Methods of inducing tolerance and reducing adverse reactions to one or more food allergens

Abstract

Provided are compositions comprising one or more allergens as well as methods of using the same to increase tolerance and / or reduce adverse reactions to one or more allergens. In some embodiments, provided are compositions comprising one or more peanut allergens and methods of using the same to increase tolerance to and / or reduce adverse reactions to one or more peanut allergens.

Description

Attorney Docket No.: 152551.8001.WO00 METHODS OF INDUCING TOLERANCE AND REDUCING ADVERSE REACTIONS TO ONE OR MORE FOOD ALLERGENS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 589,254, filed October 10, 2023, the contents of which are incorporated herein by reference in its entirety. BACKGROUND

[0002] Food allergy (FA) is a growing, worldwide health issue, which carries a heavy socioeconomic burden on all levels. The Center for Disease Control and Prevention estimates the prevalence of FA in children less than 18 years of age in the United States to be approximately 4-8%, with an estimated 18% increase from 1997-2007. These concerns are also relevant for adults, with an estimated 10.8% prevalence of FA.

[0003] Peanut allergy (PA) is one of the most common, and potentially fatal, food allergies, resulting in approximately 200 deaths per year in the US. In 1997, approximately 0.4% of the general US population reported having PA with severe and / or multiple reactions. A follow-up study 11 years later found the rate of reported PA in children alone had increased to 1.4%, and in 2017, the challenge-confirmed prevalence of PA in early childhood had risen to 1.9%.

[0004] Individuals with PA may experience symptoms ranging from oral itching and skin rash to severe gastrointestinal reactions and life-threatening anaphylaxis, leading to a decreased quality of life and other chronic health problems such as social withdrawal, poor sleep, and anxiety. Avoidance remains the primary mode of therapy for individuals with severe PA, although restrictions in the diet are also very difficult to follow, and accidental exposures with potentially life-threatening outcomes frequently occur, even after the appropriate use of auto-injectable epinephrine.

[0005] Immunotherapy (IT), a disease-modifying therapy, has been used in clinical practice for over 100 years for the treatment of respiratory allergies. IT involves the -1- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 consistent, repeated contact of an individual’s immune system with extracts containing the allergens that person is sensitive to. Despite recent advancements, current IT treatments present insufficient success rates and, in some instances, are accompanied by adverse side effects. Accordingly, novel therapies which promote immune tolerance while also reducing risk of adverse events are needed. SUMMARY

[0006] The present technology comprises pharmaceutical compositions comprising one or more allergens as well as methods of using the pharmaceutical compositions to increase tolerance to one or more allergens. For example, in some embodiments, provided is a pharmaceutical composition which increases tolerance to and / or reduces risk of adverse events in response to one or more allergens.

[0007] In some embodiments, the present technology comprises methods of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one-, two-, or three-unit doses of one or more peanut allergens once daily to the subject, the one-, two-, or three-unit dose comprising about 0.020 mg to about 50 mg of the one or more peanut allergens.

[0008] In some embodiments, the present technology comprises methods of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided as a daily dose of about 0.020 mg to about 150 mg of the one or more peanut allergens, wherein the daily dose comprises one-, two-, or three-unit doses of the one or more peanut allergens, each unit dose administered once daily, twice daily, or three times daily to the subject.

[0009] In some embodiments, the present technology comprises methods of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-140mg of one or more peanut allergens once daily to the subject. -2- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0010] In some embodiments, the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0011] In some embodiments, the present technology comprises methods of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one, two-, or three-unit doses of a pharmaceutical composition formulated for oral mucosal delivery once daily to the subject, wherein the one-, two-, or three-unit dose comprises (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50mg of the one or more peanut allergens.

[0012] In some embodiments, the present technology comprises methods of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235- 0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

[0013] In some embodiments, the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0014] In some embodiments, the present technology comprises methods of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

[0015] In some embodiments, the dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0016] In some embodiments, the one-unit dose comprises a daily dose of about 0.020 mg to about 50 mg of the one or more peanut allergens. -3- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0017] In some embodiments, the two-unit doses comprise a daily dose of about 3.5 mg to about 100 mg of the one or more peanut allergens.

[0018] In some embodiments, the three-unit doses comprise a daily dose of about 0.75 mg to about 150 mg of the one or more peanut allergens.

[0019] In some embodiments, the one-unit dose, the two-unit dose, or the three-unit dose comprises a daily dose of about 0.75 mg, about 2.25 mg, about 4.5 mg, about 6.67, about 9.0 mg, about 18 mg, about 20 mg, about 36 mg, or about 60 mg.

[0020] In some embodiments, the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

[0021] In some embodiments, the subject is administered a seventh daily dose of about 60 mg of the one or more peanut allergens.

[0022] In some embodiments, the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

[0023] In some embodiments, the subject is administered a fifth daily dose of about 60 mg of the one or more peanut allergens.

[0024] In some embodiments, the one-unit dose is provided in a daily dose comprising about 0.028 mg, about 0.042 mg about 0.251 mg, about 2.25 mg, about 9 mg, or about 40 mg of the one or more peanut allergens.

[0025] In some embodiments, the two-unit dose are provided in a daily dose of about 0.083 mg, about 4.5 mg, about 18 mg, or about 80 mg of the one or more peanut allergens.

[0026] In some embodiments, the three-unit dose are provided in a daily dose of about 0.083 mg, about 0.753 mg, or about 120 mg of the one or more peanut allergens.

[0027] In some embodiments, the present technology comprises methods of reducing levels of or preventing formation of one or more peanut allergen-specific IgE, IgG4, or IgA antibodies relative to a control in a subject in need thereof, the method comprising -4- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 administering a unit dose comprising one or more peanut allergens to the subject, wherein the peanut allergen-specific IgE, IgG4, or IgA antibodies are specific for an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9, SSP-1, SSP-2, and anti-conglutinin.

[0028] In some embodiments, the unit dose comprises about 0.020 mg to about 50 mg of the one or more peanut allergens.

[0029] In some embodiments, the unit dose comprises (a) 0.02-0.035mg, (b) 0.235- 0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50 mg of the one or more peanut allergens.

[0030] In some embodiments, the unit dose comprises (a) 0.028mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg of the one or more peanut allergens.

[0031] In some embodiments, the unit dose comprising (a) 0.28mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg is administered once per day.

[0032] In some embodiments, the unit dose comprising (c) 2.25mg, (d) 9mg, or (e) is 40mg administered twice per day.

[0033] In some embodiments, the unit dose comprising (a) 0.28mg, (b) 0.251mg, or (e) 40mg is administered three times per day.

[0034] In some embodiments, the methods comprise a daily dose of 4.5mg, 18mg, or 80mg administered as (i) two-unit doses administered together once per day or (ii) two-unit doses, each unit dose administered separately once per day, wherein the unit dose is 2.25mg, 9mg, or 40mg.

[0035] In some embodiments, the methods comprise a daily dose of 0.753mg or 120mg administered as a unit dose three times per day, wherein the unit dose is 0.028mg, 0.753mg, or 120mg.

[0036] In some embodiments, the methods comprise a daily dose of 0.083mg, 0.753mg, or 120mg administered as (i) three-unit doses administered together once per day, (ii) three-unit doses, each unit dose administered separately once per day, or (iii) three-unit doses, two unit doses administered together once per day and a third unit dose administered separately once per day, wherein the unit dose is 0.028mg, 0.251mg, or 40mg. -5- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0037] In some embodiments, the one or more peanut allergens is provided in a unit dose of about 0.020 mg to about 50 mg of the one or more peanut allergens administered once daily, twice daily, or three times daily to the subject.

[0038] In some embodiments, the twice daily or three times daily unit doses are administered to the subject together as daily dose.

[0039] In some embodiments, the daily dose is a first dose.

[0040] In some embodiments, the methods comprise administering a second unit dose of the one or more peanut allergens.

[0041] In some embodiments, the second unit dose comprises a greater amount of the one or more peanut allergens than the first unit dose.

[0042] In some embodiments, the second dose comprises about 2 times greater than the first unit dose, about 3 times greater than the first unit dose, about 4 times greater than the first unit dose, about 5 times greater than the first unit dose, about 6 times greater than the first unit dose, about 7 times greater than first unit dose, about 8 times greater than the first unit dose, about 9 times greater than the first unit dose, or about 10 times greater amount of the one or more peanut allergens than the first unit dose.

[0043] In some embodiments, the first unit dose and the second unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart.

[0044] In some embodiments, the one or more peanut allergens is formulated for oral mucosal delivery.

[0045] In some embodiments, the one or more peanut allergens comprises an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, and Ara h9.

[0046] In some embodiments, the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of at least one of the Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes. -6- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0047] In some embodiments, the unit dose comprises about (a) 0.0005-0.035mg, (b) 0.175-0.275mg, (c) 1-2.5mg, (d) 5-10mg, or (e) 20-50 mg, of at least one of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

[0048] In some embodiments, the unit dose comprises about (a) 0.005-0.009 mg, (b) 0.007-0.012 mg, (c) 0.02-0.035 mg, (d) 0.059-0.069 mg, (e) 0.078-0.092 mg, (f) 0.1-0.175 mg, (g) 0.5-0.625 mg, (h) 0.667-0.833 mg (i) 1.0-1.25 mg, (j) 2-2.5 mg, (k) 2.67-3.33 mg, (l) 4.0-5.0 mg, (m) 7.5-12.5 mg, or (n) 15-25 mg, of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitope.

[0049] In some embodiments, the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of each of the Ara h1, Ara h2, Ara h3, and Ara h6 epitopes.

[0050] In some embodiments, the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

[0051] In some embodiments, the methods comprise administering a seventh daily dose of about 60 mg of the one or more peanut allergens.

[0052] In some embodiments, the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

[0053] In some embodiments, the methods comprise administering a fifth daily dose of about 60 mg of the one or more peanut allergens.

[0054] In some embodiments, the one or more antibodies are selected from the group consisting of a peanut allergen-specific IgE, a peanut allergen -specific IgA, a peanut allergen-specific IgG4, an anti-SSP-1 antibody, an anti-SSP-2 antibody, an anti-conglutinin antibody, an anti-Ara h1 antibody, an anti-Ara h2 antibody, an anti-Ara h3 antibody, an anti- Ara h6 antibody, an anti-Ara h7 antibody, an anti-Ara h8 antibody, and an anti-Ara h9 antibody. -7- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0055] In some embodiments, tolerance to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% relative to a control.

[0056] In some embodiments, the increased tolerance reduces risk of or severity of one or more adverse reactions to the one or more peanut allergens in the subject.

[0057] In some embodiments, the one or more adverse reactions is selected from the group consisting of an adverse reaction of the throat, the tongue, the eye, the eyelid, the mouth, the nose, the lips, the hand, the back, the scalp, the head, the ear, the abdomen, the gastrointestinal system, the respiratory system, the cardiovascular system, and the nervous system.

[0058] In some embodiments, the adverse reaction of the throat is selected from the group consisting of an itching of the throat, a swelling of the throat, a numbness of the throat, a pain in the throat, a burning of the throat, a tingling of the throat, a discomfort of the throat, a dryness of the throat, a soreness of the throat, a sinus infection symptom of the throat, and a cold and flu symptom of the throat.

[0059] In some embodiments, the adverse reaction of the tongue is selected from the group consisting of itching of the tongue, a swelling of the tongue, a numbness of the tongue, a pain in the tongue, a burning of the tongue, a tingling of the tongue, a discomfort of the tongue, a dryness of the tongue, and a soreness of the tongue.

[0060] In some embodiments, the adverse reaction of the eye is selected from the group consisting of itching of the eye, a swelling of the eye, a numbness of the eye, a pain in the eye, a burning of the eye, a tingling of the eye, a discomfort of the eye, a dryness of the eye, and a soreness of the eye.

[0061] In some embodiments, the adverse reaction of the eyelid is selected from the group consisting of itching of the eyelid, a swelling of the eyelid, a numbness or the eyelid, a pain in the eyelid, a burning of the eyelid, a tingling of the eyelid, a discomfort of the eyelid, a dryness of the eyelid, and a soreness of the eyelid.

[0062] In some embodiments, the adverse reaction of the mouth is selected from the group consisting of itching of the mouth, a swelling of the mouth, a numbness of the mouth, -8- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 a pain in the mouth, a burning of the mouth, a tingling of the mouth, a discomfort of the mouth, a dryness of the mouth, a soreness of the mouth, a watery mouth, thickening saliva, and over salivating.

[0063] In some embodiments, the adverse reaction of the nose is selected from the group consisting of itching of the nose, a swelling of the nasal passage, a numbness of the nose, a burning of the nose, a tingling of the nose, a discomfort of the nose, a dryness of the nose, a soreness of the nasal passage, sneezing, runny nose, rhinorrhea, congestion, and a sinus infection symptom of the nose.

[0064] In some embodiments, the adverse reaction of the lips is selected from the group consisting of itching of the lips, a swelling of the lips, a numbness of the lips, a pain in the lips, a burning of the lips, a tingling of the lips, a discomfort of the lips, a dryness of the lips, and a soreness of the lips.

[0065] In some embodiments, the adverse reaction of the hand is selected from the group consisting of itching of the hand, a swelling of the hand, a numbness of the hand, a pain in the hand, a burning of the hand, a tingling of the hand, a discomfort of the hand, dermatitis of the hand, hives on the hand, urticaria of the hand, pruritis of the hand, and cyanosis of the hand.

[0066] In some embodiments, the adverse reaction of the back is selected from the group consisting of itching of the back, a back pain, a tingling of the back, a discomfort of the back, dermatitis of the back, hives on the back, urticaria of the back, pruritis of the back, and cyanosis of the back.

[0067] In some embodiments, the adverse reaction of the scalp is selected from the group consisting of itching of the scalp, a scalp pain, a tingling of the scalp, a discomfort of the scalp, dermatitis of the scalp, hives on the scalp, urticaria of the scalp, and pruritis of the scalp.

[0068] In some embodiments, the adverse reaction of the ear is selected from the group consisting of itching of the ear, a swelling of the ear, a numbness of the ear, a pain in the ear, a burning of the ear, a tingling of the ear, a discomfort of the ear, a soreness of the ear, a pressure in the ear, and a sinus infection symptom of the ear. -9- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0069] In some embodiments, the adverse reaction of the abdomen is selected from the group consisting of abdominal pain, abdominal cramps, or abdominal discomfort.

[0070] In some embodiments, the adverse reaction of the gastrointestinal system is selected from the group consisting of nausea, vomiting, emesis, stomach pain, stomach cramps, intestinal discomfort, diarrhea, loss of bowel control, irregular flatulence, gas pain, indigestion, acid reflux, and gastroesophageal reflux.

[0071] In some embodiments, the adverse reaction of the respiratory system is selected from the group consisting of coughing, hoarseness, stridor, dyspnea, shortness of breath, wheezing, respiratory arrest, cold-like and flu-like symptoms of the respiratory system, and anaphylaxis.

[0072] In some embodiments, the adverse reaction of the cardiovascular system is selected from the group consisting of tachycardia, dysrhythmia, bradycardia, cardiac arrest, hypotension, blood pressure collapse, and loss of consciousness.

[0073] In some embodiments, the adverse reaction of the nervous system is selected form the group consisting of a headache, loss of consciousness, and confusion.

[0074] In some embodiments, the adverse reaction of the skin is selected from the group consisting of pruritis, urticaria, hives, itchiness, allergic dermatitis, cyanosis, and flushing

[0075] In some embodiments, the adverse reaction of the immune system is selected from the group consisting of, a fever, cold sweats, body aches, cold-like symptoms, flu-like symptoms, and a severe allergic reaction.

[0076] In some embodiments, the subject is administered a first unit dose and a final unit dose, wherein the administration of the final unit dose is about 18 weeks to about 50 weeks after administration of the first unit dose.

[0077] In some embodiments, the subject is administered a first daily dose and a final daily dose, wherein the administration of the final daily dose is about 18 weeks to about 50 weeks after administration of the first daily dose. -10- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0078] In some embodiments, the subject is administered a cumulative dose of about 10 mg to about 1500 mg of the one or more peanut allergens.

[0079] In some embodiments, the cumulative dose is achieved by at least two daily doses, at least three, at least four, at least five, at least six, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, at least 28, at least 35, at least 42, at least 49, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, or at least 500 daily doses of the one or more peanut allergens.

[0080] In some embodiments, the cumulative dose is between about 10 mg and about 1500 mg of the one or more peanut allergens.

[0081] In some embodiments, the cumulative dose of the one or more peanut allergens is (a) about 10-50 mg, (b) about 51-100 mg, (c) about 101-250 mg, (d) about 251-500 mg, (e) about 501-750 mg, (f) about 751-1000 mg, or (g) about 1001-1500 mg.

[0082] In some embodiments, the method increases a maximum tolerated dose of the one or more peanut allergens in the subject by about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6- fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold compared to a control or the control.

[0083] In some embodiments, the method increases a maximum tolerated dose of the one or more peanut allergens in the subject to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% compared to a control or the control.

[0084] In some embodiments, the one or more peanut allergens is extracted from a peanut flour.

[0085] In some embodiments, the pharmaceutical composition is formulated for oral mucosal delivery as a dental hygiene product.

[0086] In some embodiments, the dental hygiene product is a toothpaste, a mouthwash, a mouthspray, a porous oral pouch, or a dental cream. -11- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0087] In some embodiments, the toothpaste comprises peanut flour, peppermint oil, a salt or derivative thereof, sodium lauryl sulfate, glycerin, glycerol, sodium saccharin, silica, trisodium phosphate, sodium phosphate monobasic, caboxylmethylcellulose USP, carbomer, titanium dioxide, FD & C Green #3, or FD & C Yellow #6.

[0088] In some embodiments, the peanut flour comprises one or more peptides derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6.

[0089] In some embodiments, the peanut flour is derived from roasted peanuts.

[0090] In some embodiments, the peppermint oil is mentha piperita oil.

[0091] In some embodiments, the cumulative dose is a maximum tolerated dose. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] FIG. 1 illustrates the dosing schema of a Phase 1 study evaluating the safety and feasibility of dosing at increased titrations (“up-dosing”) with a pharmaceutical composition in accordance with embodiments of the present technology. FIG.1A illustrates the four different dosing schemas administered to cohort 1 (n=8), cohort 2 (n=8), cohort 3 (n=8), and cohort 4 (n=8). FIG. 1B illustrates the dosing schema timeline for the subjects receiving open oral food challenge (OFC) or double-blind, placebo-controlled oral food challenge (DBPCOFC). FIG. 1C illustrates the safety of the pharmaceutical composition during different dosing stages, showing the systemic adverse reactions by stage. FIG. 1D illustrates the safety of the pharmaceutical composition during different dosing stages, showing the non-systemic adverse reactions by stage.

[0093] FIG.2 illustrates the percent of subjects receiving DBPCOFC who tolerated 300 mg of peanut protein or more following treatment with the pharmaceutical composition of FIG.1. Results are shown for subjects in the treatment groups (cohorts 2, 3, and 4, “Active”) compared to the control group (cohort 1, “control”), after 48 weeks of DBPCOFC treatment.

[0094] FIGS.3A-3D illustrates the changes in peanut lab values and antibody levels in DBPCOFC subjects from baseline and end of treatment with the pharmaceutical composition of FIG. 1. FIG. 3A illustrates the change in serum IgG4 for subjects in the treatment groups (“treatment”) relative to control group (“control”) from baseline to the end -12- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 of study. FIG. 3B illustrates the change in the IgE:IgG4 ratio for subjects in the treatment groups (“treatment”) relative to the control group (“control”) from baseline to the end of study. FIG.3C illustrates the percent of subjects in the treatment group relative to the control group having ≥1.75 kU / L Ara h 2 sIgE value at baseline. FIG. 3D illustrates the entry serum IgE levels relative to the end of study IgE levels for the treatment groups relative to the control group. End of study IgE levels are shown for subjects administered the maximum tolerated dose (MTD).

[0095] FIGS. 4A and 4B illustrates the adverse events experienced by subjects receiving treatment with the pharmaceutical composition of FIG. 1. FIG. 4A illustrates adverse events experienced under different doses and treatment lengths, categorized as “possibly,” “probably,” or “definitely” related to treatment. FIG. 4B illustrates the mean number of adverse events experienced under different doses for subjects across all treatment groups during the maintenance phase. DETAILED DESCRIPTION

[0096] While the present technology is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present technology is to be considered as an exemplification of the present technology and is not intended to limit the present technology to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the present technology in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0097] The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about.” It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about.” It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub- -13- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 range is explicitly specified. For example, a ratio in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual ratios such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0098] Also, the description of ranges is intended as a continuous range, including every value between the minimum and maximum values recited, as well as any ranges that can be formed by such values. Also provided herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a described numeric value into any other described numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances, such ratios, ranges, and ranges of ratios represent various embodiments of the present technology. Pharmaceutical Compositions Allergens

[0099] The present technology comprises pharmaceutical compositions comprising an allergen, and in some embodiments, the allergen comprises one or more allergens. The allergen in the pharmaceutical composition may comprise a protein, carbohydrate, or a lipid allergen. At some doses or levels of exposure, the allergen may elicit an immune response in individuals having an allergy to the allergen, regardless of whether the allergy has been diagnosed in the individual. The pharmaceutical compositions of the present technology comprise low-doses of allergen which may contribute to immunomodulation in the subject -14- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 following treatment with the pharmaceutical compositions. Immunomodulation occurs, at least in part, by engaging immune cells, such as Langerhans cells, and stimulating changes in immune pathways. As used herein, the term “allergen” may refer to multiple allergens, such as two or more allergens. Unless otherwise specified, the allergen may comprise one or more proteins, peptides, and / or epitopes on the peptide as the allergen.

[0100] In some embodiments, the allergen comprises a food allergen. Nonlimiting examples of food allergens include a peanut allergen, a wheat allergen, a fish allergen (e.g, salmon, tuna, catfish, white fish, and cod allergens), a shellfish allergen (e.g., prawn, crab, and lobster allergens), a milk allergen, a tree nut allergen (e.g., hazelnut, pistachio, Brazil nut, and walnut allergens), a drupe allergen (e.g., cashew, almond, olive, and coconut allergens), an egg allergen, a soybean allergen, a gluten allergen, a celery allergen, a barley allergen, an oat allergen, a lupin allergen, a mollusk allergen (e.g. mussel and oyster allergens), a mustard allergen, a soy allergen, a palm allergen, a coconut allergen, an animal fat allergen (e.g. tallow), a seed allergen (e.g., sesame seed, sunflower seed, poppy seed, flaxseed, and mustard seed allergens), a bean allergen, a pea allergen, and allergens otherwise processed or altered from their naturally occurring forms, including but not limited to, a defatted allergen (e.g., solvent defatted, including acetone defatted, methanol defatted, ethanol defatted, hexane defatted, methyloxolane defatted; water defatted; heat defatted; pressure defatted; or supercritical fluid defatted, including supercritical carbon dioxide defatted), a manufactured allergen (e.g., a non-naturally occurring allergen that is based upon or otherwise resembles at least a portion of a naturally occurring allergen), an allergen derived from a bioreactor-based process, a modified version of any of the foregoing allergens, and an allergen that is immunologically cross-reactive therewith any of the foregoing allergens. For example, the food allergen comprises one or more epitopes from a single peptide. In another example, the food allergen comprises one or more epitopes from a first peptide and one or more epitopes from a second peptide. The first peptide and the second peptide may be derived from the same proteins or from different proteins. Other combinations of proteins, peptides, and epitopes which are collectively referred to or otherwise understood to be a food allergen are possible and encompassed by the present technology. -15- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0101] The peanut allergen may be present in peanuts and / or in non-peanut legumes phylogenetically related to peanuts (e.g., beans, peas, and soy). See Burks et al., “Mapping and mutational analysis of the IgE-binding epitopes on Ara h 1, a legume vicilin protein and a major allergen in peanut hypersensitivity” (1997), the entire contents of which are incorporated herein by reference. In some embodiments, the peanut allergen is a peanut protein or portions thereof, such as peanut peptides. Nonlimiting examples of the peanut proteins or peanut peptides which may be a peanut allergen include a conglutin, a cupin, a profilin, a PR-10 protein, an oleosin, an oroleosin, a defensin, a vicilin, a glycinin, a non- specific lipid transfer protein, an Ara h protein, and other seed storage proteins. See Hemmings et al., “Ara h 2 is the dominant peanut allergen despite similarities with Ara h 6” (2020) and Zhuang and Dreskin, “Redefining the major peanut allergens” (2013), the entire contents of which are incorporated herein by reference. Peptides may comprise a single epitope or more than one epitope which elicit an immune response. In some embodiments, the peanut protein further comprises one or more epitopes, including, but not limited to an Ara h 1 epitope, an Ara h 2 epitope, an Ara h 3 epitope, an Ara h 4 epitope, an Ara h 5 epitope, an Ara h 6 epitope, an Ara h 7 epitope, an Ara h 8 epitope, an Ara h 9 epitope, an Ara h 10 epitope, an Ara h 11 epitope, an Ara h 12 epitope, an Ara h 13 epitope, an Ara h 14 epitope, an Ara h 15 epitope, an Ara h 16 epitope, and Ara h 17 epitope, an Ara h 18 epitope, an SSP-1 epitope, and an SSP-2 epitope. See Hemmings et al., “Ara h 2 is the dominant peanut allergen despite similarities with Ara h 6” (2020), the entire contents of which are incorporated herein by reference. In some embodiments, the peanut protein comprises two or more epitopes, which may be derived from peptides sourced from the same protein type or different protein types. For example, the peanut protein may comprise or consist of a first Ara h 1 epitope from a first Ara h1 peptide and a second Ara h 1 epitope from a second Ara h 1 peptide. In another example, the peanut protein may comprise or consist of an Ara h 1 epitope and an Ara h 2 epitope. In another example, the peanut protein may comprise or consist of a first Ara h 1 epitope from a first Ara h 1 peptide, a second Ara h 1 epitope from a second Ara h 1 epitope, a Ara h 2 epitope, and an Ara h 3 epitope. The terms “peanut allergen,” “peanut protein,” “peanut peptide,” and “peanut epitope” may be used interchangeably throughout and refer to a portion of the peanut which elicits the immune response in the subject. -16- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0102] In some embodiments, the one or more allergens in the pharmaceutical composition are obtained from a peanut flour. The peanut flour may be prepared from roasted or unroasted peanuts, or combination thereof. In some embodiments, the peanut flour comprises one or more epitopes. The one or more epitopes in the peanut flour may originate from roasted peanuts. In some embodiments, the one or more epitopes in the peanut flour are derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6 peptides. In some embodiments, the peanut flour is a defatted peanut flour.

[0103] In some embodiments, the one or more allergens comprise a glycerin allergen. The glycerin allergen may be present in a glycerol composition sourced from soybeans, palm, propylene, plant oils (e.g., palm oil, coconut oil, soybean oil), vegetable oils, or animal fats (e.g., tallow or animal fat soaps). The glycerin allergen may comprise an epitope having an alcohol group (e.g., a hydroxy group, a diol, or a triol) Pharmaceutically Acceptable Carriers and Excipients

[0104] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and / or excipient (e.g., water, saline, dextrose, glycerol). In some embodiments, the pharmaceutically acceptable carrier and / or excipient comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises one or more of lactose, microcrystalline cellulose (MCC), starch, glycerin, polyethylene glycol (PEG), sorbitol, silicon dioxide (SiO2), magnesium stearate, propylene glycol, polysorbate 80, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), lecithin, ethanol, water, mineral oil, talc, gelatin, sucrose, or povidone-iodine.

[0105] Nonlimiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0106] The pharmaceutically acceptable carrier may comprise one or more of an absorption delaying agent, an antioxidant, a binder, a buffering agent, a bulking agent or filler, a chelating agent, a coating, a disintegration agent, a dispersion media, a gel, an isotonic agent, a lubricant, a preservative, a salt, a solvent or co-solvent, a stabilizer, a surfactant, and / or a delivery vehicle. -17- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0107] Nonlimiting examples of an antioxidant includes ascorbic acid, methionine, and vitamin E.

[0108] Nonlimiting examples of a buffering agent includes citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, gluconate buffers, oxalate buffers, lactate buffers, acetate buffers, phosphate buffers, histidine buffers, and trimethylamine salts.

[0109] In some embodiments, the chelating agent is EDTA.

[0110] Nonlimiting examples of an isotonic agent includes polyhydric sugar alcohols including trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol.

[0111] Nonlimiting examples of a preservative includes phenol, benzyl alcohol, meta- cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides, hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0112] Stabilizers comprise a broad category of excipients which may range in function from a bulking agent to an additive which solubilizes the allergen or helps to prevent denaturation or adherence to the container wall. Typical stabilizers may include polyhydric sugar alcohols; amino acids, ornithine, L-leucine, 2-phenylalanine, E, and T; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and cyclitols, such as inositol; PEG; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, alpha-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (i.e., <10 residues); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose and glucose; disaccharides such as lactose, maltose and sucrose; trisaccharides such as raffinose, and polysaccharides such as dextran. Stabilizers are typically present in the range of from 0.1 to 10,000 parts by weight based on the allergen weight.

[0113] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt that retains the activity of the allergen and is acceptable -18- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 for pharmaceutical use. The salt may comprise a pharmaceutically acceptable acid addition salt. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids.

[0114] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable base addition salt. Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine, and the amino acids Lys or Arg. Formulations

[0115] In some embodiments, the pharmaceutical compositions of the present technology are formulated for different modes of delivery, such as oral delivery. In some embodiments the oral delivery is an oral mucosal delivery. Oral mucosal delivery may comprise administration of the pharmaceutical composition using a dental hygiene product. Nonlimiting examples of dental hygiene products include a toothpaste, a mouthwash, a mouthspray, a porous oral pouch, or a dental cream. In some embodiments, the oral delivery comprises a pacifier.

[0116] The formulation may comprise a base having one or more of an herbal oil or essence, a salt or derivative thereof, a detergent, glycerin, glycerol, sodium saccharin, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, a dye, or deionized water. The base comprises the one or more allergens and one or more excipients and / or pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition is formulated in a toothpaste, wherein the toothpaste base comprises the one or more allergens, and one or more of an herbal oil or essence, a salt or derivative thereof, a detergent, glycerin, glycerol, sodium saccharin, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, -19- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 a dye, and deionized water. In some embodiments, the toothpaste comprises a flavoring agent. In some embodiments, the flavoring agent comprises the herbal oil or the essence. In some embodiments, the toothpaste base comprises fluoride. In some embodiments, the toothpaste base comprises one or more tooth enamel builders.

[0117] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0118] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, a detergent, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0119] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, a dye, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0120] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, sodium saccharin, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0121] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, a detergent, a dye, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders. -20- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0122] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, a detergent, a sodium saccharin, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0123] In some embodiments, the toothpaste base consists of the one or more allergens and one or more of a salt or derivative thereof, a sodium saccharin, a dye, glycerin, glycerol, a silica, a trisodium phosphate, a cellulose, sodium phosphate monobasic, caboxylmethylcellulose USP, a carbomer, titanium dioxide, deionized water, fluoride, and one or more tooth enamel builders.

[0124] The one or more allergens may be added to the base by various methods or procedures. In some embodiments, the one or more allergens are directly added to the base. In some embodiments, the one or more allergens are first added to glycerin (e.g., 5% glycerin, 10% glycerin, 20% glycerin, 30% glycerin, 40% glycerin, 50% glycerin, 60% glycerin, 70% glycerin, 80% glycerin, 90% glycerin, or 100% glycerin) and the allergen- glycerin mixture is then added to the base.

[0125] In some embodiments, the one or more allergens are extracted from a food source (e.g., food flour or food liquid extract). In some embodiments, the one or more allergens extracted from the food source are lyophilized and added to the base. In some embodiments, the food source is added directly to the base and the base formulation extracts the one or more allergens from the food source.

[0126] In some embodiments, the detergent comprises sodium lauryl sulfate.

[0127] In some embodiments, the herbal oil comprises a peppermint oil. In some embodiments, the peppermint oil is mentha piperita oil.

[0128] In some embodiments, the silica comprises a dental type silica. In some embodiments, the dental type silica is a Zeodent. In some embodiments, the Zeodent is 113 or 165.

[0129] In some embodiments, the trisodium triphosphate is a trisodium phosphate anhydrous. -21- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0130] In some embodiments, the cellulose comprises a carboxylmethylcellulose.

[0131] In some embodiments, the dye comprises FD & C Green #3 (e.g., Fast Green FCF) and / or FD & C Yellow #6 (e.g., Sunset Yellow FCF).

[0132] In some embodiments, the formulation comprises sodium saccharin in an about of about 0.5%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.5%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%, 0.425% 0.45%, 0.475%, 5%, 6%, 8%, or 10%, or more, by weight of the formulation.

[0133] In some embodiments, the formulation comprises sodium saccharin in an about of at least 0.5%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.5%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%, 0.425% 0.45%, 0.475%, or 5%, 6%, 8%, or 10%, or more, by weight of the formulation.

[0134] In some embodiments, the formulation comprises sodium saccharin in an about of at least about 0.5%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.5%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%, 0.425% 0.45%, 0.475%, 5%, 6%, 8%, or 10%, or more, by weight of the formulation.

[0135] In some embodiments, the formulation comprises glycerin in an amount of about 20%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 44.061%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, or 70%, or more, by weight of the pharmaceutical composition.

[0136] In some embodiments, the formulation comprises glycerin in an amount of at least 20%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 44.061%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, or 70%, or more, by weight of the pharmaceutical composition.

[0137] In some embodiments, the formulation comprises glycerin in an amount of at least about 20%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 44.061%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, or 70%, or more, by weight of the pharmaceutical composition. -22- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0138] In some embodiments, the formulation comprises trisodium phosphate in an amount of about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.127%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0139] In some embodiments, the formulation comprises trisodium phosphate in an amount of at least 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.127%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0140] In some embodiments, the formulation comprises trisodium phosphate in an amount of at least about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.127%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0141] In some embodiments, the formulation comprises a peppermint oil in an amount of about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0142] In some embodiments, the formulation comprises a peppermint oil in an amount of at least 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0143] In some embodiments, the formulation comprises a peppermint oil in an amount of at least about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.676%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0144] In some embodiments, the formulation comprises a detergent in an amount of about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.507%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition. -23- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0145] In some embodiments, the formulation comprises a detergent in an amount of at least 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.507%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0146] In some embodiments, the formulation comprises a detergent in an amount of at least about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.507%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0147] In some embodiments, the formulation comprises a sodium monobasic in an amount of about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.564%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0148] In some embodiments, the formulation comprises a sodium monobasic in an amount of at least 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.564%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0149] In some embodiments, the formulation comprises a sodium monobasic in an amount of at least about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.564%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0150] In some embodiments, the formulation comprises a carboxymethylcellulose an amount of about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.474%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0151] In some embodiments, the formulation comprises a carboxymethylcellulose an amount of at least 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.474%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition. -24- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0152] In some embodiments, the formulation comprises a carboxymethylcellulose an amount of at least about 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.474%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0153] In some embodiments, the formulation comprises a carbomer in an amount of about 0.05%, 0.1%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0154] In some embodiments, the formulation comprises a carbomer in an amount of at least 0.05%, 0.1%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0155] In some embodiments, the formulation comprises a carbomer in an amount of at least about 0.05%, 0.1%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or more, by weight of the pharmaceutical composition.

[0156] In some embodiments, the formulation comprises titanium dioxide in an amount of about 0.01%, 0.25%,0.05%, 0.75%, 0.8%, 0.9%, 0.1%, 0.11%, 0.113%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition.

[0157] In some embodiments, the formulation comprises titanium dioxide in an amount of at least 0.01%, 0.25%,0.05%, 0.75%, 0.8%, 0.9%, 0.1%, 0.11%, 0.113%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition. -25- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0158] In some embodiments, the formulation comprises titanium dioxide in an amount of at least about 0.01%, 0.25%,0.05%, 0.75%, 0.8%, 0.9%, 0.1%, 0.11%, 0.113%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition.

[0159] In some embodiments, the formulation comprises a dye in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition.

[0160] In some embodiments, the formulation comprises a dye in an amount of at least 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition.

[0161] In some embodiments, the formulation comprises a dye in an amount of at least about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2% 0.25%, 0.3%, 0.35%, 0.372% 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, or 5%, or more, by weight of the pharmaceutical composition.

[0162] In some embodiments, the formulation comprises sodium saccharin in an amount of about 0.2% by weight of the pharmaceutical composition, deionized water in an amount of about 35% to about 36% by weight of the pharmaceutical composition, glycerin in an amount of about 45% to about 46% by weight of the pharmaceutical composition, Zeodent 165 dental type silica in an amount of about 10% by weight of the pharmaceutical composition, Zeodent 113 dental type silica in an amount of about 5% by weight of the pharmaceutical composition, trisodium phosphate anhydrous in an amount of about 1% by weight of the pharmaceutical composition, peppermint oil in an amount of about 0.6% by weight of the pharmaceutical composition, sodium lauryl sulfate in an amount of about 0.45% by weight of the pharmaceutical composition, sodium phosphate monobasic 0.5%, sodium -26- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 carboxylmethylcellulose in an amount of about 0.42% by weight of the pharmaceutical composition, carbomer in an amount of about 0.3% to about 0.4% by weight of the pharmaceutical composition, titanium dioxide in an amount of about 0.1% by weight of the pharmaceutical composition, and FD & C Green #3 dye in an amount of about 0.8% by weight of the pharmaceutical composition.

[0163] In some embodiments, the formulation comprises sodium saccharin in an amount of about 0.2% by weight of the pharmaceutical composition, deionized water in an amount of about 35% to about 36% by weight of the pharmaceutical composition, glycerin in an amount of about 45% to about 46% by weight of the pharmaceutical composition, Zeodent 165 dental type silica in an amount of about 10% by weight of the pharmaceutical composition, Zeodent 113 dental type silica in an amount of about 5% by weight of the pharmaceutical composition, trisodium phosphate anhydrous in an amount of about 1% by weight of the pharmaceutical composition, peppermint oil in an amount of about 0.6% by weight of the pharmaceutical composition, sodium lauryl sulfate in an amount of about 0.45% by weight of the pharmaceutical composition, sodium phosphate monobasic 0.5%, sodium carboxylmethylcellulose in an amount of about 0.42% by weight of the pharmaceutical composition, carbomer in an amount of about 0.3% to about 0.4% by weight of the pharmaceutical composition, titanium dioxide in an amount of about 0.1% by weight of the pharmaceutical composition, FD & C Green #3 dye in an amount of about 0.8% by weight of the pharmaceutical composition, and FD & C Yellow #6 dye in an amount of about 0.024% by weight of the pharmaceutical composition.

[0164] In some embodiments, the base of the formulation further comprises an adjuvant that promotes or enhances an immune response to the one or more allergens. In some embodiments, the formulation comprises one or more adjuvants. In some embodiments, the formulation comprises two or more adjuvants. Nonlimiting examples of adjuvants include pattern recognition receptor agonists such as toll-like receptor agonists (e.g., TLR1 agonists, TLR2 agonists, TLR3 agonists, TLR4 agonists, TLR5 agonists, TLR6 agonists, TLR7 agonists, TLR8 agonists, TLR9 agonists, TLR10 agonists), nucleotide- oligomerization domain-like receptor agonists (e.g., NOD1 agonists, NOD2 agonists, NLRP1 agonists, NLRP3 agonists), retinoic acid-inducible gene I-like receptor agonists, C-Type -27- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 lectin receptor agonists, AIM2-like receptor agonists, scavenger receptor agonists, lectin- like receptor agonists, DNA sensor agonists (e.g., cGAS agonists and STING agonists), and formyl peptide receptor agonists (e.g. FPR1 agonists, FPR2 agonists, FPR3 agonists); aluminum salts (e.g., aluminum hydroxide, aluminum phosphate, aluminum phosphate sulfate); CpG oligonucleotides, lipopolysaccharides; cytokines; oil-in-water emulsions (e.g., oil-in-water emulsions comprising squalene); monophosphoryl lipid A; saponin-derived compositions; and flagellin adjuvants. Dosing Doses

[0165] The pharmaceutical compositions of the present technology may be administered to a subject in need thereof at a dose or dosage frequency that reduces, prevents, or limits occurrence of an adverse reaction to one or more allergens. In some embodiments, the dose is a daily dose. In some embodiments, the one or more allergens may be a peanut allergen. The peanut allergen may comprise one or more peptides selected from the Ara h 1, Ara h 2, Ara h 3, or Ara h 6 peptides. In some embodiments, the peptide comprises one or more epitopes, each epitope may be derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6 peptides. The peptides may be obtained from a peanut flour (e.g., peanut flour derived from roasted peanut, peanut flour derived from unroasted peanuts, peanut flour derived from a combination of roasted and unroasted peanuts, defatted peanut flour).

[0166] In some embodiments, when the dose is administered as a daily dose, the daily dose comprises about 0.020 mg, about 0.025 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.050 mg, about 0.060 mg, about 0.070 mg, about 0.080 mg, about 0.090 mg, about 0.10 mg, about 0.125 mg, about 0.150 mg, about 0.160 mg, about 0.170 mg, about 0.180 mg, about 0.190 mg, about 0.20 mg, about 0.210 mg, about 0.220 mg, about 0.230 mg, about 0.235 mg, about 0.240 mg, about 0.245 mg, about 0.250 mg, about 0.255 mg, about 0.260 mg, about 0.265 mg, about 0.270 mg, about 0.275 mg, about 0.280 mg, about 0.290 mg, about 0.300 mg, about 0.325 mg, about 0.350 mg, about 0.375 mg, about 0.40 mg, about 0.425 mg, about 0.450 mg, about 0.475 mg, about 0.500 mg, about 0.525 mg, about 0.50 mg, about 0.575 mg, about 0.60 mg, about 0.625 mg, about 0.650 mg, about 0.675 mg, about 0.70 mg, about 0.725 mg, about 0.750 mg, about 0.775 mg, about 0.80 mg, -28- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 about 0.825 mg, about 0.850 mg, about 0.875 mg, about 0.90 mg, about 0.925 mg, about 0.950 mg, about 0.975 mg, about 1.0 mg, about 1.250 mg, about 1.50 mg, about 1.750, about 2.0 mg, about 2.10 mg, about 2.20 mg, about 2.30 mg, about 2.40 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.50 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.50 mg, about 4.75 mg, about 5.0 mg, about 5.25 mg, about 5.50 mg, about 5.75 mg, about 6.0 mg, about 6.25 mg, about 6.50 mg, about 6.75 mg, about 7.0 mg, about 7.25 mg, about 7.50 mg, about 7.75 mg, about 8.0 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9.0 mg, about 9.25 mg, about 9.50 mg, about 9.75 mg, about 10.0 mg, about 10.25 mg, about 10.50 mg, about 10.75 mg, about 11.0 mg about 11.5 mg, about 12.0 mg, about 12.5 mg, about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 16.0 mg, about 16.50 mg, about 17.0 mg, about 17.5 mg, about 18.0 mg, about 18.5 mg, about 19.0 mg, about 19.5 mg, about 20.0 mg, about 20.5 mg, about 21.0 mg, about 21.5 mg, about 22.0 mg, about 22.5 mg, about 23.0 mg, about 23.5 mg, about 24.0 mg, about 24.5 mg, about 25.0 mg, about 25.5 mg, about 26.0 mg, about 26.5 mg, about 27.0 mg, about 27.5 mg, about 28.0 mg, about 28.5 mg, about 29.0 mg, about 29.5 mg, about 30.0 mg, about 30.5 mg, about 31.0 mg, about 31.5 mg, about 32.0 mg, about 32.5 mg, about 33.0 mg, about 33.5 mg, about 34.0 mg, about 34.5 mg, about 35.0 mg, about 35.5 mg, about 36.0 mg, about 36.5 mg, about 37.0 mg, about 37.5 mg, about 38.0 mg, about 38.5 mg, about 39.0 mg, about 39.5 mg, about 40.0 mg, about 40.5 mg, about 41.0 mg, about 41.5 mg, about 42.0 mg, about 42.5 mg, about 43.0 mg, about 43.5 mg, about 44.0 mg, about 44.5 mg, about 45.0 mg, about 45.5 mg, about 46.0 mg, about 46.5 mg, about 47.0 mg, about 47.5 mg, about 48.0 mg, about 48.5 mg, about 49.0 mg, about 49.5 mg, about 50.0 mg, about 50.5 mg, about 51.0 mg, about 51.5 mg, about 52.0 mg, about 52.5 mg, about 53.0 mg, about 53.5 mg, about 54.0 mg, about 54.5 mg, about 55.0 mg, about 55.5 mg, about 56.0 mg, about 56.5 mg, about 57.0 mg, about 57.5 mg, about 58.0 mg, about 58.5 mg, about 59.0 mg, about 59.5 mg, about 60.0 mg, about 60.5 mg, about 61.0 mg, about 61.5 mg, about 62.0 mg, about 62.5 mg, about 63.0 mg, about 63.5 mg, about 64.0 mg, about 64.5 mg, about 65.0 mg, about 65.5 mg, about 66.0 mg, about 66.5 mg, about 67.0 mg, about 67.5 mg, about 68.0 mg, about 68.5 mg, about 69.0 mg, about 69.5 mg, about 70.0 mg, about 70.5 mg, about 71.0 mg, about 71.5 mg, about 72.0 mg, about 72.5 mg, about 73.0 mg, about 73.5 mg, about 74.0 mg, about -29- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 74.5 mg, about 75.0 mg, about 75.5 mg, about 76.0 mg, about 76.5 mg, about 77.0 mg, about 77.5 mg, about 78.0 mg, about 78.5 mg, about 79.0 mg, about 79.5 mg, about 80.0 mg, about 80.5 mg, about 81.0 mg, about 81.5 mg, about 82.0 mg, about 82.5 mg, about 83.0 mg, about 83.5 mg, about 84.0 mg, about 84.5 mg, about 85.0 mg, about 85.5 mg, about 86.0 mg, about 86.5 mg, about 87.0 mg, about 87.5 mg, about 88.0 mg, about 88.5 mg, about 89.0 mg, about 89.5 mg, about 90.0 mg, about 90.5 mg, about 91.0 mg, about 91.5 mg, about 92.0 mg, about 92.5 mg, about 93.0 mg, about 93.5 mg, about 94.0 mg, about 94.5 mg, about 95.0 mg, about 95.5 mg, about 96.0 mg, about 96.5 mg, about 97.0 mg, about 97.5 mg, about 98.0 mg, about 98.5 mg, about 99.0 mg, about 99.5 mg, about 100.0 mg, about 100.5 mg, about 101.0 mg, about 101.5 mg, about 102.0 mg, about 102.5 mg, about 103.0 mg, about 103.5 mg, about 104.0 mg, about 104.5 mg, about 105.0 mg, about 105.5 mg, about 106.0 mg, about 106.5 mg, about 107.0 mg, about 107.5 mg, about 108.0 mg, about 108.5 mg, about 109.0 mg, about 109.5 mg, about 110.0 mg, about 110.5 mg, about 111.0 mg, about 111.5 mg, about 112.0 mg, about 112.5 mg, about 113.0 mg, about 113.5 mg, about 114.0 mg, about 114.5 mg, about 115.0 mg, about 115.5 mg, about 116.0 mg, about 116.5 mg, about 117.0 mg, about 117.5 mg, about 118.0 mg, about 118.5 mg, about 119.0 mg, about 119.5 mg, about 120.0 mg, about 120.5 mg, about 121.0 mg, about 121.5 mg, about 122.0 mg, about 122.5 mg, about 123.0 mg, about 123.5 mg, about 124.0 mg, about 124.5 mg, about 125.0 mg, about 125.5 mg, about 126.0 mg, about 126.5 mg, about 127.0 mg, about 127.5 mg, about 128.0 mg, about 128.5 mg, about 129.0 mg, about 129.5 mg, about 130.0 mg, about 130.5 mg, about 131.0 mg, about 131.5 mg, about 132.0 mg, about 132.5 mg, about 133.0 mg, about 133.5 mg, about 134.0 mg, about 134.5 mg, about 135.0 mg, about 135.5 mg, about 136.0 mg, about 136.5 mg, about 137.0 mg, about 137.5 mg, about 138.0 mg, about 138.5 mg, about 139.0 mg, about 139.5 mg, or about 140.0 mg of one or more allergens.

[0167] In some embodiments, when the dose is administered as a daily dose, the daily dose comprises at least 0.020 mg, at least 0.025 mg, at least 0.030 mg, at least 0.035 mg, at least 0.040 mg, at least 0.050 mg, at least 0.060 mg, at least 0.070 mg, at least 0.080 mg, at least 0.090 mg, at least 0.10 mg, at least 0.125 mg, at least 0.150 mg, at least 0.160 mg, at least 0.170 mg, at least 0.180 mg, at least 0.190 mg, at least 0.20 mg, at least 0.210 mg, at least 0.220 mg, at least 0.230 mg, at least 0.235 mg, at least 0.240 mg, at least 0.245 mg, -30- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 at least 0.250 mg, at least 0.255 mg, at least 0.260 mg, at least 0.265 mg, at least 0.270 mg, at least 0.275 mg, at least 0.280 mg, at least 0.290 mg, at least 0.300 mg, at least 0.325 mg, at least 0.350 mg, at least 0.375 mg, at least 0.40 mg, at least 0.425 mg, at least 0.450 mg, at least 0.475 mg, at least 0.500 mg, at least 0.525 mg, at least 0.50 mg, at least 0.575 mg, at least 0.60 mg, at least 0.625 mg, at least 0.650 mg, at least 0.675 mg, at least 0.70 mg, at least 0.725 mg, at least 0.750 mg, at least 0.775 mg, at least 0.80 mg, at least 0.825 mg, at least 0.850 mg, at least 0.875 mg, at least 0.90 mg, at least 0.925 mg, at least 0.950 mg, at least 0.975 mg, at least 1.0 mg, at least 1.250 mg, at least 1.50 mg, at least 1.750, at least 2.0 mg, at least 2.10 mg, at least 2.20 mg, at least 2.30 mg, at least 2.40 mg, at least 2.5 mg, at least 2.75 mg, at least 3.0 mg, at least 3.25 mg, at least 3.50 mg, at least 3.75 mg, at least 4.0 mg, at least 4.25 mg, at least 4.50 mg, at least 4.75 mg, at least 5.0 mg, at least 5.25 mg, at least 5.50 mg, at least 5.75 mg, at least 6.0 mg, at least 6.25 mg, at least 6.50 mg, at least 6.75 mg, at least 7.0 mg, at least 7.25 mg, at least 7.50 mg, at least 7.75 mg, at least 8.0 mg, at least 8.25 mg, at least 8.5 mg, at least 8.75 mg, at least 9.0 mg, at least 9.25 mg, at least 9.50 mg, at least 9.75 mg, at least 10.0 mg, at least 10.25 mg, at least 10.50 mg, at least 10.75 mg, at least 11.0 mg at least 11.5 mg, at least 12.0 mg, at least 12.5 mg, at least 13.0 mg, at least 13.5 mg, at least 14.0 mg, at least 14.5 mg, at least 15.0 mg, at least 15.5 mg, at least 16.0 mg, at least 16.50 mg, at least 17.0 mg, at least 17.5 mg, at least 18.0 mg, at least 18.5 mg, at least 19.0 mg, at least 19.5 mg, at least 20.0 mg, at least 20.5 mg, at least 21.0 mg, at least 21.5 mg, at least 22.0 mg, at least 22.5 mg, at least 23.0 mg, at least 23.5 mg, at least 24.0 mg, at least 24.5 mg, at least 25.0 mg, at least 25.5 mg, at least 26.0 mg, at least 26.5 mg, at least 27.0 mg, at least 27.5 mg, at least 28.0 mg, at least 28.5 mg, at least 29.0 mg, at least 29.5 mg, at least 30.0 mg, at least 30.5 mg, at least 31.0 mg, at least 31.5 mg, at least 32.0 mg, at least 32.5 mg, at least 33.0 mg, at least 33.5 mg, at least 34.0 mg, at least 34.5 mg, at least 35.0 mg, at least 35.5 mg, at least 36.0 mg, at least 36.5 mg, at least 37.0 mg, at least 37.5 mg, at least 38.0 mg, at least 38.5 mg, at least 39.0 mg, at least 39.5 mg, at least 40.0 mg, at least 40.5 mg, at least 41.0 mg, at least 41.5 mg, at least 42.0 mg, at least 42.5 mg, at least 43.0 mg, at least 43.5 mg, at least 44.0 mg, at least 44.5 mg, at least 45.0 mg, at least 45.5 mg, at least 46.0 mg, at least 46.5 mg, at least 47.0 mg, at least 47.5 mg, at least 48.0 mg, at least 48.5 mg, at least 49.0 mg, at least 49.5 mg, at least 50.0 mg, at least 50.5 mg, at least 51.0 mg, at least 51.5 mg, at -31- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 least 52.0 mg, at least 52.5 mg, at least 53.0 mg, at least 53.5 mg, at least 54.0 mg, at least 54.5 mg, at least 55.0 mg, at least 55.5 mg, at least 56.0 mg, at least 56.5 mg, at least 57.0 mg, at least 57.5 mg, at least 58.0 mg, at least 58.5 mg, at least 59.0 mg, at least 59.5 mg, at least 60.0 mg, at least 60.5 mg, at least 61.0 mg, at least 61.5 mg, at least 62.0 mg, at least 62.5 mg, at least 63.0 mg, at least 63.5 mg, at least 64.0 mg, at least 64.5 mg, at least 65.0 mg, at least 65.5 mg, at least 66.0 mg, at least 66.5 mg, at least 67.0 mg, at least 67.5 mg, at least 68.0 mg, at least 68.5 mg, at least 69.0 mg, at least 69.5 mg, at least 70.0 mg, at least 70.5 mg, at least 71.0 mg, at least 71.5 mg, at least 72.0 mg, at least 72.5 mg, at least 73.0 mg, at least 73.5 mg, at least 74.0 mg, at least 74.5 mg, at least 75.0 mg, at least 75.5 mg, at least 76.0 mg, at least 76.5 mg, at least 77.0 mg, at least 77.5 mg, at least 78.0 mg, at least 78.5 mg, at least 79.0 mg, at least 79.5 mg, at least 80.0 mg, at least 80.5 mg, at least 81.0 mg, at least 81.5 mg, at least 82.0 mg, at least 82.5 mg, at least 83.0 mg, at least 83.5 mg, at least 84.0 mg, at least 84.5 mg, at least 85.0 mg, at least 85.5 mg, at least 86.0 mg, at least 86.5 mg, at least 87.0 mg, at least 87.5 mg, at least 88.0 mg, at least 88.5 mg, at least 89.0 mg, at least 89.5 mg, at least 90.0 mg, at least 90.5 mg, at least 91.0 mg, at least 91.5 mg, at least 92.0 mg, at least 92.5 mg, at least 93.0 mg, at least 93.5 mg, at least 94.0 mg, at least 94.5 mg, at least 95.0 mg, at least 95.5 mg, at least 96.0 mg, at least 96.5 mg, at least 97.0 mg, at least 97.5 mg, at least 98.0 mg, at least 98.5 mg, at least 99.0 mg, at least 99.5 mg, at least 100.0 mg, at least 100.5 mg, at least 101.0 mg, at least 101.5 mg, at least 102.0 mg, at least 102.5 mg, at least 103.0 mg, at least 103.5 mg, at least 104.0 mg, at least 104.5 mg, at least 105.0 mg, at least 105.5 mg, at least 106.0 mg, at least 106.5 mg, at least 107.0 mg, at least 107.5 mg, at least 108.0 mg, at least 108.5 mg, at least 109.0 mg, at least 109.5 mg, at least 110.0 mg, at least 110.5 mg, at least 111.0 mg, at least 111.5 mg, at least 112.0 mg, at least 112.5 mg, at least 113.0 mg, at least 113.5 mg, at least 114.0 mg, at least 114.5 mg, at least 115.0 mg, at least 115.5 mg, at least 116.0 mg, at least 116.5 mg, at least 117.0 mg, at least 117.5 mg, at least 118.0 mg, at least 118.5 mg, at least 119.0 mg, at least 119.5 mg, at least 120.0 mg, at least 120.5 mg, at least 121.0 mg, at least 121.5 mg, at least 122.0 mg, at least 122.5 mg, at least 123.0 mg, at least 123.5 mg, at least 124.0 mg, at least 124.5 mg, at least 125.0 mg, at least 125.5 mg, at least 126.0 mg, at least 126.5 mg, at least 127.0 mg, at least 127.5 mg, at least 128.0 mg, at least 128.5 mg, at least 129.0 mg, at least 129.5 mg, at least 130.0 mg, at least 130.5 mg, at least 131.0 mg, at least 131.5 -32- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 mg, at least 132.0 mg, at least 132.5 mg, at least 133.0 mg, at least 133.5 mg, at least 134.0 mg, at least 134.5 mg, at least 135.0 mg, at least 135.5 mg, at least 136.0 mg, at least 136.5 mg, at least 137.0 mg, at least 137.5 mg, at least 138.0 mg, at least 138.5 mg, at least 139.0 mg, at least 139.5 mg, or at least 140.0 mg of one or more allergens.

[0168] In some embodiments, when the dose is administered as a daily dose, the daily dose comprises at least about 0.020 mg, at least about 0.025 mg, at least about 0.030 mg, at least about 0.035 mg, at least about 0.040 mg, at least about 0.050 mg, at least about 0.060 mg, at least about 0.070 mg, at least about 0.080 mg, at least about 0.090 mg, at least about 0.10 mg, at least about 0.125 mg, at least about 0.150 mg, at least about 0.160 mg, at least about 0.170 mg, at least about 0.180 mg, at least about 0.190 mg, at least about 0.20 mg, at least about 0.210 mg, at least about 0.220 mg, at least about 0.230 mg, at least about 0.235 mg, at least about 0.240 mg, at least about 0.245 mg, at least about 0.250 mg, at least about 0.255 mg, at least about 0.260 mg, at least about 0.265 mg, at least about 0.270 mg, at least about 0.275 mg, at least about 0.280 mg, at least about 0.290 mg, at least about 0.300 mg, at least about 0.325 mg, at least about 0.350 mg, at least about 0.375 mg, at least about 0.40 mg, at least about 0.425 mg, at least about 0.450 mg, at least about 0.475 mg, at least about 0.500 mg, at least about 0.525 mg, at least about 0.50 mg, at least about 0.575 mg, at least about 0.60 mg, at least about 0.625 mg, at least about 0.650 mg, at least about 0.675 mg, at least about 0.70 mg, at least about 0.725 mg, at least about 0.750 mg, at least about 0.775 mg, at least about 0.80 mg, at least about 0.825 mg, at least about 0.850 mg, at least about 0.875 mg, at least about 0.90 mg, at least about 0.925 mg, at least about 0.950 mg, at least about 0.975 mg, at least about 1.0 mg, at least about 1.250 mg, at least about 1.50 mg, at least about 1.750, at least about 2.0 mg, at least about 2.10 mg, at least about 2.20 mg, at least about 2.30 mg, at least about 2.40 mg, at least about 2.5 mg, at least about 2.75 mg, at least about 3.0 mg, at least about 3.25 mg, at least about 3.50 mg, at least about 3.75 mg, at least about 4.0 mg, at least about 4.25 mg, at least about 4.50 mg, at least about 4.75 mg, at least about 5.0 mg, at least about 5.25 mg, at least about 5.50 mg, at least about 5.75 mg, at least about 6.0 mg, at least about 6.25 mg, at least about 6.50 mg, at least about 6.75 mg, at least about 7.0 mg, at least about 7.25 mg, at least about 7.50 mg, at least about 7.75 mg, at least about 8.0 mg, at least about 8.25 mg, at least about 8.5 mg, at least about 8.75 mg, at least about 9.0 mg, at least about 9.25 mg, at least about -33- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 9.50 mg, at least about 9.75 mg, at least about 10.0 mg, at least about 10.25 mg, at least about 10.50 mg, at least about 10.75 mg, at least about 11.0 mg at least about 11.5 mg, at least about 12.0 mg, at least about 12.5 mg, at least about 13.0 mg, at least about 13.5 mg, at least about 14.0 mg, at least about 14.5 mg, at least about 15.0 mg, at least about 15.5 mg, at least about 16.0 mg, at least about 16.50 mg, at least about 17.0 mg, at least about 17.5 mg, at least about 18.0 mg, at least about 18.5 mg, at least about 19.0 mg, at least about 19.5 mg, at least about 20.0 mg, at least about 20.5 mg, at least about 21.0 mg, at least about 21.5 mg, at least about 22.0 mg, at least about 22.5 mg, at least about 23.0 mg, at least about 23.5 mg, at least about 24.0 mg, at least about 24.5 mg, at least about 25.0 mg, at least about 25.5 mg, at least about 26.0 mg, at least about 26.5 mg, at least about 27.0 mg, at least about 27.5 mg, at least about 28.0 mg, at least about 28.5 mg, at least about 29.0 mg, at least about 29.5 mg, at least about 30.0 mg, at least about 30.5 mg, at least about 31.0 mg, at least about 31.5 mg, at least about 32.0 mg, at least about 32.5 mg, at least about 33.0 mg, at least about 33.5 mg, at least about 34.0 mg, at least about 34.5 mg, at least about 35.0 mg, at least about 35.5 mg, at least about 36.0 mg, at least about 36.5 mg, at least about 37.0 mg, at least about 37.5 mg, at least about 38.0 mg, at least about 38.5 mg, at least about 39.0 mg, at least about 39.5 mg, at least about 40.0 mg, at least about 40.5 mg, at least about 41.0 mg, at least about 41.5 mg, at least about 42.0 mg, at least about 42.5 mg, at least about 43.0 mg, at least about 43.5 mg, at least about 44.0 mg, at least about 44.5 mg, at least about 45.0 mg, at least about 45.5 mg, at least about 46.0 mg, at least about 46.5 mg, at least about 47.0 mg, at least about 47.5 mg, at least about 48.0 mg, at least about 48.5 mg, at least about 49.0 mg, at least about 49.5 mg, at least about 50.0 mg, at least about 50.5 mg, at least about 51.0 mg, at least about 51.5 mg, at least about 52.0 mg, at least about 52.5 mg, at least about 53.0 mg, at least about 53.5 mg, at least about 54.0 mg, at least about 54.5 mg, at least about 55.0 mg, at least about 55.5 mg, at least about 56.0 mg, at least about 56.5 mg, at least about 57.0 mg, at least about 57.5 mg, at least about 58.0 mg, at least about 58.5 mg, at least about 59.0 mg, at least about 59.5 mg, at least about 60.0 mg, at least about 60.5 mg, at least about 61.0 mg, at least about 61.5 mg, at least about 62.0 mg, at least about 62.5 mg, at least about 63.0 mg, at least about 63.5 mg, at least about 64.0 mg, at least about 64.5 mg, at least about 65.0 mg, at least about 65.5 mg, at least about 66.0 mg, at least about 66.5 mg, at least -34- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 about 67.0 mg, at least about 67.5 mg, at least about 68.0 mg, at least about 68.5 mg, at least about 69.0 mg, at least about 69.5 mg, at least about 70.0 mg, at least about 70.5 mg, at least about 71.0 mg, at least about 71.5 mg, at least about 72.0 mg, at least about 72.5 mg, at least about 73.0 mg, at least about 73.5 mg, at least about 74.0 mg, at least about 74.5 mg, at least about 75.0 mg, at least about 75.5 mg, at least about 76.0 mg, at least about 76.5 mg, at least about 77.0 mg, at least about 77.5 mg, at least about 78.0 mg, at least about 78.5 mg, at least about 79.0 mg, at least about 79.5 mg, at least about 80.0 mg, at least about 80.5 mg, at least about 81.0 mg, at least about 81.5 mg, at least about 82.0 mg, at least about 82.5 mg, at least about 83.0 mg, at least about 83.5 mg, at least about 84.0 mg, at least about 84.5 mg, at least about 85.0 mg, at least about 85.5 mg, at least about 86.0 mg, at least about 86.5 mg, at least about 87.0 mg, at least about 87.5 mg, at least about 88.0 mg, at least about 88.5 mg, at least about 89.0 mg, at least about 89.5 mg, at least about 90.0 mg, at least about 90.5 mg, at least about 91.0 mg, at least about 91.5 mg, at least about 92.0 mg, at least about 92.5 mg, at least about 93.0 mg, at least about 93.5 mg, at least about 94.0 mg, at least about 94.5 mg, at least about 95.0 mg, at least about 95.5 mg, at least about 96.0 mg, at least about 96.5 mg, at least about 97.0 mg, at least about 97.5 mg, at least about 98.0 mg, at least about 98.5 mg, at least about 99.0 mg, at least about 99.5 mg, at least about 100.0 mg, at least about 100.5 mg, at least about 101.0 mg, at least about 101.5 mg, at least about 102.0 mg, at least about 102.5 mg, at least about 103.0 mg, at least about 103.5 mg, at least about 104.0 mg, at least about 104.5 mg, at least about 105.0 mg, at least about 105.5 mg, at least about 106.0 mg, at least about 106.5 mg, at least about 107.0 mg, at least about 107.5 mg, at least about 108.0 mg, at least about 108.5 mg, at least about 109.0 mg, at least about 109.5 mg, at least about 110.0 mg, at least about 110.5 mg, at least about 111.0 mg, at least about 111.5 mg, at least about 112.0 mg, at least about 112.5 mg, at least about 113.0 mg, at least about 113.5 mg, at least about 114.0 mg, at least about 114.5 mg, at least about 115.0 mg, at least about 115.5 mg, at least about 116.0 mg, at least about 116.5 mg, at least about 117.0 mg, at least about 117.5 mg, at least about 118.0 mg, at least about 118.5 mg, at least about 119.0 mg, at least about 119.5 mg, at least about 120.0 mg, at least about 120.5 mg, at least about 121.0 mg, at least about 121.5 mg, at least about 122.0 mg, at least about 122.5 mg, at least about 123.0 mg, at least about 123.5 mg, at least about 124.0 mg, at least about 124.5 mg, at least -35- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 about 125.0 mg, at least about 125.5 mg, at least about 126.0 mg, at least about 126.5 mg, at least about 127.0 mg, at least about 127.5 mg, at least about 128.0 mg, at least about 128.5 mg, at least about 129.0 mg, at least about 129.5 mg, at least about 130.0 mg, at least about 130.5 mg, at least about 131.0 mg, at least about 131.5 mg, at least about 132.0 mg, at least about 132.5 mg, at least about 133.0 mg, at least about 133.5 mg, at least about 134.0 mg, at least about 134.5 mg, at least about 135.0 mg, at least about 135.5 mg, at least about 136.0 mg, at least about 136.5 mg, at least about 137.0 mg, at least about 137.5 mg, at least about 138.0 mg, at least about 138.5 mg, at least about 139.0 mg, at least about 139.5 mg, or at least about 140.0 mg of one or more allergens.

[0169] The daily dose may be administered to a subject in need thereof in unit doses which together comprise the full daily dose. In some embodiments, the daily dose is administered as one-unit doses, as two-unit doses, as three-unit doses, as four-unit doses, as five-unit doses, or as six-unit doses, each of which may be administered at once or separately throughout a single day to administer the full daily dose. For example, a daily dose administered as a one-unit dose refers to the total dose received by the subject in a single day being administered in one unit. In another example, a daily dose administered as a two-unit dose refers to the total dose received by the subject in a single day being administered in two units. In some embodiments, when the daily dose is administered as more than one-unit doses, the unit doses comprise or consist of the same dose. In some embodiments, when the daily dose is administered as more than one-unit doses, the unit doses comprise or consist of different doses. The unit doses may be administered hourly, daily, weekly, biweekly, monthly, or any combination thereof. One-Unit Doses, Two-Unit Doses, and Three-Unit Doses

[0170] In some embodiments, the daily dose comprises one-unit doses, two-unit doses, three-unit doses. In some embodiments, the one-unit, two-unit, or three-unit dose is provided in a daily dose comprising about 0.005 mg, about 0.075 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.03333 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.083 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.275 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.753 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.25 mg, -36- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 about 1.50 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 8.5 mg, about 9.0 mg, about 9.5 mg, about 10.0 mg, about 12.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 18.0 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 150 mg, or about 200 mg of the one or more allergens.

[0171] In some embodiments, the daily dose comprises one-unit doses, two-unit doses, three-unit doses. In some embodiments, the one-unit, two-unit, or three-unit dose is provided in a daily dose comprising at least 0.005 mg, at least 0.075 mg, at least 0.01 mg, at least 0.02 mg, at least 0.03 mg, at least 0.03333 mg, at least 0.04 mg, at least 0.05 mg, at least 0.06 mg, at least 0.07 mg, at least 0.08 mg, at least 0.083 mg, at least 0.09 mg, at least 0.1 mg, at least 0.2 mg, at least 0.25 mg, at least 0.275 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.6 mg, at least 0.7 mg, at least 0.753 mg, at least 0.8 mg, at least 0.9 mg, at least 1.0 mg, at least 1.25 mg, at least 1.50 mg, at least 1.75 mg, at least 2.0 mg, at least 2.25 mg, at least 2.5 mg, at least 2.75 mg, at least 3.0 mg, at least 3.5 mg, at least 4.0 mg, at least 4.5 mg, at least 5.0 mg, at least 5.5 mg, at least 6.0 mg, at least 6.5 mg, at least 7.0 mg, at least 7.5 mg, at least 8.0 mg, at least 8.5 mg, at least 9.0 mg, at least 9.5 mg, at least 10.0 mg, at least 12.0 mg, at least 14.0 mg, at least 15.0 mg, at least 16.0 mg, at least 18.0 mg, at least 20 mg, at least 22 mg, at least 24 mg, at least 25 mg, at least 26 mg, at least 28 mg, at least 30 mg, at least 32 mg, at least 36 mg, at least 38 mg, at least 40 mg, at least 42 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at least 150 mg, or at least 200 mg of the one or more allergens.

[0172] In some embodiments, the daily dose comprises one-unit doses, two-unit doses, three-unit doses. In some embodiments, the one-unit, two-unit, or three-unit dose is provided in a daily dose comprising at least about 0.005 mg, at least about 0.075 mg, at -37- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.03333 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.083 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.25 mg, at least about 0.275 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.753 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1.0 mg, at least about 1.25 mg, at least about 1.50 mg, at least about 1.75 mg, at least about 2.0 mg, at least about 2.25 mg, at least about 2.5 mg, at least about 2.75 mg, at least about 3.0 mg, at least about 3.5 mg, at least about 4.0 mg, at least about 4.5 mg, at least about 5.0 mg, at least about 5.5 mg, at least about 6.0 mg, at least about 6.5 mg, at least about 7.0 mg, at least about 7.5 mg, at least about 8.0 mg, at least about 8.5 mg, at least about 9.0 mg, at least about 9.5 mg, at least about 10.0 mg, at least about 12.0 mg, at least about 14.0 mg, at least about 15.0 mg, at least about 16.0 mg, at least about 18.0 mg, at least about 20 mg, at least about 22 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 28 mg, at least about 30 mg, at least about 32 mg, at least about 36 mg, at least about 38 mg, at least about 40 mg, at least about 42 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 150 mg, or at least about 200 mg of the one or more allergens. Additional Unit Doses

[0173] In some embodiments, the subject is administered a unit dose comprising about 0.001 mg to about 0.05 mg, about 0.10 mg to about 0.40 mg, about 1.0 mg to about 3.0 mg, about 6.0 mg to about 10 mg, or about 20 mg to about 80 mg.

[0174] In some embodiments, the subject is administered a unit dose comprising at least 0.001 mg to at least 0.05 mg, at least 0.10 mg to at least 0.40 mg, at least 1.0 mg to at least 3.0 mg, at least 6.0 mg to at least 10 mg, or at least 20 mg to at least 80 mg.

[0175] In some embodiments, the subject is administered a unit dose comprising at least about 0.001 mg to at least about 0.05 mg, at least about 0.10 mg to at least about 0.40 -38- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 mg, at least about 1.0 mg to at least about 3.0 mg, at least about 6.0 mg to at least about 10 mg, or at least about 20 mg to at least about 80 mg.

[0176] One or more unit doses may be administered to a subject in need thereof. For example, a subject may be administered an hourly, daily, weekly, or monthly first unit dose, and then may be administered a second unit dose after the administration of the first unit dose. In another example, a subject may be administered a first unit dose (administered as one-unit, two-unit, or three-unit doses) and is administered a second unit dose (administered as one-unit, two-unit, or three-unit doses) the following day.

[0177] In some embodiments, the subject is administered one or more doses. In some embodiments, the subject is administered two or more doses. In some embodiments, when the subject is administered two or more doses, two or more of the doses comprise the same dose. In some embodiments, when the subject is administered two or more doses, two or more of the doses consist of the same dose. In some embodiments, when the subject is administered two or more doses, two or more of the doses comprise different doses. In some embodiments, when the subject is administered two or more doses, two or more of the doses consist of different doses.

[0178] In some embodiments, a second unit dose is administered to the subject after the first unit dose. The second unit dose may be greater than the first unit dose. In some embodiments the second unit dose comprises an amount about 2 times greater than the first unit dose, about 3 times greater than the first unit dose, about 4 times greater than the first unit dose, about 5 times greater than the first unit dose, about 6 times greater than the first unit dose, about 7 times greater than first unit dose, about 8 times greater than the first unit dose, about 9 times greater than the first unit dose, or about 10 times greater amount of the one or more allergens.

[0179] In some embodiments, a second unit dose is administered to the subject after the first unit dose. The second unit dose may be greater than the first unit dose. In some embodiments the second unit dose comprises an amount at least 2 times greater than the first unit dose, at least 3 times greater than the first unit dose, at least 4 times greater than the first unit dose, at least 5 times greater than the first unit dose, at least 6 times greater than the first unit dose, at least 7 times greater than first unit dose, at least 8 times greater -39- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 than the first unit dose, at least 9 times greater than the first unit dose, or at least 10 times greater amount of the one or more allergens.

[0180] In some embodiments, a second unit dose is administered to the subject after the first unit dose. The second unit dose may be greater than the first unit dose. In some embodiments the second unit dose comprises an amount at least about 2 times greater than the first unit dose, at least about 3 times greater than the first unit dose, at least about 4 times greater than the first unit dose, at least about 5 times greater than the first unit dose, at least about 6 times greater than the first unit dose, at least about 7 times greater than first unit dose, at least about 8 times greater than the first unit dose, at least about 9 times greater than the first unit dose, or at least about 10 times greater amount of the one or more allergens.

[0181] In some embodiments, a third unit dose is administered to the subject after the second unit dose. The third unit dose may be greater than the second unit dose. In some embodiments, the third unit dose comprises an amount about 2 times greater than the second unit dose, about 3 times greater than the second unit dose, about 4 times greater than the second unit dose, about 5 times greater than the second unit dose, about 6 times greater than the second unit dose, about 7 times greater than second unit dose, about 8 times greater than the second unit dose, about 9 times greater than the second unit dose, or about 10 times greater amount of the one or more allergens.

[0182] In some embodiments, a third unit dose is administered to the subject after the second unit dose. The third unit dose may be greater than the second unit dose. In some embodiments, the third unit dose comprises an amount at least 2 times greater than the second unit dose, at least 3 times greater than the second unit dose, at least 4 times greater than the second unit dose, at least 5 times greater than the second unit dose, at least 6 times greater than the second unit dose, at least 7 times greater than second unit dose, at least 8 times greater than the second unit dose, at least 9 times greater than the second unit dose, or at least 10 times greater amount of the one or more allergens.

[0183] In some embodiments, a third unit dose is administered to the subject after the second unit dose. The third unit dose may be greater than the second unit dose. In some embodiments, the third unit dose comprises an amount at least about 2 times greater than -40- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 the second unit dose, at least about 3 times greater than the second unit dose, at least about 4 times greater than the second unit dose, at least about 5 times greater than the second unit dose, at least about 6 times greater than the second unit dose, at least about 7 times greater than second unit dose, at least about 8 times greater than the second unit dose, at least about 9 times greater than the second unit dose, or at least about 10 times greater amount of the one or more allergens.

[0184] In some embodiments, a fourth unit dose is administered to the subject after the third unit dose. The fourth unit dose may be greater than the third unit dose. In some embodiments, the fourth unit dose comprises an amount about 2 times greater than the third unit dose, about 3 times greater than the third unit dose, about 4 times greater than the third unit dose, about 5 times greater than the third unit dose, about 6 times greater than the third unit dose, about 7 times greater than third unit dose, about 8 times greater than the third unit dose, about 9 times greater than the third unit dose, or about 10 times greater amount of the one or more allergens.

[0185] In some embodiments, a fourth unit dose is administered to the subject after the third unit dose. The fourth unit dose may be greater than the third unit dose. In some embodiments, the fourth unit dose comprises an amount at least 2 times greater than the third unit dose, at least 3 times greater than the third unit dose, at least 4 times greater than the third unit dose, at least 5 times greater than the third unit dose, at least 6 times greater than the third unit dose, at least 7 times greater than third unit dose, at least 8 times greater than the third unit dose, at least 9 times greater than the third unit dose, or at least 10 times greater amount of the one or more allergens.

[0186] In some embodiments, a fourth unit dose is administered to the subject after the third unit dose. The fourth unit dose may be greater than the third unit dose. In some embodiments, the fourth unit dose comprises an amount at least about 2 times greater than the third unit dose, at least about 3 times greater than the third unit dose, at least about 4 times greater than the third unit dose, at least about 5 times greater than the third unit dose, at least about 6 times greater than the third unit dose, at least about 7 times greater than third unit dose, at least about 8 times greater than the third unit dose, at least about 9 times -41- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 greater than the third unit dose, or at least about 10 times greater amount of the one or more allergens.

[0187] In some embodiments, a fifth unit dose is administered to the subject after the fourth unit dose. The fifth unit dose may be greater than the fourth unit dose. In some embodiments, the fifth unit dose comprises an amount about 2 times greater than the fourth unit dose, about 3 times greater than the fourth unit dose, about 4 times greater than the fourth unit dose, about 5 times greater than the fourth unit dose, about 6 times greater than the fourth unit dose, about 7 times greater than fourth unit dose, about 8 times greater than the fourth unit dose, about 9 times greater than the fourth unit dose, or about 10 times greater amount of the one or more allergens.

[0188] In some embodiments, a fifth unit dose is administered to the subject after the fourth unit dose. The fifth unit dose may be greater than the fourth unit dose. In some embodiments, the fifth unit dose comprises an amount at least 2 times greater than the fourth unit dose, at least 3 times greater than the fourth unit dose, at least 4 times greater than the fourth unit dose, at least 5 times greater than the fourth unit dose, at least 6 times greater than the fourth unit dose, at least 7 times greater than fourth unit dose, at least 8 times greater than the fourth unit dose, at least 9 times greater than the fourth unit dose, or at least 10 times greater amount of the one or more allergens.

[0189] In some embodiments, a fifth unit dose is administered to the subject after the fourth unit dose. The fifth unit dose may be greater than the fourth unit dose. In some embodiments, the fifth unit dose comprises an amount at least about 2 times greater than the fourth unit dose, at least about 3 times greater than the fourth unit dose, at least about 4 times greater than the fourth unit dose, at least about 5 times greater than the fourth unit dose, at least about 6 times greater than the fourth unit dose, at least about 7 times greater than fourth unit dose, at least about 8 times greater than the fourth unit dose, at least about 9 times greater than the fourth unit dose, or at least about 10 times greater amount of the one or more allergens.

[0190] In some embodiments, a sixth unit dose is administered to the subject after the fifth unit dose. The sixth unit dose may be greater than the fifth unit dose. In some embodiments, the sixth unit dose comprises an amount about 2 times greater than the fifth -42- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 unit dose, about 3 times greater than the fifth unit dose, about 4 times greater than the fifth unit dose, about 5 times greater than the fifth unit dose, about 6 times greater than the fifth unit dose, about 7 times greater than fifth unit dose, about 8 times greater than the fifth unit dose, about 9 times greater than the fifth unit dose, or about 10 times greater amount of the one or more allergens.

[0191] In some embodiments, a sixth unit dose is administered to the subject after the fifth unit dose. The sixth unit dose may be greater than the fifth unit dose. In some embodiments, the sixth unit dose comprises an amount at least 2 times greater than the fifth unit dose, at least 3 times greater than the fifth unit dose, at least 4 times greater than the fifth unit dose, at least 5 times greater than the fifth unit dose, at least 6 times greater than the fifth unit dose, at least 7 times greater than fifth unit dose, at least 8 times greater than the fifth unit dose, at least 9 times greater than the fifth unit dose, or at least 10 times greater amount of the one or more allergens.

[0192] In some embodiments, a sixth unit dose is administered to the subject after the fifth unit dose. The sixth unit dose may be greater than the fifth unit dose. In some embodiments, the sixth unit dose comprises an amount at least about 2 times greater than the fifth unit dose, at least about 3 times greater than the fifth unit dose, at least about 4 times greater than the fifth unit dose, at least about 5 times greater than the fifth unit dose, at least about 6 times greater than the fifth unit dose, at least about 7 times greater than fifth unit dose, at least about 8 times greater than the fifth unit dose, at least about 9 times greater than the fifth unit dose, or at least about 10 times greater amount of the one or more allergens.

[0193] In some embodiments, a seventh unit dose is administered to the subject after the sixth unit dose. The seventh unit dose may be greater than the sixth unit dose. In some embodiments, the seventh unit dose comprises an amount about 2 times greater than the sixth unit dose, about 3 times greater than the sixth unit dose, about 4 times greater than the sixth unit dose, about 5 times greater than the sixth unit dose, about 6 times greater than the sixth unit dose, about 7 times greater than sixth unit dose, about 8 times greater than the sixth unit dose, about 9 times greater than the sixth unit dose, or about 10 times greater amount of the one or more allergens. -43- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0194] In some embodiments, a seventh unit dose is administered to the subject after the sixth unit dose. The seventh unit dose may be greater than the sixth unit dose. In some embodiments, the seventh unit dose comprises an amount at least 2 times greater than the sixth unit dose, at least 3 times greater than the sixth unit dose, at least 4 times greater than the sixth unit dose, at least 5 times greater than the sixth unit dose, at least 6 times greater than the sixth unit dose, at least 7 times greater than sixth unit dose, at least 8 times greater than the sixth unit dose, at least 9 times greater than the sixth unit dose, or at least 10 times greater amount of the one or more allergens.

[0195] In some embodiments, a seventh unit dose is administered to the subject after the sixth unit dose. The seventh unit dose may be greater than the sixth unit dose. In some embodiments, the seventh unit dose comprises an amount at least about 2 times greater than the sixth unit dose, at least about 3 times greater than the sixth unit dose, at least about 4 times greater than the sixth unit dose, at least about 5 times greater than the sixth unit dose, at least about 6 times greater than the sixth unit dose, at least about 7 times greater than sixth unit dose, at least about 8 times greater than the sixth unit dose, at least about 9 times greater than the sixth unit dose, or at least about 10 times greater amount of the one or more allergens.

[0196] In some embodiments, an eighth unit dose is administered to the subject after the seventh unit dose. The eighth unit dose may be greater than the seventh unit dose. In some embodiments, the eighth unit dose comprises an amount about 2 times greater than the seventh unit dose, about 3 times greater than the seventh unit dose, about 4 times greater than the seventh unit dose, about 5 times greater than the seventh unit dose, about 6 times greater than the seventh unit dose, about 7 times greater than seventh unit dose, about 8 times greater than the seventh unit dose, about 9 times greater than the seventh unit dose, or about 10 times greater amount of the one or more allergens.

[0197] In some embodiments, an eighth unit dose is administered to the subject after the seventh unit dose. The eighth unit dose may be greater than the seventh unit dose. In some embodiments, the eighth unit dose comprises an amount at least 2 times greater than the seventh unit dose, at least 3 times greater than the seventh unit dose, at least 4 times greater than the seventh unit dose, at least 5 times greater than the seventh unit dose, at -44- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 least 6 times greater than the seventh unit dose, at least 7 times greater than seventh unit dose, at least 8 times greater than the seventh unit dose, at least 9 times greater than the seventh unit dose, or at least 10 times greater amount of the one or more allergens.

[0198] In some embodiments, an eighth unit dose is administered to the subject after the seventh unit dose. The eighth unit dose may be greater than the seventh unit dose. In some embodiments, the eighth unit dose comprises an amount at least about 2 times greater than the seventh unit dose, at least about 3 times greater than the seventh unit dose, at least about 4 times greater than the seventh unit dose, at least about 5 times greater than the seventh unit dose, at least about 6 times greater than the seventh unit dose, at least about 7 times greater than seventh unit dose, at least about 8 times greater than the seventh unit dose, at least about 9 times greater than the seventh unit dose, or at least about a 10 times greater amount of the one or more allergens.

[0199] In some embodiments, a ninth unit dose is administered to the subject after the eighth unit dose. The ninth unit dose may be greater than the eighth unit dose. In some embodiments, the ninth unit dose comprises an amount about 2 times greater than the eighth unit dose, about 3 times greater than the eighth unit dose, about 4 times greater than the eighth unit dose, about 5 times greater than the eighth unit dose, about 6 times greater than the eighth unit dose, about 7 times greater than eighth unit dose, about 8 times greater than the eighth unit dose, about 9 times greater than the eighth unit dose, or about 10 times greater amount of the one or more allergens.

[0200] In some embodiments, a ninth unit dose is administered to the subject after the eighth unit dose. The ninth unit dose may be greater than the eighth unit dose. In some embodiments, the ninth unit dose comprises an amount at least 2 times greater than the eighth unit dose, at least 3 times greater than the eighth unit dose, at least 4 times greater than the eighth unit dose, at least 5 times greater than the eighth unit dose, at least 6 times greater than the eighth unit dose, at least 7 times greater than eighth unit dose, at least 8 times greater than the eighth unit dose, at least 9 times greater than the eighth unit dose, or at least 10 times greater amount of the one or more allergens.

[0201] In some embodiments, a ninth unit dose is administered to the subject after the eighth unit dose. The ninth unit dose may be greater than the eighth unit dose. In some -45- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 embodiments, the ninth unit dose comprises an amount at least about 2 times greater than the eighth unit dose, at least about 3 times greater than the eighth unit dose, at least about 4 times greater than the eighth unit dose, at least about 5 times greater than the eighth unit dose, at least about 6 times greater than the eighth unit dose, at least about 7 times greater than eighth unit dose, at least about 8 times greater than the eighth unit dose, at least about 9 times greater than the eighth unit dose, or at least about 10 times greater amount of the one or more allergens.

[0202] In some embodiments, a tenth unit dose is administered to the subject after the ninth unit dose. The tenth unit dose may be greater than the ninth unit dose. In some embodiments, the tenth unit dose comprises an amount about 2 times greater than the ninth unit dose, about 3 times greater than the ninth unit dose, about 4 times greater than the ninth unit dose, about 5 times greater than the ninth unit dose, about 6 times greater than the ninth unit dose, about 7 times greater than ninth unit dose, about 8 times greater than the ninth unit dose, about 9 times greater than the ninth unit dose, or about 10 times greater amount of the one or more allergens.

[0203] In some embodiments, a tenth unit dose is administered to the subject after the ninth unit dose. The tenth unit dose may be greater than the ninth unit dose. In some embodiments, the tenth unit dose comprises an amount at least 2 times greater than the ninth unit dose, at least 3 times greater than the ninth unit dose, at least 4 times greater than the ninth unit dose, at least 5 times greater than the ninth unit dose, at least 6 times greater than the ninth unit dose, at least 7 times greater than ninth unit dose, at least 8 times greater than the ninth unit dose, at least 9 times greater than the ninth unit dose, or at least 10 times greater amount of the one or more allergens.

[0204] In some embodiments, a tenth unit dose is administered to the subject after the ninth unit dose. The tenth unit dose may be greater than the ninth unit dose. In some embodiments, the tenth unit dose comprises an amount at least about 2 times greater than the ninth unit dose, at least about 3 times greater than the ninth unit dose, at least about 4 times greater than the ninth unit dose, at least about 5 times greater than the ninth unit dose, at least about 6 times greater than the ninth unit dose, at least about 7 times greater than ninth unit dose, at least about 8 times greater than the ninth unit dose, at least about -46- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 9 times greater than the ninth unit dose, or at least about 10 times greater amount of the one or more allergens.

[0205] In some embodiments, the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth unit dose is administered daily for about 4 days, 5 days, 7 days, 10 days, 2 weeks, or three weeks. In some embodiments, the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth unit dose is administered daily for at least 4 days, 5 days, 7 days, 10 days, 2 weeks, or three weeks. In some embodiments, the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth unit dose is administered daily for at least about 4 days, 5 days, 7 days, 10 days, 2 weeks, or three weeks.

[0206] In some embodiments, the first unit dose and the second unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the first unit dose and the second unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the first unit dose and the second unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0207] In some embodiments, the second unit dose and the third unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the second unit dose and the third unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the second unit dose and the third unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0208] In some embodiments, the third unit dose and the fourth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the third unit dose and the fourth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the third unit dose -47- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 and the fourth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0209] In some embodiments, the fourth unit dose and the fifth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the fourth unit dose and the fifth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the fourth unit dose and the fifth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0210] In some embodiments, the fifth unit dose and the sixth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the fifth unit dose and the sixth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the fifth unit dose and the sixth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0211] In some embodiments, the sixth unit dose and the seventh unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the sixth unit dose and the seventh unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the sixth unit dose and the seventh unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0212] In some embodiments, the seventh unit dose and the eighth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the seventh unit dose and the eighth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, -48- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the seventh unit dose and the eighth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0213] In some embodiments, the eighth unit dose and the ninth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the eighth unit dose and the ninth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the eighth unit dose and the ninth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0214] In some embodiments, the ninth unit dose and the tenth unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart. In some embodiments, the ninth unit dose and the tenth unit dose are administered at least a day apart, at least a week apart, at least 2 weeks apart, at least 3 weeks apart, or at least 4 weeks apart. In some embodiments, the ninth unit dose and the tenth unit dose are administered at least about a day apart, at least about a week apart, at least about 2 weeks apart, at least about 3 weeks apart, or at least about 4 weeks apart.

[0215] In some embodiments, a subject in need thereof is administered a first dose of pharmaceutical composition comprised of a one unit-dose of about 0.028 mg of one or more allergens administered once daily, providing a total of about 0.028 mg per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition comprised of a three-unit dose of about 0.028 mg of the one or more allergens administered three times daily, providing a total of about 0.083 mg per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprised of a one- unit dose of about 0.251 mg of the one or more allergens administered once daily, providing a total of about 0.251 mg per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprised of a three-unit dose of about 0.251 mg -49- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 of the one or more allergens administered three times daily, providing a total of about 0.753 mg per day.

[0216] In some embodiments, the subject is administered a first dose of the pharmaceutical composition comprised of a three-unit dose of about 0.028 mg of the one or more allergens administered three times daily, providing a total of about 0.083 mg per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprised of a one-unit dose of about 0.251 mg of the one or more allergens administered once daily, providing a total of about 0.251 mg per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprised of a three-unit dose of about 0.251 mg of the one or more allergens administered three times daily, providing a total of about 0.753 mg per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprised of a one-unit dose of about 2.25 mg of the one or more allergens administered once daily, providing a total of about 2.25 mg per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprised of a two-unit dose of about 2.25 mg of the one or more allergens administered twice daily, providing a total of about 4.5 mg per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprised of a one-unit dose of about 9.0 mg of the one or more allergens administered once daily, providing a total of about 9.0 mg per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprised of a two-unit dose of about 9.0 mg of the one or more allergens administered twice daily, providing a total of about 18.0 mg per day. In some embodiments, the subject is administered an eighth dose of the pharmaceutical composition, comprised of a one-unit dose of about 40.0 mg of the one or more allergens administered once daily, providing a total of about 40.0 mg per day. In some embodiments, the subject is administered a ninth dose of the pharmaceutical composition, comprised of a two-unit dose of about 40.0 mg of the one or more allergens administered twice daily, providing a total of about 80.0 mg per day. In some embodiments, the subject is administered a tenth dose of the pharmaceutical composition, comprised of a three-unit dose of about 120.0 mg of the one or more allergens administered three times daily, providing a total of about 120 mg per day. -50- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0217] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprised of a one-unit dose of about 0.251 mg of the one or more allergens administered once daily, providing a total of about 0.251 mg per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprised of a three-unit dose of about 0.251 mg of the one or more allergens administered three times daily, providing a total of about 0.753 mg per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprised of a one- unit dose of about 2.25 mg of the one or more allergens administered once daily, providing a total of about 2.25 mg per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprised of a two-unit dose of about 2.25 mg of the one or more allergens administered twice daily, providing a total of about 4.5 mg per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprised of a one-unit dose of about 9.0 mg of the one or more allergens administered once daily, providing a total of about 9.0 mg per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprised of a two-unit dose of about 9.0 mg of the one or more allergens administered twice daily, providing a total of about 18.0 mg per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprised of a one-unit dose of about 40.0 mg of the one or more allergens administered once daily, providing a total of about 40.0 mg per day. In some embodiments, the subject is administered an eighth dose of the pharmaceutical composition, comprised of a two-unit dose of about 40.0 mg of the one or more allergens administered twice daily, providing a total of about 80.0 mg per day.

[0218] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprised of a three-unit dose of about 0.251 mg of the one or more allergens administered three times daily, providing a total of about 0.753 mg per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprised of a one-unit dose of about 2.25 mg of the one or more allergens administered once daily, providing a total of about 2.25 mg per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprised of a two-unit dose of about 2.25 mg of the one or more allergens administered twice daily, -51- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 providing a total of about 4.5 mg per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprised of a one-unit dose of about 9.0 mg of the one or more allergens administered once daily, providing a total of about 9.0 mg per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprised of a two-unit dose of about 9.0 mg of the one or more allergens administered twice daily, providing a total of about 18.0 mg per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprised of a one-unit dose of about 40.0 mg of the one or more allergens administered once daily, providing a total of about 40.0 mg per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprised of a two-unit dose of about 40.0 mg of the one or more allergens administered twice daily, providing a total of about 80.0 mg per day.

[0219] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising about 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising about 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprising about 4.5 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising about 9.0 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising about 18 mg of the one or more allergens per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprising about 36 mg of the one or more allergens per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprising about 60 mg of the one or more allergens per day.

[0220] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising at least 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising at least 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, -52- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 comprising at least 4.5 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising at least 9.0 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising at least 18 mg of the one or more allergens per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprising at least 36 mg of the one or more allergens per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprising at least 60 mg of the one or more allergens per day.

[0221] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising at least about 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising at least about 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprising at least about 4.5 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising at least about 9.0 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising at least about 18 mg of the one or more allergens per day. In some embodiments, the subject is administered a sixth dose of the pharmaceutical composition, comprising at least about 36 mg of the one or more allergens per day. In some embodiments, the subject is administered a seventh dose of the pharmaceutical composition, comprising at least about 60 mg of the one or more allergens per day.

[0222] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising about 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising about 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprising about 6.67 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising about -53- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 20 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising about 60 mg of the one or more allergens per day.

[0223] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising at least 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising at least 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprising at least 6.67 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising at least 20 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising at least 60 mg of the one or more allergens per day.

[0224] In some embodiments, the subject is administered a first dose of the pharmaceutical composition, comprising at least about 0.75 mg of the one or more allergens per day. In some embodiments, the subject is administered a second dose of the pharmaceutical composition, comprising at least about 2.25 mg of the one or more allergens per day. In some embodiments, the subject is administered a third dose of the pharmaceutical composition, comprising at least about 6.67 mg of the one or more allergens per day. In some embodiments, the subject is administered a fourth dose of the pharmaceutical composition, comprising at least about 20 mg of the one or more allergens per day. In some embodiments, the subject is administered a fifth dose of the pharmaceutical composition, comprising at least about 60 mg of the one or more allergens per day. Maintenance Phase

[0225] Administration of the pharmaceutical composition may further comprise a maintenance phase. The maintenance phase may maintain tolerance at the subject’s highest tolerated dose for a desired period. The maintenance phase may comprise or consist of administering two different doses or two of the same doses. In some embodiments the maintenance phase comprises about a daily, twice weekly, weekly, biweekly, or monthly dose. In some embodiments, the maintenance phase may last anywhere from one week to -54- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 indefinitely. In some embodiments, the maintenance phase comprises administering a single dose.

[0226] In some embodiments, the subject is administered a first daily dose provided herein as a one-unit dose, a two-unit dose, or a three-unit dose during the maintenance phase. In some embodiments, the subject is administered a second daily dose as a one-unit dose, a two-unit dose, or a three-unit dose during the maintenance phase.

[0227] In some embodiments, the maintenance phase comprises administering to the subject one or more doses of the pharmaceutical composition comprising about 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, or about 120 mg of the one or more allergens.

[0228] In some embodiments, the maintenance phase comprises administering to the subject one or more doses of the pharmaceutical composition comprising at least 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, or about 120 mg of the one or more allergens.

[0229] In some embodiments, the maintenance phase comprises administering to the subject one or more doses of the pharmaceutical composition comprising at least about 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, or about 120 mg of the one or more allergens.

[0230] In some embodiments, the maintenance phase comprises administering to the subject two or more doses of the pharmaceutical composition comprising about 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, 120 mg or any combination thereof of the one or more allergens. In some embodiments, the doses are administered as unit-doses.

[0231] In some embodiments, the maintenance phase comprises administering to the subject two or more doses of the pharmaceutical composition comprising at least 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, 120 mg or any combination thereof of the one or more allergens. In some embodiments, the doses are administered as unit-doses. -55- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0232] In some embodiments, the maintenance phase comprises administering to the subject two or more doses of the pharmaceutical composition comprising at least about 0.083 mg, 0.251 mg, 0.753 mg, 2.25 mg, 4.5 mg, 9.0 mg, 18.0 mg, 40.0 mg, 80.0 mg, 120 mg or any combination thereof of the one or more allergens. In some embodiments, the doses are administered as unit-doses.

[0233] In some embodiments, the maintenance phase is about 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, or 50 weeks in length.

[0234] In some embodiments, the maintenance phase is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, or 50 weeks in length.

[0235] In some embodiments, the maintenance phase is at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, or 50 weeks in length. Cumulative Dose

[0236] In some embodiments, the cumulative dose administered to the subject comprises the total amount of allergen administered over the total daily doses only or the total amount of allergen administered the daily doses and the maintenance phase dose collectively. In some embodiments, the cumulative dose is about 1 mg, 2, mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 -56- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105 mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg, 1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg, 1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg, 1250 mg.

[0237] In some embodiments, the cumulative dose is at least 1 mg, 2, mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, -57- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105 mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg, 1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg, 1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg, 1250 mg.

[0238] In some embodiments, the cumulative dose is at least about 1 mg, 2, mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, -58- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105 mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg, 1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg, 1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg, 1250 mg. Associated Methods

[0239] The present technology comprises methods which comprise administration of one or more pharmaceutical compositions of the present technology to a subject in need thereof. When administered to the subject, the one or more allergens of the pharmaceutical composition are taken up by Langerhans cells in regions where Langerhans cells are concentrated (i.e., the subcutaneous space or the oral mucosa), T regulatory (Treg) cells are stimulated, up-regulating IL-10 and TGF-β transcript and protein levels, leading to an increased T-helper (Th)1 / Th2 ratio and down-regulation of the allergic response.

[0240] In some embodiments, The present technology comprises methods of immunomodulation, wherein administration of the one or more pharmaceutical compositions elicits an immune response to the one or more allergens. When the dosing of the one or more pharmaceutical compositions is complete and the subject is exposed to the one or more allergens, the subject’s immune response may be reduced or prevented relative to the subject’s immune response prior to administration of the one or more pharmaceutical compositions.

[0241] In some embodiments, The present technology comprises a method of increasing tolerance to one or more allergens in a subject in need thereof. In some embodiments, the method of increasing tolerance comprises administering the one or more allergens as a unit dose once daily.

[0242] In some embodiments, The present technology comprises a method of increasing tolerance to one or more peanut allergens. This includes reducing adverse and / or -59- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 inflammatory reactions during or after exposure to peanuts (e.g., whole peanut, peanut proteins, peanut peptides, and peanut epitopes), peanut products, and peanut extract. In some embodiments, The present technology comprises a method of increasing tolerance to an Ara h 1 epitope. In some embodiments, The present technology comprises a method of increasing tolerance to an Ara h 2 epitope. In some embodiments, The present technology comprises a method of increasing tolerance to an Ara h 3 epitope. In some embodiments, The present technology comprises a method of increasing tolerance to an Ara h 6 epitope.

[0243] In some embodiments, increasing administration duration with one or more pharmaceutical compositions of the present technology increases tolerance to the one or more food allergens relative to a shorter administration duration. In some embodiments, increasing administration duration with one or more pharmaceutical compositions of the present technology increases tolerance to the one or more peanut allergens relative to a shorter administration duration. In some embodiments, the tolerance is permanent.

[0244] In some embodiments, The present technology comprises a method of reducing risk of or severity of one or more adverse reactions to one or more allergens in a subject in need thereof relative to a control. In some embodiments, the method of reducing risk of or severity of one or more adverse reactions to one or more or more allergens comprises administering the one or more allergens as a unit dose once daily.

[0245] In some embodiments, The present technology comprises a method of reducing the need for or amount of a rescue medication during or after exposure to one or more allergens in a subject in need thereof relative to a control. “After exposure” may refer to about one second, about 30 minutes, about one hour, about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about ten weeks, about fifteen weeks, about twenty weeks, about twenty-five weeks, about thirty weeks, about thirty-five weeks, about 40 weeks, about 50 weeks, or about one year. In some embodiments, the method of reducing the need for or amount of a rescue medication during or after exposure to one or more allergens comprises administering the one or more allergens as a unit dose once daily. Nonlimiting examples of rescue medications include an antihistamine (e.g., cetirizine, loratadine, fexofenadine, and diphenhydramine), a decongestant (e.g., pseudoephedrine and phenylephrine), a corticosteroid (e.g., an oral -60- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 corticosteroid, an injectable corticosteroid, a topical corticosteroid, a nasal corticosteroid, and an inhaled corticosteroid), a leukotriene inhibitor, a mast cell stabilizer, an immunomodulator, an eye drop, a sympathomimetic agent (e.g., epinephrine), and a β2- andrenergic agonist (e.g., albuterol).

[0246] In some embodiments, The present technology comprises a method of reducing levels of or preventing formation of one or more peanut allergen-specific IgE, IgG4, or IgA antibodies relative to a control in a subject in need thereof, the method comprising administering a unit dose comprising one or more peanut allergens to the subject, wherein the peanut allergen-specific IgE, IgG4, or IgA antibodies are specific for an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9, SSP-1, SSP-2, and anti-conglutinin. In some embodiments, The present technology comprises a method of reducing levels of or reducing antibodies specific to Ara h 1, Ara h 2, Ara h 3, and Ara h 6 n some embodiments, The present technology comprises a method of reducing levels of or reducing antibodies specific to Ara h 1. In some embodiments, The present technology comprises a method of reducing levels of or reducing antibodies specific to Ara h 2. In some embodiments, The present technology comprises a method of reducing levels of or reducing antibodies specific to Ara h 3. In some embodiments, The present technology comprises a method of reducing levels of or reducing antibodies specific to Ara h 6. In some embodiments, the method of reducing levels of or preventing formation of one or more peanut specific IgE, IgG4, or IgA antibodies comprises administering the one or peanut allergens as a unit dose once daily.

[0247] In some embodiments, the subject of any one of the methods has one or more allergies or allergen sensitivities. In some embodiments, the subject is allergic to one or more peanut allergens. In some embodiments, the subject has a peanut allergen specific IgE, IgG4, or IgA response that is greater than about 0.35 kU / L. In some embodiments, the subject has a peanut allergen specific IgE, IgG4, or IgA baseline response level that is greater than about 0.40 kU / L, about 0.50 kU / L, about 0.55 kU / L, about 0.60 kU / L, about 0.65 kU / L, about 0.70 kU / L, about 0.75 kU / L, 0.80 kU / L, about 0.85 kU / L, about 0.90 kU / L, about 0.95 kU / L, or about 1.0 kU / L. -61- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0248] In some embodiments, the subject has a peanut allergen specific IgE, IgG4, or IgA baseline response level that is greater than at least 0.40 kU / L, at least 0.50 kU / L, at least 0.55 kU / L, at least 0.60 kU / L, at least 0.65 kU / L, at least 0.70 kU / L, at least 0.75 kU / L, at least 0.80 kU / L, at least 0.85 kU / L, at least 0.90 kU / L, at least 0.95 kU / L, or at least 1.0 kU / L.

[0249] In some embodiments, the subject has a peanut allergen specific IgE, IgG4, or IgA baseline response level that is greater than at least about 0.40 kU / L, at least about 0.50 kU / L, at least about 0.55 kU / L, at least about 0.60 kU / L, at least about 0.65 kU / L, at least about 0.70 kU / L, at least about 0.75 kU / L, at least about 0.80 kU / L, at least about 0.85 kU / L, at least about 0.90 kU / L, at least about 0.95 kU / L, or at least about 1.0 kU / L.

[0250] In some embodiments, any one of the methods of the present technology comprises administering to the subject in need thereof, one or more peanut allergens administered at any dose or frequency of the present technology. The subject may be male or female and may be age 18 to 65.

[0251] In some embodiments, the subject has a baseline tolerance to one or more peanut allergens that is less than or equal to about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg , 0.07 mg, 0.08 mg, 0.09 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, or 1000 mg.

[0252] In some embodiments, the subject has a baseline tolerance to one or more peanut allergens that is less than or equal to at least 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg , 0.07 mg, 0.08 mg, 0.09 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 -62- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, or 1000 mg.

[0253] In some embodiments, the subject has a baseline tolerance to one or more peanut allergens that is less than or equal to at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg , 0.07 mg, 0.08 mg, 0.09 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, or 1000 mg.

[0254] In some embodiments, the subject has a baseline skin prick test (SPT) Wheal Diameter of greater than or equal to 100 mm, 150 mm, 200 mm, 250 mm, 300 mm, 350 mm, 400 mm, 450 mm, 500 mm, or more.

[0255] In some embodiments, the methods comprise further administering a rescue medication. In some embodiments, the subject does not require administration of a rescue medication.

[0256] In some embodiments, subject administered the daily dose of the one or more allergens experiences a reduction in risk of or severity of one or more adverse reactions to one or more allergens. In some embodiments, the one or more allergens comprise a peanut allergen. In some embodiments, the peanut allergen comprises an Ara h 1 epitope, an Ara h 2 epitope, an Ara h 3 epitope, an Ara h 6 epitope, or any combination thereof.

[0257] In some embodiments, the reduced risk of or severity of one or more adverse reactions is the reaction the subject had to the one or more allergens, a related allergen, or to a non-related allergen prior to administration of one or more pharmaceutical compositions.

[0258] Nonlimiting examples of adverse reactions include an adverse reaction of the tongue, the eye, the eyelid, the mouth, the nose, the lips, the hand, the back, the scalp, the head, the ear, the abdomen, the gastrointestinal system, the respiratory system, the cardiovascular system, and the nervous system. -63- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0259] In some embodiments, the adverse reaction of the throat is selected from the group consisting of an itching of the throat, a swelling of the throat, a numbness of the throat, a pain in the throat, a burning of the throat, a tingling of the throat, a discomfort of the throat, a dryness of the throat, a soreness of the throat, a sinus infection symptom of the throat, and a cold and flu symptom of the throat.

[0260] In some embodiment, the adverse reaction of the tongue is selected from the group consisting of itching of the tongue, a swelling of the tongue, a numbness of the tongue, a pain in the tongue, a burning of the tongue, a tingling of the tongue, a discomfort of the tongue, a dryness of the tongue, and a soreness of the tongue.

[0261] In some embodiments, the adverse reaction of the eye is selected from the group consisting of itching of the eye, a swelling of the eye, a numbness of the eye, a pain in the eye, a burning of the eye, a tingling of the eye, a discomfort of the eye, a dryness of the eye, and a soreness of the eye.

[0262] In some embodiments, the eyelid is selected from the group consisting of itching of the eyelid, a swelling of the eyelid, a numbness or the eyelid, a pain in the eyelid, a burning of the eyelid, a tingling of the eyelid, a discomfort of the eyelid, a dryness of the eyelid, and a soreness of the eyelid.

[0263] In some embodiments, the adverse reaction of the mouth is selected from the group consisting of itching of the mouth, a swelling of the mouth, a numbness of the mouth, a pain in the mouth, a burning of the mouth, a tingling of the mouth, a discomfort of the mouth, a dryness of the mouth, a soreness of the mouth, a watery mouth, thickening saliva, and over salivating.

[0264] In some embodiments, the adverse reaction of the nose is selected from the group consisting of itching of the nose, a swelling of the nasal passage, a numbness of the nose, a burning of the nose, a tingling of the nose, a discomfort of the nose, a dryness of the nose, a soreness of the nasal passage, sneezing, runny nose, rhinorrhea, congestion, and a sinus infection symptom of the nose,

[0265] In some embodiments, the adverse reaction of the lips is selected from the group consisting of itching of the lips, a swelling of the lips, a numbness of the lips, a pain in -64- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 the lips, a burning of the lips, a tingling of the lips, a discomfort of the lips, a dryness of the lips, and a soreness of the lips.

[0266] In some embodiments, the adverse reaction of the hand is selected from the group consisting of itching of the hand, a swelling of the hand, a numbness of the hand, a pain in the hand, a burning of the hand, a tingling of the hand, a discomfort of the hand, dermatitis of the hand, hives on the hand, urticaria of the hand, pruritis of the hand, and cyanosis of the hand.

[0267] In some embodiments, the adverse reaction of the back is selected from the group consisting of itching of the back, a back pain, a tingling of the back, a discomfort of the back, dermatitis of the back, hives on the back, urticaria of the back, pruritis of the back, and cyanosis of the back.

[0268] In some embodiments, the adverse reaction of the scalp is selected from the group consisting of itching of the scalp, a scalp pain, a tingling of the scalp, a discomfort of the scalp, dermatitis of the scalp, hives on the scalp, urticaria of the scalp, and pruritis of the scalp.

[0269] In some embodiments, the adverse reaction of the ear is selected from the group consisting of itching of the ear, a swelling of the ear, a numbness of the ear, a pain in the ear, a burning of the ear, a tingling of the ear, a discomfort of the ear, a soreness of the ear, a pressure in the ear, and a sinus infection symptom of the ear.

[0270] In some embodiments, the adverse reaction of the abdomen is selected from the group consisting of abdominal pain, abdominal cramps, or abdominal discomfort.

[0271] In some embodiments, the adverse reaction of the gastrointestinal system is selected from the group consisting of nausea, vomiting, emesis, stomach pain, stomach cramps, intestinal discomfort, diarrhea, loss of bowel control, irregular flatulence, gas pain, indigestion, acid reflux, and gastroesophageal reflux.

[0272] In some embodiments, the adverse reaction of the respiratory system is selected from the group consisting of coughing, hoarseness, stridor, dyspnea, shortness of breath, wheezing, respiratory arrest, cold-like and flu-like symptoms of the respiratory system, and anaphylaxis. -65- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0273] In some embodiments, the adverse reaction of the cardiovascular system is selected from the group consisting of tachycardia, dysrhythmia, bradycardia, cardiac arrest, hypotension, blood pressure collapse, and loss of consciousness.

[0274] In some embodiments, the adverse reaction of the nervous system is selected form the group consisting of a headache, loss of consciousness, and confusion.

[0275] In some embodiments, the adverse reaction of the skin is selected from the group consisting of pruritis, urticaria, hives, itchiness, allergic dermatitis, cyanosis, and flushing.

[0276] In some embodiments, the adverse reaction of the immune system is selected from the group consisting of, a fever, cold sweats, body aches, cold-like symptoms, flu-like symptoms, and a severe allergic reaction.

[0277] In some embodiments, the subject administered a daily dose of one or more peanut allergens exhibits one or more of:

[0278] (a) an increase in tolerance to one or more peanut allergens by about 50%, 100%, 150%, 200%, 250%, 3005, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1100%, 1200%, 1300%, 1400%, 1500%, 1600%, 1700%, 1800%, 1900%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, 5000%, 5500%, 6000%, 6500%, 7000%, 7500%, 8000%, 8500%, 9000%, 9500%, 10000%, 15000%, 20000%, 25000%, 30000%, 35000%, 40000%, 45000%, 50000%, 55000%, 60000%, 65000%, 70000%, 75000%, 80000%, 85000%, 90000%, 95000%, 100000%, 150000%, 200000%, 250000%, 300000%, 350000%, 400000%, 450000%, 500000%, or more, relative to a control;

[0279] (b) a reduction in a peanut specific IgE by about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0280] (c) a reduction in a peanut specific IgA by about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control; -66- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0281] (d) a reduction in a peanut specific IgG by about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0282] (e) a reduction in swelling of the throat during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0283] (f) a reduction in itching of the throat during or after exposure to one or more peanut allergens relative to a control;

[0284] (h) a reduction in numbness of the throat during or after exposure to one or more peanut allergens relative to a control;

[0285] (i) a reduction in pain of the throat during or after exposure to one or more peanut allergens relative to a control;

[0286] (j) a reduction in burning of the throat during or after exposure to one or more peanut allergens relative to a control;

[0287] (k) a reduction in tingling in of the throat during or after exposure to one or more peanut allergens relative to a control;

[0288] (l) a reduction in discomfort of the throat during or after exposure to one or more peanut allergens relative to a control;

[0289] (l) a reduction in dryness of the throat during or after exposure to one or more peanut allergens relative to a control;

[0290] (m) a reduction in soreness of the throat during or after exposure to one or more peanut allergens relative to a control;

[0291] (n) a reduction in a sinus infection-like symptom during or after exposure to one or more peanut allergens relative to a control;

[0292] (o) a reduction in a cold-like symptom during or after exposure to one or more peanut allergens relative to a control; -67- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0293] (p) a reduction in a flu-like symptom during or after exposure to one or more peanut allergens relative to a control;

[0294] (q) a reduction in swelling of the tongue during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0295] (r) a reduction in itching of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0296] (s) a reduction in numbness of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0297] (t) a reduction in pain of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0298] (u) a reduction in burning of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0299] (v) a reduction in tingling in of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0300] (w) a reduction in discomfort of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0301] (x) a reduction in dryness of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0302] (y) a reduction in soreness of the tongue during or after exposure to one or more peanut allergens relative to a control;

[0303] (z) a reduction in swelling of the eye during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0304] (aa) a reduction in itching of the eye during or after exposure to one or more peanut allergens relative to a control; -68- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0305] (bb) a reduction in numbness of the eye during or after exposure to one or more peanut allergens relative to a control;

[0306] (cc) a reduction in pain of the eye during or after exposure to one or more peanut allergens relative to a control;

[0307] (dd) a reduction in burning of the eye during or after exposure to one or more peanut allergens relative to a control;

[0308] (ee) a reduction in tingling in of the eye during or after exposure to one or more peanut allergens relative to a control;

[0309] (ff) a reduction in discomfort of the eye during or after exposure to one or more peanut allergens relative to a control;

[0310] (gg) a reduction in dryness of the eye during or after exposure to one or more peanut allergens relative to a control;

[0311] (hh) a reduction in soreness of the eye during or after exposure to one or more peanut allergens relative to a control;

[0312] (ii) a reduction in swelling of the eyelid during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0313] (jj) a reduction in itching of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0314] (kk) a reduction in numbness of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0315] (ll) a reduction in pain of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0316] (mm) a reduction in burning of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0317] (nn) a reduction in tingling in of the eyelid during or after exposure to one or more peanut allergens relative to a control; -69- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0318] (oo) a reduction in discomfort of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0319] (pp) a reduction in dryness of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0320] (qq) a reduction in soreness of the eyelid during or after exposure to one or more peanut allergens relative to a control;

[0321] (rr) a reduction in swelling of the mouth during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0322] (ss) a reduction in itching of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0323] (tt) a reduction in numbness of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0324] (uu) a reduction in pain of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0325] (vv) a reduction in burning of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0326] (ww) a reduction in tingling in of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0327] (xx) a reduction in discomfort of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0328] (yy) a reduction in dryness of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0329] (zz) a reduction in soreness of the mouth during or after exposure to one or more peanut allergens relative to a control;

[0330] (aaa) a reduction in salivation during or after exposure to one or more peanut allergens relative to a control; -70- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0331] (bbb) a reduction in saliva thickness during or after exposure to one or more peanut allergens relative to a control;

[0332] (ccc) a reduction in swelling of the nasal passage during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0333] (ddd) a reduction in itching of the nose during or after exposure to one or more peanut allergens relative to a control;

[0334] (eee) a reduction in numbness of the nose during or after exposure to one or more peanut allergens relative to a control;

[0335] (fff) a reduction in pain of the nose during or after exposure to one or more peanut allergens relative to a control;

[0336] (ggg) a reduction in burning of the nose during or after exposure to one or more peanut allergens relative to a control;

[0337] (hhh) a reduction in tingling in of the nose during or after exposure to one or more peanut allergens relative to a control;

[0338] (iii) a reduction in discomfort of the nose during or after exposure to one or more peanut allergens relative to a control;

[0339] (kkk) a reduction in dryness of the nose during or after exposure to one or more peanut allergens relative to a control;

[0340] (lll) a reduction in soreness of the nose during or after exposure to one or more peanut allergens relative to a control;

[0341] (mmm) a reduction in sneezing during or after exposure to one or more peanut allergens relative to a control;

[0342] (nnn) a reduction in runniness of the nose during or after exposure to one or more peanut allergens relative to a control;

[0343] (ooo) a reduction in rhinorrhea during or after exposure to one or more peanut allergens relative to a control; -71- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0344] (ppp) a reduction in congestion during or after exposure to one or more peanut allergens relative to a control;

[0345] (qqq) a reduction in swelling of the lips during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0346] (rrr) a reduction in itching of the lips during or after exposure to one or more peanut allergens relative to a control;

[0347] (sss) a reduction in numbness of the lips during or after exposure to one or more peanut allergens relative to a control;

[0348] (ttt) a reduction in pain of the lips during or after exposure to one or more peanut allergens relative to a control;

[0349] (uuu) a reduction in burning of the lips during or after exposure to one or more peanut allergens relative to a control;

[0350] (vvv) a reduction in tingling in of the lips during or after exposure to one or more peanut allergens relative to a control;

[0351] (www) a reduction in discomfort of the lips during or after exposure to one or more peanut allergens relative to a control;

[0352] (xxx) a reduction in dryness of the lips during or after exposure to one or more peanut allergens relative to a control;

[0353] (yyy) a reduction in soreness of the lips during or after exposure to one or more peanut allergens relative to a control;

[0354] (zzz) a reduction in swelling of the hand during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0355] (aaaa) a reduction in itching of the hand during or after exposure to one or more peanut allergens relative to a control; -72- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0356] (bbbb) a reduction in numbness of the hand during or after exposure to one or more peanut allergens relative to a control;

[0357] (cccc) a reduction in pain of the hand during or after exposure to one or more peanut allergens relative to a control;

[0358] (dddd) a reduction in burning of the hand during or after exposure to one or more peanut allergens relative to a control;

[0359] (eeee) a reduction in tingling in of the hand during or after exposure to one or more peanut allergens relative to a control;

[0360] (ffff) a reduction in discomfort of the hand during or after exposure to one or more peanut allergens relative to a control;

[0361] (gggg) a reduction in dermatitis of the hand during or after exposure to one or more peanut allergens relative to a control;

[0362] (hhhh) a reduction in hives on the hand during or after exposure to one or more peanut allergens relative to a control;

[0363] (iiii) a reduction in urticaria of the hand during or after exposure to one or more peanut allergens relative to a control;

[0364] (jjjj) a reduction in pruritis of the hand during or after exposure to one or more peanut allergens relative to a control;

[0365] (kkkk) a reduction in cyanosis of the hand during or after exposure to one or more peanut allergens relative to a control;

[0366] (llll) a reduction in itching of the back during or after exposure to one or more peanut allergens relative to a control;

[0367] (mmmm) a reduction in numbness of the back during or after exposure to one or more peanut allergens relative to a control;

[0368] (nnnn) a reduction in pain of the back during or after exposure to one or more peanut allergens relative to a control; -73- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0369] (oooo) a reduction in burning of the back during or after exposure to one or more peanut allergens relative to a control;

[0370] (pppp) a reduction in tingling in of the back during or after exposure to one or more peanut allergens relative to a control;

[0371] (qqqq) a reduction in discomfort of the back during or after exposure to one or more peanut allergens relative to a control;

[0372] (rrrr) a reduction in dermatitis of the back during or after exposure to one or more peanut allergens relative to a control;

[0373] (ssss) a reduction in hives on the back during or after exposure to one or more peanut allergens relative to a control;

[0374] (tttt) a reduction in urticaria of the back during or after exposure to one or more peanut allergens relative to a control;

[0375] (uuuu) a reduction in pruritis of the back during or after exposure to one or more peanut allergens relative to a control;

[0376] (vvvv) a reduction in cyanosis of the back during or after exposure to one or more peanut allergens relative to a control;

[0377] (wwww) a reduction in itching of the scalp during or after exposure to one or more peanut allergens relative to a control;

[0378] (xxxx) a reduction in discomfort of the scalp during or after exposure to one or more peanut allergens relative to a control;

[0379] (yyyy) a reduction in dermatitis of the scalp during or after exposure to one or more peanut allergens relative to a control;

[0380] (zzzz) a reduction in hives of the scalp during or after exposure to one or more peanut allergens relative to a control;

[0381] (aaaaa) a reduction in urticaria of the scalp during or after exposure to one or more peanut allergens relative to a control; -74- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0382] (bbbbb) a reduction in pruritis of the scalp during or after exposure to one or more peanut allergens relative to a control;

[0383] (ccccc) a reduction in swelling of the ear during or after exposure to one or more peanut allergens by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control;

[0384] (ddddd) a reduction in itching of the ear during or after exposure to one or more peanut allergens relative to a control;

[0385] (eeeee) a reduction in numbness of the ear during or after exposure to one or more peanut allergens relative to a control;

[0386] (fffff) a reduction in pain of the ear during or after exposure to one or more peanut allergens relative to a control;

[0387] (ggggg) a reduction in burning of the ear during or after exposure to one or more peanut allergens relative to a control;

[0388] (hhhhh) a reduction in tingling in of the ear during or after exposure to one or more peanut allergens relative to a control;

[0389] (iiiii) a reduction in discomfort of the ear during or after exposure to one or more peanut allergens relative to a control;

[0390] (jjjjj) a reduction in dermatitis of the ear during or after exposure to one or more peanut allergens relative to a control;

[0391] (kkkkk) a reduction in pressure of the ear during or after exposure to one or more peanut allergens relative to a control;

[0392] (lllll) a reduction in abdominal pain during or after exposure to one or more peanut allergens relative to a control;

[0393] (mmmmm) a reduction in abdominal cramps during or after exposure to one or more peanut allergens relative to a control;

[0394] (nnnnn) a reduction in abdominal discomfort during or after exposure to one or more peanut allergens relative to a control; -75- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0395] (ooooo) a reduction in nausea during or after exposure to one or more peanut allergens relative to a control;

[0396] (ppppp) a reduction in vomiting during or after exposure to one or more peanut allergens relative to a control;

[0397] (qqqqq) a reduction in emesis during or after exposure to one or more peanut allergens relative to a control;

[0398] (rrrrr) a reduction in stomach pain during or after exposure to one or more peanut allergens relative to a control;

[0399] (sssss) a reduction in stomach cramps during or after exposure to one or more peanut allergens relative to a control;

[0400] (ttttt) a reduction in intestinal discomfort during or after exposure to one or more peanut allergens relative to a control;

[0401] (uuuuu) a reduction in diarrhea during or after exposure to one or more peanut allergens relative to a control;

[0402] (vvvvv) a reduction in irregular flatulence during or after exposure to one or more peanut allergens relative to a control;

[0403] (wwwww) a reduction in gas pain during or after exposure to one or more peanut allergens relative to a control;

[0404] (xxxxx) a reduction in indigestion during or after exposure to one or more peanut allergens relative to a control;

[0405] (yyyyy) a reduction in acid reflux symptoms during or after exposure to one or more peanut allergens relative to a control;

[0406] (zzzzz) a reduction in gastroesophageal reflux during or after exposure to one or more peanut allergens relative to a control;

[0407] (aaaaaa) a reduction in coughing during or after exposure to one or more peanut allergens relative to a control; -76- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0408] (bbbbbb) a reduction in hoarseness during or after exposure to one or more peanut allergens relative to a control;

[0409] (cccccc) a reduction in stridor during or after exposure to one or more peanut allergens relative to a control;

[0410] (dddddd) a reduction in dyspnea during or after exposure to one or more peanut allergens relative to a control;

[0411] (eeeeee) an increase in lung capacity during or after exposure to one or more peanut allergens relative to a control;

[0412] (ffffff) a decrease in wheezing during or after exposure to one or more peanut allergens relative to a control;

[0413] (gggggg) a reduction in pruritis during or after exposure to one or more peanut allergens relative to a control;

[0414] (hhhhhh) a reduction in hives during or after exposure to one or more peanut allergens relative to a control;

[0415] (iiiiii) a reduction in itchiness during or after exposure to one or more peanut allergens relative to a control;

[0416] (jjjjjj) a reduction in allergic dermatitis during or after exposure to one or more peanut allergens relative to a control;

[0417] (kkkkkk) a reduction in flushing during or after exposure to one or more peanut allergens relative to a control;

[0418] a reduction in cyanosis during or after exposure to one or more peanut allergens relative to a control;

[0419] (mmmmmm) a reduction in fever by about 0.5°F, 1.0°F, 1.5°F, 2.0°F, 2.5°F, 3.0°F, 3.5°F, 4.0°F, 4.5°F, 5.0°F, 5.5°F, 6.0°F, 6.5°F, 7.0°F, 7.5°F, 8.0°F, 8.5°F, or 9.0°F during or after exposure to one or more peanut allergens relative to a control;

[0420] (nnnnnn) a reduction in cold sweats during or after exposure to one or more peanut allergens relative to a control; -77- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0421] (oooooo) a reduction in body aches during or after exposure to one or more peanut allergens relative to a control;

[0422] (pppppp) a reduction in dose of a rescue medication needed during or after exposure to one or more peanut allergens relative to a control;

[0423] (qqqqqq) a reduction in an IgE level by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% during or after exposure to one or more peanut allergens relative to a control;

[0424] (rrrrrr) a reduction in an IgG4 level by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% during or after exposure to one or more peanut allergens relative to a control;

[0425] (ssssss) a reduction in an IgA level by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% during or after exposure to one or more peanut allergens relative to a control; or

[0426] (tttttt) a reduction in a wheal diameter by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% during or after a skin prick test of one or more peanut allergens relative to a control.

[0427] In some embodiments, the World Allergy Organization (WAO) standardized Systemic Reaction Grading System is used to score and / or assess any of (a)- (tttttt). -78- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 EXAMPLES A Randomized Placebo-Controlled Phase 1 Study of the Safety and Feasibility of Up-titration with INT301 in Adults with Peanut Allergy Abbreviations

[0428] ACE: Angiotensin-Converting Enzyme; AE: Adverse Event; ARB: Angiotensin Receptor Blockers; CFR: Code of Federal Regulations; CI LB: Confidence Interval Lower Bound; CI UB: Confidence Interval Upper Bound; CIOMS: Council for International Organizations of Medical Sciences; CRF: Case Report Form; CRO: Contract Research Organization; CSR: Clinical Study Report; DBPCOFC: Double-Blind Placebo-Controlled Oral Food Challenge; ER: Emergency Room; FDA: Food and Drug Administration; FEV1: Forced Expiratory Volume; FVC: Forced Vital Capacity; GCP: Good Clinical Practice; GI: Gastrointestinal; HCG: Human Chorionic Gonadotrophin; HIPAA: Health Insurance Portability and Accountability Act; ICF: Informed Consent Form; ICH: International Council for Harmonisation; ICS: Inhaled Corticosteroids; ID: Identification; IEC: Independent Ethics Committee; IgA: Immunoglobulin A; IgE: Immunoglobulin E; IgG4: Immunoglobulin G4; IMP: Investigational Medicinal Product; IND: Investigational New Drug; IRB: Institutional Review Board; IWRS: Interactive Web Response System; mg: Milligram; N / A: Not Applicable; NHLBI: National Heart, Lung, and Blood Institute; NIMP: Non-Investigational Medicinal Product; OFC: Oral Food Challenge; OMIT: Oral Mucosal Immunotherapy; OTC: Over-the- Counter; SAE: Severe Adverse Event; SAP: Statistical Analysis Plan; SPT: Skin Prick Test; TEAE: Treatment Emergent Adverse Event. Objectives and Rationale

[0429] A randomized placebo-controlled Phase 1 study was performed to evaluate the safety and feasibility of up-titration with INT301 in adults with a peanut allergy. INT301 has the ability to deliver a higher dose of peanut protein, compared to SLIT, with a once daily dosing. Because the vast majority of the product is expelled after a two-minute brushing, rather than swallowed, the incidence of adverse events compared to OIT is expected to be much lower. As this treatment fits in with the daily routine of toothbrushing, adherence was expected to be excellent, even if the product needs to be used indefinitely to sustain oral -79- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 tolerance. The flavor and smell of the toothpaste masks the odor and taste of peanuts and “smart toothbrushes,” have advancements like two-minute timers, pressure sensors, and a Bluetooth-connected app, allowing for close monitoring of the usage of the product during clinical trials.

[0430] The primary objective was evaluation of the safety of INT301 compared to placebo (control) in adult peanut allergic subjects as measured by dose escalation during study. Endpoints of the primary objective included: 1. Evaluate the percentage of subjects able to consistently tolerate the protocol- specified highest dose; 2. Evaluate the incidence of systemic adverse reactions; and 3. Evaluate the incidence of non-systemic adverse reactions.

[0431] The secondary objectives included evaluation of pharmacologic requirements as interventions for peanut allergic subjects experiencing adverse events on INT301 and determination of the maximally tolerated dose during the up-dosing phase for adults. Endpoints of the secondary objectives included: 1. Evaluate the number of subjects requiring treatment for systemic reactions related to experimental treatment or control; 2. Evaluate the number of adverse events requiring treatment for systemic reactions related to experimental treatment or control; 3. Evaluate the adherence to study treatment; and 4. Evaluate the dose amount tolerated without AEs requiring discontinuation for each subject.

[0432] Other exploratory objectives included exploring changes in peanut-specific IgG4, IgA, and IgE levels in subjects and exploring changes in patient response to oral food challenge pre-treatment and post treatment. -80- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Methods Study Design

[0433] This study comprises a Phase 1, randomized, double-blind, control-controlled study in adult subjects with peanut allergy, which included a multiple-dose escalation design having within-subject dose titration. Cohorts 1-4 consisting of 8 subjects each were selected. 6 subjects in each cohort received study intervention (“treatment”) and the other 2 subjects received matching control (“control”). Subjects in cohorts 2-4 were treated with as many as 11 doses unless they were taken off study drug due to adverse events. Subjects were randomized in a 3:1 ratio to receive either an escalating dose of INT301 or control. Treatment group was blinded to the investigator, subjects, and the study team.

[0434] The first cohort was assigned the lowest study dose or matching control. Dose escalation within this cohort continued, one dose level per study course, until the procedure halted due to safety concerns or all planned doses for this cohort were evaluated.

[0435] Safety was evaluated by the Safety Monitoring Committee before each new cohort started. The Safety Monitoring Committee reviewed the safety data available from currently enrolled patients prior to determining whether the next cohort could safely start up- dosing.

[0436] The next cohort started at the next highest dose relative to the starting dose of the previously enrolled cohort. Initial treatment of this cohort only began after at least one previous cohort received a completed course at this same dose level and no events which would halt escalation were observed. If a starting dose level was determined to be unsafe by the SMC based on reported adverse events, new subjects were enrolled at the last cohort that did not experience side-effects resulting in discontinuation.

[0437] Subjects continued up-dosing according to the schema in FIG.1A and FIG.1B until they completed all scheduled up-dosing or reached a dose that caused side effects that required stopping. Safety was assessed by stage for both the up-dosing and maintenance phases among the treatment and control groups (FIG. 1C and FIG. 1D). Instructions for rechallenging are contained in Section 6 of the protocol. The last tolerable dose was captured as the maximally tolerated dose for the patient. Once the subject reached their -81- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 maximally tolerated dose, they continued at that dose for the remaining scheduled treatment visits. Summary of Eligibility Criteria

[0438] Subjects aged 18-55 with a history of peanut allergy that was demonstrated at screening were enrolled in this study to evaluate the safety of INT301. Summary of Study Duration

[0439] Study Duration: 57 weeks. Included a maintenance period at the subject’s maximally tolerated dose. The initial cohorts included:

[0440] Cohort 1: 8 weeks up-dosing, no maintenance

[0441] Cohort 2: 20 weeks up-dosing, 28 weeks maintenance

[0442] Cohort 3: 16 weeks up-dosing, 32 weeks maintenance

[0443] Cohort 4: 14 weeks up-dosing, 34 weeks maintenance

[0444] Visit Frequency: every 2 weeks during treatment; every 4 weeks during maintenance.

[0445] Study protocols were adjusted during enrollment. As such, some of Cohort 2 and Cohort 3 subjects were assigned to protocols.

[0446] Condition / Disease: peanut allergy

[0447] Sample Size: Approximately 73 subjects were screened to achieve 32 enrolled to study. Enrolled subjects were those who had provided documented Informed Consent, completed screening procedures, and were determined to be eligible for randomization. Of the (n=32) randomized participants, 17 (53%) were female and 15 (47%) were male. In the treatment group (n=24) 13 (54.2%) were female and 11 (45.8%) were male. The median age of all randomized participants was 23, with the median in the treatment and control groups being 24 and 21.5 years respectively. 21.9% of randomized participants identified as being Hispanic or Latino. Participants reported their race as white (53%), Black (28.1%), Asian (12.5%), and Other (6.3%). Additional details are provided in Table 25. -82- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0448] Reason for participant discontinuation: Cohort completed prior to randomization (n=3), Exceeded upper age limit (n=1), Inability to discontinue antihistamines (n=1), Insufficient OFC Response (n=3), Positive Pregnancy Test (n=1), Severe anaphylaxis history (n=2), Significant Comorbidity (n=2), Significant Periodontal Disease (n=3), SPT or IgE (n=13), Uncontrolled Asthma (n=1), and Withdrawn Consent Prior to Randomization (n=11).

[0449] Three participants discontinued from the study early for the following reasons: participant was withdrawn by investigator for non-compliance with study visits, participant withdrew from study for scheduling concerns, or participant was withdrawn from study due to starting exclusionary medication (hydroxyzine) during the up-dosing period. Investigational Product

[0450] The investigational products used in this study include INT301 and control. Investigational Product Dosage and Administration

[0451] Eligible patients were randomized to either treatment or control. Subjects were started on one of 4 dose levels depending on the cohort to which they were assigned. Procedures

[0452] After signing the informed consent form (ICF) subjects entered the screening phase of the study for up to 49 days. Serious adverse events were collected from the time of signing the ICF, while adverse events and disease related events were collected post randomization and first dose of IP.

[0453] Screening evaluations included medical history and disease-related history, skin prick, oral food challenge, oral mucosal brush biopsy for IgE, physical exam, and vital signs. Blood was collected for hematology, chemistry, biomarker analysis, and for all females of childbearing potential.

[0454] At Randomization Visit, eligible subjects were randomized into the 48-week double-blind on-study evaluation period and received study treatment. Following IP administration, a 1-hour safety supervision occurred. Safety follow-up visits occurred after the last dose of IP. -83- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Double-Blind Placebo Controlled Oral Food Challenge

[0455] A Double-Blind Placebo-Controlled Oral Food Challenge (DBPCOFC) screening for cohorts 3 and 4 and the end of the treatment period for all subjects on study was conducted. While this study does not intend to determine the efficacy of INT301 in the adult population, initial results from the DBPCOFC informed the dosing regimen and design of future studies. Schedule of Activities (SoA) Screening

[0456] A Schedule of Activities (SoA) screening through Up-dosing visits are shown in Tables 1-6. Up-dosing for cohorts 1-4 was conducted according to the schema in FIG.1A and FIG. 1B. The World Allergy Organization (WAO) standardized Systemic Reaction Grading System was chosen for scoring all symptoms reported in the trial. -84- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0457] Table 1: Schedule of Activities (SoA) Screening through Up-dosing visits of week 0 to week 18 (Cohorts 1-2) Screening On-Study Period P i d Visit 9 Visit 10 Visit 11 Visit 12jeek 12 Week 14 Week 16 Week 18 84 98 112 126 3 Days +3 Days +3 Days +3 Days X X X XAttorney Docket No.: 152551.8001.WO00 X X X X X X X X X X X X X X X X X X X XAttorney Docket No.: 152551.8001.WO00Peanut specific X IgG4 INT301 or X X X X X X X X X X Control Dosing Weigh IP Tube X X X X X X X X X Post Dose 1- Hour Safety X X X X X X X X X X Supervision Distribute Subject DiaryX X X X X X X X X XCollect Subject X X X X X X X X X Diary Post Dosing Follow- Up X X X X X X X X X X CallshDental ExamXia Eligibility was confirmed prior to any randomization or treatment procedures are performed. b Physical exam includes review of systems and oral exam. c Brief physical exam focused on any reported adverse events. Oral exam was completed at each visit. d Height and weight at screening only. Pulse rate blood pressure and temperature to be collected at each treatment visit before and 30-60 minutes allenge and randomization.Attorney Docket No.: 152551.8001.WO00 otential only. health is available. week 50 (Cohorts 1-2) Off Tx Off Study Visit Visit it 18 Visit 19 Visit 20 Visit 21 ek 40 Week 44 Week 48 Week 50 80 308 336 350 Days +7 Days +7 Days +7 Days X X X X X X X X X X X X XX Adverse Events and Disease Related X X X X X X X X X Events Serious Adverse Events X X X X X X X X X Hematology, Chemistry X Pregnancy TestcX X X X X X X X X Peanut specific IgE Peanut component testing Peanut specific IgG4 -88- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 X X X X treatment visit before and 30-60 minutes otential only. eek 14 (Cohort 3) isit 7 Visit 8 Visit 9 Visit 10 eek 8 Week 10 Week 12 Week 14 56 70 84 98 3 Days +3 Days +3 Days +3 DaysAttorney Docket No.: 152551.8001.WO00 X X X X-90- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Post Dosing Follow-Up h X X X X Calls Dental ExamXitreatment visit before and 30-60 minutes allenge and randomization. otential only. health is available. week 50 (Cohort 3) Off Tx Off Study Visit Visit it 17 Visit 19 Visit 20 Visit 21 ek 40 Week 44 Week 48 Week 50 80 308 336 350 Days +7 Days +7 Days +7 Days X X X X X X X X X X X XAttorney Docket No.: 152551.8001.WO00 X X X X X X X X X X X X X X XX Peanut specific IgA Saliva X Peanut component testing X Peanut specific IgG4 X INT301 or Control Dosing X X X X X X X X Weigh IP Tube X X X X X X X X X Distribute Subject Diary X X X X X X X X Collect Subject Diary X X X X X X X X X a Physical exam includes review of systems and oral exam. b Height and weight at screening only. Pulse rate, blood pressure, and temperature to be collected at each treatment visit before and 30-60 minutes after dosing. c Serum pregnancy at Baseline, urine pregnancy test at all following visits. For subjects of childbearing potential only. -92- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 5: Schedule of Activities (SoA) Screening through Up-dosing visits of week 0 to week 12 (Cohort 4) Screening Period On-Study Period Screening Visits Up-Dosing Visits isit 6 Visit 7 Visit 8 Visit 9 eek 6 Week 8 Week 10 Week 12 42 56 70 84 3 Days +3 Days +3 Days +3 Days XX X XX X X XX X X X X X X X X X X XAttorney Docket No.: 152551.8001.WO00 X X X X X X X X X X X X X X X X X X X X X X X X X X X X treatment visit before and 30-60 minutes hallenge and randomization. otential only. l health is available.-94- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 6: Schedule of Activities (SoA) Screening through Up-dosing visits of week 14 to week 50 (Cohort 4) On-Study Period Off Tx Off Visit Study Visit Visit 18 Visit 19 Visit 20 Visit 21 Week 46 Week 44 Week 48 Week 50 322 350 336 350 +7 days +7 days +7 days +7 days X X X X XX X XX X X X X X X X X XAttorney Docket No.: 152551.8001.WO00 X X X X X X X X X X X X X X X X X X X X X X Xb Height and weight at screening only. Pulse rate, blood pressure, and temperature to be collected at each treatment visit before and 30-60 minutes after dosing. c Serum pregnancy at Baseline, urine pregnancy test at all following visits. For subjects of childbearing potential only. -96- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Risk Assessment

[0458] A general safety risk assessment and appropriate mitigation strategy for investigators and study staff is listed below in Table 7. Table 7: Risk Assessment and Mitigation Strategy Potential Risk of Clinical Rationale for Risk Mitigation Strategy Significance aff ns se ns aff ns se ns or is n e th e it. a se-97- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Investigators and study staff are trained specifically on signs se ns he re S to s. to toSAE: Serious Adverse Event Justification for Dose

[0459] In this study, the term “dose” refers to the application of the Investigational Product Oral Mucosal Immunotherapy (OMIT) toothpaste containing the active peanut allergens under investigation. The current studies using SLIT and OIT support the range of doses proposed and used in this study. The relatively low exposure of active ingredient in the starting dose and initial up-titration doses of Investigational Product reduces risk to subjects and is expected to be well-tolerated. Study Population and Inclusion Criteria

[0460] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0461] Subjects were eligible to be included in the study only if all of the following criteria applied:

[0462] Subject were 18-55 years of age inclusive, at the time of signing the informed consent.

[0463] Female subjects of childbearing potential or male subjects with female partners of child-bearing potential must utilize highly effective birth control method(s) throughout the -98- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 study and for 30 days after the final dose of study drug. Examples of acceptable methods of contraception include complete abstinence, male or female condoms with spermicide, oral, injected, or implanted contraceptives, or vasectomy.

[0464] For female subjects of child-bearing potential: Negative serum beta human chorionic gonadotrophin (HCG) pregnancy test at screening.

[0465] Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

[0466] Meets at least one of the following conditions: Positive skin prick test (SPT) (wheal at least 3 mm greater than control) AND / OR Peanut specific IgE > 0.35 kU / L.

[0467] History of documented peanut allergy diagnosis for at least 3 months prior to screening.

[0468] Failed an oral food challenge at or before dose level (OFC) of < 100 mg of peanut protein at screening.

[0469] Subject willing and able to undergo the procedures required by the protocol, including, assessment completion, protocol compliance, and participation in the control dosing period(s).

[0470] Additional subject demographics and clinical characteristics are shown in Table 8. Table 8: Demographic and Clinical Characteristics INT301 Placebo Total-99- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Age group: 18-55yrs Median 24 21.5 23Exclusion Criteria

[0471] Subjects were excluded from the study if any of the following criteria apply:

[0472] 1. History of severe anaphylaxis to peanut, defined as hypoxia, hypotension, or neurologic compromise (cyanosis or oxygen saturations < 92% at any stage, hypotension, confusion, collapse, loss of consciousness, or incontinence).

[0473] 2. Significant medical condition (e.g., liver, kidney, gastrointestinal, cardiovascular, hematologic, or pulmonary disease) which would make the subject unsuitable for induction of food reactions.

[0474] 3. Eosinophilic or other inflammatory (e.g. celiac) gastrointestinal disease. -100- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0475] 4. Psychiatric disorders that the Investigator believes would interfere with study assessments.

[0476] 5. Known glycerin allergy.

[0477] 6. Uncontrolled asthma, defined by at least one of the following conditions: FEV1 <80% of predicted, or ratio of FEV1 to forced vital capacity (FEV1 / FVC) <75% of predicted, with or without controller medications. Inhaled corticosteroids (ICS) dosing of >500 mcg daily fluticasone (or equivalent ICS based on NHLBI dosing chart. One hospitalization in the past year for asthma. An ER visit for asthma within six months prior to screening.

[0478] 7. Planned dental surgery during from screening until study exit.

[0479] 8. Moderate or advanced periodontal disease.

[0480] 9. Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy within 1 year prior to screening.

[0481] 10. Currently in a build-up phase of any allergen immunotherapy.

[0482] 11. Use of oral beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB) or calcium channel blockers within 2 weeks prior to screening.

[0483] 12. Inability to discontinue oral or nasal antihistamines, antihistamine eye drops, intranasal or oral steroids from 2 weeks prior to screening procedures to post completion of treatment.

[0484] 13. Use tricyclic antidepressants and monoamine oxidase inhibitors within 3 months prior to screening.

[0485] 14. Current pregnancy or lactating.

[0486] 15. Current use of anticoagulant therapies, including OTC baby aspirin at the time of screening, or in the 30 days prior to screening. -101- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0487] 16. Participating in any interventional study for the treatment of food allergy in the past 6 months prior to screening.

[0488] 17. Known oat flour allergy. Screen Failures

[0489] Screen failures were defined as subjects who consent to participate in the clinical study but are not subsequently randomized to study intervention. A minimal set of screen failure information was required to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).

[0490] Individuals who did not meet the criteria for participation in this study (screen failure) may be rescreened 1 time within 6 weeks of the initial screening date. Rescreened subjects were assigned a new subject number. Criteria for Temporarily Delaying

[0491] Subjects requiring unplanned dental surgery during treatment period should hold dosing on the day of surgery. Dosing may continue at the discretion of the investigator.

[0492] Subjects were instructed to hold dosing if they have a fever (> 100.40 F) until it resolves. This delay was recorded in the subject diaries. Study Intervention(s) and Concomitant Therapy

[0493] Study intervention is defined as any investigational intervention(s) and / or control, intended to be administered to a study subject according to the study protocol.

[0494] Meals and Dietary Restrictions: No food should be consumed from 30 minutes before or after dosing.

[0495] Physical Activities: Subjects were encouraged to avoid vigorous exercise for an hour before and after dosing. -102- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0496] Caffeine, Alcohol, and Tobacco: During each dosing session, subjects abstained from ingesting caffeine or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 30 minutes before the start of dosing.

[0497] Subjects who use tobacco products are instructed that use of nicotine- containing products (including nicotine patches) are not permitted during study observation.

[0498] Study interventions are shown in Table 9. Table 9: Study Intervention(s) Administered ARM Name 1 2-103- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Route of Oral- Toothpaste Oral- Toothpaste Administration at n

[0499] Characterization, identity, quality, strength, and purity of drug substance was supported by assaying total protein content in the source material used in formulation INT301, as well as the proportions of Ara h 1, 2, 3, and 6 proteins in the same source material provided by the drug substance supplier indicated below.

[0500] The glycerinated toothpaste base was mixed at the contracted manufacturing facility and consists of the inactive components listed below in Table 10. The toothpaste base was mixed with the ABS in the contracted manufacturer facility following standardized procedures. Toothpaste base components and their proportions are as listed in Table 10. Table 10: Drug Product Ingredient List (Toothpaste Base – No ABS) Trade Name % Pharmaceutical INCI Nomenclature Supplier-104- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Glycerin USP 44.061% Glycerin Quaker City Chemicalsed manufacturing facility using good manufacturing Practice (GMP) and mixed with the glycerinated toothpaste base to produce the drug product in a variety of doses. All doses and their proportions are indicated in Table 11. Table 11: Drug Product Ingredient List Trade Name COMPOUND COMPOUND COMPOUND COMPOUND COMPOUND INCI-105- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Defatted peanut flour 0.007% 0.065% 0.583% 02.330% 10.370% containing 67% ita l yld a placebo batch separate from the active products batches in controlled conditions not to expose the batch to active products. The proportions of inactive ingredients are listed in Table 12 (placebo 1) and Table 13 (placebo 2). -106- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 12: Drug Product Ingredient List - INT301 (Placebo 1) Trade Name % Pharmaceutical INCI Nomenclature composition e-107- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 13: Drug Product Ingredient List – INT301 (Placebo 2) Trade Name % Pharmaceutical INCI Nomenclature composition e-108- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Description of Drug Substances and Formulation

[0503] The drug substance in INT301 is defatted peanut (Arachis hypogaea) flour formulated to specific total protein dosages using a bicinchoninic acid (BCA) assay. The INT301 formulations are characterized to ensure that they contain 4 allergenic peanut proteins: Ara h 1, Ara h 2, Ara h 3, and Ara h 6. Measures to Minimize Bias: Randomization and Blinding

[0504] At Visit 3, subjects were assigned a unique number (randomization number) by the IWRS utilized for the study. The randomization number encodes the subject’s assignment according to the randomization schedule generated prior to the study. Each subject was dispensed blinded study intervention, labeled with his / her unique randomization number, throughout the study. Subjects were provided with a 24-hour contact should emergency unblinding need to occur after hours to address an SAE.

[0505] Unblinding the intervention assignment may be conducted for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s intervention assignment, may be sent to investigators in accordance with local regulations and / or sponsor policy. Dosing Instructions

[0506] At each dosing visit, the subject used the assigned dose amount in the office according to provided instructions. A soft bristled toothbrush was provided to each patient at the beginning of the study and replaced as necessary to ensure that the subject was using the study provided toothbrush. The subject was provided with a 2-minute timer and instructed to use it to ensure consistent usage.

[0507] The subject reviewed a list of dosing criteria at the visit. This information was included in the patient diary. Patients were reminded to hold dosing for the following conditions:

[0508] 1. Any dental work, including a cleaning- hold for at least one day and discuss restarting with investigator.

[0509] 2. Any fever- hold until fever resolves. -109- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0510] Subjects were instructed to brush with INT301 for 2 minutes at their first brushing of the day. Subjects were instructed to brush using their regular fluoride-containing toothpaste later in the day, at least 6 hours after using INT301. Study Intervention Compliance

[0511] When subjects were dosed at the site, they received study intervention directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic was recorded in the source documents and recorded. The dose of study intervention and study subject identification was confirmed at the time of dosing by a member of the study site staff other than the person administering the study intervention.

[0512] A record of the volume of INT301 dispensed to and administered by each subject was maintained and reconciled with study intervention and compliance records. Intervention start and stop dates, including dates for intervention delays and / or dose reductions were also recorded on a patient completed dosing diary.

[0513] The pump was brought to each study visit and the site weighed the pump at each visit to support compliance data collection. Dose Modification

[0514] Subjects automatically proceeded to the next assigned dose level. In the event that a subject experienced a safety or tolerability related event, including at their first dosing level, they could be placed at a lower dose level at the discretion of the investigator, in discussion with the Sponsor Medical Monitor. Rescue Medication

[0515] Subjects were provided with injectable epinephrine at the time of randomization.

[0516] Subjects were provided with training on home use of rescue injectable epinephrine should they have experienced symptoms of anaphylaxis.

[0517] Subjects were instructed to contact the study site immediately after the anaphylaxis safety plan has been completed if they required use of injectable epinephrine. -110- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0518] Subjects were provided diphenhydramine to keep on hand at home while on study in order to comply with the anaphylaxis safety plan. Concomitant Therapy

[0519] Any medication that the subject is receiving at the time of enrollment or receives during the study must be recorded along with:

[0520] 1. Reason for use.

[0521] 2. Dates of administration including start and end dates.

[0522] 3. Dosage information including dose and frequency.

[0523] The Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy. Stopping Criteria

[0524] Discontinuation of study intervention occurred if a subject experienced one of the following:

[0525] 1. A study-related Serious Adverse Event as determined by the Principal Investigator. Subjects may also stop treatment if the investigator determines that it is in the best interest of the patient.

[0526] 2. Life-threatening symptoms including, but not limited to, anaphylaxis resulting in hypotension, neurological compromise, or mechanical ventilation secondary to peanut OMIT dosing or any peanut food challenge.

[0527] 3. Severe symptoms, including, but not limited to, those that require intensive therapy (to be determined by the investigator, but may include such interventions as IV epinephrine, intubation, or admission to an intensive care unit) or those that are recurrent.

[0528] 4. Poor control or persistent activation of secondary atopic disease (e.g., atopic dermatitis, asthma).

[0529] 5. Started on angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, or other prohibited medications, with no alternative medications available per the prescribing doctor. -111- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0530] 6. Pregnancy.

[0531] 7. Non-adherence (non-compliance) as this could constitute a potential safety issue.

[0532] 8. The subject develops biopsy-documented eosinophilic esophagitis (EoE). Temporary Discontinuation

[0533] Subjects temporarily stop study treatment if they had a fever or unplanned dental surgery. Treatment may have restarted when the fever was resolved. After dental surgery, the investigator way determines when the subject may restart treatment.

[0534] Subjects who temporarily paused treatment for 3-7 cumulative days during a dosing period continued at their current dose for two weeks. Subjects who paused treatment for 8-14 cumulative days resumed treatment at one dose level lower than what was discontinued. If these missed doses occurred at the starting dose for the subject’s cohort, the subject resumed at the starting dose. That subject completed two weeks of dosing at the lower dose before continuing the up-dosing protocol. Subjects who discontinue for more than 14 cumulative days resumed treatment at two dose levels lower than what was discontinued or the starting dose of the cohort, whichever is higher. The subject completed two weeks of dosing before continuing up-dosing one dose level every two weeks. Rechallenge

[0535] Subjects that experienced low-grade side effects stopping the subject from dose escalating reverted to the last safe dose until the next study visit. The subject may, at the discretion of the investigator, repeat the up-dosing protocol at the next visit. If the subject failed an up-dosing trial or did not attempt a rechallenge, the subject continued the rest of the study period at the last safe dose. Subject Discontinuation / Withdrawal from the Study

[0536] A subject may withdraw from the study at any time at his / her own request or may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or compliance reasons. This is expected to be uncommon. -112- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0537] At the time of discontinuing from the study, if possible, an early discontinuation visit should be conducted, as shown in the SoA. See SoA for data to be collected at the time of study discontinuation and follow-up and for any further evaluations that need to be completed. • The subject was permanently discontinued both from the study intervention and from the study at that time. • If the subject withdraws consent for disclosure of future information, the sponsor may retain and continue to use any data collected before such a withdrawal of consent. • If a subject withdraws from the study, he / she may request destruction of any samples taken and not tested, and the investigator must document this in the site study records. Lost to Follow Up

[0538] A subject was considered lost to follow-up if he or she repeatedly failed to return for scheduled visits and was unable to be contacted by the study site.

[0539] The following actions were taken if a subject failed to return to the clinic for a required study visit: 1. The site must attempt to contact the subject and reschedule the missed visit as soon as possible and counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and / or should continue in the study. 2. Before a subject is deemed lost to follow up, the investigator or designee must make every effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing address or local equivalent methods). These contact attempts should be documented in the subject’s medical record. 3. Should the subject continue to be unreachable, he / she was considered to have withdrawn from the study. -113- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 4. Site personnel, or an independent third party, attempted to collect the vital status of the subject within legal and ethical boundaries for all subjects randomized, including those who did not get study intervention. Public sources may be searched for vital status information. If vital status is determined as deceased, this was documented and the subject was considered lost to follow-up. Sponsor personnel were not involved in any attempts to collect vital status information. Study Assessments and Procedures

[0540] Any immediate safety concerns were discussed with the sponsor immediately upon occurrence or awareness to determine if the subject should continue or discontinue study intervention.

[0541] Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.

[0542] All screening evaluations were completed and reviewed to confirm that potential subjects met all eligibility criteria. The investigator maintained a screening log to record details of all subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.

[0543] The maximum amount of blood collected from each subject over the duration of the study, including any extra assessments that may have been required, did not exceed 60 mL.

[0544] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples. Physical Examination

[0545] A complete physical examination included, at a minimum, assessments of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.

[0546] A brief physical examination included symptom- focused review of subject status.

[0547] An oral exam assessing changes in dental or oral health occurred at baseline and every visit from randomization forward. -114- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0548] Investigators should pay special attention to clinical signs related to previous serious illnesses. Dental Exam

[0549] Each subject underwent a dental exam to assess gingival health and determine that the subject had no conditions that required intervention. If the subject had a routine dental exam in the 6 months prior to screening, this exam, accompanied by a letter from the dentist confirming dental health, can be utilized. If no previous dental exam was available, the subject was seen by a dentist as part of screening. Vital Signs

[0550] Height and weight were measured and recorded at baseline.

[0551] Temperature, pulse rate, respiratory rate, and blood pressure were assessed at each visit.

[0552] Blood pressure and pulse measurements were preceded by at least 5 minutes of rest for the subject in a quiet setting without distractions. Open Oral Food Challenge: Preparation

[0553] An open oral food challenge was performed for all subjects at screening who consented. Subjects completed an open oral food challenge (OFC) at least 7 days after the skin prick tests and at least 7 days prior to randomization.

[0554] Subjects refrained from eating for 4 hours prior to their oral food challenge. Water could be consumed during this time. Subjects had discontinued prohibited medications according to the prohibited medications section of this protocol. Open Oral Food Challenge: Procedure

[0555] Vital signs were obtained prior to starting the OFC (including weight, temperature, respiratory rate, heart rate, blood pressure, pulse oximetry, and spirometry). A focused baseline exam of subject’s skin, nose, eyes, oropharynx, heart, and lungs was completed prior to starting the OFC. -115- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0556] Peanut protein, mixed with applesauce as a vehicle, was administered at incremental doses of 12, 25, 50, and 100 mg of peanut protein.

[0557] At least 20 minutes of observation period occurred between doses. If a subject reported no subjective symptoms and the investigator did not observe any objective reactions, the next dose of peanut could be provided if determined safe by the investigator. If the investigator identifies objective symptoms, the subject was considered to have failed the OFC. If a subject reported a subjective symptom, the subject was observed. If the subject reported a continuing symptom that did not resolve in 45 minutes, the investigator deemed it necessary to treat the subjective symptom, or the investigator observed any objective symptoms, the subject was considered to have failed the OFC.

[0558] If the subject reports that their subjective symptoms have resolved in less than 45 minutes, in the absence of any objective symptoms, the investigator may choose to continue the challenge if it is determined to be safe and appropriate.

[0559] If the subject reports the same subjective symptom at 3 subsequent doses, irrespective of when it resolves, the subject was considered to have failed the OFC.

[0560] Subjects must fail at or below the 100 mg dose of peanut protein to qualify for the study. If the subject has not displayed symptoms at 100 mg of dosing, the OFC was discontinued. Double-Blind Control Controlled Oral Food Challenge (DBPC OFC): Preparation

[0561] A double-blind control controlled oral food challenge was performed for subjects on cohorts 3-4 and end of treatment (Cohorts 2-4). The administration of active and control challenges occurred at least 3 hours apart, with separate days being acceptable. At screening, both tests needed to be completed at least 7 days after the skin prick test, and at least 7 days prior to randomization.

[0562] Subjects refrained from eating for 4 hours prior to each oral food challenge. Water can be consumed during this time. Subjects discontinued prohibited medications according to the prohibited medications section of this protocol. To maintain the blind, patients were asked to wear nose plugs during consumption of each challenge dose. -116- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Double-Blind Placebo Controlled Oral Food Challenge (DBPC OFC): Blinding

[0563] A designated unblinded clinical staff member was provided an envelope at the beginning of the OFC, indicating whether the subject started with control or peanut for the challenge. The unblinded clinical member prepared the control and active test kits for the investigator and blinded study team.

[0564] The unblinded staff person maintained source documentation regarding the challenge until completion and the principle investigator determined the results of both challenges.

[0565] Unblinding for the DBPC OFC occurred at completion of the second test, at both screening and end of treatment challenges. Double-Blind Placebo Controlled Oral Food Challenge (DBPC:OFC): Unblinding

[0566] Vital signs were obtained prior to starting the DBPC OFC (including weight, temperature, respiratory rate, heart rate, blood pressure, pulse oximetry, and spirometry). A focused baseline exam of subject’s skin, nose, eyes, oropharynx, heart, and lungs was completed prior to starting the DBPC OFC.

[0567] The screening DBPC OFC consisted of either control or 4 incremental doses (12, 25, 50, and 100 mg) of peanut protein at intervals of at least 20 minutes. Active challenge doses contained peanut protein and the control contained toasted oat flour. The end of treatment DBPC OFC consisted of control or 6 incremental doses of peanut protein (3, 10, 30, 100, 300, 600 mg). The peanut protein or toasted oat flour (control) was delivered using applesauce or pudding as a vehicle.

[0568] At least 20 minutes of observation period occurred between doses. If a subject reported no subjective symptoms and the investigator did not observe any objective reactions, the next dose of peanut was provided if determined safe by the investigator. If the investigator identified objective symptoms, the subject was considered to have failed the DBPC OFC. If a subject reported a subjective symptom, the subject was observed. If the subject reported a continuing symptom that does not resolve in 45 minutes, the investigator deemed it necessary to treat the subjective symptom, or the investigator observed any objective symptoms, the subject was considered to have failed the DBPC OFC. -117- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0569] If the subject reports that their subjective symptoms had resolved in less than 45 minutes, in the absence of any objective symptoms, the investigator may have chosen to continue the challenge if it was determined to be safe and appropriate.

[0570] If the subject reported the same subjective symptom at 3 subsequent doses, irrespective of when it resolved, the subject was considered to have failed the DBPC OFC.

[0571] For the screening DBPC OFC, subjects must have failed at or below the 100 mg dose of peanut protein to qualify for the study. The DBPC OFC was discontinued at 100 mg during screening.

[0572] The following were reported during the DBPC OFC:

[0573] Eliciting Dose: This is the dose (grams of peanut protein) at which an oral food challenge is stopped due to either objective symptoms or significant subjective symptoms.

[0574] Tolerated Dose: This is the dose (grams of protein) just prior to the eliciting dose in an oral food challenge.

[0575] Cumulative Reactive Dose: This is the sum of all the doses in an oral food challenge including the eliciting dose. Safety Precautions

[0576] The investigator, or medically qualified designee, was available in the office during the entire challenge, including any observation period.

[0577] Appropriate rescue medications, according to physician’s local practice was prepared and available prior to starting the procedure.

[0578] Subjects who had a positive peanut challenge were monitored for 2-4 hours after resolution of symptoms prior to discharge from the clinic.

[0579] Subjects who had a negative peanut challenge were monitored for at least 1 hour after the last dose prior to discharge from clinic. Anaphylaxis Emergency Action Plan

[0580] The subject and Investigator completed a copy of the American Academy of Allergy, Asthma, and Immunology’s Anaphylaxis Emergency Action Plan at the time of the -118- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 first Screening Visit, before a skin prick or oral food challenge test is done. The subject was encouraged to carry the form and injectable epinephrine with them while on study. Clinical Safety Laboratory Assessments

[0581] A hematology and chemistry assessment was performed at baseline and at the end of the dosing period. The investigator reviewed the laboratory report, document this review, and record any clinically significant changes occurring during the study as an AE.

[0582] Abnormal laboratory findings associated with the underlying disease were not considered clinically significant unless judged by the investigator to be more severe than expected for the subject’s condition.

[0583] All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 30 days after the last dose of study intervention were repeated until the values return to normal or baseline or are no longer considered clinically significant by the investigator or medical monitor.

[0584] If clinically significant values did not return to normal / baseline within a period of time judged reasonable by the investigator, the etiology was identified, and the sponsor notified.

[0585] If laboratory values from non-protocol specified laboratory tests performed at the institution’s local laboratory required a change in subject management or were considered clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results were recorded. Peanut Allergen Testing

[0586] A peanut specific IgE, IgG4, and component testing for Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, and Ara h9 were obtained for each subject according to the SoA. A saliva sample was collected for IgA. Oral Mucosal Brush Biopsy- Specific IgE and IgA

[0587] A 73 / 4inch standard cytology brush (Aeromed, Glastonbury, CT) was inserted along the gingivobuccal sulcus, rotated and moved back and forth approximately 10 times in the upper left quadrant, lower left quadrant, upper right quadrant and lower right quadrant, -119- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 using a separate brush for each side. After the procedure, the brushes were rinsed in phosphate buffered saline (PBS) to extract mucus and epithelial cells. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting

[0588] An AE was considered untoward medical occurrence in a clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

[0589] An AE can therefore be considered any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.

[0590] An unsolicited adverse event was considered an adverse event that was not solicited using a Subject Diary and that is communicated by a subject who has signed the informed consent. Unsolicited AEs include serious and non-serious AEs.

[0591] Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a hospitalization, or emergency room visit, or visit to / by a health care provider). The subject was instructed to contact the site as soon as possible to report medically attended event(s), as well as any events that, though not medically attended, are of subject concern.

[0592] Unsolicited AEs that were not medically attended nor perceived as a concern by subject were collected during interview with the subject and by review of available medical records at the next visit.

[0593] Solicited AEs were predefined local and systemic events for which the subject is specifically questioned, and which were noted by the subject in their diary.

[0594] AEs were reported by the subject. The investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and remain responsible for following up all AEs. Study-Specific Definitions for Anaphylaxis Adverse Events

[0595] Any anaphylaxis event, irrespective of grade, was be reported to the sponsor, using the EDC, within 24 hours of learning of the event. -120- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Time Period and Frequency for Collecting AE and SAE Information

[0596] All SAEs were collected from signing the ICF until 30 days after completion of study.

[0597] All AEs were collected from randomization and post 1st dose until completion of study.

[0598] Medical occurrences that began before the start of study intervention but after obtaining informed consent were recorded as Medical History / Current Medical Conditions, not as AEs.

[0599] All SAEs were recorded and reported to the sponsor or designee immediately and under no circumstance should this exceed 24 hours. The investigator submitted any updated SAE data to the sponsor within 24 hours of it being available.

[0600] Investigators were obligated to actively seek information on AEs or SAEs beginning after conclusion of the study participation. However, if the investigator learned of any SAE, including a death, at any time after a subject has been discharged from the study, and he / she considers the event to be reasonably related to the study intervention or study participation, the investigator must promptly notify the sponsor. Method of Detecting AEs and SAEs

[0601] Care was taken not to introduce bias when detecting AEs and / or SAEs. Open- ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrences. Follow-up of AEs and SAEs

[0602] After the initial AE / SAE report, the investigator was required to proactively follow each subject at subsequent visits / contacts. All SAEs and AEs were followed until resolution, stabilization, the event was otherwise explained, or the subject was lost to follow-up. Regulatory Reporting Requirements for SAEs

[0603] Prompt notification by the investigator to the sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of subjects and the safety of a study intervention under clinical investigation are met. -121- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0604] The sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. The sponsor complied with country-specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Boards (IRB) / Independent Ethics Committees (IEC), and investigators.

[0605] An investigator who receives an investigator safety report describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from the sponsor reviewed and then file it along with the Investigator’s Brochure and notified the IRB / IEC, if appropriate according to local requirements. Extended Safety Follow-up

[0606] Subjects with unresolved AEs “possibly,” “probably,” or “definitely” related to study treatment at study exit were followed until resolution or return to baseline condition. Subjects with upper gastrointestinal symptoms concerning for development of eosinophilic esophagitis were referred to gastroenterology for review. These AEs were followed until resolution or return to baseline, irrespective of relationship to study drug. Statistical Considerations

[0607] Missing data: The amount and nature of missing data were characterized and no method of imputation was used for missing data. A summary of missing data was provided according to the number of subjects and the time points where the data are missing. We acknowledge the possibility of informative missingness, that is, the probability of a particular observation being missing may be related to the health of a subject, and therefore all analyses were interpreted with caution.

[0608] Analyses: Measured outcome variables were summarized overall and by relevant demographic and baseline variables. Descriptive statistics such as frequencies and relative frequencies were computed for all categorical variables. Numeric variables were summarized using simple descriptive statistics such as the mean, standard deviation and range. A variety of graphical techniques were used to display data. To accommodate the expected within-subject dependence structure, mixed linear models or generalized linear models with a generalized estimating equations approach (GEE) to parameter estimation -122- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 was used as appropriate for exploratory analyses examining the effect of dose level on subject outcomes. The probability of an adverse event at a given dose was estimated along with the 95% exact confidence interval based on the method of Clopper and Pearson. Group comparisons with regards to oral food challenge results (pass vs. fail) was done using Fisher’s exact test. All analyses were carried out using SAS version 9.4 (or higher) statistical software (Cary, NC). Sample Size Determination

[0609] The proposed analysis plan is largely descriptive and thus sample size justification based on formal hypothesis evaluation is not applicable. The proposed cohort sample size is that which is most common with Phase I design; see Buoen et al. (2005). The probability of observing an adverse event within this study is a function of the true unknown probability of an adverse event corresponding to the study population. Table 14 below contains the probability of observing at least one adverse event within our study of 24 subjects receiving study intervention for a variety of values of the true probability within the population. Table 14: Adverse Event Probabilities Probability of True AE

[0610] The calculatiption that the study sample may be treated as a random sample from the population of interest with the probability being based on the binomial cumulative distribution function. If there does exist an unacceptable -123- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 safety profile associated with the study intervention defined by a higher probability of experiencing adverse events, there is an adequate probability of observing such events within the study. Analysis software

[0611] All statistical was performed using the SAS statistical software package (SAS Institute Inc., Cary, NC), version 9.4 or higher, or Microsoft® Excel 2019 or higher (Microsoft Corp., Redmond, WA). Analysis Sets

[0612] The definition for each subject analysis set should be defined at the subject level. Optionally, to implement the estimand framework, defined analysis data sets may be included here in a separate table that specify the set of data used in the analysis for a given estimand (or family of estimands that differ only in endpoint) based on how key intercurrent events were handled for that estimand. Analysis sets are defined in Table 15 and Table 16. Table 15: Subject Analysis Set Subject Analysis Set Description eTable 16: Defined Analysis Data Sets Defined Analysis Data Description-124- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Defined set 2 All randomized subjects who are exposed to study intervention. For subjects who discontinue study

[0613] Other than study cohort and dose received, due to limited sample size, there were no additionally defined study subgroup definitions to be utilized in analysis of study data. Analyses

[0614] The final statistical analysis was performed by the study statistician. The study statistician performs or oversees and approves all descriptive analyses and generation of all tables, figures and listings based on study data. This analysis was conducted in full compliance with the analysis plan, the study protocol, and all applicable U.S. Food and Drug Administration regulations.

[0615] The following is the general approach to all analyses: Categorical variables are summarized as frequencies and percentages in each category. In general, the denominator for percentages were the number of subjects within the defined data set. Percentages were reported to one decimal place. In general, continuous variables were summarized by numbers of subjects, means, standard deviations, medians, and ranges. -125- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0616] The number of decimal places for minimums and maximums were the same as the original data. The number of decimal places for means, medians, and interquartile ranges are the same as the original data plus one. The number of decimal places for measures of variance is the same as the original data plus two. Laboratory data with qualifiers (e.g., “<”) are listed with but summarized without the qualifier. All performed statistical tests are two-sided. P-values are presented to four decimal places if 0.0001 or greater. P-values < 0.0001 are presented as “< 0.0001.” There are no significance level adjustments to control type I error.

[0617] Analyses are performed for all previously defined subject analysis sets. In addition to comparisons between study cohorts and assigned treatment, summaries also accounted for differences in protocol specified dose schedules and participation within the maintenance period. Analysis of Primary Objective: Primary Analyses

[0618] The primary analysis of tolerability of the protocol-specified highest dose is a descriptive summarized 1) overall and 2) by study cohort. Systemic and non-systemic adverse reaction events are a descriptive summarized by 1) the cross-classification of study cohort and dose level received, and 2) only dose level received. In addition to summary statistics, a listing of the adverse reactions is also provided. The probabilities of tolerability of the protocol-specified highest dose and dose-specific systemic and non-systemic adverse reactions incidence was estimated along with the 95% exact confidence interval based on the method of Clopper and Pearson (1934). Analysis of Primary Objective: Supportive Analyses

[0619] Additional model-based analyses took place in the examination of systemic and non-systemic adverse reaction events, making use of the repeated measures observed for each subject. In order to accommodate the expected within-subject dependence structure, mixed linear models or generalized linear models with a generalized estimating equations approach (GEE) to parameter estimation were used for exploratory analyses examining the effect of dose level received on subject outcomes. -126- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Analysis of Secondary Objective

[0620] Secondary endpoints are a descriptive summarized by 1) the cross- classification of study cohort and dose level received, and 2) only dose level received. Analysis of Exploratory Objective

[0621] In all data presentations (except listings), values beyond the limit of quantification (LQ) were set to the LQ. In listings, LQ values are reported as “>LQ” or “<LQ”, as appropriate, where LQ is replaced with the value for the limit of quantification.

[0622] Pre-treatment and post-treatment IgG4, IgA and IgE level values and within- subject changes in these values were assessed using descriptive statistics. The association between changes in these collected quantitative variables with covariates such as subject age, food allergy status, whether the subject entered the maintenance period or not, OFC response, etc., were examined using linear models in an exploratory fashion.

[0623] Patient response to pre-treatment and post treatment oral food challenges is also summarized. As not all patients have an observed eliciting dose during the OFC, distributional estimates pertaining to subject eliciting dose, tolerated dose, and cumulative reactive dose, and changes in these quantities from baseline to end-of-treatment, was obtained using the product-limit based Kaplan Meier method. Estimated percentiles from these distributional estimates were then obtained. Between treatment group comparisons were performed using the log-rank test. In addition, the observed eliciting dose or highest dose received was calculated for each patient, summarized, and then compared between groups using standard methods, with a similar statistical approach taken for tolerated dose and cumulative reactive dose. Handling of Missing Values

[0624] The amount and nature of missing data was characterized, and no method of imputation was used for missing data. A summary of missing data is provided according to the number of subjects, the time points where the data are missing, and clinical center. For each clinical center, the number and percent of subjects with no missing data is presented in tabular form. There is a possibility of informative missingness, that is, the probability of a -127- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 particular observation being missing may be related to the health of a subject, and therefore analyses are interpreted with caution. Analysis of Baseline Variables

[0625] Baseline characteristics such as demographics and baseline physical exam results are tabulated and listed. This was done overall and by 1) study cohort and 2) dose level received. Informed Consent Process

[0626] Informed consent, data protection, safety review, and data quality assurance were conducted under all applicable guidelines necessary for this study. Results Self-Reported Adherence

[0627] Self-reported adherence was recorded by the subject. Results of self-reported adherence are detailed in Table 17 and Table 18. Table 17: Self-Reported Adherence Based on Data Diary Only Toothpaste Use: Toothpaste Use: Compliance-128- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Cohort 2 1 134 135 99% Cohort 2 2 127 129 98%Table 18: Summary of Self-Reported Adherence Based on Data Diary Only Among all Cohorts Toothpaste Use: Toothpaste Use: Compliance-129- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Early Termination Details

[0628] A total of 4 subjects terminated the study early. Details of the early termination of these subjects is detailed in Table 19. Table 19: Early Termination Details Total Days Max Dose Cohort on Treatment Received Reason for Early TerminationSubject recalls using IP through December and losing IP in January, but last diary entry was Nov-20. Actual IP usage is probably around 185-200 days total. **Subject misplaced diaries before EOT visit and was not sure what last day using IP was. Actual IP usage is probably around 70-80 days total. ***Subject misplaced IP on 11 / 13, but last diary entry was 11 / 1. Actual IP usage is probably around 75-85 days total. Protocol Deviations

[0629] There were 122 protocol deviations that occurred during the study.

[0630] Participants by Protocol-Defined Analysis Set: Safety (All patients that received at least one dose of assigned treatment): 32 subjects; Per Protocol (All randomized patients that receive assigned treatment as dictated per protocol): 27 subjects; Efficacy Evaluable Set (All randomized patients that receive assigned treatment with no more than 14 days noncompliance with study treatment during the course of the study): 31 subjects; OFC Evaluable Set (All randomized patients that underwent a baseline and end of treatment Oral Food Challenge): 14 subjects.

[0631] Dose Modifications included the following: -130- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0632] A first subject from Cohort 2: One day after the subject's Week 18 visit, the subject's dose was decreased from 80 mg daily to 40 mg daily until their next visit which was the off-treatment visit. This was due to a face rash adverse event.

[0633] A second subject from Cohort 2: the subject stayed at a dose level of 9 mg daily rather than increasing the dose level to 18 mg daily as the protocol dictates. This was due to asthma and cough adverse events.7 days later the subject increased to 18 mg daily and resumed the protocol specified up dosing schedule for all subsequent visits.

[0634] A subject from Cohort 1: the subject's dose was held due to a mouth sores adverse event. The subject's dose was resumed on January 8, 2022 at the subject's last tolerable dose which was .083 mg daily. After resuming a dose hold at the subject's last tolerable dose of 0.083 mg daily, the subject also did not up dose to the next dose level at their next visit. Due to nasal itching and running nose adverse events, the subject remained at 0.083 mg daily.

[0635] A first subject from Cohort 4: The subject stayed at a dose level of 18 mg daily rather than increasing the dose level to 40mg daily as the protocol dictates. This was due to experiencing a throat swelling adverse event at the study visit. At the subject's next visit 2 weeks later, the subject increased to 40 mg daily and resumed the protocol specified up- dosing schedule for all subsequent visits.

[0636] A second subject from Cohort 4: The subject stayed at a dose level of 2.25 mg daily rather than increasing the dose level to 4.5 mg daily as the protocol dictates. This was due to an investigator decision and related to compliance issues with the subject using the study treatment. The same decision was made at the subject's next visit. The subject remained at 2.25 mg daily again due to compliance issues. The subject's dose did increase to 4.5 mg daily at the next visit. The subject was reduced from 4.5 mg daily to 0.753 mg daily due to a >14-day lapse in using study treatment which was due to misplacing the IP. End of Study Tolerance Changes

[0637] Increase in max tolerated dose of peanut protein was observed in subjects across cohorts 2, 3, and 4 from baseline to end of study and / or after 48 weeks. Select patient details are shown in Tables 20-23 and illustrated in FIG. 2. As shown in FIG. 2, among -131- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 subjects who performed DBPCOFC at entry, 100% of treatment group subjects (n=3) passed, and 50% of control group subjects (n=20 passed food challenges comprising 300 mg of peanut protein or more. Of 9 subjects in cohorts 1-3 enrolled using open OFCs (i.e., were informed they were ingesting peanut), 79% of treatment group subjects (n=9) passed exit DBPCOFC at 300 mg or more of peanut protein compared to 60% of control group subjects (n=5). Table 20: End of Study, Un-blinded Oral Food Challenge in 14 Patients Patient Profile Max Tolerated Intervention Dose of Peanut emg of peanut protein. Maximum tolerated dose is highest dose increment taken without need for rescue medication.2Baseline OFC began at 12mg with incremental doses of 25+50+100mg of peanut protein. A patient not able to ingest 12mg means they could not even ingest the lowest dose administered. -132- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 21: Active Long-Term Safety Group Entry and Exit Measurements Max Max Tolerated Cumulative Wheal Entry Exit Entry Exit Entry Exit Entry Exit Tolerated D e lbut yl ylTable 22: Short Term Safety Group Entry and Exit Measurements Wheal Entry Exit Entry Exit Entry Exit Entry Exit Study OL Gender Age Dia sIgE sIgE Ara h Ara h IgG4 IgG4 IgE / IgG IgE / IgG 8 9 5 6 7 3-133- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Y 2 M 30 12.4 29.2 >100 8.1 61.7 0.27 2.19 108.15 45.66 Median 21 11.4 10.2 8.9 2.31 2.5 0.33 0.47 15.69 13.38 1 5Max Max Cumulative Wheal Entry Exit Entry Exit Entry Exit Entry Exit Tolerated Tolerated Study Dose Rescue ds ne ne tec ne neEnd of Study Antibody Changes

[0638] Peanut specific immunoglobulins (IgE, IgG4 and IgE / IgG4 ratio) were also measured at baseline and at study exit to assess if OMIT with INT301 induced an immunomodulatory response in treated subjects relative to control subjects. Changes in peanut lab values and peanut-specific antibody levels were also observed in DBPCOFC subjects from baseline to the end of study (FIGS.3A-3D and Tables 24 and 25). While trends in peanut lab value changes from baseline to end of study were variable, changes in peanut- specific antibodies were more distinct in treatment groups relative to control (FIG.3B). When comparing study entry to study exit IgE:IgG4 ratios, there was a greater reduction in the ratio in treatment group subjects relative to control group suspects, which may be representative of a immunologic response to INT301 treatment (FIG.3A).

[0639] Across subjects entering the study with ≥ 1.75 KU / L, there were 4 of 5 subjects in the treatment group who passed OFC at ≥ 300 mg of peanut protein compared to 1 of 3 -134- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 subjects in the control group. (FIG. 3B). At end of study, 80% (n=4 of 5) treatment group subjects having total serum IgE at entry above 12 kUA / L + skin prick test (SPT) Wheal Diameter ≥ 300 mm passed OFC at ≥ 300 mg of peanut protein (FIG.3C). No (n=0) control group subjects entered the study with levels at or above that threshold.

[0640] No statistical difference in sIgE was observed in treated subjects compared with control subjects in any of the Cohorts, both at baseline and at end of study.

[0641] The serum level of IgG4 in Cohort 1 (group 1) remained unchanged from baseline to end of study in both active and placebo subjects.

[0642] However, a statistically significant increase in IgG4 (p<0.046) was observed in treated subjects in group 2 (a&b) who participated in the long-term safety assessment of INT301, relative to control subjects. Within-subject Percentage Difference in IgG4 Value from Baseline to End of Study for Study Group 2: Control (n=4, Estimated Mean=68.2%, 95% CI LB=-0.72%, 95% CI UB=135.7%), Treatment (n=9, Estimated Mean=666.2%, 95% CI LB=80.6%, 95% CI UB=1251.8%), Diff (1-2) (Estimated Mean=-598.0%, 95% CI LB=- 1184.7%, 95% CI UB=11.6%, T-test p-value=0.046). There was a statistically significance between the mean percent changes for control and treatment arms as determined by the two-sample t-test (p-value >0.046). Participants in this group completed a combination of open OFC at entry and completed a DBPCOFC at study exit.

[0643] IgE / IgG4 Ratio: The increase in IgG4 in group 2 subjects (a&b) inversely correlated with decrease in IgE / IgG4 ratio, consistent with an immunomodulatory response to treatment. This ratio change was only observed in subjects who completed the long terms safety assessment of OMIT with INT301. Table 24: Percent Change of Values Between End of Treatment Visit and Screening Visit* % % % %-135- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 1 0% 36% 51% 25% 60% 0% 0% -24% 18% 1 -19% 28% 34% 0% 43% -2% 0% 0% 11% % % % % % % % % % % % % % % % % % % % % % % % % %Table 25: Antibody Changes and Demographics Group 1 Group 2A Group 2B Total Group 2 (A+B) Drop-outs Sh tt Sf t L t Sf t L t Sf t L t Sf t mt-136- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 N 3 10 3 6 2 3 5 9 5 Age Median 25.5 (23, 18 (18, 35) 25 (18, 47) 20 (20, 25) 22 (20, 29) 29 (25, 51) 23 (20, 28) 25 (20, 51) 21 (18, 27) Mi M 28 0, 8, 1, 2, 1, 1,Adverse Data Summary

[0644] A total of 490 AEs were reported among subjects during the Phase I study FIGS. 4A and 4B). Details of reported AE’s are detailed in Tables 26-50.

[0645] Treatment Groups AE Summary (n=24): All TEAEs (n=692, 100%), Treatment- related AEs (n=641, 92.6%)*, Fatal AEs (n=0, 0%), SAEs (n=2, 0.3%), Treatment-related SAEs (n=0, 0%)*, AEs leading to discontinuation of investigational intervention (n=0, 0%), AEs leading to discontinuation from study (n=0, 0%), AEs of special interest (n=1, 0%)**. *Treatment-related AEs and SAEs included those deemed possibly, probably, or definitely related to study drug. ** AE of Special Interest Anaphylaxis was related to exposure to non- peanut allergens.

[0646] Control Groups Data Summary (N=8): All TEAEs (n=350, 100%), Treatment- related AEs (n=299, 85.4%)*, Fatal AEs (n=0, 0%), SAEs (n=0, 0%), Treatment-related -137- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 SAEs (n=0, 0%)*, AEs leading to discontinuation of investigational intervention (n=0, 0%), AEs leading to discontinuation from study (n=0, 0%), AEs of special interest (n=0, 0%). *Treatment-related AEs and SAEs included those deemed possibly, probably, or definitely related to study drug. ** AE of Special Interest Anaphylaxis was related to exposure to non- peanut allergens.

[0647] Frequency of Participants that Experienced an AE:

[0648] The number and percentage of participants in both treatment and control groups that experienced an AE was recorded over the duration of the study.

[0649] 12.5% (1 / 8) control subjects and 4.2% (1 / 24) treatment subjects experienced a systemic AE possibly, probably or definitely related to study drug. All of these systemic AEs were possibly related to study drug and mild.

[0650] 87.5% (7 / 8) control subjects and 87.5% (21 / 24) treatment subjects experienced a non-systemic AE possibly, probably or definitely related to study drug. All of these non- systemic AEs were mild.

[0651] No moderate or severe AEs were experienced by control subjects.2 moderate and 1 severe AE were experienced by treatment subjects with all 3 of these AEs unlikely related or unrelated to study drug.

[0652] 3 systemic and 10 non-systemic AEs required treatment. All 3 of the systemic AEs requiring treatment were experienced by participants in the treatment group and were unrelated to study drug. The 10 non-systemic AEs requiring treatment were experienced by 6 different participants, 5 in the treatment group and 1 in the control group. Of these non- systemic AEs requiring treatment, 3 instances were unrelated to study drug, 2 instances were unlikely related to study drug, 3 instances were possibly related to study drug, and 2 instances were probably related to study drug. All AEs that required treatment are recovered / resolved.

[0653] Tables 29-32 show the AE frequency per severity, relationship to study drug, and between the control and treatment groups. 87.5% (7 / 8) control subjects and 91.7% (22 / 24) treatment subjects experienced an AE while on study. -138- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0654] Cohort 3 experienced the most AE’s and experienced the longest-lasting average AE when compared to Cohort 2 and Cohort 4. Of total AE’s experienced among subjects, the majority were mild, especially when the AE’s were categorized as bring only “possibly,” “probably,” or “definitely” related to INT301 treatment.

[0655] Cohort 3 also experienced the most AE’s compared to Cohort 2 and Cohort 4 during the maintenance phase, including when the AE’s were categorized as bring only “possibly,” “probably,” or “definitely” related to INT301 treatment .

[0656] The most common lowest level term and preferred term AE’s among subjects were itching mouth, itching tongue, and throat swelling and oral pruritus and pharyngeal swelling, respectively. The most common system organ class (SOC) associated with AE’s were gastrointestinal disorders. However, among AE’s with at least 5 instances categorized as being “possibly,” “probably,” or “definitely” related to INT301 treatment, nausea and nasal itching lasted the longest.

[0657] Table 41 shows the number of participants who reported a TEAE during each study phase: initial dose, dose escalation and maintenance phases, respectively. A slight increase in localized oral and nasal symptoms were reported in active, relative to placebo subjects, including oral pruritis, lip swelling, nasal congestion and rhinorrhea. All AEs were reported to be localized, mild, transient, and occurred mainly during the up-dosing phase, consistent with an immunological response to treatment. Once the maintenance dose was achieved, a gradual decrease in the frequency of these symptoms was observed during the remaining course of the study.

[0658] A few participants had a disproportionate number of AE’s which accounted for approximately 30% of all reported AE’s. For example, in the control group, the majority of the AE’s were reported by a single subject. This subject was assigned to cohort 3 / group 2A and self-reported a total of 292 AE’s. Notably, this subject was part of the control arm and did not receive active treatment. Therefore, with this subject demonstrating a disproportionate number of AE’s, this resulted in a considerable increased the total number of reported AE’s in the study. -139- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0659] A subject in the treatment group self-reported 200 AE’s all of which were considered mild and resolve effectively with symptomatic treatment. This patient was assigned to cohort 3 / group 2A.

[0660] Similar swimmer plots were generated for Cohorts 1, 2 and 4 however the number of reported AE’s in all participants in these Cohorts was significantly lower, relative to the above-noted subjects.

[0661] Deaths: There were no deaths of subjects during the course of the study. Table 26: Count of Subjects in each Cohort Experiencing an AE at a Given Dose Level CohortTable 27: Count of Subjects in Each Cohort Experiencing an AE at a Given Dose Level (Filtered to Only “possibly,” “probably,” or “definitely” Related to Study Drug) Administered Cohort-140- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Number of Subjects Grand Experiencing AE Total Table 28: Total AOnly “possibly,” “probably,” or “definitely” Related to Study Drug) Cohort-141- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 29: Total Count of Subjects Experiencing an AE per Severity (Filtered to “possibly,” “probably,” “definitely,” “unlikely,” or “unrelated” Related to Study Drug) AE Relationship to Total AE Control AE Treatment AE D F F F Table 30: Toibly,” “probably,” “definitely,” “unlikely,” or “unrelated” Related to Study Drug) AE Relationship to Total AE Control AE Treatment AETable 31: Total Count of Subjects Experiencing a Moderate AE (Filtered to “possibly,” “probably,” “definitely,” “unlikely,” or “unrelated” Related to Study Drug) AE Relationshi to Total AE Control AE Treatment AE-142- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 32: Total Count of Subjects Experiencing a Severe AE (Filtered to “possibly,” “probably,” “definitely,” “unlikely,” or “unrelated” Related to Study Drug) AE Relationship to Total AE Control AE Treatment AE D F F F Table 33: Cointenance Phase Distinct Count of Subject Cohort alTable 34: Count of Subjects in Each Cohort Experiencing AEs for Each Maintenance Phase (Filtered to Only “possibly,” “probably,” or “definitely” Related to Study Drug) Distinct Count of Subject Cohort al-143- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 8-12 Weeks 1 3 3 7 12-16 Weeks 1 4 1 6 TaDistinct Count of Subject Cohort C h t al Table 36: Total AEs in Each Cohort for Each Maintenance Phase (Filtered to Only “possibly,” “probably,” or “definitely” Related to Study Drug) Distinct Count of Subject Cohort al-144- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 24-28 Weeks 4 51 10 65 28-32 Weeks 0 46 10 56 TaCategory Count of LLT Nausea 12Table 38: Most Common AEs – Preferred Term (PT) Category Count of LLT Name-145- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Urticaria 58 Pharyngeal swelling 71SOC Count of AEs Gastrointestinal disorders 671 Ta# of other Aes T t l d ith D P ti t Did ti t H d d d i *EacTable 41: Treatment Emergent Adverse Events (≥5% ) in Participants 18 to 55 Years of Age, According to Trial Phase e l )-146- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Gingival Pruritis0(0.0%)0(0.0%) 2(8.3%) 0(0.0%) 0(0.0%) 0(0.0%) ) ) ) ) ) ) ) ) ) )-147- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Pharyngeal Swelling / Edema0(0.0%)0(0.0%) 5(20.8%) 2(25.0%) 3(25.0%) 2(40.0%) ) ) ) ) ) ) )Table 42: Average Length of AE for Each Cohort (Days) Average Length of AE-148- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Grand Total 797 4.00635“probably,” or “definitely” Related to Study Drug) Average Length of AE Cohort (Days) Table 44: Averaed to Only “possibly,” “probably,” or “definitely” Related to Study Drug) Average Length of AE-149- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 45: Average Length of AE (Days) for Each AE with at least 5 instances (Filtered to Only “possibly,” “probably,” or “definitely” Related to Study Drug) AE CategoryAverage of Length of AE (Days) Mouth Pain 1.00Table 46: Dose at Which AEs were Experienced When Occurred on Day of Up-dosing GrandTable 47: Average Length of AE when AE Occurred on Day of Up-dosing Average of-150- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 1 9.40 2 1.00 Table 48: Type of AEAE Category Count of AEsTable 49: Percentage of Total Subjects who Experienced a Given AE (Lowest Level Term) AE Category Percent of Subjects (%)-151- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Lip swelling 34.375-152- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Table 50: Percentage of Total Subjects who Experienced a Given AE (by SOC) SOC Percent of Subjects (%) Gastrointestinal disorders 84.375

[0662] All instances of urticaria on hands occurred with 1 subject, but instances of hives on mouth / face occurred with all 5 subjects.

[0663] There were 2 serious adverse events during the study (Table 51). Table 51: Serious Adverse Events Subject Action Relations Take Was Cohort*AEn Was AE hip to Treatme Outcome Preferred e li r

[0664] There were 9 instances of discontinuation of study treatment or dose modifications due to adverse events (Table 52). Table 52: Adverse Events Resulting in Dose Discontinuation or Modification Subject Action Relation Was Cohort* Was AE Taken e ti-153- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 3 Flu- Like Dose Recovere Influenza Symptom Interrupt d / like s No Moderate Unlikely ed Yes Resolved illness e r a li r**Indicates AEs reported by the same individual

[0665] One participant in Cohort 3 experienced anaphylaxis in an accidental exposure incident that was not related to study drug or the consumption of peanuts. Table 53: Adverse Events of Special Interest Action Relationship Taken Was ityEvaluation of Clinical Laboratory Tests

[0666] There were no Adverse Events related to clinical lab results across the entire study. As such, no assessment of the difference between treatment or control was warranted. Other Safety Evaluations -154- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0667] There were no clinically significant findings in the vital signs measurements, physical examination assessments, or other observations related to safety in this study. The assessments and observations were comparable across study arms.

[0668] No changes in oral health were noted on the regular oral exams conducted during the trial. A full dental exam was performed at screening to ensure eligibility. At each subsequent up-dosing visit and at study exit, an oral exam was performed by the Investigator according to the schedule of events. Physical Examination Findings

[0669] No significant changes were identified in physical examinations in either the treatment or control group. Evaluation of Response to Study Intervention

[0670] Study data were summarized by group using percentages, means, or medians, for data which are binary, numeric, or numeric subject to censoring, respectively. Corresponding 95% confidence intervals (CI) were calculated. Group differences were statistically assessed using Barnard’s test, the two-sample t-test, or the log-rank test, as appropriate, with p-values < 0.05 denoting statistical significance. Interpretation of the DBPCOFC outcomes in Cohort 4 (group 2b)

[0671] Results for Cohort 4 (Group 2b)

[0672] Table 54 shows the eliciting oral food challenge doses for both treatment and control assignments in group 2b at baseline as described by the median and corresponding 95% confidence interval for each group. Note upper CI bounds were not able to be calculated due to an insufficient number of events. At baseline, no significant difference between the two groups was observed, as determined by the log-rank test (p-value = 0.7) however the median eliciting dose in the control group was 18.5 mg and the median eliciting dose in treatment group was 12 mg. This difference may indicate a slightly more allergic population in the treatment group, however this was not significant. Table 54: Eliciting Oral Food Challenge Doses at Baseline- Group 2b -155- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 Randomized Treatment Sample Number of Estimated 95% CI 95% CI Log rank test Variable Assi nment size reactions Median LB UB -value t andcontrol assignments in group 2b at end of study. There was no significant difference between the two groups as determined by the log-rank test (p-value = 0.89). The median eliciting dose in the treatment group was estimated to be 600 mg. Estimation of the median in the control group and calculation of the upper bounds of the confidence intervals in both groups was not possible due to smaller sample size and lack of events. Not all participants showed an eliciting dose at end of study as some did not meet criteria for the eliciting dose when they were challenged at the maximum dose of 600 mg.

[0674] Similar tabulated comparisons of the baseline and end of study eliciting dose were recorded for Cohort 2 & 3 (group 2 a). However, because the subjects in Cohort 4 / group 2b were the only participants to undergo a DPBCOFC both at study entry and study exit, only this subset of participants were evaluable for the investigation of efficacy of INT301. Table 55: Eliciting Oral Food Challenge Doses at End of Study- Group 2b Randomized Treatment Sampl Number of Estimated 95% CI 95% CI Log rank test

[0675] An exemplary case study control subject was assessed, and results are shown in Table 56. The subject was a 24-year-old female subject with a history of seasonal and perennial allergic rhinitis who met entry criteria for the peanut study including a positive oral food challenge. This subject experienced several local adverse events (AEs) including mouth, throat, and tongue itching reported to be possibly related to study drug. The subject underwent DBPCOFC at study entry and exit. At study entry, subject failed oral challenge at 25 mg of orally ingested peanut. Despite having been randomized to the control group and -156- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 receiving no active treatment, this subject tolerated orally ingested 600 mg peanut at study exit. The subject’s entry laboratory values were at lower end of protocol inclusion criteria, questioning true allergy to peanut, and the exit laboratory values were inconsistent with clear immunologic response to therapy. This subject had isolated, elevated entry value of component Ara h 8 at 16.6 kU / L, a marker of mild reactions consistent with tolerance to peanuts and consistent with pollen food allergy syndrome. Table 56: Case Study Control Subject Open Study Group Wheal Entry Exit Entry Exit Entry Exit Entry Exit Entry Exit Entry Exit Entry Exit Cum. Rescue Label Cohort Dia. sIgE sIgE Ara Ara Ara Ara Ara Ara IgG IgG IgE / IgG IgE / IgG MTD MTD Dose Meds Entry (mm) (kU / L) (kU / L) h 2 h 2 h 8 h 8 h 9 h 9 (kU / L) (kU / L) Ratio Ratio (mg) (mg) (mg) F e odchallenge; MTD = maximum tolerated dose.

[0677] This demonstrates that Ara h 8 screening, in addition to other peanut components, may be useful as a standard part of the entry criteria into peanut immunotherapy clinical trials. Isolated sensitization to Ara h 8 may be secondary to birch pollen sensitization and may be associated with tolerance to peanut allergens with limited symptoms. Component diagnostics may facilitate the differentiation between different phenotypes of peanut sensitized patients. Additional Embodiments

[0678] The present technology includes, but is not limited to, the following specific embodiments set forth herein below in paragraphs

[0679] -

[0848] :

[0679] 1. A method of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one-, two-, or three-unit doses of one or more peanut allergens once daily to the subject, the one-, two-, or three-unit dose comprising about 0.020 mg to about 50 mg of the one or more peanut allergens.

[0680] 2. A method of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided as a daily dose of about 0.020 mg to about 150 mg of the one or more peanut -157- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 allergens, wherein the daily dose comprises one-, two-, or three-unit doses of the one or more peanut allergens, each unit dose administered once daily, twice daily, or three times daily to the subject.

[0681] 3. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-140mg of one or more peanut allergens once daily to the subject.

[0682] 4. The method of embodiment 3, wherein the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0683] 5. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one, two-, or three-unit doses of a pharmaceutical composition formulated for oral mucosal delivery once daily to the subject, wherein the one-, two-, or three-unit dose comprises (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50mg of the one or more peanut allergens.

[0684] 6. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02- 0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

[0685] 7. The method of embodiment 6, wherein the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0686] 8. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once -158- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

[0687] 9. The method of embodiment 8, wherein the dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

[0688] 10. The method of any one of embodiments 1, 2, 4, 5, 7, and 9, wherein the one-unit dose comprises a daily dose of about 0.020 mg to about 50 mg of the one or more peanut allergens.

[0689] 11. The method of any one of embodiments 1, 2, 4, 5, 7, and 9, wherein the two-unit doses comprise a daily dose of about 3.5 mg to about 100 mg of the one or more peanut allergens.

[0690] 12. The method of any one of embodiments 1, 2, 4, 5, 7, and 9, wherein the three-unit doses comprise a daily dose of about 0.75 mg to about 150 mg of the one or more peanut allergens.

[0691] 13. The method of any one of embodiments 1, 2, 4, 5, 7, and 9-12, wherein the one-unit dose, the two-unit dose, or the three-unit dose comprises a daily dose of about 0.75 mg, about 2.25 mg, about 4.5 mg, about 6.67, about 9.0 mg, about 18 mg, about 20 mg, about 36 mg, or about 60 mg.

[0692] 14. The method of any one of embodiments 1, 2, 4, 5, 7, and 9-13, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

[0693] 15. The method of embodiment 14, wherein the subject is administered a seventh daily dose of about 60 mg of the one or more peanut allergens.

[0694] 16. The method of any one of embodiments 1, 2, 4, 5, 7, and 9-15, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about -159- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

[0695] 17. The method of embodiment 16, wherein the subject is administered a fifth daily dose of about 60 mg of the one or more peanut allergens.

[0696] 18. The method of embodiment 10, wherein the one-unit dose is provided in a daily dose comprising about 0.028 mg, about 0.042 mg about 0.251 mg, about 2.25 mg, about 9 mg, or about 40 mg of the one or more peanut allergens.

[0697] 19. The method of embodiment 11, wherein the two-unit dose are provided in a daily dose of about 0.083 mg, about 4.5 mg, about 18 mg, or about 80 mg of the one or more peanut allergens.

[0698] 20. The method of embodiment 12, wherein the three-unit dose are provided in a daily dose of about 0.083 mg, about 0.753 mg, or about 120 mg of the one or more peanut allergens.

[0699] 21. A method of reducing levels of or preventing formation of one or more peanut allergen-specific IgE, IgG4, or IgA antibodies relative to a control in a subject in need thereof, the method comprising administering a unit dose comprising one or more peanut allergens to the subject, wherein the peanut allergen-specific IgE, IgG4, or IgA antibodies are specific for an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9, SSP-1, SSP-2, and anti-conglutinin.

[0700] 22. The method of embodiment 21, wherein the unit dose comprises about 0.020 mg to about 50 mg of the one or more peanut allergens.

[0701] 23. The method of embodiment 21 or 22, wherein the unit dose comprises (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50 mg of the one or more peanut allergens.

[0702] 24. The method of any one of embodiments 21-23, wherein the unit dose comprises (a) 0.028mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg of the one or more peanut allergens. -160- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0703] 25. The method of embodiment 24, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg is administered once per day.

[0704] 26. The method of embodiment 24, wherein the unit dose comprising (c) 2.25mg, (d) 9mg, or (e) is 40mg administered twice per day.

[0705] 27. The method of embodiment 24, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, or (e) 40mg is administered three times per day.

[0706] 28. The method of embodiment 21, comprising a daily dose of 4.5mg, 18mg, or 80mg administered as (i) two-unit doses administered together once per day or (ii) two-unit doses, each unit dose administered separately once per day, wherein the unit dose is 2.25mg, 9mg, or 40mg.

[0707] 29. The method of embodiment 21, comprising a daily dose of 0.753mg or 120mg administered as a unit dose three times per day, wherein the unit dose is 0.028mg, 0.753mg, or 120mg.

[0708] 30. The method of embodiment 21, comprising a daily dose of 0.083mg, 0.753mg, or 120mg administered as (i) three-unit doses administered together once per day, (ii) three-unit doses, each unit dose administered separately once per day, or (iii) three-unit doses, two unit doses administered together once per day and a third unit dose administered separately once per day, wherein the unit dose is 0.028mg, 0.251mg, or 40mg.

[0709] 31. The method of embodiment 21, wherein the one or more peanut allergens is provided in a unit dose of about 0.020 mg to about 50 mg of the one or more peanut allergens administered once daily, twice daily, or three times daily to the subject.

[0710] 32. The method of any one of embodiments 2, 6, 8, and 26, wherein the twice daily or three times daily unit doses are administered to the subject together as daily dose.

[0711] 33. The method of any one of embodiments 8-19 and 23-27, wherein the daily dose is a first dose.

[0712] 34. The method of any one of embodiments 1-33, further comprising administering a second unit dose of the one or more peanut allergens. -161- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0713] 35. The method of embodiment 34, wherein the second unit dose comprises a greater amount of the one or more peanut allergens than the first unit dose.

[0714] 36. The method of embodiment 23, wherein the second dose comprises about 2 times greater than the first unit dose, about 3 times greater than the first unit dose, about 4 times greater than the first unit dose, about 5 times greater than the first unit dose, about 6 times greater than the first unit dose, about 7 times greater than first unit dose, about 8 times greater than the first unit dose, about 9 times greater than the first unit dose, or about 10 times greater amount of the one or more peanut allergens than the first unit dose.

[0715] 37. The method of any one of embodiments 34-36, wherein the first unit dose and the second unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart.

[0716] 38. The method of any one of embodiments 1 or 21-37, wherein the one or more peanut allergens is formulated for oral mucosal delivery.

[0717] 39. The method of any one of embodiments 1-38, wherein the one or more peanut allergens comprises an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, and Ara h9.

[0718] 40. The method of embodiment 39, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of at least one of the Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

[0719] 41. The method of embodiment 40, wherein the unit dose comprises about (a) 0.0005-0.035mg, (b) 0.175-0.275mg, (c) 1-2.5mg, (d) 5-10mg, or (e) 20-50 mg, of at least one of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

[0720] 42. The method of embodiment 41, wherein the unit dose comprises about (a) 0.005-0.009 mg, (b) 0.007-0.012 mg, (c) 0.02-0.035 mg, (d) 0.059-0.069 mg, (e) 0.078- 0.092 mg, (f) 0.1-0.175 mg, (g) 0.5-0.625 mg, (h) 0.667-0.833 mg (i) 1.0-1.25 mg, (j) 2-2.5 mg, (k) 2.67-3.33 mg, (l) 4.0-5.0 mg, (m) 7.5-12.5 mg, or (n) 15-25 mg, of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitope. -162- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0721] 43. The method of any one of embodiments 39-42, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of each of the Ara h1, Ara h2, Ara h3, and Ara h6 epitopes.

[0722] 44. The method of embodiment 43, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

[0723] 45. The method of embodiment 44, further comprising a seventh daily dose of about 60 mg of the one or more peanut allergens.

[0724] 46. The method of embodiment 43, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

[0725] 47. The method of embodiment 46, further comprising a fifth daily dose of about 60 mg of the one or more peanut allergens.

[0726] 48. The method of any one of embodiments 21-47, wherein the one or more antibodies are selected from the group consisting of a peanut allergen-specific IgE, a peanut allergen -specific IgA, a peanut allergen-specific IgG4, an anti-SSP-1 antibody, an anti-SSP- 2 antibody, an anti-conglutinin antibody, an anti-Ara h1 antibody, an anti-Ara h2 antibody, an anti-Ara h3 antibody, an anti-Ara h6 antibody, an anti-Ara h7 antibody, an anti-Ara h8 antibody, and an anti-Ara h9 antibody.

[0727] 49. The method of embodiment 1 or 2, wherein tolerance to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% relative to a control.

[0728] 50. The method of any one of embodiments 1, 2, and 40, wherein the increased tolerance reduces risk of or severity of one or more adverse reactions to the one or more peanut allergens in the subject.

[0729] 51. The method of any one of embodiments 3, 5, 6, 8, and 41, wherein the one or more adverse reactions is selected from the group consisting of an adverse reaction -163- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 of the throat, the tongue, the eye, the eyelid, the mouth, the nose, the lips, the hand, the back, the scalp, the head, the ear, the abdomen, the gastrointestinal system, the respiratory system, the cardiovascular system, and the nervous system.

[0730] 52. The method of embodiment 51, wherein the adverse reaction of the throat is selected from the group consisting of an itching of the throat, a swelling of the throat, a numbness of the throat, a pain in the throat, a burning of the throat, a tingling of the throat, a discomfort of the throat, a dryness of the throat, a soreness of the throat, a sinus infection symptom of the throat, and a cold and flu symptom of the throat.

[0731] 53. The method of embodiment 51, wherein the adverse reaction of the tongue is selected from the group consisting of itching of the tongue, a swelling of the tongue, a numbness of the tongue, a pain in the tongue, a burning of the tongue, a tingling of the tongue, a discomfort of the tongue, a dryness of the tongue, and a soreness of the tongue.

[0732] 54. The method of embodiment 51, wherein the adverse reaction of the eye is selected from the group consisting of itching of the eye, a swelling of the eye, a numbness of the eye, a pain in the eye, a burning of the eye, a tingling of the eye, a discomfort of the eye, a dryness of the eye, and a soreness of the eye.

[0733] 55. The method of embodiment 51, wherein the adverse reaction of the eyelid is selected from the group consisting of itching of the eyelid, a swelling of the eyelid, a numbness or the eyelid, a pain in the eyelid, a burning of the eyelid, a tingling of the eyelid, a discomfort of the eyelid, a dryness of the eyelid, and a soreness of the eyelid.

[0734] 56. The method of embodiment 51, wherein the adverse reaction of the mouth is selected from the group consisting of itching of the mouth, a swelling of the mouth, a numbness of the mouth, a pain in the mouth, a burning of the mouth, a tingling of the mouth, a discomfort of the mouth, a dryness of the mouth, a soreness of the mouth, a watery mouth, thickening saliva, and over salivating.

[0735] 57. The method of embodiment 51, wherein the adverse reaction of the nose is selected from the group consisting of itching of the nose, a swelling of the nasal passage, a numbness of the nose, a burning of the nose, a tingling of the nose, a discomfort -164- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 of the nose, a dryness of the nose, a soreness of the nasal passage, sneezing, runny nose, rhinorrhea, congestion, and a sinus infection symptom of the nose.

[0736] 58. The method of embodiment 51, wherein the adverse reaction of the lips is selected from the group consisting of itching of the lips, a swelling of the lips, a numbness of the lips, a pain in the lips, a burning of the lips, a tingling of the lips, a discomfort of the lips, a dryness of the lips, and a soreness of the lips.

[0737] 59. The method of embodiment 51, wherein the adverse reaction of the hand is selected from the group consisting of itching of the hand, a swelling of the hand, a numbness of the hand, a pain in the hand, a burning of the hand, a tingling of the hand, a discomfort of the hand, dermatitis of the hand, hives on the hand, urticaria of the hand, pruritis of the hand, and cyanosis of the hand.

[0738] 60. The method of embodiment 51, wherein the adverse reaction of the back is selected from the group consisting of itching of the back, a back pain, a tingling of the back, a discomfort of the back, dermatitis of the back, hives on the back, urticaria of the back, pruritis of the back, and cyanosis of the back.

[0739] 61. The method of embodiment 51, wherein the adverse reaction of the scalp is selected from the group consisting of itching of the scalp, a scalp pain, a tingling of the scalp, a discomfort of the scalp, dermatitis of the scalp, hives on the scalp, urticaria of the scalp, and pruritis of the scalp.

[0740] 62. The method of embodiment 51, wherein the adverse reaction of the ear is selected from the group consisting of itching of the ear, a swelling of the ear, a numbness of the ear, a pain in the ear, a burning of the ear, a tingling of the ear, a discomfort of the ear, a soreness of the ear, a pressure in the ear, and a sinus infection symptom of the ear.

[0741] 63. The method of embodiment 51, wherein the adverse reaction of the abdomen is selected from the group consisting of abdominal pain, abdominal cramps, or abdominal discomfort.

[0742] 64. The method of embodiment 51, wherein the adverse reaction of the gastrointestinal system is selected from the group consisting of nausea, vomiting, emesis, -165- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 stomach pain, stomach cramps, intestinal discomfort, diarrhea, loss of bowel control, irregular flatulence, gas pain, indigestion, acid reflux, and gastroesophageal reflux.

[0743] 65. The method of embodiment 51, wherein the adverse reaction of the respiratory system is selected from the group consisting of coughing, hoarseness, stridor, dyspnea, shortness of breath, wheezing, respiratory arrest, cold-like and flu-like symptoms of the respiratory system, and anaphylaxis.

[0744] 66. The method of embodiment 51, wherein the adverse reaction of the cardiovascular system is selected from the group consisting of tachycardia, dysrhythmia, bradycardia, cardiac arrest, hypotension, blood pressure collapse, and loss of consciousness.

[0745] 67. The method of embodiment 51, wherein the adverse reaction of the nervous system is selected form the group consisting of a headache, loss of consciousness, and confusion.

[0746] 68. The method of embodiment 51, wherein the adverse reaction of the skin is selected from the group consisting of pruritis, urticaria, hives, itchiness, allergic dermatitis, cyanosis, and flushing.

[0747] 69. The method of embodiment 51, wherein the adverse reaction of the immune system is selected from the group consisting of, a fever, cold sweats, body aches, cold-like symptoms, flu-like symptoms, and a severe allergic reaction.

[0748] 70. The method of any one of embodiments 1-69, wherein the subject is administered a first unit dose and a final unit dose, wherein the administration of the final unit dose is about 18 weeks to about 50 weeks after administration of the first unit dose.

[0749] 71. The method of any one of embodiments 1-70, wherein the subject is administered a first daily dose and a final daily dose, wherein the administration of the final daily dose is about 18 weeks to about 50 weeks after administration of the first daily dose.

[0750] 72. The method of any one of embodiments 1-71, wherein the subject is administered a cumulative dose of about 10 mg to about 1500 mg of the one or more peanut allergens. -166- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0751] 73. The method of embodiment 72, wherein the cumulative dose is achieved by at least two daily doses, at least three, at least four, at least five, at least six, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, at least 28, at least 35, at least 42, at least 49, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, or at least 500 daily doses of the one or more peanut allergens.

[0752] 74. The method of embodiment 72 or 73, wherein the cumulative dose is between about 10 mg and about 1500 mg of the one or more peanut allergens.

[0753] 75. The method of any one of embodiments 72-74, wherein the cumulative dose of the one or more peanut allergens is (a) about 10-50 mg, (b) about 51-100 mg, (c) about 101-250 mg, (d) about 251-500 mg, (e) about 501-750 mg, (f) about 751-1000 mg, or (g) about 1001-1500 mg.

[0754] 76. The method of any one of embodiments 1-75 wherein the method increases a maximum tolerated dose of the one or more peanut allergens in the subject by about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30- fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold compared to a control or the control.

[0755] 77. The method of any one of embodiments 1-75, wherein the method increases a maximum tolerated dose of the one or more peanut allergens in the subject to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% compared to a control or the control.

[0756] 78. The method of any one of embodiments 1-77, wherein the one or more peanut allergens is extracted from a peanut flour.

[0757] 79. The method of any one of embodiments 3-78, wherein the pharmaceutical composition is formulated for oral mucosal delivery as a dental hygiene product.

[0758] 80. The method of embodiment 79, wherein the dental hygiene product is a toothpaste, a mouthwash, a mouthspray, a porous oral pouch, or a dental cream. -167- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0759] 81. The method of embodiment 80, wherein the toothpaste comprises peanut flour, peppermint oil, a salt or derivative thereof, sodium lauryl sulfate, glycerin, glycerol, sodium saccharin, silica, trisodium phosphate, sodium phosphate monobasic, caboxylmethylcellulose USP, carbomer, titanium dioxide, FD & C Green #3, or FD & C Yellow #6.

[0760] 82. The method of embodiment 78 or 81, wherein the peanut flour comprises one or more peptides derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6.

[0761] 83. The method of embodiment 78, 81, or 82, wherein the peanut flour is derived from roasted peanuts.

[0762] 84. The method of embodiment 81, wherein the peppermint oil is mentha piperita oil.

[0763] 85. The method of any one of embodiments 72-84, wherein the cumulative dose is a maximum tolerated dose.

[0764] 86. Use of a unit dose comprising about 0.020 mg to about 50 mg of one or more peanut allergens for increasing tolerance to the one or more peanut allergens in a subject in need thereof, wherein one-, two-, or three-unit doses of one or more peanut allergens are administered once daily to the subject.

[0765] 87. Use of a daily dose of about 0.020 mg to about 150 mg of one or more peanut allergens for increasing tolerance to one or more peanut allergens in a subject in need thereof, wherein the daily dose comprises one-, two-, or three-unit doses of the one or more peanut allergens, each unit dose administered once daily, twice daily, or three times daily to the subject.

[0766] 88. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-140mg of one or more peanut allergens is administered once daily to the subject. -168- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00

[0767] 89. The use of embodiment 88, wherein the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens are administered to the subject.

[0768] 90. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose comprising one, two-, or three-unit doses of the pharmaceutical composition is formulated for oral mucosal delivery and is administered once daily to the subject, wherein the one, two-, or three-unit doses comprises (a) 0.02-0.035mg, (b) 0.235- 0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50mg of the one or more peanut allergens.

[0769] 91. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose comprising...

Claims

Attorney Docket No.: 152551.8001.WO00 CLAIMS I / We claim:

1. A method of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one-, two-, or three-unit doses of one or more peanut allergens once daily to the subject, the one-, two-, or three-unit dose comprising about 0.020 mg to about 50 mg of the one or more peanut allergens.

2. A method of increasing tolerance to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided as a daily dose of about 0.020 mg to about 150 mg of the one or more peanut allergens, wherein the daily dose comprises one-, two-, or three-unit doses of the one or more peanut allergens, each unit dose administered once daily, twice daily, or three times daily to the subject.

3. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-140mg of one or more peanut allergens once daily to the subject.

4. The method of claim 3, wherein the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

5. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one, two-, or three-unit doses of a pharmaceutical composition formulated for oral mucosal delivery once daily to the subject, wherein the one-, -180- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 two-, or three-unit dose comprises (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8- 10mg, or (e) 30-50mg of the one or more peanut allergens.

6. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering a daily dose comprising one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2- 2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

7. The method of claim 6, wherein the daily dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens to the subject.

8. A method of reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, the method comprising administering one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg once, twice, or three times daily to the subject.

9. The method of claim 8, wherein the dose is provided as one-, two-, or three- unit doses of the one or more peanut allergens to the subject.

10. The method of any one of claims 1, 2, 4, 5, 7, and 9, wherein the one-unit dose comprises a daily dose of about 0.020 mg to about 50 mg of the one or more peanut allergens. -181- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 11. The method of any one of claims 1, 2, 4, 5, 7, and 9, wherein the two-unit doses comprise a daily dose of about 3.5 mg to about 100 mg of the one or more peanut allergens.

12. The method of any one of claims 1, 2, 4, 5, 7, and 9, wherein the three-unit doses comprise a daily dose of about 0.75 mg to about 150 mg of the one or more peanut allergens.

13. The method of any one of claims 1, 2, 4, 5, 7, and 9-12, wherein the one-unit dose, the two-unit dose, or the three-unit dose comprises a daily dose of about 0.75 mg, about 2.25 mg, about 4.5 mg, about 6.67, about 9.0 mg, about 18 mg, about 20 mg, about 36 mg, or about 60 mg.

14. The method of any one of claims 1, 2, 4, 5, 7, and 9-13, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

15. The method of claim 14, wherein the subject is administered a seventh daily dose of about 60 mg of the one or more peanut allergens.

16. The method of any one of claims 1, 2, 4, 5, 7, and 9-15, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

17. The method of claim 16, wherein the subject is administered a fifth daily dose of about 60 mg of the one or more peanut allergens. -182- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 18. The method of claim 10, wherein the one-unit dose is provided in a daily dose comprising about 0.028 mg, about 0.042 mg about 0.251 mg, about 2.25 mg, about 9 mg, or about 40 mg of the one or more peanut allergens.

19. The method of claim 11, wherein the two-unit dose are provided in a daily dose of about 0.083 mg, about 4.5 mg, about 18 mg, or about 80 mg of the one or more peanut allergens.

20. The method of claim 12, wherein the three-unit dose are provided in a daily dose of about 0.083 mg, about 0.753 mg, or about 120 mg of the one or more peanut allergens.

21. A method of reducing levels of or preventing formation of one or more peanut allergen-specific IgE, IgG4, or IgA antibodies relative to a control in a subject in need thereof, the method comprising administering a unit dose comprising one or more peanut allergens to the subject, wherein the peanut allergen-specific IgE, IgG4, or IgA antibodies are specific for an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9, SSP-1, SSP-2, and anti-conglutinin.

22. The method of claim 21, wherein the unit dose comprises about 0.020 mg to about 50 mg of the one or more peanut allergens.

23. The method of claim 21 or 22, wherein the unit dose comprises (a) 0.02- 0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50 mg of the one or more peanut allergens.

24. The method of any one of claims 21-23, wherein the unit dose comprises (a) 0.028mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg of the one or more peanut allergens.

25. The method of claim 24, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg is administered once per day. -183- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 26. The method of claim 24, wherein the unit dose comprising (c) 2.25mg, (d) 9mg, or (e) is 40mg administered twice per day.

27. The method of claim 24, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, or (e) 40mg is administered three times per day.

28. The method of claim 21, comprising a daily dose of 4.5mg, 18mg, or 80mg administered as (i) two-unit doses administered together once per day or (ii) two-unit doses, each unit dose administered separately once per day, wherein the unit dose is 2.25mg, 9mg, or 40mg.

29. The method of claim 21, comprising a daily dose of 0.753mg or 120mg administered as a unit dose three times per day, wherein the unit dose is 0.028mg, 0.753mg, or 120mg.

30. The method of claim 21, comprising a daily dose of 0.083mg, 0.753mg, or 120mg administered as (i) three-unit doses administered together once per day, (ii) three- unit doses, each unit dose administered separately once per day, or (iii) three-unit doses, two unit doses administered together once per day and a third unit dose administered separately once per day, wherein the unit dose is 0.028mg, 0.251mg, or 40mg.

31. The method of claim 21, wherein the one or more peanut allergens is provided in a unit dose of about 0.020 mg to about 50 mg of the one or more peanut allergens administered once daily, twice daily, or three times daily to the subject.

32. The method of any one of claims 2, 6, 8, and 26, wherein the twice daily or three times daily unit doses are administered to the subject together as daily dose.

33. The method of any one of claims 8-19 and 23-27, wherein the daily dose is a first dose. -184- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 34. The method of any one of claims 1-33, further comprising administering a second unit dose of the one or more peanut allergens.

35. The method of claim 34, wherein the second unit dose comprises a greater amount of the one or more peanut allergens than the first unit dose.

36. The method of claim 23, wherein the second dose comprises about 2 times greater than the first unit dose, about 3 times greater than the first unit dose, about 4 times greater than the first unit dose, about 5 times greater than the first unit dose, about 6 times greater than the first unit dose, about 7 times greater than first unit dose, about 8 times greater than the first unit dose, about 9 times greater than the first unit dose, or about 10 times greater amount of the one or more peanut allergens than the first unit dose.

37. The method of any one of claims 34-36, wherein the first unit dose and the second unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart.

38. The method of any one of claims 1 or 21-37, wherein the one or more peanut allergens is formulated for oral mucosal delivery.

39. The method of any one of claims 1-38, wherein the one or more peanut allergens comprises an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, and Ara h9.

40. The method of claim 39, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of at least one of the Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

41. The method of claim 40, wherein the unit dose comprises about (a) 0.0005- 0.035mg, (b) 0.175-0.275mg, (c) 1-2.5mg, (d) 5-10mg, or (e) 20-50 mg, of at least one of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes. -185- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 42. The method of claim 41, wherein the unit dose comprises about (a) 0.005- 0.009 mg, (b) 0.007-0.012 mg, (c) 0.02-0.035 mg, (d) 0.059-0.069 mg, (e) 0.078-0.092 mg, (f) 0.1-0.175 mg, (g) 0.5-0.625 mg, (h) 0.667-0.833 mg (i) 1.0-1.25 mg, (j) 2-2.5 mg, (k) 2.67- 3.33 mg, (l) 4.0-5.0 mg, (m) 7.5-12.5 mg, or (n) 15-25 mg, of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitope.

43. The method of any one of claims 39-42, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of each of the Ara h1, Ara h2, Ara h3, and Ara h6 epitopes.

44. The method of claim 43, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

45. The method of claim 44, further comprising a seventh daily dose of about 60 mg of the one or more peanut allergens.

46. The method of claim 43, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

47. The method of claim 46, further comprising a fifth daily dose of about 60 mg of the one or more peanut allergens.

48. The method of any one of claims 21-47, wherein the one or more antibodies are selected from the group consisting of a peanut allergen-specific IgE, a peanut allergen - specific IgA, a peanut allergen-specific IgG4, an anti-SSP-1 antibody, an anti-SSP-2 antibody, an anti-conglutinin antibody, an anti-Ara h1 antibody, an anti-Ara h2 antibody, an anti-Ara h3 antibody, an anti-Ara h6 antibody, an anti-Ara h7 antibody, an anti-Ara h8 antibody, and an anti-Ara h9 antibody. -186- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 49. The method of claim 1 or 2, wherein tolerance to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% relative to a control.

50. The method of any one of claims 1, 2, and 40, wherein the increased tolerance reduces risk of or severity of one or more adverse reactions to the one or more peanut allergens in the subject.

51. The method of any one of claims 3, 5, 6, 8, and 41, wherein the one or more adverse reactions is selected from the group consisting of an adverse reaction of the throat, the tongue, the eye, the eyelid, the mouth, the nose, the lips, the hand, the back, the scalp, the head, the ear, the abdomen, the gastrointestinal system, the respiratory system, the cardiovascular system, and the nervous system.

52. The method of claim 51, wherein the adverse reaction of the throat is selected from the group consisting of an itching of the throat, a swelling of the throat, a numbness of the throat, a pain in the throat, a burning of the throat, a tingling of the throat, a discomfort of the throat, a dryness of the throat, a soreness of the throat, a sinus infection symptom of the throat, and a cold and flu symptom of the throat.

53. The method of claim 51, wherein the adverse reaction of the tongue is selected from the group consisting of itching of the tongue, a swelling of the tongue, a numbness of the tongue, a pain in the tongue, a burning of the tongue, a tingling of the tongue, a discomfort of the tongue, a dryness of the tongue, and a soreness of the tongue.

54. The method of claim 51, wherein the adverse reaction of the eye is selected from the group consisting of itching of the eye, a swelling of the eye, a numbness of the eye, a pain in the eye, a burning of the eye, a tingling of the eye, a discomfort of the eye, a dryness of the eye, and a soreness of the eye. -187- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 55. The method of claim 51, wherein the adverse reaction of the eyelid is selected from the group consisting of itching of the eyelid, a swelling of the eyelid, a numbness or the eyelid, a pain in the eyelid, a burning of the eyelid, a tingling of the eyelid, a discomfort of the eyelid, a dryness of the eyelid, and a soreness of the eyelid.

56. The method of claim 51, wherein the adverse reaction of the mouth is selected from the group consisting of itching of the mouth, a swelling of the mouth, a numbness of the mouth, a pain in the mouth, a burning of the mouth, a tingling of the mouth, a discomfort of the mouth, a dryness of the mouth, a soreness of the mouth, a watery mouth, thickening saliva, and over salivating.

57. The method of claim 51, wherein the adverse reaction of the nose is selected from the group consisting of itching of the nose, a swelling of the nasal passage, a numbness of the nose, a burning of the nose, a tingling of the nose, a discomfort of the nose, a dryness of the nose, a soreness of the nasal passage, sneezing, runny nose, rhinorrhea, congestion, and a sinus infection symptom of the nose.

58. The method of claim 51, wherein the adverse reaction of the lips is selected from the group consisting of itching of the lips, a swelling of the lips, a numbness of the lips, a pain in the lips, a burning of the lips, a tingling of the lips, a discomfort of the lips, a dryness of the lips, and a soreness of the lips.

59. The method of claim 51, wherein the adverse reaction of the hand is selected from the group consisting of itching of the hand, a swelling of the hand, a numbness of the hand, a pain in the hand, a burning of the hand, a tingling of the hand, a discomfort of the hand, dermatitis of the hand, hives on the hand, urticaria of the hand, pruritis of the hand, and cyanosis of the hand.

60. The method of claim 51, wherein the adverse reaction of the back is selected from the group consisting of itching of the back, a back pain, a tingling of the back, a -188- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 discomfort of the back, dermatitis of the back, hives on the back, urticaria of the back, pruritis of the back, and cyanosis of the back.

61. The method of claim 51, wherein the adverse reaction of the scalp is selected from the group consisting of itching of the scalp, a scalp pain, a tingling of the scalp, a discomfort of the scalp, dermatitis of the scalp, hives on the scalp, urticaria of the scalp, and pruritis of the scalp.

62. The method of claim 51, wherein the adverse reaction of the ear is selected from the group consisting of itching of the ear, a swelling of the ear, a numbness of the ear, a pain in the ear, a burning of the ear, a tingling of the ear, a discomfort of the ear, a soreness of the ear, a pressure in the ear, and a sinus infection symptom of the ear.

63. The method of claim 51, wherein the adverse reaction of the abdomen is selected from the group consisting of abdominal pain, abdominal cramps, or abdominal discomfort.

64. The method of claim 51, wherein the adverse reaction of the gastrointestinal system is selected from the group consisting of nausea, vomiting, emesis, stomach pain, stomach cramps, intestinal discomfort, diarrhea, loss of bowel control, irregular flatulence, gas pain, indigestion, acid reflux, and gastroesophageal reflux.

65. The method of claim 51, wherein the adverse reaction of the respiratory system is selected from the group consisting of coughing, hoarseness, stridor, dyspnea, shortness of breath, wheezing, respiratory arrest, cold-like and flu-like symptoms of the respiratory system, and anaphylaxis.

66. The method of claim 51, wherein the adverse reaction of the cardiovascular system is selected from the group consisting of tachycardia, dysrhythmia, bradycardia, cardiac arrest, hypotension, blood pressure collapse, and loss of consciousness. -189- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 67. The method of claim 51, wherein the adverse reaction of the nervous system is selected form the group consisting of a headache, loss of consciousness, and confusion.

68. The method of claim 51, wherein the adverse reaction of the skin is selected from the group consisting of pruritis, urticaria, hives, itchiness, allergic dermatitis, cyanosis, and flushing.

69. The method of claim 51, wherein the adverse reaction of the immune system is selected from the group consisting of, a fever, cold sweats, body aches, cold-like symptoms, flu-like symptoms, and a severe allergic reaction.

70. The method of any one of claims 1-69, wherein the subject is administered a first unit dose and a final unit dose, wherein the administration of the final unit dose is about 18 weeks to about 50 weeks after administration of the first unit dose.

71. The method of any one of claims 1-70, wherein the subject is administered a first daily dose and a final daily dose, wherein the administration of the final daily dose is about 18 weeks to about 50 weeks after administration of the first daily dose.

72. The method of any one of claims 1-71, wherein the subject is administered a cumulative dose of about 10 mg to about 1500 mg of the one or more peanut allergens.

73. The method of claim 72, wherein the cumulative dose is achieved by at least two daily doses, at least three, at least four, at least five, at least six, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, at least 28, at least 35, at least 42, at least 49, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, or at least 500 daily doses of the one or more peanut allergens.

74. The method of claim 72 or 73, wherein the cumulative dose is between about 10 mg and about 1500 mg of the one or more peanut allergens. -190- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 75. The method of any one of claims 72-74, wherein the cumulative dose of the one or more peanut allergens is (a) about 10-50 mg, (b) about 51-100 mg, (c) about 101- 250 mg, (d) about 251-500 mg, (e) about 501-750 mg, (f) about 751-1000 mg, or (g) about 1001-1500 mg.

76. The method of any one of claims 1-75 wherein the method increases a maximum tolerated dose of the one or more peanut allergens in the subject by about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50- fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold compared to a control or the control.

77. The method of any one of claims 1-75, wherein the method increases a maximum tolerated dose of the one or more peanut allergens in the subject to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% compared to a control or the control.

78. The method of any one of claims 1-77, wherein the one or more peanut allergens is extracted from a peanut flour.

79. The method of any one of claims 3-78, wherein the pharmaceutical composition is formulated for oral mucosal delivery as a dental hygiene product.

80. The method of claim 79, wherein the dental hygiene product is a toothpaste, a mouthwash, a mouthspray, a porous oral pouch, or a dental cream.

81. The method of claim 80, wherein the toothpaste comprises peanut flour, peppermint oil, a salt or derivative thereof, sodium lauryl sulfate, glycerin, glycerol, sodium saccharin, silica, trisodium phosphate, sodium phosphate monobasic, caboxylmethylcellulose USP, carbomer, titanium dioxide, FD & C Green #3, or FD & C Yellow #6. -191- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 82. The method of claim 78 or 81, wherein the peanut flour comprises one or more peptides derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6.

83. The method of claim 78, 81, or 82, wherein the peanut flour is derived from roasted peanuts.

84. The method of claim 81, wherein the peppermint oil is mentha piperita oil.

85. The method of any one of claims 72-84, wherein the cumulative dose is a maximum tolerated dose.

86. Use of a unit dose comprising about 0.020 mg to about 50 mg of one or more peanut allergens for increasing tolerance to the one or more peanut allergens in a subject in need thereof, wherein one-, two-, or three-unit doses of one or more peanut allergens are administered once daily to the subject.

87. Use of a daily dose of about 0.020 mg to about 150 mg of one or more peanut allergens for increasing tolerance to one or more peanut allergens in a subject in need thereof, wherein the daily dose comprises one-, two-, or three-unit doses of the one or more peanut allergens, each unit dose administered once daily, twice daily, or three times daily to the subject.

88. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-140mg of one or more peanut allergens is administered once daily to the subject.

89. The use of claim 88, wherein the daily dose is provided as one-, two-, or three- unit doses of the one or more peanut allergens are administered to the subject. -192- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 90. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose comprising one, two-, or three-unit doses of the pharmaceutical composition is formulated for oral mucosal delivery and is administered once daily to the subject, wherein the one, two-, or three-unit doses comprises (a) 0.02-0.035mg, (b) 0.235- 0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50mg of the one or more peanut allergens.

91. Use of a pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein a daily dose comprising one or more peanut allergens provided in a unit dose of a pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg administered once, twice, or three times daily to the subject.

92. The use of claim 91, wherein the daily dose is provided as one-, two-, or three- unit doses of the one or more peanut allergens are administered to the subject.

93. Use of pharmaceutical composition for reducing risk of or severity of one or more adverse reactions to one or more peanut allergens in a subject in need thereof, wherein one or more peanut allergens provided in a unit dose of the pharmaceutical composition formulated for oral mucosal delivery of (a) 0.02-0.035mg once daily or three times daily, (b) 0.235-0.275mg once daily or three times daily, (c) 2-2.5mg once daily or twice daily, (d) 8-10mg once daily or twice daily, or (e) 30-140mg administered once, twice, or three times daily to the subject.

94. The use of claim 93, wherein the dose is provided as one-, two-, or three-unit doses of the one or more peanut allergens are administered to the subject.

95. The use of any one of claims 86-94, wherein the one-unit dose comprises a daily dose of about 0.020 mg to about 50 mg of the one or more peanut allergens. -193- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 96. The use of any one of claims 86-94, wherein the two-unit doses comprise a daily dose of about 3.5 mg to about 100 mg of the one or more peanut allergens.

97. The use of any one of claims 86-94, wherein the three-unit doses comprise a daily dose of about 0.75 mg to about 150 mg of the one or more peanut allergens.

98. The use of claim 86, wherein the one-unit dose is provided in a daily dose comprising about 0.028 mg, about 0.042 mg about 0.251 mg, about 2.25 mg, about 9 mg, or about 40 mg of the one or more peanut allergens.

99. The use of claim 96, wherein the two-unit dose are provided in a daily dose of about 0.083 mg, about 4.5 mg, about 18 mg, or about 80 mg of the one or more peanut allergens.

100. The use of claim 97, wherein the three-unit dose are provided in a daily dose of about 0.083 mg, about 0.753 mg, or about 120 mg of the one or more peanut allergens.

101. The use of any one of claims 86-100, wherein the one-unit dose, the two-unit dose, or the three-unit dose comprises a daily dose of about 0.75 mg, about 2.25 mg, about 4.5 mg, about 6.67, about 9.0 mg, about 18 mg, about 20 mg, about 36 mg, or about 60 mg.

102. The use of any one of claims 86-101, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

103. The use of claim 102, wherein the subject is administered a seventh daily dose of about 60 mg of the one or more peanut allergens. -194- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 104. The use of any one of claims 86-101, wherein the subject is administered a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

105. The use of claim 104, wherein the subject is administered a fifth daily dose of about 60 mg of the one or more peanut allergens.

106. Use of a unit dose comprising one or more peanut allergens for reducing levels of or preventing formation of one or more peanut allergen-specific IgE, IgG4, or IgA antibodies relative to a control in a subject in need thereof, wherein the unit dose comprising one or more peanut allergens is administered to the subject, wherein the peanut allergen- specific IgE, IgG4, or IgA antibodies are specific for an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, Ara h9, SSP-1, SSP-2, and anti-conglutinin.

107. The use of claim 106, wherein the unit dose comprises about 0.020 mg to about 50 mg of the one or more peanut allergens.

108. The use of claim 106 or 107, wherein the unit dose comprises (a) 0.02- 0.035mg, (b) 0.235-0.275mg, (c) 2-2.5mg, (d) 8-10mg, or (e) 30-50 mg of the one or more peanut allergens.

109. The use of any one of claims 106-108, wherein the unit dose comprises (a) 0.028mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg of the one or more peanut allergens.

110. The use of claim 109, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, (c) 2.25mg, (d) 9mg, or (e) 40mg is administered once per day.

111. The use of claim 109, wherein the unit dose comprising (c) 2.25mg, (d) 9mg, or (e) is 40mg administered twice per day. -195- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 112. The use of claim 109, wherein the unit dose comprising (a) 0.28mg, (b) 0.251mg, or (e) 40mg is administered three times per day.

113. The use of claim 106, comprising a daily dose of 4.5mg, 18mg, or 80mg administered as (i) two-unit doses administered together once per day or (ii) two-unit doses, each unit dose administered separately once per day, wherein the unit dose is 2.25mg, 9mg, or 40mg.

114. The use of claim 106, comprising a daily dose of 0.753mg or 120mg administered as a unit dose three times per day, wherein the unit dose is 0.028mg, 0.753mg, or 120mg.

115. The use of claim 106, comprising a daily dose of 0.083mg, 0.753mg, or 120mg administered as (i) three-unit doses administered together once per day, (ii) three-unit doses, each unit dose administered separately once per day, or (iii) three-unit doses, two unit doses administered together once per day and a third unit dose administered separately once per day, wherein the unit dose is 0.028mg, 0.251mg, or 40mg.

116. The use of claim 106, wherein the one or more peanut allergens is provided in a unit dose of about 0.020 mg to about 50 mg of the one or more peanut allergens administered once daily, twice daily, or three times daily to the subject.

117. The use of any one of claims 87-116, wherein the twice daily or three times daily unit doses are administered to the subject together as daily dose.

118. The use of any one of claims 93-117, wherein the daily dose is a first dose.

119. The use of any one of claims 86-118, further comprising administering a second unit dose of the one or more peanut allergens. -196- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 120. The use of claim 119, wherein the second unit dose comprises a greater amount of the one or more peanut allergens than the first unit dose.

121. The use of claim 108, wherein the second dose comprises about 2 times greater than the first unit dose, about 3 times greater than the first unit dose, about 4 times greater than the first unit dose, about 5 times greater than the first unit dose, about 6 times greater than the first unit dose, about 7 times greater than first unit dose, about 8 times greater than the first unit dose, about 9 times greater than the first unit dose, or about 10 times greater amount of the one or more peanut allergens than the first unit dose.

122. The use of any one of claims 119-121, wherein the first unit dose and the second unit dose are administered about a day apart, about a week apart, about 2 weeks apart, about 3 weeks apart, or about 4 weeks apart.

123. The use of any one of claims 86 or 106-122, wherein the one or more peanut allergens is formulated for oral mucosal delivery.

124. The use of any one of claims 86-123, wherein the one or more peanut allergens comprises an epitope on a peanut protein selected from the group consisting of Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, and Ara h9.

125. The use of claim 124, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of at least one of the Ara h1, Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

126. The use of claim 125, wherein the unit dose comprises about (a) 0.0005- 0.035mg, (b) 0.175-0.275mg, (c) 1-2.5mg, (d) 5-10mg, or (e) 20-50 mg, of at least one of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitopes.

127. The use of claim 126, wherein the unit dose comprises about (a) 0.005-0.009 mg, (b) 0.007-0.012 mg, (c) 0.02-0.035 mg, (d) 0.059-0.069 mg, (e) 0.078-0.092 mg, (f) 0.1- -197- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 0.175 mg, (g) 0.5-0.625 mg, (h) 0.667-0.833 mg (i) 1.0-1.25 mg, (j) 2-2.5 mg, (k) 2.67-3.33 mg, (l) 4.0-5.0 mg, (m) 7.5-12.5 mg, or (n) 15-25 mg, of the Ara h2, Ara h3, Ara h6, Ara h8, or Ara h9 epitope.

128. The use of any one of claims 124-127, wherein the unit dose or the daily dose comprises about 0.005 mg to about 150 mg of each of the Ara h1, Ara h2, Ara h3, and Ara h6 epitopes.

129. The use of claim 128, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 4.5 mg, a fourth daily dose of about 9.0 mg, a fifth daily dose of about 18 mg, and a sixth daily dose of about 36 mg of the one or more peanut allergens.

130. The use of claim 129, further comprising a seventh daily dose of about 60 mg of the one or more peanut allergens.

131. The use of claim 128, wherein the daily dose comprises a first daily dose of about 0.75 mg, a second daily dose of about 2.25 mg, a third daily dose of about 6.67 mg, and a fourth daily dose of about 20 mg of the one or more peanut allergens.

132. The use of claim 131, further comprising a fifth daily dose of about 60 mg of the one or more peanut allergens.

133. The use of any one of claims 106-132, wherein the one or more antibodies are selected from the group consisting of a peanut allergen-specific IgE, a peanut allergen - specific IgA, a peanut allergen-specific IgG4, an anti-SSP-1 antibody, an anti-SSP-2 antibody, an anti-conglutinin antibody, an anti-Ara h1 antibody, an anti-Ara h2 antibody, an anti-Ara h3 antibody, an anti-Ara h6 antibody, an anti-Ara h7 antibody, an anti-Ara h8 antibody, and an anti-Ara h9 antibody. -198- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 134. The use of claim 86 or 87, wherein tolerance to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% relative to a control.

135. The use of any one of claims 86, 87, and 137, wherein the increased tolerance reduces risk of or severity of one or more adverse reactions to the one or more peanut allergens in the subject.

136. The use of any one of claims 88, 90, 91, 93, and 135, wherein the one or more adverse reactions is selected from the group consisting of an adverse reaction of the throat, the tongue, the eye, the eyelid, the mouth, the nose, the lips, the hand, the back, the scalp, the head, the ear, the abdomen, the gastrointestinal system, the respiratory system, the cardiovascular system, and the nervous system.

137. The use of claim 136, wherein the adverse reaction of the throat is selected from the group consisting of an itching of the throat, a swelling of the throat, a numbness of the throat, a pain in the throat, a burning of the throat, a tingling of the throat, a discomfort of the throat, a dryness of the throat, a soreness of the throat, a sinus infection symptom of the throat, and a cold and flu symptom of the throat.

138. The use of claim 136, wherein the adverse reaction of the tongue is selected from the group consisting of itching of the tongue, a swelling of the tongue, a numbness of the tongue, a pain in the tongue, a burning of the tongue, a tingling of the tongue, a discomfort of the tongue, a dryness of the tongue, and a soreness of the tongue.

139. The use of claim 136, wherein the adverse reaction of the eye is selected from the group consisting of itching of the eye, a swelling of the eye, a numbness of the eye, a pain in the eye, a burning of the eye, a tingling of the eye, a discomfort of the eye, a dryness of the eye, and a soreness of the eye. -199- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 140. The use of claim 136, wherein the adverse reaction of the eyelid is selected from the group consisting of itching of the eyelid, a swelling of the eyelid, a numbness or the eyelid, a pain in the eyelid, a burning of the eyelid, a tingling of the eyelid, a discomfort of the eyelid, a dryness of the eyelid, and a soreness of the eyelid.

141. The use of claim 136, wherein the adverse reaction of the mouth is selected from the group consisting of itching of the mouth, a swelling of the mouth, a numbness of the mouth, a pain in the mouth, a burning of the mouth, a tingling of the mouth, a discomfort of the mouth, a dryness of the mouth, a soreness of the mouth, a watery mouth, thickening saliva, and over salivating.

142. The use of claim 136, wherein the adverse reaction of the nose is selected from the group consisting of itching of the nose, a swelling of the nasal passage, a numbness of the nose, a burning of the nose, a tingling of the nose, a discomfort of the nose, a dryness of the nose, a soreness of the nasal passage, sneezing, runny nose, rhinorrhea, congestion, and a sinus infection symptom of the nose.

143. The use of claim 136, wherein the adverse reaction of the lips is selected from the group consisting of itching of the lips, a swelling of the lips, a numbness of the lips, a pain in the lips, a burning of the lips, a tingling of the lips, a discomfort of the lips, a dryness of the lips, and a soreness of the lips.

144. The use of claim 136, wherein the adverse reaction of the hand is selected from the group consisting of itching of the hand, a swelling of the hand, a numbness of the hand, a pain in the hand, a burning of the hand, a tingling of the hand, a discomfort of the hand, dermatitis of the hand, hives on the hand, urticaria of the hand, pruritis of the hand, and cyanosis of the hand.

145. The use of claim 136, wherein the adverse reaction of the back is selected from the group consisting of itching of the back, a back pain, a tingling of the back, a -200- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 discomfort of the back, dermatitis of the back, hives on the back, urticaria of the back, pruritis of the back, and cyanosis of the back.

146. The use of claim 136, wherein the adverse reaction of the scalp is selected from the group consisting of itching of the scalp, a scalp pain, a tingling of the scalp, a discomfort of the scalp, dermatitis of the scalp, hives on the scalp, urticaria of the scalp, and pruritis of the scalp.

147. The use of claim 136, wherein the adverse reaction of the ear is selected from the group consisting of itching of the ear, a swelling of the ear, a numbness of the ear, a pain in the ear, a burning of the ear, a tingling of the ear, a discomfort of the ear, a soreness of the ear, a pressure in the ear, and a sinus infection symptom of the ear.

148. The use of claim 136, wherein the adverse reaction of the abdomen is selected from the group consisting of abdominal pain, abdominal cramps, or abdominal discomfort.

149. The use of claim 136, wherein the adverse reaction of the gastrointestinal system is selected from the group consisting of nausea, vomiting, emesis, stomach pain, stomach cramps, intestinal discomfort, diarrhea, loss of bowel control, irregular flatulence, gas pain, indigestion, acid reflux, and gastroesophageal reflux.

150. The use of claim 136, wherein the adverse reaction of the respiratory system is selected from the group consisting of coughing, hoarseness, stridor, dyspnea, shortness of breath, wheezing, respiratory arrest, cold-like and flu-like symptoms of the respiratory system, and anaphylaxis.

151. The use of claim 136, wherein the adverse reaction of the cardiovascular system is selected from the group consisting of tachycardia, dysrhythmia, bradycardia, cardiac arrest, hypotension, blood pressure collapse, and loss of consciousness. -201- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 152. The use of claim 136, wherein the adverse reaction of the nervous system is selected form the group consisting of a headache, loss of consciousness, and confusion.

153. The use of claim 136, wherein the adverse reaction of the skin is selected from the group consisting of pruritis, urticaria, hives, itchiness, allergic dermatitis, cyanosis, and flushing.

154. The use of claim 136, wherein the adverse reaction of the immune system is selected from the group consisting of, a fever, cold sweats, body aches, cold-like symptoms, flu-like symptoms, and a severe allergic reaction.

155. The use of any one of claims 86-154, wherein the subject is administered a first unit dose and a final unit dose, wherein the administration of the final unit dose is about 18 weeks to about 50 weeks after administration of the first unit dose.

156. The use of any one of claims 86-155, wherein the subject is administered a first daily dose and a final daily dose, wherein the administration of the final daily dose is about 18 weeks to about 50 weeks after administration of the first daily dose.

157. The use of any one of claims 86-156, wherein the subject is administered a cumulative dose of about 10 mg to about 1500 mg of the one or more peanut allergens.

158. The use of claim 157, wherein the cumulative dose is achieved by at least two daily doses, at least three, at least four, at least five, at least six, at least 7, at least 8, at least 9, at least 10, at least 14, at least 21, at least 28, at least 35, at least 42, at least 49, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, or at least 500 daily doses of the one or more peanut allergens.

159. The use of claim 157 or 158, wherein the cumulative dose is between about 10 mg and about 1500 mg of the one or more peanut allergens. -202- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 160. The use of any one of claims 157-159, wherein the cumulative dose of the one or more peanut allergens is (a) about 10-50 mg, (b) about 51-100 mg, (c) about 101-250 mg, (d) about 251-500 mg, (e) about 501-750 mg, (f) about 751-1000 mg, or (g) about 1001- 1500 mg.

161. The use of any one of claims 86-160, wherein the use increases a maximum tolerated dose of the one or more peanut allergens in the subject by about 1-fold, 2-fold, 3- fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60- fold, 70-fold, 80-fold, 90-fold, or 100-fold compared to a control or the control.

162. The use of any one of claims 86-160, wherein the use increases a maximum tolerated dose of the one or more peanut allergens in the subject to the one or more peanut allergens is increased by at least 100%, 200%, at least 500%, at least 1000%, or at least about 50000%, at least about 100000%, or at least about 500000% compared to a control or the control.

163. The use of any one of claims 86-162, wherein the one or more peanut allergens is extracted from a peanut flour.

164. The use of any one of claims 88-163, wherein the pharmaceutical composition is formulated for oral mucosal delivery as a dental hygiene product.

165. The use of claim 164, wherein the dental hygiene product is a toothpaste, a mouthwash, a mouthspray, a porous oral pouch, or a dental cream.

166. The use of claim 165, wherein the toothpaste comprises peanut flour, peppermint oil, a salt or derivative thereof, sodium lauryl sulfate, glycerin, glycerol, sodium saccharin, silica, trisodium phosphate, sodium phosphate monobasic, caboxylmethylcellulose USP, carbomer, titanium dioxide, FD & C Green #3, or FD & C Yellow #6. -203- 152511.8001.WO00\169170466.16Attorney Docket No.: 152551.8001.WO00 167. The use of claim 163 or 166, wherein the peanut flour comprises one or more peptides derived from Ara h 1, Ara h 2, Ara h 3, or Ara h 6.

168. The use of claim 163, 166, or 167, wherein the peanut flour is derived from roasted peanuts.

169. The use of claim 166, wherein the peppermint oil is mentha piperita oil.

170. The use of any one of claims 157-169, wherein the cumulative dose is a maximum tolerated dose. -204- 152511.8001.WO00\169170466.16

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