Methods for treating mast cell disorders with Anti-CD117 antibodies

Abstract

Provided herein are compositions and methods related to depletion of mast cells using an anti-c-kit antibody. The compositions and methods described herein may be used to treat a subject in need of mast cell depletion due to a variety of diseases or disorders, such as chronic spontaneous urticaria (CSU).

Description

Attorney Docket Number: JATH-023 / 02WO 335666-2215METHODS FOR TREATING MAST CELL DISORDERS WITH ANTI-CD117 ANTIBODIESRELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Patent Application No.63 / 742,811 filed on January 7, 2025, and U. S. Provisional Patent Application No. 63 / 755,855 filed on February 7, 2025, each of which is incorporated herein by reference in its entirety.STATEMENT REGARDING SEQUENCE LISTING

[0002] The Sequence Listing XML associated with this application is provided in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is JATH 023 02WO SeqList ST26.xml. The XML file is 43,846 bytes, and created on January 7, 2025, and is being submitted electronically via USPTO Patent Center,FIELD OF THE INVENTION

[0003] The present disclosure relates to compositions and methods for regulating mast cell activity, e.g,, to reduce the release of histamine by activated mast cells. The compositions and methods described herein may be used to treat patients with mast cell-related diseases or disorders, including but not limited to chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU).BACKGROUND

[0004] Mast cells are immune cells that play a key role in the inflammatory response to pathogens or injury and are typically found in the skin, lungs, digestive track, conjunctiva of the eye and the mucosal linings of the mouth and nose. Typically, mast cells are triggered by a specific antigen or antibody interaction to release histamine, a variety of cytokines, and other chemical mediators in order fight a potential infection and to recruit additional types of immune cells to aid in the body’s response. However, with certain diseases, such as, e.g., CSU, CIndU, allergic asthma, prurigo nodularis, and eosinophilic esophagitis, the mast cell response is dysregulated and may lead to unwanted responses such as hives, airway constriction or conjunctivitis.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0005] Current therapeutic approaches to controlling mast cell response include the use of antihistamines to counteract the release of histamine by activated mast cells, and anti-IgE antibody therapy to try to eliminate the antibodies responsible for triggering mast cell activation. However, some patients do not respond to Hl -antihistamines. Treatment alternatives for Hl-antihistamine refractory CSU participants include immunosuppressive agents such as cyclosporine A, or repeated exposure to oral glucocorticoids. There are potential significant adverse effects associated with both alternatives (e.g., high blood pressure, increased risk of infection, acne, increased risk of diabetes and osteoporosis, nephrotoxicity, hepatotoxicity, fatigue, depression).

[0006] Accordingly, there is a need in the art for additional therapies for controlling mast cell response and treating diseases and disorders associated with mast cells, such as CSU and CIndU.BRIEF SUMMARY OF THE INVENTION

[0007] The present disclosure provides inter alia methods for treating mast cell-related diseases and disorders, e.g., by administering anti-c-kit antibodies or antigen-binding fragments thereof, e.g., JSP191, to a subject in need thereof.

[0008] In related aspects, the disclosure provides a method of depleting mast cells in a subject, comprising administering to the subject an anti-c-kit antibody, e.g., JSP191, or an antigenbinding fragment thereof, to the subject. Any of the methods of treatment disclosed herein may also be used to deplete mast cells in a subject.

[0009] In one aspect, the disclosure provides a method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 === RASESVD1YGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in the following order:a) one or more induction dose, wherein each induction dose comprises about 200 mg to about 400 mg of the anti-c-kit IgG antibody;b) two or more maintenance doses, wherein each maintenance dose comprises about 80 mg to about 200 mg of the anti-c-kit IgG antibody, wherein at least two of the maintenance doses are less than the one or more induction dose,Attorney Docket Number: JATH-023 / 02WO 335666-2215wherein each of the doses is administered between about four weeks to about eight weeks apart, between about four weeks to about 10 weeks apart, or between about six weeks to about ten weeks apart.

[0010] In one aspect, the disclosure provides a method of treating, inhibiting, or preventing a mast cell -related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 - RASES VDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in the following order:a) one or more induction dose, wherein each induction dose comprises an amount of the anti- c-kit IgG antibody sufficient to achieve a Cmax > 10 ug / mL and / or an AUCiast > 100 ug X day / mL;b) two or more maintenance doses, wherein each maintenance dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve or maintain (i) a Cmax > 5 ug / mL, a Cmax > 6 ug / mL, a Cmax > 7 ug / mL, a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, or a Cmax > 10 ug / mL and / or (ii) an AUCiast > 50 ug X day / mL, an AUCiast > 60 ug X day / mL, an AUCiast > 70 ug X day / mL, an AUCiast > 80 ug X day / mL, an AUCiast > 90 ug X day / mL, or an AUCiast > 100 ug X day / mL, wherein at least two of the maintenance doses are less than the one or more induction dose, wherein each of the doses is administered between about four weeks to about eight weeks apart or between about six -weeks to about ten weeks apart.

[0011] In one aspect, the disclosure provides a method of treating, inhibiting, or preventing atopic dermatitis, optionally allergen-induced dermatitis, hapten-induced dermatitis or MC903-induced dermatitis, or inhibiting or preventing allergic disease, optionally resulting from atopic dermatitis, in a mammalian subject, comprising administering to the subject an anti-c-kit IgG antibody or antigen-binding fragment thereof comprising heavy chain CDRs: VH CDR1 === YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDRS = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 =- LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11).

[0012] In embodiments of any ofthe methods disclosed herein, the antibody or antigen-binding fragment thereof is delivered to the subject systemically, optionally wherein the antigen¬ binding fragment is delivered intravenously or subcutaneously. In embodiments of any of the methods disclosed herein, the antibody or antigen-binding fragment thereof is delivered to theAttorney Docket Number: JATH-023 / 02WO 335666-2215subject locally, optionally wherein the antigen-binding fragment is delivered directly to the skin.

[0013] In embodiments of the disclosed methods, the method depletes mast cells, induces mast cell apoptosis, and / or inhibits mast cell degranulation. In certain embodiments, the method depletes mast cells, induces mast cell apoptosis, and / or inhibits mast cell degranulation by at least 50% at about two weeks following administration of the antibody or antigen-binding fragment thereof. In certain embodiments, the subject’s mast cells are depleted by 20% or less at about 3-4 months following administration of the antibody or antigen-binding fragment thereof.

[0014] In embodiments of any aspect, the anti-c-kit antibody is JSP191.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG, 1 is a diagram of the Phase lb / 2a BEACON study in chronic spontaneous urticaria trial design described in Example 1, which was conducted in about 30 sites in the Unites States and Europe.

[0016] FIG. 2 provides graphs showing the change in UAS7 following treatment with placebo or briquilimab according to the indicated dosing regimens. A >2 Ipt reduction in UAS7 from baseline was observed in multiple dosing regimens > I20mg.

[0017] FIG. 3 provides graphs showing the percentage of patients who demonstrated a complete response (UAS7 = 0) following treatment with placebo or briquilimab according to the indicated dosing regimens, with a dose dependent increase in patients achieving complete response (UAS7:==0). Complete response was observed at all doses > 80mg.

[0018] FIG. 4 provides graphs showing the percentage of patients who demonstrated well- controlled disease (UAS7 < 6) following treatment with placebo or briquilimab according to the indicated dosing regimens. 50% or more of patients achieved well-controlled disease four weeks post-dosing in multiple dose regimens.

[0019] FIGs. 5A-5B provide graphs showing clinical response to briquilimab treatment, including the percentage of patients who achieved complete response (CR) or well-controlled response (WC) following treatment with briquilimab. FIG. 5 A shows results from Cohort 9.1, an initial dose of 240 mg briquilimab at Week 0, followed by a 180 mg maintenance dose of briquilimab Q8W, Complete (CR) or Well Controlled (WC). At Week 5, the top line corresponds to CR or WC, and the bottom line corresponds to CR. FIG. 5B shows clinical responses in Cohort 9.1 patients treated with an initial dose of 240 mg briquilimab at Week 0,Attorney Docket Number: JATH-023 / 02WO 335666-2215followed by a 180 mg maintenance dose of briquilimab at Week 8. The solid bar indicates CR, and the hatched bar indicated partial response (PR).

[0020] FIGs. 6A-6B are graphs showing weekly UAS scores observed for the indicated treatments with placebo or briquilimab. All patients in the 240mg single-dose cohort maintained complete response (CR) to eight weeks (FIG. 6A), with deeper UAS7 reductions observed in subsequent doses. In FIG, 6A, the lines at Week 3 correspond from top to bottom as placebo, 180mg Q8W, 120mg Q8W, and 240mg SD. Cohort 9.1 patients treated with 240mg / 180mg Q8W demonstrated a rapid and sustained UAS7 response (FIG. 6B). In FIG.6B, at Week 3, the top line is placebo, and the bottom line is briquilimab treatment.

[0021] FIGs. 7A and 7B are graphs showing the decrease in serum tryptase levels in patients following treatment with placebo or briquilimab according to the indicated dosing regimens. IN FIG. 7A, at Day 15, the lines from top to bottom correspond to placebo, 80mg Q8W, 120mg pooled, 180 mg pooled, and 240 mg SD. At the time this graph was made, the LLOQ for the assay was 1.6 and the 240mg group n=3. In FIG. 7B, at Week 0, the lines from top to bottom correspond to 240mg (SD), placebo, 240mg Q8W, 240mg to 180mg Q8W, and 360mg (SD). LLOQ = lower limit of quantification.

[0022] FIG. 8 is a graph showing briquilimab serum concentration overtime in CSU patients following subcutaneous administration. At 1 week, the lines from top to bottom correlate to: 240 mg, 180 mg, 120 mg, 80 mg, 40 mg, and 10 mg.

[0023] FIG, 9 is a graph showing briquilimab Cmax vs, maximum change in UCT score after the first dose.

[0024] FIG. 10 is a graph showing briquilimab AUClast vs. maximum change in UCT score after the first dose.

[0025] FIG. 11 is a graph showing briquilimab dose (mg / kg) vs. maximum change in UCT score after the first dose.

[0026] FIG. 12 is a graph showing briquilimab dose (mg / kg) vs. maximum change in UAS7 score after the first dose. UAS7 scores only until Week 8 for single dose cohorts.

[0027] FIG. 13 is a graph showing briquilimab AUCiast vs. maximum change in UAS7 score after the first dose. UAS7 scores only until Week 8 for single dose cohorts.

[0028] FIG. 14 is a table showing mean (%CV) briquilimab pharmacokinetic parameters in CSU patients. For Cohorts 4a and 4b combined: Mean (%CV) Cmax after 120 mg = 9.14 (48%) pg / mL, Median [range] Tmax after 120 mg = 4 [1 - 7] days; for Cohorts 5 and 5b combined: Mean (%CV) Cmax after 180 mg === 14.1 (37%) pg / mL, Median [range] Tmax after 180 mg::::4 [1 - 14] days.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0029] FIG. 15 provides schema of prophylactic and therapeutic mouse models used to demonstrate the effectiveness of briquilimab in treating and preventing MC903-induced dermatitis.

[0030] FIGs. 16A and 16B show dermal mast cell reduction following a single treatment with briquilimab. FIG. 16A provides representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalm-fixed, paraffin-embedded tissue sections showing dermal MCs and histological features, respectively, in back skin 20 day after briquilimab or placebo treatment. FIG. I6B provides graphs of dermal mast cell (MC) densities in toluidine blue-stained tissue sections at 6 days (upper panel) and 20 days (lower panel) following briquilimab (25 mg / kg) or placebo treatment. * P < 0,05 vs, placebo-treated vehicle control mice. N = 3-5 per group.

[0031] FIGs. 17A-I7D show the prophylactic effect of briquilimab treatment on the MC903-induced dermatitis model in h / mCD117 mice. * P < 0.05 vs. placebo-treated vehicle control mice, *P< 0.05 vs. placebo-treated MC903-induced dermatitis model. N = 3-5 per group. Red arrows indicate mast cells. FIG. 17A provides representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalin-fixed, paraffin-embedded tissue sections showing dermal MCs and leukocytes, respectively, in back skin 20 days after briquilimab or placebo treatment. Arrows indicate mast cells, FIG. 17B provides quantification of dermal mast cell densities in toluidine blue-stained tissue sections. FIG. 17C provides quantification of dermal leukocyte densities in H& E-stained tissue sections. FIG. 17D provides clinical scores of skin condition assessed one day after the final e.c. MC903 application, with scores assigned for redness, bleeding, eruption, and scaling on a scale of 0 (none) to 3 (severe). Clinical scores (0-12) correspond to: redness (0-3); bleeding (0-3); eruption (0-3); and scaling (0-3).

[0032] FIGs. 18A-18D show the therapeutic effect of briquilimab treatment on MC903-induced dermatitis model in h / mCDl 17 mice. * P < 0.05 vs, placebo-treated vehicle control mice,+P < 0.05 vs. placebo-treated MC903-induced dermatitis model. N = 3-5 per group. Red arrows indicate mast cells. FIG. 18A provides representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalin-fixed, paraffin-embedded tissue sections showing dermal MCs and leukocytes, respectively, in back skin 6 days after briquilimab or placebo treatment. FIG. 18B provides quantification of dermal mast cell densities in toluidine blue-stained tissue sections. FIG. 18C provides quantification of dermal leukocyte densities in H& E-stained tissue sections. FIG. 18D provides clinical scores of skinAttorney Docket Number: JATH-023 / 02WO 335666-2215condition assessed one day after the final e.c. MC903 application, with scores assigned for redness, bleeding, eruption, and scaling on a scale of 0 (none) to 3 (severe). Clinical scores (0-12) correspond to: redness (0-3); bleeding (0-3); eruption (0-3); and scaling (0-3).

[0033] Fig. 19 shows the experimental protocol. The dermatitis model was induced by epicutaneous (e.c.) application of oxazolone on days 1, 7, and 9. Briquilimab or placebo treatment was administered 10 days prior to the first e.c. application of oxazolone or ethanol (vehicle control for oxazolone). Necropsy and tissue collection were conducted one day after the final e.c. application of oxazolone or vehicle ethanol.

[0034] FIG. 20 is a graph showing the effect of briquilimab treatment on skin condition in the Oxazolone-induced dermatitis model in h / mCD l 17 mice. Skin condition was assessed one day after the final epicutaneous application of oxazolone, with scores assigned for redness, bleeding, eruption, and scaling on a scale of 0 (none) to 3 (severe). ** P < 0.01 between the indicated groups; n = 3-4 per group,

[0035] FIGs. 21A-21B show' the effect of briquilimab treatment on dermal mast cell counts in the Oxazolone-induced dermatitis model in h / mCD117 mice. FIG. 21A show's representative images of toluidine blue-stained, formalin-fixed, paraffin-embedded tissue sections demonstrating dermal mast cells in the back skin one day after the final e.c. application of oxazolone or vehicle (ethanol), scale bar = 100 um. FIG. 21B shows quantification of dermal mast cell densities from toluidine blue-stained tissue sections, ns, not significant; **, ***, or **** P < 0.01, 0.005, or 0.001 between the indicated groups; n = 2-4 per group,

[0036] FIG. 22 shows the effect of briquilimab treatment on dermal leukocyte infiltration in the Oxazolone-induced dermatitis model in h / mCDl 17 mice in representative images of H& E-stained, formalin-fixed, paraffin-embedded tissue sections showing histological features and dermal leukocytes (lower panels) in the back skin one day after the final e.c. application of oxazolone or vehicle (ethanol), scale bar = 100 um.

[0037] FIG. 23 shows quantification of dermal leukocyte densities from H& E-stained tissue sections, ** P < 0.01 between the indicated groups; n = 3-4 per group, demonstrating the effect of briquilimab treatment on dermal leukocyte infiltration in the Oxazolone-induced dermatitis model in h / mCDl 17 mice.

[0038] FIG. 24 is a diagram of the chronic urticaria open label extension study

[0039] FIG. 25 is a graph showing UAS7 score post-briquilimab treatment.

[0040] FIG. 26 is a graph show ing CR % and CR or WV % over time in response to briquilimab treatment. At Week 8, the top line corresponds to CR or W C %, and the bottom line corresponds to CR %.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0041] FIG. 27 provides a comparison of UAS7 and CR & WC following treatment of briquilimab or barzolvolimab. Mean UAS7 change from baseline was conducted using observed cases at the timepoint, or discontinued treatment, they were not included in this analysis

[0042] FIG. 28 provides a comparison or mean UAS7 following treatment with various dosages of briquilimab and barzolvolimab. At Week 4, the lines from top to bottom correspond to: placebo (barzolvolimab), placebo (briquilimab), 150 mg Q4W barzolvolimab, 300 mg Q8W barzolvolimab, 180 mg Q8W briquilimab, 360 mg single dose briquilimab, 240mg initial dose followed by 180 mg Q8W briquilimab (cohort 9.1), and 240 mg single dose briquilimab,

[0043] FIG. 29 shows clinical response over time. The solid portion of each bar corresponds to complete response (CR), and the hatched portion of each bar corresponds to CR + partial response (PR).

[0044] FIG. 30 is a graph showing IJAS7 following briquilimab treatment with the indicated dosing regimens. At 40 days, the lines from top to bottom correspond to: placebo; < 1.5 mg / kg; 1.5 - 2.0 mg / kg: 2.0 - 2.5 mg / kg; 2.5 - 3.0 mg / kg, and > 3.0 mg / kg. Note: <1.5mg / kg - All BEACON and OLE patients; > 1.5 mg / kg - BEACON and OLE patients with WC or CR of at least 1 week only. Data are presented as mean SEM.

[0045] FIG. 31 is a graph showing UAS7 following treatment with briquilimab at < 2.0 mg / kg and > 2.0 mg / kg. At 30 wrecks, the top line corresponds to < 2.0 mg / kg, and the bottom line corresponds to > 2.0 mg / kg. Non responders who did not achieve CR or WC at any time point are excluded. Data are presented as mean SEM.

[0046] FIGs. 32A-32C are diagrams of the Briquilimab Phase lb / 2a SPOTLIGHT Study in CIndU. FIG. 32A shows a timeline of treatment and follow-up, and FIG. 32B shows treatments and tests. FIG. 32C show's how the UCT score w as determined.

[0047] FIG. 33 is a bar graph showing clinical responses maintained through 24 weeks with 180mg Q8W. FIG. 33 depicts clinical response follow ing treatment with briquilimab over the indicated w eeks time course. The solid portion of each bar indicated complete response (CR), and the hatched portion of each bar indicates partial response (PR).

[0048] FIG. 34 is a diagram of the Briquilimab Phase lb / 2a ETESIAN Study in Allergic Asthma.

[0049] FIG. 35 provides graphs showing the change in FEVi (%) following treatment with placebo or briquilimab. For both graphs, at 60 minutes post-challenge, the lines from top to bottom correspond to week six challenges, week 12 challenge, and pre dose challenge,Attorney Docket Number: JATH-023 / 02WO 335666-2215demonstrating that briquilimab mitigates the effects of allergen challenge on FEVi response and showing robust and sustained impact of mast-cell depletion on asthmatic response at 6 and 12 weeks.

[0050] FIG. 36 shows sputum eosinophils (%) at each allergen challenge. The top line is placebo, and the bottom line is briquilimab.

[0051] FIG, 37 shows methacholine PD20 shift at screening and two allergen challenges. At challenge 1, the top line corresponds to briquilimab, and the bottom line corresponds to placebo.DETAILED DESCRIPTION OF THE INVENTION

[0052] The present disclosure provides inter alia treatments for mast cell-related diseases and disorders using anti-c-kit antibodies and fragments thereof in a dose effective to deplete mast cells in a subject being treated. In certain embodiments, the methods are used to treat chronic spontaneous urticaria (CSU), chronic inducible urticaria (ClndU), prurigo nodularis, eosinophilic esophagitis, allergic asthma and se vere, asthma, inflammatory bowel disease, and other mast cell-related diseases and disorders, including, but not limited to, those disclosed herein.

[0053] In particular embodiments, the disclosure provides agents and dosing regimens effective in depleting mast cells while not adversely depleting healthy hematopoietic stem cells in treated patients, and related methods of treating mast cell-related diseases and disorders.

[0054] In particular embodiments, the methods are practiced using the anti-c-Kit antibody, JSP191 or briquilimab, a humanized, aglycosylated IgGl inhibitor of c-Kit signaling on mast cells, which directly blocks stem cell factor (SCF) binding to CD117. Briquilimab’s sequence / structure and mechanism of action provide it with a potency and a half-life that is advantageous for depleting mast cells without substantially depleting healthy hematopoietic stem cells, thus making briquilimab superior for treating, preventing, or inhibiting mast cell- related diseases and disorders. The disclosure further provides dosing regimens that facilitate treatment, prevention, and inhibition of various types of mast cell-related diseases and disorders, including but not limited to single high dose regimens and repeat dosing regimens with intervals between doses.Definitions

[0055] It is to be understood that this invention is not limited to the particular methodology, products, apparatus and factors described, as such methods, apparatus and formulations may, of course, vary. It is also to be understood that the terminology used herein is for the purposeAttorney Docket Number: JATH-023 / 02WO 335666-2215of describing particular embodiments only, and it is not intended to limit the scope of the present invention which will be limited only by appended claims.

[0056] It must be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drag candidate" refers to one or mixtures of such candidates, reference to "the method" includes reference to equivalent steps and methods known to those skilled in the art and so forth, and, for example, "an antibody," is understood to represent one or more antibodies. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0057] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry', described herein, are those well-known and commonly used in the art.

[0058] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. The disclosure also contemplates ranges having upper and lower limits defined by any two numerical values disclosed separately herein,

[0059] As used herein, "antibody" includes reference to an immunoglobulin molecule immunologically reactive with a particular antigen, and includes both polyclonal and monoclonal antibodies. In certain embodiments, an antibody comprises two heavy chains and two light chains, wherein each light chain is bound to a different heavy chain, and the two heavy chains are bound to each oilier. Five types of immunoglobulins include IgM, IgG, IgA, IgE, and IgD2. Antibodies may be any of these, and in certain embodiments are IgG. The term also includes genetically engineered forms such as humanized antibodies, chimeric antibodies (e.g., humanized murine antibodies) and heteroconjugate antibodies. An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof. Thus, the term "antibody" includes any protein or peptide containing molecule that comprises at least aAttorney Docket Number: JATH-023 / 02WO 335666-2215portion of an immunoglobulin molecule having biological activity of binding to the antigen. Examples of such include, but are not limited to a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein. The term "antibody" also includes antigen-binding forms of antibodies, including fragments with antigen-binding capability (e.g.. Fab', F(ab')2, Fab, Fv and rlgG. The term also refers to recombinant single chain Fv fragments (scFv). The term antibody also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies.

[0060] The terms "antibody fragment" or "antigen-binding fragment", as used herein, is a portion of an antibody such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, and the like. Regardless of structure, an antibody fragment binds to the same antigen that is recognized by the intact antibody. The term "antibody fragment" includes aptamers, spiegelmers, and diabodies. The term "antibody fragment" also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.

[0061] A "humanized antibody" is an immunoglobulin molecule which contains minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity'. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, a humanized antibody will comprise substantially all of at least one, and typically' two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0062] Selection of antibodies for cell ablation, e.g., ablation of endogenous mast cells, may be based on a variety of criteria, including selectivity, affinity', cytotoxicity, etc. By "specifically binds" or "has specificity to," it is generally meant that an antibody binds to an epitope via its anti gen -binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody' is said to "specifically bind" to an epitope when it binds to thatAttorney Docket Number: JATH-023 / 02WO 335666-2215epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope. Thus, the phrase “specifically (or selectively) binds”, when referring to an antibody binding to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, in a heterogeneous population of proteins and / or other biologies. The term "specificity" is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody " A" may be deemed to have a higher specificity tor a given epitope than antibody " B," or antibody " A" may be said to bind to epitope " C" with a higher specificity than it has for related epitope " D." Thus, in some embodiments, under designated immunoassay conditions, the specified antibodies bind to a particular protein sequence at least two times the background binding and more typically more than 10 to 100 times background binding.

[0063] Monoclonal antibodies may be prepared using hybridoma methods. In a hybridoma method, an appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell.

[0064] Human antibodies can be produced using various techniques known in the art, including phage display libraries. Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g. mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.

[0065] Antibodies also exist as a number of well-characterized fragments produced by digestion with various peptidases. Pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab’)2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab’)2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab’)2 dimer into a Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region. While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or thoseAttorney Docket Number: JATH-023 / 02WO 335666-2215synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries.

[0066] The selectivity of a particular antibody is typically determined by the ability of one antibody to competitively inhibit binding of the second antibody to the antigen, or by the ability of an antibody to cross-react with multiple epitopes. Any of a number of competitive binding assays can be used to measure competition between two antibodies to the same antigen, or between two antigens to one antibody. An exemplary' assay is a BIACORE™ assay. Briefly in these assays, binding sites can be mapped in structural terms by testing the ability of interactants, e.g., different antibodies, to inhibit the binding of another. Injecting two consecutive antibody or antigen samples in sufficient concentration can identify pairs of competing antibodies for the same binding epitope. The antibody samples should have tire potential to reach a significant saturation with each injection. The net binding of the second antibody injection is indicative for binding epitope analysis. Two response levels can be used to describe the boundaries of perfect competition versus non-competing binding due to distinct epitopes. The relative amount of binding response of the second antibody injection relative to the binding of identical and distinct binding epitopes determines the degree of epitope overlap.

[0067] The term "polynucleotide" refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs or mixtures thereof. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide or nucleoside analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, includes, but is not limited to, double-and single-stranded molecules, and mixtures thereof. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form, whether as RNA or DNA, or a mixture thereof.

[0068] " Encoding" refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces tire protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, usedAttorney Docket Number: JATH-023 / 02WO 335666-2215as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA

[0069] As used herein, the terms "polypeptide," "peptide," and "protein" refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, to include disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component. The term "polypeptide" is intended to encompass a singular "polypeptide" as well as plural "polypeptides," and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term "polypeptide" refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product. Thus, peptides, dipeptides, tripeptides, oligopeptides, "protein," "amino acid chain," or any other term used to refer to a chain or chains of two or more amino acids, are included within the definition of "polypeptide," and the term "polypeptide" may be used instead of, or interchangeably with any of these terms. The term "polypeptide" is also intended to refer to the products of post¬ expression modifications of the polypeptide, including without limitation glycosylation, acety lation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, or modification by non- naturally occurring amino acids. A polypeptide may be derived from a natural biological source or produced by recombinant technology, but is not necessarily translated from a designated nucleic acid sequence. It may be generated in any manner, including by chemical synthesis.

[0070] As used herein, the terms “identity” and “identical” refer, with respect to a polypeptide or polynucleotide sequence-of-interest, to the percentage of exact matching residues in an alignment of that the sequence-of-interest to a reference sequence, such as an alignment generated by the BLAST algorithm. Identity is calculated, unless specified otherwise, across the full length of the reference sequence. Thus a sequence-of-interest “shares at least x% identity to” a reference sequence if, when the reference sequence is aligned (as a query¬ sequence) is aligned to the sequence-of-interest (as subject sequence), at least x% (rounded down) of the residues in the subject sequence are aligned as an exact match to a corresponding residue in the query sequence, the denominator being the full length of the reference sequence plus the lengths of any gaps inserted into the reference sequence by alignment of the reference sequence to the sequence-of-interest. Where the subject sequence has variable positions (e.g., residues denoted X), an alignment to any residue in the query- sequence is counted as a match. Sequence similarity (i.e., identity) can be determined in a number of different manners. To determine sequence identity-, sequences can be aligned using the methods and computerAttorney Docket Number: JATH-023 / 02WO 335666-2215programs, including BLAST, available over the worldwide web at ncbi.nlm.nih.gov / BLAST / . Sequence alignments may be performed using the NCBI Blast sendee (BLAST+ version 2.12.0) or another program giving the same results. Unless indicated to the contrary, sequence identity is determined using the BLAST algorithm (e.g., bl2seq) with default parameters.

[0071] ITie term "native" or “wild-type” as used herein refers to a nucleotide sequence, e.g., gene, or gene product, e.g., RNA or polypeptide, that is present in a wild-type cell, tissue, organ or organism. The term “variant” as used herein refers to a mutant of a reference polynucleotide or polypeptide sequence, for example a native polynucleotide or polypeptide sequence, i.e., having less than 100% sequence identity with the reference polynucleotide or polypeptide sequence. Put another way, a variant comprises at least one amino acid difference (e.g., amino acid substitution, amino acid insertion, amino acid deletion) relative to a reference polynucleotide sequence, e.g., a native polynucleotide or polypeptide sequence. For example, a variant may be a polynucleotide having a sequence identity of 50% or more, 60% or more, or 70% or more with a full length native polynucleotide sequence, e.g., an identity of 75% or 80% or more, such as 85%, 90%, or 95% or more, for example, 98% or 99° / o identity with the full length native polynucleotide sequence. As another example, a variant may be a polypeptide having a sequence identity of 70% or more with a full length native polypeptide sequence, e.g., an identity of 75% or 80% or more, such as 85%, 90%, or 95% or more, for example, 98% or 99% identity with tire full length native polypeptide sequence. Variants may also include variant fragments of a reference, e.g., native, sequence sharing a sequence identity’ of 70% or more with a fragment of the reference, e.g., native, sequence, e.g., an identity of 75% or 80% or more, such as 85 %, 90%, or 95% or more, for example, 98% or 99% identity with the native sequence.

[0072] Tire term “stem cell” as used herein refers to a mammalian cell that has the ability both to self-renew, and to generate differentiated progeny (see Morrison et al. (1997) Cell 88:287- 298). Endogenous stem cells may be characterized by the presence of markers associated with specific epitopes. The term “hematopoietic stem cells (HSC)” as used herein refers to multipotent cells that reside in tire bone marrow (BM) and are responsible for the life-long production of mature blood cells. HSCs have the capacity to give rise to all the different types of mature blood cells, including red blood cells (erythrocytes), white blood cells (leukocytes), and platelets.

[0073] “Hematopoietic stem and progenitor cells” (HSPCs) are a group of cells that are responsible for the generation and replenishment of all the different types of blood cells in the body. They are located primarily in tire bone marrow, although small populations can also beAttorney Docket Number: JATH-023 / 02WO 335666-2215found in peripheral blood and umbilical cord blood. HSCs are the most primitive and selfrenewing cells within the HSPC population. They possess the ability to both replicate themselves through self-renewal and differentiate into multiple specialized cell types. HSPCs also include progenitor cells, which are more committed and lineage-restricted than HSCs. Progenitor cells arise from HSCs and undergo a limited number of cell divisions before differentiating into specific blood cell lineages. Progenitor cells are considered to be more differentiated than HSCs but less differentiated than fully mature blood cells.

[0074] The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease, " Treatment" as used herein covers any treatment of a disease in a mammal, and includes, e.g.: (a) inhibiting the progression of a disease, i.e., arresting or delaying its development; (b) reducing the severity of the disease; or (c) relieving the disease, i.e., causing regression of the disease. “Treatment” is an intervention performed with the intention of preventing the progression of, or altering the pathology of, a disease or disorder. Accordingly, “treat” or “treatment” refers to therapeutic treatment, whereas “prevent” or “prevention” refers to prophylactic or preventative measures, including delaying the onset of a disease or disorder or recurrence of a disease or disorder. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. In particular embodiments, treatment results in improvement in one or more symptoms of the disease. To “inhibit” or “prevent” a disease or disorder includes delaying the onset or reducing the severity of a disease or disorder, or causing the disease or disorder to not occur, e.g., an allergic reaction.

[0075] As used herein, the phrase “therapeutically effective amount,” in the context of treating a mast cell-related disease or disorder, is meant to refer to an amount of therapeutic or prophylactic anti-CD 117 antibody that provides a reduction in mast cell number and / or activity', reduction in fibroid elements or their precursors, or that provides a reduction in the severity or progression of symptoms associated with a mast cell-related disease (i.e., that provides “therapeutic efficacy”).

[0076] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, human and non-human primates, including simians and humans; mammalian sport animals (e.g., horses); mammalian farm animals (e.g., sheep, goats, etc.); mammalian pets (dogs, cats, etc.); and rodents (e.g., mice, rats, etc.).

[0077] As used herein, the term “substantially” means by a significant or large amount or degree. For example, to “substantially” increase may' mean to increase by at least two-fold, atAttorney Docket Number: JATH-023 / 02WO 335666-2215least three-fold, at least four-fold, at least five-fold, or at least ten-fold, and to “substantially” decrease may mean to decrease by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In the following description, numerous specific details are set forth to provide a more thorough understanding of the present invention. However, it will be apparent to one of skill in the art that the present invention may be practiced without one or more of these specific details. In other instances, well-known features and procedures well known to those skilled in the art have not been described in order to avoid obscuring the invention.

[0078] Generally, conventional methods of protein synthesis, recombinant cell culture and protein isolation, and recombinant DNA techniques within the skill of the art are employed in the present invention. Such techniques are explained fully in the literature, see, e.g., Maniatis, Fritsch & Sambrook, Molecular Cloning: A Laboratory Manual (1982); Sambrook, Russell and Sambrook, Molecular Cloning: A Laboratory Manual (2001); Harlow, Lane and Harlow, Using Antibodies: A Laboratory' Manual: Portable Protocol No. I, Cold Spring Harbor Laboratory' (1998); and Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory'; (1988).Treatment of Mast Cell-Related Diseases and Disorders

[0079] The tyrosine-protein kinase KIT is also known as c-KIT, CD117 (cluster of differentiation 117) or SCFR (mast / stem cell growth factor receptor). C-KIT is expressed on the surface of hematopoietic stem cells, mast cells, neural crest-derived melanocytes, and germ cells. C-KIT binds to stem cell factor (SCP) and forms a dimer that activates its intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell,

[0080] Tire human c-KIT protein has an extracellular domain (ECD) with 5 Ig-like domains (D1-D5), which are implicated in ligand binding and homodimerization, a transmembrane domain, and an intracellular domain (ICD). Protein processing of c-KIT includes N-linked glycosylation and phosphorylation on both tyrosine and serine residues. When SCP dimers bind to c-KIT, the binding induces c-KIT dimerization, conformational change of both ECD and ICD, ICD trans-phosphorylation and binding of various partners.

[0081] Mast cells are a key cellular target for a variety of inflammatory’ and immune diseases, including autoimmune diseases. CD117 is important for the development and differentiation of mast cells from hematopoietic stem cells in the bone marrow. The binding of stem cell factor (SCF) to CD117 initiates signaling cascades that promote mast cell groyvth and maturation.Attorney Docket Number: JATH-023 / 02WO 335666-2215CD117 signaling through SCF is crucial for the survival and proliferation of mast cells. SCF binding to CD117 activates various intracellular signaling pathways, including the PI3K-AKT and MAPK pathways, which regulate cell survival and cell cycle progression. CD117 is also involved in mast cell migration and homing to various tissues. Mast cells express CD117 on their surface, allowing them to respond to SCF gradients and migrate to specific locations where SCF is present, such as the skin, respiratory’ tract, and gastrointestinal tract. CD 117 signaling contributes to mast cell activation and degranulation. When mast cells encounter allergens or antigens, cross-linking of IgE antibodies bound to FcsRI receptors on the mast cell surface triggers a signaling cascade that involves CD 117. This signaling enhances the release of various inflammatory mediators, such as histamine, cytokines, chemokines, and proteases, which are responsible for allergic reactions and immune responses. CD117 signaling influences multiple aspects of mast cell function. It modulates the expression of cell surface receptors, such as FCERI and other immune receptors, and regulates the production and release of various cytokines and chemokines by mast cells. These processes contribute to the immune response and the recruitment of other immune cells to the site of inflammation.

[0082] Inhibition of c-Kit signaling can lead to organized cell death and phagocytic clearance of mast cells. On the one hand, however, the blockade needs to be higher than a threshold level to deplete the mast cells, as partial c-Kit inhibition can only inhibit mast cell activation. On the other hand, sustained c-Kit blockade can result in undesirable effects on other c-Kit-expressing cells. Such a tension, therefore, presents a significant challenge for developing c-Kit antibodies for treating mast cell-mediated diseases and disorders.

[0083] Briquilimab (JSP191) is an anti-c-Kit antibody under clinical development. Activation of the c-Kit upon binding by stem cell factor (SCF) leads to dimerization, autophosphorylation and receptor internalization. It has been shown that briquilimab blocks the interaction between c-Kit and SCF directly.

[0084] In accordance with certain embodiments of the present disclosure, provided is a method for treating a mast cell-related or mast cell-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of an anti-CD117 antibody or an antigen binding fragment thereof. Illustrative antibodies and antigen-binding fragments thereof include, but are not limited to, those disclosed herein. In certain embodiments, the anti-CD117 antibody comprises a heavy chain variable region comprising the amino acid sequence of the heavy chain variable region of JSP191 and a light chain variable region comprising the amino acid sequence of the light chain variable region of JSP191. In certain embodiment, the antibody is JSP191 or an antigen binding fragment thereof.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0085] The disclosure contemplates the treatment or prevention of any mast cell-related or mast cell-mediated disease or disorder, and these terms are used interchangeably herein. In some embodiments, the mast cell-mediated disease or disorder is selected from the group consisting of urticaria, asthma, COPD, chronic rhinosinusitis (optionally with nasal polyps), pningo nodularis (PN), eosinophilic esophagitis (EoE), mastocytosis, urticaria pigmentosa, anaphylaxis, inflammatory’ bowel diseases (IBDs; e.g., Crohn’s disease, ulcerative colitis, and indeterminate colitis), endometriosis, interstitial cystitis, and mast cell activation syndrome (MCAS). In particular embodiments, the mast cell-related disease or disorder is selected from the group consisting of: urticarias, including chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), chronic idiopathic urticaria (CIU), or urticaria pigmentosa, prurigo nodularis, esophagitis, optionally eosinophilic esophagitis, asthma, allergic diseases and disorders, optionally allergic asthma, anaphylaxis, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, dermatitis (e.g,, atopic dermatitis), atherosclerosis, endometriosis, interstitial cystitis and inflammatory bowel disease.

[0086] In some embodiments, the mast cell-mediated disease or disorder is a urticaria, e.g., a chronic urticaria. In some embodiments, the chronic urticaria is chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CIndU). In some embodiments, the CIndU is Cold urticaria (ColdU) or Symptomatic Dermographism (SD).

[0087] In some embodiments, the methods and treatments described herein deplete mast cells from a subject by administering an anti-c-kit antibody or fragment thereof to the subject (e.g., briquilimab or a JSP191 (Fab’jz). In some embodiments, the mast cells comprise activated mast cells. In some embodiments, the mast cells are depleted from one or more tissues or organs of the subject, e.g., in certain embodiments, mast cells are depleted from the skin or lung of the subject. Tn some embodiments, mast cells are depleted from the subject, or a tissue or organ of the subject, by at least or about 2%, at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99%, or about 100% of total mast cells in the subject, or the tissue or organ of the subject. In certain embodiments, the treatments completely or almost completely deplete mast cells from the subject, or one or more tissue or organ of the subject. In certain embodiments, the tissue or organ is skin or lung,

[0088] In some embodiments, the methods and treatments described herein induce apoptosis of mast cells in a subject by administering an anti-c-kit antibody (e.g., briquilimab) or antigen¬ binding fragment thereof to the subject. In some embodiments, the mast cells compriseAttorney Docket Number: JATH-023 / 02WO 335666-2215activated mast cells. In some embodiments, the methods induce apoptosis of mast cells in one or more tissues or organs of the subject, e.g., in certain embodiments, in the skin or lung of the subject. In some embodiments, the methods induce apoptosis of mast cells in the subject, or in a tissue or organ of the subject, by at least or about 2%, at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99%, or at least or about 100% of total mast cells in the subject, or the tissue or organ of the subject. In certain embodiments, the treatments induce apoptosis of completely or almost completely all mast cells in the subject, or one or more tissue or organ of the subject. In certain embodiments, tire tissue or organ is skin or lung.

[0089] In some embodiments, the treatments described herein selectively deplete or induce apoptosis of activated mast cells in a subject. In particular embodiments, selective depletion or apoptosis of activated mast cells according to a disclosed method results in the depletion or apoptosis of a greater number or percentage of activated mast cells as compared to the number or percentage of non-activated mast cells that are depleted or undergo apoptosis.

[0090] In certain embodiments, methods disclosed herein are used to modulate one or more mast cell activities, e.g., to inhibit mast cell growth and maturation, inhibit mast cell survival and proliferation, inhibit activation of mast cell intracellular signaling pathways, including the PI3K-AKT and MAPK pathways, inhibit mast cell migration and homing to various tissues, e.g., skin, respiratory tract, and gastrointestinal tract tissues, inhibit mast cell activation and degranulation, and / or inhibit mast cell release of various inflammatory mediators, such as histamine, cytokines, chemokines, and proteases.

[0091] In some embodiments, the methods described herein deplete mast cells from a subject by administering an anti-c-kit antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab h fragment, to the subject. In some embodiments, the mast cells comprise activated mast cells. In some embodiments, the mast cells are depleted from one or more tissues or organs of the subject, e.g., in certain embodiments, mast cells are depleted from tire skin or lung of the subject. In some embodiments, mast cells are depleted from the subject, or a tissue or organ of the subject, by at least or about 2%, at least or about 5%, at least or about 10%, at least or about 20%, at least or about 30%, at least or about 40%, at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99%, or at least or about 100% of total mast cells in the subject, or the tissue or organ of the subject. In certain embodiments, the treatments completelyAttorney Docket Number: JATH-023 / 02WO 335666-2215or almost completely deplete mast cells from the subject, or one or more tissue or organ of the subject. In certain embodiments, the tissue or organ is skin or lung.

[0092] In particular embodiments, the methods deplete mast cells, induce mast cell apoptosis, and / or inhibit mast cell degranulation. In certain embodiments, the methods deplete at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or all of the subject’s mast cells, or induces apoptosis of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 10%, at least about 80%, at least about 90%, or all of the subject’s mast cells, at about one week, two weeks, three weeks, or one month following administration of the antibody. In certain embodiments, the subject’s mast cells are depleted by about 5% or less, about 10% or less, or about 20% or less at about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about 11 months, or about 12 months following administration of the antibody. In particular embodiments, the depleted mast cells comprise or are activated mast cells.

[0093] In some embodiments, the treatments described herein selectively deplete activated mast cells in a subject. In particular embodiments, selective depletion of activated mast cells according to a disclosed method results in the depletion of a greater number or percentage of activated mast cells as compared to the number or percentage of non-activated mast cells that are depleted.

[0094] In some embodiments, the methods and treatments described herein selectively deplete mast cells as opposed to hematopoietic stem and progenitor cells (HSPCs). In particular embodiments, the methods result in depletion of less than about 10%, less than about 20%, less than about 30%, less than about 40%, or less than about 50% of the subject’s HSPCs at about one week, two weeks, three weeks, or one month following administration of the antibody. In particular embodiments, the methods result in depletion of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the subject’s activated mast cells or total mast cells. In particular embodiments, HSPCs refer to those measured in the subject’s bone marrow, blood or serum, in particular embodiments, mast cells (activated or not) refer to those measured in the subject’s bone marrow, blood or serum, or in a tissue sample of the subject, e.g., a skin biopsy.

[0095] Without wishing to be bound to any particular theory, the anti-c-Kit antibodies disclosed herein are shown to induce apoptosis of mast cells. In particular embodiments, they may be used to treat mast cell diseases and disorders. For example, the disclosure contemplatesAttorney Docket Number: JATH-023 / 02WO 335666-2215that an anti-c-Kit antibody, e.g., JSP191, or fragment thereof, is administered to a subject having a mast cell -related disease or disorder at a dosage sufficient to cause mast cell depletion. Tire mast cells undergo apoptosis, which occurs within hours to days following administration of the anti-c-Kit antibody or fragment thereof. The mast cells are then phagocytized with depletion occurring as early as day 7 with robust depletion at day 29 (about two weeks or more to leave the skin), after which it typically takes mast cells about three months or longer to recover in the skin. JSP191 has a PK clearance half-life of about nine days. Following a dose free interval, e.g., anywhere between about four week to about six months or about eight weeks to about six months, e.g., about eight weeks to about 12 weeks or about 4 week to about 12 weeks or about 4 weeks to about 8 weeks.which allows for return of c-Kit signaling in other c- Kit expressing cells, the subject may be re-dosed with the anti-c-Kit antibody or fragment thereof, e.g., JSP191, or fragment thereof, which causes the apoptosis and phagocytosis of any newly formed mast cells or mast cell progenitors. This cycle of re -dosing may be continued in order to keep mast cell levels low.

[0096] In particular embodiments, the anti-c-kit antibody or fragment thereof is provided to the subject in a dose effective to deplete mast cells in a subject being treated.

[0097] In particular embodiments, the anti-c-Kit antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)?, is administered subcutaneously.

[0098] In certain embodiments, the patients are treated with the monoclonal anti-c-kit IgG antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)? fragment, about once every’ four to ten weeks, six to ten weeks, or four to eight weeks, e.g., about once even eight weeks. In certain embodiments, the patients are treated with the monoclonal anti-c-kit IgG antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)? fragment, about once evety four to eight weeks. In certain embodiments, the patients are treated with the monoclonal anti-c-kit IgG antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)? fragment, about once every eight weeks. In certain embodiments, the patients are treated with the monoclonal anti-c-kit IgG antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)? fragment, about once every’ four weeks. In certain embodiments, the patients are treated with the monoclonal anti-c-kit IgG antibody or fragment thereof, e.g., JSP191 or a JSP191 (Fab’)? fragment, about once every four to eight yveeks. In some embodiments, the administration is subcutaneous, intravenous, or intramuscular injection. In a particular embodiment, the administration is subcutaneous. In some embodiments, a first dose of the administration results in mast cell count reduction in the subject for at least 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, theAttorney Docket Number: JATH-023 / 02WO 335666-2215anti-CD117 antibody or fragment thereof comprises an IgG Fc fragment not capable of activating antibody-dependent cellular cytotoxicity (ADCC)

[0099] Compositions and methods disclosed herein may be used to treat or prevent mast cell- related diseases and disorders, including but not limited to those involving chronically active mast cells, e.g., by administering an anti-c-kit antibody, e.g., JSP191, or an antigen binding fragment thereof, e.g., a JSP191 (Fab’ fragment, to the subject. For example, in particular embodiments, the disclosed methods may be used to prevent or reduce an allergic response or to prevent recurrence of asthma exacerbation following allergen exposure. So, for example, the anti-c-kit antibody^ or antigen-binding fragment thereof may be administered to the subject prior to exposure to an allergen, or prior to re-exposure to an allergen,

[0100] Compositions and methods disclosed herein may be used prophylactically to inhibit or prevent a mast cell-related disease or disorder from developing, and they may be used therapeutically to treat a mast cell-related disease or disorder. In particular embodiments, a subject exposed to an allergen may be treated according to the disclosed methods to prevent, inhibit, or reduce an allergic response to the allergen.

[0101] While mast cell-related diseases and disorders include those wherein the mast cell itself is diseased or has a pathology, mast cell-related disease and disorders also include diseases and disorders that result in mast cell activation and / or release of cytokines, which can, in some instances, lead to inflammation and other problems. In certain embodiments, the compositions and methods disclosed herein are used to treat inflammation or inflammatory diseases and disorders. In certain embodiments, the compositions and methods disclosed herein are used to treat diseases and disorders associated with an innate immune response and / or an adaptive immune response, including but not limited to autoimmune diseases, such as, e.g., autoimmune psoriasis.

[0102] Mast cell-related diseases and disorders include both IgE-mediated mast cell-related diseases and disorders and IgE-independent mast cell -related disease and disorders. In certain embodiments, both IgE-mediated mast cell-related diseases and disorders and IgE-independent mast cell-related disease and disorders can result in anaphylactoid reactions and / or allergic reactions. Non-limiting examples of IgE-mediated mast cell-related diseases and disorders include anaphylaxis, e.g., passive anaphylaxis, systemic anaphylaxis, passive systemic anaphylaxis, and allergic reactions, such as allergen-induced dermatitis (e.g., allergen-induced atopic dermatitis) and allergen-induced asthma (e.g., allergen-induced allergic asthma). Mast cell diseases and disorders may also result in allergic inflammation and tissue remodeling in asthma. Non-limiting examples of IgE-independent mast cell-related diseases and disordersAttorney Docket Number: JATH-023 / 02WO 335666-2215include anaphylaxis (e.g., severe anaphylaxis), and C48 / 80-mediated anaphylactoid reactions. Anaphylactoid shock is a fatal hypersensitivity' response caused by non-IgE-mediated mast cell activation.

[0103] Mast cells and / or their secretory products are involved in the pathogenesis of a variety of diseases and disorders. Examples of mast cell-related diseases and disorders include mast cell activation related disorders (MCAD), which are a heterogenous group of conditions that may be associated with an increased number of mast cells and / or hyperactive mast cells. These disorders can vary in severity, but common symptoms include often severe reactions to insect stings, and in rare cases to foods or drugs. MCAD comprise clonal (e.g., mastocytosis) and nonclonal (idiopathic) variants. Clonal MC disorders (CMD) may be characterized by intrinsic MC defects, such as KIT mutation D816V, and / or expression of aberrant MC receptors, which may cause a “hyperactive” state of MCs leading to excessive release of mediators. Non-limiting examples of mast cell activation disorders include allergic disorders, mastocytosis, e.g., intestinal mastocytosis, such as intestinal mastocytosis following helmith infection, anaphylaxis, mast cell activation syndromes (MCAS), primary MCAS, secondary MCAS, mixed MCAS, and idiopathic MCAS. See, e.g., Gulen et al., Immunology an Allergy Clinics, Vol. 42, Issue 1, p45-63, February72022.

[0104] Mast cells play a central role in many diseases and disorders, including but not limited to dermatological diseases, respiratory disease and disorders, gastrointestinal diseases and disorders, and many others. The methods disclosed herein may be used to treat any of these diseases or disorders. Non-limiting examples of mast cell-mediated diseases or disorders include urticaria, asthma, prurigo nodularis (PN), eosinophilic esophagitis (EoE), mastocytosis, urticaria pigmentosa, anaphylaxis, endometriosis, interstitial cystitis, and mast cell activation syndrome (MCAS). In a particular example, the mast cell-mediated disease or disorder is chronic urticaria, such as chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU). Specific examples of dermatological diseases and disorders that may be treated according to the methods disclosed herein include, but are not limited to: urticarias (e.g., chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CindU)), dermatitis (e.g., allergic contact dermatitis and atopic dermatitis), alopecia (e.g., alopecia areata), bullous pemphigoid, prurigo nodularis, psoriasis, and rosacea. Specific examples of respiratory diseases and disorders that may be treated according to the methods disclosed herein include, but are not limited to: asthma, rhinitis (e.g., allergic rhinitis), aspirin exacerbated respiratory- disease (AERD), chronic obstiuctive pulmonary disease (COPD), rhinosinusitis (e.g., chronic rhinosinusitis with nasal polyps (CRSwNP)), and pulmonary fibrosis (e.g., idiopathicAttorney Docket Number: JATH-023 / 02WO 335666-2215pulmonary fibrosis). Specific examples of gastrointestinal diseases and disorders that may be treated according to the methods disclosed herein include, but are not limited to: eosinophilic esophagitis (EoE), food allergy, oral immunotherapy, inflammatory bowel diseases (IBDs) (e.g., Crohn’s disease and ulcerative colitis), and irritable bowel syndrome (IBS). Specific examples of other diseases and disorders that may be treated according to the methods disclosed herein include, but are not limited to: allergic conjunctivitis, age-related macular degeneration (AMD), alpha-1 antitrypsin deficiency, Alzheimer’s disease, angioedema, celiac disease, dermatitis herpetiformis, graft versus host disease (e.g., chronic graft versus host disease), cystitis, endometriosis, fibromyalgia, hereditary' alpha tryptascmia (HaT), anaphylaxis (e.g., idiopathic anaphylaxis), insulin-dependent diabetes mellitus, mast cell activation syndrome (MCAS), mast cell leukemia, mastocytosis (e.g., KIT negative), migraine, multiple sclerosis, pancreatitis (acute / chronic), arthritis (e.g., rheumatoid arthritis), and sickle cell disease (sickle crisis)

[0105] Mast cells are a key cellular target for a variety of inflammatory- or autoimmune diseases that may be treated with the compositions and methods disclosed herein, including but not limited to, e.g., urticaria, chronic urticaria, chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), prurigo nodularis, eosinophilic esophagitis, asthma, e.g., allergic asthma, inflammatory- bowel disease, fibrosis, scleroderma, systemic sclerosis.

[0106] In certain embodiments, the compositions and methods disclosed herein are used to treat inflammation or inflammatory- diseases and disorders. In certain embodiments, the compositions and methods disclosed herein are used to treat diseases and disorders associated with an innate immune response and / or an adaptive immune response, including but not limited to autoimmune diseases, such as, e.g., autoimmune psoriasis.

[0107] In particular embodiments, a subject exposed to an allergen may be treated according to the disclosed methods to prevent, inhibit, or reduce an allergic response to tire allergen.Chronic Urticaria

[0108] Chronic urticaria is a skin condition characterized by the presence of hives or welts that persist for more than six weeks. The condition can be caused by a variety of factors, including autoimmune disorders, infections, medications, and physical stimuli such as heat, cold, or pressure. There are multiple causes of chronic urticaria, such as infection, stress, or autoimmune diseases. In many cases, however, the cause is unknown. These cases are known as chronic idiopathic urticaria (CIU) or chronic spontaneous urticaria (CSU). Chronic urticaria is currently treated with medications to lessen the itch and relieve discomfort. There are also ways to prevent and improve symptoms at home, such as applying cold compresses to theAttorney Docket Number: JATH-023 / 02WO 335666-2215affected skin. Stress management can help with treatment, as increased stress can worsen hives. Long-term hives can also cause more stress, leading to mental health challenges such as anxiety and depression. While current treatment options include antihistamines, corticosteroids, and immunosuppressants, they target the symptoms rather than the underlying diseases. Improved treatments are therefore needed.

[0109] Chronic spontaneous urticaria (CSU) affects about 1% of the population worldwide of all ages. It mainly affects young to middle-aged adults (disease onset at the age of approx. 30 to 50 years) and is more common in women then in men (Goncalo et al. 2021). CSU is defined by the presentation of pruritic wheals (hives) and / or angioedema, which occur for more than six weeks without an identifiable specific trigger. The elevated lesions are accompanied by redness and intense continuous itching, which directly impacts many dimensions of a patient’s quality of life. In many participants, CSU is of long duration, 5 to 7 years on average (Kolkhir et al. 2022). Tire manifestations have a strong effect on health-related quality of life, including sleep impairment, diminished physical and emotional -well- being and poor performance at school or work.

[0110] CSU is associated with considerable healthcare utilization and economic burden, including both regular and unanticipated healthcare visits, costs due to laboratory’ expenses and indirect costs due to the absence from -work or reduced efficiency. If s well-characterized that greater disease severity is associated with greater impact on quality of life (Aimstrong 2023, Maurer 2017, Vietri 2015). In a recent trial characterizing the HRQoL burden on CSU patients, the most significantly affected aspects of HRQoL in severe patients despite treatment (UAS7> I6) were diminished physical well-being (pain / discomfort in -70% of patients), emotional well-being (anxiety / depression in -55% of patients), sleep impairment (-50% of patients) and poor work performance (-20% of patients mi ssed at least 1 hour of work in past 7 days due to CSU symptoms) (Maurer 2017).

[0111] Although the cause of CSU is not fully understood yet, several molecular mechanisms leading to mast cell activation have been described to date. Activation and degranulation of skin mast cells and the release of histamine or other mediators (e.g., tryptase, TNF, different interleukins) are tlie key drivers of the development of symptoms.

[0112] Current standard-of-care of CSU includes oral Hl -antihistamines, as well as second-and third line therapies, i.e., omalizumab and cyclosporine, respectively (Metz et al. 2021; Kolkhir et al. 2022; Zuberbier et al. 2022). However, about 40-50% of patients have uncontrolled symptoms, despite being administered doses higher than FDA-approved doses (Maurer 2017, Guillen-Aguinaga 2016), and more than 25% of cases are resistant toAttorney Docket Number: JATH-023 / 02WO 335666-2215antihistamines, even at higher doses. Omalizumab, an anti-IgE antibody, was licensed as a treatment agent of CSU in antihistamine-refractory participants and may be used as an add-on therapy to antihistamines. However, less than 50% of patients have complete symptom resolution (Maurer 2013, Saini 2015). In addition to tlie incomplete symptom control, omalizumab has a boxed warning for anaphylaxis, deeming some patients ineligible (Xolair Prescribing Information 2023), Omalizumab’s risk of allergic reaction is not dissimilar to other FDA approved biologies for dermatologic conditions, including dupilumab for atopic dermatitis, which holds a warning for hypersensitivity reactions (Dupixent Prescribing Information 2022). Altogether, there is a significant group of moderate-to-severe CSU patients who remain symptomatic despite treatment with omalizumab or who cannot tolerate omalizumab. The development of further novel therapies is, therefore, strongly recommended.

[0113] In certain embodiments, methods disclosed herein are used to treat patients with CSU, e.g., optionally who remain symptomatic despite treatment with antihistamine or who cannot tolerate antihistamine. In particular embodiments, the antihistamine is an Hl -antihistamine. In certain embodiments, methods disclosed herein are used to treat patients with CSU, e.g., optionally who remain symptomatic despite treatment with omalizumab or who cannot tolerate omalizumab (Xolair®). In certain embodiments, methods disclosed herein are used to treat patients with CSU who are Xolair®-naive and / or Xolair®-failed.Chronic Inducible Urticaria (CIndU)

[0114] Chronic inducible urticaria (CIndU) is a subtype of urticaria characterized by the recurrence of symptoms (itchy wheals and / or angioedema) recurring for longer than six weeks. Similar to CSU, CIndU is characterized by development of hives and / or angioedema and redness in the skin. Unlike CSU, tire trigger for CIndU patients can be diagnosed by assessment of various common provocations such as cold, heat, pressure, vibration and others. The two most common forms of CINdU are symptomatic dermographism (SD) and cold contact urticaria (ColdU). CIndU is thought to affect over one million patients in the United States, France, Germany, Italy, Spain and the United Kingdom. Approximately 40% of these patients’ CIndU is not controlled by first line anti -histamines and these patients could be eligible for biologic therapy depending on disease severity.

[0115] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing CIndU in a mammalian, e.g., human, subject. In certain embodiments, the subject has cold urticaria and / or symptomatic dermographism.Attorney Docket Number: JATH-023 / 02WO 335666-2215Prurigo Nodularis

[0116] Prurigo Nodularis is also a disease that manifests in the skin. Patients develop severe itch and firm bumps on the skin, called nodules, that may lead to loss of sleep and bleeding due to scratching. Degranulation of mast cells in the skin is thought to trigger peripheral sensory neurons in the skin leading to itch. Various medications are used to treat Prurigo Nodularis including anti -itch creams and topical steroids. For cases that remain uncontrolled physicians may prescribe anti-histamines or biologies such as dupilumab. PN is also known as Hyde prurigo nodularis, Picker's nodules, atypical nodular form of neurodermatitis circumscripta, lichen comeus obtusus.

[0117] The cause of prurigo nodularis is unknown, although other conditions may induce PN. PN has been linked to Becker's nevus, linear IgA disease, an autoimmune condition, liver disease and T cells. Systemic pruritus has been linked to cholestasis, thyroid disease, polycythaemia rubra vera, uraemia, Hodgkins disease, HIV and other immunodeficiency diseases. Internal malignancies, liver failure, kidney failure, and psychiatric illnesses have been considered to induce PN, although more recent research has refuted a psychiatric cause for PN. Patients report an ongoing battle to distinguish themselves from those with psychiatric disorders, such as delusions of parasitosis and other psychiatric conditions,

[0118] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing Prurigo nodularis in a mammalian, e.g., human, subject.Eosinophilic Esophagitis

[0119] Eosinophilic esophagitis is an immune disorder leading to build up of eosinophils in the esophagus and causes difficulty in eating, chronic reflux and / or the sensation of heartbum. Along with the buildup of eosinophils, there is typically buildup of other immune cells in the affected area including mast cells, basophils and lymphocytes. In healthy individuals, the esophagus is ty pically devoid of eosinophils. In EoE, eosinophils migrate to the esophagus in large numbers. When a trigger food is eaten, the eosinophils contribute to tissue damage and inflammation. Symptoms include swallowing difficulty, food impaction, vomiting, and heartbum. Symptoms include swallowing difficulty, food impaction, vomiting, and heartbum. Patients may be treated with changes to diet, use of proton pump inhibitors, antihistamines and dupilumab.

[0120] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing eosinophilic esophagitis in a mammalian, e.g., human, subject.AsthmaAttorney Docket Number: JATH-023 / 02WO 335666-2215

[0121] Asthma is a long-term inflammatory disease of the airways of the lungs, characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise. Asthma is thought to be caused by a combination of genetic and environmental factors. Environmental factors include exposure to air pollution and allergens. Other potential triggers include medications such as aspirin and beta blockers. Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry lung function testing. Asthma is classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. It may also be classified as atopic or non-atopic, where atopy refers to a predisposition toward developing a type 1 hypersensitivity reaction.

[0122] Methods and compositions disclosed herein may be used to treat asthma. Mast cells are distributed throughout multiple compartments in the lung. Mast cells release / activate various mediators that drive asthma pathophysiology. Early phase in asthma is driven by mast cell degranulation (and release of histamine, prostaglandins, leukotrienes, IL-5, IL-13, IL-4 and CXCR2, and may also drive the late phase recruitment of other cell ty pes to the lung. Current therapeutic strategies in asthma target specific upstream (IgE, TSLP) or downstream mediators (IL-5, IL-4 / IL- 13) but do not broadly inhibit mast cells. Methods and compositions disclosed herein may be used to treat asthma, and in particular embodiments, e.g., to induce mast cell apoptosis, inhibit release of mediators that drive asthma pathophysiology, and / or inhibit recruitment of other cell types to the lungs.

[0123] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing asthma or an allergic reaction in a mammalian, e.g., human, subject.

[0124] In certain embodiments, methods and compositions disclosed herein are used to treat, inhibit, or prevent severe asthma, including severe asthma independent of Type 2 inflammation. Tryptase in bronchoalveolar lavage (BAL) and plasma are significantly elevated in severe asthma as compared to healthy subjects or subjects with mild or moderate asthma. For example, normalized BAL tryptase levels may be greater than about 100 pg / mL or greater than about 125 pg / mL, and plasma tryptase levels may be greater than about 2000 pg / mL or greater than or about 4000 pg / mL. Tins elevated tryptase in severe asthma is independent of Type 2 inflammation. In particular embodiments, the methods and compositions disclosed herein are used to treat severe refractory asthma. They may be used to treat severe asthma with or without Type 2 inflammation.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0125] Allergic asthma, also referred to herein as allergen-induced asthma and allergy-induced asthma, (e.g., allergen-induced allergic asthma) is a form of asthma triggered by specific allergens that leads to constriction of smooth muscles in the airways, cellular infiltration of various immune mediators and excess production of mucus. Allergic asthma may be associated with inflammation and tissue remodeling. Patients with allergic asthma may have an increased number of mast cells in the bronchi and may be responsive to agents that modulate mast cell response, including anti-histamines and anti-IgE monoclonal antibody therapy.

[0126] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing an allergic reaction, e.g., allergic asthma, in a mammalian, e.g., human, subject.

[0127] In particular embodiments, methods and compositions disclosed herein are used to treat, inhibit, or prevent any type of asthma, including asthma in patients who are not indicated for current biologic agents or remain refractory to them. In particular embodiments, the methods and compositions disclosed herein are used to treat moderate-to-severe (e.g,, severe) asthma in patients refractory' to one or more other treatment, e.g., refractory' asthmatics with inadequate response to inhaled corticosteroids (ICS), long-acting β2-agonists (LABA), and / or long-acting muscarinic antagonists (LAMA). Severe asthma is a potentially life-threatening inflammatory disorder characterized by persistent asthma symptoms, despite use of high doses of ICS and LABA / LAMA (2022 GINA Main Report. Global Initiative for Asthma - GINA). Asthma severity increases with age and the median age of severe asthma is 45-60 years (Ronnebjerg, L. et al. J Asthma Allergy. 2021:14:1105-1115 and Zein, JG et al., PLoS One.2015: 10(7):e0133490). Approximately 300,000 patients currently receive biologic therapies in the US and EU. Selection of biologic therapy in severe asthma is based on disease biomarkers. Severe asthma may be divided into two classes: Type 2 High and Type 2 Low. Type 2 High include the following asthma endotypes: eosinophilic only asthma, eosinophilic and allergic asthma, and allergic only asthma (2022 GINA Main Report. Global Initiative for Asthma - GINA). Biomarkers for Type 2 High severe asthma include high FeNO in airways, high serum IgE, high serum periostin, high IFN-y levels, and high blood / sputum eosinophils. Biomarkers for Type 2 Low severe asthma include neutrophil accumulation in the airw ays, low blood / sputum eosinophils, high TNF-a levels in the BAL, and high YKL-40 levels in the blood. In certain embodiments, type 2 low' severe asthma patients have peripheral blood eosinophil counts < 300 / ul. Patients with type 2 allergic only asthma or type 2 low asthma have limited treatment choices compared to patients with eosinophilic disease. For example, type 2 high eosinophilic only asthma patients may be treated with a variety of FDA approvedAttorney Docket Number: JATH-023 / 02WO 335666-2215therapies, including the following drugs and targets, e.g., Nucala® (mepolizumab; 11.5). Cinqair® (reslizumab; IL5), Fasenra® (benralizumab; IL5), Dupixent® (dupilumab; IL4 / IL13), and Tezspire® (tezepelumab; TSLP). Type 2 allergic only asthma patients may be treated with FDA approved Xolair® (omalizumab; IgE) or Tezspire® (tezepelumab; TSLP), and Type 2 low asthma patients may be treated with Tezspire® (TSLP). In certain embodiments, methods and compositions disclosed herein may be used to treat any moderate-to-severe or severe asthma, such as, e.g.. Type 2 High severe asthma and Type 2 Low severe asthma, including any form or endotype, e.g., type 2 high allergic only or type 2 low asthma. In particular embodiments, the treatment is provided subcutaneously.Anaphylaxis

[0128] Anaphylaxis is as an acute, severe, systemic hypersensitivity reaction and represents an example of excessive MC activation resulting in the release of various mediators. Anaphylaxis can affect multiple organ systems and present with an array of symptoms. In certain embodiments, anaphylaxis comprises concurrent occurrence in at least two organ systems, which, in certain embodiments, include the cutaneous, gastrointestinal (Gl), respiratory, and / or cardiovascular systems. Anaphylaxis comprises a heterogeneous group of conditions regarding the nature and route of exposure to triggers, organ involvement, severity, and time course. Anaphylaxis has a variety of causes. For example, food-induced systemic reaction is a leading cause of anaphylaxis in children, whereas venom- or drug-induced reactions account for most adult cases. From this perspective, severe anaphylaxis (S ) is a distinct anaphylaxis phenotype, ■which may involve hypotension and / or loss of consciousness. In particular embodiments, methods disclosed herein may be used to treat any type of anaphylaxis, e.g., IgE-mediated anaphylaxis and non-IgE anaphylaxis. A variety of drags have been shown to cause IgE- mediated anaphylaxis, including, e.g., anti -anaphylaxis agents, chemotherapy agents, diseasemodifying antirheumatic drugs (DMARDS), antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, radiocontrast agents, intraoperative agents, monoclonal antibodies, and others, such as, e.g., human IgG, lisinopril, morphine, and ondansetron. Examples of drugs implicated in non-IgE anaphylaxis include, e.g., fluoroquinolones, opioids, such as morphine and sufentanil, radiocontrast agents, atracurium, paclitaxel, and vancomycin. Many opioids, e.g., morphine, are potent histamine releasers producing a variety of haemodynamic changes and anaphylactoid reactions. Methods disclosed herein may be used to treat opioid-mediated or opioid receptor-mediated anaphylaxis.

[0129] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing anaphylaxis or an anaphylactoid reaction in a mammalian, e.g., human, subject.Attorney Docket Number: JATH-023 / 02WO 335666-2215Mastocytosis

[0130] Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called mastocytes) and CD341 mast cell precursors. People affected by mastocytosis are susceptible to a variety of symptoms, including itching, hives, and anaphylactic shock, caused by tire release of histamine and other pro-inflammatory’ substances from mast cells. Mastocytosis is characterized by excessive accumulation, proliferation, and activation of abnormal MCs in several organs, including the skin, bone marrow, and GI tract. Mastocytosis includes both cutaneous mastocytosis (CM) and systemic mastocytosis (SM) involving at least one extracutaneous organ. SM includes indolent SM (ISM) and more aggressive variants of the disease. Mastocytosis includes intestinal mastocytosis, e.g., intestinal mastocytosis following helminth infection.

[0131] Urticaria pigmentosa, also known as generalized eruption of cutaneous mastocytosis (childhood type), is the most common form of cutaneous mastocytosis. It is a rare disease caused by excessive numbers of mast cells in the skin that produce hives or lesions on the skin when irritated. Urticaria pigmentosa is characterized by excessive amounts of mast cells in the skin. Red or brown spots are often seen on the skin, typically around the chest, forehead, and back. These mast cells, when irritated (e.g., by rubbing the skin, heat exposure), produce too much histamine, triggering an allergic reaction that leads to hives localized to the area of irritation, sometimes referred to as Darier's sign. Severe itching usually follows, and scratching the area only serves to further symptoms. Symptoms can be mild (flushing and hives that require no treatment), moderate (diarrhea, tachycardia, nausea / vomiting, headache, and fainting), or life-threatening (vascular collapse requiring emergency treatment and hospitalization).

[0132] The majority of urticaria pigmentosa cases are caused by a point mutation at amino acid 816 of the proto-oncogene c-Kit. Mutations in position 816 of c-Kit can result in a constant division signal being sent to the mast cells, resulting in abnormal proliferation. Different mutations have been linked to different onset times of the disease. For example, the Asp81 6Phe and Asp816Val mutations (the aspartate normally at position 816 in the c-kit protein has been replaced with phenylalanine or valine respectively) have been associated with early- manifestation of the disease.

[0133] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing mastocytosis, e.g., urticaria pigmentosa, in a mammalian, e.g., human, subjectAttorney Docket Number: JATH-023 / 02WO 335666-2215Mast Cell Activation Syndrome

[0134] MC activation syndrome (MCAS) is a disorder of MC activation with various causes all resulting in severe, recurrent, and episodic symptoms due to systemic MC mediator release. Patients with MCAS often present with symptoms of anaphylaxis. However, neither all anaphylaxis fulfill diagnostic criteria of MCAS nor do all MCAS episodes reach tire severity of anaphylaxis. MC activation can manifest as a less severe and / or chronic condition.

[0135] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing MCAS in a mammalian, e.g., human, subjectFibrosis

[0136] Methods disclosed herein may be used to treat fibrotic diseases and disorders. As used herein the term ‘''fibrotic disease or disorder’’ refers to conditions involving fibrosis in one or more tissues As used herein fee term “fibrosis"’ refers to aberrant formation or development of excess fibrous connective tissue in an organ or tissue as a reactive process, as opposed to formation of fibrous tissue as a normal constituent or healing of an organ or tissue. Fibrosis is characterized by fibroblast accumulation and collagen deposition in excess of normal deposition in any particular tissue. As used herein the term “fibrosis” includes aberrant healing, involving mesenchymal-fibroblast cell transformation, excessive fibroblast proliferation, activity and deposition of collagens and other extracellular matrix proteins. Compositions and methods disclosed herein may also be used io treat atherosclerosis. Vascular fibrosis, characterized by reduced lumen diameter and arterial wall thickening attributable to excessive deposition of extracellular matrix (ECM), is associated with many clinical diseases and pathological progresses including atherosclerosis.

[0137] Mast ceil number and mast cell mediators are significantly elevated in most human fibrotic diseases, including but not limited to, idiopathic pulmonary fibrosis (IFF) and scleroderma. Differential mast cell phenotypes are detected in some scleroderma patients and in the Tsk mouse model of scleroderma. An aggressive systemic form of mastocytosis may be characterized by myelofibrosis indicating that roast cells can be effector cells n fibrosis.

[0138] Examples of mast cell associated fibrotic diseases include, but are not limited to, pathological fibrosis or scarring (including endocardial sclerosis), idiopathic interstitial fibrosis, interstitial pulmonary fibrosis, penmuscular fibrosis, Symmers* fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, biliary cirrhosis, alcoholic cirrhosis, acute pulmonary- fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, kidney fibrosis / glomerulonephritis, kidney fibrosis / diabetic nephropathy, sclerodernm / systemic, scleroderma / local, keloids, hypertrophic scars, severe joint adhesions / arthritis, myelofibrosis.Attorney Docket Number: JATH-023 / 02WO 335666-2215corneal scarring, cystic fibrosis, muscular dystrophy (duchenne's), cardiac fibrosis, muscular fibros-s / rctinai separation, esophageal stricture and payronles disease. Further fibrotic disorders may be induced or initiated by surgery, including scar revision / plas c surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren's contracture, OB / GYN adhesions / fibrosis, pelvic adhesions, peridural fibrosis, restenosis. It is also contemplated that fibrotic conditions where deposition of fibronectin is a causative factor can be treated according to the invention. Idiopathic pulmonary fibrosis, bleomycin lung, cystic fibrosis, and glomerular nephropathy, iuclud-ng disease characterized by Fn deposits in the kidneys ultimately leading to renal failure are examples of conditions which can also be treated in accordance with the present invention. Inflammation involving activation of the immune system and where mast ceils secrete inflammatory cytokines such as TNF, and can acti vate and directly interact with lymphocytes can also be treated in accordance with the present invention

[0139] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing fibrosis or a fibrotic disease or disorder in a mammalian, e.g., human, subject.Allergic Diseases and Disorders

[0140] The role of mast cells in allergic diseases has been clinically validated by drugs that block mast cell specific mediators such as histamine and corticosteroids, which among their activities cause mast cell apoptosis. Additional mast cell-related diseases include, e.g., histamine-mediated allergic reactions that can be treated by inhibiting chemokine-induced mast cell and basophil degranulation and release of histamine. Additional examples of mast cell associated disorders or diseases which may be effectively treated with the subject methods and compositions also include, but are not limited to, contact dermatitis, atopic dermatitis, allergic dermatitis (e.g,, allergen -induced atopic dermatitis), allergic asthma, eczematous dermatitis, allergen-induced forms of dermatitis specifically, including atopic, contact, and allergic dermatitis, dermatitis caused by insect bites or stings, and allergic diarrhea.

[0141] In certain embodiments, the methods disclosed herein are used to treat, inhibit, or prevent atopic dermatitis, including allergen-induced dermatitis, hapten-induced dermatitis or MC903-induced dermatitis. MC903 is a low-calcemic analog of vitamin D3 that induces production of the cytokine thymic stromal lymphopoietin (TSLP), thus activating dendritic cells and promoting T cell differentiation, TSLP acts as a master switch that triggers both the initiation and maintenance of atopic dermatitis and the atopic march. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. Idris association, which suggests a role for AD in subsequent allergic disease, is aAttorney Docket Number: JATH-023 / 02WO 335666-2215phenomenon known as the "atopic march." Evidence suggests a role for the cytokine thymic stromal lymphopoietin (TSLP) in the atopic march. Han H, Xu W, Headley MB, Jessup HK, Lee KS, Omori M, Comeau MR, Marshak-Rothstein A, Ziegler SF. Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma. See, e.g., Mucosal Immunol. 2012 May;5(3):342-51. doi: 10.1038 / mi.2012.14. Epub 2012 Feb 22. Erratum in: Mucosal Immunol. 2012 Jul;5(4):468. PMID: 22354320; PMCID: PMC3328620, which indicates that skin-derived TSLP may represent an important factor that triggers progression from AD to asthma. MC903 represents a distinct class of molecules compared to allergens, characterized by its ability' to disrupt epidermal barrier function and trigger robust immune responses through keratinocyte activation and cytokine production, particularly thymic stromal lymphopoietin (TSLP). Mouse models of MC903-induced dermatitis are widely used to replicate key features of dermatitis, with TSLP playing a pivotal role in initiating and amplifying the inflammatory’ cascade by activating dendritic cells and promoting T-cell differentiation. In this context, MCs further contribute to the inflammatory process by enhancing immune cell recruitment, amplifying cytokine signaling, and driving tissue damage.

[0142] In certain embodiments, the disclosed methods inhibit TSLP production, e.g., in response to an antigen, inhibit T cell differentiation, inhibit activation of dendritic cells, inhibit immune cell recruitment, inhibit cytokine signaling, and / or inhibit tissue damage. In certain embodiments, the disclosed methods inhibit allergic disease, e.g., allergic disease progressing from or resulting from dermatitis, e.g,, AD. Any of these methods may be practiced using one or more doses of JSP191 or an antigen-binding fragment thereof, at any of the doses or dosing regimens disclosed herein.

[0143] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing an allergic disease or disorder in a mammalian, e.g., a human, subject.

[0144] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing allergen-induced asthma (i.e., allergic asthma) in a mammalian, e.g., a human, subject,

[0145] In certain embodiments for inhibiting or preventing an allergic reaction, a subject is administered an anti-c-kit antibody or antigen-binding fragment thereof prior to an initial or subsequent contact with or exposure to an allergen, e.g., to prevent an allergic reaction to the allergen exposure.Inflammatory’ Bowel Disease (IBP)

[0146] Inflammatory bowel disease (IBD) is a chronic inflammatory condition that primarily affects the gastrointestinal tract. There are two main types of IBD: Crohn's disease andAttorney Docket Number: JATH-023 / 02WO 335666-2215ulcerative colitis. Crohn's disease can affect any part of the digestive tract; however, it most commonly affects the small intestine and the beginning of the large intestine (colon). The inflammation in Crohn's disease is characterized by transmural involvement, meaning it affects all layers of the intestinal wall, potentially causing the formation of ulcers, strictures, and fistulas. In contrast, ulcerative colitis primarily affects the colon and the rectum. The inflammation in ulcerative colitis is usually limited to the inner lining of the colon, known as the mucosa. It typically begins in the rectum and can spread to involve different parts of the colon. Both Crohn's disease and ulcerative colitis are believed to result from an inappropriate immune response in genetically susceptible individuals.

[0147] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing an IBD in a mammalian, e.g., human, subject.Other Mast Cell-mediated Diseases and Disorders

[0148] Other mast cell-related indications suitable for treatment by the methods and compositions of the invention include pulmonary inflammatory conditions in interstitial lung diseases for example sarcoidosis, neonatal respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and conditions characterized by an elevation in serum PLA2 activity, such as adult RDS (ARDS), Others include arthritis, including both osteoarthritis and rheumatoid arthritis, anaphylaxis, endometriosis, interstitial cystitis (IC), septic shock, pancreatitis, collagen vascular diseases, acute renal failure, peritonitis, and autoimmune uveitis. Studies also suggest that mast cells participate in the pathophysiology of multiple sclerosis. Thus, it is contemplated that tire methods and compositions of the invention are suitable for treatment or amelioration of the morbidity associated with multiple sclerosis.

[0149] Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways with progressive and irreversible decline in lung function caused by airway obstruction and destruction of parenchyma. Three pathological disorders, including chronic bronchitis, small airway disease, and emphysema, existing either separately or in combination culminate in COPD Chronic inflammation is the hallmark of COPD, involving the interplay of a wide variety of cells in the lung microenvironment. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are generally considered the key inflammatory cells involved in COPD. However, an increase in the density of mast cells of the MCTC subtype has been reported in the alveolar parenchyma and airway smooth muscle in COPD. Thus, methods disclosed herein may be used to treat COPD. Other mixed inflammatory or allergic airway inflammatory- disorders may also be treated.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0150] Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of tire following: an itchy rash, throat closing due to swelling that can obstruct or stop breathing; severe tongue swelling that can also interfere with or stop breathing; shortness of breath, vomiting, lightheadedness, loss of consciousness, low blood pressure, and medical shock. Common causes include allergies to insect bites and stings, foods, sulfites, medications, general anaesthetic, contrast agents, or latex. The mechanism involves the release of inflammatory mediators in a rapidly escalating cascade from certain ty pes of white blood cells triggered by either immunologic or non- immunologic mechanisms.

[0151] Endometriosis is a disease of the female reproductive system in which cells in the layer of tissue that normally covers the inside of the uterus grow outside the uterus. Lesions can be found on ovaries, fallopian tubes, tissue around the uterus and ovaries (peritoneum), intestines, bladder, and diaphragm; it may also occur in other parts of the body. Symptoms include pelvic pain, heavy and painful periods, pain with bowel movements, painful urination, pain during sexual intercourse and infertility. Clinical data demonstrates a disproportionate mast cell infiltrate into endometriotic lesions suggestive that mast cells are a key driver of symptoms including chronic pain.

[0152] Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor. Symptoms include feeling the need to urinate right away, needing to urinate often, and pain with sex. The cause of IC / BPS is not well understood. Evidence from clinical and laboratory studies confirms that mast cells play a central role in IC / BPS possibly due to their ability to release histamine and cause pain, swelling, scarring, and interfere with healing.

[0153] These and other mast cell-related diseases and disorders may be treating using the agents and dosing regimens disclosed herein.

[0154] In certain embodiments, the disclosure provides a method for treating, inhibiting, or preventing any mast cell-related disease or disorder in a mammalian, e.g., human, subject.Dosage and Administration

[0155] According to particular embodiments related to treatment of mast cell-related diseases or disorders, the anti-c-kit antibody treatments described herein may be administered in dosing regimens that deplete mast cells, e.g., via apoptosis. Any of the dosing regimens disclosedAttorney Docket Number: JATH-023 / 02WO 335666-2215herein or described herein for another mast cell-related disease may be used for other mast cell-related diseases and disorders.

[0156] In certain embodiments, a subject is initially treated with one or more induction dose of the anti-c-kit antibody or antigen binding fragment thereof, e.g., JSP191, followed by two or more maintenance doses of the anti-c-kit antibody or antigen binding fragment thereof, e.g., JSP191, In particular embodiments, the maintenance doses are lower than the one or more induction dose. In certain embodiments, the subject is initially treated with a single induction dose, followed by two or more maintenance doses. In particular embodiments, each of the doses are administered about four weeks to about 12 weeks apart, about four weeks to about ten weeks apart, about six to about 12 weeks apart, or about six weeks to about ten weeks apart, e.g., about 8 or about 10 weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, the amount of time between various doses may vary; for example, a dose may be given earlier than planned f the patient shows increasing disease symptoms or a decreased level of the antibody of fragment thereof in their blood. In embodiments, each of the doses are administered about four weeks apart or about eight weeks apart. In particular embodiments, the doses are administered about eight weeks apart. In particular embodiments, each dose comprises at least 2 mg / kg subject body weight. In particular embodiments, tire induction dose(s) and / or the maintenance dose(s) comprise at least 2 mg / kg subject body weight or at least 2.5 mg / kg subject body weight. In particular embodiments, each induction dose and / or each maintenance dose comprises between about 2.0 mg / kg subject body weight to about 6.0 mg / kg subject body weight, between about 2.0 mg / kg subject body weight to about 5.0 mg / kg subject body weight, or between about about 2.0 mg / kg subject body weight to about 5.0 mg / kg subject body weight.

[0157] In some embodiments, each induction dose comprises about 100 mg to about 500 mg, about 180 mg to about 360 mg, or about 200 mg to about 400 mg of the anti-c-kit IgG antibody. In some embodiments, each induction dose comprises about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, or about 400 mg of the anti-c-kit IgG antibody, optionally JSP191. In embodiments, the induction dose comprises about 120 mg, about 180 mg, about 240 mg, about 300 mg, or about 360 mg of the anti-c-kit IgG antibody, optionally J SP 191. In particular embodiments, an induction dose comprises about 240 mg or about 360 mg of the anti-c-kit IgG antibody. In embodiments, an induction dose comprises about 240 mg of the anti-c-kit IgG antibody.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0158] In some embodiments, each maintenance dose comprises about 80 mg to about 200 mg, or about 120 mg to about 180 mg of the anti-c-kit IgG antibody. In some embodiments, each maintenance dose comprises about 40 mg to about 400 mg, about 90 mg to about 270 mg, about 80 mg to about 270 mg, about 80 mg to about 320 mg, about 120 mg to about 240 mg, about 140 mg to about 180 mg, about 120 mg to about 270 mg, about 40 mg to about 360 mg, about 40 mg to about 320 mg, about 40 mg to about 240 mg, about 40 mg to about 180 mg, about 40 mg to about 120 mg, about 80 mg to about 180 mg, about 80 mg to about 120 mg, about 80 mg to about 180 mg, or about 80 mg to about 360 mg of the anti-c-kit IgG antibody. In some embodiments, each maintenance dose comprises about 40 mg, about 80 mg, about 90 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 270 mg, about 320 mg, or about 360 mg of the anti-c-kit IgG antibody, optionally JSP 191. In some embodiments, each maintenance dose comprises about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg of the anti-c-kit IgG antibody, optionally JSP191, In particular embodiments, each of the maintenance doses comprises about 120 mg or about 180 mg of the anti-c-kit IgG antibody. In embodiments, each of the maintenance doses comprises about 180 mg of the anti-c-kit IgG antibody.

[0159] In embodiments, the maintenance dose amounts may be the same or different. For example, in embodiments, the first maintenance dose may be higher than a subsequent maintenance dose, and in other embodiments, the first maintenance dose may be lower than a subsequent maintenance dose. In embodiments, the maintenance doses may be administered at the same time interval, while in embodiments, the maintenance doses may be administered at different time intervals. In embodiments, the first maintenance dose may be administered a shorter amount of time after the induction dose than the amount of time between maintenance doses. For example, the first maintenance dose may be administered about four weeks after the induction dose, and the second maintenance doses administered eight weeks after first maintenance dose.

[0160] In embodiments, a subject may be administered an induction dose and / or maintenance dose that is lower or higher than those explicitly described herein. For example, a subject may be administered one or more lower doses if the subject has a low or lower than average body weight, and / or a subject may be administered one or more higher doses if the subject has a higher or higher than average body weight. In another example, a subject may be administered one or more lower doses if the subject has a body weight at or below a designated cut-off body¬ weight, and / or a subject may be administered one or more higher doses if the subject has a higher or higher than average body weigh has a body weight at or above a designated cut-offAttorney Docket Number: JATH-023 / 02WO 335666-2215body weight. In embodiments, examples of designated cut-off values include, but are not limited to, 60 kilograms, 70 kilograms, 80 kilograms, 90 kilograms, 100 kilograms, and 120 kilograms. In embodiments, the designated cut-off value is 80 kilograms. In embodiments, the designated cut-off value is 90 kilograms. In embodiments where a subject is administered a lower dose, the lower dose may be between about 50% and about 90% of the reference dose, between about 70% and about 80% of the reference dose, e.g., about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of the reference dose. In embodiments where a subject is administered a higher dose, the higher dose may be between about 125% and about 500% of the reference dose, between about 125% and about 300% of the reference dose, between about 125% and about 200% of the reference dose e.g., about 125%, about 150%, about 200%, about 250%, about 300%, about 350%. about 400?% about 450%, or about 500% of the reference dose.

[0161] In embodiments, each induction dose comprises about 120 mg to about 360 mg of the anti-c-kit IgG antibody, and each maintenance dose comprises about 80 mg to about 240 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is JSP191. In certain embodiments, the doses are administered about four weeks apart. In certain embodiments, the doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight -weeks apart. In embodiments, each induction dose comprises about 120 mg to about 360 mg of the anti-c-kit IgG antibody, and each of the maintenance doses compri ses about 180 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is JSP191. In certain embodiments, each of the doses are administered about eight weeks apart. In certain embodiments, the doses are administered about four weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In embodiments, each of the induction doses comprises about 120 mg to about 360 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 180 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is JSP191. In certain embodiments, each ofthe doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each ofthe doses are administered about four weeks apart. In embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma.

[0162] In embodiments, each induction dose comprises about 240 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 80 mg to about 180 mg of theAttorney Docket Number: JATH-023 / 02WO 335666-2215anti-c-kit IgG antibody or about 120 mg to about 180 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is ISP 191. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, each of the doses are administered about eight weeks apart. In embodiments, tire doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma.

[0163] In embodiments, each induction dose comprises about 240 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 180 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is JSP191. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, each of the doses are administered about eight weeks apart. In embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma.

[0164] In embodiments, each induction dose comprises about 240 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 120 mg of the anti-c-kit IgG antibody, optionally wherein the antibody is JSP191, In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, each of the doses are administered about eight weeks apart. In embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma.

[0165] In embodiments, the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 180 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, the doses are administered subcutaneously. In embodiments, the antibody is JSP191. In embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma,

[0166] In embodiments, the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 120 mg of the anti-c-kit IgG antibody, whereinAttorney Docket Number: JATH-023 / 02WO 335666-2215each of the doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In certain embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP191.

[0167] In embodiments, the subject is administered an induction dose comprising about 180 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 140 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP191.

[0168] In embodiments, the subject is administered a single induction dose comprising about 120 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 90 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart. In embodiments, each of the doses are admini stered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP191.

[0169] In embodiments, the subject is administered a single induction dose comprising about 360 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 270 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart. In embodiments, each of the doses are administered from about four to about eight weeks apart. In embodiments, each of the doses are administered about four weeks apart. In certain embodiments, the doses are administered subcutaneously. In embodiments, the mast cell disease being treated is CSU, CIndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP191.

[0170] In embodiments, the subject is administered a single induction dose comprising about 120 mg to about 360 mg of the anti-c-kit IgG antibody, e.g., briquilimab, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 90 mg to about 270 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about four week to about eight weeks apart. In certain embodiments, the doses are administeredAttorney Docket Number: JATH-023 / 02WO 335666-2215subcutaneously. In embodiments, the mast cell disease being treated is CSU, ClndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP 191.

[0171] In embodiments, the subject is administered a single induction dose comprising about 120 mg to about 360 mg of the anti-c-kit IgG antibody, e.g., briquilimab, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 90 mg to about 270 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about four week to about eight weeks apart. In certain embodiments, the doses are administered subcutaneously. In certain embodiments, the doses are administered subcutaneously. In embodiments, tire mast cell disease being treated is CS U, ClndU (optionally cold induced), or allergic asthma. In embodiments, the antibody is JSP 191.

[0172] Tire amount of the anti-c-kit IgG antibody, e.g., briquilimab, administered to the subject for tire induction dose and / or the maintenance dose(s) may vary depending upon the subject / s body weight. In embodiments, patients may be stratified into two, three or more groups based on their weight. In embodiments, each group is administered an induction dose and / or maintenance dose(s) of at least 2.0 mg / kg body weight or at least 2.5 mg / kg body weight.

[0173] In embodiments, patients are stratified into two groups based on their weight, and patients above a certain weight are given higher doses than patients at or lower than the certain weight. In embodiments, each group is administered an induction dose and / or maintenance dose(s) of at least 2.0 mg / kg body weight or at least 2.5 mg / kg body weight.

[0174] In embodiments, patients at or below 90 kilograms body weight are treated with an induction dose of about 240 mg, and patients greater than 90 kilograms body weight are treated with an induction dose of about 360 mg. In embodiments, patients at or below 90 kilograms body weight are further treated with one or more maintenance dose of about 180 mg, and patients greater than 90 kilograms body weight are further treated with one or more maintenance dose of about 270 mg. In embodiments, the antibody is briquilimab, tire patient is being treated for CSU, ClndU, or allergic asthma, and the bruiquilimab is administered subcutaneously.

[0175] In embodiments, patients at or below 90 kilograms body weight are treated with an induction dose of about 180 mg to about 320 mg, and patients greater than 90 kilograms body weight are treated with an induction dose of about 320 mg to about 400 mg. In embodiments, patients at or bel ow 90 kil ograms body weight are further treated with one or more maintenance dose of about 140 mg to about 240 mg, and patients greater than 90 kilograms body weight are further treated with one or more maintenance dose of about 240 mg to about 400 mg. InAttorney Docket Number: JATH-023 / 02WO 335666-2215embodiments, the antibody is briquilimab, the patient is being treated for CSU, CIndU, or allergic asthma, and the bruiquilimab is administered subcutaneously.

[0176] In embodiments, patients at or below 80 kilograms body weight are treated with an induction dose of about 180 mg, and patients greater than 80 kilograms body weight are treated with an induction dose of about 320 mg. In embodiments, patients at or below 80 kilograms body weight are further treated with one or more maintenance dose of about 140 mg, and patients greater than 80 kilograms body weight are further treated with one or more maintenance dose of about 240 mg. In embodiments, the antibody is briquilimab, the patient is being treated for CSU, CIndU, or allergic asthma, and the bruiquilimab is administered subcutaneously.

[0177] In embodiments, patients are treated by induction and maintenance amounts of anti-c-kit antibody, e.g., briquilimab, according to one of the dosing regimens shown below.Regimen Body Induction dose Maintenance Induction Maintenance # ~ weight cutfor pts. at or dose(s)for pts. dose for pts. dose(s)for pts.offs) below cut-off at or below above cut-off above cut-off (kilograms) weight (mg) cut-off weight weight (mg) weight (mg) (mg)1 90 180 - 400 80 - 400 180 - 400 80 - 400 2 90 180 - 360 80 - 270 180 - 360 80 - 270 3 90 180 - 320 80 - 320 320 - 400 80 - 360 4 90 180 - 320 120 - 240 320 - 400 240 - 360 5 90 180 - 240 140 - 180 240 - 360 180 - 270 6 90 240 - 320 180 - 240 360 - 400 270 - 360 7 90 240 120 - 240 360 120 - 360 8 90 240 180 360 2709 90 240 180 360 18010 80 120 - 360 40 - 360 120 - 360 40 - 360 11 80 120 - 320 40 - 320 120 - 320 40 - 320 12 80 120 - 240 40 - 240 240 - 360 40 - 320 13 80 120 - 240 80 - 180 240 - 360 80 - 320 14 80 120 - 180 80 - 120 180 - 320 80 - 320 15 80 180 - 240 120 - 240 320 - 360 240 - 270 16 80 180 80 - 180 320 80 - 320 17 80 180 140 320 24018 80 180 140 320 180Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0178] In embodiments, patients are stratified into three groups based on their weight, with in the lowest weight group being given lower doses than patients in the two higher weight groups, patients in the middle weight group being given intermediate doses as compared to the two other weight groups, and patients in the highest weight group being given higher doses than patients at in the two lower weight groups.

[0179] In certain embodiments patients are stratified into three groups: (i) at or below 60 kg body weight; (ii) greater than 60 kg body weight up to and including 120 kg body weight; and (iii) greater than 120 kg body weight. In one example, patients in group (i) are treated with an induction dose of about 120 mg; patients in group (ii) are treated with an induction dose of about 240 mg; and patients in group (iii) are treated with about 360 mg. In this example, patients in group (i) are further treated with one or more maintenance dose of about 80 mg to about 120 mg (optionally about 80 mg); patients in group (ii) are further treated with one or more maintenance dose of about 180 mg to about 240 mg (optionally about 180 mg); and patients in group (iii) are further treated with one or more maintenance dose of about 180 mg to about 360 mg (optionally about 240 mg). In embodiments, the antibody is briquilimab, the patient is being treated for CSU, CIndU, or allergic asthma, and the bruiquilimab is administered subcutaneously. In embodiments, the antibody is briquilimab, the patient is being treated for CSU, CIndU, or allergic asthma, and the bruiquilimab is administered subcutaneously.

[0180] Various other combinations of induction doses and maintenance doses may be administered in different amounts to patients in different body weight groups. In embodiments, the induction doses are selected to be at least 2 mg / kg patient body weight or at least 2.5 mg / kg patient body weight. In embodiments, the induction doses are between 2 mg / kg patient body weight and 6 mg / kg patient body weight.

[0181] In related embodiments, the disclosure provides a method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the subject an amount of an anti -c -kit IgG antibody or antigen-binding fragment thereof sufficient to achieve a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, a Cmax > 10 ug / mL, a Cmax > 12 ug / mL and / or an AUCiast > 100 ug X day / mL. In embodiments, the amount of anti-c-kit IgG antibody or antigen-binding fragment achieves a Cmax <15 ug / mL, a Cmax < 20 ug / mL, a Cmax < 25 ug / mL, or a Cmax < 40 ug / mL. In particular embodiments, the antibody comprises the CDRs present in JSP191 or is JSP191. In particular embodiments, the disease or disorder is CSU, CIndU or allergen-induced asthma.

[0182] In particular embodiments, the subject is administered in the following order:Attomey Docket Number: JATH-023 / 02WO 335666-2215a) one or more induction dose, wherein each induction dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, a Cmax > 10 ug / mL, and / or an AUCiast > 100 ug X day / mL; andb) two or more maintenance doses, wherein each maintenance dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve or maintain a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, a Cmax > 10 ug / mL, and / or an AUCiast > 100 ug X day / mL.

[0183] In certain embodiments, each of the one or more induction dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve (i) a Cmax of 8 ug / mL to 25 ug / mL, a Cmax of 10 ug / mL to 25 ug / mL, a Cmax > 5 ug / mL, a Cmax > 6 ug / mL, a Cmax > 7 ug / mL, a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, or a Cmax > 10 ug / raL and / or (ii) an AUCiast of 100 ug X day / mL to 1,000 ug X day / mL, an AUCiast > 50 ug X day / mL, an AUCiast > 60 ug X day / mL, an AUCiast > 70 ug X day / mL, an AUCiast > 80 ug X day / mL, an AUCiast > 90 ug X day / mL, or an AUCiast > 100 ug X day / mL. In particular embodiments, the subject is administered one or two induction doses. In certain embodiments, each of the one or more maintenance dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve a Cmax of 8 ug / mL to 25 ug / mL, a Cmax of 10 ug / mL to 25 ug / mL, and / or an AUCiast of 100 ug X day / mL to 1,000 ug X day / mL. In certain embodiments, each of the maintenance doses is lower than the one or more induction dose. In certain embodiments, each of the doses is administered between about four weeks to about eight weeks apart or between about six weeks to about ten weeks apart, e.g., about eight weeks apart. In particular embodiments, the doses are administered subcutaneously,

[0184] In some embodiments, the dosing regimen is continued for about or at least a month, about or at least 6 months, about or at least a year, about or at least 2 years, about or at least 3 years, or about or at least 5 years. In some embodiments, the dosing regimen is continued until the subject is disease-free. In some embodiments wherein a subject is administered two or more doses of the anti-c-kit antibody, the subject’s disease symptoms are monitored following each dose, and the subject is administered another dose when symptoms of the disease recur or become more prominent.

[0185] According to embodiments of tire methods disclosed herein, monotherapy treatment with the anti-c-kit antibody is sufficient, and the subject does not need to be treated with another therapeutic agent for the disease being treated. In other embodiments, the subject is treated with the anti-c-kit antibody is combination with immunotherapy for treatment of the disease being treated. In some embodiments, the subject is treated with the anti-c-kit antibody in combination with anti-histamines. In some embodiment, the subject is treated with the anti-c-Attorney Docket Number: JATH-023 / 02WO 335666-2215kit antibody in combination with an immunosuppressive agent, such as, e.g., cyclosporine A or a glucocorticoid, e.g., repeated administration of oral glucocorticoids.

[0186] In some embodiments, the anti-c-kit antibody therapy (or combination therapy) may be delivered orally, subcutaneously, intravenously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly. In some embodiments, the anti-c-kit antibody, e.g.. JSP191, is administered locally or systemically, e.g., intravenously or subcutaneously. In some embodiments, an anti-c-kit antibody is delivered to the skin, e.g., by local injection or application, or subcutaneously.

[0187] In particular embodiments, treatment results in improvement in one or more symptoms of the disease or disorder. For example, the methods and dosing regimens disclosed herein may result in:a) a > 25% reduction in the subject’s UAS7 score for at least eight weeks following the one or more induction doses;b) a UAS7 < 6 for at least eight eeks following one or more induction doses; and / or c) a reduction of mast cells of at least 50%, at least 70%, at least 70?% at least 80?% or at least 90?% and / orc) a UCT score of > 12, indicating well-controlled disease, for at least eight weeks following one or more induction doses.

[0188] In particular embodiments, e.g., for the treatment of CSUd, treatment results in an improvement in the subject’s UAS7 score following treatment. In certain embodiments, the UAS7 score is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80?% at least 90%, or by 100% as compared to the subject’s UAS7 score prior to treatment or at the time of first dose. In some embodiments, the subject’s UAS7 score following treatment is less than or equal to 4, less than or equal to 5, less than or equal to 6, less than or equal to 7, or less than or equal to 8. In some embodiments, the subject’s UAS7 score following treatment is less than or equal to 6. In some embodiments, the subject’s UCT score following treatment is greater than or equal to 10, greater than or equal to 11, greater than or equal to 12, greater than or equal to 13, or greater than or equal to 14.

[0189] In some embodiments, e.g., for the treatment of CSU, CIndU, or allergic asthma, the subject's UCT score at some time following treatment is greater than or equal to 12.

[0190] In some embodiments, the UAS7 scores and / or UCT are determined prior to treatment or at tire time of first dose administration and then again at about 4, 6, 8, 12, 16, or 24 weeks following administration of the first dose. In some embodiments, the UAS7 scores and / or UCT are determined prior to treatment or at the time of first dose administration and then again atAttorney Docket Number: JATH-023 / 02WO 335666-2215about 8 or 12 weeks following administration of the first dose of the anti-c-kit antibody or fragment thereof, e.g., briquilimab.

[0191] In embodiments, a subject is treated as described in any of the accompanying Examples.Anti-c-Kit Antibodies

[0192] Methods disclosed herein contemplate the use of an anti-c-kit antibody. In some embodiments, the disclosure provides methods for selectively depleting endogenous mast cells and / or diseased hematopoietic stem cells (HSCs) in a subject by administering an anti-c-kit antibody or antigen-binding fragment thereof, e.g., a (Fab’)2 fragment. In some embodiments, the compositions and methods disclosed herein may be applicable to any anti-c-kit antibody that blocks stem cell factor (SCF) binding to a c-kit / CDl 17 protein of an endogenous HSC. In some embodiments the antibody is a monoclonal anti-human c-kit antibody. In some embodiments, the antibody is an antigen-binding fragment of an antibody that blocks stem cell factor (SCF) binding.

[0193] In particular embodiments, methods disclosed herein are practiced using an (Fab’)?, fragment, e.g., a JSPI91 (Fab’)2 antibody fragment. The (l ab’).- fragment refers to a specific antibody fragment that is generated by enzymatic cleavage of the intact antibody molecule with pepsin. Pepsin cleaves the antibody just below or within the hinge region. The (Fab’)2 fragment includes two Fab joined together through disulfide bonds, so they are divalent with a molecular weight of about 110 kDa, as compared to about 150 kDa for a whole IgG antibody. The (Fab’)2 contains the vanable regions of both the heavy and light chains, which contribute to the specificity of the antibody. Thus, the (Fab’)2 fragment retains the antigen-binding capabilities of the intact antibody but lacks the Fc region. (Fab’)2 fragments may be produced by digestion of a full IgG antibody with pepsin or other enzymes, such as digestion at a single site below the hinge of IgG using the site-specific cysteine proease FabRICATOR (IdeS)(Genovis Inc,, USA). (Fab’)2 may also be produced recombinantly, e.g., by expressing full antibody light chains and truncated antibody heavy chains that lack the Fc region but include the variable region and some or all of the hinge region. For additional methods of producing (Fab’)2, see, e.g., Rosenstein, s. et al., Curr Protoc Mol Biuol. 2020 Jun; 131(l):ell9,

[0194] A number of antibodies and fragments thereof, including (Fab’)2, contemplated by the disclosure that specifically bind human CD 117 are known in the art and / or commercially available, including without limitation JSP- 191, SRI, 2B8, ACK2, YB5-B8, 57A5, and 104D2. In certain embodiments, the anti-c-kit antibody is selected from the group consisting of: JSP 191Attorney Docket Number: JATH-023 / 02WO 335666-2215(Jasper Therapeutics; Redwood City, CA); CDX-0158 (formerly KTN0158) or CDX-0159 (Celldex Therapeutics, Hampton, NJ); MGTA-117 (AB85) (Magenta Therapeutics, Cambridge, MA); CK6 (Magenta Therapeutics, Cambridge, MA); AB249 (Magenta Therapeutics, Cambridge, MA); and FSI-174 (Gilead, Foster City, CA). Antibodies from Magenta Therapeutics contemplated by the disclosure include but are not limited to those that are disclosed in US Patent Application Publication No. 20190153114, PCT Application Publication Nos. W02019084064, W02020 / 219748, and W02020 / 219770. The FSI-174 antibody is disclosed in PCT application Publication No. W02020 / 112687 and U. S. Patent Application Publication No. 20200165337. Hie disclosure includes but is not limited to any anti-c-kit antibodies and / or CDR sets disclosed in any of the patent application disclosed herein, which are all incorporated by reference in their entireties.

[0195] In certain embodiments, the anti-c-kit antibody binds to the extracellular region of CD117, i.e., amino acids 26-524. The sequence of this region is shown below:QPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFVKWTFEILDETNENKQNEWIT EKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKEDNDTLVRCPLTDP EVTNY SLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRLCLHCSVDQEGKSVLSE KFILKVRPAFKAVPWSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQ EKYNSWTRIGDFNYERQATLTISSARXTIDSGVFMCYANNTFGSANVTTTLEVVDKGF INIFPMINn’VFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENES NIRYVSELHLTRI GTEGGTYTFLA'SNSDWAAIAFNWWTKPEIUFYDRIA'TQGML QCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFK HNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTP (SEQ ID NO: 1).

[0196] Illustrative anti-c-kit antibodies include, but are not limited to, SR-1, JSP191, 8D7, K45, 104D2, CK6, YB5. B8, AF-2-1, AF11, AF12, AF112, AF-3, AF-1-1, NF, NF-2-1, NF11, NF12, NF112, NF-3, HF11, FIF12, and HF112. A number of antibodies contemplated by the disclosure that specifically bind human CD117 are commercially available, including without limitation SRI, 2B8, ACK2, YB5-B8, 57A5, 104D2, etc. In certain embodiments, the anti-c-kit antibody is selected from the group consisting of: JSP191, CDX-0159 (from Celldex Therapeutics, Hampton, NJ), MGTA-117 (AB85) (from Magenta Therapeutics, Cambridge, MA), CK6 (from Magenta Therapeutics, Cambridge, MA), AB249 (from Magenta Therapeutics, Cambridge, MA), and FSI-174 (from Gilead, South San Francisco, CA), The antibodies from Magenta Therapeutics are disclosed in US Patent Application Publication No.20190153114. In certain embodiments, the antibody is one disclosed in any of US Pat. Nos.7,915,391, US 8,436,150, or US 8,791,249. In certain embodiments, the antibody is oneAttorney Docket Number: JATH-023 / 02WO 335666-2215disclosed in US Pat. Application Publ. No 20200165337 or any of PCT Publication Nos. WO 2020 / 112687, W02020 / 219748, WO 2020 / 219770, or WO 2019 / 084064.

[0197] In particular embodiments, the antibody is a humanized form of SRI, a murine anti-c-kit antibody described in U. S. Pat. Nos. 5,919,911 and 5,489,516. The humanized form, referred to as JSP191 or briquilimab, is disclosed in U. S. Patent Nos. 7,915,391, 8,436,150, and 8,791,249. JSP191 is an aglycosylated IgGl humanized antibody with the N-linked glycosylation site removed from the IgGl constant region. JSPI91 specifically binds to human CD117, a receptor for stem cell factor (SCF), which is expressed on the surface of a variety of cell types, including mast cells, hematopoietic stem and progenitor cells, melanocytes, germ cells, and interstitial cells of Cajal. JSP191 blocks SCF from binding to CD117 and disrupts stem cell factor (SCF) signaling. JSP19I binding to c-Kit inhibits the binding of the ligand stem cell factor (SCF). In cultured mast cells, JSP 191 can inhibit IgE-mediated mast cell degranulation. In a human mast cell survival bioassay, JSP 191 has an IC50 of about 12.5 nM. In mast cells, activated KIT potentiates degranulation and regulates MC growth, differentiation, survival and chemotaxis (Gilfillan, Austin, and Metcalfe 2011). Inhibition of SCF signaling through c-Kit on mast cells leads to their apoptosis. JSP191 has a half-life of about 9 days. PK clearance of JSP191 allows for restoration of c-Kit signaling on other c-Kit expressing cells once mast cells are depleted. Following depletion, tissue mast cells likely take more than 8 weeks to be replenished through differentiation from hematopoietic stem cells.

[0198] JSP 191 (briquililmab) is a heterotetramer consisting of 2 heavy chains of the IgGl subclass and 2 light chains of the kappa subclass, which are covalently linked through disulfide bonds. There are no N-linked glycans on JSP191 due to an intentional substitution from an asparagine to glutamine at heavy chain residue 297. The sequences of the heavy chains and light chains of JSP 191 are disclosed as SEQ ID NO: 4 from US8436150 and SEQ ID NO: 2 from US 8436150, respectively.[00199jThe sequences of the heavy chains and light chains of JSP191 are disclosed as SEQ ID NO: 4 from U. S. Patent No, 8,436,150 and SEQ ID NO: 2 from U. S, Patent No. 8,436,150, respectively. Tire sequences of the heavy and light chains of JSP 191 are:Heavy Chain:MDWTWRVFCLLAVAPGAHSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMH WVRQAPGQGLEWMGVIY SGNGDTSYNQKFKGRVTITADKSTSTAYMELS SLRSEDT AVYYCARERDTRFGNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPFA' FNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKriSKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSAttorney Docket Number: JATH-023 / 02WO 335666-2215DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK (SEQ ID NO: 2)andLight Chain:MVLQ TQVFISLLLWISGAYGDIVMTQSPDSLAVSLGERATINCRASESVDIYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQN NEDPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKFIKVYACEVTHQGLSSPV TKSFNRGEC (SEQ ID NO: 3).

[0200] In certain embodiments, the variable heavy domain of JSP191 comprises the following sequence:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGVIYSG NGDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQG TLVTVSS (SEQ ID NO: 4).

[0201] In certain embodiments, the variable light chain domain of JSP191 comprises the following sequence:DIVMTQSPDSLAVSLGERATINCRASESVDIYGNSFMHWYQQKPGQPPKLLIYLASN LESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDP YTFGGGTKVEIK (SEQ ID NO: 5).

[0202] The CDRs present in JSP 191 are as follows: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); VH CDR3 = ERDTRFGN (SEQ ID NO: 8); VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 - LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11).

[0203] CDX-0159 is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. CDX-0159 is designed to block KIT activation by disrupting both SCF binding and KIT dimerization. CDX-0159 and other anti-c-kit antibodies are described in U. S. Patent No, 10,781,267, and in particular embodiments, an anti-c-kit disclosed herein comprises the CDRs of any of the antibodies disclosed therein, in certain embodiments, the anti-c-kit antibody comprises: (i) a light chain variable region (" VL") comprising the amino acid sequence:DIVMTQSPSXK1LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKXK2LIYSASYR YSGVPDRFXK3SGSGSGTDFTLTISSLQXK4IEDFAXK5SYXK6CQQYNSYPRTFGGGTKVEIK(SEQ ID NO: 12), wherein XK1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, XK2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain, XK3 is an amino acid with an aliphatic hydroxyl side chain, XK4 is an amino acid with an aliphatic hydroxyl sideAttorney Docket Number: JATH-023 / 02WO 335666-2215chain or is P, XK5 is an amino acid with a charged or acidic side chain, and XK6 is an amino acid with an aromatic side chain; and (ii) a heavy chain variable region (" VH") comprising the amino acid sequence:QVQLVQSGAEXHlKKPGASVKXH2SCKASGYTTDYYINAVVXH3QAPGKGLEWIARI YPGSGNTYYNEKFKGRXH4TXH5IAXH6KSTSTAYMXH7LSSLRSEDXH8AVYFCARGV YYFDYWGQGTTVTVSS (SEQ ID NO: 13), wherein XH1 is an amino acid with an aliphatic side chain, XH2 is an amino acid with an aliphatic side chain, XH3 is an amino acid with a polar or basic side chain, XH4 is an amino acid with an aliphatic side chain, XH5 is an amino acid with an aliphatic side chain, XH6 is an amino acid with an acidic side chain, XH7 is an amino acid with an acidic or amide derivative side chain, and XH8 is an amino acid with an aliphatic hydroxyl side chain. In specific aspects, described herein are antibodies (e.g., human or humanized antibodies), including antigen-binding fragments thereof, comprising: (i) VH CDRs of a VH domain compri sing the amino acid sequence:QVQLKQSGAELVRPGASVKLSCKASGYTFTDYYINWVKQRPGQGLEWIARIYPG SGNTYYNEKFKGKATLTAEKSSSTAYMQLSSLTSEDSAVYFCARGVYYFDYWGQ GTTLTVSS (SEQ ID NO: 14) orQVQLKQSGAEEVRPGA SVKESCKA SGYTFTDYYINWVKQRPGQGLEWIARIYPG SGNTYYNEKFKGKATLTAEKSSSTAYMQLSSLTSEDSAVYFCARGVYYFDYWGQ GTFLTVSA (SEQ ID NO: 15), and(ii) VE CDRs of a VL domain comprising the amino acid sequence:DIVMTQSQKFMSTSVGDRVSVTCKASQNVRTNVAWYQQKPGQSPKALIYSASYRYS GVPDRFTGSGSGTDFTLTI SNVQSEDLADYFCQQYNSYPRTFGGGTKLEIKR (SEQ ID NO: 16).

[0204] MGTA-117 (AB85) is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, which is being developed for patients undergoing immune reset through either autologous or allogeneic stem cell transplant. MGTA-117 depletes hematopoietic stem and progenitor cells, and this antibody and others contemplated by the disclosure are described in U. S. Application Publication No. 20200407440 and / or PCT Application Publication No. W02019084064. Epitope analysis of AB85 binding to CD117 is described in PCT Application Publication No. WO2020219770, which identified the following two epitopes within CD117:EKAEATNTGKYTCTNKHGLSNSIYVFVRDPA (SEQ ID NO: 17; amino acids 60-90), and RCPLTDPEVTNYSLKGCQGKP (SEQ ID NO: 18; amino acids 100-130).Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0205] The sequences of the variable heavy chain and variable light chains of AB85 are disclosed as SEQ ID NO: 143 and SEQ ID NO: 144 from PCT Application Publication No. WO2019084064, respectively.

[0206] The heavy chain variable region (VH) amino acid sequence of Ab85 is:EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYWIGWVRQMPGKGLEWMAIINPRDS DTRYRPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARHGRGYEGYEGAFDI WGQGTLVTVSS (SEQ ID NO: 19).

[0207] The VH CDR amino acid sequences of AB85 are as follows: NYWIG (SEQ ID NO: 20; VH CDR1); IINPRDSDTRYRPSFQG (SEQ ID NO: 21; VH CDR2); and HGRGYEGYEGAFDI (SEQ ID NO: 22; VH CDR3).

[0208] The light chain variable region (VL) amino acid sequence of AB85 is:DIVMTQSPSSLSASVGDRVTITCRSSQGIRSDLGWYQQKPGKAPKLLIYDASNLETGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANGFPLTFGGGTKVEIK (SEQ ID NO: 23).

[0209] The VL CDR amino acid sequences of AB85 are as follows: RSSQGIRSDLG (SEQ ID NO: 24; VL CDR1); DASNLET (SEQ ID NO: 25; VL CDR2); and QQANGFPLT (SEQ ID NO: 26; VL CDR3).

[0210] FSI-174 is an anti-cKIT antibody being developed in combination with 5F9 as a nontoxic transplant conditioning regimen, as well as a treatment for targeted hematologic malignancies. The sequences of FSI-174 are disclosed in PCT Application Publication No.2020 / 112687, U. S. Patent Application Publication No. 20200165337, and U. S. Patent No.11,041,022. In particular embodiments, an anti-c-kit antibody comprises the three CD Rs or variable heavy chain regions present in any of AHI, AH2, AH3, AH4, or AH5 disclosed therein, and / or the three CDRs or variable heavy chain regions present in any of AL I or AL2 disclosed therein.

[0211] In certain embodiments, the CDRs present in FSI-174 and related antibodies are as follows: VH CDRI = SYNMH (SEQ ID NO: 27); VH CDR2 = VIYSGNGDTSY(A / N)QKF(K / Q)G (SEQ ID NO: 28); VH CDR3 = ERDTRFGN (SEQ ID NO: 29); VL CDRI - RAS(D / E)SVDIYG(N / Q)SFMH (SEQ ID NO: 30); VL CDR2 - LASNLES (SEQ ID NO: 31); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 32). A / N and the like indicate that the amino acid position may be either of the two amino acids, in this example, A or N. In certain embodiments, CDRs present in the heavy variable region are CDRs Hl, H2 and H3 as defined by Kabat: Hl === SYNMH (SEQ ID NO: 27); H2 = VIYSGNGDTSYAQKFKG (SEQ ID NO: 33); H3 = ERDTRFGN (SEQ ID NO: 29); and theAttorney Docket Number: JATH-023 / 02WO 335666-2215CDRs present in the light variable region are CDRs LI, L2 and L3 as defined by Kabat: L1 = RASESVDIYGQSFMH (SEQ ID NO: 34); L2 = LASNLES (SEQ ID NO: 31); and L3 = QQNNEDPYT (SEQ ID NO: 32), respectively except that 1, 2, or 3 CDR residue substitutions is / are present selected from N to A at heavy chain position 60, K to Q at heavy chain position 64 and N to Q at light chain position 30, positions being numbered according to Kabat. In certain embodiments, the antibody comprises any of the heavy chain variable region sequences (AH2, AII3, AII4) and / or light chain variable chain region sequences provided below (AL2), or the CDRs therein shown underlined:AH2:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYMNHWVRQAPGQGLEWMGVIYSG NGDTSYAQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQG TLVTVSS (SEQ ID NO: 35)AH3:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYMNHWVRQAPGQGLEWMGVIYSG NGDTSYNQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQG TLVTVSS (SEQ ID NO: 36)AH4: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYMNHWVRQAPGQGLEWMGVIYSG NGDTSYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQG TLVTVSS (SEQ ID NO: 37)AL2:DIVMTQSPLSLPVTPGEPASISCRASESVDIYGQSFMHWYQQKPGQPPKLLIYLASNL ESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQNNEDPYTFGGGTKVEIK (SEQ ID NO: 38).

[0212] In certain embodiments, the anti-c-kit antibody comprises the full heavy chain and / or full light chain of any of the antibodies disclosed herein, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identity to a heavy or light chain disclosed herein, e.g., a JSP191 heavy or light chain. In certain embodiments, the anti-c-kit antibody comprises the variable region of a heavy chain and / or light chain of any of the antibodies disclosed herein, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identity to the variable region of a heavy or light chain disclosed herein, e.g., a JSP191 heavy or light chain variable region. In certain embodiments, the anti-c-kit antibody comprises a heavy chain and / or a light chain comprising one or more CDRs of an antibody disclosed herein, e.g., two, three, four, five or six CDRs of an antibody disclosed herein, e.g., a JSP191 antibody. In particular embodiments, the anti-c-kit antibody comprises a heavy chain or variable region thereof comprising one, two, or three heavy chainAttorney Docket Number: JATH-023 / 02WO 335666-2215CDRs disclosed herein, e.g., a JSP191 heavy chain. In particular embodiments, the anti-c-kit antibody comprises a light chain or variable region thereof comprising one, two, or three light chain CDRs disclosed herein, e.g., a JSP191 light chain.

[0213] CDX-0159 is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. CDX-0159 is designed to block KIT activation by disrupting both SCF binding and KIT dimerization,

[0214] MGTA-117 is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, which is being developed for patients undergoing immune reset through either autologous or allogeneic stem cell transplant. MGTA-117 depletes hematopoietic stem and progenitor cells and this antibody and others contemplated by the disclosure are described in US 20200407440.

[0215] FSI-174 is an anti-c-kit antibody being develop in combination with 5F9 as a non-toxic transplant conditioning regimen, as well as a treatment for targeted hematologic malignancies.

[0216] In particular embodiments, the antibody may include one or more CDR with at least 70%, 80%, 90%, 95%, or 99% amino acid or nucleotide sequence identity to a CDR present in a humanized monoclonal antibody that binds c-kit, e.g., an antibody derived from any of the mouse antibodies SRI, ACK2, ACK4, 2B8, 3C11, MR-1, and CD122. In some embodiments, the an tibody blocks the binding of stem cell factor (SCF) to stem cell factor receptor (CD117). Illustrative embodiments of anti-c-kit antibodies that may be used include JSP191, as well as those described in WO2007127317A2 and US20200165337A1, both incorporated herein in their entirety.

[0217] In certain embodiments, the anti-c-kit antibody comprises the full heavy chain and / or full light chain of any of the antibodies disclosed herein, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identity to a heavy or light chain disclosed herein, e.g., a JSP191 heavy or light chain. In certain embodiments, the anti-c- kit antibody comprises the variable region of a heavy chain and / or light chain of any of the antibodies disclosed herein, or an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identity to the variable region of a heavy or light chain disclosed herein, e.g., a JSP191 heavy or light chain variable region. In certain embodiments, the anti-c-kit antibody comprises a heavy chain and / or a light chain comprising one or more CDRs of an antibody disclosed herein, e.g., two, three, four, five or six CDRs of an antibody disclosed herein, e.g., a JSP191 antibody. In particular embodiments, the anti-c-kit antibody comprises a heavy chain or variable region thereof comprising one, two, or three heavy chain CDRs disclosed herein, e.g., a ISP 191 heavy chain. In particular embodiments, the anti-c-kitAttorney Docket Number: JATH-023 / 02WO 335666-2215antibody comprises a light chain or variable region thereof comprising one, two, or three light chain CDRs disclosed herein, e.g., a JSP191 light chain.Pharmaceutical Compositions, Unit Dosage Forms and Kits

[0277] In some embodiments, the anti-c-kit antibody or fragment thereof (or combination therapy) is present in a pharmaceutical composition. The present disclosure provides pharmaceutical compositions useful for the treatments disclosed herein. Such compositions comprise an effective amount of an antibody or fragment thereof, and an acceptable carrier. In some embodiments, the composition further includes a second therapeutic agent (e.g., an antihistamine),

[0278] In particular embodiments, the pharmaceutical compositions may be in a water- soluble form, such as in pharmaceutically acceptable salts, which is meant to include both acid and base addition salts. Pharmaceutically acceptable acid addition salts include but are not limited to: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0279] In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Further, a "pharmaceutically acceptable carrier" will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Pharmaceutical compositions as described herein may also include one or more of the following: carrier proteins such as serum albumin; buffers; fillers such as microcrystalline cellulose, lactose, com and other starches; binding agents; and polyethylene glycol.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0280] The term "carrier" refers to a diluent, adj uvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.

[0281] These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W Martin, incorporated herein by reference.

[0282] Such compositions may contain a therapeutically effective amount of the antigenbinding poly peptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0283] In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous or subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, tire composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of activeAttorney Docket Number: JATH-023 / 02WO 335666-2215agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0284] The compounds of the disclosure can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0285] The compositions for administration will commonly include the antibody or fragment thereof dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline, the composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH and buffering agents, toxicity countering agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of active agents in the formulations can vary and are selected based on fluid volumes, viscosities, and body weight in accordance with the particular mode of administration selected and the patient's needs (e.g., Remington's Pharmaceutical Science (15 th ed., 1980) and Goodman & Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)).

[0286] The disclosure provides pharmaceutical compositions and unit dosage forms comprising an effective amount of an anti-c-kit antibody or antigen-binding fragment thereof.

[0287] The disclosure further provides kits comprising an anti-c-kit antibody or antigen¬ binding fragment thereof as described herein, e.g., a kit for administration of the anti-c-kit antibody or fragment thereof by a medical professional or the subject in need thereof. The kit may comprise for example, a container, and one or more doses of the anti-c-kit antibody, and instructions for use thereof. In certain embodiments, the kit comprises multiple doses of the anti-c-kit antibody or fragment thereof, suitable for a dosing regimen over a period of time. In certain embodiments, each dose comprises the same amount of the anti-c-kit antibody, while in other embodiments, the kit may comprises two or more different doses of the anti-c-kit antibody or fragment thereof. In certain embodiments, each dose in present within a separate container. In particular embodiments, the kit comprises two or more doses of a monoclonal anti-c-kit IgG antibody or antigen binding fragment thereof, optionally JSP191, wherein the kit comprises: one or more induction dose, wherein each induction dose comprises about 200 mgAttorney Docket Number: JATH-023 / 02WO 335666-2215to about 400 mg of the anti-c-kit IgG antibody; and two or more maintenance doses, wherein each maintenance dose comprises about 80 mg to about 200 mg of the anti-c-kit IgG antibody, wherein each of the maintenance doses is less than the one or more induction dose.EXAMPLESExample 1PHASE 1B / 2A, DOSE ESCALATION STUDY OF PHARMACOKINETIC / PHARMACODYNAMIC AND PRELIMINARY CLINICAL ACTIVITY OF BRIQUILIMAB IN ADULT PATIENTS WITH CHRONIC SPONTANEOUS URTICARIA (CSU) WHO REMAIN SYMPTOMATIC DESPITE TREATMENT WITH, OR WHO CANNOT TOLERATE, OM LIZUMAB

[0288] Stem Cell Factor (SCF) signaling through c-Kit (CD 117) plays a key role in mast cell differentiation and survival. Briquilimab, a humanized aglycosylated monoclonal antibody targeting CD 117, blocks SCF binding to CD 117 and SCF / CD117 signaling, leading to apoptosis of mast cells,

[0289] A randomized phase lb / 2a, multiple ascending dose trial divided into three distinct Parts was conducted to demonstrate the safety, tolerability, and efficacy of different dose levels of briquilimab in adult participants with CSU, who remain symptomatic despite treatment with Hl -antihistamines and / or omalizumab or who cannot tolerate omalizumab (BEACON). The double-blind placebo-controlled trial explored seven ascending dose levels, as shown in FIG.1. Briquilimab was administered subcutaneously. Briquilimab consisted of 50 mg / mL active ingredient in a solution containing sodium acetate anhydrous, sucrose, polysorbate 20, and water for injection. Placebo consisted of inactive solution containing sodium acetate anhydrous, sucrose, polysorbate 20, and water for injection.

[0290] The trial was divided into the following three Parts (conducted in series):Part 1 (Cohorts 1 and 2)Open label dose cohorts» Screening Period: 28 days (4 weeks)• Treatment Period: 24 weekso Cohort 1 (n = 3 to 6): Participants received 10 mg briquilimab at Week 0, 4, 12 and 20.o Cohort 2 (n = 3 to 6): Participants received 40 mg briquilimab at Week 0, 4, 12 and 20.Attorney Docket Number: JATH-023 / 02WO 335666-2215Part 2 (Cohorts 3. 4a, 4b. 5 and 5b)Randomized, double-blind, placebo-controlled cohorts• Screening Period: 28 days (4 weeks)• Treatment Period: 24 weekso Cohort 3 (n = 8): Participants were randomized in a 3: 1 ratio to receive 80 mg briquilimab or placebo at 8-week intervals (Week 0, 8, 16, and 24).o Cohort 4 (n = 12): Participants were randomized in a 2: 1 ratio to receive 120 mg briquilimab or placebo during the Treatment Period. The first 6 participants entered Cohort 4a and were treated at 12-week intervals (Week 0, 12, and 24). The next 6 participants entered Cohort 4b and were treated at 8-week intervals (Week 0, 8, 16, and 24).o Cohort 5 (n = 9): Participants were randomized in a 3: 1 ratio to receive 180 mg briquilimab or placebo at 12-week intervals (Week 0, 12 and 24).o Cohort 5b (n = 10): Participants were randomized in a 3: 1 ratio to receive 180 mg briquilimab or placebo once every 8 weeks (Q8W) (Weeks 0, 8, 16, and 24).Part 3 (Cohorts 6 and 7)Randomized, double-blind, placebo-controlled dose cohorts• Screening Period: 28 days (4 weeks)• Treatment Period: 24 weekso Cohort 6 (n = 8): Participants were randomized in a 3: 1 ratio to receive a single dose of 240 mg briquilimab or placebo at Week 0.o Cohort 7 (n = 8): Participants were randomized in a 3: 1 ratio to receive a single dose of 360 mg briquilimab or placebo at Week 0.

[0291] Participants in the randomized cohorts in Parts 2 and 3 remained blinded to the identity of their treatment assignment until completion of the trial.Part 4 (Cohorts 8 and 9) was subsequently conductedRandomized, double-blind, placebo-controlled dose cohorts• Screening Period: 28 days (4 weeks)• Treatment Period: 24 weekso Cohort 8 (n = 9): Participants were randomized in a 3: 1 ratio to receive 240 mg briquilimab or placebo every 8-weeks (Week 0, 8, 16, and 24). Patients had not yet reached the 12 week efficacy endpoint.Attorney Docket Number: JATH-023 / 02WO 335666-2215o Cohort 9 (n = 9): Participants were randomized in a 3: 1 ratio to receive a single loading dose of 240 mg briquilimab or placebo at Week 0, followed by a 180 mg maintenance dose of briquilimab or placebo at Week 8.o Cohort 9.1 (n = 8): Participants were randomized in a 3: 1 ratio to receive a single loading dose of 240 mg briquilimab or placebo at Week 0, followed by a 180 mg maintenance dose of briquilimab or placebo at Week 8. Results were analyzed up to 12 weeks of treatment.

[0292] Participants in the randomized cohorts in Parts 8, 9 and 9.1 remained blinded to the identity of their treatment assignment until completion of the trial.

[0293] Patients included males and females, >18 years old with a diagnosis of symptomatic CSU despite treatment as defined by:a. diagnosis of CSU for > 6 monthsb. the presence of itch and hives for > 8 consecutive weeks at any time prior to Screening despite current use of Hl-antihistamines (as reported by the participant) c. The presence of itch and hives for > 8 consecutive weeks at any time prior to Screening despite treatment with omalizumab or intolerance to omalizumab (as reported by the participant); andd. UAS7 of > 16 and ISS7 of > 8 on Days -10 through Day -3 of Screening, and with use of Hl-antihistamines on stable dose up to 4-fold of the approved dose. Baseline demographics were generally balanced across the cohorts. All patients were refractory or intolerant to omalizumab, thus representing a CSU population of highest unmet medical need.Duration of treatment:Part 1Duration of the trial (per participant): Screening Period (4 weeks), Treatment Period (24 weeks) and Safety Follow-up Period (24 weeks), approximately 52 weeks.Part 2Duration of the trial (per participant): Screening Period (4 weeks), Treatment Period (24 weeks) and Safety Follow-up Period (24 weeks), approximately 52 weeks.Part 3Duration of the trial (per participant): Screening Period (4 weeks), Treatment Period (24 weeks) and Safety Follow-up Period (24 weeks), is approximately 52 weeks.Attorney Docket Number: JATH-023 / 02WO 335666-2215Part 4Duration of the trial (per participant): Screening Period (4 weeks), Treatment Period (24 weeks) and Safety Follow-up Period (24 weeks), approximately 52 weeks.Safety:

[0294] Safety was assessed by regularly performed laboratory testing (hematology, clinical chemistry, urinalysis), physical examinations, vital signs, ECG, taste change test, hair color change tests and by monitoring and evaluating adverse events (AEs) and treatment emergent adverse events (TEAEs) from signing the informed consent form through the end of treatment visit.Efficacy:

[0295] Efficacy was measured via the Urticaria Activity Score (UAS7), as the sum of the Hives Severity Score (HSS7) and Itch Severity Score (ISS7), which was completed daily, and the Urticaria Control Test (UCT) completed periodically by the participants. The main efficacy analyses are be based on the absolute and relative change from baseline scores of UAS7, ISS7, HSS7, and UCT at Week 12. The scores at other timepoints were also be analyzed.

[0296] The UAS7 was assessed by the participant by completing the HSS and ISS daily.

[0297] The UAS7 is the sum of the daily hives severity score (HSS) score and the daily itch severity score (ISS) score for seven consecutive days. The possible range of the weekly UAS7 score is 0 - 42 with higher values indicating higher disease severity (Hollis et al. 2018; Mathias et al. 2018). The minimal important difference was defined as 9.5 to 10.5 points (Mathias et al.2015).

[0298] The wheals (hives) severity score (HSS), defined by number of hives, was recorded by the participant daily, on a scale of 0 (none) to 3 (intense / severe) (see Table 1). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score is 0 - 21 with higher values indicating greater hives severity (Hawro et al. 2018). Complete hives response is defined as HSS7 == 0, the minimal important difference 'as defined as 5 to 5.5 points (Mathias et al, 2015).Table 1. Scoring of Hives Severity ScoreScore Wheal (Hives)0 None1 Mild (1-20 hives / 24 hours)2 Moderate (21-50 hives / 24 hours)3 Severe (>51 hives / 24hours)Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0299] The severity of the itch (ISS) was recorded by the participant twice daily, on a scale of 0 (none) to 3 (intense / severe) (see Table 2). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was 0 - 21 with higher values indicating higher itch severity (Hawro et al. 2018). Complete itch response is defined as ISS7 = 0. The minimal important difference was defined as 4.5 to 5.0 points (Mathias et al. 2015).Table 2. Scoring of Itch Severity ScoreScore Wheal (Hives)0 None1 Mild (minimal awareness; easily tolerated)2 Moderate (definite awareness; bothersome but tolerable)3 Severe difficult to tolerate)

[0300] Complete response rate: Proportion of participants who were urticaria free based on UAS7 = 0. Well-controlled rate: Proportion of participants who were well controlled based on UAS7 < 6 or UCT > 12.

[0301] Participants completed the UCT periodically. The UCT is a disease-specific measure consisting of four questions that retrospectively assesses participants’ burden of disease over the previous 4 weeks. Disease control is a major treatment aim in CSU, and the UCT was specifically developed and validated to measure this in all forms of CU (Weller 2014). Concepts covered include disease activity, QOL survey, disease control, and therapy. Each of the four questions are scored on a scale of 0 to 4 (see Fig. 3). The UCT score is derived by adding up the scores from each of the four questions. A total score from 0 (no control) to 16 points (complete control) is derived, with a score of > 12 indicating well-controlled disease. The UCT has high levels of validity and reliability’, and accurately identifies participants with insufficiently controlled disease. Its minimal clinically important difference (MCID) is 3 points (Kulthanan 2016, Ohanyan 2017).

[0302] The primary efficacy analysis was based on the modified intention to treat (mlTT) analysis set.

[0303] For the UAS7, HSS7, ISS7 and UCT scores, change from baseline at Week 12 were summarized by cohort and by cohort and arm if the cohort was randomized. Point estimates and 95% confidence intervals are presented. For between group comparisons in the randomized cohorts, statistical test of the change from baseline values at Week 12 based on ANCOVAAttorney Docket Number: JATH-023 / 02WO 335666-2215(analysis of covariance) adjusting for the baseline UAS7, HSS7 and ISS7 scores, respectively, or an appropriate nonparametric test is performed. Similar analyses were performed for the change from baseline at other times such as weeks 4 and 8. In addition to the change from baseline, percent change from baseline are summarized.

[0304] The proportion of participants who were urticaria free based on UAS7=0 or are well controlled based on UCT>12 and based on UAS7 <6, respectively, was summarized at each time point (e.g., weeks 4, 8, 12). Additional summaries based on more detailed categorization of the UAS7 score are also provided. The categories are defined as follows: urticaria-free=0; well-controlled urticaria=l--6; mild =7-15; moderate =16-27; and severe urticaria=28-42.

[0305] Time to reach urticaria-free (UAS7=0), well -control led urticaria based on UAS7 <6 and based on UCT>12 as analyzed separately using the Kaplan-Meier method. Descriptive summaries are provided for participants who reach the criteria for each endpoint.

[0306] For participants who have achieved well-controlled urticaria based on UAS7 <6, time to relapse, defined as UAS7>12, is estimated using the Kaplan-Meier method.

[0307] Similar analyses are performed for the HSS7 and ISS7 scores as those proposed for the UAS7. Relevant thresholds are used to define the endpoints for each scale respectively.

[0308] Sensitivity analyses addressing imputation of potential missing data and modelling repeated measures using mixed effect models may be considered and additional details provided in the statistical analysis plan.Pharmacokinetics:

[0309] Whole blood samples were collected for analysis of serum concentrations of briquilimab by a validated assay. PK parameters for briquilimab were estimated following SC administration by non-compartmental method. The PK blood sampling was performed at specific PK-Sampling visits during the first days after first dose of IP and at follow-up visits in accordance with the Schedule of Assessments, which indicates PK assessment at baseline week 0, and at weeks 1, 2, 4, 6, 8, 10, and 12. Briquilimab pharmacokinetic parameters were estimated by non-compartmental method. Briquilimab pharmacokinetic parameter estimates include peak concentrations (Cmax), time to reach Cmax (tmax) and area under the concentration-time curve from dosing time to last quantifiable concentration (AUClast). Briquilimab serum concentrations and pharmacokinetic parameters were summarized using descriptive statistics.Pharmacodynamics:

[0310] Serum tryptase, anti-drug antibody blood sampling, and skin prick test with codeine were performed at Baseline (prior to first dosing), and at follow-up visits in accordance withAttorney Docket Number: JATH-023 / 02WO 335666-2215the Schedule of Assessments. Skin biopsies (voluntary; for participants willing to participate, only) were performed at Baseline, Week 4, and Week 12. Pharmacodynamic data and ADA data was summarized using descriptive statistics.Results:

[0311] Targeting mast cells with briquilimab was expected to provide clinical benefit in CS U by decreasing the number and activity’ of mast cells. Briquilimab was expected to reduce mast cell density wheal responses in CSU participants, which is evaluated, e.g., through changes from baseline in participant reported clinical outcome measures, skin biopsies, and serum tryptase levels.

[0312] Part 1 results indicated that targeting mast cells with briquilimab provided clinical benefit in CSU. Briquilimab was administered to patients at Day 0, Week 4, Week 12 and Week 20. Three patients were administered 10 mg of briquilimab, and three patients were administered 40 mg of briquilimab. Administration of 10 mg of briquilimab (subcutaneously) to patients with CSU did not appear to be efficacious at each dosing timepoint. However, administration of 40 mg of briquilimab to patients with CSU did appear to be efficacious after dosing. A complete response was seen in one patient treated with 40 mg of briquilimab (subcutaneously) by Week 2, and a durable response was observed prior to the next dose at Week 4. Repeated dose administration (per protocol) resulted in meaningful reductions in UAS-7. A second patient with more severe disease at baseline treated with 40 mg of briquilimab (subcutaneously) showed improvements in UAS-7 on first and second doses. A third patient treated with 40 mg of briquilimab (subcutaneously) saw early reduction in UAS-7 after the first dose.

[0313] Part 2 results showed that briquilimab caused a deep reduction in UAS7 scores, with a greater than 25 percent reduction in UAS7 noted in multiple dosing regimens >120mg (FIG, 2). Treatment with briquilimab resulted in a dose dependent increase in patients achieving complete response (FIG. 3) or w e 11 -controlled disease (FIG. 4). Complete responses were noted at all doses >80mg, and 50% or more of patients achieved well-controlled disease four weeks post-dosing in multiple regimens. All patients in the 240 mg single-dose cohort achieved complete response by week 2 and maintained complete response to eight weeks (FIG. 5A). Dose dependent UAS7 reductions were observed over 20 weeks with deeper UAS7 reductions observed in subsequent doses (FIG. 6A), Dose dependent reductions in serum tryptase were also observed, and a reduction to LLOQ was seen in multiple patients at 180mg Q8W and all patients at 240mg dose levels (FIG. 7A).Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0314] 12 week data for all 8 patients enrolled in Cohort 9.1 of Part 4 (6 briquilimab, 2 placebo) showed a mean reduction in UAS7 scores of 31 points at Week 12 (FIG. 27, left panel). Cohort 9.1 patients demonstrated a rapid and sustained UAS7 response (FIG. 6B). Rapid onset of the effect continued to be observed with CRs reported in the majority of patients by Week 2 (FIG. 5B). Complete responses were observed as early as week 2, with 67% Complete Responses reported at week 12 (n=6) (FIG. 5C). Cohort 9.1 patients showed rapid and deep reductions in tryptase following the initial subcutaneous dose of briquilimab (FIG.7B). Briquilimab related adverse events (AEs) were predominantly low frequency, transient, low-grade events that resolved while on study.

[0315] Briquilimab PK demonstrated an early Cmax consistent with rapid onset of response in CSU patients (FIG. 8). Preliminary PK data in patients with CSU indicated that briquilimab PK is comparable to historical data in healthy volunteers. 240 mg briquilimab SC Tmax was 4-7 days with a half-life of approximately 9 days. No accumulation was predicted for repeat dosing of 240mg SC briquilimab on a Q8W dosing schedule. 6 out of 7 patients with a briquilimab Cmax of approximately 12 ug / mL or higher had UCT score increases of around 11 points (FIG. 9). Briquilimab AUClast vs. maximum change in UCT score after the first dose is shown in FIG. 10. The maximum change in UCT score after the first dose for various doses is shown in FIG. 11. Briquilimab Cmax vs. the maximum change in UAS7 score after the first dose is shown in FIG. 12. Briquilimab Cmax as low as 6 to 9 ug / mL resulted in a 20-point reduction in UAS7 scores in a substantial number of patients, Briquilimab AUClast vs. maximum change in UAS7 score after the first dose is shown in FIG. 13. Briquilimab AUClast as low as 100 ugxday / mL resulted in a 20-point reduction in UAS7 scores in a substantial number of patients. A summary of briquilimab pharmacokinetic (PK) parameters in CSU patients is provided in FIG. 14,

[0316] Briquilimab was well tolerated and demonstrated a favorable safety profile. Safety observations possibly related to c-Kit blockade were infrequent and generally limited to low-grade events. The majority resolved during repeat dosing and none resulted in discontinuations or dose delays. Neutrophil counts generally remained stable, with a small predictable reduction at week 4 post-first dose which recovered prior to next dose. There were no discontinuations or dose delays due to reductions in neutrophil counts.Conclusions:

[0317] The preliminary results of this clinical trial demonstrate that briquilimab was able to achieve rapid, deep and durable responses in patients with moderate to severe CSU. Briquilimab demonstrated rapid and deep disease control, with a rapid onset of effect withAttorney Docket Number: JATH-023 / 02WO 335666-2215clinical responses as early as one week post first dose. Multiple dosing regimens >120mg demonstrated UAS7 changes of more than -25 points, with the deepest responses shown of -29 on the UAS7 scale. Complete responses were seen at all dose cohorts ≥80mg. 100% complete control was demonstrated for 240 mg by week 2 and was durable to 8 weeks. Repeat dosing showed deepening clinical responses across multiple dose cohorts. Rapid, dose -dependent tryptase reductions correlated with early onset of clinical response. A high proportion of tryptase measurements fell below the detection limit, and 100% of 240 mg patients had tryptase declines at or below the detection limit as early as week one.

[0318] These results demonstrated that a briquilimab body weight normalized dose greater than about 2 mg / kg resulted in an approximately 11 -point increase in UCT score. Thus, a briquilimab dose of about 240 mg would be expected to provide sufficient drug exposure in patients weighing up to 120 kg.Example 2BRIQUILIMAB, AN ANTI -HUMAN CD117 (C-KIT) ANTIBODY, TREATS LOW-CALCEMIC VITAMIN D3 ANALOG MC903-INDUCED DERMATITIS IN MOUSE MODEL EXPRESSING CHIMERIC HUMAN / MOUSE CD 117

[0319] MC903, a vitamin D3 analog, represents a distinct class of molecules as compared to allergens, characterized by its ability to disrupt epidermal barrier function and trigger robust immune responses through keratinocyte activation and cytokine production, particularly thymic stromal lymphopoietin (TSLP). Mouse models of MC903-induced dermatitis are widely used to replicate key features of dermatitis, with TSLP playing a pivotal role in initiating and amplifying the inflammatory cascade by activating dendritic cells and promoting T-cell differentiation. In this context, MCs further contribute to the inflammatory process by enhancing immune cell recruitment, amplifying cytokine signaling, and driving tissue damage. The present study utilized MC903 -induced dermatitis models in h / mCD117 mice to establish a robust preclinical framework for evaluating briquilimab treatment for dermatitis.

[0320] For evaluating prophylactic effectiveness of briquilimab, in h / mCDl 17 mice, which express chimeric human extracellular and mouse intracellular domains of CD 117 in lieu of wild-type CD 117, dermatitis features were induced through epicutaneous (e.c.) application with 4 nmol MC903 in 0.04 mL ethanol to the back skin on days 1, 3, and 6. Fourteen days prior to the first MC903 application, tire mice received an intraperitoneal (i.p.) dose of either 25 mg / kg briquilimab or saline (placebo). A separate control group received e.c. application of vehicle ethanol instead of MC903 on days 1, 3, and 6 and received an i.p. dose of either 25Attorney Docket Number: JATH-023 / 02WO 335666-2215mg / kg briquilimab or normal saline (placebo) 14 days prior to the first e.c. application of vehicle ethanol. Endpoint evaluations on day 7 included assessments of skin condition, dermal MC density, and inflammatory leukocyte infiltration (diagrammed in FIG. 15, upper panel).

[0321] For evaluating therapeutic effectiveness of briquilimab, in h / mCD117 mice, dermatitis features were induced through epicutaneous (e.c.) application with 4 nmol MC903 in 0.04 ml. ethanol to the back skin on days 1, 2, and 3. On day 4, the mice received an intraperitoneal (i.p.) dose of either 25 mg / kg briquilimab or normal saline (placebo). A separate control group received e.c. application of vehicle ethanol instead of MC903 on days 1, 2, and 3 and received an i.p. dose of 25 mg / kg briquilimab or placebo on day 4. On day 9, all groups received an additional e.c. application of MC903 or ethanol. Endpoint evaluations on day 10 included assessments of skin condition, dermal MC density, and inflammatory leukocyte infiltration (diagrammed in FIG. 15, lower panel)).

[0322] For both prophylactic and therapeutic models, skin condition was assessed by a trained observer using the following metrics: redness, bleeding, eruption, and scaling. Each metric was scored on a scale from 0 (none) to 3 (severe), and the scores were summed for each animal within tire experimental groups (briquilimab-treated vs. placebo-treated). Dorsal skin specimens from each animal were collected, fixed in 10% formalin, embedded in paraffin, sectioned, and stained with toluidine blue for MCs and hematoxylin and eosin (H&E) for inflammatory leukocytes, respectively. The densities of MCs and inflammatory leukocytes were calculated by imaging the sections and dividing cell counts within the field of view by the exposed area. Statistical comparisons between the placebo and briquilimab-treated groups for skin condition scores and leukocyte densities were performed using Welch’s t-test. MC density comparisons were analyzed using one-way ANO VA followed by Tukey’s HSD test to account for multiple comparisons,

[0323] A single dose of briquilimab (25 mg / kg) in control mice reduced dermal MCs by 36% at 6 days and 67% at 20 days, respectively (P < 0.05 for both). Representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalin-fixed, paraffin-embedded tissue sections showing dermal MCs and histological features, respectively, in back skin 20 days after briquilimab or placebo treatment (FIG. 16A). Quantification of dermal MC densities in toluidine blue-stained tissue sections at 6 days (upper panel) and 20 days (lower panel) following briquilimab (25 mg / kg) or placebo treatment, * P < 0.05 vs, placebo-treated vehicle control mice. N = 3-5 per group (FIG. 16B).

[0324] In the prophylactic model, a single dose of briquilimab (25 mg / kg) reduced dermal MCs by 67% at 20 days in vehicle control mice (no dermatitis). Dermatitis mouse modelsAttorney Docket Number: JATH-023 / 02WO 335666-2215prophylactically treated with briquilimab exhibited significantly healthier skin, with reduced dermal MC and leukocyte densities compared to placebo-treated dermatitis mouse models. Representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalin-fixed, paraffin-embedded tissue sections showing dermal MCs and leukocytes, respectively, in back skin 20 days after briquilimab or placebo treatment (FIG.17A). Quantification of dermal mast cell densities in toluidine blue-stained tissue sections (FIG. 17B). Quantification of dermal leukocyte densities in H& E-stained tissue sections (FIG.17C). Skin condition was assessed one day after the final e.c. MC903 application, with scores assigned for redness, bleeding, eruption, and scaling on a scale of 0 (none) to 3 (severe) (FIG.17D). * P < 0.05 vs. placebo-treated vehicle control mice,+P < 0.05 vs. placebo-treated MC903-induced dermatitis model. N = 3-5 per group. Red arrows indicate mast cells,

[0325] in the therapeutic model, a single dose of briquilimab (25 mg / kg) reduced dermal MCs by 36% at 6 days in vehicle control mice (no dermatitis). Dermatitis mouse models therapeutically treated with briquilimab (25 mg / kg) exhibited significantly healthier skin, with reduced dermal MC and leukocytes densities compared to placebo-treated dermatitis model. Representative images of toluidine blue-stained (upper panels) and H& E-stained (lower panels), formalin-fixed, paraffin-embedded tissue sections showing dermal mast cells and leukocytes, respectively, in the back skin 6 day after briquilimab or placebo treatment (FIG.18A). Quantification of dermal MC densities in toluidine blue-stained tissue sections (FIG.18B). Quantification of dermal leukocyte densities in H& E-stained tissue sections (FIG. 18C). Skin condition was assessed one day after the final e.c. MC903 application, with scores assigned for redness, bleeding, eruption, and scaling on a scale of 0 (none) to 3 (severe) (FIG.18D). * P < 0.05 vs. placebo-treated vehicle control mice,+P < 0.05 vs. placebo-treated MC903 -induced dermatitis model. N = 3-5 per group. Red arrows indicate mast cells.

[0326] A single dose of briquilimab effectively depleted mast cells (MCs) in healthy h / mCDl 17 mice as well as in dermatitis models induced by epicutaneous MC903 in h / mCDl 17 mice. Briquilimab-mediated MC depletion significantly contributed to its prophylactic and therapeutic effects in MC903-induced dermatitis models in h / mCD117 mice. MCs play a critical role in the pathogenesis of MC903 -induced skin conditions, which develop independently of specific allergen exposure. Briquilimab shows potential as a therapeutic agent for targeting MCs in complex skin conditions driven by allergen-independent mechanisms, including TSLP-driven Th2-mediated dermal inflammation.Attorney Docket Number: JATH-023 / 02WO 335666-2215Example 3BRIQUILIMAB, AN ANTI-HUMAN C-KIT ANTIBODY, PREVENTS EPICUT ANEOUS OXAZOLONE- INDUCED FEATU ES OF DE MATITIS IN MOUSE MODEL EXP ESSING CHIMERIC HU AN / MOUSE C-KIT

[0327] Haptens, such as oxazolone, represent a distinct class of molecules compared to allergens, characterized by unique physical and chemical properties that enable them to covalently bind to skin proteins and elicit T-cell-mediated immune responses. In this context, mast cells play a crucial role in amplifying and sustaining the inflammatory response by promoting immune cell recruitment, T-cell activation, and tissue damage.

[0328] The present study employed an oxazolone-induced dermatitis model in h / mCDl 17 mice, alongside previous studies in allergen-induced models, to provide a comprehensive preclinical evaluation of briquilimab treatment.

[0329] In h / mCD117 mice, which express chimeric human extracellular and mouse intracellular domains of GDI 17 in lieu of wild-type CD 117, dermatitis was induced through abdominal epicutaneous (e.c.) sensitization with 2% oxazolone on day 1, followed by dorsal e.c. challenge with 0.5% oxazolone on days 7 and 9. Eleven days prior to sensitization, the mice received an intraperitoneal (i.p.) dose of either 25 mg / 'kg briquilimab or normal saline (placebo). A separate control group of h / mCDl 17 mice received e.c. vehicle ethanol instead of oxazolone on days 1, 7, and 9 and received either an i.p. dose of 25 mg / 'kg briquilimab or placebo 11 days prior to the first dermal ethanol application (day 1). Endpoint evaluations on day 10 included assessments of skin condition, dermal MC density, and inflammatory leukocyte infiltration (diagrammed in FIG. 19). Skin condition was assessed by a trained observer using the following metrics: redness, bleeding, eruption, and scaling. Each metric was scored on a scale from 0 (none) to 3 (severe), and the scores were summed for each animal within experimental groups (briquilimab-treated vs. placebo-treated). Dorsal skin from each animal was collected, fixed in 10% formalin, embedded in paraffin, sectioned, and stained with toluidine blue for MCs and hematoxylin and eosin (H& E) for inflammatory leukocytes, respectively. Tire densities of MCs and inflammatory leukocytes were determined by imaging the sections and dividing cell counts within the field of view by the exposed area. Statistical comparisons between experimental groups for skin condition scores and leukocyte densities were performed using Welch’s t-test. Comparison of MC densities were conducted using oneway ANOVA followed by Dunnett’s test to account for the multiple comparisons.

[0330] Following e.c. exposure to oxazolone, briquilimab-treated mice exhibited significantly healthier skin, as indicated by' markedly lower clinical scores (3.6 ± 0.8) comparedAttorney Docket Number: JATH-023 / 02WO 335666-2215to the placebo-treated group, which displayed more severe skin condition (clinical scores 8.5 ± 1.0, P < 0.05 vs. briquilimab-treated group, FIG. 20). In control mice that received epicutaneous ethanol, briquilimab treatment significantly reduced dermal MC counts compared to the placebo treatment (28.3 ± 2.1 vs. 86.4 ± 2.2 cells / mm2; P < 0.01 (FIG. 21A). Placebo- treated dermatitis models exhibited significantly elevated dermal MC counts compared to the control mice that received placebo (2.2 ± 0.2 * 102vs. 86.4 ± 2.2 cells / mm2, P < 0.005). However, briquilimab-treated dermatitis models showed a significantly reduced dermal MC count (32.8 ± 10.6 cells / mm2) compared to placebo-treated dermatitis models (P<0.001, FIG.21B). Briquilimab treatment significantly reduced dermal leukocyte infiltration in the dorsal skin of oxazolone-induced dermatitis models, with leukocyte densities of 2.2 ± 0.2 * 102cells / mm2, compared to substantially higher densities in the placebo-treated group (9.5 ± 1.1 102cells / mm2) (FIG. 22). This reduction highlights the potent anti-inflammatory effect of briquilimab and was statistically significant P < 0,01, FIG. 23),

[0331] A single dose of briquilimab effectively depleted MCs in h / mCD117 mice that are healthy and that have epicutaneous oxazolone-induced dermatitis. Briquilimab’s MC-depleting activity' provided significant protection against the development of oxazolone-induced dermatitis in h / mCD117 mice. Mast cells play a critical role in the pathogenesis of hapten-induced dermatitis, including oxazolone-induced dermatitis. Briquilimab shows strong potential as a therapeutic agent for hapten-induced dermatitis by effectively targeting MCs.

[0332] Briquilimab-mediated mast cell depletion shows versatility' and effectiveness in regulating diverse inflammatory pathways involved in skin disorders, thereby advancing its potential as a therapeutic agent across distinct mechanisms of dermatitis induction.Example 4OPEN LABEL. EXTENSION STUDY OF PHASE 1B / 2A CLINICAL. TRIALS FOR CSU AND CINDU

[0333] An open label extension (OLE) study was conducted, which enrolled patients from the prior CSU (Beacon) and CIndU (Spotlight) trials. To enroll, patients from the trials had to either: wait for symptoms to return following dosing (defined as UAS7 > 16 for CSU, UCT < 12 for CIndU); or complete the Beacon or Spotlight trials. Results were obtained from 46 CSU patients treated with 180mg briquilimab Q8W through 24 weeks (38 patients at Week 8, 36 patients at Week 16, and 27 patients at Week 24) and 17 CIndU patients treated with 180mg briquilimab Q8W through 24 weeks. Key objectives were to generate additional safety, efficacy, and durability at 180mg Q8W dose schedule for both CSU and CIndU programs. A diagram of the OLE study' is provided in FIG. 24.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0334] Treatment with briquilimab rapidly and sustainedly lowered UAS7 in OLE CSU patients, reaching the lowest levels approximately four weeks following each administration (FIG. 25). CRs were observed as early as Week 2, with 60% CR reported at Week 20 (FIG.26). Briquilimab was well tolerated with a favorable safety profile in the OLE study, showing only a low rate of safety / tolerability observations possibly related to KIT blockade in OLE. This OLE study demonstrated robust levels of clinical response and deep reductions in UAS7 at Week 12, and a higher level of CR than barzolvolimab (FIG. 27; right panel). Briquilimab demonstrated more rapid onset of durable disease control than barzolvolimab (Phase II) (FIG.28). The results of the OLE continue to show increasing efficacy overtime in CSU patients, as increased reductions in UAS7 were observed on subsequent doses with 22.4% reduction in UAS7 at Week 12 (FIG. 25). CRs were observed as early as Week 2, with 60% CR reported at Week 20 (FIG. 29).

[0335] Data from the BEACON study and CSU patients in the OLE showed that patients with an initial exposure to briquilimab of 2 to 2.5 mg / kg or above were more likely to have a durable response through eight weeks (FIG. 30). Clinical CR or WV responders in the OLE showed better and more durable disease control at or above 2.0 mg / kg briquilimab (FIG. 31).

[0336] The Spotlight study was a phase IB / 2A, dose escalation study of briquilimab in adult patients (18+ years) diagnosed with Cold Urticaria (ColdU) or Symptomatic Dermographism (SD) for > 3 months and for whom Hl -antihistamine treatment failed was conducted. Key assessments included: (i) provocation test (TempTest (ColdU), FricTest (SD); (ii) diseases scores measured by UCT, mast cell depletion and recovery' assayed by serum tryptase, skin biopsies, and codeine skin tests; and (iii) safety assessed by TEAEs and SAEs (diagrammed in FIG. 32).

[0337] 17 CIndU patients rolled over from the Spotlight CIndU clinical trial were analyzed in the OLE study, in which they were treated with 180mg briquilimab Q8W.

[0338] Data from the CIndU patients in the OLE demonstrated a rapid onset of effect following briquilimab treatment with 11 of 17 patients (65%) achieving either CR or PR by Week 2 (FIG. 33). The effect w as durable even at eight weeks post-dose, and 11 of 17 patients (65%) maintained clinical response even at Week 16 (FIG. 33). AEs continued to be predominantly low frequency, transient, low-grade events that resolved while on study.Attorney Docket Number: JATH-023 / 02WO 335666-2215Example 5PHASE 1B / 2A STUDY OF BRIQUILIMAB IN ALLERGIC ASTHMA

[0339] A double-blind, placebo-controlled, single dose, challenge study was conducted to assess briquilimab treatment of allergic asthma (Etesian). Patient eligibility required a diagnosis of stable allergic asthma, a baseline FEVi 70% of predicted value, positive methacholine challenge as baseline, and 18-65 years of age. Key assessments included: (i) early and late asthmatic response: % decrease in FEVi from baseline; (ii) changes in airway hyperresponsiveness: metacholine PD20 24 hours after allergen challenge; and (iii) mast cell depletion and recovery assayed by serum tryptase; and (iv) safety assayed by treatment- emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of interests (AEIs), and adverse events (AEs).

[0340] Related assessments included: (i) Allergen-induced early asthmatic response (EAR) at Week 6 and Week 12 as measured by maximum percentage fall in FEVI and area under the FEVI time-response curve [AUG] during the period 0-2 hours after the allergen challenge; (ii) Allergen-induced late asthmatic response (LAR) at Week 6 and / or Week 12 as measured by maximum percentage fall in FEVi and area under the FEVi time -response curve [AUC] during the period 3-7 hours after the allergen challenge; (iii) Comparison of the allergen-induced shift in airway hyperresponsiveness (AFIR) to methacholine (PD?.o) pre- and post- allergen challenge; (iv) Comparison of the allergen-induced shift in fractional exhaled nitric oxide (FeNO) at 24 hours after the allergen challenge; (v) Changes from pre-allergen challenge sputum leukocytes to 7 hours and 24 hours after the allergen challenge; (vi) Changes from pre¬ allergen challenge sputum inflammatory mediators to 7 hours and 24 hours after the allergen challenge.

[0341] 17 patients were randomized 1: 1 for treatment with 180 mg (single dose) briquilimab or placebo. At Day 0, patients were dosed subcutaneously with briquilimab or placebo, and different groups of patients were subjected to an inhalation allergen challenge at Week -2, Week 6 or Week 12, Follow-up was observed at Week 14. A diagram of this study is provided in FIG. 34. Different groups of patients were also subjected to one or more methacholine challenges at Week -2, Week 0, Week 6 or Week 12, staggered approximately 1 day before and / or 1 day after an inhalation allergen challenge.

[0342] An allergy skin test, also called a skin prick test, was used to determine the allergen that was given to each patient in tire inhalation allergen challenge. It is performed by applying an extract of an allergen to the skin, scratching or pricking the skin to allow exposure, and then evaluating the local reaction in the skin. Standard allergen extracts from allergens including,Attorney Docket Number: JATH-023 / 02WO 335666-2215but are not limited to, ragweed, tree mix, grass mix, dog, cat, horse, feathers, dust mites (Dermatophagoides farincte and D. pteronyssinus), Altemaria, and Aspergillus were used. A positive control ( 1 mg / mL histamine) and a negative control (diluent) were applied to the skin. A raised itchy bump (wheal) develops if an allergen pro voked an allergic reaction. The size of the wheal (the raised area, not the redness) was measured and recorded with a ruler in millimeters in the horizontal and vertical directions, perpendicular to each other, after approximately 15 minutes. The size of the wheal for each antigen is recorded, along with any observed adverse reaction or event and any actions taken. A reaction greater than 2 x 2 mm was regarded as positive, provided that the positive and negative controls were appropriately positive (histamine) and negative (diluent), respectively. The investigator chose an allergen for inhalation on the basis of the largest skin response.

[0343] Briquilimab treatment mitigated the effects of allergen challenge of FEVi response, showing a robust and sustained impact of mast cell depletion on asthmatic response at six and 12 weeks challenge (FIG. 35). Sputum eosinophil response was suppressed by briquilimab, with substantial eosinophil reduction at both Week 6 and Week 12 allergen challenge timepoints (FIG. 36). A single subcutaneous 180mg dose of briquilimab demonstrated substantial reductions in sputum eosinophils at both six and twelve weeks, as well as improvements over baseline in FEVi in both Early Asthmatic Response (EAR) and Late Asthmatic Response (LAR). Significant reductions in serum tryptase were observed, consistent with reductions observed in other briquilimab studies at the 180mg dose level. In addition, briquilimab reduced airway hyper-responsiveness, with an increased concentration of methacholine needed to drive a 20% drop in FEVi (PD20) (FIG. 37). Briquilimab was well tolerated in the study, demonstrating a favorable safety profile.Example 6PHASE 1B / 2A, DOSE ESCALATION STUDY OF SAFETY, PHARMACOKINETIC / PHARMACODYNAMIC AND PRELIMINARY CLINICAL. ACTIVITY OF BRIQUILIMAB IN ADULT PATIENTS WITH CHRONIC INDUCIBLE URTICARIA (CINDU) WHO REMAIN SYMPTOMATIC DESPITE TREATMENT WITHHI-ANTIHISTAMINES

[0344] A randomized phase lb / 2a, multiple ascending dose trial divided into three distinct Parts was conducted to demonstrate the safety, tolerability, and efficacy of briquilimab in participants with Cold urticaria (ColdU) or Symptomatic Dermographism (SD), who remain symptomatic despite the use of Hl -antihistamines (SPOTLIGHT) (FIGs. 32A and 32B). The trial explored three ascending dose levels that are tested in three sequential cohorts.Attorney Docket Number: JATH-023 / 02WO 335666-2215Briquilimab was administered subcutaneously. Briquilimab consisted of 50 mg / mL active ingredient in a solution containing sodium acetate anhydrous, sucrose, polysorbate 20, and water for injection. Placebo consisted of inactive solution containing sodium acetate anhydrous, sucrose, polysorbate 20, and water for injection.

[0345] In each cohort, the trial was divided into three periods as follows and shown in FIG.28:• Screening Period: up to two weeks® Treatment Period: twelve weekso Cohort 1 (n = 3 to 6): Participants receive 40 mg briquilimab subcutaneously (SC) on Day 1 (Baseline),o Cohort 2 (n = 12): Participants receive 120 mg briquilimab SC at Day 1 (Baseline). o Cohort 3 (n = 12): Participants receive 180 mg briquilimab SC at Day 1 (Baseline).Through at least week 12 of the trial, participants should maintain stable doses of their urticaria concomitant medication as per standard of care (pre-screening therapy with Hl antihistamines at approved or increased doses up to four-fold).

[0346] Patients included males and females, >18 years old with a diagnosis of ColdU or SD for > 3 months despite the use of Hl -antihistamines as defined by:a. Diagnosis of ColdU or SD for > 3 months, symptoms must comprise both wheal and itch or painful sensation;b. The presence of itch and hives for > 6 consecutive weeks at any time prior to Screening despite current use of Hl -antihistamines (as reported by the participant); c. ColdU participants must have a positive cold stimulation test above 4°C using TempTest® (wheal and itch or painful sensation) on site during screening using TempTest® to be eligible; andd. SD participants must have a positive FricTests® with 3 pins (wheal and itch) on site during Screening to be eligible,and with use of Hl -antihistamines on stable dose up to 4-fold of the approved dose.Duration of treatment:

[0347] Participants were treated once with either 40 mg (Cohort 1), 120 mg (Cohort 2), or 180 mg (Cohort 3) briquilimab. The trial was open-label.Safety:

[0348] Safety was assessed by regularly performed laboratory' testing (hematology, clinical chemistry, urinalysis), physical examinations, vital signs, ECG, taste change test, hair color change tests and by monitoring and evaluating adverse events (AEs) and treatment emergentAttorney Docket Number: JATH-023 / 02WO 335666-2215adverse events (TEAEs) from signing the informed consent form through the end of treatment visit.Efficacy:

[0349] Provocation tests were performed for evaluation of eligibility criteria (confirmation of ColdU and SD) and to assess the critical thresholds at visits. Efficacy was measured via provocation testing (TempTest® for ColdU and FricTest® for SD) performed on site and via the Urticaria Control Test (UCT) which was completed by tire participants per guidance. Testing was carried out at skin sites that were not affected by urticaria in the last 24 hours. Usually, provocation testing, in positive participants, results in the rapid development of urticarial reactions. Wheals usually develop within minutes after provocation. (Magerl et al, 2016).

[0350] The provocation test for ColdU was the TempTest®. The TempTest® is an electronic testing device consisting of metallic cooling elements that can maintain a precise pre-set temperature from 4°- 44° C, applied to the skin. The participants place the inner forearm on an aluminum stencil on the device for 5 minutes. The stencil shows the temperature range continuously. After 10 minutes, the wheals appearing on the aim are compared to the stencil and the threshold temperature, where wheals are triggered, is recorded in °C. The critical temperature threshold (CTT) is the highest temperature sufficient to induce a positive test reaction (development of wheals). A positive provocation test at Screening is defined as wheal and itch or painful sensation at 4°C or higher.

[0351] Tire provocation test for SD was the FricTest® (Mlynek et al. 2013). FricTest® is a comb-like instrument with four tips of different lengths which allows for simultaneous dermal stimulation in four different provocation levels, from I (tire weakest) to IV (the strongest). To obtain a response, FricTest® is placed vertically so that the four tips are touching the skin, and then stroked once wi th moderate pressure across the -width of the volar surface of the forearm (or the patient's back) for a distance of approximately 6 centimeters. A positive response is defined by a palpable wheal of > 3 mm in width (the diameter of FricTest® tips) at 10 min after provocation. Positive responses were documented for all provocation levels at which they occured. If all four provocation levels induced wheals, the reaction was considered severe. The critical friction threshold (CFf) is the weakest provocation level sufficient to induce a positive test reaction. A positive provocation test at Screening was defined as a positive test response (wheal and itch or painful sensation) to provocation with the longest FricTest® tip provocation (level IV) which confirms the presence of SD.Attorney Docket Number: JATH-023 / 02WO 335666-2215Pharmacokinetics:

[0352] Whole blood samples were collected for analysis of serum concentrations of briquilimab by a validated assay. PK parameters for briquilimab were estimated following SC administration by non-compartmental method. Tire PK blood sampling was performed in accordance with the Schedule of Assessments. Briquilimab pharmacokinetic parameters were estimated by non-compartmental method. Briquilimab pharmacokinetic parameter estimates included peak concentrations (Cmax), time to reach Cmax (tmax) and area under the concentration-time curve from dosing time to last quantifiable concentration (AUClast). Additional applicable parameters may be estimated. Briquilimab serum concentrations and pharmacokinetic parameters were summarized using descriptive statistics.Pharmacodynamics:

[0353] Serum tryptase, stem cell factor (SCF), and anti-drug antibodies (ADAs) were assessed at Baseline (prior to first dosing) and at subsequent visits in accordance with the Schedule of Assessments. Mast cell counts were measured in skin biopsies (optional) and mast cell changes in nasal / buccal swabs (optional).Urticaria Control Test (UCT):

[0354] Participants (ColdU and SD) complete the UCT. The UCT is a disease-specific measure consisting of four questions that retrospectively assesses participants’ burden of disease over the previous 4 weeks. Disease control is a major treatment aim in chronic urticaria (CU), and the UCT was specifically developed and validated to measure this in all forms of CU, including inducible urticaria such as ColdU and SD (Weller et al. 2014). Concepts covered include disease activity, QoL survey, disease control, and therapy. Each of the four questions are scored on a scale of 0 to 4 (see FIG. 32C). The UCT score is derived by adding up the scores from each of the four questions. A total score from 0 (no control) to 16 points (complete control) is derived, with a score of > 12 indicating well-controlled disease. The UCT has high levels of validity and reliability, and accurately identifies participants with insufficiently controlled disease. Its minimal clinically important difference is 3 points (Kulthanan et al.2016; Ohanyan et al. 2017).Results:

[0355] Targeting mast cells with briquilimab was expected to provide clinical benefit in CIndU by decreasing the number and activity of mast cells. This was evaluated, e.g., through changes from baseline in participant reported clinical outcome measures, skin biopsies, and serum tryptase levels.Attorney Docket Number: JATH-023 / 02WO 335666-2215

[0356] Results indicated that targeting mast cells with briquilimab provided clinical benefit in ColdU and SD. Three patients were dosed at 40 mg of briquilimab subcutaneously (two patients with SD and one patient with ColdU). One of the two SD patients dosed at 40 mg showed a complete response. Twelve patients were dosed at 120 mg of briquilimab subcutaneously (eight with SD and four with ColdU). Seven of the SD patients and 3 of the ColdU patients dosed at 120 mg showed complete responses. For patients dosed at 120 mg, five of the eight patients with SD and three of the four patients with ColdU exhibited clinical response by day 15, and six of the eight patients with SD and three of the four patients with ColdU exhibited clinical response by day 29.Enumerated EmbodimentsThe disclosure includes the following enumerated embodiments:1. A method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 =IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in the following order:a) one or more induction dose, wherein each induction dose comprises about 200 mg to about 400 mg of the anti-c-kit IgG antibody;b) two or more maintenance doses, wherein each maintenance dose comprises about 80 mg to about 200 mg of the anti-c-kit IgG antibody, wherein at least two of the maintenance doses are less than the one or more induction dose,wherein each of the doses is administered between about four weeks to about eight weeks apart, between about four weeks to about 10 weeks apart, or between about six weeks to about ten weeks apart.2. The method of embodiment 1, wherein the subject is administered one or tw o induction doses.3. The method of embodiment 1 or embodiment 2, wherein each of the one or more induction dose comprises about 240 mg or about 360 mg of the anti-c-kit IgG antibody.Attorney Docket Number: JATH-023 / 02WO 335666-22154. The method of any one of embodiments 1-3, wherein each of the maintenance doses comprises about 120 mg or about 180 mg of the anti-c-kit IgG antibody.5. The method of embodiment 4, wherein each of the one or more induction dose comprises about 240 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 180 mg of the anti-c-kit IgG antibody.6. Tire method of any one of embodiments 1-5, wherein each of the doses are administered about eight weeks apart.7. The method of embodiment 6, wherein the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 180 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart.8. The method of embodiment 6, wherein the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 120 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered between about four weeks and about eight weeks apart, optionally about eight weeks apart.9. The method of any one of claims 1-8, wherein the doses are administered subcutaneously.10. The method of any one of embodiments 1 -9, wherein the disease or disorder is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic inducible urticaria (ClndU), chronic idiopathic urticaria (CIU), urticaria pigmentosa, prurigo nodularis, esophagitis (optionally, eosinophilic esophagitis), asthma, anaphylaxis, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and disorders, dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.11. The method of any one of embodiments 1-10, wherein the method resul ts in:a) a > 25% reduction in the subject’s UAS7 score for at least eight weeks following the one or more induction doses;Attorney Docket Number: JATH-023 / 02WO 335666-2215b) a UAS7 < 6 for at least eight weeks following one or more induction doses; and / or c) a reduction of mast cells of at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.12. The method of any one of embodiments 1-10, wherein the anti-c-kit IgG antibody comprises two variable heavy chains comprising SEQ ID NO: 4 and two variable light chains comprising SEQ ID NO: 5.13. The method of embodiment 11, wherein the anti-c-kit IgG antibody comprises two heavy chains comprising SEQ ID NO: 2 and two light chains comprising SEQ ID NO: 3.14. A method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in tire following order:a) one or more induction dose, wherein each induction dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve a Cmax > 10 ug / m L and / or an AUCiast > 100 ug X day / mL;b) two or more maintenance doses, wherein each maintenance dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve or maintain (i) a Cmax > 5 ug / mL, a Cmax > 6 ug / mL, a Cmax > 7 ug / mL, a Cmax > 8 ug / mL, a Cmax > 9 ug / mL, or a Cmax > 10 ug / mL and / or (ii) an AUCiast > 50 ug X day / mL, an AUCiast > 60 ug X day / mL, an AUCiast > 70 ug X day / mL, an AUCiast > 80 ug X day / mL, an AUCiast > 90 ug X day / mL, or an AUCiast > 100 ug X day / mL, wherein at least two of the maintenance doses are less than the one or more induction dose,wherein each of the doses is administered between about four weeks to about eight weeks apart or between about six weeks to about ten weeks apart.15. The method of embodiment 14, wherein tire subject is administered one or two induction doses.Attorney Docket Number: JATH-023 / 02WO 335666-221516. The method of embodiment 14 or embodiment 15, wherein each of the one or more induction dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve a Cmax of 10 ug / mL to 25 ug / mL and / or an AUCiast of 100 ug X day / mL to 1,000 ug X day / mL.17. The method of any one of embodiments 14-16, wherein each of the doses are administered about eight weeks apart,18. The method of any one of embodiments 14-17, wherein the doses are administered subcutaneously.19. The method of any one of embodiments 14-18, wherein the disease or disorder is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic inducible urticaria (ClndU), chronic idiopathic urticaria (CIU), urticaria pigmentosa, prurigo nodularis, esophagitis (optionally, eosinophilic esophagitis), asthma, anaphylaxis, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and disorders, (e.g., allergic asthma), dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.20. Tire method of any one of embodiments 14-19, wherein the method results in:a) a > 25% reduction in the subject’s UAS7 score for at least eight weeks following the one or more induction doses;b) a UAS7 < 6 for at least eight weeks following one or more induction doses; and / or c) a reduction of mast cells of at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%,21. The method of any one of embodiments 14-20, w herein the anti-c-kit IgG antibody comprises two variable heavy chains comprising SEQ ID NO: 4 and two variable light chains comprising SEQ ID NO: 5.22. The method of embodiment 21, w herein the anti-c-kit IgG antibody comprises two heavy chains comprising SEQ ID NO: 2 and two light chains comprising SEQ ID NO: 3.23. A method of treating, inhibiting, or preventing atopic dermatitis, optionally allergen-induced dermatitis, hapten-induced dermatitis or MC903 -induced dermatitis, or inhibiting orAttorney Docket Number: JATH-023 / 02WO 335666-2215preventing allergic disease, optionally resulting from atopic dermatitis, in a mammalian subject, comprising administering to the subject an anti-c-kit IgG antibody or antigen-binding fragment thereof comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 - ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11).24. The method of embodiment 23, wherein the subject is a human, and the subject is administered one or more doses of about 50 mg to about 500 mg of the antibody or antigen¬ binding fragment thereof, optionally wherein each of the one or more doses comprises about 60 mg to about 400 mg, about 120 mg to about 360 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 320 mg, or about 360 mg of the antibody or antigen-binding fragment thereof.25. The method of any one of embodiments 1-24, wherein the induction dose and / or the maintenance doses are determined, in part, based on the subject’s body weight.26. Ihe method of any one of claims 1-25, wherein the subject is administered an induction dose of at least 2,0 mg of the antibody or antigen-binding fragment thereof per kilogram subject body weight.27. The method of any one of embodiments 1-25, wherein the subject is administered an induction dose of at least 2.0 mg or at least 2.5 mg of the antibody or antigen -binding fragment thereof per kilogram subject body weight.28. Hie method of any one of embodiments 1-27, for treating, inhibiting, or preventing CSU, wherein the subject is subcutaneously administered one or more induction doses of at least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of the doses is administered between about four weeks to about 8 weeks apart,29. The method of embodiment 28, wherein each maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.Attorney Docket Number: JATH-023 / 02WO 335666-221530. The method of embodiment 28, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg.31. Hie method of any one of embodiments 1-27, for treating, inhibiting, or preventing CIndU, wherein the subject is subcutaneously administered one or more induction doses of at least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of the doses is administered between about four weeks to about 8 weeks apart.32. The method of embodiment 31, wherein each of the maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.33. Tire method of embodiment 31, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg.34. The method of any one of embodiments 1 -27, for treating, inhibiting, or preventing allergic asthma, wherein the subject is subcutaneously administered one or more induction doses of at least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of the doses is administered between about four weeks to about 8 weeks apart.35. The method of embodiment 34, wherein each of the maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.36. The method of embodiment 34, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg.37. The method of any one of embodiments 1-36, wherein if the subject has a body weight greater than 80 kilograms, one or more dose administered (optionally all doses administered), is between 120% and 300% (optionally about 150%) of the recited dose amount.Attorney Docket Number: JATH-023 / 02WO 335666-221538. The method of any one of embodiments 1-37, wherein if the subject has a body weight greater than 90 kilograms, one or more dose administered (optionally all doses administered), is between 120% and 300% (optionally about 150%) of the recited dose amount.39. The method of any one of embodiments 1-36, wherein if the subject has a body weight lower than 60 kilograms, one or more dose administered (optionally all doses administered), is between 50% and 80% (optionally about 75%) of the recited dose amount.* * *

[0357] Tire various embodiments described above can be combined to provide further embodiments. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, application and publications to provide yet further embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come w ithin the scope of the appended claims and their equivalents. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be constiued to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be constiued to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

[0358] All of the U. S. patents, U. S. patent application publications, U. S. patent application, foreign patents, foreign patent application and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entireties.

Claims

Attorney Docket Number: JATH-023 / 02WO 335666-2215Claims1. A method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = lYSGNGDTSY’NQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in the following order:a) one or more induction dose, wherein each induction dose comprises about 200 mg to about 400 mg of the anti-c-kit IgG antibody;b) two or more maintenance doses, wherein each maintenance dose comprises about 80 mg to about 200 mg of the anti-c-kit IgG antibody, wherein at least two of the maintenance doses are less than the one or more induction dose,wherein each of the doses is administered between about four weeks to about 10 weeks apart or between about six weeks to about ten weeks apart.

2. The method of claim 1, wherein the subject is administered one or two induction doses.

3. The method of claim 1 or claim 2, wherein each of the one or more induction dose comprises about 240 mg or about 360 mg of the anti-c-kit IgG antibody.

4. Tire method of any one of claims 1-3, wherein each of the maintenance doses comprises about 120 mg or about 180 mg of the anti-c-kit IgG antibody.

5. The method of claim 4, wherein each of the one or more induction dose comprises about 240 mg of the anti-c-kit IgG antibody, and each of the maintenance doses comprises about 180 mg of the anti-c-kit IgG antibody.

6. The method of any one of claims 1-5, wherein each of the doses are administered about eight weeks apart.

7. The method of claim 6, wherein the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered twoAttorney Docket Number: JATH-023 / 02WO 335666-2215or more maintenance doses, each maintenance dose comprising about 180 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart.

8. The method of claim 6, wherein the subject is administered a single induction dose comprising about 240 mg of the anti-c-kit IgG antibody, and subsequently administered two or more maintenance doses, each maintenance dose comprising about 120 mg of the anti-c-kit IgG antibody, wherein each of the doses are administered about eight weeks apart.

9. The method of any one of claims 1-8, wherein the doses are administered subcutaneously.

10. The method of any one of claims 1-9, wherein the disease or disorder is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), chronic idiopathic urticaria (CIU), urticaria pigmentosa, prurigo nodularis, esophagitis (optionally, eosinophilic esophagitis), asthma, anaphylaxis, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and disorders, dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.

11. The method of any one of claims 1-10, wherein the method results in:a) a > 25% reduction in the subject’s UAS7 score for at least eight weeks following the one or more induction doses;b) a UAS7 < 6 for at least eight weeks following one or more induction doses; and / or c) a reduction of mast cells of at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

12. The method of any one of claims 1-10, wherein the anti-c-kit IgG antibody comprises two variable heavy chains comprising SEQ ID NO: 4 and two variable light chains comprising SEQ ID NO: 5.

13. The method of claim 11, wherein the anti-c-kit IgG antibody comprises tw o heavy chains comprising SEQ ID NO: 2 and two light chains comprising SEQ ID NO: 3.

14. A method of treating, inhibiting, or preventing a mast cell-related disease or disorder in a human subject, comprising administering to the human subject an anti-c-kit IgG antibody comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 =Attorney Docket Number: JATH-023 / 02WO 335666-2215IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered in the following order:a) one or more induction dose, wherein each induction dose comprises an amount of the anti -c -kit IgG antibody sufficient to achieve a Cmax > 10 ug / m L and / or an AUCiast > 100 ug X day / mL;b) two or more maintenance doses, wherein each maintenance dose comprises an amount of the anti -c -kit IgG antibody sufficient to maintain a Cmax > 10 ug / mL and / or an AUCiast > 100 ug X day / mL, wherein at least two of the maintenance doses are less than the one or more induction dose,wherein each of the doses is administered between about four weeks to about eight weeks apart or between about six weeks to about ten weeks apart.

15. The method of claim 14, wherein the subject is administered one or two induction doses.

16. The method of claim 14 or claim 15, wherein each of the one or more induction dose comprises an amount of the anti-c-kit IgG antibody sufficient to achieve a Cmax of 10 ug / mL to 25 ug / mL and / or an AUCiast of 100 ug X day / mL to 1,000 ug X day / mL.

17. Tire method of any one of claims 14-16, wherein each of tire doses are administered about eight weeks apart.

18. The method of any one of claims 14-17, wherein the doses are administered subcutaneously.

19. Tire method of any one of claims 14-18, wherein the disease or disorder is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), chronic idiopathic urticaria (CIU), urticaria pigmentosa, prurigo nodularis, esophagitis (optionally, eosinophilic esophagitis), asthma, anaphylaxis, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and disorders (e.g., allergic asthma), dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.Attorney Docket Number: JATH-023 / 02WO 335666-221520. The method of any one of claims 14-19, wherein the method results in:a) a > 25% reduction in the subject’s UAS7 score for at least eight weeks following the one or more induction doses;b) a UAS7 < 6 for at least eight weeks following one or more induction doses; and / or c) a reduction of mast cells of at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

21. The method of any one of claims 14-20, wherein the anti -c -kit IgG antibody comprises two variable heavy chains comprising SEQ ID NO: 4 and two variable light chains comprising SEQ ID NO: 5.

22. The method of claim 21, wherein the anti-c-kit IgG antibody comprises two heavy chains comprising SEQ ID NO: 2 and two light chains comprising SEQ ID NO: 3.

23. A method of treating, inhibiting, or preventing atopic dermatitis, optionally allergen- induced dermatitis, hapten-induced dermatitis or MC903-induced dermatitis, or inhibiting or preventing allergic disease, optionally resulting from atopic dermatitis, in a mammalian subject, comprising administering to the subject an anti-c-kit IgG antibody or antigen-binding fragment thereof comprising heavy chain CDRs: VH CDR1 = YNMH (SEQ ID NO: 6); VH CDR2 = IYSGNGDTSYNQKFKG (SEQ ID NO: 7); and VH CDR3 = ERDTRFGN (SEQ ID NO: 8) and light chain CDRs: VL CDR1 = RASESVDIYGNSFMH (SEQ ID NO: 9); VL CDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11).

24. The method of claim 23, wherein the subject is a human, and the subject is administered one or more doses of about 50 mg to about 500 mg of the antibody or an tigen-binding fragment thereof, optionally w herein each of the one or more doses comprises about 60 mg to about 400 mg, about 120 mg to about 360 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 240 mg, about 280 mg, about 320 mg, or about 360 mg of the antibody or antigen-binding fragment thereof.

25. The method of any one of claims 1 -24, wherein the induction dose and / or the maintenance doses are determined, in part, based on the subject’s body weight.Attorney Docket Number: JATH-023 / 02WO 335666-221526. The method of any one of claims 1-25. wherein the subject is administered an induction dose of at least 2.0 mg of the antibody or antigen-binding fragment thereof per kilogram subject body -weight.

27. The method of any one of claims 1-25, wherein the subject is administered an induction dose of at least 2.0 mg or at least 2.5 mg of the antibody or antigen-binding fragment thereof per kilogram subject body weight.

28. The method of any one of claims 1-27, for treating, inhibiting, or preventing CSU, wherein the subject is subcutaneously administered one or more induction doses of at least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of tire doses is administered between about four weeks to about 8 weeks apart.

29. The method of claim 28, wherein each maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.

30. The method of claim 28, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg.

31. Tire method of any one of claims 1-27, for treating, inhibiting, or preventing CIndU, wherein the subject is subcutaneously administered one or more induction doses of at least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of the doses is administered between about four weeks to about 8 weeks apart.

32. Tire method of claim 31, wherein each of the maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.

33. The method of claim 31, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg,34. The method of any one of claims 1-27, for treating, inhibiting, or preventing allergic asthma, wherein the subject is subcutaneously administered one or more induction doses of atAttorney Docket Number: JATH-023 / 02WO 335666-2215least 2.0 mg of briquilimab per kilogram subject body weight and one or more maintenance doses of briquilimab, and wherein each of the doses is administered between about four weeks to about 8 weeks apart.

35. Hie method of claim 34, wherein each of tire maintenance doses is at least 2.0 mg of briquilimab per kilogram subject body weight.

36. The method of claim 34, wherein each induction dose is about 240 mg and each maintenance dose is about 180 mg.

37. The method of any one of claims 1-36, wherein if the subject has a body weight greater than 80 kilograms, one or more dose administered (optionally all doses administered), is between 120% and 300% (optionally about 150%) of the recited dose amount.

38. The method of any one of claims 1-37, wherein if the subject has a body weight greater than 90 kilograms, one or more dose administered (optionally all doses administered), is between 120% and 300% (optionally about 150%) of the recited dose amount,39. Hie method of any one of claims 1-36, wherein if the subject has a body weight lower than 60 kilograms, one or more dose administered (optionally all doses administered), is between 50% and 80% (optionally about 75%) of the recited dose amount.

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