Compositions and methods for depleting mast cells

Abstract

This article provides compositions and methods related to the consumption of mast cells using anti-c-kit antibodies. The compositions and methods described herein can be used to treat subjects who require mast cell consumption due to various diseases or conditions, such as chronic spontaneous urticaria (CSU).

Description

Cross-reference to related applications

[0001] This application claims U.S. Provisional Patent Application No. 63 / 543,215, filed October 9, 2023; U.S. Provisional Patent Application No. 63 / 555,780, filed February 20, 2024; U.S. Provisional Patent Application No. 63 / 645,821, filed May 10, 2024; U.S. Provisional Patent Application No. 63 / 649,158, filed May 17, 2024; U.S. Provisional Patent Application No. 63 / 659,296, filed June 12, 2024; and U.S. Provisional Patent Application No. 63 / 543, filed October 9, 2023. Priority claims are made to U.S. Provisional Patent Application No. 245, filed February 21, 2024; U.S. Provisional Patent Application No. 63 / 556,342, filed May 10, 2024; U.S. Provisional Patent Application No. 63 / 645,820, filed May 17, 2024; U.S. Provisional Patent Application No. 63 / 659,293, filed June 12, 2024; and U.S. Provisional Patent Application No. 63 / 604,178, filed November 29, 2023, each of which is incorporated herein by reference in its entirety.

[0002] Reference to the electronic sequence list The contents of the electronic sequence list (JATH_017_05WO_SeqList_ST26.xml; size: 43,800 bytes; and creation date: October 7, 2024) are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to compositions and methods for modulating mast cell activity, for example, to reduce histamine release from activated mast cells. The compositions and methods described herein can be used to treat patients with mast cell-related diseases or conditions, including but not limited to chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). Background Technology

[0004] Mast cells are immune cells that play a crucial role in the inflammatory response to pathogens or injury, and are commonly found in the skin, lungs, digestive tract, conjunctiva of the eye, and the inner lining of the mucous membranes of the mouth and nose. Normally, mast cells are triggered by specific antigen-antibody interactions to release histamine, various cytokines, and other chemical mediators to combat underlying infection and recruit other types of immune cells to aid the body's response. However, in certain diseases, such as CSU, CIndU, allergic asthma, nodular prurigo, and eosinophilic esophagitis, mast cell responses are dysregulated and may lead to unwanted responses such as urticaria, airway narrowing, or conjunctivitis.

[0005] Current treatments for controlling mast cell responses include the use of antihistamines to counteract the release of histamine from activated mast cells, and the use of anti-IgE antibody therapy to attempt to eliminate the antibodies that trigger mast cell activation. However, some patients do not respond to H1 antihistamines. Alternative treatment options for participants with H1 antihistamine-refractory CSU include immunosuppressants such as cyclosporine A, or repeated exposure to oral corticosteroids. Potential serious side effects associated with both alternatives exist (e.g., hypertension, increased risk of infection, acne, increased risk of diabetes and osteoporosis, nephrotoxicity, hepatotoxicity, fatigue, depression).

[0006] Therefore, there is a need in the art for alternative therapies for controlling mast cell responses and treating mast cell-related diseases and conditions such as CSU and CIndU. Summary of the Invention

[0007] This disclosure provides, in particular, a method for treating mast cell-related diseases and conditions, for example, by administering an anti-c-kit antibody or its antigen-binding fragment to a subject in need.

[0008] On one hand, this disclosure provides a method for depleting mast cells in a subject, the method comprising administering to the subject an anti-c-kit antibody (e.g., JSP191) or an antigen-binding fragment thereof, such as (Fab')2, e.g., JSP191(Fab')2, wherein the method results in a reduction in the amount of mast cells in the subject, for example, immediately after administration of the antibody or its antigen-binding fragment, or after approximately one day, two days, three days, four days, five days, six days, ten days, one week, two weeks, one month, two months, four months, or six months after administration of the antibody or its antigen-binding fragment. In some embodiments, the method comprises administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit IgG antibody, such as JSP191, wherein each dose comprises approximately 40 mg to approximately 360 mg, approximately 50 mg to approximately 300 mg, or approximately 120 ng to approximately 180 mg of the anti-c-kit antibody. In some embodiments, the method reduces the amount of mast cells in the subject, for example, immediately after treatment, or approximately one, two, three, four, five, six, ten days, one week, two weeks, one month, two months, four months, or six months after treatment. In some embodiments, the method selectively consumes mast cells, rather than HSPCs, from the subject.

[0009] In a related aspect, this disclosure provides a method for treating a subject with a mast cell-related disease or condition, the method comprising administering to the subject one or more therapeutically effective doses of an anti-c-kit antibody (e.g., JSP191) or its antigen-binding fragment (e.g., F(ab')2). In some embodiments, the subject is unresponsive to treatment with an antihistamine, or is unresponsive to or intolerant of omalizumab. In specific embodiments, the mast cell-related disease or condition is selected from the group consisting of: urticaria, optionally chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), chronic idiopathic urticaria (CIU) or pigmented urticaria, nodular prurigo, esophagitis, optionally eosinophilic esophagitis, asthma, allergic diseases and conditions, optionally allergic asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, dermatitis, atherosclerosis, endometriosis, interstitial cystitis, and inflammatory bowel disease. In one embodiment, the method comprises administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit IgG antibody, such as JSP191, wherein each dose comprises about 50 mg to about 300 mg or about 50 ng to about 600 mg of the anti-c-kit antibody. In some embodiments, a single dose of about 1 mg / kg body weight to about 4 mg / kg body weight is administered to the subject. In some embodiments, the method selectively consumes mast cells, rather than HSPCs, from the subject.

[0010] In a particular embodiment, a method is provided for treating a mast cell-mediated disease or condition in a subject of need, the method comprising administering to the subject an effective amount of an anti-CD117 antibody or a fragment thereof, wherein the anti-CD117 antibody comprises a heavy chain variable region and a light chain variable region of JSP191. In some embodiments, the subject has not responded to treatment with an antihistamine, or has not responded to or is intolerant of omalizumab. In some embodiments, the mast cell-mediated disease or condition is selected from the group consisting of: urticaria, optionally chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), chronic idiopathic urticaria (CIU) or pigmented urticaria, nodular prurigo, esophagitis, optionally eosinophilic esophagitis, asthma, allergic diseases and conditions, optionally allergic asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, dermatitis, atherosclerosis, endometriosis, interstitial cystitis, and inflammatory bowel disease. In some embodiments, the disease or condition is selected from urticaria, asthma, nodular prurigo (PN), eosinophilic esophagitis (EoE), mastocytosis, pigmented urticaria, allergy, endometriosis, interstitial cystitis, and mast cell activation syndrome (MCAS). In some embodiments, the mast cell-mediated disease or condition is chronic urticaria. In some embodiments, the chronic urticaria is chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CIndU). In some embodiments, the administration is performed approximately every 2-12 weeks. In some embodiments, the administration is performed approximately every 4-8 weeks. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 0.8 mg / kg to 5 mg / kg. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 1 mg / kg to 2 mg / kg. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 1.2 mg / kg to 1.8 mg / kg. In some embodiments, the administration is by subcutaneous injection, intravenous injection, or intramuscular injection. In certain embodiments, the administration is subcutaneous. In some embodiments, the first dose administered causes a reduction in mast cell count in the subject for at least one week, at least two weeks, at least three weeks, or at least four weeks. In some embodiments, the anti-CD117 antibody or a fragment thereof comprises an IgG Fc fragment that does not activate antibody-dependent cytotoxicity (ADCC). In some embodiments, the antibody is JSP191.

[0011] In some embodiments of any of the methods disclosed herein, the subject is administered two or more doses of the anti-c-kit antibody, which may be the same or different amounts of the anti-c-kit antibody. In specific embodiments, each of the doses is administered at intervals of eight weeks to one year, eight weeks to six months, eight weeks to four months, twelve weeks to one year, twelve weeks to six months, twelve weeks to four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about twelve months, about ten months, or about one year, optionally wherein the time interval between each dose is different. In some embodiments, the time interval between doses is about two weeks to about 24 weeks, about four weeks to about 16 weeks, about eight weeks to about 12 weeks, about two months to about six months, about one month to about six months, about two months to about four months, or about two months to about three months. In some embodiments, the time interval between doses is at least four weeks, at least six weeks, or at least eight weeks. In some embodiments, the time interval between doses is at most six months. In some embodiments, the subject is administered two or more doses of the antibody or its antigen-binding fragment. In some embodiments, one of two or more doses is administered every two to six months, every four to four months, every two to 16 weeks, every four to 12 weeks, every six to ten weeks, every seven to nine weeks, approximately every four weeks, approximately every five weeks, approximately every six weeks, approximately every seven weeks, approximately every eight weeks, approximately every nine weeks, approximately every ten weeks, approximately every eleven weeks, or approximately every twelve weeks, optionally with different time intervals between each dose. In some embodiments, the time interval between doses is approximately two weeks to approximately 24 weeks, approximately four weeks to approximately 16 weeks, approximately eight weeks to approximately 12 weeks, approximately two months to approximately six months, approximately one month to approximately six months, approximately two months to approximately four months, or approximately two months to approximately three months. In some embodiments, the time interval between doses is at least four weeks, at least six weeks, or at least eight weeks. In some embodiments, the time interval between doses is at most six months.

[0012] In some embodiments, a single high dose of an anti-CD117 antibody (e.g., JSP191) or its antigen-binding fragment (e.g., a JSP191(Fab')2) is administered to the subject. In specific embodiments, the single high dose is about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, for example, about 0.5 mg / kg, mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In certain embodiments, a single high dose is about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, for example, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In some embodiments, the method results in a reduction of UAS7 ≤ 6 or mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

[0013] In some embodiments of any of the methods disclosed herein, the subject is administered one or more doses (e.g., intravenous or subcutaneous) of an antibody or antigen-binding fragment thereof of about 14.5 mg to about 200 mg, about 20 mg to about 500 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 60 mg to about 300 mg, about 60 mg to about 200 mg, about 60 mg to about 150 mg, about 60 mg to about 100 mg, about 70 mg to about 300 mg, about 70 mg to about 200 mg, about 70 mg to about 150 mg, or about 70 mg to about 100 mg, optionally about 14.5 mg to about 175 mg, about 20 mg to about 150 mg, about 25 mg to about 250 mg, about 35 mg to about 240 mg, about 35 mg to about 180 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg. mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg anti-c-kit antibody, optionally wherein the disease or condition is mast cell disease or condition. In some embodiments, the subject is administered an antibody or an antigen-binding fragment thereof in doses of about 25 mg, about 30 mg, about 35 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 130 mg, about 150 mg, about 180 mg, about 200 mg, about 150 mg, about 175 mg, about 240 mg, about 280 mg, or about 300 mg. In particular embodiments, the subject is administered one or more doses of an anti-c-kit antibody or an antigen-binding fragment thereof, such as JSP191, wherein each dose is between 40 mg and 360 mg or between 120 mg and 240 mg, and each dose is administered subcutaneously at intervals of about eight weeks to about six months.

[0014] In some embodiments of any of the disclosed methods, the subject is administered one or more doses of an anti-c-kit antibody or an antigen-binding fragment thereof, each dose being about 0.0073 mg / kg to about 7.3 mg / kg or about 0.01 mg / kg to about 10 mg / kg of the antibody or an antigen-binding fragment thereof, optionally about 0.073 mg / kg to about 7.3 mg / kg or 0.1 mg / kg to about 10 mg / kg of the antigen-binding fragment. In some embodiments, subjects are administered an antibody or an antigen-binding fragment thereof at doses of about 0.3 mg / kg, 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.67 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, or about 2 mg / kg.

[0015] In embodiments of any of the methods disclosed herein, the antibody or its antigen-binding fragment is systematically delivered to the subject, optionally wherein the antigen-binding fragment is delivered intravenously or subcutaneously. In embodiments of any of the methods disclosed herein, the antibody or its antigen-binding fragment is locally delivered to the subject, optionally wherein the antigen-binding fragment is delivered directly to the skin.

[0016] In specific embodiments of the disclosed method, where the disease or condition is a mast cell disease or condition, the method consumes mast cells, induces mast cell apoptosis, and / or inhibits mast cell degranulation. In some embodiments, the method consumes mast cells, induces mast cell apoptosis, and / or inhibits mast cell degranulation by at least 50% approximately 2 weeks after administration of the antibody or its antigen-binding fragment. In some embodiments, the subject's mast cells are consumed by 20% or less approximately 3-4 months after administration of the antibody or its antigen-binding fragment.

[0017] In some embodiments, this disclosure provides pharmaceutical compositions, unit dosage forms, and kits comprising one or more doses of a monoclonal anti-c-kit IgG antibody or an antigen-binding fragment thereof, wherein each of the one or more doses comprises about 40 mg to about 360 mg, about 50 mg to about 600 mg, or about 50 mg to about 300 mg of the anti-c-kit antibody or a fragment thereof, optionally wherein the anti-c-kit antibody is JSP191.

[0018] In some embodiments of any method, composition, unit dosage form, or kit disclosed herein, the anti-c-kit antibody or its antigen-binding fragment comprises one or more, three or more, four or more, or five or more, optionally six complementarity-determining regions (CDRs) present in a monoclonal antibody selected from the group consisting of: SR-1, JSP191, MGTA-117, FSI-174, CDX-0159, 8D7, K45, 104D2, CK6, AB249, YB5.B8, AF-2-1, AF11, AF12, AF112, AF-3, AF-1-1, NF, NF-2-1, NF11, NF12, NF112, NF-3, HF11, HF12, and HF112. In some embodiments, the anti-c-kit antibody comprises one, three or more, four or more, or five or more of a humanized version of a monoclonal antibody selected from the group consisting of six complementarity-determining regions (CDRs): ACK2, ACK4, 2B8, 3C11, MR-1, and CD122, optionally wherein the antibody is an IgG antibody. In some embodiments, the anti-c-kit antibody or its antigen-binding fragment comprises a CDR of an antibody that blocks the binding of stem cell factor (SCF) to the stem cell factor receptor (CD117), optionally wherein the antibody is JSP191 (also known as beretricilimab) or its antigen-binding fragment is JSP191 (Fab')2.

[0019] In some embodiments of any of the methods, compositions, unit dosage forms, or kits disclosed herein, each dose comprises about 50 mg to about 600 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 120 mg to about 240 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 26 ... The dosage may contain approximately 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg of anti-c-kit antibody, or a combination thereof, optionally wherein the antibody is JSP191. In some embodiments, each dose comprises approximately 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg of anti-c-kit antibody, optionally wherein the antibody is JSP191. In some embodiments, the anti-c-kit antibody is systemically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously. In some embodiments, the anti-c-kit antibody is locally delivered to the subject, optionally wherein the anti-c-kit antibody is delivered directly to the skin.

[0020] On the other hand, this disclosure provides a method for altering the differentiation pathways of HSCs and / or HSPCs, the method comprising contacting the cells with a monoclonal anti-c-kit IgG antibody or an antigen-binding fragment thereof, wherein the monoclonal anti-c-kit IgG antibody comprises five or more CDRs present in an antibody that inhibits the binding of SCF to c-kit on the cell surface. In a particular embodiment, the method results in increased differentiation of the cells along the megakaryocyte lineage. In a particular embodiment, the anti-c-kit IgG antibody is JSP-191 or an antigen-binding fragment thereof, such as F(ab')2. Attached Figure Description

[0021] Figure 1 This is a diagram of the trial design for the clinical trial described in Example 9.

[0022] Figure 2This is a graph showing the timeline of participants in the clinical trial described in Example 9.

[0023] Figure 3 It is a graph used to determine the questions and response options for UCT scoring, and the score for each response.

[0024] Figure 4 This figure illustrates the prevention of IgE-induced PSA by beretrilimab in hmCD117 mice. hmCD117 mice were treated with 5 mg / kg beretrilimab three times weekly for three weeks or with a 25 mg / kg bolus injection for two weeks prior to sensitization with anti-DNPIgE and challenged with DNP-HSA 24 hours later. Data are presented as mean ± SEM. Statistical analysis was performed by comparing group means from 0 to 60 minutes. (By Welch) t The test showed that **p<0.01.

[0025] Figure 5 This is a schematic diagram illustrating how beretrialimab can provide protection against severe anaphylactic reactions.

[0026] Figures 6A-6C This demonstrates that beretrilimab prevents IgE-mediated allergic reactions. Figure 6A This is a diagram of the experimental design. Figure 6B A graph of animal core body temperature at indicated time points is provided following challenge at weeks 1–4 after beretricilib treatment or no treatment. Figure 6C A graph is provided showing the clinical scores determined at the indicated time points after stimulation at weeks 1–4 following beretricilib treatment or no treatment.

[0027] Figure 7A and 7B The kinetics of mast cell consumption and recovery following beretriamalbazide administration are shown in various tissues. Figure 7A The number of mast cells at indicated time points following beretrilimab treatment in the ear skin, stomach, and tongue is provided. Figure 7B A representative image of mast cells from the stomach is shown (stained dark purple; indicated by arrows).

[0028] Figure 8 This is a schematic diagram illustrating how beretroviral therapy can provide protection against severe anaphylactic reactions.

[0029] Figures 9A-9C This demonstrates that beretrilimab prevents IgE-mediated allergic reactions. Figure 9A This is a diagram of the experimental design. Figure 9B A graph of animal core body temperature at indicated time points is provided following challenge at weeks 2–4 after beretricilib treatment or no treatment. Figure 9CA graph is provided showing the clinical scores determined at the indicated time points after stimulation at weeks 2–4 following beretricilib treatment or no treatment.

[0030] Figure 10A and 10B The kinetics of mast cell consumption and recovery following a single beretriamab treatment in various tissues are shown. Figure 10A The number of mast cells at indicated time points following beretrilimab treatment in the ear skin, stomach, and tongue is provided. Figure 10B A representative image of mast cells in the ear skin is shown (stained dark purple; indicated by arrows).

[0031] Figure 11 This graph shows the serum concentrations of beretrilimab at the indicated time points after administration of the indicated dose. At each time point, the lower left group of circles represents 5 mg / kg, the middle group of circles represents 10 mg / kg, and the lower right group of circles represents 25 mg / ml, which represents the highest level of beretrilimab.

[0032] Figure 12 A diagram is provided showing the protocol for an asthma prevention and treatment model tested in h / mCD117 mice.

[0033] Figure 13 The figure shows the inhibition of airway inflammation by beretrilimab after sensitization and provocation to cockroach allergens. The top figure provides representative images of the airways from non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab). The bottom figure shows the amounts of BALF neutrophils, airway-infiltrating neutrophils, and airway-infiltrating eosinophils in non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab).

[0034] Figure 14 The reduction in mast cells after treatment with beretrilimab is shown. The top image provides representative images of lung mast cells (lung MCs) and dorsal skin mast cells (dorsal skin MCs) from non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab), with darkly stained mast cells indicated by arrows. The bottom image provides a graph showing the amount of lung and dorsal skin mast cells from non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + Briq).

[0035] Figure 15The diagram illustrates the prevention of asthma exacerbation and relapse following allergen exposure with beretrilimab. These figures provide representative images of the airways from non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab), along with a graph summarizing the amounts of BALF PMN and airway PMN present. The line graph provides a representation of lung resistance after treatment with the indicated amount of methacholine in non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab). At 40 mg / ml methacholine, the lines from top to bottom correspond to asthma, asthma + beretrilimab, and non-asthmatic (PBS).

[0036] Figure 16 The diagram illustrates the reduction of mast cells by beretrilimab after allergen exposure. The top image provides representative images of lung and back skin tissue, showing the presence of mast cells (MCs) in non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + beretrilimab). Darkly stained mast cells are indicated by arrows. The bottom image provides a graph showing the amount of mast cells in the lung and back skin of non-asthmatic (PBS), asthmatic, and asthmatic animals treated with beretrilimab (asthma + Briq).

[0037] Figure 17A-17L The study showed that beretricilumab depleted MC in various tissues of NHP. Figure 17A Following a single subcutaneous administration (0.1 mg / kg, 1 mg / kg, 10 mg / kg) of beretriamalumab to sexually mature male African green monkeys, the mean serum concentration-time curve and ( Figure 17B Nonlinear PK was observed in the average PK parameter values. max The dose increased 25-fold from 0.1 mg / kg to 1 mg / kg, and 9.7-fold from 1 mg / kg to 10 mg / kg. The AUC was [data missing] when the dose increased 10-fold from 0.1 mg / kg to 1 mg / kg and from 1 mg / kg to 10 mg / kg. last These represent increases of 78 times and 17 times respectively. Figure 17C 49 days after a single dose of beretriamalumab at 1 mg / kg or 10 mg / kg, c-Kit was observed in the submucosa of the colon. + The number of molars (MCs) was significantly reduced. The number of MCs in the 0.1 mg / kg dose group was also lower than the control, although this was not statistically significant. Figure 17D Use of trypsin + Quantitative analysis of MC as a biomarker revealed a similar pattern of dose-dependent reduction in MC by beretrilimab. Figure 17EFollowing skin incision trauma, the number of adjacent skin moles (MCs) initially decreased, independent of beretrilimab treatment, reaching its lowest point 3–7 days post-traumatically. In the absence of beretrilimab, MC numbers subsequently increased, while a single dose of 10 mg / kg beretrilimab maintained low MC numbers throughout the study period. At beretrilimab doses below 10 mg / kg, skin MC suppression was more moderate, and MC numbers rebounded as the wound healed, although still lower than in the control group. Figure 17F Repeated doses of beretricilimab administered weekly for 4 weeks to African green monkeys (0 mg / kg (excipient / placebo), 0.3 mg / kg, 1 or 3 mg / kg) resulted in a dose-dependent reduction in submucosal mesenteric cells (MCs) in the colon, with a reduction of 50% to 99% compared to baseline on day 28. Figure 17G and 17H The efficacy of beretricilimab treatment was also evaluated in wound skin biopsies on days 0, 4, 7, 14, and 21. While skin incision wounds led to an increase in perilesional dermal medullaris (MC) in the placebo control group over time, this increase was prevented by all three doses of the tested beretricilimab, as shown by c-Kit at each time point compared to day 0. + and( Figure 17H Trypsin + The percentage of MC is shown. Figure 17I-17L ) Residing in the interstitium (within the alveolar walls; Figure 17I and 17J ) and the peribronchial region (near the hilum); Figure 17K and 17L On day 28, lung MCs were consumed in a dose-dependent manner, ranging from 5% to 50% of those in the placebo control group. The extent of consumption varied depending on the MC markers used and the morphological location of the lung.

[0038] Figures 18A-18C This demonstrates that beretricilumab is generally well-tolerated in NHP. Figure 18A Bérithiomab was administered subcutaneously to cynomolgus monkeys weekly at doses of 1 mg / kg / day, 10 mg / kg / day, and 300 mg / kg / day for one month. The treatment was well-tolerated in both sexes (female data are shown). On day 15 of the administration phase, all doses of bérithiomab resulted in a transient decrease in absolute reticulocyte count. Figure 18B Within the hematological reference range for cynomolgus monkeys, red blood cell mass (hemoglobin levels are shown as representative data) and ( Figure 18CThe white blood cell count (showing neutrophil data) also remained slightly to moderately decreased (6% to 10% from pre-dose levels at 1 mg / kg / dose, and 14% to 19% from pre-dose levels at 10 mg / kg / dose and 300 mg / kg / dose, respectively) (Koo et al.).

[0039] Figures 19A-19E This study demonstrated that beretrilimab exhibits dose-dependent mast cell depletion and predictable pharmacokinetics in healthy volunteers. Figure 19A The graph shows the maximum serum concentrations of beretrilimab typically observed within one week of administration, and the overall serum concentration-time curves suggest nonlinear pharmacokinetics attributable to target-mediated drug disposition. At the highest dose levels of 158 mg and 280 mg, serum exposure to beretrilimab increased proportionally with dose increases beyond the range of 0.7 mg to 280 mg, as assessed with nearly proportional dose increases. Figure 19B and Figure 19C Serum C of beretricilimab in female and male participants is shown. max and AUC last The values ​​(showing data at dose levels ≥42 mg) are comparable, indicating no difference in pharmacokinetics. Figure 19D The study demonstrated dose-related impairment in MC recovery with beretrilimab, as evidenced by significantly lower c-Kit-positive skin MCs on day 29 at dose levels ≥ 84 mg, compared to placebo and lower dose levels (data shown only for the 42 mg dose level). On day 29, compared to baseline, the mean percentage of c-Kit-positive skin MCs increased by 121% and 64% after treatment with placebo and 42 mg beretrilimab, respectively, and decreased by 58%, 75%, and 84% after treatment with 84 mg, 158 mg, and 280 mg beretrilimab, respectively. Figure 19E The diagram illustrates the depletion of CD117-positive (left panel) and trypsin-positive (right panel) mast cells (MCs) after 29 days of indicated beretricilumab treatment. On day 29, the lines from top to bottom in the left panel correlate with: placebo; 10 mg SC; 20 mg SC; 42 mg SC; 0.5 mg IV; 84 mg SC; 158 mg SC; and 280 mg SC. On day 29, the lines from top to bottom in the right panel correlate with: 0.5 mg IV; 10 mg SC; 20 mg SC; placebo; 42 mg SC; 84 mg SC; 158 mg SC; and 280 mg SC.

[0040] Figures 20A-20C This study demonstrates that beretrilimab causes a transient decrease in white blood cells, neutrophils, and hemoglobin in healthy volunteers. It also shows white blood cell counts at beretrilimab dose levels ≥ 42 mg. Figure 20A ), neutrophils ( Figure 20B ) and hemoglobin ( Figure 20C The values ​​are the average values, and the shaded areas represent the range of values ​​observed in participants receiving a placebo. Decreases in laboratory values ​​are transient, reversible, and without clinical signs or symptoms.

[0041] Figure 21A-21K Beritralimab demonstrated that it was more effective than JSP084 and imatinib in inhibiting SCF / c-Kit signaling, MC degranulation, and survival. Figure 21A An antibody that binds to c-Kit is shown; Figure 21B This demonstrates the blocking of SCF binding to c-Kit; Figure 21C This demonstrates the inhibition of SCF-mediated c-Kit receptor internalization; and Figure 21D c-Kit phosphorylation induced by beretricilib, JSP084, and imatinib is shown in M-07e cells. Figure 21E The level of c-Kit phosphorylation in M-07e cells was shown, and Figure 21F This study demonstrates the phosphorylation of Akt in the Ba / F3 cell line stably transduced to overexpress human c-Kit, and its inhibition by beretricilumab and JSP084. Inhibition of M-07e cell proliferation by beretricilumab, JSP084, and imatinib is also shown. Figure 21G Survival of primary MCs differentiated from human CD34 cells ( Figure 21H ) and IgE-dependent MC granulation ( Figure 21I Deglycosylated beretrilimab obtained through the N297Q mutation does not respond to IFNg ( Figure 21J ) or ADCC on M-07e target cells ( Figure 21K ( ) to induce FcgR-mediated degranulation in primary MC cells.

[0042] Figures 22A-22D This demonstrates the binding of beretricilib to c-Kit ( Figure 22A ), blocking the binding of SCF to c-Kit ( Figure 22B SCF-mediated c-Kit internalization ( Figure 22C ), and c-Kit phosphorylation in M-07e cells ( Figure 22D ).

[0043] Figures 23A-23B This demonstrates that beretrilimab does not induce apoptosis in healthy HSCs. Figure 23A The total viable cells after the indicated treatment are shown, and Figure 23B The number of live and apoptotic cells after the indicated treatment is shown.

[0044] Figures 24A-24D This study showed that beretrilimab skews HSC differentiation toward alternative pathways. Figure 24A The flow cytometry plots of CD34 and CD38 expression are shown, along with the fold change in mean fluorescence intensity (MFI) of CD34 and CD38 expression on the cell surface after the indicated treatment at the indicated time points. Figure 24B The figures show the number of HSCs and each progenitor cell type at the indicated time points following the indicated treatment, based on cell markers. Pluripotent progenitor cells: MPP (CD34+CD38-CD90-CD45RA-), common myeloid progenitor cells: CMP (CD34+CD38+CD45RA-CD123-), granulocyte-monocyte progenitor cells: GMP (CD34+CD38+CD45RA+CD123-), megakaryocyte-erythrocyte progenitor cells: MEP (CD34+CD38+CD45RA-CD123-). Figure 24C This diagram illustrates the classic scheme of HSC differentiation into myeloid lineages, as well as the expression patterns of CD34 and CD38 in HSCs and progenitor cells. Figure 24D Flow cytometry plots of c-Kit expression in each group are provided, along with a graph showing the fold change in c-Kit expression on the cell surface at the indicated time points following the indicated treatment.

[0045] Figure 25 A hypothetical working model is provided to illustrate how blocking SCF / c-Kit signaling with beretrilimab in in vitro culture can cause HSCs to deviate towards different alternative HSC differentiation pathways.

[0046] Figure 26A and 26B The pharmacokinetic characteristics of beretrilimab (JSP191) and bazolimab (CDX-0159) in humans after intravenous injection were compared. Serum concentrations of beretrilimab relative to drug dose were plotted in patients with severe combined immunodeficiency (SCID) following intravenous (IV) injection. Figure 26A Reported pharmacokinetic (PK) plots of bazolimumab (CDX-0159) following intravenous (IV) administration in healthy volunteers were included as... Figure 26B For comparison. Figure 26B In the diagram, the lines from top to bottom at 21 days correspond to the doses indicated in the top-to-bottom legend.

[0047] Figure 27A and 27B Comparison of beretricilumab in human body after subcutaneous (SC) injection ( Figure 27A ) and bazolimab ( Figure 27B The pharmacokinetic characteristics of ).

[0048] Figure 28 This is a diagram of the trial design for the clinical trial described in Example 10. Detailed Implementation

[0049] This disclosure particularly provides treatment for mast cell-related diseases and conditions using anti-c-kit antibodies and fragments thereof, wherein the dosage of the anti-c-kit antibodies and fragments thereof is effective in depleting mast cells in the treated subject. In some embodiments, the method is used to treat chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), nodular prurigo, eosinophilic esophagitis, allergic asthma and severe asthma, inflammatory bowel disease, and other mast cell-related diseases and conditions, including but not limited to those disclosed herein.

[0050] In specific embodiments, this disclosure provides agents and dosing regimens for effectively depleting mast cells in treated patients without adversely depleting healthy hematopoietic stem cells, as well as related methods for treating mast cell-related diseases and conditions. In specific embodiments, the methods are carried out using anti-c-Kit antibodies, JSP191, or beretrilimab (a humanized, deglycosylated IgG1 inhibitor of c-Kit signaling on mast cells that directly blocks the binding of stem cell factor (SCF) to CD117). The sequence / structure and mechanism of action of beretrilimab provide it with potency and half-life that favorably depletes mast cells while substantially not depleting healthy hematopoietic stem cells, thus making beretrilimab superior in treating, preventing, or inhibiting mast cell-related diseases and conditions. This disclosure further provides dosing regimens that facilitate the treatment, prevention, and inhibition of various types of mast cell-related diseases and conditions, including but not limited to single high-dose regimens and repeated dosing regimens with intervals between doses.

[0051] This disclosure also provides treatments for hematopoietic stem cell / progenitor cell diseases and conditions using anti-c-kit antibodies and fragments thereof.

[0052] definition It should be understood that the present invention is not limited to the specific methods, products, apparatus, and factors described, as such methods, apparatus, and formulations can certainly vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the appended claims.

[0053] It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / a(a)”, “and”, and “the” as used herein and in the appended claims include plural indicators. Thus, for example, reference to “pharmaceutical candidate” means one or a mixture of such candidates, reference to “method” includes reference to equivalent steps and methods known to those skilled in the art, and for example, “antibody” is understood to mean one or more antibodies. Therefore, the terms “a / a(a)” (or “a / a(an)”), “a / a or more / a”, and “at least one / a” are used interchangeably herein.

[0054] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques used in conjunction with those described herein in the fields of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry are well-known and commonly used in the art.

[0055] Where a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of the range (to one-tenth of the lower limit unit, unless the context clearly indicates otherwise) and any other stated values ​​or intermediate values ​​within the range are covered within this invention. The upper and lower limits of these smaller ranges may be independently included in a smaller range and also covered within this invention, subject to any exact exclusion of any limit value within the stated range. Where a stated range includes one or both limit values, the range excluding any one or both of those included limit values ​​is also included in this invention. This disclosure also considers ranges having upper and lower limits defined by any two numerical values ​​separately disclosed herein.

[0056] As used herein, “antibody” includes immunoglobulin molecules that are immunoreactive to a specific antigen, and includes both polyclonal and monoclonal antibodies. In some embodiments, an antibody comprises two heavy chains and two light chains, wherein each light chain binds to a different heavy chain, and the two heavy chains bind to each other. The five types of immunoglobulins include IgM, IgG, IgA, IgE, and IgD2. An antibody can be any of these, and in some embodiments, is IgG. The term also includes genetically engineered forms such as humanized antibodies, chimeric antibodies (e.g., humanized mouse antibodies), and heteroconjugate antibodies. An antibody can be a whole antibody and any of its antigen-binding fragments or single chains. Thus, the term “antibody” includes any protein or peptide containing a molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to an antigen. Examples of such molecules include, but are not limited to, variable regions of heavy or light chains, constant regions of heavy or light chains, framework (FR) regions, or any portion thereof, or at least a portion of a binding protein. The term "antibody" also includes antigen-binding forms of antibodies, including fragments with antigen-binding capabilities (e.g., Fab', F(ab')2, Fab, Fv, and rIgG). The term also refers to recombinant single-chain Fv fragments (scFv). The term "antibody" also includes bivalent or bispecific molecules, bifunctional antibodies, trifunctional antibodies, and tetrafunctional antibodies.

[0057] As used herein, the term "antibody fragment" or "antigen-binding fragment" refers to a portion of an antibody, such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc. Regardless of structure, an antibody fragment binds to the same antigen recognized by the intact antibody. The term "antibody fragment" includes aptamers, mirror-image aptamers, and bifunctional antibodies. The term "antibody fragment" also includes any synthetic or genetically engineered protein that functions as an antibody by binding to a specific antigen to form a complex.

[0058] A "humanized antibody" is an immunoglobulin molecule containing a minimal sequence derived from a non-human immunoglobulin. Humanized antibodies comprise human immunoglobulins (recipient antibodies) in which residues of the complementarity-determining region (CDR) from the recipient are replaced by residues of the CDR from a non-human species (donor antibody) with the desired specificity, affinity, and capability, such as mouse, rat, or rabbit. In some cases, Fv frame residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also contain residues not found in the recipient antibody or in the input CDR or frame sequence. Typically, a humanized antibody will contain at least one and usually two variable domains, substantially all of which are variable domains, wherein all or substantially all of the CDR regions correspond to the CDR regions of the non-human immunoglobulin, and all or substantially all of the frame (FR) regions are FR regions of the human immunoglobulin common sequence. Preferably, the humanized antibody will also also contain at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the human immunoglobulin constant region.

[0059] The selection of antibodies used for cell ablation, such as the ablation of endogenous mast cells, can be based on a variety of criteria, including selectivity, affinity, cytotoxicity, etc. "Specifically binding" or "specific to" generally means that an antibody binds to an epitope through its antigen-binding domain, and that this binding requires some complementarity between the antigen-binding domain and the epitope. According to this definition, when an antibody binds to an epitope through its antigen-binding domain, the antibody is said to "specifically bind to the epitope," which is easier than binding to a random, unrelated epitope. Therefore, when referring to antibodies binding to proteins or peptides, the phrase "specifically (or selectively) binding" means a binding reaction that determines the presence of a protein within a heterogeneous population of proteins and / or other biological products. The term "specific" is used herein to modify the relative affinity of a particular antibody for a particular epitope. For example, antibody "A" can be considered to have higher specificity for a given epitope than antibody "B," or antibody "A" can be considered to have higher binding specificity to epitope "C" than to its binding specificity to related epitope "D." Therefore, in some embodiments, under specified immunoassay conditions, the binding of a specific antibody to a specific protein sequence is at least twice that of background binding, and more typically more than 10 to 100 times that of background binding.

[0060] Monoclonal antibodies can be prepared using the hybridoma method. In the hybridoma method, a suitable host animal is typically immunized with an immunizing agent to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with an immortalized cell line using a suitable fusion agent such as polyethylene glycol to form hybridoma cells.

[0061] Human antibodies can be generated using a variety of techniques known in the art, including phage display libraries. Similarly, human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals, such as mice in which endogenous immunoglobulin genes have been partially or completely inactivated. Upon stimulation, human antibody production is observed, closely resembling that seen in humans in all respects, including gene rearrangement, assembly, and antibody library formation.

[0062] Antibodies also exist in the form of many well-defined fragments produced by digestion with various peptidases. Pepsin digests antibodies under disulfide bonds in the hinge region to produce Fab dimers F(ab')2, which are themselves light chains linked to VH-CH1 by disulfide bonds. F(ab')2 can be reduced under mild conditions to break the disulfide bonds in the hinge region, thereby converting the F(ab')2 dimer into Fab' monomers. Fab' monomers are essentially Fabs with partially hinge regions. Although various antibody fragments are defined for the digestion of whole antibodies, those skilled in the art will understand that such fragments can be resynthesized chemically or using recombinant DNA methods. Therefore, the term antibody, as used herein, also includes antibody fragments produced by modifying whole antibodies, or antibody fragments resynthesized using recombinant DNA methods (e.g., single-chain Fv), or antibody fragments identified using phage display libraries.

[0063] The selectivity of a particular antibody is typically determined by the ability of one antibody to competitively inhibit the binding of a second antibody to an antigen, or by the ability of an antibody to cross-react with multiple epitopes. Any of many competitive binding assays can be used to measure the competition between two antibodies for the same antigen, or between two antigens for one antibody. An exemplary assay is the BIACORE™ assay. In short, in these assays, binding sites are structurally mapped by testing the ability of interacting agents (e.g., different antibodies) to inhibit the binding of one another. Injecting two consecutive antibody or antigen samples at sufficient concentrations can identify paired competing antibodies against the same binding epitope. The antibody samples should have the potential to reach significant saturation with each injection. The net binding of the second antibody injection indicates the binding epitope analysis. Due to the different epitopes, the boundary between fully competitive and non-competitive binding can be described using two reaction levels. The relative amount of binding reaction of the second antibody injection relative to the binding of the same and different binding epitopes determines the degree of epitope overlap.

[0064] The term "polynucleotide" refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs or mixtures thereof. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and nucleotide or nucleoside analogs, and may be interrupted by non-nucleotide components. If present, the nucleotide structure may be modified before or after polymer assembly. As used herein, the term polynucleotide includes, but is not limited to, double-stranded and single-stranded molecules and mixtures thereof. Unless otherwise specified or required, any embodiment of the invention described herein as a polynucleotide covers both double-stranded forms and each of two complementary single-stranded forms known or predicted to constitute a double-stranded form, whether RNA or DNA, or mixtures thereof.

[0065] "Encoding" refers to the inherent properties of a specific sequence of nucleotides in a polynucleotide such as a gene, cDNA, or mRNA, which serves as a template for the synthesis of other polymers and macromolecules in biological processes, having defined nucleotide sequences (i.e., rRNA, tRNA, and mRNA) or defined amino acid sequences and the biological properties produced therefrom. Therefore, if the transcription and translation of mRNA corresponding to a gene produces a protein in a cell or other biological system, then the gene encodes that protein. Both the coding strand (whose nucleotide sequence is identical to the mRNA sequence and is typically provided in a sequence listing) and the non-coding strand (which serves as a template for gene or cDNA transcription) can be referred to as encoding the protein or other product of that gene or cDNA.

[0066] As used herein, the terms “polypeptide,” “peptide,” and “protein” refer to polymers of amino acids of any length. These terms also cover modified amino acid polymers; for example, modified to include disulfide bond formation, glycosylation, esterification, phosphorylation, or conjugation with a labeled component. The term “polypeptide” is intended to cover both the singular and plural “polypeptide” 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 one or more chains of two or more amino acids and does not indicate a specific length of the product. Therefore, peptide, dipeptide, tripeptide, oligopeptide, “protein,” “amino acid chain,” or any other term used to refer to one or more chains of two or more amino acids are included within the definition of “polypeptide,” and the term “polypeptide” may be used in place of or interchangeably with any of these terms. The term “polypeptide” is also intended to refer to products of post-expression modifications of a polypeptide, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization of known protecting / blocking groups, protein hydrolysis, or modification with non-naturally occurring amino acids. Peptides can be derived from natural biological sources or produced through recombinant technologies, but they are not necessarily translated from a specified nucleic acid sequence. They can be produced in any way, including through chemical synthesis.

[0067] As used herein, the terms “identity” and “sameness” relative to the polypeptide or polynucleotide sequence of interest refer to the percentage of exact matching residues in an alignment of the sequence of interest with a reference sequence (such as an alignment generated by the BLAST algorithm). Unless otherwise stated, identity is calculated across the full length of the reference sequence. Therefore, the sequence of interest “shares at least x% identity” with the reference sequence if, when the reference sequence (as the query sequence) is aligned with the sequence of interest (as the subject sequence), at least x% (rounded down) of residues in the subject sequence exactly matches the corresponding residues in the query sequence, with the denominator being the full length of the reference sequence plus the length of any gaps inserted into the reference sequence obtained by aligning the reference sequence with the sequence of interest. When the subject sequence has variable positions (e.g., residues labeled X), an alignment with any residue in the query sequence is considered a match. Sequence similarity (i.e., identity) can be determined in many different ways. To determine sequence identity, sequences can be aligned using methods and computer programs including BLAST, which is available on the World Wide Web at ncbi.nlm.nih.gov / BLAST / . Sequence alignment can be performed using the NCBI Blast service (BLAST+ version 2.12.0) or another program that produces the same results. Unless otherwise indicated, sequence identity is determined using the BLAST algorithm (e.g., bl2seq) and default parameters.

[0068] As used herein, the terms “natural” or “wild-type” refer to a nucleotide sequence (e.g., a gene) or gene product (e.g., RNA or polypeptide) present in wild-type cells, tissues, organs, or organisms. As used herein, the term “variant” refers to a mutant of a reference polynucleotide or polypeptide sequence, such as a natural polynucleotide or polypeptide sequence, i.e., having less than 100% sequence identity with the reference polynucleotide or polypeptide sequence. In other words, a variant contains at least one amino acid difference relative to a reference polynucleotide sequence, such as a natural polynucleotide or polypeptide sequence (e.g., amino acid substitution, amino acid insertion, amino acid deletion). For example, a variant may be a polynucleotide with 50% or more, 60% or more, or 70% or more sequence identity with a full-length natural polynucleotide sequence, such as 75% or 80% or more, such as 85%, 90%, or 95% or more, such as 98% or 99% identity. As another example, a variant can be a polypeptide with 70% or higher sequence identity to a full-length natural polypeptide sequence, such as 75% or 80% or higher, for example 85%, 90%, or 95% or higher, such as 98% or 99% identity. Variants can also include variant fragments of a reference sequence (e.g., a natural sequence) that share 70% or more sequence identity with a reference sequence (e.g., a natural sequence), such as 75% or 80% or more, for example 85%, 90%, or 95% or more, such as 98% or 99% identity.

[0069] As used herein, the term "stem cell" refers to a mammalian cell capable of self-renewal and producing differentiated offspring (see Morrison et al. (1997) Cell 88:287-298). Endogenous stem cells can be characterized by the presence of biomarkers associated with specific epitopes. As used herein, the term "hematopoietic stem cell (HSC)" refers to pluripotent cells located in the bone marrow (BM) and responsible for producing mature blood cells throughout life. HSCs are capable of producing all different types of mature blood cells, including red blood cells (erythrocytes), white blood cells (leukocytes), and platelets.

[0070] Hematopoietic stem cells and progenitor cells (HSPCs) are a group of cells responsible for the production and replenishment of all different types of blood cells in the body. They are primarily located in the bone marrow, although small amounts can also be found in peripheral blood and cord blood. HSCs are the most primitive and self-renewing cells in the HSPC population. They have the ability to replicate themselves through self-renewal and differentiate into a variety of specific cell types. HSPCs also include progenitor cells, which are more directional and lineage-restricted than HSCs. Progenitor cells originate 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.

[0071] The terms “treatment,” “treating,” etc., are used herein to generally mean achieving a desired pharmacological and / or physiological effect. This effect may be therapeutic in relation to the partial or complete cure of a disease and / or side effects attributable to said disease. As used herein, “treatment” covers any treatment of a disease in mammals and includes, for example: (a) inhibiting the development of the disease, i.e., stopping or delaying its development; (b) reducing the severity of the disease; or (c) alleviating the disease, i.e., causing the disease to subside. “Treatment” is an intervention aimed at preventing the development of a disease or condition or altering its pathology. Thus, “treatment” or “curing” refers to therapeutic treatment, while “prevention” or “preventive” refers to preventive or preventive measures, including delaying the onset or recurrence of a disease or condition. Patients requiring treatment include those who already have said condition and those who need to prevent said condition. In a particular embodiment, treatment results in improvement of one or more symptoms of the disease. “Inhibiting” or “preventing” a disease or condition includes delaying the onset of the disease or condition or reducing its severity, or preventing the disease or condition from occurring, such as an allergic reaction.

[0072] As used herein, in the context of treating mast cell-related diseases or conditions, the phrase “therapeutic effective amount” refers to the amount of therapeutic or prophylactic antiCD117 antibody that provides a reduction in the number and / or activity of mast cells, a reduction in fibromatosis elements or their precursors, or a reduction in the severity or progression of symptoms associated with mast cell-related diseases (i.e., provides “therapeutic efficacy”).

[0073] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably in this document and refer to mammals, including but not limited to: human and non-human primates, including apes and humans; mammalian locomotion animals (e.g., horses); mammalian farm animals (e.g., sheep, goats, etc.); mammalian pets (dogs, cats, etc.); and rodents (e.g., mice, rats, etc.).

[0074] As used herein, the term "substantially" means significantly, substantially, or to a great extent. For example, "substantially" increasing can mean an increase of at least two times, at least three times, at least four times, at least five times, or at least ten times, and "substantially" decreasing can mean a decrease of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. Numerous specific details are set forth in the following description to provide a more thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention can be practiced without one or more of these specific details. In other instances, well-known features and procedures familiar to those skilled in the art have not been described in order to avoid obscuring the invention.

[0075] Generally, this invention employs conventional methods of protein synthesis, recombinant cell culture, and protein isolation, as well as recombinant DNA technology, which are within the scope of the art. Such techniques are well explained in the following references, see, for example, Maniatis, Fritsch and 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).

[0076] Treatment of mast cell-related diseases and symptoms Tyrosine protein kinase KIT is also known as c-KIT, CD117 (differentiation cluster 117), or SCFR (mast cell / 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 inherent tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate signals within the cell.

[0077] Human c-KIT protein possesses an extracellular domain (ECD), a transmembrane domain, and an intracellular domain (ICD). The ECD contains five lg-like domains (D1-D5) associated with ligand binding and homodimerization. C-KIT protein processing involves N-linked glycosylation and phosphorylation of tyrosine and serine residues. When the SCP dimer binds to c-KIT, this binding induces c-KIT dimerization, conformational changes in both the ECD and ICD, ICD transphosphorylation, and binding of various partner molecules.

[0078] Mast cells are key cellular targets in a variety of inflammatory and immune diseases, including autoimmune diseases. CD117 is crucial for the development and differentiation of mast cells and hematopoietic stem cells in the bone marrow. The binding of stem cell factor (SCF) to CD117 initiates a signaling cascade that promotes mast cell growth and maturation. CD117 signaling via SCF is essential for mast cell survival and proliferation. SCF binding to CD117 activates various intracellular signaling pathways that regulate cell survival and cell cycle progression, including the PI3K-AKT and MAPK pathways. 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. CD117 signaling contributes to mast cell activation and degranulation. When mast cells encounter allergens or antigens, cross-linking of IgE antibodies that bind to FcεRI receptors on the mast cell surface triggers a signaling cascade involving CD117. This signaling enhances the release of various inflammatory mediators responsible for allergic reactions and immune responses, such as histamine, cytokines, chemokines, and proteases. CD117 signaling affects multiple aspects of mast cell function. It regulates the expression of cell surface receptors (such as FcεRI and other immune receptors) and modulates 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 sites of inflammation.

[0079] Inhibition of c-Kit signaling can lead to organized cell death and mast cell phagocytosis and clearance. However, on the one hand, blockade needs to be above a threshold level to deplete mast cells, as partial c-Kit inhibition only suppresses mast cell activation. On the other hand, sustained c-Kit blockade may have undesirable effects on other c-Kit-expressing cells. Therefore, these tensions pose a significant challenge to the development of c-Kit antibodies for the treatment of mast cell-mediated diseases and conditions.

[0080] Béritristimab (JSP191) is an anti-c-Kit antibody in clinical development. A benchmark anti-c-Kit antibody is bazolimumab (CDX-0159), developed by Celldex Therapeutics Inc. In an unexpected finding, beritristimab exhibited faster pharmacokinetic clearance compared to bazolimumab. However, the shortened drug exposure was still sufficient to deplete mast cells, which also occurred quite rapidly. Therefore, this improved clearance rate provides a unique advantage for beritristimab as it can help minimize adverse effects on other non-targeting c-Kit-positive cells.

[0081] However, another advantage of beretrilimab is that it may be more effective than bazolimab, at least at lower doses. While the clinical dose of bazolimab used to treat chronic urticaria is 3 mg / kg (Terhorst-Malawi et al., *Allergy*... Allergy (2023;78:1269-1279), but at doses as low as approximately 1 mg / kg, beretrilimab showed effective and durable efficacy.

[0082] Activation of c-Kit upon binding to stem cell factor (SCP) leads to dimerization, autophosphorylation, and receptor internalization. The conventional antibody bazolimumab inhibits c-Kit activity by suppressing c-Kit dimerization. However, it has been shown that beretrillumab directly blocks the interaction between c-Kit and SCP, thus its receptor antagonistic effect may be more potent.

[0083] According to certain embodiments of this disclosure, a method is provided for treating a mast cell-related or mast cell-mediated disease or condition in a subject of need, the method 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 some embodiments, the anti-CD117 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence of the heavy chain variable region of JSP191, and the light chain variable region comprising the amino acid sequence of the light chain variable region of JSP191. In some embodiments, the antibody is JSP191 or an antigen-binding fragment thereof.

[0084] This disclosure considers the treatment or prevention of any mast cell-related or mast cell-mediated disease or condition, and these terms are used interchangeably herein. In some embodiments, mast cell-mediated diseases or conditions are selected from the group consisting of: urticaria, asthma, nodular prurigo (PN), eosinophilic esophagitis (EoE), mastocytosis, pigmented urticaria, allergies, endometriosis, interstitial cystitis, and mast cell activation syndrome (MCAS). In a particular embodiment, the mast cell-related disease or condition is selected from the group consisting of: urticaria, optionally chronic spontaneous urticaria (CSU), chronic induced urticaria (CIndU), chronic idiopathic urticaria (CIU) or pigmented urticaria, nodular prurigo, esophagitis, optionally eosinophilic esophagitis, asthma, allergic diseases and conditions, optionally allergic asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, dermatitis, atherosclerosis, endometriosis, interstitial cystitis and inflammatory bowel disease.

[0085] In some embodiments, the mast cell-mediated disease or condition is urticaria, such as chronic urticaria. In some embodiments, the chronic urticaria is chronic spontaneous urticaria (CSU) or chronic induced urticaria (CIndU). In some embodiments, the CIndU is cold urticaria (ColdU) or symptomatic dermatographia (SD).

[0086] In some embodiments, the methods and treatments described herein consume mast cells from a subject by administering an anti-c-kit antibody or a fragment thereof (e.g., beretrilimab or JSP191 (Fab')2). In some embodiments, the mast cells comprise activated mast cells. In some embodiments, mast cells are consumed from one or more tissues or organs of the subject, for example, in some embodiments, mast cells are consumed from the subject's skin or lungs. In some embodiments, mast cells are consumed from the subject or the subject's tissues or organs, consuming 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 the total mast cells in the subject or the subject's tissues or organs. In some embodiments, the tissue or organ is skin or lungs.

[0087] 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., beretricilib) or its antigen-binding fragment thereof to the subject. In some embodiments, the mast cells comprise activated 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 some embodiments, in the skin or lungs of the subject). In some embodiments, the methods induce apoptosis of mast cells in the subject or the subject's tissues or organs, inducing 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 the total mast cells in the subject or the subject's tissues or organs. In some embodiments, the tissue or organ is skin or lungs.

[0088] In some embodiments, the treatment described herein selectively consumes or induces apoptosis of activated mast cells in a subject. In particular embodiments, selective consumption or apoptosis of activated mast cells according to the disclosed method results in a greater number or percentage of activated mast cells being consumed or undergoing apoptosis compared to the number or percentage of unactivated mast cells that are consumed or undergo apoptosis.

[0089] In some embodiments, the methods disclosed herein are used to modulate one or more mast cell activities, for example, to inhibit mast cell growth and maturation, to inhibit mast cell survival and proliferation, to inhibit activation of intracellular mast cell signaling pathways (including the PI3K-AKT and MAPK pathways), to inhibit mast cell migration and homing to various tissues (e.g., skin, respiratory tract, and gastrointestinal tissues), to inhibit mast cell activation and degranulation, and / or to inhibit mast cell release of various inflammatory mediators (such as histamine, cytokines, chemokines, and proteases).

[0090] In some embodiments, the methods described herein consume mast cells from a subject by administering an anti-c-kit antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2 fragment) to the subject. In some embodiments, the mast cells comprise activated mast cells. In some embodiments, mast cells are consumed from one or more tissues or organs of the subject, for example, in some embodiments, mast cells are consumed from the subject's skin or lungs. In some embodiments, mast cells are consumed from the subject or the subject's tissues or organs, consuming 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 the total mast cells in the subject or the subject's tissues or organs. In some embodiments, the tissue or organ is skin or lungs.

[0091] In certain embodiments, the method consumes mast cells, induces mast cell apoptosis, and / or inhibits mast cell degranulation. In some embodiments, the method consumes 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 at approximately one week, two weeks, three weeks, or one month after antibody administration, or induces apoptosis in 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. In some embodiments, at approximately three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months after antibody administration, the subject's mast cells are consumed by about 5%, about 10%, or about 20%, or less. In a particular embodiment, the consumed mast cells include or are activated mast cells.

[0092] In some embodiments, the treatment described herein selectively consumes activated mast cells in a subject. In a particular embodiment, the selective consumption of activated mast cells according to the disclosed method results in the consumption of a greater number or percentage of activated mast cells compared to the number or percentage of inactive mast cells consumed.

[0093] In some embodiments, the methods and treatments described herein selectively deplete mast cells compared to hematopoietic stem cells and progenitor cells (HSPCs). In specific embodiments, the methods result in the depletion of HSPCs in the subject being less than about 10%, less than about 20%, less than about 30%, less than about 40%, or less than about 50% at approximately one week, two weeks, three weeks, or one month after antibody administration. In specific embodiments, the methods result in the 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 specific embodiments, HSPCs refer to those measured in the subject's bone marrow, blood, or serum. In specific embodiments, mast cells (activated or inactivated) refer to those measured in the subject's bone marrow, blood, or serum, or in a tissue sample (e.g., skin biopsy) from the subject.

[0094] Not wishing to be bound by any particular theory, the anti-c-Kit antibodies disclosed herein exhibit the ability to induce mast cell apoptosis. In certain embodiments, the antibodies can be used to treat mast cell diseases and conditions. For example, this disclosure contemplates administering an anti-c-Kit antibody, such as JSP191 or a fragment thereof, to a subject suffering from a mast cell-related disease or condition at a dose sufficient to induce mast cell consumption. Mast cells undergo apoptosis, which occurs within hours to days following administration of the anti-c-Kit antibody or a fragment thereof. The mast cells are then phagocytosed, with consumption occurring as early as day 7 and in large quantities by day 29 (leaving the skin after approximately two weeks or more), thereafter typically requiring approximately three months or more for mast cells to recover in the skin. The PK clearance half-life of JSP191 is approximately nine days. After a no-dose interval, such as at any time between approximately eight weeks and approximately six months, for example, approximately eight weeks to approximately 12 weeks, this allows c-Kit signaling to be restored in other c-Kit-expressing cells. The subject can then be re-administered with an anti-c-Kit antibody or a fragment thereof (e.g., JSP191 or a fragment thereof), which induces apoptosis and phagocytosis of any newly formed mast cells or mast cell progenitors. This cycle of re-administration can continue to maintain low mast cell levels. Alternatively, a single dose may be sufficient to deplete mast cells associated with mast cell-related diseases or conditions, and re-administration to remove newly formed mast cells, which may be healthy and / or inactive or unrelated to the disease or condition, may not be necessary. In some embodiments, the method provides the advantage of long-term depletion of disease- or condition-related mast cells while still allowing other cells to resume c-Kit signaling once the anti-c-Kit antibody is cleared.

[0095] In a particular embodiment, the anti-c-kit antibody or a fragment thereof is provided to the subject in a dose that can effectively deplete mast cells in the treated subject.

[0096] In certain embodiments, subjects are provided with two or more doses of anti-c-Kit antibody or a fragment thereof, such as JSP191, each dose being about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, for example, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 0.8 mg / kg to 5 mg / kg. In some embodiments, the administration is performed about every 2-12 weeks or every 8 weeks to 6 months. In some embodiments, the administration is performed every 4-8 weeks, every 8-16 weeks, or every 6-16 weeks. In some embodiments, the method induces apoptosis of mast cells.

[0097] In certain embodiments, the subject is given a single (e.g., high) dose of anti-c-Kit antibody or a fragment thereof (e.g., JSP191) at a dose of about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In some embodiments, the method induces apoptosis of mast cells.

[0098] In a particular embodiment, the anti-c-Kit antibody or a fragment thereof (e.g., JSP191 or a fragment thereof) is administered as one or more doses of about 0.1 mg / kg to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg to about 3.0 mg / kg, about 0.3 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, or about 120 mg / kg.

[0099] In certain embodiments, the anti-c-Kit antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2) is administered subcutaneously.

[0100] In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 10 weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 1 mg / kg to 2 mg / kg. In some embodiments, the anti-CD117 antibody or a fragment thereof is administered at a dose of 1.2 mg / kg to 1.8 mg / kg. In some embodiments, the administration is subcutaneous, intravenous, or intramuscular. In a particular embodiment, the administration is subcutaneous. In some embodiments, the first dose administered results in a reduction in mast cell count in the subject for at least 1, 2, 3, or 4 weeks. In some embodiments, the anti-CD117 antibody or a fragment thereof comprises an IgG Fc fragment that does not activate antibody-dependent cytotoxicity (ADCC).

[0101] The compositions and methods disclosed herein can be used, for example, to treat or prevent mast cell-related diseases and conditions, including but not limited to those involving chronically active mast cells, by administering an anti-c-kit antibody (e.g., JSP191) or a fragment thereof (e.g., the JSP191 (Fab')2 fragment) to a subject. For example, in certain embodiments, the disclosed methods can be used to prevent or reduce allergic responses or to prevent recurrence of asthma exacerbations following allergen exposure. Thus, for example, an anti-c-kit antibody or an antigen-binding fragment thereof can be administered to a subject before or after exposure to an allergen.

[0102] The compositions and methods disclosed herein can be used preventively to inhibit or prevent the development of mast cell-related diseases or conditions, and they can be used therapeutically to treat mast cell-related diseases or conditions. In certain embodiments, subjects exposed to allergens can be treated according to the disclosed methods to prevent, inhibit, or reduce allergic responses to the allergens.

[0103] While mast cell-related diseases and conditions include those in which mast cells themselves are diseased or pathological, they also include those that lead to mast cell activation and / or the release of cytokines, which in some cases can result in inflammation and other problems. In some embodiments, the compositions and methods disclosed herein are used to treat inflammatory or inflammatory diseases and conditions. In some embodiments, the compositions and methods disclosed herein are used to treat diseases and conditions associated with innate and / or acquired immune responses, including but not limited to autoimmune diseases such as autoimmune psoriasis.

[0104] Mast cell-related diseases and conditions include both IgE-mediated and IgE-independent mast cell-related diseases and conditions. In some embodiments, both IgE-mediated and IgE-independent mast cell-related diseases and conditions can lead to anaphylactic-like reactions and / or anaphylactic reactions. Non-limiting examples of IgE-mediated mast cell-related diseases and conditions include anaphylaxis, such as passive anaphylaxis, systemic anaphylaxis, passive generalized anaphylaxis, and anaphylactic 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 conditions can also lead to anaphylactic inflammation and tissue remodeling in asthma. Non-limiting examples of IgE-independent mast cell-related diseases and conditions include anaphylaxis (e.g., severe anaphylaxis) and C48 / 80-mediated anaphylactic-like reactions. Anaphylactic shock-like shock is a fatal hypersensitivity response caused by non-IgE-mediated mast cell activation.

[0105] Mast cells and / or their secretory products are involved in the pathogenesis of a variety of diseases and conditions. Examples of mast cell-related diseases and conditions include mast cell activation-related diseases (MCAD), a heterogeneous group of symptoms that may be associated with an increased number of mast cells and / or mast cell hyperactivity. The severity of these conditions can vary, but common symptoms often include a severe reaction to insect bites, and in rare cases, a severe reaction to food or drugs. MCAD includes clonal (e.g., mastocytosis) and nonclonal (idiopathic) variants. Clonal MC diseases (CMD) can be caused by intrinsic MC defects (such as... KITCharacterized by the expression of mutated D816V and / or aberrant MC receptors, this can lead to an "overactive" state of MCs, resulting in the excessive release of mediators. Non-limiting examples of mast cell activation disorders include allergic disorders, mastocytosis such as intestinal mastocytosis, such as post-helmintic intestinal mastocytosis, allergies, mast cell activation syndrome (MCAS), primary MCAS, secondary MCAS, mixed MCAS, and idiopathic MCAS. See, for example, Gulen et al., *Immunology and Allergy Clinics*, Vol. 42, No. 1, pp. 45-63, February 2022.

[0106] Mast cells play a vital role in many diseases and conditions, including but not limited to skin diseases, respiratory diseases and conditions, gastrointestinal diseases and conditions, and many other diseases and conditions. The methods disclosed herein can be used to treat any of these diseases or conditions. Non-limiting examples of mast cell-mediated diseases or conditions include urticaria, asthma, nodular prurigo (PN), eosinophilic esophagitis (EoE), mastocytosis, pigmented urticaria, allergies, endometriosis, interstitial cystitis, and mast cell activation syndrome (MCAS). In specific instances, mast cell-mediated diseases or conditions are chronic urticaria, such as chronic spontaneous urticaria (CSU) or chronic induced urticaria (CindU). Specific examples of skin diseases and conditions that can be treated according to the methods disclosed herein include, but are not limited to: urticaria (e.g., chronic spontaneous urticaria (CSU) and chronic induced urticaria (CIndU)), dermatitis (e.g., allergic contact dermatitis and atopic dermatitis), alopecia (e.g., alopecia areata), bullous pemphigoid, nodular prurigo, psoriasis, and rosacea. Specific examples of respiratory diseases and conditions that can 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 obstructive pulmonary disease (COPD), sinusitis (e.g., chronic sinusitis with nasal polyps (CRSwNP)), and pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis). Specific examples of gastrointestinal diseases and conditions that can be treated according to the methods disclosed herein include, but are not limited to: eosinophilic esophagitis (EoE), food allergies, oral immunotherapy, inflammatory bowel disease (IBD) (e.g., Crohn's disease and ulcerative colitis), and irritable bowel syndrome (IBS). Specific examples of other diseases and conditions that can 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, herpetic dermatitis, graft-versus-host disease (e.g., chronic graft-versus-host disease), cystitis, endometriosis, fibromyalgia, hereditary alpha-trypsinemia (HaT), allergies (e.g., idiopathic allergy), 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 cell crisis).

[0107] Mast cells are key cellular targets for a variety of inflammatory or autoimmune diseases (including, but not limited to, urticaria, chronic urticaria, chronic spontaneous urticaria (CSU), chronic induced urticaria (CIndU), nodular prurigo, eosinophilic esophagitis, asthma such as allergic asthma, inflammatory bowel disease, fibrosis, scleroderma, and systemic sclerosis) that can be treated with the compositions and methods disclosed herein.

[0108] In some embodiments, the compositions and methods disclosed herein are used to treat inflammatory or inflammatory diseases and conditions. In some embodiments, the compositions and methods disclosed herein are used to treat diseases and conditions associated with innate and / or acquired immune responses, including but not limited to autoimmune diseases such as autoimmune psoriasis.

[0109] In certain embodiments, subjects exposed to allergens may be treated according to the disclosed methods to prevent, suppress, or reduce allergic responses to the allergens.

[0110] Chronic urticaria Chronic urticaria is a skin condition characterized by the presence of hives or streaks that persist for more than six weeks. The condition can be caused by a variety of factors, including autoimmune diseases, infections, medications, and physical stimuli such as heat, cold, or stress. Chronic urticaria has multiple causes, such as infection, stress, or autoimmune diseases. However, in many cases, the cause is unclear. These cases are called chronic idiopathic urticaria (CIU) or chronic spontaneous urticaria (CSU). Chronic urticaria is currently treated with medication to reduce itching and alleviate discomfort. There are also methods for preventing and improving symptoms at home, such as applying cold compresses to the affected skin. Stress management can help with treatment, as increased stress can worsen urticaria. Long-term urticaria can also cause further stress, leading to mental health challenges such as anxiety and depression. While current treatment options include antihistamines, corticosteroids, and immunosuppressants, they target symptoms rather than the underlying disease. Therefore, improved treatment methods are needed.

[0111] Chronic spontaneous urticaria (CSU) affects approximately 1% of the world's population of all ages. It primarily affects young to middle-aged adults (with onset typically between 30 and 50 years of age) and is more common in women than men (Goncalo et al. 2021). CSU is defined as the presentation of pruritic wheals (urticaria) and / or angioedema lasting longer than six weeks without an identifiable specific trigger. The elevated lesions are accompanied by redness and intense, persistent itching, which directly impacts many aspects of a patient's quality of life. In many participants, CSU has a long duration, averaging 5 to 7 years (Kolkhir et al. 2022). These manifestations have a strong impact on health-related quality of life, including sleep disturbances, decreased physical and emotional health, and poor performance at school or work.

[0112] CSU is associated with significant healthcare utilization and financial burden, including regular and unexpected healthcare visits, costs incurred due to laboratory fees, and indirect costs due to absence or reduced efficiency. Characteristically, the more severe the disease, the greater the impact on quality of life (Armstrong 2023, Maurer 2017, Vietri 2015). In a recent trial characterizing the HRQoL burden in CSU patients, despite treatment (UAS7 ≥ 16), aspects significantly affecting HRQoL in severely ill patients included declining physical health (approximately 70% experienced pain / discomfort), declining mood health (approximately 55% experienced anxiety / depression), sleep disturbances (approximately 50% of patients), and poor work performance (approximately 20% of patients were absent from work for at least 1 hour in the past 7 days due to CSU symptoms) (Maurer 2017).

[0113] Although the etiology of CSU is not fully understood, several molecular mechanisms leading to mast cell activation have been described to date. Activation and degranulation of skin mast cells, as well as the release of histamine or other mediators (e.g., trypsin inhibitors, TNF, various interleukins), are key drivers of symptom development.

[0114] Current standard treatment for CSU includes oral H1 antihistamines and second- and third-line therapies, namely omalizumab and cyclosporine, respectively (Metz et al. 2021; Kolkhir et al. 2022; Zuberbier et al. 2022). However, despite doses higher than FDA-approved levels, approximately 40–50% of patients still experience uncontrolled symptoms (Maurer 2017, Guillén-Aguinaga 2016), and over 25% of cases exhibit antihistamine resistance, even at higher doses. Omalizumab, an anti-IgE antibody, is approved as a treatment for CSU in participants refractory to antihistamines and can be used as adjunctive therapy to antihistamines. However, less than 50% of patients achieve complete symptom resolution (Maurer 2013, Saini 2015). In addition to incomplete symptom control, omalizumab has a boxed warning for allergies, indicating that some patients are ineligible (Xolair Prescribing Information 2023). The risk of allergic reactions to omalizumab is no different from that of other FDA-approved biologics for skin conditions, including dupilumab for atopic dermatitis, which carries a hypersensitivity warning (Dupixent Prescribing Information 2022). In summary, a significant number of patients with moderate to severe CSU remain symptomatic or are intolerant to omalizumab. Therefore, further development of novel therapies is strongly recommended.

[0115] In some embodiments, the methods disclosed herein are used to treat patients with CSU, such as patients who are symptomatic despite treatment with antihistamines or who cannot tolerate antihistamines. In a particular embodiment, the antihistamine is an H1 antihistamine. In some embodiments, the methods disclosed herein are used to treat patients with CSU, such as patients who are symptomatic despite treatment with omalizumab or who cannot tolerate omalizumab (Xolair®). In some embodiments, the methods disclosed herein are used to treat patients with CSU who have not used Xolair® and / or whose Xolair® treatment has failed.

[0116] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing CSU in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit IgG antibody or a fragment thereof, such as JSP191 or JSP191 (Fab')2, wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2). In some embodiments, the patient has previously responded poorly to or is intolerant of H1 antihistamines and / or omalizumab, and in some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every ten weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. Optionally, the subject is administered one or more doses (e.g., a single dose) of approximately 1 mg / kg body weight to approximately 4 mg / kg body weight (e.g., approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, or approximately 4 mg / kg). In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally. In some embodiments, the antibody is administered subcutaneously.

[0117] In one embodiment of treating, inhibiting, or preventing CSU, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg. The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In certain embodiments, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks. In some embodiments, despite treatment with H1-antihistamines and / or omalizumab, the human subject remains symptomatic or cannot tolerate omalizumab.

[0118] In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0119] In a particular embodiment, the anti-c-Kit antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2) is administered as one or more doses of about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight or about 0.5 mg / kg to about 2.0 mg / kg (e.g., about 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 40 mg to about 200 mg, such as about 80 mg, about 90 mg / kg, about 100 mg, about 110 mg, or about 120 mg). In a particular embodiment, the anti-c-Kit antibody (e.g., JSP191) or a fragment thereof (e.g., JSP191 (Fab')2) is administered in one or more doses, such as about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In certain embodiments, the anti-c-Kit antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2) is administered subcutaneously.

[0120] Chronic induced urticaria (CIndU) Chronic induced urticaria (CIndU) is a subtype of urticaria characterized by recurrent symptoms (pruritic wheals and / or angioedema) lasting more than six weeks. Similar to CSU, CIndU is characterized by the presence of urticaria and / or angioedema and skin redness. Unlike CSU, triggering factors for CIndU can be diagnosed through evaluation of various common stimuli (such as cold, heat, pressure, vibration, etc.). The two most common forms of CIndU are symptomatic dermatographia (SD) and cold contact urticaria (ColdU). CIndU is believed to affect more than one million patients in the United States, France, Germany, Italy, Spain, and the United Kingdom. Approximately 40% of these patients with CIndU are not controlled by first-line antihistamines, and these patients may be eligible for biologic therapy depending on the severity of their disease.

[0121] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing CIndU in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), for example, wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0122] In some embodiments, a single dose is administered to the subject. In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0123] In some embodiments, the subject suffered from cold urticaria and / or symptomatic dermatographia.

[0124] In one embodiment of treating, inhibiting, or preventing CIndU, a dose of JSP191 is administered subcutaneously to a human subject (e.g., an adult), wherein said dose is about 40 mg to about 500 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 60 mg to about 500 mg, about 60 mg to about 400 mg, about 60 mg to about 300 mg, about 60 mg to about 200 mg, about 80 mg to about 500 mg, about 80 mg to about 400 mg, about 80 mg to about 300 mg, about 80 mg to about 200 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 120 mg. The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg of JSP191. In certain embodiments, the subject is administered at least or approximately 80 mg, at least or approximately 100 mg, at least or approximately 120 mg, at least or approximately 160 mg, at least or approximately 180 mg, at least or approximately 200 mg, or at least or approximately 240 mg of JSP191. In certain embodiments, the subject is diagnosed with CIndU, such as ColdU or SD, despite the use of an H1 antihistamine.

[0125] In one embodiment of treating, inhibiting, or preventing CIndU, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg. The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0126] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered in one or more doses, such as about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg to about 150 mg, about 40 mg to about 200 mg, such as about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg. In certain embodiments, the anti-c-Kit antibody, such as JSP191, is administered subcutaneously.

[0127] nodular prurigo Nodular prurigo is also a skin condition. Patients experience severe itching and hard lumps (called nodules) on the skin, which can lead to insomnia and bleeding from scratching. Degranulation of mast cells in the skin is thought to trigger peripheral sensory neurons in the skin, causing the itching. Various medications are used to treat nodular prurigo, including antipruritic creams and topical steroids. For cases that remain uncontrolled, doctors may prescribe antihistamines or biologics, such as dupilumab. PN is also known as Heide's nodular prurigo, Picker's nodules, atypical nodular localized neurodermatitis, or keratotic lichen planus.

[0128] The etiology of nodular prurigo is unclear, although other conditions may also induce PN. PN is associated with Becker's nevus, linear IgA disease, autoimmune diseases, liver disease, and T-cell disorders. Generalized prurigo is associated with cholestasis, thyroid disease, polycythemia vera, uremia, Hodgkin's disease, HIV, and other immunodeficiency diseases. Internal malignancies, liver failure, kidney failure, and mental illness are thought to induce PN, although recent studies have ruled out a psychotic cause for PN. Patients report an ongoing effort to distinguish themselves from patients with psychotic conditions such as parasitic delusions and other psychotic symptoms.

[0129] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing nodular prurigo in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0130] In some embodiments, a single dose is administered to the subject. In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0131] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, about 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg to about 150 mg, about 40 mg to about 200 mg, such as about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0132] In some embodiments, a single dose is administered to the subject. In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0133] In one embodiment of treating, inhibiting, or preventing PN, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 2 ... The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0134] eosinophilic esophagitis Eosinophilic esophagitis (EoE) is an autoimmune disorder that causes the accumulation of eosinophils in the esophagus, leading to difficulty eating, chronic reflux, and / or heartburn. Along with the accumulation of eosinophils, other immune cells, including mast cells, basophils, and lymphocytes, often accumulate in the affected areas. In healthy individuals, the esophagus typically lacks eosinophils. In EoE, eosinophils migrate extensively into the esophagus. When triggered by certain foods, these eosinophils cause tissue damage and inflammation. Symptoms include dysphagia, food impaction, vomiting, and heartburn. Treatment options include dietary changes, the use of proton pump inhibitors, antihistamines, and dupilumab.

[0135] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing eosinophilic esophagitis in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), or about 30 mg to about 150 mg, about 40 mg to about 200 mg, such as about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg, optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, or about 5 mg / kg. A single dose of approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0136] In some embodiments, a single dose is administered to the subject. In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0137] In one embodiment of treating, inhibiting, or preventing EoE, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 2 ... The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0138] asthma Asthma is a chronic inflammatory disease of the lungs characterized by recurrent, variable, reversible bronchospasm that is easily triggered by airflow obstruction. Symptoms include wheezing, coughing, chest tightness, and shortness of breath. These may occur several times a day or several times a week. Asthma symptoms may worsen at night or during exercise, varying from person to person. Asthma is believed 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 typically based on symptom patterns, response to therapy over time, and pulmonary function tests including vital capacity measurement. Asthma is classified according to symptom frequency, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. It can also be classified as atopic or non-atopic, with atopic referring to a predisposition to type 1 hypersensitivity reactions.

[0139] The methods and compositions disclosed herein can be used to treat asthma. Mast cells are distributed in multiple compartments of the lungs. Mast cells release / activate various mediators that drive the pathophysiology of asthma. The early stages of asthma are driven by mast cell degranulation (and the release of histamine, prostaglandins, leukotrienes, IL-5, IL-13, IL-4, and CXCR2), and may also drive the late recruitment of other cell types to the lungs. Current asthma treatment strategies target specific upstream (IgE, TSLP) or downstream mediators (IL-5, IL-4 / IL-13), but do not broadly inhibit mast cells. The methods and compositions disclosed herein can be used to treat asthma, and in certain embodiments, for example, to induce mast cell apoptosis, inhibit the release of mediators driving the pathophysiology of asthma, and / or inhibit the recruitment of other cell types to the lungs.

[0140] In some embodiments, this disclosure provides a method for treating, suppressing, or preventing asthma or allergic reactions in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2), wherein each dose comprises about 0.2 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 2.0 mg / kg, about 0.8 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, or about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 200 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2) or about 30 mg to about 150 mg, about 40 mg to about 200 mg, such as about 60 mg, about 70 mg, about 80 mg, etc. mg, about 90 mg or about 100 mg, optionally wherein the subject is given a single dose of about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg or about 2 mg / kg to about 4 mg / kg, such as about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg or about 5 mg / kg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every ten weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0141] In some embodiments, a single dose is administered to the subject. In some embodiments, a single dose of an anti-c-kit antibody or its antigen-binding fragment, such as JSP191 or JSP191 (Fab')2, is administered to the subject, wherein the dose is any dose disclosed herein, including doses disclosed for treatment regimens comprising administering two or more doses.

[0142] In some embodiments of suppressing or preventing allergic reactions or asthma, an anti-c-kit antibody or its antigen-binding fragment is administered to the subject prior to initial or subsequent contact with or exposure to the allergen, for example, to prevent a recurrence of asthma exacerbation after exposure to the allergen.

[0143] In certain embodiments, the anti-c-Kit antibody or a fragment thereof (e.g., JSP191) is administered in one or more doses from about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, or from about 0.5 mg / kg to about 2.0 mg / kg (e.g., about 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 40 mg to about 200 mg, such as about 80 mg, about 90 mg / kg, about 100 mg, about 110 mg, or about 120 mg). In certain embodiments, the anti-c-Kit antibody or a fragment thereof, such as JSP191, is administered subcutaneously.

[0144] In one embodiment of treating, suppressing, or preventing asthma or allergic reactions, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg. The doses are approximately 1 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is about six weeks to about six months, about eight weeks to about six months, about eight weeks to about four months, about twelve weeks to about six months, about twelve weeks to about four months, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about four months, or about six months, optionally with different time intervals between each dose. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0145] In some embodiments, the methods and compositions disclosed herein are used to treat, suppress, or prevent severe asthma, including severe asthma unrelated to type 2 inflammation. Patients with severe asthma have significantly elevated levels of trypsin in their bronchoalveolar lavage fluid (BAL) and plasma compared to healthy subjects or subjects with mild or moderate asthma. For example, normalized BAL trypsin levels can be greater than about 100 pg / mL or greater than about 125 pg / mL, and plasma trypsin levels can be greater than about 2000 pg / mL or greater than or about 4000 pg / mL. This elevation of trypsin in severe asthma is unrelated to type 2 inflammation. In specific embodiments, the methods and compositions disclosed herein are used to treat severe, refractory asthma. They can be used to treat severe asthma with or without type 2 inflammation.

[0146] Allergic asthma (e.g., allergen-induced allergic asthma) is a form of asthma triggered by specific allergens, leading to airway smooth muscle contraction, cellular infiltration of various immune mediators, and excessive mucus production. Allergic asthma may be associated with inflammation and tissue remodeling. Patients with allergic asthma may have an increased number of mast cells in their bronchi and may be responsive to agents that modulate mast cell responses, including antihistamines and anti-IgE monoclonal antibody therapy.

[0147] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing an allergic reaction (e.g., allergic asthma) in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of mg / kg, such as about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally. In some embodiments, a single dose is administered to the subject. In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.67 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg.In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every ten weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0148] In specific embodiments, the methods and compositions disclosed herein are used to treat, suppress, or prevent any type of asthma, including asthma in patients who are not suited to or remain refractory to current biologics. In specific 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 treatments, such as refractory asthma that does not respond adequately to inhaled corticosteroids (ICS), long-acting β2-agonists (LABA), and / or long-acting muscarinic antagonists (LAMA). Severe asthma is a potentially life-threatening inflammatory disease characterized by persistent asthma symptoms despite the 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 for 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). Currently, approximately 300,000 patients in the United States and the European Union are receiving biotherapy. The choice of biotherapy for severe asthma is based on disease biomarkers. Severe asthma can be classified into two categories: Type 2 High and Type 2 Low. Type 2 High includes the following intra-asthmatic types: eosinophilic asthma only, eosinophilic and allergic asthma, and allergic asthma only (2022 GINA Thematic Report Global Asthma Initiative - GINA). Biomarkers for type 2 severe asthma include high levels of FeNO in the airways, high serum IgE, high serum periostrin, high IFN-γ levels, and high blood / sputum eosinophil counts. Biomarkers for type 2 low-severe asthma include neutrophil accumulation in the airways, low blood / sputum eosinophil counts, high TNF-α levels in the BAL (basal albumin), and high YKL-40 levels in the blood. In some embodiments, patients with type 2 low-severe asthma have a peripheral blood eosinophil count <300 / µL. Patients with type 2 allergic simple asthma or type 2 low-severe asthma have limited treatment options compared to patients with eosinophilic disease. For example, patients with type 2 high eosinophilic simple asthma can be treated with a variety of FDA-approved therapies, including drugs and targets such as Nucala® (mepolizumab; IL5), Cinqair® (relizumab; IL5), Fasenra® (benazolizumab; IL5), Dupixent® (dupixumab; IL4 / IL13), and Tezspire® (teseruzumab; TSLP).Patients with type 2 allergic simple asthma can be treated with FDA-approved Xolair® (omalizumab; IgE) or Tezspire® (teseruzumab; TSLP), and patients with type 2 low-grade asthma can be treated with Tezspire® (TSLP). In some embodiments, the methods and compositions disclosed herein can be used to treat any moderate to severe or severe asthma, such as type 2 high-severe asthma and type 2 low-severe asthma, including any form or type, such as type 2 high-severe allergic simple asthma or type 2 low-grade asthma only. In certain embodiments, the treatment is administered subcutaneously.

[0149] Allergies Allergic reactions are acute, severe, systemic hypersensitivity reactions and represent instances of excessive activation of the MC (metastatic mediator) leading to the release of multiple mediators. Allergic reactions can affect multiple organ systems and manifest as a range of symptoms. In some embodiments, an allergic reaction involves the simultaneous occurrence of at least two organ systems, including the skin, gastrointestinal (GI), respiratory, and / or cardiovascular systems. Allergic reactions encompass a heterogeneous set of symptoms related to the nature and route of exposure to the triggering factor, organ involvement, severity, and time course. Allergic reactions have a variety of causes. For example, food-induced systemic reactions are a leading cause of allergic reactions in children, while venom or drug-induced reactions are the cause of most adult cases. From this perspective, severe anaphylaxis (SA) is a unique phenotype of allergic reaction that may involve hypotension and / or loss of consciousness. In certain embodiments, the methods disclosed herein can be used to treat any type of allergic reaction, such as IgE-mediated allergic reactions and non-IgE allergic reactions. Many drugs have been shown to cause IgE-mediated allergies, including, for example, antihistamines, chemotherapy agents, disease-modifying antirheumatic drugs (DMARDs), antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, radioactive contrast agents, intraoperative medications, monoclonal antibodies, and other drugs such as human IgG, lisinopril, morphine, and ondansetron. Examples of drugs involved in non-IgE allergies include, for example, fluoroquinolones, opioids (such as morphine and sufentanil), radioactive contrast agents, atracurium, paclitaxel, and vancomycin. Many opioids (e.g., morphine) are potent histamine releasers, producing a variety of hemodynamic changes and allergy-like reactions. The methods disclosed herein can be used to treat opioid-mediated or opioid receptor-mediated allergies.

[0150] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing allergic or anaphylactic reactions in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0151] In some embodiments, a single dose is administered to the subject.

[0152] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0153] In one embodiment of treating, suppressing, or preventing allergies, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg. The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0154] mastocytosis Mastocytosis is a mast cell disorder, a rare condition affecting children and adults, caused by the accumulation of dysfunctional mast cells (also known as mast cells) and CD34+ mast cell precursors. People affected by mastocytosis are prone to a variety of symptoms caused by the release of histamine and other pro-inflammatory substances from mast cells, including itching, urticaria, and anaphylactic shock. Mastocytosis is characterized by the excessive accumulation, proliferation, and activation of abnormal mast cells in several organs, including the skin, bone marrow, and GI tracts. Mastocytosis includes cutaneous mastocytosis (CM) and generalized mastocytosis (SM) involving at least one extracutaneous organ. SM includes indolent SM (ISM) and more aggressive variants. Mastocytosis also includes intestinal mastocytosis, such as post-worm intestinal mastocytosis.

[0155] Pigmented urticaria, also known as generalized eruption (childhood type) of cutaneous mastocytosis, is the most common form of cutaneous mastocytosis. It is a rare condition caused by an excess of mast cells in the skin, which, when stimulated, produce hives or lesions on the skin. Pigmented urticaria is characterized by an overabundance of mast cells in the skin. Red or brown spots often appear on the skin, typically on the chest, forehead, and back. These mast cells produce excess histamine when stimulated (e.g., by rubbing the skin, heat exposure), triggering an allergic reaction that results in hives in the irritated area, sometimes called Darier's sign. Severe itching usually accompanies the condition, and scratching the affected area only worsens the symptoms. Symptoms can be mild (untreated flushing and hives), moderate (diarrhea, tachycardia, nausea / vomiting, headache, and fainting), or life-threatening (vascular collapse requiring emergency treatment and hospitalization).

[0156] Most cases of pigmented urticaria are caused by a point mutation at amino acid 816 of the proto-oncogene c-Kit. Mutations at position 816 in c-Kit can lead to the transmission of constant division signals to mast cells, resulting in abnormal proliferation. Different mutations are associated with different onset times of the disease. For example, the Asp8 l 6Phe and Asp816Val mutations (typically where the aspartic acid at position 816 in the c-kit protein is replaced by phenylalanine or valine, respectively) are associated with earlier manifestations of the disease.

[0157] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing mastocytosis (e.g., pigmented urticaria) in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg. From mg / kg to about 4 mg / kg, for example, a single dose of about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0158] In some embodiments, a single dose is administered to the subject.

[0159] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0160] In one embodiment of treating, inhibiting, or preventing mastocytosis, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg. The doses are approximately 1 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is about six weeks to about six months, about eight weeks to about six months, about eight weeks to about four months, about twelve weeks to about six months, about twelve weeks to about four months, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about four months, or about six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0161] mast cell activation syndrome MC activation syndrome (MCAS) is a condition caused by various etiologies that leads to severe, recurrent, and sporadic symptoms due to the systemic release of MC mediators. Patients with MCAS frequently experience symptoms of allergies. However, not all allergies meet the diagnostic criteria for MCAS, nor do all MCAS events reach the severity of an allergic reaction. MC activation can manifest as less severe and / or chronic symptoms.

[0162] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing MCAS in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0163] In some embodiments, a single dose is administered to the subject.

[0164] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0165] In one embodiment of treating, inhibiting, or preventing MCAS, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg. The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0166] fibrosis The methods disclosed herein can be used to treat fibrotic diseases and conditions. As used herein, the term "fibrotic disease or condition" refers to a condition involving fibrosis in one or more tissues. As used herein, the term "fibrosis" refers to the abnormal formation or development of excessive fibrous connective tissue in an organ or tissue as a reactive process, compared to the formation of fibrous tissue as a normal component or healing process of an organ or tissue. Fibrosis is characterized by the accumulation of fibroblasts and collagen deposition exceeding normal deposition in any given tissue. As used herein, the term "fibrosis" includes abnormal healing involving mesenchymal-fibroblast transformation, excessive fibroblast proliferation, and the activity and deposition of collagen and other extracellular matrix proteins. The compositions and methods disclosed herein can also be used to treat atherosclerosis. Vascular fibrosis, characterized by reduced luminal diameter and thickening of the arterial wall due to excessive deposition of the extracellular matrix (ECM), is associated with many clinical diseases and pathological processes, including atherosclerosis.

[0167] Mast cell numbers and mast cell mediators are significantly elevated in most human fibrotic diseases, including but not limited to idiopathic pulmonary fibrosis (IPF) and scleroderma. Differential mast cell phenotypes have been detected in some scleroderma patients and Tsk mouse models of scleroderma. The aggressive, systemic form of mastocytosis can be characterized by myelofibrosis, suggesting that mast cells may be effector cells in fibrosis.

[0168] 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, perimuscular fibrosis, Simmons fibrosis, pericentral fibrosis, hepatitis, dermatofibroma, biliary cirrhosis, alcoholic cirrhosis, acute pulmonary fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, renal fibrosis / glomerulonephritis, renal fibrosis / diabetic nephropathy, scleroderma / systemic, scleroderma / localized, keloid, proliferative scar, severe joint adhesions / arthritis, myelofibrosis, corneal scarring, cystic fibrosis, muscular dystrophy (Duchenne's disease), cardiac fibrosis, muscle fibrosis / retinal detachment, esophageal stricture, and Payronles' disease. Other fibrotic conditions can be induced or triggered by surgery, including scar revision / plastic surgery, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft-versus-host disease, tendon surgery, nerve entrapment, Dupuytren contracture, OB / GYN adhesions / fibrosis, pelvic adhesions, epidural fibrosis, and restenosis. It is also contemplated that fibrotic conditions in which fibronectin deposition is a causative factor can be treated according to the invention. Idiopathic pulmonary fibrosis, bleomycin-induced lung, cystic fibrosis, and glomerulonephropathy, including diseases characterized by Fn deposition in the kidneys and ultimately leading to renal failure, are examples of conditions that can also be treated according to the invention. Inflammation involving immune system activation in which mast cells secrete inflammatory cytokines such as TNF and can activate and directly interact with lymphocytes can also be treated according to the invention.

[0169] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing fibrosis or fibrotic diseases or conditions in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0170] In some embodiments, a single dose is administered to the subject.

[0171] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0172] In one embodiment of treating, inhibiting, or preventing fibrosis or fibrotic diseases, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg. The doses are approximately 1 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is about six weeks to about six months, about eight weeks to about six months, about eight weeks to about four months, about twelve weeks to about six months, about twelve weeks to about four months, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about four months, or about six months, optionally with different time intervals between each dose. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0173] Allergic diseases and conditions 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), one of whose activities is to induce mast cell apoptosis. Other mast cell-related diseases include, for example, histamine-mediated anaphylactic reactions, which can be treated by inhibiting chemokine-induced mast cell and basophil degranulation and histamine release. Further examples of mast cell-related conditions or diseases that can be effectively treated with the methods and compositions of this invention include, but are not limited to, contact dermatitis, atopic dermatitis, allergic dermatitis (e.g., allergen-induced atopic dermatitis), allergic asthma, eczematous dermatitis, dermatitis caused by insect bites or stings, and allergic diarrhea.

[0174] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing an allergic disease or condition in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0175] In some embodiments, a single dose is administered to the subject.

[0176] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0177] In one embodiment of treating, inhibiting, or preventing allergies or allergic diseases, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg. The doses are approximately 1 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is about six weeks to about six months, about eight weeks to about six months, about eight weeks to about four months, about twelve weeks to about six months, about twelve weeks to about four months, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about four months, or about six months, optionally with different time intervals between each dose. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0178] In some embodiments of suppressing or preventing allergic reactions, an anti-c-kit antibody or its antigen-binding fragment is administered to the subject prior to initial or subsequent contact with or exposure to the allergen, for example, to prevent an allergic reaction to allergen exposure.

[0179] Inflammatory bowel disease (IBD) 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 and ulcerative colitis. Crohn's disease can affect any part of the digestive tract; however, it most commonly affects the beginnings of the small intestine and large intestine (colon). Inflammation in Crohn's disease is characterized by transmural involvement, meaning it affects all layers of the intestinal wall, potentially leading to ulcers, strictures, and fistula formation. In contrast, ulcerative colitis primarily affects the colon and rectum. Inflammation in ulcerative colitis is usually confined to the inner lining of the colon, called the mucosa. It typically begins in the rectum and can spread to affect different parts of the colon. Both Crohn's disease and ulcerative colitis are thought to be caused by an inappropriate immune response in genetically susceptible individuals.

[0180] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing IBD in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0181] In some embodiments, a single dose is administered to the subject.

[0182] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0183] In one embodiment of treating, inhibiting, or preventing IBD, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 120 mg to approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 2 ... The doses are approximately 500 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately six weeks to approximately six months, approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0184] Other mast cell-mediated diseases and conditions Other mast cell-related indications suitable for treatment by the methods and compositions of the present invention include pulmonary inflammatory conditions in interstitial lung diseases, such as sarcoidosis, neonatal respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and conditions characterized by elevated serum PLA2 activity, such as adult RDS (ARDS). Others include arthritis (including both osteoarthritis and rheumatoid arthritis), allergies, endometriosis, interstitial cystitis (IC), septic shock, pancreatitis, collagen vascular disease, acute renal failure, peritonitis, and autoimmune uveitis. Studies have also shown that mast cells are involved in the pathophysiology of multiple sclerosis. Therefore, the methods and compositions of the present invention are expected to be suitable for treating or improving the morbidity associated with multiple sclerosis.

[0185] Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease characterized by a progressive and irreversible decline in lung function caused by airway obstruction and parenchymal damage. Three pathological conditions, including chronic bronchitis, small airway disease, and emphysema, exist alone or in combination, ultimately leading to COPD. Chronic inflammation is a hallmark of COPD, involving the interaction of multiple cells within the lung microenvironment. Macrophages, neutrophils, dendritic cells, and CD8+ T lymphocytes are generally considered key inflammatory cells involved in COPD. However, it has been reported that macrophages (MCs) play a more significant role in COPD by affecting alveolar parenchyma and airway smooth muscle. TC The density of mast cells in this subtype is increased. Therefore, the method disclosed in this article can be used to treat COPD. It can also be used to treat other mixed inflammatory or allergic airway inflammation conditions.

[0186] An allergic reaction is a serious, potentially fatal anaphylactic reaction and medical emergency that develops rapidly and requires immediate medical attention, regardless of whether emergency medications are administered on-site. It typically causes more than one of the following symptoms: pruritus, swelling that causes the throat to close, potentially obstructing or stopping breathing; severe swelling of the tongue that can also interfere with or stop breathing; shortness of breath, vomiting, dizziness, loss of consciousness, low blood pressure, and medical shock. Common causes include allergies to insect bites and stings, food, sulfites, medications, general anesthetics, contrast agents, or latex. The mechanism involves the release of inflammatory mediators by certain types of white blood cells in a rapidly escalating cascade, triggered by immunological or non-immunological mechanisms.

[0187] Endometriosis is a female reproductive system disorder in which cells that normally line the uterus grow outside the uterus. Lesions can be found in the ovaries, fallopian tubes, the peritoneum surrounding the uterus and ovaries, the intestines, bladder, and diaphragm; they can also occur in other parts of the body. Symptoms include pelvic pain, heaviness and pain during menstruation, painful bowel movements, painful urination, painful intercourse, and infertility. Clinical data demonstrate that mast cells disproportionately infiltrate endometriotic lesions, suggesting that mast cells are a key driver of symptoms, including chronic pain.

[0188] Interstitial cystitis (IC) is a type of bladder pain syndrome (BPS), characterized by chronic pain in the bladder and pelvic floor. Symptoms include a feeling of needing to urinate immediately, frequent urination, and painful intercourse. The etiology of IC / BPS is not fully understood. Evidence from clinical and laboratory studies suggests that mast cells play an important role in IC / BPS, likely due to their ability to release histamine and cause pain, swelling, scarring, and impaired healing.

[0189] These and other mast cell-related diseases and conditions can be treated with the medications and dosing regimens disclosed in this article.

[0190] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing any mast cell-related disease or condition in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg. A single dose of approximately 0.3 mg / kg, such as approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 1 mg / kg, approximately 1.5 mg / kg, approximately 2 mg / kg, approximately 2.5 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4 mg / kg, approximately 4.5 mg / kg, or approximately 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally.

[0191] In some embodiments, a single dose is administered to the subject.

[0192] In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191(Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0193] In one embodiment of treating, inhibiting, or preventing mast cell-related diseases or conditions, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg. The doses are approximately 1 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least six weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is about six weeks to about six months, about eight weeks to about six months, about eight weeks to about four months, about twelve weeks to about six months, about twelve weeks to about four months, about 8 weeks, about 9 weeks, about 10 weeks, about 12 weeks, about four months, or about six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 40 mg, at least or about 60 mg, at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0194] Dosage and administration According to specific embodiments related to the treatment of mast cell-related diseases or conditions, the anti-c-kit antibody treatment described herein can be administered using a dosing regimen, for example, by depleting mast cells through apoptosis. Any dosing regimen disclosed herein or described herein for another mast cell-related disease can be used for other mast cell-related diseases and conditions.

[0195] In some embodiments, anti-c-kit antibodies are administered to subjects in need at doses of about 0.01 mg / kg to about 20 mg / kg.

[0196] In certain embodiments, a single high dose of anti-c-Kit antibody (e.g., JSP191) is administered to the subject at a dose of about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In some embodiments, the anti-c-kit antibody is any one of SR-1, JSP191, MGTA-117, FSI-174, CDX-0159, 8D7, K45, 104D2, CK6, AB249, YB5.B8, AF-2-1, AF11, AF12, AF112, AF-3, AF-1-1, NF, NF-2-1, NF11, NF12, NF112, NF-3, HF11, HF12, and HF112 administered at a dose of about 0.01 mg / kg to about 20 mg / kg of the subject's body weight.

[0197] In some embodiments, the anti-c-kit antibody (e.g., beretricilimab) is administered at doses of approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, approximately 0.4 mg / kg, approximately 0.5 mg / kg, approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately 0.9 mg / kg, approximately 1.0 mg / kg, approximately 1.1 mg / kg, approximately 1.2 mg / kg, approximately 1.3 mg / kg, approximately 1.4 mg / kg, approximately 1.5 mg / kg, approximately 1.6 mg / kg, approximately 1.7 mg / kg, approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2.0 mg / kg, approximately 2.25 mg / kg, approximately 2.5 mg / kg, approximately 2.75 mg / kg, approximately 3.0 mg / kg, approximately 3.25 mg / kg, approximately 3.5 mg / kg, approximately 3.75 mg / kg, and approximately 4.0 mg / kg. The anti-c-Kit antibody is administered at doses of approximately 0.01 mg / kg to about 20 mg / kg, approximately 0.1 mg / kg to about 10 mg / kg, approximately 0.1 mg / kg to about 5.0 mg / kg, approximately 0.1 mg / kg to about 4 mg / kg, approximately 0.5 mg / kg to about 5.0 mg / kg, approximately 0.5 mg / kg to about 4.0 mg / kg, approximately 0.5 mg / kg to about 3.0 mg / kg, or approximately 0.5 mg / kg to about 2.0 mg / kg. In specific embodiments, JSP191 is administered at any of these doses. In certain embodiments, a single high-dose anti-c-Kit antibody (e.g., JSP191) is administered to the subject at a dose of about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In certain embodiments, CDX0158 or CDX0159 is administered at any of these doses. In certain embodiments, FSI-174 is administered at any of these doses.

[0198] In some embodiments, a single dose of the anti-c-kit antibody as described herein is administered to a subject in need. In some embodiments, two or more doses of the anti-c-kit antibody are administered to a subject.

[0199] In specific embodiments of the methods disclosed herein, including, for example, consuming mast cells or treating mast cell-related diseases or conditions, administering to a subject one or more doses of about 10 mg to about 1000 mg, about 20 mg to about 1000 mg, about 20 mg to about 500 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, or about 20 mg to about 300 mg of an anti-c-kit antibody, such as JSP191. In some embodiments, the subject is administered about 25 mg to about 250 mg, about 50 mg to about 240 mg, about 100 mg to about 250 mg, about 50 mg to about 250 mg, about 100 mg to about 200 mg, about 80 mg to about 180 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 250 mg. A dose of anti-c-kit antibody, such as JSP191, of mg or about 300 mg may be administered to the subject. In some embodiments, a dose of anti-c-kit antibody, such as JSP191, of about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg may be administered to the subject.

[0200] In some embodiments, any mast cell-related disease or condition may be treated by subcutaneous administration of two or more doses of JSP-191 to a subject in need, wherein each dose comprises about 40 mg to about 360 mg of JSP-191, about 40 mg to about 240 mg of JSP-191, or about 120 mg to about 240 mg of JSP-191, such as about 40 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg, wherein each of the two or more doses of JSP-191 is administered at least eight weeks apart, such as about every eight weeks to about six months, or about every eight weeks to about four months, or about every three months to about six months, or about every eight weeks.

[0201] In some embodiments, the anti-c-kit antibody, such as JSP-191, is administered to the subject at a dosing schedule of approximately weekly, approximately every 2 weeks, approximately every 3 weeks, approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks, approximately every 7 weeks, approximately every 8 weeks, approximately every 9 weeks, approximately every 10 weeks, approximately every 11 weeks, approximately every 12 weeks, approximately every 13 weeks, approximately every 14 weeks, approximately every 15 weeks, approximately every 16 weeks, approximately every 17 weeks, approximately every 18 weeks, approximately every 19 weeks, approximately every 20 weeks, approximately once a month, approximately once every two months, approximately once every three months, approximately once every four months, approximately once every six months, or approximately once a year.

[0202] In some embodiments, the subject is administered two or more doses of an anti-c-kit antibody, such as JSP191, wherein each dose is about 20 mg to about 300 mg of anti-c-kit antibody, or about 50 mg to about 300 mg of anti-c-kit antibody, or about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg of anti-c-kit antibody. In some embodiments, one of two or more doses is administered every two weeks to six months, every four weeks to four months, every two weeks to 16 weeks, every four weeks to 12 weeks, every six weeks to ten weeks, every seven weeks to nine weeks, about every four weeks, about every five weeks, about every six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, about twelve weeks, about 16 weeks, about four months, about six months, or about one year, optionally wherein the time interval between each dose is different. In some embodiments, each dose of anti-c-kit antibody (e.g., JSP191) is about 35 mg to about 240 mg, about 35 mg to about 180 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240 mg of anti-c-kit antibody, such as JSP191. In some embodiments, a dose of anti-c-kit antibody, such as JSP191, of about 35 mg, about 80 mg, about 100 mg, about 180 mg, or about 240 mg is administered to the subject. In some embodiments, a dose of anti-c-kit antibody, such as JSP191, of about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg is administered to the subject about every eight weeks.

[0203] In some embodiments, the subject is administered two or more doses of an anti-c-kit antibody, such as JSP191. In some embodiments, one of two or more doses is administered every two to 16 weeks, every four to 12 weeks, every six to 10 weeks, every seven to nine weeks, approximately every four weeks, approximately every five weeks, approximately every six weeks, approximately every seven weeks, approximately every eight weeks, approximately every nine weeks, approximately every 10 weeks, approximately every 11 weeks, approximately every 12 weeks, approximately every 16 weeks, approximately every four months, approximately every six months, or approximately every year, optionally with different time intervals between each dose.

[0204] In some embodiments, the subject is administered two or more doses of an anti-c-kit antibody, such as JSP-191, wherein the time interval between each dose administration is at least eight weeks, at least ten weeks, at least twelve weeks, at least sixteen weeks, at least six months, or at least one year, optionally wherein the time interval between each dose is different. In some embodiments, the maximum time interval between each dose administration is about eight weeks, about twelve weeks, about four months, about six months, or about one year. In some embodiments, each dose is about 20 mg to about 275 mg of anti-c-kit antibody or about 50 mg to about 300 mg of anti-c-kit antibody, such as about 35 mg to about 180 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 300 mg, or about 360 mg of anti-c-kit antibody, such as JSP191. In some embodiments, the subject is administered an anti-c-kit antibody, such as JSP191, in doses of about 35 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg, or about 360 mg.

[0205] In some embodiments, the dosing regimen for administering the anti-c-kit antibody to the subject varies, with different time intervals between each dose. For example, the subject may receive a dose approximately once weekly for about 4 weeks, followed by a dose approximately every 2 weeks for about 8 weeks, and combinations thereof. In some embodiments, the subject may receive a dose approximately every 8–12 weeks.

[0206] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing mast cell disease or condition in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit IgG antibody or a fragment thereof, such as JSP191 or JSP191 (Fab')2, wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2). In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., JSP191 or JSP191 (Fab')2) about every eight weeks to about six months, for example, about every eight weeks to about 12 weeks, for example, about every eight weeks, about every ten weeks, about every 12 weeks, about every four months, or about every six months. Optionally, the subject may be administered one or more doses (e.g., a single dose) of about 1 mg / kg body weight to about 4 mg / kg body weight (e.g., about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg). In certain embodiments, the antibody or a fragment thereof may be administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally. In some embodiments, the antibody may be administered subcutaneously.

[0207] In one embodiment of treating mast cell-related diseases or conditions, two or more doses of JSP191 are administered subcutaneously to a human subject (e.g., an adult), wherein each dose is approximately 40 mg to approximately 500 mg, approximately 40 mg to approximately 360 mg, approximately 40 mg to approximately 400 mg, approximately 40 mg to approximately 300 mg, approximately 40 mg to approximately 200 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 200 mg, approximately 60 mg to approximately 500 mg, approximately 60 mg to approximately 400 mg, approximately 60 mg to approximately 300 mg, approximately 60 mg to approximately 200 mg, approximately 80 mg to approximately 500 mg, approximately 80 mg to approximately 400 mg, approximately 80 mg to approximately 300 mg, approximately 80 mg to approximately 200 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 4 ... The doses are approximately 200 mg to 200 mg, approximately 120 mg to 500 mg, approximately 120 mg to 400 mg, approximately 120 mg to 300 mg, approximately 120 mg to 200 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 180 mg, approximately 240 mg, or approximately 360 mg JSP191, and each of the two or more doses is administered to the subject at an interval of at least four weeks, at least eight weeks, at least twelve weeks, at least four months, or at least six months. For example, the interval between each of the two or more doses is approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different. In a particular embodiment, a subject is administered at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191. In one embodiment, a subject is administered two or more doses of JSP191, wherein each dose is about 80 mg to about 280 mg, optionally about 80 mg, about 120 mg, about 180 mg, or about 240 mg, and said doses are administered at intervals of about eight weeks to about four months or at intervals of about eight weeks to six months, optionally at intervals of about eight weeks or about twelve weeks.

[0208] In some embodiments of treating mast cell-related diseases and conditions, a dose of JSP191 is administered subcutaneously to a human subject (e.g., an adult), wherein said dose is about 40 mg to about 500 mg, about 40 mg to about 360 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 60 mg to about 500 mg, about 60 mg to about 400 mg, about 60 mg to about 300 mg, about 60 mg to about 200 mg, about 80 mg to about 500 mg, about 80 mg to about 400 mg, about 80 mg to about 300 mg, about 80 mg to about 200 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 300 mg, about 100 mg to about 500 mg, about 100 mg to about 4 ...300 mg, about 100 mg to about 500 mg, about 100 mg to about 300 mg, about 100 mg to about 500 mg, about 100 mg to about 500 mg, about 100 mg to about 300 mg, about 100 mg to about JSP191 is administered to a subject at least or about 200 mg, about 120 mg to about 500 mg, about 120 mg to about 400 mg, about 120 mg to about 300 mg, about 120 mg to about 200 mg, about 80 mg, about 100 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg. In certain embodiments, the subject is given at least or about 80 mg, at least or about 100 mg, at least or about 120 mg, at least or about 160 mg, at least or about 180 mg, at least or about 200 mg, or at least or about 240 mg of JSP191.

[0209] In some embodiments, a single high dose of anti-c-Kit antibody (e.g., JSP191) of about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg, is administered to the subject intravenously or subcutaneously.

[0210] In some embodiments, this disclosure provides a method for treating mast cell-related diseases or conditions, such as any mast cell-related disease or condition disclosed herein, the method comprising administering one or more doses of JSP-191 to a subject suffering from a mast cell-related disease or condition, wherein each dose is about 50 mg to about 500 mg or about 80 mg to about 280 mg, for example about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg. In particular embodiments, two or more doses of JSP-191 are administered to the subject, wherein each dose is administered at intervals of about four weeks to about one year, about eight weeks to about one year, about eight weeks to about six months, about eight weeks to about four months, or about eight weeks to about twelve weeks. In particular embodiments, the doses are administered intravenously or subcutaneously. In particular embodiments, the disease being treated is CSU. In particular embodiments, the disease being treated is an allergy or a specific form thereof, such as opioid-mediated allergy.

[0211] In some embodiments, the dosing regimen lasts for about or at least one month, about or at least six months, about or at least one year, about or at least two years, about or at least three years, or about or at least five years. In some embodiments, the dosing regimen continues until the subject is disease-free. In some embodiments, the subject is given two or more doses of the anti-c-kit antibody, the subject's disease symptoms are monitored after each dose, and another dose is given to the subject when the disease symptoms recur or become more pronounced.

[0212] According to embodiments of the methods disclosed herein, monotherapy with an anti-c-kit antibody is sufficient, and the subject does not require treatment with another therapeutic agent for the disease being treated. In other embodiments, the subject is treated with a combination of an anti-c-kit antibody and immunotherapy to treat the disease being treated. In some embodiments, the subject is treated with a combination of an anti-c-kit antibody and an antihistamine. In some embodiments, the subject is treated with a combination of an anti-c-kit antibody and an immunosuppressant (e.g., cyclosporine A or glucocorticoids, such as repeated oral glucocorticoids).

[0213] In some embodiments, anti-c-kit antibody therapy (or combination therapy) may be delivered orally, subcutaneously, intravenously, intranasally, percutaneously, intraperitoneally, intramuscularly, intrapulmonaryly, vaginally, rectally, or intraocularly. In some embodiments, anti-c-kit antibodies (e.g., JSP191) are administered locally or systemically (e.g., intravenously or subcutaneously). In some embodiments, anti-c-kit antibodies are delivered to the skin, for example, by local injection or application, or subcutaneously.

[0214] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing mast cell-related diseases or conditions (including, but not limited to, any diseases or conditions disclosed herein) in a mammalian (e.g., human) subject, the method comprising administering to the subject one or more therapeutically effective doses of a monoclonal anti-c-kit antibody (e.g., JSP191) or a fragment thereof (e.g., JSP191 (Fab')2), wherein each dose comprises about 30 mg to about 250 mg, about 30 mg to about 300 mg, about 40 mg to about 300 mg, about 50 mg to about 300 mg, or about 50 mg to about 600 mg of the anti-c-kit antibody or a fragment thereof (e.g., JSP191 (Fab')2), optionally wherein the subject is administered about 0.3 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 600 mg, or about 30 mg / kg to about 300 mg / kg. mg / kg to about 4 mg / kg or about 2 mg / kg to about 4 mg / kg, for example, a single dose of about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In certain embodiments, the antibody or a fragment thereof is administered systemically (e.g., intravenously (iv), subcutaneously (sc), or intraperitoneally (ip)) or locally. In some embodiments, a single dose is administered to the subject. In certain embodiments, an anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg to about 200 mg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg.In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0215] In embodiments, this disclosure provides methods for treating, inhibiting, or preventing mast cell disease in a subject, such as any of the methods disclosed herein, such as CSU or CIndU, the methods comprising administering an anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a therapeutically effective dose or dosing regimen.

[0216] In one embodiment, the amount of the antibody (e.g., JSP191) or its antigen-binding fragment applied is from 0.5 mg / kg to 5 mg / kg. In some embodiments, the amount applied is at least 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 4.5 mg / kg. In some embodiments, the amount applied is no greater than 5 mg / kg, 4.5 mg / kg, 4.0 mg / kg, 3.5 mg / kg, 3.0 mg / kg, 2.9 mg / kg, 2.8 mg / kg, 2.7 mg / kg, 2.6 mg / kg, 2.5 mg / kg, 2.4 mg / kg, 2.3 mg / kg, 2.2 mg / kg, 2.1 mg / kg, 2.0 mg / kg, 1.9 mg / kg, 1.8 mg / kg, 1.7 mg / kg, 1.6 mg / kg, 1.5 mg / kg, 1.4 mg / kg, 1.3 mg / kg, 1.2 mg / kg, 1.1 mg / kg, 1.0 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, or 0.6 mg / kg.

[0217] In some embodiments, the amount of the applied antibody (e.g., JSP191) or its antigen-binding fragment is 0.5 mg / kg to 4.5 mg / kg, 0.5 mg / kg to 4 mg / kg, 0.5 mg / kg to 3.5 mg / kg, 0.5 mg / kg to 3 mg / kg, 0.5 mg / kg to 2.5 mg / kg, 1.5 mg / kg to 2.5 mg / kg, 1.8 mg / kg to 2.2 mg / kg, 1 mg / kg to 2 mg / kg, 1.2 mg / kg to 1.8 mg / kg, 1.3 mg / kg to 1.7 mg / kg, 1.4 mg / kg to 1.6 mg / kg, 0.5 mg / kg to 1.5 mg / kg, 0.7 mg / kg to 1.3 mg / kg, 0.8 mg / kg to 1.2 mg / kg, or 0.9 mg / kg to 1.1 mg / kg.

[0218] In one embodiment, the amount of the antibody (e.g., JSP191) or its antigen-binding fragment applied is from 35 mg to 350 mg. In some embodiments, the amount applied is at least 35 mg, 42 mg, 49 mg, 56 mg, 63 mg, 70 mg, 77 mg, 84 mg, 91 mg, 98 mg, 105 mg, 112 mg, 119 mg, 126 mg, 133 mg, 140 mg, 147 mg, 154 mg, 161 mg, 168 mg, 175 mg, 182 mg, 189 mg, 196 mg, 203 mg, 210 mg, 245 mg, 280 mg, or 315 mg.

[0219] In some embodiments, the amount applied is no greater than 350 mg, 315 mg, 280 mg, 245 mg, 210 mg, 203 mg, 196 mg, 189 mg, 182 mg, 175 mg, 168 mg, 161 mg, 154 mg, 147 mg, 140 mg, 133 mg, 126 mg, 119 mg, 112 mg, 105 mg, 98 mg, 91 mg, 84 mg, 77 mg, 70 mg, 63 mg, 56 mg, 49 mg, or 42 mg.

[0220] In some embodiments, the amount of the antibody (e.g., JSP191) or its antigen-binding fragment applied is 35 mg to 315 mg, 35 mg to 280 mg, 35 mg to 245 mg, 35 mg to 210 mg, 35 mg to 175 mg, 105 mg to 175 mg, 126 mg to 156 mg, 70 mg to 140 mg, 98 mg to 126 mg, 91 mg to 109 mg, 98 mg to 112 mg, 35 mg to 105 mg, 49 mg to 91 mg, 56 mg to 84 mg, or 63 mg to 77 mg.

[0221] In one embodiment, the application is once every 2-24 weeks. In one embodiment, the application is once every 3-18 weeks. In one embodiment, the application is once every 3-15 weeks. In one embodiment, the application is once every 2-12 weeks. In one embodiment, the application is once every 4-15 weeks. In one embodiment, the application is once every 4-12 weeks. In one embodiment, the application is once every 4-8 weeks. In one embodiment, the application is once every 5-7 weeks. In one embodiment, the application is once every 2-12 weeks. In some embodiments, the application is not more than once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 11 weeks. In some embodiments, the application is at least once every 12 weeks, 11 weeks, 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, or 3 weeks.

[0222] In some embodiments, the administration is subcutaneous. In some embodiments, the administration is intravenous injection. In some embodiments, the administration is intramuscular injection.

[0223] In some embodiments, the administered first dose causes a reduction in mast cell count in the subject for at least 1, 2, 3, or 4 weeks.

[0224] In one embodiment, this disclosure provides a method for treating, inhibiting, or preventing mast cell-mediated diseases or conditions in a subject of need by administering an effective amount of the disclosed anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a dose of 0.5 mg / kg to 5 mg / kg every 2-12 weeks.

[0225] In another embodiment, a method is provided for treating, inhibiting, or preventing mast cell-mediated diseases or conditions in a subject of need by administering an effective amount of the disclosed anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a dose of 1 mg / kg to 2 mg / kg every 3-10 weeks.

[0226] In another embodiment, a method is provided for treating, inhibiting, or preventing mast cell-mediated diseases or conditions in a subject of need by administering an effective amount of the disclosed anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a dose of 1.2 mg / kg to 1.8 mg / kg every 4-8 weeks.

[0227] In one embodiment, this disclosure provides a method for treating, inhibiting, or preventing mast cell-mediated disease or condition in a subject of need by administering an effective amount of the disclosed anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a dose of 35 mg to 350 mg every 2 to 12 weeks.

[0228] In another embodiment, a method is provided for treating, inhibiting, or preventing mast cell-mediated diseases or conditions in a subject of need by administering an effective amount of the disclosed anti-CD117 antibody (e.g., JSP191) or a fragment thereof to the subject at a dose of 70 mg to 140 mg every 3 to 10 weeks.

[0229] In another embodiment, a method is provided for treating, inhibiting, or preventing mast cell-mediated diseases or conditions in a subject of need by administering an effective amount of the disclosed anti-CD117 (e.g., JSP191) antibody or a fragment thereof to the subject at a dose of 84 mg to 126 mg every 4-8 weeks.

[0230] In certain embodiments, the treatment results in improvement of one or more symptoms of the disease or condition. In certain embodiments, for example, for treatment of CSU or CInU, the treatment results in an improvement in the subject's UAS7 score after treatment. In some 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 100% compared to the subject's UAS7 score before treatment or at the first dose. In some embodiments, the subject's UAS7 score after 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 after treatment is less than or equal to 6. In some embodiments, the subject's UCT score after 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. In some embodiments, the subject's UCT score after treatment is greater than or equal to 12. In some embodiments, the UAS7 score and / or UCT are determined before treatment or at the time of the first dose administration, and then re-determined at approximately 4, 6, 8, 12, 16, or 24 weeks after the first dose administration. In some embodiments, the UAS7 score and / or UCT are determined before treatment or at the time of the first dose administration, and then re-determined at approximately 12 weeks after the first dose administration.

[0231] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing CSU in a mammalian subject (e.g., a human), the method comprising administering an effective amount of an anti-c-Kit antibody, such as beretricilimab, to the subject, wherein the anti-c-Kit antibody is administered subcutaneously at a dose of about 50 mg to about 300 mg or about 0.5 mg / kg to about 5 mg / kg. In some embodiments, one or more doses of the anti-c-Kit antibody are administered to the subject.

[0232] In some embodiments, this disclosure provides a method for treating, inhibiting, or preventing an allergic-like reaction in a mammalian subject (e.g., a human), the method comprising administering to the subject an effective amount of an anti-c-Kit antibody, such as beretricilrumb, wherein the anti-c-Kit antibody is administered subcutaneously or intravenously at a dose of about 50 mg to about 300 mg or about 0.5 mg / kg to about 5 mg / kg. In some embodiments, one or more doses of the anti-c-Kit antibody are administered to the subject. In a particular embodiment, the anti-c-Kit antibody (e.g., JSP191) is administered at one or more doses of about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight or about 0.5 mg / kg to about 2.0 mg / kg (e.g., about 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 40 mg to about 200 mg, such as about 80 mg, about 90 mg / kg, about 100 mg, about 110 mg, or about 120 mg). In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody (e.g., JSP191) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In certain embodiments, the anti-c-kit antibody, such as JSP191, is administered subcutaneously.

[0233] In some embodiments, this disclosure provides a method for treating, suppressing, or preventing an allergic reaction in a mammalian subject (e.g., a human), the method comprising administering to the subject an effective amount of an anti-c-Kit antibody, such as beretricilrumb, wherein the anti-c-Kit antibody is administered subcutaneously or intravenously at a dose of about 50 mg to about 300 mg or about 0.5 mg / kg to about 5 mg / kg. In some embodiments, one or more doses of the anti-c-Kit antibody are administered to the subject. In a particular embodiment, the allergic reaction is a severe allergic reaction. In a particular embodiment, the allergic reaction is allergen-induced atopic dermatitis. In a particular embodiment, the allergic reaction is a severe allergic reaction. In some embodiments, the allergic reaction is allergen-induced asthma.

[0234] Hematopoietic stem cell / progenitor cell diseases and conditions Hematopoietic stem cells and progenitor cells (HSPCs) play a crucial role in the development and maintenance of the blood and immune system. They are capable of differentiating into various types of blood cells, including red blood cells, white blood cells, and platelets. Due to their regenerative and immune properties, HSPCs are extensively studied in the context of a variety of diseases. CD117 is highly expressed on HSPCs, particularly on pluripotent progenitor cells and early hematopoietic stem cells (HSCs). CD117 expression is also found on certain cancer cells, including acute myeloid leukemia (AML).

[0235] Therefore, there is a need in the art for compositions and methods for consuming mast cells and / or hematopoietic stem cells and progenitor cells (HSPCs) and for treating mast cell diseases and conditions, as well as HSPC diseases and conditions.

[0236] The compositions and methods disclosed herein can be used to treat hematopoietic stem cell / progenitor cell diseases and conditions, including but not limited to malignant diseases.

[0237] CD117, also known as c-kit or stem cell factor receptor, plays a crucial role in hematopoietic stem cells (HSCs), which are responsible for generating different types of blood cells and HSCs. HSC Maintenance and Self-Renewal: CD117 plays a role in maintaining the HSC pool and promoting its self-renewal capacity. The binding of stem cell factor (SCF) to CD117 activates signaling pathways that support HSC survival, inhibit their differentiation, and promote their division and ability to generate new HSCs. Downregulation of CD117 is essential for HSC differentiation into different blood cell lineages. Under normal circumstances, the regulation of CD117 expression is tightly controlled to ensure an appropriate balance between HSC self-renewal and differentiation. CD117 signaling is involved in the mobilization of HSCs from the bone marrow to the peripheral blood. The interaction between CD117-expressing HSCs and the bone marrow microenvironment (also known as the stem cell microenvironment) is crucial for the maintenance and regulation of HSCs. CD117 expression on HSCs allows them to respond to SCF, which is produced by various cells within the bone marrow microenvironment. The binding of SCF to CD117 facilitates the interaction between HSCs and their microenvironments, providing essential signals for HSC survival, quiescence, and regulation.

[0238] In some embodiments, the methods disclosed herein are used to modulate the activity of one or more HSCs or HSPCs, for example, by inhibiting HSPC maintenance, inhibiting HSPC self-renewal, promoting HSPC differentiation, inhibiting HSPC mobilization, or inhibiting the interaction between HSPCs and the bone marrow microenvironment.

[0239] In some embodiments, this disclosure provides a method for consuming HSPCs in a subject, the method comprising administering an anti-c-kit antibody (e.g., JSP191) or an antigen-binding fragment thereof, such as (Fab')2, e.g., JSP191 (Fab')2, to the subject, wherein the method reduces the amount of HSPCs in the subject, for example, immediately after administration of the antibody or its antigen-binding fragment, or after approximately one day, two days, three days, four days, five days, six days, ten days, one week, two weeks, one month, two months, four months, or six months following administration of the antibody or its antigen-binding fragment. In some embodiments, the method reduces the amount of HSPCs in the subject, for example, immediately after treatment, or after approximately one day, two days, three days, four days, five days, six days, ten days, one week, two weeks, one month, two months, four months, or six months following treatment. In a particular embodiment, the HSPC is diseased HSPC. In some embodiments, the method described herein consumes diseased HSPCs from the subject by administering an anti-c-kit antibody or a fragment thereof (e.g., a (Fab')2 fragment) to the subject. In some embodiments, diseased HSPCs are consumed from the subject or the subject's tissues or organs, consuming 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 the total diseased HSPCs in the subject. In some embodiments, the treatment completely or almost completely consumes the diseased HSPCs in the subject.

[0240] In some embodiments, the treatment described herein selectively consumes diseased HSPCs in a subject. In specific embodiments, selective consumption of diseased HSPCs according to the disclosed method results in the consumption of a greater number or percentage of diseased HSPCs compared to the number or percentage of non-disease-free HSPCs consumed. In specific embodiments, the method consumes diseased HSPCs and / or induces apoptosis in diseased HSPCs. In some embodiments, the method consumes 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 diseased HSPC cells approximately two weeks after administration of the antigen-binding fragment, or induces apoptosis in 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 diseased HSPCs. In some embodiments, approximately 3-4 months after administration of the antigen-binding fragment, the subject's HSPCs or diseased HSPCs decrease by about 5%, about 10%, or about 20%, or less.

[0241] In certain embodiments, an anti-c-kit antibody or a fragment thereof (e.g., a (Fab')2 fragment) is administered to the subject at a dose that can effectively deplete diseased HSPCs in the treated subject. In some embodiments, the method induces apoptosis in the HSPCs. In certain embodiments, the anti-c-Kit antibody (e.g., JSP191) or a fragment thereof is administered as one or more doses of about 0.1 mg / kg of patient body weight to about 2.0 mg / kg of patient body weight, about 0.2 mg / kg of patient body weight to about 3.0 mg / kg of patient body weight, about 0.3 mg / kg to about 1.5 mg / kg, 0.5 mg / kg to about 2.0 mg / kg, such as about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, 0.8 mg / kg, or 1.0 mg / kg, or 2.0 mg / kg, or about 30 mg / kg to about 150 mg / kg, about 40 mg / kg to about 200 mg / kg, such as about 60 mg / kg, about 70 mg / kg, about 80 mg, about 90 mg / kg, or about 100 mg. In some embodiments, the patient is treated with a monoclonal anti-c-kit IgG antibody or a fragment thereof (e.g., the JSP191 (Fab')2 fragment) approximately every eight weeks to approximately six months, for example, approximately every eight weeks to approximately 12 weeks, for example, approximately every eight weeks, approximately every 12 weeks, approximately every four months, or approximately every six months. In specific embodiments, the anti-c-kit antibody, such as JSP191, is administered intravenously or subcutaneously. In some embodiments, prior to treatment, the subject's bone marrow contains at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, or at least 20% of healthy HSCs.

[0242] In related embodiments, this disclosure provides a method for treating hematopoietic stem cell / progenitor cell (HSPC) disease or condition in a human subject, the method comprising administering an anti-c-kit antibody or an antigen-binding fragment thereof to the subject, optionally wherein the antigen-binding fragment is F(ab')2. In some embodiments, approximately 7-15 days after administration of the antibody or its antigen-binding fragment, the subject's HSPC is consumed by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0243] In a particular embodiment, the method is used to treat diseases or conditions selected from the group consisting of: myelodysplastic syndromes, leukemia, optionally acute myeloid leukemia (AML), and clonal hematopoiesis of undetermined potential (CHIP).

[0244] Myelodysplastic syndromes (MDS) are a hematologic malignancy characterized by the presence of defective hematopoietic stem cells (HSCs). Current treatments for MDS include hematopoietic stimulants for temporary relief of related symptoms. These treatments may include long-term blood transfusions, erythropoietin stimulants, or various chemotherapy therapies. However, there are currently no treatments that specifically target diseased HSCs relative to healthy HSCs. Therefore, there is a need for innovative agents and therapies that selectively target diseased HSCs while allowing healthy HSCs to perform normal hematopoiesis in the bone marrow. This disclosure addresses this need by providing agents and regimens for selectively depleting diseased HSCs in MDS, acute myeloid leukemia (AML), and other conditions.

[0245] Leukemia is a group of cancers that affect the blood and bone marrow, where blood cells are produced. They are caused by the abnormal growth and proliferation of immature blood cells, such as hematopoietic stem cells / progenitor cells. Based on their progression and the types of blood cells affected, leukemia can be classified into four main types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

[0246] ALL is the most common type of leukemia in children, although it can also affect adults. ALL originates from abnormal lymphocyte precursors, a type of white blood cell involved in the immune response. The disease progresses rapidly as immature lymphoblasts crowd out normal cells in the bone marrow and interfere with their function.

[0247] AML typically affects adults, but can also occur in children. It develops from abnormal myeloid cells that produce various types of mature blood cells, including red blood cells, platelets, and certain types of white blood cells. In AML, immature myeloid cells accumulate in the bone marrow and bloodstream, disrupting normal blood cell production.

[0248] CLL primarily affects older adults and is characterized by the accumulation of abnormally mature lymphocytes. These cells originate from B lymphocytes, gradually replacing normal white blood cells in the bone marrow and circulating in the bloodstream. CLL typically progresses slowly and may not cause symptoms in its early stages.

[0249] CML typically affects adults and is characterized by the overproduction of granulocytes (a type of white blood cell). It is associated with a specific genetic abnormality called the Philadelphia chromosome, which leads to the formation of an abnormal fusion protein called BCR-ABL. CML progresses slowly, in three phases: a chronic phase, an accelerated phase, and a blast crisis phase.

[0250] CHIP is a condition characterized by the presence of genetically distinct populations of blood cells in an individual's bone marrow and peripheral blood. In CHIP, specific mutations occur in the DNA of hematopoietic stem cells, resulting in abnormal cell clones appearing alongside normal cells in the blood. While other mutations can occur, the specific mutations typically associated with CHIP are found in genes such as DNMT3A, TET2, and ASXL1. CHIP does not cause any obvious symptoms or clinical manifestations, and people with CHIP usually have normal blood cell counts and do not show any signs of bone marrow dysfunction or blood-related symptoms. However, CHIP is associated with an increased risk of developing certain hematologic malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Over time, the presence of mutations in CHIP increases the likelihood of progression to these diseases. The risk of progression depends on specific gene mutations and other factors.

[0251] anti-c-Kit antibody The methods disclosed herein consider the use of anti-c-kit antibodies. In some embodiments, this disclosure provides methods for selectively consuming endogenous mast cells and / or diseased hematopoietic stem cells (HSCs) in a subject by administering an anti-c-kit antibody or an antigen-binding fragment thereof (e.g., a (Fab')2 fragment). In some embodiments, the compositions and methods disclosed herein may be adapted to any anti-c-kit antibody that blocks the binding of stem cell factor (SCF) to the c-kit / CD117 protein of endogenous HSCs. 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 the binding of stem cell factor (SCF).

[0252] In certain embodiments, the methods disclosed herein are implemented using (Fab')2 fragments (e.g., the JSP191 (Fab')2 antibody fragment). A (Fab')2 fragment is a specific antibody fragment produced by enzymatic cleavage of an intact antibody molecule with pepsin. Pepsin cleaves the antibody below or inside the hinge region. The (Fab')2 fragment comprises two Fabs linked together by disulfide bonds, thus they are divalent, with a molecular weight of approximately 110 kDa, while the molecular weight of an intact IgG antibody is approximately 150 kDa. (Fab')2 contains variable regions of both the heavy and light chains, which contributes to antibody specificity. Therefore, the (Fab')2 fragment retains the antigen-binding capacity of the intact antibody but lacks the Fc region. The (Fab')2 fragment can be produced by digesting a whole IgG antibody with pepsin or other enzymes, such as using a site-specific cysteine ​​protease FabRICATOR (IdeS) (Genovis Inc., USA) for digestion at a single site below the IgG hinge. (Fab')2 can also be generated by recombination, for example, by expressing a complete antibody light chain lacking the Fc region but including the variable region and some or all of the hinge region, and a truncated antibody heavy chain. For other methods of generating (Fab')2, see, for example, Rosenstein, S. et al., *Curr Protoc Mol Biuol.*, June 2020; 131(1):e119.

[0253] Many antibodies and fragments thereof that specifically bind to human CD117 as described in this disclosure (including (Fab')2) are known in the art and / or commercially available, including but not limited to JSP-191, SR1, 2B8, ACK2, YB5-B8, 57A5 and 104D2. In some embodiments, the anti-c-kit antibody is selected from the group consisting of: JSP191 (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). The antibodies from Magenta Therapeutics considered in this disclosure include, but are not limited to, those disclosed in U.S. Patent Application Publication No. 20190153114, PCT Application Publication Nos. WO2019084064, WO2020 / 219748, and WO2020 / 219770. The FSI-174 antibody is disclosed in PCT Application Publication No. WO2020 / 112687 and U.S. Patent Application Publication No. 20200165337. This disclosure includes, but is not limited to, any anti-c-kit antibodies and / or CDR groups disclosed in any of the patent applications disclosed herein, all of which are incorporated herein by reference in their entirety.

[0254] In some 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: QPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFVKWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLVDRSLYGKEDNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYHRCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSSSVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSANVTTTLEVVDKGFINIFPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVSELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTP (SEQ ID NO: 1).

[0255] Explanatory 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, HF12, and HF112. Many antibodies that specifically bind to human CD117 as described in this disclosure are commercially available, including but not limited to SR1, 2B8, ACK2, YB5-B8, 57A5, 104D2, etc. In some embodiments, the anti-c-kit antibody is selected from the group consisting of: JSP191, CDX-0159 (from Syds Medical, Hampton, NJ), MGTA-117 (AB85) (from Magenta Therapeutics, Cambridge, Massachusetts), CK6 (from Magenta Therapeutics, Cambridge, Massachusetts), AB249 (from Magenta Therapeutics, Cambridge, Massachusetts), and FSI-174 (from Gilead Sciences, South San Francisco, California). The antibody from Magenta Therapeutics is disclosed in U.S. Patent Application Publication No. 20190153114. In some embodiments, the antibody is the antibody disclosed in any one of U.S. Patent Nos. 7,915,391, 8,436,150, or 8,791,249. In some embodiments, the antibody is an antibody disclosed in any one of U.S. Patent Application Publication No. 20200165337 or PCT Publications No. 2020 / 112687, 2020 / 219748, 2020 / 219770 or 2019 / 084064.

[0256] In a particular embodiment, the antibody is a humanized form of SR1, namely the mouse anti-c-kit antibody described in U.S. Patent Nos. 5,919,911 and 5,489,516. Humanized forms known as JSP191 or beretricilimab are disclosed in U.S. Patent Nos. 7,915,391, 8,436,150, and 8,791,249. JSP191 is a deglycosylated IgG1 humanized antibody with N-linked glycosylation sites removed from the IgG1 constant region. JSP191 specifically binds to human CD117 (a receptor for stem cell factor (SCF) expressed on the surface of various cell types, including mast cells, hematopoietic stem cells and progenitor cells, melanocytes, germ cells, and Cajal mesenchymal cells). JSP191 blocks the binding of SCF to CD117 and disrupts stem cell factor (SCF) signaling. JSP191 binding to c-Kit inhibits the binding of ligand stem cell factor (SCF). In cultured mast cells, JSP191 inhibits IgE-mediated mast cell degranulation. The IC50 of JSP191 in human mast cell survival bioassays is approximately 12.5 nM. In mast cells, activated KIT enhances degranulation and regulates MC growth, differentiation, survival, and chemotaxis (Gilfillan, Austin, and Metcalfe 2011). Inhibition of SCF signaling by c-Kit on mast cells leads to apoptosis. The half-life of JSP191 is approximately 9 days. Once mast cells are consumed, PK clearance by JSP191 allows the restoration of c-Kit signaling in other c-Kit-expressing cells. After consumption, tissue mast cells may require more than 8 weeks to be replenished through hematopoietic stem cell differentiation.

[0257] JSP191 (beretrilimab) is a heterotetramer composed of two heavy chains from the IgG1 subclass and two light chains from the κ subclass, covalently linked by disulfide bonds. Due to the intentional substitution of asparagine for glutamine at residue 297 of the heavy chain, JSP191 lacks N-linked glycans. The heavy and light chain sequences of JSP191 are disclosed as SEQ ID NO: 4 and SEQ ID NO: 2, respectively, from US8436150.

[0258] The heavy chain and light chain sequences of JSP191 are disclosed as SEQ ID NO:4 and SEQ ID NO:2, respectively, from U.S. Patent No. 8,436,150. The heavy chain and light chain sequences of JSP191 are: Heavy chain: MDWTWRVFCLLAVAPGAHSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGVIYSGNGDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 2) and Light chain: MVLQTQVFISLLLWISGAYGDIVMTQSPDSLAVSLGERATINCRASESVDIYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDPYTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 3).

[0259] In certain embodiments, the variable heavy domain of JSP191 comprises the following sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGVIYSGNGDTSYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARERDTRFGNWGQGTLVTVSS (SEQ ID NO: 4).

[0260] In some embodiments, the variable light chain structure domain of JSP191 contains the following sequence: DIVMTQSPDSLAVSLGERATINCRASESVDIYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQNNEDP YTFGGGTKVEIK (SEQ ID NO: 5).

[0261] The CDRs present in JSP191 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).

[0262] CDX-0159 is a humanized monoclonal antibody that binds specifically to the receptor tyrosine kinase KIT with high specificity and effectively inhibits its activity. CDX-0159 is engineered to block KIT activation by disrupting 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 certain embodiments, the anti-c-kit disclosed herein comprises the CDR of any antibody disclosed herein. In some embodiments, the anti-c-kit antibody comprises: (i) a light chain variable region (“VL”) comprising the following amino acid sequence: DIVMTQSPSX K1 LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKX K2 LIYSASYRYSGVPDRFX K3 GSGSGTDFTLTISSLQX K4 EDFAX K5 YX K6 CQQYNSYPRTFGGGTKVEIK (SEQ ID NO: 12), where X K1 It is an amino acid with an aromatic or aliphatic hydroxyl side chain, X K2 It is an amino acid with an aliphatic or aliphatic hydroxyl side chain, X K3 It is an amino acid with an aliphatic hydroxyl side chain, X K4It is an amino acid with an aliphatic hydroxyl side chain or P,X K5 It is an amino acid with charged or acidic side chains, and X K6 (i) amino acids having aromatic side chains; and (ii) heavy chain variable regions (“VH”) containing the following amino acid sequences: QVQLVQSGAEX H1 KKPGASVKX H2 SCKASGYTFTDYYINAVVX H3 QAPGKGLEWIARIYPGSGNTYYNEKFKGRX H4 TX H5 TAX H6 KSTSTAYMX H7 LSSLRSEDX H8 AVYFCARGVYYFDYWGQGTTVTVSS (SEQ ID NO: 13), where X H1 It is an amino acid with an aliphatic side chain, X H2 It is an amino acid with an aliphatic side chain, X H3 It is an amino acid with a polar or basic side chain, X H4 It is an amino acid with an aliphatic side chain, X H5 It is an amino acid with an aliphatic side chain, X H6 It is an amino acid with an acidic side chain, X H7 It is an amino acid with an acidic or amide derivative side chain, and X H8 It is an amino acid with an aliphatic hydroxyl side chain. In a specific aspect, this document describes antibodies (e.g., human or humanized antibodies) including their antigen-binding fragments, said antibodies comprising: (i) a VH CDR containing a VH domain comprising the following amino acid sequence: or and (ii) VL CDRs containing the following amino acid sequence: DIVMTQSQKFMSTSVGDRVSVTCKASQNVRTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYNSYPRTFGGGTKLEIKR (SEQ ID NO: 16).

[0263] MGTA-117 (AB85) is a transplant-enhanced, CD117-targeting antibody conjugated with muscarinic acid, developed for patients undergoing immune reset via autologous or allogeneic stem cell transplantation. MGTA-117 consumes hematopoietic stem cells and progenitor cells, and this antibody, along with other antibodies considered in this disclosure, is described in U.S. Patent Application Publication No. 20200407440 and / or PCT Application Publication No. WO2019084064. PCT Application Publication No. WO2020219770 describes an epitope analysis of AB85 binding to CD117, which identifies the following two epitopes in CD117: EKAEATNTGKYTCTNKHGLSNSIYVFVRDPA (SEQ ID NO: 17; amino acids 60-90), and RCPLTDPEVTNYSLKGCQGKP (SEQ ID NO: 18; amino acids 100-130).

[0264] The sequences of the variable heavy chain and variable light chain of AB85 are disclosed as SEQ ID NO: 143 and SEQ ID NO: 144, respectively, from PCT application publication No. WO2019084064.

[0265] The amino acid sequence of the heavy chain variable region (VH) of Ab85 is as follows: EVQLVQSGAEVKKPGESLKISCKGSGYSFT NYWIG WVRQMPGKGLEWMA IINPRDSDTRYRPSFQG QVTISADKSISTAYLQWSSLKASDTAMYYCAR HGRGYEGYEGAFDI WGQGTLVTVSS (SEQ ID NO: 19).

[0266] 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; VHCDR3).

[0267] The amino acid sequence of the light chain variable region (VL) of AB85 is as follows: DIQMTQSPSSLSASVGDRVTITC RSSQGIRSDLG WYQQKPGKAPKLLIY DASNLET GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQANGFPLT FGGGTKVEIK (SEQ ID NO: 23).

[0268] 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).

[0269] FSI-174 is an anti-cKIT antibody being developed in combination with 5F9 as a non-toxic transplant conditioning regimen and for the treatment of hematologic malignancies. The sequence of FSI-174 is disclosed in PCT Application Publication No. 2020 / 112687, U.S. Patent Application Publication No. 20200165337, and U.S. Patent No. 11,041,022. In certain embodiments, the anti-c-kit antibody comprises three CDRs or variable heavy chain regions present in any of the disclosed AH1, AH2, AH3, AH4, or AH5, and / or three CDRs or variable heavy chain regions present in any of the disclosed AL1 or AL2.

[0270] In some embodiments, the CDRs present in FSI-174 and the associated antibody are as follows: VH CDR1 = 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 CDR1 = RAS(D / E)SVDIYG(N / Q)SFMH (SEQ ID NO: 30); VLCDR2 = LASNLES (SEQ ID NO: 31); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 32). The A / N and other indicator amino acid positions can be either of the two amino acids, in this example, A or N. In some embodiments, the CDRs present in the heavy variable region are CDRs H1, H2, and H3, as defined by Kabat: H1 = SYNMH (SEQ ID NO: 27); H2 = VIYSGNGDTSYAQKFKG (SEQ ID NO: 33); H3 = ERDTRFGN (SEQ ID NO: 29); and the CDRs present in the light variable region are CDRs L1, 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), except that there are one, two, or three CDR residues selected from N to A at position 60 of the heavy chain, K to Q at position 64 of the heavy chain, and N to Q at position 30 of the light chain, respectively, the positions of which are numbered according to Kabat. In some embodiments, the antibody comprises any of the heavy chain variable region sequences (AH2, AH3, AH4) and / or the light chain variable region sequence (AL2) provided below, or any of the underlined CDRs shown therein: AH2:QVQLVQSGAEVKKPGASVKVSCKASGYTFT SYMNH WVRQAPGQGLEWMG VIYSGNGDTSYAQKF KG RVTITADKSTSTAYMELSSLRSEDTAVYYCAR ERDTRFGN WGQGTLVTVSS (SEQ ID NO: 35) AH3:QVQLVQSGAEVKKPGASVKVSCKASGYTFT SYMNH WVRQAPGQGLEWMG VIYSGNGDTSYNQKF QGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR ERDTRFGN WGQGTLVTVSS (SEQ ID NO: 36) AH4 QVQLVQSGAEVKKPGASVKVSCKASGYTFT SYMNH WVRQAPGQGLEWMG VIYSGNGDTSYAQKF QG RVTITADKSTSTAYMELSSLRSEDTAVYYCAR ERDTRFGN WGQGTLVTVSS (SEQ ID NO: 37) AL2: DIVMTQSPLSLPVTPGEPASISC RASESVDIYGQSFMH WYQQKPGQPPKLLIY LASNLES GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC QQNNEDPYT FGGGTKVEIK (SEQ ID NO: 38).

[0271] In some embodiments, the anti-c-kit antibody comprises the entire heavy chain and / or the entire light chain of any antibody disclosed herein, or has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with the heavy chain or light chain disclosed herein (e.g., the JSP191 heavy chain or light chain). In some embodiments, the anti-c-kit antibody comprises the heavy chain and / or light chain variable region of any antibody disclosed herein, or has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with the heavy chain or light chain variable region disclosed herein (e.g., the JSP191 heavy chain or light chain variable region). In some 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, such as two, three, four, five, or six CDRs of an antibody disclosed herein (e.g., the JSP191 antibody). In certain embodiments, the anti-c-kit antibody comprises a heavy chain or a variable region thereof, the heavy chain or the variable region comprising one, two or three heavy chain CDRs disclosed herein, such as the JSP191 heavy chain. In certain embodiments, the anti-c-kit antibody comprises a light chain or a variable region thereof, the light chain or the variable region comprising one, two or three light chain CDRs disclosed herein, such as the JSP191 light chain.

[0272] CDX-0159 is a humanized monoclonal antibody that binds specifically to the receptor tyrosine kinase KIT with high specificity and effectively inhibits its activity. CDX-0159 is engineered to block KIT activation by disrupting SCF binding and KIT dimerization.

[0273] MGTA-117 is a transplant-enhanced, CD117-targeting antibody conjugated with muscarinic acid, which was developed for patients undergoing immune reset via autologous or allogeneic stem cell transplantation. MGTA-117 consumes hematopoietic stem cells and progenitor cells, and this antibody, along with other antibodies considered in this disclosure, is described in US 20200407440.

[0274] FSI-174 is an anti-c-kit antibody that is being developed in combination with 5F9 as a non-toxic transplant conditioning regimen and for the treatment of targeted hematologic malignancies.

[0275] In certain embodiments, the antibody may include one or more CDRs having at least 70%, 80%, 90%, 95%, or 99% amino acid or nucleotide sequence identity with a CDR present in a humanized monoclonal antibody that binds to c-kit (e.g., an antibody derived from any one of mouse antibodies SR1, ACK2, ACK4, 2B8, 3C11, MR-1, and CD122). In some embodiments, the antibody blocks the binding of stem cell factor (SCF) to the stem cell factor receptor (CD117). Illustrative examples of anti-c-kit antibodies that may be used include JSP191, as well as those described in WO2007127317A2 and US20200165337A1, both of which are incorporated herein by reference in their entirety.

[0276] In some embodiments, the anti-c-kit antibody comprises the entire heavy chain and / or the entire light chain of any antibody disclosed herein, or has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with the heavy chain or light chain disclosed herein (e.g., the JSP191 heavy chain or light chain). In some embodiments, the anti-c-kit antibody comprises the heavy chain and / or light chain variable region of any antibody disclosed herein, or has an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identity with the heavy chain or light chain variable region disclosed herein (e.g., the JSP191 heavy chain or light chain variable region). In some 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, such as two, three, four, five, or six CDRs of an antibody disclosed herein (e.g., the JSP191 antibody). In certain embodiments, the anti-c-kit antibody comprises a heavy chain or a variable region thereof, the heavy chain or the variable region comprising one, two or three heavy chain CDRs disclosed herein, such as the JSP191 heavy chain. In certain embodiments, the anti-c-kit antibody comprises a light chain or a variable region thereof, the light chain or the variable region comprising one, two or three light chain CDRs disclosed herein, such as the JSP191 light chain.

[0277] Drug compositions, unit dosage forms and reagent kits In some embodiments, an anti-c-kit antibody or a fragment thereof (or combination therapy) is present in the pharmaceutical composition. This disclosure provides pharmaceutical compositions that can be used for the treatments disclosed herein. Such compositions comprise an effective amount of an antibody or a fragment thereof, and an acceptable carrier. In some embodiments, the composition further comprises a second therapeutic agent (e.g., an antihistamine).

[0278] In certain embodiments, the pharmaceutical composition may be in a water-soluble form, such as pharmaceutically acceptable salts, meaning that it includes 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, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts include base addition salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Salts derived from pharmaceutically acceptable non-toxic organic 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 specific embodiments, the term "pharmaceuticalally acceptable" means a substance approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more specifically in humans. Further, "pharmaceuticalally acceptable carrier" will generally be any type of non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. 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, corn starch, and other starches; binders; and polyethylene glycol.

[0280] The term "carrier" refers to a diluent, adjuvant, excipient, or catalyst that is administered with the therapeutic agent. Such drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is the preferred carrier when the drug composition is administered intravenously. Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, specifically for injectable solutions. Suitable drug excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. If desired, the composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers, such as acetates, citrates, or phosphates. Antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; and agents for regulating stress, such as sodium chloride or dextrose.

[0281] These compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. They can be formulated into suppositories using traditional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in EW Martin's "Remington's Pharmaceutical Sciences" (incorporated hereby by reference).

[0282] Such compositions may contain a therapeutically effective amount of an antigen-binding polypeptide, preferably in a purified form, along with a suitable amount of carrier to provide an appropriate form for administration to the patient. The formulation should be suitable for the administration method. The parent formulation may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0283] In one embodiment, the composition is formulated according to conventional procedures to be suitable for intravenous or subcutaneous administration to human subjects. Typically, the composition for intravenous administration is a solution in a sterile isotonic buffer solution. If necessary, the composition may also include a solubilizer and a local anesthetic, such as lidocaine, to reduce pain at the injection site. Generally, the components are provided separately or mixed together in unit dosage forms, for example, as a lyophilized powder or anhydrous concentrate in a hermetically sealed container, such as an ampoule or capsule indicating the amount of active agent. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, ampoules of sterile water for injection or saline can be provided so that the components can be mixed prior to administration.

[0284] The compositions disclosed herein can be formulated into neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those formed with cations, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0285] Compositions intended for administration will typically comprise an antibody or fragment thereof dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. Various aqueous carriers can be used, such as buffered saline. The composition may contain pharmaceutically acceptable excipients close to physiological conditions, such as pH adjusters and buffers, and toxicity antagonists, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the active agent in the formulation can vary depending on the chosen specific administration modality and the patient's needs, and is selected based on fluid volume, viscosity, and body weight (e.g., Remington's Pharmaceutical Sciences (15th edition, 1980) and Goodman and Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)).

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

[0287] This disclosure further provides kits comprising anti-c-kit antibodies or antigen-binding fragments thereof as described herein, for example, kits for administration of anti-c-kit antibodies or fragments thereof by a medical professional or a subject in need. The kit may comprise, for example, a container and one or more doses of anti-c-kit antibodies and instructions for use. In some embodiments, the kit comprises multiple doses of anti-c-kit antibodies or fragments thereof suitable for a dosing regimen over a period of time. In some embodiments, each dose comprises the same amount of anti-c-kit antibody, while in other embodiments, the kit may comprise two or more different doses of anti-c-kit antibodies or fragments thereof. In some embodiments, each dose is present in a separate container. In a particular embodiment, each of one or more doses comprises about 0.5 mg to about 800 mg of anti-c-kit antibody or fragments thereof, optionally about 5 mg to about 800 mg of anti-c-kit antibody. In certain embodiments, one or more doses comprise about 80 mg to about 280 mg, optionally about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of anti-c-kit antibody or a fragment thereof. In certain embodiments, one or more doses comprise about 120 mg to about 240 mg, optionally about 120 mg, 180 mg, or about 240 mg of anti-c-kit antibody or a fragment thereof.

[0288] In some embodiments, this disclosure provides pharmaceutical compositions, unit dosage forms, and kits comprising one or more doses of a monoclonal anti-c-kit IgG antibody or an antigen-binding fragment thereof, wherein each of the one or more doses comprises about 40 mg to about 360 mg, about 50 mg to about 600 mg, or about 50 mg to about 300 mg of the anti-c-kit antibody or a fragment thereof, optionally wherein the anti-c-kit antibody is JSP191. In a particular embodiment, each of the one or more doses comprises about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 320 mg, about 340 mg, or about 360 mg. mg anti-c-kit antibody or a component thereof. In some embodiments, the kit comprises one or more doses, each dose independently containing about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg, or about 360 mg of anti-c-kit antibody or a fragment thereof, optionally wherein said anti-c-kit antibody is JSP191. In particular embodiments, the kit comprises two or more doses of anti-c-kit antibody. In some embodiments, each of the two or more doses of anti-c-kit antibody contains about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg of anti-c-kit antibody, optionally wherein said anti-c-kit antibody is JSP191.

[0289] On the other hand, this disclosure provides pharmaceutical compositions, unit dosage forms, and kits comprising one or more doses of a monoclonal anti-c-kit IgG antibody (e.g., JSP191), wherein each of the one or more doses comprises about 40 mg to about 360 mg, about 50 mg to about 600 kg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, or about 50 mg to about 300 mg of anti-c-kit antibody, optionally wherein the anti-c-kit antibody is JSP191. In some embodiments, each of the one or more doses comprises about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 450 mg. The kit may contain, or consist of, an anti-c-kit antibody of, mg, about 500 mg, about 550 mg, or about 600 mg. In some embodiments, the kit comprises one or more doses of an anti-c-kit antibody of, or consist of, about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg, or about 360 mg, optionally wherein the anti-c-kit antibody is JSP191.

[0290] In certain embodiments, the pharmaceutical composition, unit dosage form, and kit contain a single high dose of an anti-c-kit antibody (e.g., JSP191) in an amount sufficient to administer to a subject from about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg. In some embodiments, the kit contains two or more doses of the anti-c-kit antibody. In some embodiments, each of the two or more doses of the anti-c-kit antibody contains about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 280 mg of the anti-c-kit antibody, optionally wherein the anti-c-kit antibody is JSP191.

[0291] In related aspects, this disclosure provides pharmaceutical compositions, unit dosage forms, and kits comprising one or more doses of an antigen-binding fragment of an anti-c-kit antibody, wherein the antigen-binding fragment is F(ab')2 (e.g., JSP191(Fab')2). In some embodiments, each of the one or more doses comprises about 14.5 mg to about 200 mg or about 20 mg to about 500 mg of an antigen-binding fragment, optionally about 14.5 mg to about 175 mg, about 20 mg to about 150 mg, about 25 mg to about 250 mg, about 35 mg to about 240 mg, about 35 mg to about 180 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240 mg. mg antigen-binding fragment. In some embodiments, the kit comprises one or more doses, the one or more doses comprising about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 150 mg, about 180 mg, about 200 mg, about 250 mg, about 300 mg, or about 350 mg of antigen-binding fragment. In some embodiments, the kit comprises one or more doses comprising about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 450 mg, or about 500 mg of an antigen-binding fragment (e.g., JSP191(Fab')2).In a particular embodiment, the kit comprises a single high dose sufficient to administer to a subject about 0.3 mg / kg to about 3.0 mg / kg, about 0.4 mg / kg to about 4.0 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 0.67 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, or about 2 mg / kg to about 4 mg / kg, such as about 0.5 mg / kg, mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, or about 5 mg / kg of an antibody or fragment thereof (e.g., a JSP191 (Fab')2).

[0292] In some embodiments, the anti-c-kit antibody comprises five or more complementarity-determining regions (CDRs) present in a monoclonal antibody selected from the group consisting of: SR-1, JSP191, MGTA-117, FSI-174, CDX-0159, 8D7, K45, 104D2, CK6, AB249, YB5.B8, AF-2-1, AF11, AF12, AF112, AF-3, AF-1-1, NF, NF-2-1, NF11, NF12, NF112, NF-3, HF11, HF12, and HF112, optionally wherein said antibody is an IgG antibody. In a particular embodiment, the anti-c-kit antibody comprises five or more complementarity-determining regions (CDRs) present in a humanized version of a monoclonal antibody selected from the group consisting of: ACK2, ACK4, 2B8, 3C11, MR-1, and CD122, optionally wherein said antibody is an IgG antibody. In a particular embodiment, the anti-c-kit antibody comprises a CDR of an antibody that blocks the binding of stem cell factor (SCF) to stem cell factor receptor (CD117), optionally wherein the antibody is JSP191.

[0293] Differentiation methods In some embodiments, this disclosure provides a method for altering the differentiation pathways of HSCs and / or HSPCs, the method comprising contacting cells with a monoclonal anti-c-kit IgG antibody (including, but not limited to, any antibody disclosed herein). In a particular embodiment, the monoclonal anti-c-kit IgG antibody comprises five or more CDRs present in an antibody that inhibits the binding of SCF to c-kit on the cell surface, such as five or more CDRs present in JSP-191. In a particular embodiment, the anti-c-kit antibody is JSP-191. In a particular embodiment, the method results in increased differentiation of the cells along the megakaryocyte lineage. In various embodiments, cells are contacted with the anti-c-kit IgG antibody in vitro, ex vivo, or in vivo.

[0294] Listed Examples The following are non-limiting examples of certain aspects of this disclosure.

[0295] 1. A method for treating, inhibiting, or preventing mast cell-related disease or condition in a human subject, the method comprising administering an anti-c-kit IgG antibody to the human subject, the 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); VLCDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered: a) Two or more doses of the anti-c-kit IgG antibody, wherein each dose contains about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody, and wherein each dose is administered at intervals of eight weeks to six months; or b) A dose of the anti-c-kit IgG antibody, wherein the dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody.

[0296] 2. The method according to Example 1, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or about 360 mg. mg of the anti-c-kit IgG antibody or composed thereof.

[0297] 3. The method according to Example 2, wherein each dose contains about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit IgG antibody.

[0298] 4. The method according to any one of Examples 1 to 3, wherein the disease or condition is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic induced urticaria (CIndU), chronic idiopathic urticaria (CIU), pigmented urticaria, nodular prurigo, esophagitis (optionally eosinophilic esophagitis), asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and conditions, dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.

[0299] 5. The method according to Example 4, wherein the disease or condition is chronic spontaneous urticaria (CSU), optionally wherein the subject retains symptoms despite treatment with antihistamines, and wherein the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, about 320 mg, or about 320 mg. The anti-c-kit antibody was administered at doses of approximately 340 mg or 360 mg, with each dose administered at intervals of eight weeks to six months.

[0300] 6. The method according to Example 4, wherein the disease or condition is chronic inducible urticaria (CIndU), optionally cold urticaria (ColdU), or symptomatic dermatographia (SD), and the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 280 mg. The anti-c-kit antibody is administered at doses of approximately 300 mg, 320 mg, 340 mg, or 360 mg, with each dose administered at intervals of eight weeks to six months.

[0301] 7. The method according to any one of Examples 1 to 6, wherein the anti-c-kit antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

[0302] 8. The method according to any one of Examples 1 to 7, wherein two or more doses of the anti-c-kit IgG antibody are administered to the subject, and wherein each of the doses is administered at intervals of approximately eight weeks to approximately six months, approximately eight weeks to approximately four months, approximately eight weeks to approximately twelve weeks, approximately twelve weeks to approximately six months, approximately twelve weeks to approximately four months, approximately eight weeks, approximately nine weeks, approximately ten weeks, approximately twelve weeks, approximately four months, or approximately six months, optionally wherein the time interval between each dose is different.

[0303] 9. The method according to any one of Examples 1 to 8, wherein the method results in a reduction of UAS7 ≤ 6 or mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

[0304] 10. The method according to any one of Examples 1 to 9, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO: 5.

[0305] 11. The method according to Example 10, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO: 3.

[0306] 12. A method for selectively consuming mast cells rather than hematopoietic stem cells and progenitor cells (HSPCs) in a subject, the method comprising administering to the subject one or more therapeutically effective doses of an anti-c-kit IgG antibody, the 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 each dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody.

[0307] 13. The method according to Example 12, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 320 mg, or about 320 mg. mg, about 340 mg or about 360 mg of the anti-c-kit IgG antibody or composed thereof.

[0308] 14. The method according to Example 13, wherein each dose comprises about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit IgG antibody.

[0309] 15. The method according to any one of Examples 12 to 14, wherein the anti-c-kit IgG antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

[0310] 16. The method according to any one of Examples 12 to 15, wherein two or more doses of the anti-c-kit antibody are administered to the subject.

[0311] 17. The method according to Example 16, wherein each dose is administered at intervals of eight weeks to one year, eight weeks to six months, eight weeks to four months, twelve weeks to one year, twelve weeks to six months, twelve weeks to four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about four months, about six months, eight months, about ten months, or about one year, optionally wherein the time interval between each dose is different.

[0312] 18. The method according to any one of Examples 12 to 17, wherein the method reduces mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%, and reduces HSPC by less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%.

[0313] 19. The method according to any one of Examples 12 to 18, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO: 5.

[0314] 20. The method according to Example 19, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO: 3.

[0315] 21. A kit comprising one or more doses of anti-c-kit IgG antibody, said 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 each of said one or more doses comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of said anti-c-kit IgG antibody.

[0316] 22. The kit according to Example 21, wherein each of the one or more doses comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or about 40 mg. The anti-c-kit IgG antibody or composed thereof is available in mg, approximately 320 mg, approximately 340 mg or approximately 360 mg.

[0317] 23. The kit according to Example 22, wherein the kit comprises one or more doses, the one or more doses comprising about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit IgG antibody.

[0318] 24. The kit according to any one of Examples 21 to 23, wherein the kit comprises two or more doses of the anti-c-kit IgG antibody.

[0319] 25. The kit according to Example 24, wherein each of the two or more doses of the anti-c-kit IgG antibody comprises about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit antibody.

[0320] 26. The kit according to any one of Examples 21 to 25, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4 and the variable light chain comprising SEQ ID NO: 5.

[0321] 27. The kit according to Example 26, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO: 3.

[0322] 28. A method for altering the differentiation pathway of hematopoietic stem cells (HSCs) and / or hematopoietic stem cells and progenitor cells (HSPCs), the method comprising contacting the HSCs and / or the HSPCs with an anti-c-kit IgG antibody or an antigen-binding fragment thereof, wherein the anti-c-kit antibody inhibits stem cell factor (SCF) binding to c-kit on the cell surface.

[0323] 29. The method according to Example 28, wherein the method causes the cells to differentiate along the megakaryocyte lineage.

[0324] 30. The method according to Example 28 or Example 29, wherein the anti-c-kit antibody or its antigen-binding fragment comprises at least five CDRs selected from the following: 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).

[0325] 31. The method according to any one of Examples 28 to 30, wherein the anti-c-kit antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO: 5.

[0326] 32. The method according to Example 31, wherein the anti-c-kit antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO: 3.

[0327] 33. Use of an anti-c-kit IgG antibody, said 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); VLCDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), said anti-c-kit IgG antibody being used to prepare a medicament for treating, inhibiting, or preventing mast cell-related diseases or conditions in a human subject, wherein the subject is administered: a) Two or more doses of the anti-c-kit IgG antibody, wherein each dose contains about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody, and wherein each dose is administered at intervals of eight weeks to six months; or b) A dose of the anti-c-kit IgG antibody, wherein the dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody.

[0328] 34. The use according to Example 33, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 320 mg, or about 320 mg. mg, about 340 mg or about 360 mg of the anti-c-kit IgG antibody or composed thereof.

[0329] 35. The use according to Example 34, wherein each dose comprises about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit IgG antibody.

[0330] 36. The use according to any one of Examples 33 to 35, wherein the disease or condition is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic induced urticaria (CIndU), chronic idiopathic urticaria (CIU), pigmented urticaria, nodular prurigo, esophagitis (optionally eosinophilic esophagitis), asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and conditions, dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.

[0331] 37. The use according to Example 36, wherein the disease or condition is chronic spontaneous urticaria (CSU), optionally wherein the subject retains symptoms despite treatment with antihistamines, and wherein the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, or about 400 mg. The anti-c-kit antibody is administered at doses of approximately 320 mg, 340 mg, or 360 mg, with each dose administered at intervals of eight weeks to six months.

[0332] 38. According to the use described in Example 36, wherein the disease or condition is chronic inducible urticaria (CIndU), optionally cold urticaria (ColdU), or symptomatic dermatographia (SD), and the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 280 mg. The anti-c-kit antibody is administered at doses of approximately 300 mg, 320 mg, 340 mg, or 360 mg, with each dose administered at intervals of eight weeks to six months.

[0333] 39. The use according to any one of Examples 33 to 38, wherein the anti-c-kit antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

[0334] 40. The use according to any one of Examples 33 to 39, wherein two or more doses of the anti-c-kit IgG antibody are administered to the subject, and wherein each of the doses is administered at intervals of about eight weeks to about six months, about eight weeks to about four months, about eight weeks to about twelve weeks, about twelve weeks to about six months, about twelve weeks to about four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about four months, or about six months, optionally wherein the time interval between each dose is different.

[0335] 41. The use according to any one of Examples 33 to 40, wherein the method results in a reduction of UAS7 ≤ 6 or mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

[0336] 42. The method according to any one of Examples 33 to 41, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO: 5.

[0337] 43. The use according to claim 42, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2, and the light chain comprising SEQ ID NO: 3.

[0338] 44. Use of an anti-c-kit IgG antibody, said 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); VLCDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), said anti-c-kit IgG antibody for preparing a medicament for selectively depleting mast cells rather than hematopoietic stem cells and progenitor cells (HSPCs) in a subject, said method comprising administering to said subject one or more therapeutically effective doses of the anti-c-kit IgG antibody, wherein each dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg or about 50 mg. The anti-c-kit IgG antibody is measured in mg to approximately 300 mg.

[0339] 45. The use according to Example 44, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 320 mg, or about 320 mg. mg, about 340 mg or about 360 mg of the anti-c-kit IgG antibody or composed thereof.

[0340] 46. ​​The use according to Example 45, wherein each dose comprises about 80 mg, about 120 mg, about 180 mg, about 240 mg, about 280 mg or about 360 mg of the anti-c-kit IgG antibody.

[0341] 47. The use according to any one of Examples 44 to 46, wherein the anti-c-kit IgG antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

[0342] 48. The use according to any one of Examples 44 to 47, wherein two or more doses of the anti-c-kit antibody are administered to the subject.

[0343] 49. In accordance with the use described in Example 48, the doses are administered at intervals of eight weeks to one year, eight weeks to six months, eight weeks to four months, twelve weeks to one year, twelve weeks to six months, twelve weeks to four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about four months, about six months, eight months, about ten months, or about one year, optionally with different time intervals between each dose.

[0344] 50. The use according to any one of Examples 44 to 49, wherein the method reduces mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%, and reduces HSPC by less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%.

[0345] 51. The use according to any one of Examples 44 to 50, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4 and the variable light chain comprising SEQ ID NO: 5.

[0346] 52. The use according to Example 51, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO: 3.

[0347] Example Example 1 Beritrelimab prevents passive systemic anaphylaxis in chimeric human / mouse CD117-expressing mice. Stem cell factor (SCF) signaling via c-Kit (CD117) plays a crucial role in mast cell differentiation and survival. Beretricilimab is a humanized deglycosylated monoclonal antibody targeting CD117, blocking the binding of SCF to CD117 and SCF / CD117 signaling, leading to mast cell apoptosis. Figure 5 As shown, the SCF / CD117 pathway is crucial for mast cell function and survival.

[0348] Béritristimab was evaluated in a mouse model of IgE-induced passive systemic anaphylaxis (PSA). Since c-Kit antibodies designed for the human receptor do not bind to wild-type mouse c-Kit, a transgenic mouse model with chimeric CD117 containing both the human c-Kit extracellular domain and the mouse c-Kit intracellular domain was developed to allow direct in vivo testing of c-Kit antibodies, including JSP191. The human extracellular domain binds to JSP191 and mouse stem cell factor (SCF), while the mouse intracellular domain retains normal signal transduction. Transgenic mice expressing only chimeric CD117 (h / mCD117) (composed of the human extracellular and mouse intracellular regions of CD117 replacing wild-type mouse CD117) were generated. The pharmacokinetics, pharmacodynamics, and effect on PSA responses of béritristimab were evaluated in h / mCD117 mice.

[0349] Chimeric h / mCD117 responds to mouse SCF and is recognized by beretrilimab. Treatment of h / mCD117 mice with beretrilimab (5 mg / kg, 10 mg / kg, and 25 mg / kg, IV) resulted in a transient, modest decrease in peripheral blood cell counts and transient depletion of CD117-expressing hematopoietic stem cells. The pharmacokinetic clearance of beretrilimab in serum is dose-dependent in a non-linear manner.

[0350] In the h / mCD117 mouse model, beretrilimab prevented IgE-dependent hypersensitivity. Figure 6A This paper presents the experimental protocol for assessing PSA in h / mCD117 mice after a single administration of berituximab (25 mg / kg IV), compared to a control group untreated with berituximab. PSA challenge at specific time points following berituximab administration involved administration of α-dinitrophenol (DNP)-IgE IP followed by IV administration of DNP-HAS (human serum albumin), which crosslinks DNP-IgE. Changes in core body temperature and clinical signs (clinical allergy score) over time were monitored after PSA challenge at specific time points following berituximab administration. Figure 6BAs shown, while untreated mice (lined with squares) exhibited a significant decrease in core body temperature (hypothermia) in response to PSA stimulation, mice treated with beretrilimab (lined with triangles) were partially or completely protected from severe hypothermia 1–4 weeks after beretrilimab treatment. Lines with squares represent animals that received neither beretrilimab nor PSA stimulation and were given only isoflurane. Figure 6C Clinical allergy scores are shown in relation to the severity of hypothermia.

[0351] Treatment with beretrilimab at 5 mg / kg three times a week for three weeks, followed by IgE-induced PSA challenge, resulted in a reduced allergic response.

[0352] Notably, treatment with a single 25 mg / kg dose of beretricilumab two weeks prior to PSA challenge completely prevented the allergic response, indicating that a single high dose of beretricilumab effectively blocked the PSA response in h / mCD117 mice. Figure 4 ).

[0353] Following a single intravenous (IV) administration of beretrilimab to h / mCD117 mice, mast cell consumption in various tissues was assessed. Mast cells were detected by toluidine blue staining of tissue sections. As shown in Figure 7, differential mast cell consumption and recovery kinetics following beretrilimab administration were observed in various tissues of h / mCD117 mice. Figure 7A The number of mast cells in the ear skin, stomach, and tongue of h / mCD117 mice 1–4 weeks after a single 25 mg / kg IV beretrillimab treatment is shown (left bar). Figure 7B A representative image of mast cells from the stomach is shown (stained dark purple, indicated by red arrows).

[0354] This study demonstrates that beretrilimab is a promising treatment option for mast cell-mediated conditions, including but not limited to allergies.

[0355] Example 2 Beritrelimab prevents IgE-independent hypersensitivity in chimeric human / mouse CD117-...

Claims

1. A method for treating, inhibiting, or preventing mast cell-related disease or condition in a human subject, the method comprising administering an anti-c-kit IgG antibody to the human subject, the 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); VLCDR2 = LASNLES (SEQ ID NO: 10); and VL CDR3 = QQNNEDPYT (SEQ ID NO: 11), wherein the subject is administered: a) Two or more doses of the anti-c-kit IgG antibody, wherein each dose contains about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody, and wherein each dose is administered at intervals of eight weeks to six months; or b) A dose of the anti-c-kit IgG antibody, wherein the dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody.

2. The method of claim 1, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or about 360 mg. mg of the anti-c-kit IgG antibody or composed thereof.

3. The method of claim 2, wherein each dose comprises about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg of the anti-c-kit IgG antibody.

4. The method according to any one of claims 1 to 3, wherein the disease or condition is selected from the group consisting of: urticaria, chronic spontaneous urticaria (CSU), chronic induced urticaria (CIndU), chronic idiopathic urticaria (CIU), pigmented urticaria, nodular prurigo, esophagitis (optionally eosinophilic esophagitis), asthma, allergy, mastocytosis, mast cell activation syndrome (MCAS), fibrosis, atherosclerosis, allergic diseases and conditions, dermatitis, endometriosis, interstitial cystitis, and inflammatory bowel disease.

5. The method of claim 4, wherein the disease or condition is chronic spontaneous urticaria (CSU), optionally wherein the subject retains symptoms despite treatment with antihistamines, and wherein the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, about 320 mg, or about 320 mg. The anti-c-kit antibody was administered at doses of approximately 340 mg or 360 mg, with each dose administered at intervals of eight weeks to six months.

6. The method of claim 4, wherein the disease or condition is chronic inducible urticaria (CIndU), optionally cold urticaria (ColdU), or symptomatic dermatographia (SD), and the subject is administered two or more doses of the anti-c-kit IgG antibody, wherein each dose comprises about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 300 mg, or about 400 mg. The anti-c-kit antibody is administered at doses of approximately 320 mg, 340 mg, or 360 mg, with each dose administered at intervals of eight weeks to six months.

7. The method according to any one of claims 1 to 6, wherein the anti-c-kit antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

8. The method according to any one of claims 1 to 7, wherein the subject is administered two or more doses of the anti-c-kit IgG antibody, and wherein each of the doses is administered at intervals of about eight weeks to about six months, about eight weeks to about four months, about eight weeks to about twelve weeks, about twelve weeks to about six months, about twelve weeks to about four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about four months, or about six months, optionally wherein the time interval between each dose is different.

9. The method according to any one of claims 1 to 8, wherein the method results in a reduction of UAS7 ≤ 6 or mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%.

10. The method according to any one of claims 1 to 9, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO:

5.

11. The method of claim 10, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2, and the light chain comprising SEQ ID NO:

3.

12. A method for selectively consuming mast cells rather than hematopoietic stem cells and progenitor cells (HSPCs) in a subject, the method comprising administering to the subject one or more therapeutically effective doses of an anti-c-kit IgG antibody, the 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 each dose comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of the anti-c-kit IgG antibody.

13. The method of claim 12, wherein each dose comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or about 360 mg. mg of the anti-c-kit IgG antibody or composed thereof.

14. The method of claim 13, wherein each dose comprises about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg of the anti-c-kit IgG antibody.

15. The method according to any one of claims 12 to 14, wherein the anti-c-kit IgG antibody is systematically delivered to the subject, optionally wherein the anti-c-kit antibody is delivered intravenously or subcutaneously.

16. The method according to any one of claims 12 to 15, wherein two or more doses of the anti-c-kit antibody are administered to the subject.

17. The method of claim 16, wherein each of the doses is administered at intervals of eight weeks to one year, eight weeks to six months, eight weeks to four months, twelve weeks to one year, twelve weeks to six months, twelve weeks to four months, about eight weeks, about nine weeks, about ten weeks, about twelve weeks, about four months, about six months, eight months, about ten months, or about one year, optionally wherein the time interval between each dose is different.

18. The method according to any one of claims 12 to 17, wherein the method reduces mast cells by at least 50%, at least 70%, at least 70%, at least 80%, or at least 90%, and reduces HSPC by less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%.

19. The method according to any one of claims 12 to 18, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO:

5.

20. The method of claim 19, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO:

3.

21. A kit comprising one or more doses of anti-c-kit IgG antibody, said 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 each of said one or more doses comprises about 20 mg to about 500 mg, optionally about 35 mg to about 350 mg, or about 50 mg to about 300 mg of said anti-c-kit IgG antibody.

22. The kit of claim 21, wherein each of the one or more doses comprises about 40 mg to about 360 mg, about 50 mg to about 300 mg, about 50 mg to about 280 mg, about 50 mg to about 240 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, or about 40 mg. The anti-c-kit IgG antibody or composed thereof is available in mg, approximately 320 mg, approximately 340 mg or approximately 360 mg.

23. The kit of claim 22, wherein the kit comprises one or more doses, the one or more doses comprising about 80 mg, about 120 mg, about 180 mg, about 240 mg or about 360 mg of the anti-c-kit IgG antibody.

24. The kit according to any one of claims 21 to 23, wherein the kit comprises two or more doses of the anti-c-kit IgG antibody.

25. The kit of claim 24, wherein each of the two or more doses of the anti-c-kit IgG antibody comprises about 80 mg, about 120 mg, about 180 mg, about 240 mg, or about 360 mg of the anti-c-kit antibody.

26. The kit according to any one of claims 21 to 25, wherein the anti-c-kit IgG antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO:

5.

27. The kit of claim 26, wherein the anti-c-kit IgG antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2 and the light chain comprising SEQ ID NO:

3.

28. A method for altering the differentiation pathway of hematopoietic stem cells (HSCs) and / or hematopoietic stem cells and progenitor cells (HSPCs), the method comprising contacting the HSCs and / or the HSPCs with an anti-c-kit IgG antibody or an antigen-binding fragment thereof, wherein the anti-c-kit antibody inhibits stem cell factor (SCF) binding to c-kit on the cell surface.

29. The method of claim 28, wherein the method causes the cells to differentiate along the megakaryocyte lineage.

30. The method of claim 28 or claim 29, wherein the anti-c-kit antibody or its antigen-binding fragment comprises at least five CDRs selected from the following: 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).

31. The method according to any one of claims 28 to 30, wherein the anti-c-kit antibody comprises a variable heavy chain and a variable light chain, the variable heavy chain comprising SEQ ID NO: 4, and the variable light chain comprising SEQ ID NO:

5.

32. The method of claim 31, wherein the anti-c-kit antibody comprises a heavy chain and a light chain, the heavy chain comprising SEQ ID NO: 2, and the light chain comprising SEQ ID NO: 3.

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