bar graphs showing the effect on serum OVA specific IgE levels of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.21, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.21, right panel). Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. **P<0.01 and ***P<0.001.

[0040] FIG.22 provides bar graphs showing the effect on levels of Interleukin-4 (IL- 4) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.22, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.22, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0041] FIG.23 provides bar graphs showing the effect on levels of IL-5 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.23, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.23, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. ***P<0.001.

[0042] FIG.24 provides bar graphs showing the effect on levels of IL-13 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.24, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104  8Attorney Docket No.:  409176‐1182001WO (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.24, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. **P<0.01 and ***P<0.001.

[0043] FIG.25 provides bar graphs showing the effect on levels of Keratinocyte Chemoattractant (KC) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.25, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.25, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group.

[0044] FIG.26 provides bar graphs showing the effect on levels of IL-10 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.26, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.26, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0045] FIG.27 provides bar graphs showing the effect on levels of IL-12 p70 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.27, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.27, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0046] FIG.28 provides bar graphs showing the effect on levels of IL-17 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v)  9Attorney Docket No.:  409176‐1182001WO aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.28, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.28, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05 and ***P<0.001.

[0047] FIG.29 provides bar graphs showing the effect on levels of Eotaxin-1 in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.29, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.29, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. **P<0.01 and ***P<0.001.

[0048] FIG.30 provides bar graphs showing the effect on levels of Granulocyte- Macrophage Colony-Stimulating Factor (GM-CSF) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.30, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.30, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0049] FIG.31 provides bar graphs showing the effect on levels of Granulocyte Colony-Stimulating Factor (G-CSF) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.31, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.31, right panel). BALF was collected 24 hours after the final OVA challenge. Each  10Attorney Docket No.:  409176‐1182001WO column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group.

[0050] FIG.32 provides bar graphs showing the effect on levels of Monocyte Chemoattractant Protein-1 (MCP-1) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.32, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.32, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05 and ***P<0.001.

[0051] FIG.33 provides bar graphs showing the effect on levels of Periostin in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.33, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.33, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0052] FIG.34 provides bar graphs showing the effect on levels of Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) in BALF of sensitized animals (i) treated on days 15, 16 and 17 prior to daily PBS or OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV) or vehicle at Day 18 (FIG.34, left panel); or (ii) treated on days 15, 16, and 17 prior to daily OVA (1% w / v) aerosol challenge with ‘1104 (80 μg / kg, SL1), ‘1104 (80 μg / kg, SL2), ‘1104 (80 μg / kg, IV), or vehicle with further OVA challenge on days 27, 28, and 29 but without any additional ‘1104 or vehicle treatment (FIG.34, right panel). BALF was collected 24 hours after the final OVA challenge. Each column represents the mean and each bar represents the S.E. mean of n=8. Statistical analysis one-way ANOVA followed by a Dunnett's test vs OVA / vehicle group. *P<0.05, **P<0.01, and ***P<0.001.

[0053] FIG.35 provides a semi-log plot of the pharmacokinetic data of the SL and IV administrations of 2 mg / kg ‘1104.  11Attorney Docket No.:  409176‐1182001WO DETAILED DESCRIPTION OF THE INVENTION

[0054] The subject innovation is now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It may be evident, however, that the present invention may be practiced without these specific details. In other instances, well-known structures and devices are shown in block diagram form in order to facilitate describing the present invention. It is to be appreciated that certain aspects, modes, embodiments, variations and features of the invention are described below in various levels of detail in order to provide a substantial understanding of the present invention. DEFINITIONS

[0055] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0056] As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, and the like.

[0057] As used herein, the term "approximately" or "about" in reference to a value or parameter are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value). As used herein, reference to "approximately" or "about" a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, description referring to "about X" includes description of "X".

[0058] As used herein, the term “or” means “and / or.” The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is  12Attorney Docket No.:  409176‐1182001WO intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0059] As used herein, the term "comprising" means that other elements can also be present in addition to the defined elements presented. The use of "comprising" indicates inclusion rather than limitation.

[0060] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0061] As used herein the term "consisting essentially of" refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[0062] The term "statistically significant" or "significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.

[0063] As used herein, the term "relapsing-remitting condition” refers to conditions such as an inflammatory condition, autoimmune disorders, and an allergic condition. In some embodiments, the relapsing-remitting condition is an inflammatory condition. Examples of inflammatory condition include, but is not limited to, asthma, Crohn’s disease, allergic inflammatory conditions such as atopic dermatitis and rhinitis, rheumatoid arthritis and inflammatory bowel disease. In some embodiments, the relapsing-remitting condition is an autoimmune disorder. Examples of autoimmune disorders include, but are not limited to, hemolytic anemia, thrombocytopenia, pernicious anemia, Addison’s disease, autoimmune diabetes, insulin dependent diabetes mellitus, myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, autoimmune encephalitis, connective tissue disease, multiple sclerosis (including relapsing multiple sclerosis), autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, graft-versus-host disease and autoimmune inflammatory eye disease. Preferred autoimmune disorders include rheumatoid arthritis, and systemic lupus erythematosus. In some embodiments, the relapsing-remitting condition is an allergic condition. Examples of allergic conditions and disorders, but is not limited to, eczema, atopic dermatitis, allergic rhinitis (hay fever), allergic airways diseases, hyper-eosinophilic syndrome, respiratory diseases characterized by eosinophilic airway inflammation and airway hyper-responsiveness, such as asthma, including allergic asthma and intrinsic asthma, allergic bronchopulmonary aspergillosis, eosinophilic pneumonia, allergic bronchitis bronchiectasis, interstitial lung disease, hyper- eosinophilic syndrome, urticaria, angioedema, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis and giant papillary conjunctivitis. Preferred allergic disorders and conditions include asthma,  13Attorney Docket No.:  409176‐1182001WO allergic rhinitis, and atopic dermatitis. In another aspect, the condition involves viral exacerbations of allergic conditions including asthma. In another aspect, the condition involves exacerbations associated with bacterial infections.

[0064] As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” when used in reference to a disease, disorder or medical condition, refer to therapeutic treatments for a condition, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a symptom or condition. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition. Treatment is generally “effective” if one or more symptoms or clinical parameters are improved. Alternatively, treatment is “effective” if the progression of a condition is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or clinical parameters, but also a cessation or at least slowing down of progression or worsening of symptoms that would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of the deficit, stabilized (i.e., not worsening) state of a relapsing-remitting condition.

[0065] As used herein, the terms "effective amount" and “therapeutically effective amount” include an amount sufficient to prevent or ameliorate a manifestation of a relapsing- remitting condition. It will be appreciated that there will be many ways known in the art to determine the effective amount for a given application. For example, the pharmacological methods for dosage determination may be used in the therapeutic context. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds.

[0066] As used herein, the term "subject" refers to a mammal, including but not limited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, or primate. Subjects can be house pets (e.g., dogs, cats), agricultural stock animals (e.g., cows, horses, pigs, chickens, etc.), laboratory animals (e.g., mice, rats, rabbits, etc.), but are not so limited. Subjects include human subjects. The human subject may be a pediatric, adult, or a geriatric subject. The human subject may be of either sex. The term subject is used interchangeably with the term patient.

[0067] The term “acute treatment” is used to mean that the peptide is administered at the onset of or during a period of relapse of the condition, but that it is not necessary for the peptide to be continuously administered. In particular, it may not be necessary for the  14Attorney Docket No.:  409176‐1182001WO peptide to be administered during periods of remission of the condition. Thus, the “acute treatment” according to the present invention can be distinguished from known methods for the treatment of relapsing-remitting conditions which provide chronic therapy requiring continuous, long-term administration of the pharmaceutical without any breaks in treatment. The provision of an acute treatment provides significant advantages to the patient. Since the peptides of the invention only need to be administered over a short period of time, side effects, for example injection site reactions are reduced. In addition, during periods of remission patients enjoy an improved lifestyle, without the need to remember dosage regimens. Without being bound by theory, it is understood that the peptides of the invention do not simply affect the symptoms of the condition or disease, but rather they modify the underlying condition or disease itself. Thus, administration of the peptide of the invention has a long-term effect.

[0068] In some embodiments, a single dose of the peptide molecule is administered to the subject. In alternative embodiments, two or more doses (e.g., 3, 4, 5, or more doses) are administered over a short period of time, for example over a period of one day, three days, 28 days, 56 days or 112 days. The time between dose administration to the subject may be three hours, one day, 14 days, 28 days or 56 days after the previous dose.

[0069] Remission usually comprises the reduction, alleviation or elimination of one or more symptoms of the condition. Typically, remission or clinical remission comprises a period with no symptoms associated with the relapsing-remitting disease or a period during which the symptoms associated with the disease have decreased in severity and / or in number. A symptom associated with a condition, disease or disorder includes any clinical or laboratory manifestation associated with the disease or disorder. Clinical remission may therefore be measured according to the relevant scale or remission indicators, and well known in the medical field by for example, clinicians and researchers. Conversely, relapse of the condition may be defined as the increase or appearance of one or more symptoms of the condition. For example, symptoms of asthma may be shortness of breath, difficulty breathing, chest tightness, coughing, reduced lung capacity, trouble sleeping caused by shortness of breath, coughing or wheezing, a whistling or wheezing sound when inhaling, coughing or wheezing attacks that are worsened by a respiratory virus such as cold or flu. Additionally, symptoms may include hospitalization or loss of work / school attendance.

[0070] A reduction or elimination of one or more symptoms is typically a significant reduction or elimination of one or more symptoms as identified by a physician. Symptoms of the relapsing-remitting conditions can be measured and quantified using well-known diagnostic tests. For example, lung function tests such as spirometry and methacholine challenge tests can be used to quantify the symptoms of asthma, using ACQ scores. The ACQ is a simple questionnaire to measure the adequacy of asthma control and change in  15Attorney Docket No.:  409176‐1182001WO asthma control which occurs either spontaneously or as a result of treatment. ACQ has a multidimensional construct assessing symptoms (5 items-self-administered) and rescue bronchodilator use (1 item-self-administered) and forced expiratory volume in 1 minute (FEV1) (1 item) completed by clinic staff.8

[0071] As well as providing a clinical definition of remission, it is also possible to define a biological or mechanistic definition of remission. In some embodiments, the condition is associated with eosinophilia and / or neutrophilia. In this case, remission comprises a significant reduction in the number of neutrophils and / or the number of eosinophils trafficking to a site of inflammation in the human or animal subject relative to a control subject who has not been administered the peptide molecule. If the condition is a pulmonary condition, remission comprises a significant reduction in the number of neutrophils and / or the number of eosinophils recruited to the lungs or found within the circulatory system.

[0072] Remission may also be associated with a significant reduction in the number of lymphocytes or a significant increase in the number of macrophages in the human subject relative to a control subject. Remission may further be associated with a significant change in the amount of one or more inflammatory markers such as cytokines, for example IL-4, IL-5, IL-10, or IL-13 in the human subject relative to a control subject. Remission may comprise a significant increase in the amount of IL-10 in the human subject relative to a control subject. Remission may comprise a significant reduction in the amount of IL-4, IL-5 or IL-13 in the human subject relative to a control subject.

[0073] A relapsing-remitting condition is any condition which has one or more periods of relapse, wherein each relapse is followed by a period of remission. During these symptom free periods or periods of remission, patients do not require quantifiable circulating levels of the therapeutic peptide. In a preferred embodiment remission is maintained when the plasma peptide concentration is below the lower limit of quantification. This limit of quantification may vary depending on the detection method employed. Typically, the plasma peptide concentration is undetectable at circulating levels of less than 40 ng / mL, for example less than 30 ng / mL or 20 ng / mL. A typical method for determining the plasma peptide concentration is high resolution accurate mass (HRAM) LC-MS / MS. In a preferred embodiment remission of the condition is for a period of at least 7 days, for example 14 days, at least 28 days, more preferably at least 6 months after the concentration of the peptide molecule in the plasma of the subject is undetectable. In another embodiment remission of the condition is for a period of at least 7 days, optionally at least 14 days, optionally at least 28 days, optionally at least 6 months after administration of the final dose of the peptide.  16Attorney Docket No.:  409176‐1182001WO

[0074] As used herein, the term "long-term" administration means that the therapeutic agent or drug is administered for a period of at least 12 weeks. This includes that the therapeutic agent or drug is administered such that it is effective over, or for, a period of at least 12 weeks and does not necessarily imply that the administration itself takes place for 12 weeks, e.g., if sustained release compositions or long-acting therapeutic agent or drug is used. Thus, the subject is treated for a period of at least 12 weeks. In many cases, long-term administration is for at least 4, 5, 6, 7, 8, 9 months or more, or for at least 1, 2, 3, 5, 7 or 10 years, or more.

[0075] The administration of the compositions contemplated herein may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. In a preferred embodiment, compositions are administered parenterally. The phrases “parenteral administration” and “administered parenterally” as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravascular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intratumoral, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. In one embodiment, the compositions contemplated herein are administered to a subject by direct injection into a tumor, lymph node, or site of infection.

[0076] The terms “decrease,” “reduced,” “reduction,” or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.

[0077] The terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase 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  17Attorney Docket No.:  409176‐1182001WO about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an “increase” is a statistically significant increase in such level. PHARMACEUTICAL COMPOSITIONS

[0078] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive corn, sunflower, grapeseed, vegetable, fish oil, or injectable organic esters. The excipients can be chosen, for example, to effectuate delayed release of an agent or to selectively target one or more cells, tissues or organs.

[0079] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, decrease degradation, rejection or clearance, increase solubility, increase immunogenicity, or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; adjuvants (e.g., Alum, MF59, AS01 / 03 / 04, CpG1018) or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-micro emulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0080] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, metals, radioactive isotope / radiation particles, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use  18Attorney Docket No.:  409176‐1182001WO in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, rejection, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0081] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, vegetable oil, cottonseed oil, safflower oil, sesame oil, olive oil, sunflower oil, grapeseed oil, fish oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar, Matrigel or hydrogel; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) nanoparticles such as liposomes, polymers, micelles, metal nanoparticles, carbon nanotubes, solid lipid nanoparticles, noisomes, and dendrimers; (22) extracellular vesicles; and (23) other non-toxic compatible substances employed in pharmaceutical formulations.

[0082] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0083] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.  19Attorney Docket No.:  409176‐1182001WO

[0084] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0085] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0086] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or clearance of the particular compound(s) being employed, the duration or frequency of the treatment, other drugs that may interact with or affect the metabolism or efficacy of the compound of the invention, compounds and / or materials (e.g., vaccines, antibodies and derivatives) used in combination with the particular compound(s) employed, other therapeutic approaches (e.g., surgery, cell-based therapy, chemotherapy, radiotherapy, interventional therapy), the age, sex, body weight, conditions or comorbidities, diet, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0087] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the body weight, sex, age, comorbidities, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, therapeutic approaches, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art. See, e.g., Isselbacher et al. (1996).9

[0088] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent or combined with a therapeutic approach (e.g., surgery, chemotherapy, radiotherapy, interventional therapy).  20Attorney Docket No.:  409176‐1182001WO

[0089] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, animal models, (engineered or genetically modified) cells, organoids, constructs, vectors, carriers, adjuvants, compounds, drug delivery system, antibodies and derivatives, vaccines, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy;10The Encyclopedia of Molecular Cell Biology and Molecular Medicine;11Molecular Biology and Biotechnology: a Comprehensive Desk Reference;12Immunology;13Janeway's Immunobiology;14Lewin's Genes XI;15Molecular Cloning: A Laboratory Manual.;16Basic Methods in Molecular Biology;17Laboratory Methods in Enzymology;18Current Protocols in Molecular Biology (CPMB);19Current Protocols in Protein Science (CPPS);20and Current Protocols in Immunology (CPI).21

[0090] In some embodiments of any of the aspects, the disclosure described herein does not concern a process for cloning human beings, processes for modifying the germ line genetic identity of human beings, uses of human embryos for industrial or commercial purposes or processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes.

[0091] Other terms are defined herein within the description of the various aspects of the invention. CHAPERONIN 60.1-RELATED PEPTIDES

[0092] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0093] Compositions useful in the methods and formulations of the present invention include, but are not limited to: DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD (SEQ ID NO: 1) (‘1104); DGSVVVNKVSELPAGH (SEQ ID NO: 2); GLNVNTLSYGDLAAD (SEQ ID NO: 3); SELPAGHGLNVNLTS (SEQ ID NO: 4); DGSVVVNKVS (SEQ ID NO: 5);  21Attorney Docket No.:  409176‐1182001WO ELPAGHGLNV (SEQ ID NO: 6); NTLSYGDLAAD (SEQ ID NO: 7); or a functionally equivalent fragment or variant thereof.

[0094] Other compositions useful in the methods and formulations of the present invention include, but are not limited to, Cpn60.1-related peptides disclosed in United States Published Patent Application No.2004013216322and United States Patent Nos. 11,098,090;239,320,791;249,085,632.25

[0095] In certain aspects, a Cpn60.1-related peptide is composed of amino acid residues. As used herein, the term “amino acid residue” is used interchangeably with the terms “amino acid” or “aa” to refer to an amino acid which is part of a peptide or protein. In some such aspects, an agonist or ligand of the present invention is composed of amino acids with the standard structure NH2—C(H)(R)—COOH, where R represents an individual amino acid side chain. In certain aspects, an agonist or ligand is composed of amino acid residues which are naturally occurring amino acids. In certain aspects, a naturally occurring amino acid includes one of the twenty standard amino acids found in naturally occurring peptides and proteins. In some such aspects, an agonist or ligand is composed of at least one naturally occurring amino acid residue which is alanine (“A”), arginine (“R”), asparagine (“N”), aspartic acid (“D”), cysteine (“C”), glutamine (“Q”), glutamic acid (“E”), glycine (“G”), histidine (“H”), isoleucine (“I”), leucine (“L”), lysine (“K”), methionine (“M”), phenylalanine (“F”), proline (“P”), serine (“S”), threonine (“T”), tryptophan (“W”), tyrosine (“Y”), or valine (“V”).

[0096] In other aspects a Cpn60.1-related peptide used in the methods of the present invention is composed of at least one amino acid residue which is an unnatural or synthetic amino acid. In some such aspects, an unnatural or synthetic amino is a chemically modified amino acid including but not limited to amino acids which have been modified by methylation, amidation, acetylation, protecting groups, and / or substitution with other chemical groups that can change the physiochemical properties of a peptide. In further aspects, an unnatural or synthetic amino is a chemically modified amino acid which has been modified with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, and the like).

[0097] In further aspects, a Cpn60.1-related peptide used in the methods of the present invention is composed of at least one amino acid which has an L-configuration (the chirality of an L-amino acid). In additional aspects, a Cpn60.1-related peptide used in the methods of the present invention is composed of at least one amino acid which has a D- configuration (the chirality of a D-amino acid).  22Attorney Docket No.:  409176‐1182001WO

[0098] In certain aspects, an agonist or ligand of the present invention is about 50 aa in length; 49 aa in length; 48 aa in length; 47 aa in length; 46 aa in length; 45 aa in length; 44 aa in length; 43 aa in length; 42 aa in length; 41 aa in length; 40 aa in length; 39 aa in length; 39 aa in length; 38 aa in length; 37 aa in length; 36 aa in length; 35 aa in length; 34 aa in length; 33 aa in length; 32 aa in length; 31 aa in length; 30 aa in length; 29 aa in length; 28 aa in length; 27 aa in length; 26 aa in length; 25 aa in length; 24 aa in length; 23 aa in length; 22 aa in length; 21 aa in length; or 20 aa in length; 19 aa in length; 18 aa in length; 17 aa in length; 16 aa in length; 15 aa in length; 14 aa in length; 13 aa in length; 12 aa in length; 11 aa in length; 10 aa in length; 9 aa in length; 8 aa in length; 7 aa in length; 6 aa in length; or 5 aa in length.

[0099] In certain aspects, compositions of the present invention are administered to a patient by any appropriate route known and / or employed by those skilled in the art. In some aspects, compositions of the present invention are administered by oral (PO), intravenous (IV), intramuscular (IM), intra-arterial, intramedullary, intrathecal, sublingual (SL), intraventricular, transdermal, interdermal, intradermal, rectal (PR), vaginal, intraperitoneal (IP), intragastric (IG), topical (e.g., by powders, ointments, creams, gels, lotions, and / or drops), mucosal, intranasal, buccal, enteral, intravitreal, sublingual, by intratracheal instillation, bronchial instillation, and / or inhalation, as an oral spray, nasal spray, aerosol, and / or through a portal vein catheter.

[0100] In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered intravenously, for example, by intravenous infusion. In further aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered by intramuscular injection. In more aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered by intratumoral injection. In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered by sublingual injection. In further aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered via portal vein catheter. In more aspects, the invention encompasses the delivery of a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof by any appropriate route taking into consideration likely advances in the art of drug delivery.

[0101] In some aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof may be administered at dosage levels sufficient to deliver from about 0.001 mg / kg to 100 mg / kg, from about 0.01 mg / kg to 50 mg / kg, from about 0.1 mg / kg to 40 mg / kg, from about 0.5 mg / kg to 30 mg / kg, from about  23Attorney Docket No.:  409176‐1182001WO 0.01 mg / kg to 10 mg / kg, from about 0.1 mg / kg to 10 mg / kg, or from about 1 mg / kg to 25 mg / kg of patient body weight per day to obtain the desired therapeutic effect. In certain aspects, the desired dosage may be delivered more than three times per day, three times per day, two times per day, once per day, once every other day, once every third day, once every week, once every two weeks, once every three weeks, once every four weeks, once every two months, once every six months, or once every twelve months. In certain aspects, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain aspects, the desired dosage may be delivered using one or more administrations during an initial period of time, followed by a period of time in which no dosage is administered.

[0102] In further aspects, a Cpn60.1-related peptide used in the methods of the present invention may be utilized for prophylactic applications. In more aspects, prophylactic applications involve systems and methods for preventing, inhibiting progression of, and / or delaying the onset of a relapsing-remitting condition, in individuals susceptible to and / or displaying symptoms of a relapsing-remitting condition.

[0103] In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention is administered to a target cell in vivo. In other aspects, a Cpn60.1-related peptide used in the methods of the present invention is administered to a target cell ex vivo. In additional aspects, a Cpn60.1-related peptide used in the methods of the present invention is administered to a target cell ex vivo, then the target cell is re-introduced into an organism. In some such aspects, the target cell is cultured into multiple progeny cells ex vivo before being re-introduced in an organism. In more aspects, the organism is a human. In further aspects, the organism is a human patient. In certain aspects, the target cell was originally derived from the organism to which it is re-introduced. In other aspects, the target cell was originally derived from a different organism to which it is re-introduced.

[0104] In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof are employed in combination therapies for treating or reducing the risk of a relapsing-remitting condition. In such aspects, administration can be in combination with one or more additional therapeutic agents. As used herein, the phrases “combination therapy,” “combined with,” “in combination,” and the like, refer to the use of more than one medication or treatment simultaneously to increase the response. In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof are administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention and / or pharmaceutical compositions thereof are administered in  24Attorney Docket No.:  409176‐1182001WO combination together in a single composition or administered separately in different compositions.

[0105] In certain aspects, the particular combination of therapies to employ in a combination regimen will generally take into account the compatibility of the desired therapeutics and / or procedures, and the desired therapeutic effect to be achieved. In further aspects, the therapies employed may achieve a desired effect for the same purpose (e.g., a Cpn60.1-related peptide used in the methods of the present invention which is useful for treating, preventing, and / or delaying the onset of a relapsing-remitting condition may be administered concurrently with another therapeutic agent which is also useful for treating, preventing, and / or delaying the onset of a relapsing-remitting condition symptoms), or they may achieve different effects. In further aspects, the combination of therapies employed may achieve the same or a substantially similar desired effect for the same disease, condition or disorder; may achieve the same or a substantially similar desired effect for one or more different diseases, conditions or disorders; may achieve different desired effects for the same disease, condition or disorder; or may achieve different desired effects for one or more different diseases, conditions or disorders.

[0106] In additional aspects, the delivery of a Cpn60.1-related peptide used in the methods of the present invention as a pharmaceutical composition is in combination with one or more additional components that may improve the bioavailability of the Cpn60.1- related peptide used in the methods of the present invention, reduce and / or modify its metabolism, inhibit its excretion, and / or modify its distribution in the body.

[0107] In certain aspects, combination therapy may involve administrations of a plurality of Cpn60.1-related peptides in accordance with the present invention. In further aspects, combination therapy may involve administrations of a plurality of a Cpn60.1-related peptides that treat, prevent, improve, achieve remission of, and / or reduce the risk of a relapsing- remitting condition. In more aspects, combination therapy can be a plurality of Cpn60.1- related peptides that treat, prevent, improve, achieve remission of, and / or reduce the risk of a relapsing-remitting condition.

[0108] In certain aspects, a Cpn60.1-related peptide used in the methods of the present invention is combined with at least one pharmaceutically acceptable excipient, in the form of a pharmaceutical composition. As used herein, “pharmaceutical composition” refers to a formulation containing an active ingredient, and optionally a pharmaceutically acceptable carrier, diluent or excipient. The term “active ingredient” can interchangeably refer to an “effective ingredient,” and is meant to refer to any agent that is capable of inducing a sought- after effect upon administration. Examples of active ingredient include, but are not limited to, chemical compound, drug, therapeutic agent, small molecule, and the like.  25Attorney Docket No.:  409176‐1182001WO

[0109] In certain aspects of the present invention, the active ingredient is a Cpn60.1- related peptide as disclosed herein. In particular aspects, the active ingredient is PIN201104, or a derivative thereof. In certain aspects, the active ingredient is PIN201360, PIN201361, PIN201362, PIN201116, PIN201105 or a derivative thereof. In further aspects, the active ingredient is a peptide described in WO2009 / 106819, or a derivative thereof.

[0110] In certain aspects, the pharmaceutical compositions are useful in medicine or the manufacture of medicaments. In further aspects, the pharmaceutical compositions are useful in one or more of the therapeutic applications disclosed herein, for example, in an individual suffering from a relapsing-remitting condition. In additional aspects, the pharmaceutical compositions are formulated for administration to a human patient.

[0111] In certain aspects, the pharmaceutical composition is in a sterile injectable form (e.g., a form that is suitable for sublingual injection or intravenous infusion). In more aspects, the pharmaceutical composition is in a liquid dosage form that is suitable for injection. In further aspects, the pharmaceutical composition is in a powder (e.g., lyophilized and / or sterilized), optionally under vacuum, which is reconstituted with an aqueous diluent (e.g., water; buffer; salt solution, and the like) prior to injection. In additional aspects, the pharmaceutical composition is diluted and / or reconstituted in an aqueous diluent (e.g., water, sodium chloride solution, sodium acetate solution, benzyl alcohol solution, phosphate buffered saline, and the like). In certain aspects, the pharmaceutical composition is in a form that can be refrigerated and / or frozen. In further aspects, the pharmaceutical composition is in a form that cannot be refrigerated and / or frozen. In certain aspects, the pharmaceutical composition is a reconstituted solution and / or liquid dosage form which can be stored for a certain period of time after reconstitution (e.g., 2 hours, 12 hours, 24 hours, 2 days, 5 days, 7 days, 10 days, 2 weeks, a month, two months, or longer).

[0112] In certain aspects, preparatory methods for pharmaceutical compositions include the step of bringing the active ingredient (e.g., a Cpn60.1-related peptide used in the methods of the present invention) into association with one or more pharmaceutically acceptable excipients and then shaping and / or packaging the product into a desired single- or multi-dose unit. A pharmaceutical composition in accordance with the invention may be prepared, packaged in bulk, packaged as a single unit dose, and / or packaged as a plurality of single unit doses. As used herein, a “unit dose” refers to a discrete amount of the pharmaceutical composition including a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to a dose that would be administered to a subject and / or a convenient fraction of such a dose such as, for example, one-half or one- third of such a dose. The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition in accordance with the invention may vary, depending upon the identity, size, and / or condition of the  26Attorney Docket No.:  409176‐1182001WO subject treated and / or depending upon the route by which the composition is to be administered. In certain aspects, for example, the composition may include between about 0.1% to 100% (w / w) of an active ingredient.

[0113] In another aspect, the present invention includes kits that are useful for carrying out the methods of the present invention. The components contained in the kit depend on a number of factors, including the particular application (e.g., the particular route of administration to be employed, or the particular disease, condition or disorder to be treated). In certain aspects, the present invention provides a kit for administering a Cpn60.1- related peptide in accordance with the present invention to treat a disease, condition or disorder disclosed herein. In some such aspects, the kit further includes instructions for administration. In certain aspects, the kit is for administering a Cpn60.1-related peptide to treat a patient with a relapsing-remitting condition. In certain aspects, the kits contain one or more a Cpn60.1-related peptides. In certain aspects, the kit includes a number of unit doses of a pharmaceutical composition containing a Cpn60.1-related peptide. In additional aspects, kits for use in accordance with the present invention include instructions (e.g., for administration, for storage, and the like), buffers and / or other reagents. In some such aspects, the kit includes (i) at least one Cpn60.1-related peptide, (ii) an applicator, or the like for administration of the at least one Cpn60.1-related peptide to a patient, and (iii) instructions for use. In further aspects, the kit includes a treatment schedule designating when the unit dosages are to be administered. In more aspects, placebo dosages, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, are included. In certain aspects, kits include one or more containers so that certain of the individual components or reagents may be separately housed. In certain aspects, kits may include a means for enclosing the individual containers in relatively close confinement for commercial sale, e.g., a plastic box, in which instructions, packaging materials such as Styrofoam, and the like, may be enclosed. PRE-GASTRIC ABSORPTION OF PEPTIDES DERIVED FROM CHAPERONIN 60.1

[0114] In clinical studies conducted to date, peptides derived from Chaperonin 60.1 have been administered by intravenous (IV) infusion of reconstituted lyophilized powder. However, IV administration requires access to a medical facility with trained medical professionals, which is prohibitive to many patients due to the distance or travel to medical facilities. Furthermore, IV administration typically requires a trained medical professional to set-up an IV infusion, set and determine appropriate dosing / infusion rate, and time required before, during, and after the actual infusion for the preparation, infusion duration, and observation post-infusion. In addition to the risk of infection at the injection site, IV  27Attorney Docket No.:  409176‐1182001WO administration is also associated with the risk of systemic infection, potential exposure to IV particulate matter, and exposure to hospital-acquired infections.

[0115] Oral administration of peptides such as Chaperonin 60.1-derived peptides are highly susceptible to degradation from gastric digestive enzymes. As such, there is considerable interest in “pre-gastric absorption” of active ingredients. Pre-gastric absorption is the absorption of active ingredients from that part of the alimentary canal prior to the stomach. Pre-gastric absorption thus includes buccal, sublingual, oropharyngeal and esophageal absorption. Medicaments absorbed by such pre-gastric absorption pass straight into the systemic circulatory system, thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of agents absorbed in this way may also be increased. This means that the dose of such agents may be reduced while still producing the desired beneficial effects, and this decrease in dose may result in a corresponding reduction of unwanted side effects. transmucosal routes, such as intranasal and sublingual provide attractive alternatives due to their high accessibility and permeability. Among these, sublingual administration has emerged as a promising option, characterized by increased patient preference and reduced formulation requirements, such as pH and osmolarity. FORMULATIONS FOR SUBLINGUAL ADMINISTRATION

[0116] ‘1104 is a peptide derived from M. tuberculosis (mTB) bacterial chaperonin 60.1 which has shown immunomodulatory and anti-inflammatory properties in a range of preclinical models of lung inflammation. Despite a very short half-life (about 10-15 min across species), ‘1104 shows a long-lasting effect in models of allergic inflammation of up to 14 days or longer. ‘1104 appears to be effective in resetting the immune system from an inflammatory state and in inducing inflammatory disease remission in nonclinical models. Its short pharmacokinetic (PK) terminal elimination half-life (t1 / 2) decreases the potential for the negative off-target effects associated with current therapies.

[0117] In clinical studies conducted to date, ‘1104 was administered by intravenous (IV) infusion of reconstituted lyophilized powder containing 8 mg of IRL201104. The reconstituted dose was prepared at either 0.8 mg / mL or 2.0 mg / mL strength. The qualitative and quantitative composition of IRL201104 reconstituted solution for injection is shown in Table 1.  28Attorney Docket No.:  409176‐1182001WO Table 1: Composition of ‘1104 Formulation for IV AdministrationAbbreviations: Percent weight in volume (% w / v); Quantum satis (q.s. or Q.S.).

[0118] While the IV infusion delivery form is adequate for early clinical development, different delivery forms are preferred for the marketed product. Transmucosal routes, such as intranasal, sublingual and intravaginal delivery, provide attractive alternatives due to their high accessibility and permeability. In addition to reduced concentrations of digestive enzymes, these alternative routes also allow bypassing of first-pass metabolism. All of the above contribute to increased absorption of biological drugs from the mucosal routes. Among these, sublingual administration has emerged as a promising option, characterized by increased patient preference and reduced formulation requirements, such as pH and osmolarity.26

[0119] Sublingual (SL) administration provides a simple and non-invasive alternative and offers numerous advantages over IV infusion (e.g., self-administration by patient in home, superior dosing compliance, no risk of infusion site infection). Sublingual delivery also boasts convenience and rapid absorption, which is particularly beneficial for emergent conditions. Further, administration at home reduces the risk of exposure to hospital- acquired infections.

[0120] However, thick, mucinous fluid secreted by sublingual glands and the tight epithelial layer under the mucus minimize drug absorption, especially for large molecules, which is quite challenging for low solubility peptides such as ‘1104. Other disadvantages for efficient sublingual drug delivery include: (i) small surface area for absorption; (ii) limited dose and volume; (iii) dissolution issues in patients with dry mouth condition; and solution with unpalatable taste. Accordingly, research efforts were initiated to develop pharmaceutical ‘1104 formulations suitable for sublingual delivery and assess whether sublingual delivery is a feasible delivery route for ‘1104.  29Attorney Docket No.:  409176‐1182001WO

[0121] In the first study described below in Example 1, ‘1104 is delivered in a liquid sublingual formulation. Sublingual delivery of a liquid formulation can lead to improper dosage due to improper measurement by the patient and / or dilution with the patient’s saliva leading to part of the dosage being swallowed.

[0122] Efforts have been made on the development of oral solid pharmaceutical dosage forms that rapidly disintegrate in the mouth. These fast dispersing dosage forms can comprise a porous skeletal structure of a water soluble, hydratable gel or foam forming material which has been hydrated with water. The gel or foam forming material may be rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0ºC or below to leave spaces in place of the hydration liquid. The solid dosage forms as disclosed comprise an open matrix network carrying the ‘1104, with the open matrix comprising a water-soluble or water-dispersible carrier material that is inert towards the ‘1104. The solid dosage forms can be prepared by the sublimation or removal of solvent from a solution or suspension comprising the ‘1104 and the carrier material. Sublimation or removal of solvent can be carried out by freeze-drying, or lyophilization. A typical approach is to dose a drug solution or suspension into free-form blisters followed by rapidly freezing the solution or suspension and then freeze-drying. Freeze-drying removes the ice to leave a porous tablet that, when placed on the tongue, disperses in a few seconds.

[0123] A typical matrix forming agent is gelatin. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dispersion of the dosage form. Gelatin, which is normally utilized in such sublingual formulations, is defined as a protein obtained by partial hydrolysis of mammalian collagenous tissues, such as skins, tendons, ligaments and bones. Gelatin may also be derived from fish. In comparing gelatin sources, the required heating step of processing mammalian gelatin increases processing time and costs, thereby increasing the overall costs of the process, compared to that for fish gelatin. Additionally, various cultural and religious factors, along with perceptions of health risk in bovine and porcine products, may make fish gelatin more attractive than mammalian gelatin to consumers. Particularly for pharmaceutical formulations, an advantageous alternative to the use of mammalian derived gelatin is the use of fish gelatin, especially non-gelling fish gelatin. Non-gelling fish gelatin is preferably obtained from cold water fish and has a sol-gel transition temperature, that is, the temperature at which a given solution of gelatin in water, transitions between a liquid and a gel state, that is lower than that of most mammalian derived gelatins. There appears to be a relationship between the temperature at which the animal or fish metabolizes food and the properties of the skin and resultant extracted gelatins.  30Attorney Docket No.:  409176‐1182001WO

[0124] As mentioned above, ‘1104 is a low solubility peptide. Development of sublingual tablets for pre-gastric delivery can be challenging when an active pharmaceutical ingredient (API) has low solubility and / or permeability. Absorption of an API can be strongly influenced by the physicochemical properties of the API such as molecular weight, solubility, hydrophilicity, and lipophilicity, as well as by factors such as drug loading, mucosal contact time, the drug formulation, and excipients used. APIs with poor solubility and / or permeability characteristics can give rise to poor absorption and variable drug bioavailability.

[0125] Various formulation approaches have been used to improve the absorption of drugs with poor permeability and / or low solubility, including the addition of permeation enhancers (PEs) also known as permeation agents (PAs). The selection of appropriate PEs for each type of API is largely based on empirical, trial-and-error experience, and most work on PEs to date has focused on improving drug permeation of intestinal and dermal tissues. The effect of PEs on pre-gastric absorption through the oral mucosal tissue, especially in a freeze-dried orally dissolvable tablet (ODT) format, is less established. As a result, formulations are often unsuccessful, and the required reformulation activities increase drug development time and incur additional development costs.

[0126] In some embodiments, a pharmaceutical composition includes a pharmaceutically effective amount of ‘1104; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10, a bile salt, a micelle, or a fatty acid; a matrix former; and a structure former. In some embodiments, the permeation enhancer comprises a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10. In some embodiments, a molar ratio of ‘1104 to the surfactant is 5:1 to 1:5 and / or the pharmaceutical composition comprises 0.5-20 wt % the surfactant. In some embodiments, the pharmaceutical composition includes a pH modifier. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, a molar ratio of ‘1104 to the bile salt is 15:1 to 1:15 and / or the pharmaceutical composition comprises 1-20 wt % the bile salt. In some embodiments, the permeation enhancer comprises a fatty acid. In some embodiments, a molar ratio of ‘1104 to fatty acid is 3:1 to 1:3 and / or the pharmaceutical composition comprises 0.25-5 wt % fatty acid. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, a molar ratio of ‘1104 to counterions is 6:1 to 1:6 and / or the pharmaceutical composition comprises 0.1-25 wt % counterions. In some embodiments, the pharmaceutical composition includes a pH modifier. In some embodiments, the pharmaceutical composition includes 25-60 wt % matrix former. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or combinations thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the gelatin is fish gelatin, and the  31Attorney Docket No.:  409176‐1182001WO fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition includes 20-45 wt % structure former. In some embodiments, the structure former comprises mannitol. In some embodiments, the pharmaceutical composition comprises 1-35 wt % the ‘1104.

[0127] The pharmaceutical formulations disclosed herein can include a matrix former such as fish gelatin. Specifically, the fish gelatin can be high molecular weight fish gelatin, standard molecular weight fish gelatin, or combinations thereof. High molecular weight fish gelatin is defined as a fish gelatin in which more than 50% of the molecular weight distribution is greater than 30,000 Daltons. Standard molecular weight fish gelatin is defined as fish gelatin in which more than 50% of the molecular weight distribution is below 30,000 Daltons. In some embodiments, the pharmaceutical formulation can include, without limitation, other gelatin, starch, or combinations thereof. Additional matrix formers can be found in EP 2624815 B1. The other gelatin can be bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the amount of high molecular weight fish gelatin in the pharmaceutical formulation (prior to freeze drying) can be about 2-8% w / w, 3- 7% w / w, or 4-6% w / w. Unless otherwise stated herein, % w / w refers to the formulation prior to freeze drying. In some embodiments, the amount of high molecular weight fish gelatin in the pharmaceutical formulation can be less than or equal to 8% w / w, less than or equal to 7% w / w, less than or equal to 6% w / w, less than or equal to 5 w / w, less than or equal to 4% w / w, or less than or equal to 3% w / w. In some embodiments, the amount of high molecular weight fish gelatin in the pharmaceutical formulation can be more than or equal to 2% w / w, more than or equal to 3% w / w, more than or equal to 4% w / w, more than or equal to 5% w / w, more than or equal to 6% w / w, or more than or equal to 7% w / w.

[0128] The pharmaceutical formulation can also include a structure former. Suitable structure formers can include sugars including, but not limited to, mannitol, dextrose, lactose, galactose, cyclodextrin, or combinations thereof. The structure former can be used in freeze drying as a bulking agent as it crystalizes to provide structural robustness to the freeze-dried dosage form. In some embodiments, the amount of structure former in the pharmaceutical formulation can be about 1-8% w / w, 2-6% w / w, 3-6% w / w, 3-5.5% w / w, 3-5% w / w, or 3.3-5% w / w. In some embodiments, the amount of structure former in the pharmaceutical formulation can be less than or equal to 8% w / w, less than or equal to 7% w / w, less than or equal to 6% w / w, less than or equal to 5% w / w, less than or equal to 4% w / w, less than or equal to 3.3% w / w, less than or equal to 3% w / w, or less than or equal to 2% w / w. In some embodiments, the amount of structure former in the pharmaceutical formulation can be more than or equal to 1% w / w, more than or equal to 2% w / w, more than or equal to 3% w / w, more than or equal to 3.3% w / w, more than or equal to 4% w / w, more than or equal to 5% w / w, more than or equal to 6% w / w, or more than or equal to 7% w / w.  32Attorney Docket No.:  409176‐1182001WO

[0129] ‘1104, the API, is present in the pharmaceutical formulation in an amount that is necessary to exhibit the required physiological effect as established by clinical studies. In some embodiments, the amount of API in the pharmaceutical formulation can be about 0.05- 30% w / w, 0.1-25% w / w, 2-25% w / w, 5-25% w / w, or 10-15% w / w. In some embodiments, the amount of API in the pharmaceutical formulation can be about 0.05-5% w / w, 0.1-3% w / w, or 0.2-2% w / w. In some embodiments, the amount of API in the pharmaceutical suspension can be about 0.1-10% w / w. In some embodiments, the amount of API in the pharmaceutical composition can be less than or equal to 30% w / w, less than or equal to 25 w / w, less than or equal to 20% w / w, less than or equal to 15% w / w, less than or equal to 10% w / w, less than or equal to 5% w / w, less than or equal to 2% w / w, or less than or equal to 2% w / w. In some embodiments, the amount of API in the pharmaceutical composition can be more than or equal to 0.05% w / w, more than or equal to 0.1% w / w, more than or equal to 1% w / w, more than or equal to 2% w / w, more than or equal to 5% w / w, more than or equal to 10% w / w, more than or equal to 15 w / w, more than or equal to 20% w / w, or more than or equal to 25% w / w. In some embodiments, a person of ordinary skill in the art can readily determine an appropriate amount of API to include in the dosage form or pharmaceutical composition made according to the present disclosure.

[0130] In some embodiments, the pharmaceutical formulations disclosed herein include a surfactant. In some embodiments, the surfactant can be a non-ionic surfactant. In some embodiments, the non-ionic surfactant can include a polyoxyethylene- polyoxypropylene copolymer. In some embodiments, the surfactant comprises poloxamer 188 (e.g., Kolliphor® P188 by BASF) which is a non-ionic surfactant. In some embodiments, the surfactant may comprise sodium lauryl sulfate (anionic) and / or docusate sodium (anionic). The inclusion of a small amount of surfactant in the pharmaceutical formulation can improve the flow characteristics of the pharmaceutical formulation during dosing. Specifically, the amount of surfactant in the pharmaceutical formulation can be about 0.001- 0.5% w / w, about 0.01-0.3% w / w, or about 0.02-0.2% w / w. In some embodiments, the amount of surfactant in the pharmaceutical formulation may be less than or equal to 0.5% w / w, less than or equal to 0.4% w / w, less than or equal to 0.3% w / w, less than or equal to 0.2% w / w, less than or equal to 0.1% w / w, less than or equal to 0.05 w / w, less than or equal to 0.02% w / w, less than or equal to 0.01% w / w, or less than or equal to 0.005% w / w. In some embodiments, the amount of surfactant in the pharmaceutical formulation may be more than 0.001% w / w, more than 0.005% w / w, more than 0.01% w / w, more than 0.02% w / w, more than 0.05% w / w, more than 0.1% w / w, more than 0.2% w / w, more than 0.3% w / w, or more than 0.4% w / w. In some embodiments, as the amount of surfactant in a pharmaceutical formulation increases, the surface tension will also decrease. However, at a certain point, the surface tension may no longer decrease (i.e., the surface tension may  33Attorney Docket No.:  409176‐1182001WO plateau as the amount of surfactant increases, and / or may increase slightly); once this point is reached, additional surfactant may not have a positive effect on the surface tension of the pharmaceutical formulation.

[0131] The pharmaceutical formulation may also contain additional pharmaceutically acceptable agents or excipients. Such additional pharmaceutically acceptable agents or excipients include, without limitation, sugars, such as mannitol, dextrose, and lactose, inorganic salts, such as sodium chloride and aluminum silicates, gelatins of mammalian origin, fish gelatin, modified starches, preservatives, antioxidants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners, taste-masking agents, and combinations thereof. Suitable coloring agents can include red, black and yellow iron oxides and FD & C dyes such as PD & C Blue No.2 and FD & C Red No.40, and combinations thereof. Suitable flavoring agents can include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry (e.g., black cherry), and grape flavors and combinations of these. In some embodiments, the pharmaceutical formulation can include at least one flavoring agent in an amount of 0.1-5% w / w, 0.1-1% w / w, 0.25-0.75% w / w, 0.4-0.6% w / w, or 0.5% w / w. In some embodiments, the pharmaceutical formulation can include at least one flavoring agent in an amount of 0.1-0.5 w / w. In some embodiments, the amount of flavoring agent in the pharmaceutical formulation can be at least 0.1% w / w, at least 0.2% w / w, at least 0.3% w / w, at least 0.4% w / w, at least 0.5% w / w. In some embodiments, the amount of flavoring agent in the pharmaceutical formulation can be at most 0.5 w / w, at most 0.4% w / w, at most 0.3% w / w, or at most 0.2% w / w.

[0132] Suitable pH modifiers can include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (e.g., 3% w / w sodium hydroxide solution), and combinations thereof. In some embodiments, the pharmaceutical formulation has an amount of a pH modifier (i.e., Q.S. target pH) to maintain a target pH of about 4-6, about 4.5- 5.5, about 4.7-5.3, about 4.7-5, or about 4.8-4.9. In some embodiments, the pharmaceutical formulation can include 0.05-0.3% w / w pH modifier. In some embodiments, the pharmaceutical formulation can include at least 0.05% w / w, at least 0.1% w / w, at least 0.15% w / w, at least 0.2% w / w, at least 0.25% w / w, or at least 0.3% w / w pH modifier. In some embodiments, the pharmaceutical formulation can include at most 0.3% w / w, at most 0.25% w / w, at most 0.2% w / w, at most 0.15% w / w, or at most 0.1% w / w pH modifier.

[0133] Suitable sweeteners can include sucralose, aspartame, acesulfame K and thaumatin, and combinations thereof. In some embodiments, the pharmaceutical formulation can include at least one sweetener in an amount of 0.1-1% w / w, 0.2-0.5% w / w, 0.2-0.4% w / w, 0.3-0.4% w / w, or 0.35% w / w. In some embodiments, the pharmaceutical formulation can include at least one sweetener in an amount of at least 0.2% w / w, at least 0.25% w / w, at least 0.3% w / w, or at least 0.35% w / w. In some embodiments, the  34Attorney Docket No.:  409176‐1182001WO pharmaceutical formulation can include at least one sweetener in an amount of at most 0.4% w / w, at most % w / w, at most 0.3% w / w, or at most 0.25% w / w.

[0134] Suitable taste-masking agents can include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives, and combinations thereof. One of ordinary skill in the art can readily determine suitable amounts of these various additional excipients, if desired.

[0135] The pharmaceutical formulation can also include a solvent. In some embodiments, the solvent can be ethanol, isopropanol, other lower alkanols, water (e.g., purified water), or combinations thereof. In some embodiments, the balance remaining of the pharmaceutical formulation is the solvent (i.e., Q.S.100%). In some embodiments, the pharmaceutical formulation can include 77.5-92.54% w / w solvent.

[0136] In some embodiments, the pharmaceutical formulation can also include a muco-adhesive such as gum. Suitable gums include, but are not limited to, acacia, guar, agar, xanthan, gellan, carageenan, curdlan, konjac, locust bean, welan, gum tragacanth, gum arabic, gum karaya, gum ghatti, pectins, dextran, glucomannan, and alginates, or combinations thereof.

[0137] In some embodiments, a pharmaceutical composition includes: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1-1 mg / mL and a log P value of 1-2.5; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10, a bile salt, or a micelle; a matrix former; and a structure former. In some embodiments, the permeation enhancer comprises a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10. In some embodiments, a molar ratio of API to surfactant is 5:1 to 1:5 and / or the pharmaceutical composition comprises 0.5-20 wt % surfactant. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, a molar ratio of API to bile salt is 15:1 to 1:15 and / or the pharmaceutical composition comprises 1-20 wt % bile salt. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, a molar ratio of API to counterions is 6:1 to 1:6 and / or the pharmaceutical composition comprises 0.1-25 wt % counterions. In some embodiments, the pharmaceutical composition includes a pH modifier. In some embodiments, the pharmaceutical composition includes 1- 35 wt % the pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1-1 mg / mL and a log P value of 1-2.5. In some embodiments, the pharmaceutical composition includes 25-60 wt % matrix former. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or combinations thereof.  35Attorney Docket No.:  409176‐1182001WO In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition includes 20-45 wt % structure former. In some embodiments, the structure former comprises mannitol.

[0138] In some embodiments, a pharmaceutical composition includes: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class III active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 1-10 mg / mL and a log P value of less than 1; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, or a bile salt; a matrix former; and a structure former. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, a molar ratio of API to bile salt is 15:1 to 1:15 and / or the pharmaceutical composition comprises 1-20 wt % bile salt. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, a molar ratio of API to counterions is 6:1 to 1:6 and / or the pharmaceutical composition comprises 0.1-25 wt % counterions. In some embodiments, the pharmaceutical composition includes a pH modifier. In some embodiments, a pharmaceutical composition includes 25- 60 wt % matrix former. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or combinations thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition includes 20-45 wt % structure former. In some embodiments, the structure former comprises mannitol. In some embodiments, the pharmaceutical composition includes 1-35 wt % the BCS Class III API or pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, a pharmaceutical composition includes a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class III active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 10-33 mg / mL and a log P value of less than 1; a permeation enhancer comprising at least one selected from the group of counterions or a pH modifier; a matrix former; and a structure former. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, a molar ratio of API to counterions is 6:1 to 1:6 and / or the pharmaceutical composition comprises 0.1-25 wt % counterions. In some embodiments, the pharmaceutical composition includes 25-60 wt % matrix former. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or combinations thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is  36Attorney Docket No.:  409176‐1182001WO high molecular weight fish gelatin. In some embodiments, the pharmaceutical compositions include 20-45 wt % structure former. In some embodiments, the structure former comprises mannitol. In some embodiments, the pharmaceutical composition includes 1-35 wt % the pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 10-33 mg / mL and a log P value of less than 1.

[0140] In some embodiments, the pharmaceutical composition is a solid dosage form. In some embodiments, a method of treating a patient includes placing the solid dosage form in an oral cavity of a person in need of the treatment. In some embodiments, the placement in the oral cavity is placement on or under the tongue or in the buccal or pharyngeal region. In some embodiments, a method of forming a solid dosage form includes: dosing a pharmaceutical formulation into a preformed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of less than 0.1 mg / mL and a log P value greater than 2.5; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10, a bile salt, a micelle, or a fatty acid; 1-10 wt % matrix former; and 1-10 wt % of a structure former; freezing the dosed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the permeation enhancer comprises a surfactant with a hydrophilic lipophilic balance greater than 10. In some embodiments, the pharmaceutical formulation comprises 0.01-5 wt % the surfactant. In some embodiments, the surfactant has a concentration of 0.1-30× its critical micellar concentrations (CMC) in the pharmaceutical formulation. In some embodiments, the surfactant has a concentration of 0.5-3×CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to the surfactant of 5:1 to 1:5. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, the pharmaceutical formulation comprises 0.25-5 wt % bile salt. In some embodiments, the bile salt has a concentration of 0.5-5×CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to the bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the permeation enhancer comprises a fatty acid. In some embodiments, the pharmaceutical formulation comprises 0.03-0.15 wt % fatty acid. In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acid of 3:1 to 1:3. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, the pharmaceutical formulation comprises 0.025-5 wt % counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API  37Attorney Docket No.:  409176‐1182001WO to counterions of 6:1 to 1:6. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the pharmaceutical formulation comprises 0.1-5 wt % the BCS Class II API or pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments, a method of forming a solid dosage form includes: dosing a pharmaceutical formulation into a preformed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1-1 mg / mL and a log P value 1-2.5; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, a surfactant with a hydrophilic lipophilic balance (HLB) greater than 10, a bile salt, or a micelles; 1-10 wt % matrix former; and 1-10 wt % of a structure former; freezing the dosed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the permeation enhancer comprises a surfactant with a hydrophilic lipophilic balance greater than 10. In some embodiments, the pharmaceutical formulation comprises 0.01-5 wt % the surfactant. In some embodiments, the surfactant has a concentration 0.1-30× its critical micellar concentrations (CMC) of in the pharmaceutical formulation. In some embodiments, the surfactant has a concentration of 0.5-3×CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to the surfactant of 5:1 to 1:5. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, the pharmaceutical formulation comprises 0.25-5 wt % bile salt. In some embodiments, the bile salt has a concentration of 0.5-5×CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to the bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, the pharmaceutical formulation comprises 0.025-5 wt % counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:6. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the pharmaceutical formulation comprises 0.1-5 wt % BCS Class II API or pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, a method of forming a solid dosage form includes: dosing a pharmaceutical formulation into a preformed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class III active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 1-10 mg / mL and a  38Attorney Docket No.:  409176‐1182001WO log P value less than 1; a permeation enhancer comprising at least one selected from the group of counterions, a pH modifier, or a bile salt; 1-10 wt % matrix former; and 1-10 wt % of a structure former; freezing the dosed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the permeation enhancer comprises a bile salt. In some embodiments, the pharmaceutical formulation comprises 0.25-5 wt % bile salt. In some embodiments, the bile salt has a concentration of 0.5-5×CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to the bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, the pharmaceutical formulation comprises 0.025-5 wt % counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:6. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises 0.1-5 wt % BCS Class III API or pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, a method of forming a solid dosage form includes: dosing a pharmaceutical formulation into a preformed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class III active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 10-33 mg / mL and a log P value less than 1; a permeation enhancer comprising at least one selected from the group of counterions or a pH modifier, 1-10 wt % matrix former; and 1-10 wt % of a structure former; freezing the dosed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the permeation enhancer comprises counterions. In some embodiments, the pharmaceutical formulation comprises 0.025-5 wt % counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:6. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the pharmaceutical formulation comprises 0.1-5 wt % BCS Class III API or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or combinations thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the structure former comprises mannitol.

[0144] In some embodiments, a pharmaceutical composition includes: a pharmaceutically effective amount of a biopharmaceutics classification system (BCS) Class  39Attorney Docket No.:  409176‐1182001WO II active pharmaceutical ingredient (API) or pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1-1 mg / mL and a log P value of 1-2.5; a permeation inhibitor r comprising at least one selected from the group of a surfactant with a hydrophilic lipophilic balance (HLB) less than 10 or a fatty acid; a matrix former; and a structure former. In some embodiments, the permeation inhibitor comprises a fatty acid. In some embodiments, the pharmaceutical formulation comprises 0.25-0.5 wt % fatty acid. In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acid of 3:1 to 1:3. In some embodiments, the permeation inhibitor comprises the surfactant with a HLB less than 10. In some embodiments, a molar ratio of API to surfactant is 5:1 to 1:5.

[0145] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0146] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0147] The technology described herein is further illustrated by the following examples which in no way should be construed as being further limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.  40Attorney Docket No.:  409176‐1182001WO EXAMPLES

[0148] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention. EXAMPLE 1 EFFECTIVENESS OF SUBLINGUAL ‘1104 FORMULATIONS IN A MOUSE OVA ASTHMA MODEL

[0149] The present study was designed to evaluate the efficacy of ‘1104 administered sublingually compared to intravenous administration in a mouse OVA asthma model. In addition, the pharmacokinetics (pK) of ‘1104 administered sublingually was also compared to intravenous administration in separate satellite groups. MATERIALS AND METHODS

[0150] Study design: The design protocol is summarized in Table 2. Table 2 – Study Design Protocol

[0151] Animals: Female Balb / c mice (15-25 g, Charles Rivers UK Ltd) were housed for 7 days prior to commencement of the study in cages of four and were subject to a 12:12 hour light dark cycle. Mice were fed a standard mouse chow and water was available ad libitum.  41Attorney Docket No.:  409176‐1182001WO

[0152] Animal welfare: On arrival from the supplier, animals were placed into cages of four, as outlined above, and the welfare of all animals was checked on a daily basis. Mice were acclimatized for period of 7 days before start of experimental procedures. Room temperature and humidity were maintained between 17-24^C and 40-70%, respectively. Environmental enrichment was provided in all cages.

[0153] Throughout the study, the following guidelines were used to assess non- specific or unexpected adverse effects in animals undergoing regulated, relating to either the procedure or test compound dosing. ^ Body weight loss greater than 20% of the highest measured individual body weight. ^ Marked piloerection with other signs of dehydration such as skin tenting. ^ Unresponsive to activity and provocation. ^ Hunched persistently (frozen). ^ Distressed- persistent vocalization. ^ Oculo-nasal discharge persistent and copious. ^ Labored respiration. ^ Persistent tremors. ^ Persistent convulsions.

[0154] Animals showing two or more of any of the limiting clinical signs in the category equivalent to the protocol severity limit were to be removed from the study. However, during this study, no animals were removed.

[0155] Allergen exposure: Mice were actively sensitized with ovalbumin (15 μg, s.c.) and 25 μL of Imject Alum as an adjuvant on days 1 and 7. In order to elicit a local inflammatory response in the lungs, mice were repeatedly challenged on day’s 15, 16 and 17 with an aerosol of either 1% w / v ovalbumin in phosphate buffered saline (PBS) or just PBS, generated with an ultrasonic nebulizer (Aerogen) for 20 min. BALF was collected (Groups 1 to 6) 24 hours after the final challenge to OVA or PBS on day 18.

[0156] In a separate cohort of animals (Groups 7 to 12), a second series of challenges on days 27, 28 and 29 with an aerosol of 1% w / v ovalbumin or PBS were carried out. BALF was collected from these animals 24 hours after the final challenge on day 30. FORMULATION OF ‘1104 AND VEHICLE:

[0157] Intravenous formulation of ‘1104: ‘1104 was formulated in PBS supplemented with 0.1% Bovine Serum Albumin (BSA) to make the required dosing concentrations to administer 80 μg / kg in a dose volume of 5 mL / kg.

[0158] Sublingual liquid formulation of ‘1104: ‘1104 was formulated in PBS supplemented with 0.1% Bovine Serum Albumin (BSA) to make the required dosing concentrations to administer 80 μg / kg in a dose volume of 5 mL / kg.  42Attorney Docket No.:  409176‐1182001WO

[0159] 1104 and vehicle treatment: A single treatment of ‘1104 (80 μg / kg) or vehicle (10 mL / kg dose volume) was administered sublingually (10 μL) or intravenously (5 mL / kg) 15 minutes prior to the OVA or PBS challenges on days 15, 16, and 17.

[0160] Animals receiving sublingual administrations were lightly sedated with a combination of Ketamine (40 mg / kg) and Xylazine (4 mg / kg) administered subcutaneously 5 min before dosing. Following sedation, each animal was scuffed behind the neck and held in a vertical position. Using forceps the tongue was elevated so as to allow exposure to the floor of the mouth and the dorsal surface of the tongue. The dosing formulation was pipetted onto the floor of the mouth. After dosing, the animals were held vertically for another three minutes before being placed in an anteflexion position within the cage while they recovered from sedation and thus minimizing the possibility of the sublingual formulation being swallowed. Animals recovered from the sedation approximately 10 minutes after dosing.

[0161] Blood sample collection: Blood samples were taken by venipuncture (via the lateral tail vein) 24 hours after the final OVA or PBS challenges on days 17 and 29 and placed into serum tubes. Each serum sample was kept at room temperature for 45 minutes to allow coagulation, before being centrifuged (2000g, 15 min at 4^C), from which the resulting supernatant was extracted, aliquoted and stored at -80^C for analysis.

[0162] Bronchoalveolar Lavage (BAL) and Cell Counts: Immediately after blood collection, the animals were culled by an overdose with pentobarbital. The trachea was then isolated by a midline incision in the neck and separation of the muscle layers. A small incision was made into the trachea and a plastic cannula was inserted and secured in place with a suture. The airway was then lavaged by flushing out the lungs using 0.5 mL of phosphate buffered saline. This procedure was repeated until the recovered volume was 1.6 mL. The isolated BALF was then centrifuged at 1500 rpm for 10 mins at 4^C and the supernatant was aliquoted (400 μL) at -80^C for future cytokine analysis. The cell pellets were then re-suspended in 1.6 mL of phosphate buffered saline and the BAL cells were then analyzed for total and differential numbers.

[0163] Total and differential cell counts of the BAL fluid samples were measured using a XT-2000iV analyzer (Sysmex). Results were expressed as cells / mL (total and differential). Cell types differentially classified were neutrophils, eosinophils, lymphocytes or macrophages.

[0164] Lung collection: Following BALF collection, the trachea and lungs were dissected free from each animal and immediately rinsed with physiological saline before being blotted dry. One lung lobe was placed in sterile container before being snap frozen  43Attorney Docket No.:  409176‐1182001WO and stored at -80^C while a second lobe was placed in 10% formalin and stored at room temperature. Statistical Analysis

[0165] Data are shown as mean ± S.E.M. (standard error of the mean). Inter-group deviations were statistically analyzed by a one-way analysis of variance (ANOVA) followed by a Bonferroni / Dunn test. P< 0.05 is considered statistically significant. RESULTS

[0166] As shown in FIGS.1-5, exposure to OVA aerosol triggered an inflammatory infiltration in the lung 24 hours post-challenge at day 18 (Groups 2 and 5) and at day 30 (Groups 7 and 11) when compared to PBS + vehicle (Groups 1 and 4 – day 18; Groups 6 and 10 – day 30) as measured by BALF differential cell counts.

[0167] As shown in FIGS.1A-5A, ‘1104 administered both SL and IV significantly reduced OVA-induced lung infiltration of total cells, eosinophils, neutrophils, lymphocytes, and macrophages.

[0168] The effects were maintained upon OVA re-challenge (day 30), 13 days after the last dose of the ‘1104. As shown in FIGS.1B-5B, ‘1104 administered IV significantly reduced OVA-induced lung infiltration of total cells, eosinophils, neutrophils, lymphocytes, and macrophages. When administered SL, ‘1104 also reduced OVA-induced lung infiltration of total cells, eosinophils, neutrophils, lymphocytes, and macrophages, but the reductions only reached statistical significance for total cells (FIG.1B), eosinophils (FIG.2B), and neutrophils (FIG.3B). The reductions in lymphocytes (FIG.4B), and macrophages (FIG. 5B), however, did not reach statistical significance. Further studies with higher doses or different SL formulations are warranted. CONCLUSIONS

[0169] The present study support the SL administration of peptide derived from Chaperonin 60.1, such as ‘1104, to produce an anti-inflammatory activity and / or efficiently reduces the recruitment or trafficking of cells including, but not limited to, eosinophils, neutrophils, lymphocytes, and macrophages to the site of inflammation in the human or animal subject relative to a control subject who has not been administered the Chaperonin 60.1-related peptide molecule. EXAMPLE 2 MANUFACTURE OF SUBLINGUAL RAPIDLY-DISSOLVING TABLET FORMULATIONS

[0170] The present Example describes the manufacture of gelatin-based and non- gelatin-based rapidly dissolving tablet formulations for delivery of ‘1104 sublingually. The study sought to optimize the human dose formulation (8 mg) by reducing the unit size. This  44Attorney Docket No.:  409176‐1182001WO was to be achieved by assessing 2.30% w / w and 2.00% w / w IRL201104 free peptide concentrations, dosed as either a 350 mg fill into 500 mg blister pockets or a 400 mg fill into 500 mg blister pockets, respectively. The study also investigated the feasibility of incorporating the IRL201104 peptide at the higher API concentrations in both gelatin and non-gelatin based formulations. The study further assessed the use of glycine as a structural promoter in the formulation due to the increase in API concentration and evaluated the requirement to adjust the pH of the pre-mix prior to API addition.

[0171] This study was built upon previous feasibility work that focused on incorporating IRL201104 into the self-dissolving sublingual tablet form. The formulations in the present study were designed specifically to investigate the impact of smaller wet fill weights (wfw) (<1000 mg), as suggested by the outcomes of earlier solubility and feasibility studies (not shown). MATERIALS AND METHODS

[0172] Manufacture of ‘1104 SC formulations: The present study involved the manufacture and assessment of six batches, as summarized in Table 3. Five batches (Z6218 / 82 / 1-5) were manufactured to reflect varying API concentrations, wet fill weights, and matrix types (gelatin based and non-gelatin based). An additional gelatin based placebo batch (Z6218 / 82 / 6) was also manufactured for Analytical Development purposes.

[0173] Each batch was intended to be dosed at approximately the 0-hour and 48- hour solution hold (SH) time points, using different wet fill weights and administered into 500 mg blister pocket-sized trays,

[0174] In-process stability assessments, including macroscopic appearance and pH measurements, were recorded at the 0-hour, 24-hour, and 48-hour SH time points. Samples of the mix from selected batches (Z6218 / 82 / 1, Z6218 / 82 / 3, and Z6218 / 82 / 4) were also provided for in-process assay testing. Finished product testing was conducted on all batches, evaluating the physical characteristics of the units, including appearance, dispersion time, assay, and related substances.

[0175] The finished product was sacheted and stored under frozen conditions (~ - 20°C) at the end of the study. The manufacturing process for batches Z6218 / 82 / 1-6 is summarized in FIGs.6-7.

[0176] The components include: (i) IRL201104 (API); (ii) Gelatin (matrix / structure former}; (iii) Mannitol EP / USP (matrix / structure former}; (iv) Glucidex 6 (matrix / structure former}; (v) Methocel (hydroxypropyl methylcellulose; matrix / structure former}; (vi) Super Refined Polysorbate 80-LQ-(MH) (Tween 80; surfactant / solubilizing / wetting agent); (vii) Glycine (structural promoter / flavoring agent); (viii) Sucralose (sweetener); (ix) Flavor Mint  45Attorney Docket No.:  409176‐1182001WO 51.296 Powder (flavoring agent); (x) Sodium Hydroxide (NaOH solution; pH modifier); and (xi) purified water. Table 3 – Formulation Details for Batches Z6218 / 82 / 1-6

[0177] Packaging Materials and Equipment: Table 4 lists the packaging materials used in this study and Table 5 lists the equipment used in this study. Table 4 – Packaging MaterialsTable 5 – Equipment Used for Batches Z6218 / 82 / 1-6  46Attorney Docket No.:  409176‐1182001WO

[0178] Batch Details: Two stock pre-mixes (a gelatin based pre-mix Z6218 / 82 / 1S and a non-gelatin pre-mix Z6218 / 82 / 2S) were initially prepared. The formulation details of these stock pre-mixes are provided in Table 6.

[0179] Aliquots of the stock pre-mixes were then dispensed and used for the manufacture of the active and placebo batches (Z6218 / 82 / 1-6). The formulation details for batches Z6218 / 82 / 1-6 are presented in Table 7. Table 6 – Packaging Materials  47Attorney Docket No.:  409176‐1182001WO Table 7 – Packaging Materials  48Attorney Docket No.:  409176‐1182001WO

[0180] Testing: Table 8 and Table 9 detail the in-process and finished product testing performed during the study.  49Attorney Docket No.:  409176‐1182001WO Table 8 – In-Process TestingTable 9 – Finished Product Testing

[0181] The following sections document any manufacturing events / observations reported during the manufacturing process of batches Z6218 / 82 / 1-6.

[0182] Dispensing and Mixing: Due to the small batch size (80g), stock gelatin and non-gelatin pre-mixes (Z6218 / 82 / 1S-2S) were prepared to mitigate the effect of evaporative losses on the final mix size as a result of heating the pre-mixes to 60°C ±2°C. No issues were reported during the preparation of the stock pre-mixes.

[0183] Aliquots of the appropriate stock pre-mix were then dispensed for the manufacture of the six batches (Z6218 / 82 / 1-6). The pH of the pre-mixes of batches Z6218 / 82 / 1, 2, 4, and 5 was successfully adjusted to 9.00 ±0.20 prior to the addition of the API.

[0184] During the preparation of the Tween 80 solution, the required amount of Tween 80 (undiluted) was dispensed into a glass vial and subsequently added to purified water in an SSV to make the 5% w / w solution. It was noted during this process that due to  50Attorney Docket No.:  409176‐1182001WO the viscous nature of Tween 80, minor residues remained in the glass vial following addition to the SSV. This was observed despite rinsing the vial three times in order to transfer the maximum amount possible to the SSV containing the final Tween 80 solution. Therefore, it is expected that the concentration of the Tween 80 solution was slightly less than 5% w / w. This observation highlights the need to dispense the Tween 80 directly into the SSV intended to hold the final 5% w / w solution in future studies. However, this observation is anticipated to have minimum impact on the batches at this early stage of development.

[0185] Following API incorporation, the mixes of all batches were white and opaque in appearance with visible agglomerates. All batches (Z6218 / 82 / 1-5) required a high stirrer speed to generate a sufficiently strong vortex to facilitate the incorporation of the API into the pre-mixes. The poor solubility of the API in the pre-mixes is attributed to the drop in pH that occurs upon IRL201104 addition. As a result, all mixes required pH adjustment to increase the pH to 9.00 ±0.20 post-API addition. Following pH adjustment and final water addition, the API was fully in solution in all the mixes. No obvious difference was reported in the ease of API incorporation between batch Z6218 / 82 / 3 (unadjusted pre-mix pH) and the remaining batches; this suggests that from an operational standpoint, the pre-mix pH adjustment step is not required prior to API addition. However, it is to be noted that adjusting the pH only after API addition requires a greater overall amount of NaOH (refer to section 2.4) which might be detrimental to the appearance of the finished product.

[0186] Dosing: The product was dosed with either a 350 mg (batches Z6218 / 82 / 1,3,4,6) or 400 mg (batches Z6218 / 82 / 2,5) wfw into 500mg blister pockets. All mixes were dosed within the target dose weight range of ±2% using the Hibar pump. However, due to ice build-up on the freeze tunnel, the product could not be dosed at the 0- hour SH timepoint. Consequently, all batches Z6218 / 82 / 1-6 were dosed at the approximately 24-hour SH timepoint instead. This deviation from the 0-hour SH timepoint is not expected to significantly impact the analytical testing of the finished product, as assay and related substances testing will be performed on the in-process mix samples (sampled at the 0SH and 48SH timepoints). All product was subsequently dosed at the 48-hour SH timepoint with no further issues.

[0187] Freezing and Frozen Storage: No issues were recorded during freezing at the 24-hour and 48-hour SH timepoints. All product was frozen at -70°C with a freeze tunnel residence time of 3 minutes and 15 seconds. The product was reported to be frozen following a single pass through the freeze tunnel at both the 24-hour and 48-hour SH timepoints. The frozen product was stored in the RSC at ≤-15°C (freezer set up at approximately – 20°C to -25°C) until loading into the freeze dryer. This is referred to as the frozen hold time. Frozen hold can be a critical part of the process for some products, especially solution products, allowing any amorphous mannitol to crystallize giving added  51Attorney Docket No.:  409176‐1182001WO strength to the tablet. The exact product specific requirement for a frozen hold will be assessed during a later stage of development; however, as this is a solution product, a minimum 12-hour frozen hold time was applied. The actual frozen hold durations for each batch are provided in Table 10. No issues were reported during frozen storage. Table 10 – Frozen Hold Times for Batches Z6218 / 82 / 1-6

[0188] Freeze Drying: All product was freeze dried in two loads. The product was dried at -5°C for 12 hours. The actual drying times are shown in Table 11. Table 11 – Freeze Drying Times for Batches Z6218 / 82 / 1-6

[0189] Sacheting: All product was sacheted following finished product inspection. The heat sealer used a pressure of 52-54 psi, with a temperature of 160°C and a dwell time of 0.3 seconds. Then, all sacheted product was transferred to chest freezer 2. No issues were reported during sacheting. RESULTS AND DISCUSSION

[0190] pH Profile: The pH measurements for each batch and at each timepoint are summarized in Table 12.  52Attorney Docket No.:  409176‐1182001WO Table 12 – pH Data for Batches Z6218 / 82 / 1-6

[0191] The results indicate a decrease in pH occurred over the 48-hour SH period, which is expected when the mixes are adjusted to an alkaline pH. This drop in pH is likely due to carbon dioxide dissolving in the mixes over time. It is to be noted that the pH of non- gelatin based (Z6218 / 82 / 4-5) active formulations decreased to a lesser extent as compared to the non-gelatin batches from the earlier feasibility study 1. This reduced variability in pH over the 48 hour SH period may be attributed to the higher API concentrations (2.30 and 2.00% w / w), and therefore, the larger buffering effect exerted by the API on the mixes within the current study, as compared to the first feasibility study. Also, the smallest reduction in pH over the 48 hour SH period was observed for the mix of batch Z6218 / 82 / 3. However, this may be attributed to the initially higher pH of the mix at the 0-hour SH timepoint (9.26) as compared to the other batches. This high pH result at the 0-hour SH timepoint may be explained by the large quantity of sodium hydroxide solution that was required to adjust the pH of this mix post-API addition.

[0192] Macroscopic Appearance: The macroscopic appearance of the mixes from each batch was observed at the 0-hour, 24-hour, and 48-hour SH timepoints. The mix appearance was observed from aliquots in vials for each batch. The observations recorded for each batch and timepoint are summarized and illustrated in FIGS.8-10.

[0193] The results show that there were no significant changes in the macroscopic appearance of the mixes from batches Z6218 / 82 / 1-6 over the 48-hour hold period. The gelatin based mixes (Z6218 / 82 / 2-3 and Z6218 / 82 / 6) were transparent whilst the non-gelatin based mixes were translucent (Z6218 / 82 / 4-5). However, these differences are expected since the non-gelatin pre-mixes are translucent to start with. For batch Z6218 / 82 / 1, the mix became slightly translucent at the 48-hour SH timepoint; this suggests that a small  53Attorney Docket No.:  409176‐1182001WO proportion of the API may have precipitated out of the mix in this batch. Conversely, batch Z6218 / 82 / 3 which has the same API concentration remained transparent. This may be due to the addition of glycine aiding solubility or a difference in pH.

[0194] Finished Product Appearance: The finished product from all batches was inspected and observations were recorded in the batch manufacturing record. The surface of the dried units was inspected, and observations noted. The units were then carefully removed from the blister pockets, and further observations with respect to ease of removal and unit appearance were recorded. Table 13 provides a description of common appearance terms. Table 13 – Common Appearance Terms  54Attorney Docket No.:  409176‐1182001WO

[0195] Unit appearances are shown in FIG.11A-L, and observations and any noted defects are recorded in Table 14. Table 14 – Finished Product Observations for Batches Z6218 / 82 / 1-6  55Attorney Docket No.:  409176‐1182001WO

[0196] The finished product results in FIG.11A-L show that all units had a good appearance. The units were white in colour with a good deboss. Units were also easy to remove, leaving minimal to no residue in the blister pockets.

[0197] The presence of feathering and air bubbles is common at bench scale manufacturing due to manual dosing; these defects are expected to be reduced at the commercial manufacturing scale as a result of the automated dosing process. Some popping out of units was reported for batches Z6218 / 82 / 1, Z6218 / 82 / 4, Z6218 / 82 / 524 SH and Z6218 / 82 / 4-548 SH. However, further optimization of the formulation during development can reduce the risk of popping out.

[0198] Nodules were observed in units across all batches (Z6218 / 82 / 1-6) at both the 24 SH and 48 SH timepoints. Nodules are categorized as either major or minor based on their size and quantity (refer also to Appendix 1 for further details). Minor nodules were  56Attorney Docket No.:  409176‐1182001WO observed in product from all batches, whilst major nodules were identified in batches Z6218 / 82 / 2 (24 SH and 48 SH) and Z6218 / 82 / 4 (24 SH). Nodules are a cosmetic defect, with formulations containing fish gelatin being more prone to displaying this defect than bovine gelatin based formulations. The formation of nodules is associated with events within the freeze tunnel; as a result, the occurrence of nodules may not be seen to the same degree on the GMP lines. Therefore, the presence of nodules is not a cause for concern at this early stage of development. Future formulation optimizations studies can also be utilized to assess suitable concentrations of matrix formers and processing parameters to reduce the risk of nodules.

[0199] Overall, the units from all batches were of a very good quality for this stage of development.

[0200] Dispersion Time: The dispersion time is an in-process test. The units are placed bottom surface facing down in a beaker filled with purified water at 20±5°C. The length of time for the unit to fully wet is timed using a calibrated stopwatch. This process is carried out for five units in total for information during development. The dispersion time results for batches Z6218 / 82 / 1-6 are summarized in Table 15.

[0201] At the T=0 dispersion testing, there was significant variability in the dispersion times within and between the active batches for both the gelatin based (Z6218 / 82 / 1-3) and non-gelatin based (Z6218 / 82 / 4-5) formulations, as seen in Table 15. For instance, some batches (for example Z6218 / 82 / 124SH) had a prolonged dispersion time, where the surface of the unit remained intact (as shown in FIG.12) and could be removed from the water.

[0202] It is possible that a delay between removing the units from the blister pockets and conducting the dispersion time measurements may have contributed to the observed variability. Moreover, the API may be hygroscopic, which would have resulted in moisture uptake by the units and subsequent micro-collapse, thereby impacting the dispersion times. Table 15 – Dispersion Time for Batches Z6218 / 82 / 1-6     57Attorney Docket No.:  409176‐1182001WO

[0203] Furthermore, this variability and the atypical dispersion times may have been exacerbated by environmental factors, such as the relative humidity. For example, the relative humidity in the laboratory at the time of the 0-hour inspection was approximately 30%. Although this humidity level is still within the required limits for the non-GMP development laboratory, it may have resulted in some moisture absorption by the units, potentially causing partial shrinkage or collapse, and ultimately, affecting the dispersion time. However, at the 48-hour inspection, the relative humidity was approximately 22% yet the dispersion times remained highly variable. Therefore, it is unlikely that the relative humidity significantly affected the dispersion time.

[0204] Thus, at the T=0 dispersion testing, most of the batches did not meet the acceptance criteria of dispersing in ≤10 seconds.

[0205] Dispersion testing was repeated approximately 1 month post-manufacture (T=~1M) to re-evaluate the dispersion times due to the initial variation and atypical results seen at T=0 testing. This testing was also repeated following observations of slow unit dissolution from batch Z6218 / 82 / 4 during sample preparation.

[0206] During testing at T=~1M, the units wetted but did not break apart. The surface of units from batches Z6218 / 82 / 1, Z6218 / 82 / 2 (24SH and 48SH), and Z6218 / 82 / 3 (48SH) could be removed from the water without breaking apart. In contrast, units from batch Z6218 / 82 / 324SH (gelatin based formulation containing glycine) and the non-gelatin based batches (Z6218 / 82 / 4 and Z6218 / 82 / 524SH and 48SH) dispersed well during the repeat tests. Moreover, the product from batch Z6218 / 82 / 324SH showed similar dispersion behavior to the placebo (Z6218 / 82 / 6). However, this effect was only observed in the samples dosed at the 24-hour SH timepoint, and the reason for this remains unknown.

[0207] Although the non-gelatin based product showed improved dispersion times compared to the gelatin based formulations, wetted residues were still observed in these batches (Z6218 / 82 / 4 and Z6218 / 82 / 5). This may also correlate with the slow dissolution reported by the Analytical Development team during sample preparation for batch Z6218 / 82 / 4.

[0208] The variability in dispersion times across the batches may be explained by interaction effects between sodium hydroxide and the API (a peptide acetate salt) in the formulations, resulting in the formation of sodium acetate. It is also to be noted that the product contained a significant amount of sodium hydroxide, which was required to adjust all mixes to the target pH of 9.00 ±0.20. The formation of sodium acetate may have caused sub-optimal freezing drying of the units since the salt can depress the freezing point of the product.  58Attorney Docket No.:  409176‐1182001WO

[0209] Furthermore, it is also plausible that the longer dispersion times observed for most of the gelatin based batches may be attributed to interaction effects between the gelatin and API in the formulations, particularly as the API is a peptide. However, for batch Z6218 / 82 / 3, the faster dispersion times compared to the other gelatin based batches may be explained by the presence of glycine in this batch. Glycine is known to exert cryoprotective and stabilizing properties on peptides during freeze drying. Therefore, it is possible that the presence of glycine in batch Z6218 / 82 / 3 improved the micro-structure (and ultimately the dispersion times) of the finished product. Glycine may also reduce gelatin-peptide interactions.

[0210] Overall, dispersion testing was challenging to assess and subject to variability among the operators due to the subjective nature of the test.

[0211] Analytical Data: The assay data, obtained for the in-process solutions (Z6218 / 82 / 1, Z6218 / 82 / 3, and Z6218 / 82 / 4) at the 0-hour and 48-hour SH timepoints, and finished product (Z6218 / 82 / 1-5) dosed at the 24-hour and 48-hour SH timepoints, is presented in Table 16 and Table 17, respectively. Table 16 – Assay Results for In-Process Control (IPC) Samples  59Attorney Docket No.:  409176‐1182001WO Table 17 – Assay Results for Batches Z6218 / 82 / 1-5

[0212] The in-process assay values, reflected in Table 16 for batches Z6218 / 82 / 1, Z6218 / 82 / 3, and Z6218 / 82 / 4, indicate that the API was stable in both the gelatin based and non-gelatin based mixes over the 48-hour SH period. In particular, the assay recovery and stability over the 48-hour SH period for the non-gelatin based mix (Z6218 / 82 / 4) was improved compared to the first feasibility study.

[0213] The results in Table 17 show that the assay remained relatively consistent for both the gelatin based mixes (batches Z6218 / 82 / 1-3) and the non-gelatin based mixes (batches Z6218 / 82 / 4-5) over the 48-hour solution hold period. This consistency across the time points indicates that the API showed good stability during the evaluated solution hold period. The assay results for the finished product batches are well within the target range of 90.0-110.0% label claim (LC). The skewing of the assay values towards the higher end of the specification is expected to be due to some water evaporation during mixing and solution hold period due to the small batch size (80 g), which in turn would make the final mix more concentrated. It can also be attributed to dosing; the dose weights recorded during manufacture were leaning towards the upper end of the acceptable range (either 350.0 mg ± 2% or 400.0 mg ± 2%) and this would be reflected in the assay results. Furthermore, based on the consistency in assay results between the in-process samples and the finished  60Attorney Docket No.:  409176‐1182001WO product, it can be inferred that the freezing and freeze drying processes do not impact API stability.

[0214] Since finished product could not be produced at the 0-hour SH timepoint, related substances data was also obtained for the in-process samples. The mean related substances data for the in-process solutions (Z6218 / 82 / 1, Z6218 / 82 / 3, Z6218 / 82 / 4) sampled at the 0-hour and 48-hour SH timepoints, and also the finished product (Z6218 / 82 / 1-5) dosed at the 24-hour and 48-hour SH timepoints, is presented in Table 18 and Table 19, respectively. Table 18 – Related Substances Data for IPC samples (Batches Z6218 / 82 / 1,3,4)Abbreviations: IPC = In-process control, RRT = Relative Retention Time, LOQ = Limit of Quantitation (0.10%), ND = None detected (<0.05%). NR = Not Reported. Note: Data displayed are the mean reported results.  61Attorney Docket No.:  409176‐1182001WO Table 19 – Assay Results for Batches Z6218 / 82 / 1-5Abbreviations: IPC = In-process control, RRT = Relative Retention Time, LOQ = Limit of Quantitation (0.10%), ND = None detected (<0.05%). NR = Not Reported. Note: data displayed are the mean reported results.

[0215] The data presented in Table 18 and Table 19 shows that the non-gelatin based batches (Z6218 / 82 / 4-5) exhibited some impurities recorded at RRTs 0.98, 0.983, and 1.02 across both the IPC samples (Z6218 / 82 / 4) and finished product (Z6218 / 82 / 4-5). The total impurities recorded in the non-gelatin based batches (Z6218 / 82 / 4-5) ranged between  62Attorney Docket No.:  409176‐1182001WO 0.41-0.56%. However, it is to be noted that the impurities at RRTs 0.98 and 1.02 are API (raw material)-related and not process impurities since they are also present in the raw material.

[0216] The API-related impurities at RRTs 0.98 and 0.983 were absent from all gelatin-based IPC samples (Z6218 / 82 / 1 and Z6218 / 82 / 3) and finished product batches (Z6218 / 82 / 1-3). However, this is due to the gelatin peak masking the impurity peaks, leading to an underestimation of the overall total impurities in the gelatin based batches. Impurities were also reported in all gelatin-based batches at RRTs 1.02 and 1.07 (raw material related impurities), and at RRT 1.05 for batch Z6218 / 82 / 3.

[0217] Overall, there is no clear data to suggest that impurities have formed during the manufacturing process for the non-gelatin batches although no conclusive data exists to determine the same for the gelatin based batches; this is due to the gelatin peak eluting at the same retention time as some of the impurities. CONCLUSIONS

[0218] Five active batches (three gelatin based and two non-gelatin based) and one gelatin-based placebo batch, were successfully manufactured for the purpose of further evaluating the feasibility of formulating ’1104 into rapidly dissolving tablet formulations for sublingually delivery of 8 mg dose strength using 350 mg and 400 mg wet fill weights.

[0219] The API incorporated well into the gelatin and non-gelatin pre-mixes at the higher drug substance concentrations of 2.00% and 2.30% w / w (‘1104 free peptide concentrations). The API went into solution for all active batches upon adjustment of mixes to pH 9.00 ±0.20 and final water addition. Macroscopic appearance remained consistent over 48-hour SH period. The exception was for batch Z6218 / 82 / 1, which was very slightly translucent at 48-hour SH timepoint.

[0220] A drop in pH was reported over 48-hour SH period. However, this is frequently observed when the mixes are adjusted to alkaline pH.

[0221] From a processing standpoint, there was no requirement to pH adjust the pre- mix prior to API addition. The ease of API incorporation into the pre-mixes was comparable between the batch with pH adjustment prior to API addition (Z6218 / 82 / 3) and the other batches which did not have this initial adjustment step. However, the batches which did include both pH adjustment steps appeared to require less sodium hydroxide solution overall to adjust the batches to the target pH. It is suspected that the API may be interacting with the sodium hydroxide to form a sodium acetate salt, which may explain the sub-optimal dispersion times of the finished product. Therefore, both pH adjustment steps will be included in the informal stability manufacture in order to reduce the total amount of sodium hydroxide required in the formulations. The target pH for the informal stability batches will  63Attorney Docket No.:  409176‐1182001WO also be reduced from 9.00 to 8.70 to further reduce the overall amount of sodium hydroxide required.

[0222] The appearance of the finished product was very good. Some typical bench scale defects will be reduced as the process becomes more automated throughout development (e.g., feathering, air bubbles). Popping out can be optimized at the next stage of development.

[0223] There was no observable difference in finished product quality between the glycine-containing batch (Z6218 / 82 / 3) and the corresponding non-glycine containing batch (Z6218 / 82 / 1). This suggests the warmer freeze tunnel temperature (-70°C) or the reduction of the unit size may have offset any potential cracking.

[0224] Dispersion times were highly variable within and between batches. The units wetted but did not break apart. The dispersion testing was challenging to assess and exact dispersion times were subject to variability among the operators. It is possible that the variability was due to the formation of sodium acetate, resulting in a depression of the freezing point and sub-optimal freeze drying of the product. Despite the challenges in assessing the dispersion times, the non-gelatin based batches (24SH and 48SH) and the glycine-containing gelatin batch (dosed 24SH only) clearly showed faster dispersion times compared to the non-glycine-containing gelatin based batches during the repeat dispersion testing. It is possible that the API (a peptide salt) may be interacting with gelatin, and glycine may reduce these gelatin-peptide interactions. Glycine is also known to have cryoprotective and stabilizing properties on peptides during freeze drying, which may also have contributed to the improved dispersion times for this batch (Z6218 / 82 / 324SH). However, the cause of the long dispersion times in the equivalent formulation dosed at the 48-hour SH timepoint remains unclear.

[0225] The in-process and finished product assay results indicated that the API remained stable over the 48-hour SH period, with no impact observed during downstream processing (i.e., freezing and freeze drying). The assay results were also within the target acceptance criteria for all batches. The skewness of the assay results above 100% LC is due to water evaporation during the process related to the small batch size and the amount of mix dosed into the blister pockets (dose weights ±2% of target). Overall, the in-process mixes and finished product retained API potency effectively. The related substances results showed that both gelatin and non-gelatin based batches exhibited some impurities. However, it is to be noted that the impurities at RRTs 0.98, 1.02 and 1.07 are API-related since they are also present in the raw material. Impurities below RRT 1.02 were absent in the gelatin based batches due to the gelatin peak masking them, making it difficult to assess the impurity levels. While no evidence suggests impurities formed during the manufacture  64Attorney Docket No.:  409176‐1182001WO for the non-gelatin batches, the impact on the gelatin based batches remains unclear, and further monitoring of related substances is planned for subsequent studies. EXAMPLE 3 ADDITIONAL FORMULATIONS OF SUBLINGUAL ‘1104 RAPIDLY-DISSOLVING TABLETS

[0226] The present study assessed three new potential fast dissolving sublingual ‘1104 formulations, two gelatin-based formulations (with and without glycine) and a non- gelatin-based formulation, compared to intravenous administration in a mouse model of allergic inflammation. MATERIALS AND METHODS

[0227] ‘1104 Stability Manufacture: The formulation details for three rapidly dissolving tablet formulations (two gelatin-based and one non-gelatin-based) are summarized in Table 20. The components include: (i) IRL201104 (API); (ii) Gelatin (matrix / structure former}; (iii) Mannitol EP / USP (matrix / structure former}; (iv) Glucidex 6 (matrix / structure former}; (v) Methocel (hydroxypropyl methylcellulose; matrix / structure former}; (vi) Super Refined Polysorbate 80-LQ-(MH) (Tween 80; solubilizing / wetting agent); (vii) Glycine (structural promoter); (viii) Sucralose (sweetener); (ix) Flavor Mint 51.296 Powder (flavoring agent); (x) Sodium Hydroxide (NaOH solution; pH modifier); and (xi) purified water. Table 20 – Formulation Details (%)

[0228] Pre-Mix Preparation: Gelatin and non-gelatin stock pre-mixes were prepared by adding gelatin / maltodextrin, methocel, and mannitol to purified water and heating to 60°C ±2°C. Pre-mixes were cooled to 23°C ±2°C. 5% w / w Tween 80, sucralose  65Attorney Docket No.:  409176‐1182001WO and mint were added. Three pre-mix aliquots were dispensed. Glycine was added to batch 2. Pre-mixes were then cooled to 10°C ±2°C and pre-mixes were pH adjusted to 8.70 ± 0.20 prior to API addition. Adjustments to the pH are summarized in Table 21. Table 21 – pH Adjustments

[0229] Mixing: The API, ‘1104, was then added in small increments to each pre-mix using a spatula whilst maintaining the pre-mix stirring. The mixes were viscous, white and opaque in appearance with agglomerates visible. A high vortex speed was required to incorporate the API.

[0230] Following API addition, the batches were pH adjusted with 10% w / w NaOH(aq). Final water was added to all batches to achieve 100% batch size. Adjustments to the pH are summarized in Table 22. Table 22 – pH Adjustments

[0231] The API was observed to be fully in solution following pH adjustment (post- API addition) and final water addition, for all batches (i.e., at the 0-hour SH timepoint).

[0232] Macroscopic Appearance: The macroscopic appearance of the mixes from each batch was observed at the 0-hour SH timepoint. The mix appearance was observed from aliquots in vials for each batch.

[0233] As shown in FIG.13, the macroscopic appearance of the mixes were colorless. Gelatin mixes (batches 1-2) were transparent. Non-gelatin mix (batch 3) was translucent. The API was in solution for all batches.

[0234] Dosing: All product was dosed at 0-hour SH. Mixes were dosed at 10°C ±2 °C using Hibar pump with a 348 mg wet fill weight in 500 mg blister pockets.

[0235] Freezing: The freezing parameters were -70°C for 3 minutes and 15 seconds. All product frozen upon exit from freeze tunnel (single pass).  66Attorney Docket No.:  409176‐1182001WO

[0236] Frozen Hold: A minimum 12-hour frozen hold was applied to all products. Products were held in the RSC at ≤-15°C during this time.

[0237] Freeze Drying: All product was dried at -8°C for 18 hours.

[0238] Finished Product Observations: Finished products are shown in FIG.14A- C. Gelatin-based units (FIG.14A-B) and non-gelatin-based units (FIG.14C) were white with matte top surface and shiny base. Units were easy to remove with no residue remaining and good deboss. Non-gelatin-based units had some minor nodules: 4 / 302 (1.3%) and some major nodules: 3 / 302 (1.0%).

[0239] Dispersion Times: Dispersion times were measured as described in Example 2 and are presented in Table 23. Dispersion time endpoint difficult to assess, particularly for batches 1 and 2. Table 23 – Dispersion Times* Units start to disperse and be wetted but center at the surface of the units remained dry. Test stopped at 60 seconds. ** Similar to batch 1, except that the units became fully wetted.

[0240] Dispersion time results did not meet specification of ≤10 seconds for batch 1. Some improvement observed with glycine-containing batch; however, dispersions times were sub-optimal and end point of dispersion test difficult to assess. These results were observed despite reducing the target pH of the mixes (although this did not lower that total amount of pure NaOH required in the formulations) and applying a safer freeze-drying cycle. Gelatin-peptide interactions may be responsible for slow dispersion times.

[0241] In summary, the API incorporated into the pre-mixes at the 2.69% w / w concentration (acetate salt). The mixes formed solutions following pH adjustment to 8.70 ±0.20 and final water addition and remained in solution, as confirmed by macroscopic appearance testing performed at the same time. The finished product appearance was very good across all three batches.  67Attorney Docket No.:  409176‐1182001WO EXAMPLE 4 EFFECTIVENESS OF SUBLINGUAL ‘1104 RAPIDLY-DISSOLVING TABLET FORMULATIONS IN A MOUSE MODEL OF ALLERGIC INFLAMMATION

[0242] The present study was designed to evaluate the efficacy of two fast dissolving sublingual ‘1104 formulations, a gelatin-based formulation and a non-gelatin-based formulation, compared to intravenous administration in a mouse model of allergic inflammation. MATERIALS AND METHODS

[0243] ‘1104 Rapidly-Dissolving Tablet Formulations for Mouse Model: The formulations for the mouse model were produced essentially as described in Example 2. The formulation details for two rapidly dissolving tablet formulations (gelatin-based and one non-gelatin-based) are summarized in Table 24. Table 24 – Formulation Details (%)

[0244] Study design for the mouse model of allergic inflammation: The design protocol is diagrammatically represented in FIG.15 and summarized in Table 25. Table 25 – Study Design Protocol  68Attorney Docket No.:  409176‐1182001WO

[0245] Animals: Female Balb / c mice (15-25 g, Charles Rivers UK Ltd) were housed for 7 days prior to commencement of the study in cages of four and were subject to a 12:12 hour light dark cycle. Mice were fed a standard mouse chow and water was available ad libitum.

[0246] Animal welfare: On arrival from the supplier, animals were placed into cages of four, as outlined above, and the welfare of all animals was checked on a daily basis. Mice were acclimatized for period of 7 days before start of experimental procedures. Room temperature and humidity were maintained between 17-24^C and 40-70%, respectively. Environmental enrichment was provided in all cages.

[0247] Throughout the study, the following guidelines were used to assess non- specific or unexpected adverse effects in animals undergoing regulated, relating to either the procedure or test compound dosing: ^ Body weight loss greater than 20% of the highest measured individual body weight. ^ Marked piloerection with other signs of dehydration such as skin tenting. ^ Unresponsive to activity and provocation. ^ Hunched persistently (frozen). ^ Distressed- persistent vocalization. ^ Oculo-nasal discharge persistent and copious. ^ Labored respiration. ^ Persistent tremors. ^ Persistent convulsions.

[0248] Animals showing two or more of any of the limiting clinical signs in the category equivalent to the protocol severity limit were to be removed from the study. However, during this study, no animals were removed.  69Attorney Docket No.:  409176‐1182001WO

[0249] Allergen exposure: Mice were actively sensitized with ovalbumin (15 μg, s.c.) and 25 μL of Imject Alum as an adjuvant on days 1 and 7. In order to elicit a local inflammatory response in the lungs, mice were repeatedly challenged on day’s 15, 16 and 17 with an aerosol of either 1% w / v ovalbumin in phosphate buffered saline (PBS) or just PBS, generated with an ultrasonic nebulizer (Aerogen) for 20 min. BALF was collected (Groups 1 to 6) 24 hours after the final challenge to OVA or PBS on day 18.

[0250] In a separate cohort of animals (Groups 7 to 12), a second series of challenges on days 27, 28 and 29 with an aerosol of 1% w / v ovalbumin or PBS were carried out. BALF was collected from these animals 24 hours after the final challenge on day 30.

[0251] 1104 and vehicle treatment: A single treatment of ‘1104 (80 μg / kg) or vehicle (10 mL / kg dose volume) was administered sublingually (2 μg) or intravenously (5 mL / kg) 15 minutes prior to the OVA or PBS challenges on days 15, 16, and 17.

[0252] Animals receiving sublingual administrations were lightly sedated with a combination of Ketamine (40 mg / kg) and Xylazine (4 mg / kg) administered subcutaneously 5 min before dosing. Following sedation, each animal was scuffed behind the neck and held in a vertical position. Using forceps the tongue was elevated so as to allow exposure to the floor of the mouth and the dorsal surface of the tongue. The rapidly dissolving tablet was placed under the tongue onto the floor of the mouth. After dosing, the animals were held vertically for another three minutes before being placed in an anteflexion position within the cage while they recovered from sedation and thus minimizing the possibility of the sublingual formulation being swallowed. Animals recovered from the sedation approximately 10 minutes after dosing.

[0253] Blood sample collection: Blood samples were taken by venipuncture (via the lateral tail vein) 24 hours after the final OVA or PBS challenges on days 17 and 29 and placed into serum tubes. Each serum sample was kept at room temperature for 45 minutes to allow coagulation, before being centrifuged (2000g, 15 min at 4^C), from which the resulting supernatant was extracted, aliquoted and stored at -80^C for analysis. pK Plasma Collection (pK Satellite Groups)

[0254] Blood samples were collected by venipuncture, via the lateral tail vein, 2, 15, 60 min and 24 hours after dosing on day 21 (n=3 per administration route) and 2, 15, 60 min and 24 hours after dosing on day 34 (n=3 per administration route) of IRL201104 (group 7 and group 8). Each blood sample was placed into polypropylene tubes containing anticoagulant (heparin) before being mixed gently and centrifuged (2000g, 15 min at 4^C) from which the resulting plasma was extracted, aliquoted and stored at -80^C for bioanalysis.  70Attorney Docket No.:  409176‐1182001WO

[0255] Bronchoalveolar Lavage (BAL) and Cell Counts: Immediately after blood collection, the animals were culled by an overdose with pentobarbital. The trachea was then isolated by a midline incision in the neck and separation of the muscle layers. A small incision was made into the trachea and a plastic cannula was inserted and secured in place with a suture. The airway was then lavaged by flushing out the lungs using 0.5 mL of phosphate buffered saline. This procedure was repeated until the recovered volume was 1.6 mL. The isolated BALF was then centrifuged at 1500 rpm for 10 mins at 4^C and the supernatant was aliquoted (400 μL) at -80^C for future cytokine analysis. The cell pellets were then re-suspended in 1.6 mL of phosphate buffered saline and the BAL cells were then analyzed for total and differential numbers.

[0256] Total and differential cell counts of the BAL fluid samples were measured using a XT-2000iV analyzer (Sysmex). Results were expressed as cells / mL (total and differential). Cell types differentially classified were neutrophils, eosinophils, lymphocytes or macrophages.

[0257] Lung tissue collection: Following BALF collection, the trachea and lungs were dissected free from each animal and immediately rinsed with physiological saline before being blotted dry. One lung lobe was placed in sterile container before being snap frozen and stored at -80^C while a second lobe was placed in 10% formalin and stored at room temperature.

[0258] HDM specific IgE ELISA assay: Serum supernatant was evaluated for HDM specific IgE concentrations using ELISA kit (Condrex Inc.) as per the manufacturer’s instructions. Optical density was measured at 450 nM using a microplate reader (SpectraMax 340PC). Concentrations of IgE were determined using SoftMax Pro v.6.4 (Molecular Devices). Data were reported as HDM specific IgE (pg / mL), mean ± S.E.M. (standard error of the mean).

[0259] Cytokine Analysis: Cytokine levels (see below for details of cytokines to be evaluated) of BALF supernatant (all groups) were measured using magnetic multiplex assays as per the manufacturer’s instructions. Levels were measured using a Magpix system (Luminex Corp.).

[0260] Cytokine levels of 13 mouse cytokine / chemokine using a magnetic multiplex panel (Biotechne): IL-4, IL-5, IL-10, IL-12(p70), IL-13, Eotaxin-1, IL-17, G-CSF, GM-CSF, KC, RANTES, Periostin, and MCP-1.

[0261] Data Analysis: Inter-group deviations were statistically analyzed by a one- way analysis of variance (ANOVA). In the case of significant difference in the mean values among the different levels of treatment, comparisons versus the vehicle group will be carried out using the Dunnett’s test. In case the equal variance test fails, a Kruskal-Wallis one-way  71Attorney Docket No.:  409176‐1182001WO analysis of variance on ranks followed by a Dunn’s test will be proposed. p< 0.05 will be considered statistically significant. RESULTS

[0262] As shown in FIG.16, exposure to OVA aerosol triggered an inflammatory infiltration in the lung 24 hours post-challenge at day 18 (FIG.16, left panel) and at day 30 (FIG.16, right panel) in the OVA / vehicle group (black bars) when compared to the Saline / vehicle group (white bars) as measured by BALF differential cell counts. ‘1104 administered both SL (SL1 and SL2) and IV (OVA / IRL20110480 mg / kg, blue bars) significantly reduced OVA-induced lung infiltration of total cells at day 18 (FIG.17, left panel) compared to the OVA / vehicle group (black bars). The effects were maintained upon OVA re-challenge at day 30, 13 days after the last dose of the ‘1104 (FIG.16, right panel).

[0263] As shown in FIGS.17-20, exposure to OVA aerosol triggered an inflammatory infiltration of eosinophils (FIG.17), neutrophils (FIG.18), lymphocytes (FIG.19), and macrophages (FIG.20) in the lung 24 hours post-challenge at day 18 (left panels) and at day 30 (right panels) in the OVA / vehicle group (black bars) when compared to the Saline / vehicle group (white bars) as measured by BALF differential cell counts. ‘1104 administered both SL (SL1 and SL2) and IV (black bars) (OVA / IRL20110480 mg / kg, blue bars) significantly reduced OVA-induced lung infiltration of eosinophils (FIG.17), neutrophils (FIG.18), lymphocytes (FIG.19), and macrophages (FIG.20) in the lung 24 hours post- challenge at day 18 (left panels) when compared to the OVA / vehicle group (black bars). The effects were maintained upon OVA re-challenge at day 30, 13 days after the last dose of the ‘1104 (FIGS.17-20, right panels).

[0264] As shown in FIG.21, exposure to OVA aerosol triggered a significant increase in serum OVA specific IgE levels 24 hours post-challenge at day 18 (FIG.21, left panel) and at day 30 (FIG.21, right panel) in the OVA / vehicle group (black bars) when compared to the Saline / vehicle group (white bars). ‘1104 administered both SL (SL1 and SL2) and IV (OVA / IRL20110480 mg / kg, blue bars) significantly reduced OVA-induced lung infiltration of total cells (FIG.21, left panel) when compared to the OVA / vehicle group (black bars). The effects were maintained upon OVA re-challenge at day 30, 13 days after the last dose of the ‘1104 (FIG.21, right panel).

[0265] As shown in FIGS.22-25, exposure to OVA aerosol triggered a significant increase in BAL levels of IL-4 (FIG.22), IL-5 (FIG.23), IL-13 (FIG.24), IL-10 (FIG.26), IL-12(p70) (FIG.27), IL-17 (FIG.28), Eotaxin-1 (FIG.29), GM-CSF (FIG.30), MCP-1 (FIG.32), Periostin (FIG.33), and RANTES (FIG.34) 24 hours post-challenge at day 18 (left panels) and at day 30 (right panels) in the OVA / vehicle group (black bars) when compared  72Attorney Docket No.:  409176‐1182001WO to the Saline / vehicle group (white bars). Although the levels of KC (FIG.25) and G-CSF (FIG.31) were also increased, this increase did not reach statistical significance.

[0266] 1104 administered both SL (SL1 and SL2) and IV (OVA / IRL201104 80 mg / kg, blue bars) significantly reduced BAL levels of IL-4 (FIG.22), IL-5 (FIG.23), IL-13 (FIG.24), IL-10 (FIG.26), IL-12(p70) (FIG.27), IL-17 (FIG.28), Eotaxin-1 (FIG.29), GM-CSF (FIG.30), MCP-1 (FIG.32), and Periostin (FIG.33) 24 hours post-challenge at day 18 (FIGS.24-34, left panels) when compared to the OVA / vehicle group (black bars). The effects were maintained upon OVA re-challenge at day 30, 13 days after the last dose of the ‘1104 (FIGS.22-34, right panels). Again, the levels of KC (FIG.25) and G-CSF (FIG.31) were reduced, this reduction did not reach statistical significance. Although the levels of RANTES were significantly reduced at day 18 (FIG.34, left panel), this reduction did not reach statistical significance at day 30 (FIG.34, right panel).

[0267] In summary, the present study indicates that ‘1104 significantly reduced inflammatory infiltration through both the intravenous and sublingual routes. All three formulations of ‘1104 showed significant reduction of total cells, eosinophils, neutrophils, macrophages and lymphocytes. Furthermore, at day 30, 13 days after the last dose of the ‘1104 was given, ‘1104 still showed a significant effect on all inflammatory cell populations through both routes of administration.

[0268] Additionally, at day 18, ‘1104 significantly suppressed pro-inflammatory cytokines / chemokines such us IL-4, IL-5, IL-13 and Eotaxin, as well as Periostin a known marker of T2 inflammation, and OVA specific IgE through both routes of administration. This effect was maintained at day 30, 13 days after the last dose of the compound.

[0269] The bioanalytical data from the plasma samples taken on Day 15 and Day 17 for the SL and IV administrations are summarized in Table 26. Table 26 – Pharmacokinetic Data  73Attorney Docket No.:  409176‐1182001WO

[0270] Tmax (0.03 h) was identical for IV and SL ‘1104 dosing on both days, indicating almost instantaneous systemic exposure consistent with a rapid-distribution small peptide. The maximum plasma concentration (Cmax) values were slightly higher after IV dosing (5,387 ng / mL on Day 15 and 7,663 ng / mL on Day 17) relative to SL dosing (4,059 ng / mL and 5,114 ng / mL, respectively), reflecting the absence of an absorption barrier with IV administration. AUC last followed the same trend, with IV exposures of 1,574 and 1,871 hr*ng / mL versus 1,113 and 1,788 hr*ng / mL for SL on Days 15 and 17, respectively. The day-to-day consistency supports pK reproducibility. Initial concentrations (C₀) mirrored Cmax trends, again slightly higher for IV (6,488 and 8,876 ng / mL) than SL (5,025 and 5,878 ng / mL) administration. Elimination half-life (t½) could not be reliably estimated (“nr”) due to the steep early decline and short sampling window.

[0271] A graphic representation of the pK data for the SL and IV administrations of ‘1104 is shown in FIG.35. The semi-log plot combines Day 15 and Day 17 data for each route. Both IV (green) and SL (red) profiles show a sharp mono-exponential decline from peak levels at time zero to ~0.1 µg / mL within the first hour. A horizontal reference line at 1,100 ng / mL (1.1^µg / mL) highlights the rapid drop below this threshold by approximately 0.25^hr. Throughout the 4-hour sampling window, the SL curve parallels, but remains consistently ~30^% lower than the IV curve. The average SL plasma concentration across the three measured points is ~70% of the IV concentration, demonstrating substantial systemic exposure via the sublingual route.

[0272] Collectively, the data demonstrate that sublingual administration achieves rapid systemic delivery comparable to IV injection with a relative bioavailability of ~70%. The near-identical Tmax values indicate negligible absorption lag, while the proportional reductions in Cmax and AUC suggest first-pass losses are minimal and chiefly attributable to incomplete transmucosal absorption. These findings support the sublingual route as a viable, patient-friendly alternative to IV dosing.  74Attorney Docket No.:  409176‐1182001WO CONCLUSIONS

[0273] As seen with other routes of administration, ‘1104 showed a similar wide spectrum long-lasting immunomodulatory profile when administered through sublingually through a liquid formulation or a rapidly dissolving tablet. The studies described in the present disclosure demonstrate the potential of the sublingual route to be used in the clinical setting for the treatment of relapsing-remitting conditions, such as asthma and other allergic and inflammatory diseases. REFERENCES:  1Ranford, J.C., et al. (2000). “Chaperonins are cell signaling polypeptides:--the unfolding biology of molecular chaperones.” Exp. Rev. Mol. Med., 15;2(8):1-17.2International Patent Application, Publication Number WO 2002 / 040037A2. “Biological Materials and Uses Thereof.” Published 23 May 2002.3United States Patent No.9,085,632. “Biological Materials and Uses Thereof.” Issued July 21, 2015.4United States Patent No.11,479,585. “Method for the Treatment of a Relapsing-Remitting Condition.” Issued October 25, 2022.5International Patent Application, Publication Number WO 2023 / 223015A1. “Methods and Compositions for Preventing or Treating Food Allergies.” Published 23 November 2023.6International Patent Application PCT / IB2024 / 25253. “Methods and Compositions for Preventing or Treating Eosinophilic Esophagitis.” Filed 18 April 2024.7Wu, J., et al. (2024). “Systemic delivery of proteins using novel peptides via the sublingual route.” J. of Controlled Release, 368: 290-302.8Juniper, E.F., et al. (1999). “Development and validation of a questionnaire to measure asthma control.” Eur. Respir. J.14(4): 902-907.9Isselbacher, et al. (1996). HARRISON’S PRINCIPLES OF INTERNAL MEDICINE, 13 ed., 1814-1882.10THE MERCK MANUAL OF DIAGNOSIS AND THERAPY, (2011).19thEdition, published by Merck Sharp & Dohme Corp., (ISBN 978-0-911910-19-3).11THE ENCYCLOPEDIA OF MOLECULAR CELL BIOLOGY AND MOLECULAR MEDICINE, Robert S. Porter et al. (eds.), published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908).12MOLECULAR BIOLOGY AND BIOTECHNOLOGY: A COMPREHENSIVE DESK REFERENCE, (1995). Robert A. Meyers (ed.), published by VCH Publishers, Inc. (ISBN 1-56081-569-8).13IMMUNOLOGY, (2006). Werner Luttmann, published by Elsevier.14JANEWAY'S IMMUNOBIOLOGY, (2014). Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, (ISBN 0815345305, 9780815345305).15LEWIN'S GENES XI, (2014). published by Jones & Bartlett Publishers (ISBN-1449659055).16Michael Richard Green and Joseph Sambrook, (2012). MOLECULAR CLONING: A LABORATORY MANUAL, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (ISBN 1936113414).17Davis et al., (2012). BASIC METHODS IN MOLECULAR BIOLOGY, Elsevier Science Publishing, Inc., New York, USA (ISBN 044460149X).18LABORATORY METHODS IN ENZYMOLOGY: DNA, (2013). Jon Lorsch (ed.) Elsevier (ISBN 0124199542).19CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (CPMB), (2014). Frederick M. Ausubel (ed.), John Wiley and Sons (ISBN 047150338X, 9780471503385).  75Attorney Docket No.:  409176‐1182001WO  20CURRENT PROTOCOLS IN PROTEIN SCIENCE (CPPS), (2005). John E. Coligan (ed.), John Wiley and Sons, Inc.21CURRENT PROTOCOLS IN IMMUNOLOGY (CPI) (2003). John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc. (ISBN 0471142735, 9780471142737).22United States Patent Published Patent Application No.20040132163 entitled: “Biological materials and uses thereof.” Published: July 8, 2004.23United States Patent No.11,098,090 entitled: “Mycobacteria tuberculosis chaperonin 60.1 peptides and uses thereof.” Issued: Aug.24, 2021.24United States Patent No.9,320,791 entitled: “Peptides from the polypeptide chaperonin 60.1, and their use in medicine for the treatment of inflammatory conditions are described.” Issued: Apr.26, 2016.25United States Patent No.9,085,632 entitled: “Biological materials and uses thereof.” Issued: Jul. 21, 2015.26Wu, J., et al. (2024). “Systemic delivery of proteins using novel peptides via the sublingual route.” J. of Controlled Release, 368: 290-302.  76PATENT  Attorney Docket No.:  409176‐1182001WO

[0274] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0275] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the present aspects and embodiments. The present aspects and embodiments are not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect and other functionally equivalent embodiments are within the scope of the disclosure. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects described herein are not necessarily encompassed by each embodiment. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims.  77

Claims

Attorney Docket No.:  409176‐1182001WO CLAIMS WHAT IS CLAIMED IS:

1. A dissolvable tablet pharmaceutical formulation for sublingual administration of a peptide having SEQ ID NO: 1, wherein the dissolvable tablet pharmaceutical formulation comprises: (a) a peptide having SEQ ID NO: 1; (b) at least one matrix-forming agent; (c) at least one surfactant; (d) at least one sweetener, flavor enhancer or flavoring agent; (f) at least one pH modifier; and (g) at least one solvent.

2. The dissolvable tablet pharmaceutical formulation of claim 1, wherein the sublingual administration achieves rapid systemic delivery comparable to IV administration with a relative bioavailability of at least 50%.

3. The dissolvable tablet pharmaceutical formulation of any one of claims 1-2, wherein the at least one matrix-forming agent is selected from the group consisting of: gelatin, mannitol, glucidex, methocel, dextrose, lactose, galactose, and cyclodextrin, or combinations thereof.

4. The dissolvable tablet pharmaceutical formulation of any one of claims 1-3, wherein the at least one surfactant is a non-ionic surfactant or an anionic surfactant.

5. The dissolvable tablet pharmaceutical formulation of claim 4, wherein the non-ionic surfactant is selected from the group consisting of: Tween 80, poloxamer 188, and a polyoxyethylene-polyoxypropylene copolymer.

6. The dissolvable tablet pharmaceutical formulation of claim 4, wherein the anionic surfactant is sodium lauryl sulfate or docusate sodium.

7. The dissolvable tablet pharmaceutical formulation of any one of claims 1-6, wherein the at least one sweetener is selected from the group consisting of: sucralose, aspartame, acesulfame K and thaumatin, or combinations thereof.

8. The dissolvable tablet pharmaceutical formulation of any one of claims 1-7, wherein the at least one flavor enhancer or flavoring agent is selected from the group consisting of: glycine, mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors, or combinations thereof.

9. The dissolvable tablet pharmaceutical formulation of any one of claims 1-8, wherein the at least one pH modifier is selected from the group consisting of: citric acid, tartaric acid,  78Attorney Docket No.:  409176‐1182001WO phosphoric acid, hydrochloric acid, maleic acid, and sodium hydroxide, or combinations thereof.

10. The dissolvable tablet pharmaceutical formulation of any one of claims 1-9, wherein the at least one solvent is selected from the group consisting of: methanol, ethanol, butanol, isopropanol, and water, or combinations thereof.

11. A dissolvable tablet pharmaceutical formulation for sublingual administration of a peptide having SEQ ID NO: 1, wherein the dissolvable tablet pharmaceutical formulation comprises: (a) a peptide having SEQ ID NO: 1; (b) at least one matrix-forming agent; (c) at least one surfactant; (d) at least one sweetener, flavor enhancer or flavoring agent; (f) at least one pH modifier; and (g) at least one solvent.

12. A dissolvable tablet pharmaceutical formulation for sublingual administration of a peptide having SEQ ID NO: 1, wherein the dissolvable tablet pharmaceutical formulation comprises: (a) a peptide having SEQ ID NO: 1; (b) gelatin; (c) mannitol; (d) Tween 80; (f) sucralose; (g) mint; (h) sodium hydroxide; and (i) water.

13. The dissolvable tablet pharmaceutical formulation of claim 12, further comprising glycine.

14. A dissolvable tablet pharmaceutical formulation for sublingual administration of a peptide having SEQ ID NO: 1, wherein the dissolvable tablet pharmaceutical formulation comprises: (a) a peptide having SEQ ID NO: 1; (b) mannitol; (c) Glucidex 6; (d) Methocel E15; (e) Tween 80; (f) sucralose; (g) mint; (h) sodium hydroxide; and (i) water.

15. A liquid pharmaceutical formulation for sublingual administration of a peptide having SEQ ID NO: 1, wherein the liquid pharmaceutical formulation comprises: (a) a peptide having SEQ ID NO: 1; (b) bovine serum albumin (BSA); (c) phosphate-buffered saline (PBS).

16. The pharmaceutical formulation for sublingual administration of any one of claims 1-15, wherein sublingual administration reduces recruitment of white blood cells to a site of inflammation.

17. The pharmaceutical formulation for sublingual administration of claim 16, wherein the white blood cells are selected from the group consisting of: eosinophils, neutrophils, lymphocytes, and macrophages.  79