Treatment of chronic prurigo

Abstract

Provided herein are methods and uses of inhibitors of the receptor tyrosine kinase KIT, such as antibodies and antigen-binding fragments that immunospecifically bind to KIT, for managing, treating, or preventing chronic prurigo, including prurigo nodularis (PN). Also provided are improved antibodies for use in such methods and uses.

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 140,621, filed January 22, 2021, and U.S. Provisional Application No. 63 / 238,688, filed August 30, 2021, which are incorporated by reference in their entireties.

[0002] (Reference to electronically submitted sequence listing) This application incorporates by reference the Sequence Listing submitted herewith as a text file entitled "Seqlisting_12638-171-228.txt", created on January 6, 2022, and having a size of 44,163 bytes.

[0003] (1. Field) Provided herein are methods and uses of inhibitors of the receptor tyrosine kinase KIT, such as antibodies and antigen-binding fragments that immunospecifically bind to KIT, for managing, treating, or preventing chronic prurigo, including prurigo nodularis (PN). Also provided are improved antibodies for use in such methods and uses. [Background technology]

[0004] (2.Background) KIT (or c-Kit) is a type III receptor tyrosine kinase encoded by the c-kit gene. KIT contains five extracellular immunoglobulin (Ig)-like domains, a single transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment (see, e.g., Yarden et al., Nature, 1986, 323:226-232; Ullrich and Schlessinger, Cell, 1990, 61:203-212; Clifford et al., J. Biol. Chem., 2003, 278:31461-31464). The human c-kit gene encoding the KIT receptor was cloned as described in Yarden et al., EMBO J., 1987, 6:3341-3351. KIT is also known as CD117 or stem cell factor receptor ("SCFR"), since it is the receptor for stem cell factor ("SCF") ligand (also known as Steel factor or Kit ligand). Binding of SCF ligand to the first three extracellular Ig-like domains of KIT induces receptor dimerization, thereby activating intrinsic tyrosine kinase activity through phosphorylation of specific tyrosine residues in the juxtamembrane domain and kinase domain (see, e.g., Weiss and Schlessinger, Cell, 1998, 94:277-280; Clifford et al., J. Biol. Chem., 2003, 278:31461-31464). Members of the Stat, Src, ERK, and AKT signaling pathways have been shown to be downstream signal transducers of KIT signaling.

[0005] The fourth (D4) and fifth (D5) extracellular Ig-like domains of KIT are believed to mediate receptor dimerization (see, e.g., International Patent Application Publication No. WO 2008 / 153926; Yuzawa et al., Cell, 2007, 130:323-334).

[0006] Expression of KIT has been detected in a variety of cell types, including mast cells, stem cells, brain cells, melanoblasts, ovarian cells, and cancer cells (e.g., leukemia cells) (see, e.g., Besmer, P., Curr. Opin. Cell Biol., 1991, 3:939-946; Lyman et al., Blood, 1998, 91:1101-1134; Ashman, LK, Int. J. Biochem. Cell Biol., 1999, 31:1037-1051; Kitamura et al., Mutat. Res., 2001, 477:165-171; Mol et al., J. Biol. Chem., 2003, 278:31461-31464). In addition, KIT plays important roles in hematopoiesis, melanogenesis, and gametogenesis (see Ueda et al., Blood, 2002, 99:3342-3349).

[0007] Antibodies against human KIT are known, for example, from International Patent Publication WO2014018625A1, which is incorporated herein by reference in its entirety.

[0008] Chronic prurigo (CPG) is a disease characterized by both chronic pruritus (itch) and the presence of multiple localized or generalized pruritic skin lesions.

[0009] Prurigo nodularis (PN; also known as nodular prurigo) is a distinctive clinical disorder defined by the presence of both chronic pruritus and multiple localized or generalized, elevated, indurated, and nodular skin lesions. The underlying cause of PN is unknown, but both neurological and immunological processes are thought to play a role in its development (Elmariah et al., Practical approaches for diagnosis and management of prurigo nodularis: US expert panel consensus, Journal of the American Academy of Dermatology, 2020, S0190-9622(20):32189-32187). Also cited are Periera et al., Journal of the European Academy of Dermatology and Venereology (JEADV), 2018, 32:1059-1065 and Zeidler et al., Acta Derm Venereol, 2018, 98:173-179).

[0010] There is a need for therapies to effectively manage or treat chronic prurigo, including prurigo nodularis, and there is also a need to provide improved antibodies for use in such treatments. Summary of the Invention

[0011] (3. Overview) In one aspect, provided herein is a method of preventing, treating, or managing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof.

[0012] In another aspect, provided herein is the use of an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof, for the manufacture of a medicament for preventing, treating, or managing chronic prurigo in a subject.

[0013] In another aspect, provided herein is an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof, for use in a method of preventing, treating, or managing chronic prurigo in a subject.

[0014] In a specific embodiment, human KIT comprises the amino acid sequence of SEQ ID NO:1.

[0015] In a specific embodiment, the chronic prurigo is prurigo nodularis.

[0016] In a specific embodiment, the antibody is a bivalent monospecific antibody. In a specific embodiment, the antibody is a bispecific antibody.

[0017] In a specific embodiment, the antibody is a humanized antibody.

[0018] In a specific embodiment, the antibody comprises an altered (eg, mutated) Fc region or domain.

[0019] In a specific embodiment, the antibody has reduced Fc receptor binding activity (particularly reduced FcγR binding activity).

[0020] In a specific embodiment, the antibody does not induce significant degranulation of human mast cells expressing FcgRI.

[0021] In a specific embodiment, the antibody does not exhibit significant Fc receptor-dependent KIT agonist activity.

[0022] In a specific embodiment, the antibody specifically binds to the D4 or D5 region of human KIT.

[0023] In a specific embodiment, the antibody comprises: (A)(i) a light chain variable region ("VL") comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a heavy chain variable region ("VH") comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; (B)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively; (C)(i) a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively. and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:31, and SEQ ID NO:32, respectively; (D)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:27, respectively; or (E)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:35, SEQ ID NO:36, and SEQ ID NO:37, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:38, SEQ ID NO:39, and SEQ ID NO:40, respectively.

[0024] In a specific embodiment, the antibody comprises a light chain variable region ("VL") comprising VL CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 2-4, respectively, and a heavy chain variable region ("VH") comprising VH CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 5-7, respectively.

[0025] In a specific embodiment, the antibody has (i) the amino acid sequence: [ka] (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid having an aromatic side chain; and (ii) a VL comprising the amino acid sequence: [ka] (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 In a specific embodiment, X is an amino acid having an aliphatic hydroxyl side chain. K1 is the amino acid F or S, and X K2 is the amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is the amino acid K or R, and X H4 is an amino acid V or A, and X H5is an amino acid L or I, and X H6 is the amino acid E or D, and X H7 is the amino acid Q or E, and X H8 is the amino acid S or T.

[0026] In a specific embodiment, the antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12.

[0027] In a specific embodiment, the antibody comprises a human light chain constant region. In a specific embodiment, the antibody comprises a human heavy chain constant region. In a specific embodiment, the human heavy chain constant region is a human IgG constant region. In a specific embodiment, the human heavy chain constant region is a human IgG1 constant region.

[0028] In a specific embodiment, the antibody comprises a modified (e.g., mutated) human Fc region or domain. In a specific embodiment, the antibody comprises a modified (e.g., mutated) human IgG1 Fc region or domain. In a specific embodiment, the modified (e.g., mutated) human IgG1 Fc region or domain comprises the non-natural amino acids 234A, 235Q, and 322Q, as numbered by the EU index in Kabat. In a specific embodiment, the modified (e.g., mutated) human IgG1 Fc region or domain further comprises the non-natural amino acids 252Y, 254T, and 256E, as numbered by the EU index in Kabat.

[0029] In a specific embodiment, the antibody comprises: (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising the non-natural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference.

[0030] In a specific embodiment, the antibody comprises: (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E, as numbered by the EU index as set forth in the Kabat reference.

[0031] In a specific embodiment, the antibody has the amino acid sequence: [ka] The heavy chain comprises:

[0032] In a specific embodiment, the antibody has the amino acid sequence: [ka] The light chain comprises

[0033] In a specific embodiment, the antibody has the amino acid sequence: [ka] and a heavy chain comprising the amino acid sequence: [ka] The light chain comprises

[0034] In a specific embodiment, the subject is a human adult. In a specific embodiment, the subject is a human child. 3.1 Exemplary Implementations (3.1.1 Set 1) 1. A method for preventing, treating, or managing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody, or antigen-binding fragment thereof, that immunospecifically binds to human KIT. 2. The method of embodiment 1, wherein the human KIT comprises the amino acid sequence of SEQ ID NO:1. 3. The method of embodiment 1 or 2, wherein the chronic prurigo is prurigo nodularis. 4. The method of any one of embodiments 1 to 3, wherein the antibody is a bivalent, monospecific antibody. 5. The method of any one of embodiments 1 to 3, wherein the antibody is a bispecific antibody. 6. The method of any one of embodiments 1 to 5, wherein the antibody is a humanized antibody. 7. The method of any one of embodiments 1 to 6, wherein the antibody comprises an altered (e.g., mutated) Fc region or domain. 8. The method of any one of embodiments 1 to 7, wherein the antibody has reduced Fc receptor binding activity. 9. The method of any one of embodiments 1 to 8, wherein the antibody has reduced FcγR binding activity. 10. A method according to any one of embodiments 1 to 9, wherein the antibody does not induce significant degranulation of human mast cells expressing FcgRI. 11. A method according to any one of embodiments 1 to 10, wherein the antibody does not exhibit significant Fc receptor-dependent KIT agonist activity. 12. A method according to any one of embodiments 1 to 11, wherein the antibody specifically binds to the D4 or D5 region of human KIT. 13. The antibody, (A)(i) a light chain variable region ("VL") comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a heavy chain variable region ("VH") comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; (B)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively; (C)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:31, and SEQ ID NO:32, respectively; (D)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 27, respectively; (E)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; The method of any one of embodiments 1 to 12, comprising: 14. The method of embodiment 13, wherein the antibody comprises a VL comprising VL CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 2 to 4, respectively, and a VH comprising VH CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 5 to 7, respectively. 15. The antibody, (i) Amino acid sequence: [ka] (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6is an amino acid having an aromatic side chain; and (ii) Amino acid sequence: [ka] (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain) The method of any one of embodiments 1 to 14, comprising: 16. X K1 is an amino acid F or S, and X K2 is an amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is an amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is amino acid E or D, and X H7 is an amino acid Q or E, and X H8 is the amino acid S or T. 17. The method of any one of embodiments 1 to 16, wherein the antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12. 18. The method of any one of embodiments 1 to 17, wherein the antibody comprises a human light chain constant region. 19. The method of any one of embodiments 1 to 18, wherein the antibody comprises a human heavy chain constant region. 20. The method of embodiment 19, wherein the human heavy chain constant region is a human IgG constant region. 21. The method of embodiment 20, wherein the human heavy chain constant region is a human IgG1 constant region. 22. The method of any one of embodiments 1 to 21, wherein the antibody comprises an altered (e.g., mutated) human Fc region or domain. 23. The method of any one of embodiments 1 to 21, wherein the antibody comprises an altered (e.g., mutated) human IgG1 Fc region or domain. 24. The method of embodiment 23, wherein the modified (e.g., mutated) human IgG1 Fc region or domain comprises the unnatural amino acids 234A, 235Q and 322Q, as numbered by the EU index as set forth in the Kabat reference. 25. The method of embodiment 24, wherein the modified (e.g., mutated) human IgG1 Fc region or domain further comprises the unnatural amino acids 252Y, 254T and 256E, as numbered by the EU index as set forth in the Kabat reference. 26. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain containing the unnatural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference. The method of any one of embodiments 1 to 25, comprising: 27. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that contains the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index as set forth in the Kabat reference. The method of any one of embodiments 1 to 25, comprising: 28. The antibody comprises the amino acid sequence: [ka] The method of any one of embodiments 1 to 25, comprising a heavy chain comprising: 29. The antibody comprises the amino acid sequence: [ka] The method of any one of embodiments 1-25, comprising a light chain comprising: 30. The antibody comprises the amino acid sequence: [ka] and a heavy chain comprising the amino acid sequence: [ka] The method of any one of embodiments 1-25, comprising a light chain comprising: 31. The method of any one of embodiments 1 to 30, wherein the subject is an adult human. 32. The method of any one of embodiments 1 to 30, wherein the subject is a human child. (3.1.2 Set 2) 1. Use of an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof, for the manufacture of a medicament for preventing, treating, or managing chronic prurigo in a subject. 2. The use according to embodiment 1, wherein the human KIT comprises the amino acid sequence of SEQ ID NO:1. 3. The use according to embodiment 1 or 2, wherein the chronic prurigo is prurigo nodularis. 4. The use according to any one of embodiments 1 to 3, wherein the antibody is a bivalent, monospecific antibody. 5. The use according to any one of embodiments 1 to 3, wherein the antibody is a bispecific antibody. 6. The use according to any one of embodiments 1 to 5, wherein the antibody is a humanized antibody. 7. The use according to any one of embodiments 1 to 6, wherein the antibody comprises an altered (e.g., mutated) Fc region or domain. 8. The use according to any one of embodiments 1 to 7, wherein the antibody has reduced Fc receptor binding activity. 9. The use according to any one of embodiments 1 to 8, wherein the antibody has reduced FcγR binding activity. 10. The use according to any one of embodiments 1 to 9, wherein the antibody does not induce significant degranulation of human mast cells expressing FcgRI. 11. The use according to any one of embodiments 1 to 10, wherein the antibody does not exhibit significant Fc receptor-dependent KIT agonist activity. 12. The use according to any one of embodiments 1 to 11, wherein the antibody specifically binds to the D4 or D5 region of human KIT. 13. The antibody, (A)(i) a light chain variable region ("VL") comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a heavy chain variable region ("VH") comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; (B)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively; (C)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:31, and SEQ ID NO:32, respectively; (D)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 27, respectively; (E)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; The use according to any one of embodiments 1 to 12, comprising: 14. The use according to any one of embodiments 1 to 13, wherein the antibody comprises a VL comprising VL CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 2 to 4, respectively, and a VH comprising VH CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 5 to 7, respectively. 15. The antibody, (i) Amino acid sequence: [ka] (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid having an aromatic side chain; and (ii) Amino acid sequence: [ka] (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain) The use according to any one of embodiments 1 to 13, comprising: 16. X K1 is an amino acid F or S, and X K2 is an amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is an amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is amino acid E or D, and X H7 is an amino acid Q or E, and X H8 is the amino acid S or T. 17. The use of any one of embodiments 1 to 16, wherein the antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12. 18. The use according to any one of embodiments 1 to 17, wherein the antibody comprises a human light chain constant region. 19. The use according to any one of embodiments 1 to 18, wherein the antibody comprises a human heavy chain constant region. 20. The use of embodiment 19, wherein the human heavy chain constant region is a human IgG constant region. 21. The use according to embodiment 20, wherein the human heavy chain constant region is a human IgG1 constant region. 22. The use according to any one of embodiments 1 to 21, wherein the antibody comprises a modified (e.g., mutated) human Fc region or domain. 23. The use according to any one of embodiments 1 to 21, wherein the antibody comprises an altered (e.g., mutated) human IgG1 Fc region or domain. 24. The use according to embodiment 23, wherein the modified (e.g. mutated) human IgG1 Fc region or domain comprises the unnatural amino acids 234A, 235Q and 322Q, as numbered by the EU index as set out in the Kabat reference. 25. The use of embodiment 24, wherein the modified (e.g., mutated) human IgG1 Fc region or domain further comprises the unnatural amino acids 252Y, 254T and 256E, as numbered by the EU index as set out in the Kabat reference. 26. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain containing the unnatural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference. The use according to any one of embodiments 1 to 25, comprising: 27. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that contains the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index as set forth in the Kabat reference. The use according to any one of embodiments 1 to 25, comprising: 28. The antibody comprises the amino acid sequence: [ka] The use according to any one of embodiments 1 to 25, comprising a heavy chain comprising: 29. The antibody comprises the amino acid sequence: [ka] The use according to any one of embodiments 1 to 25, comprising a light chain comprising: 30. The antibody comprises the amino acid sequence: [ka] and a heavy chain comprising the amino acid sequence: [ka] The use according to any one of embodiments 1 to 25, comprising a light chain comprising: 31. The use according to any one of embodiments 1 to 30, wherein the subject is an adult human. 32. The use according to any one of embodiments 1 to 30, wherein the subject is a human child. (3.1.3 Set 3) 1. An antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof, for use in a method of preventing, treating, or managing chronic prurigo in a subject. 2. The antibody or antigen-binding fragment thereof for use according to embodiment 1, wherein human KIT comprises the amino acid sequence of SEQ ID NO:1. 3. The antibody or antigen-binding fragment thereof for use according to embodiment 1 or 2, wherein the chronic prurigo is prurigo nodularis. 4. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 3, wherein the antibody is a bivalent, monospecific antibody. 5. An antibody or an antigen-binding fragment thereof for use according to any one of embodiments 1 to 3, wherein the antibody is a bispecific antibody. 6. An antibody or an antigen-binding fragment thereof for use according to any one of embodiments 1 to 5, wherein the antibody is a humanized antibody. 7. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 6, wherein the antibody comprises an altered (e.g., mutated) Fc region or domain. 8. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 7, wherein the antibody has reduced Fc receptor binding activity. 9. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 8, wherein the antibody has reduced FcγR binding activity. 10. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 9, wherein the antibody does not induce significant degranulation of human mast cells expressing FcgRI. 11. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 10, wherein the antibody does not exhibit significant Fc receptor-dependent KIT agonist activity. 12. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 11, wherein the antibody specifically binds to the D4 or D5 region of human KIT. 13. The antibody, (A)(i) a light chain variable region ("VL") comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a heavy chain variable region ("VH") comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; (B)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively; (C)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:31, and SEQ ID NO:32, respectively; (D)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 27, respectively; (E)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; 13. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 12, comprising: 14. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 13, wherein the antibody comprises a VL comprising VL CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 2 to 4, respectively, and a VH comprising VH CDR1 to 3 comprising the amino acid sequences of SEQ ID NOs: 5 to 7, respectively. 15. The antibody, (i) Amino acid sequence: [ka] (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; XK5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid having an aromatic side chain; and (ii) Amino acid sequence: [ka] (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain) 15. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 14, comprising: 16. X K1 is an amino acid F or S, and X K2 is an amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is an amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is amino acid E or D, and X H7 is an amino acid Q or E, and X H8 is the amino acid S or T. 17. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 16, wherein the antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12. 18. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 17, wherein the antibody comprises a human light chain constant region. 19. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 18, wherein the antibody comprises a human heavy chain constant region. 20. The antibody or antigen-binding fragment thereof for use according to embodiment 19, wherein the human heavy chain constant region is a human IgG constant region. 21. The antibody or antigen-binding fragment thereof for use according to embodiment 20, wherein the human heavy chain constant region is a human IgG1 constant region. 22. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 21, wherein the antibody comprises a modified (e.g., mutated) human Fc region or domain. 23. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 21, wherein the antibody comprises an altered (e.g., mutated) human IgG1 Fc region or domain. 24. The antibody or antigen-binding fragment thereof for use according to embodiment 23, wherein the modified (e.g., mutated) human IgG1 Fc region or domain comprises the unnatural amino acids 234A, 235Q and 322Q, as numbered by the EU index as set out in the Kabat reference. 25. The antibody or antigen-binding fragment thereof for use according to embodiment 24, wherein the modified (e.g., mutated) human IgG1 Fc region or domain further comprises the unnatural amino acids 252Y, 254T and 256E, as numbered by the EU index as set out in the Kabat reference. 26. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain containing the unnatural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference. 26. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 25, comprising: 27. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that contains the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index as set forth in the Kabat reference. 26. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 25, comprising: 28. The antibody comprises the amino acid sequence: [ka] 26. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 25, comprising a heavy chain comprising: 29. The antibody comprises the amino acid sequence: [ka] 26. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 25, comprising a light chain comprising: 30. The antibody comprises the amino acid sequence: [ka] and a heavy chain comprising the amino acid sequence: [ka] 26. The antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 25, comprising a light chain comprising: 31. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 30, wherein the subject is an adult human. 32. An antibody or antigen-binding fragment thereof for use according to any one of embodiments 1 to 30, wherein the subject is a human child. [Brief description of the drawings]

[0035] (4. BRIEF DESCRIPTION OF THE DRAWINGS) [Figure 1] 1 shows the amino acid sequence of full-length human KIT (SEQ ID NO:1), GenBank™ Accession No. AAC50969. The first through fifth extracellular Ig-like domains (i.e., D1, D2, D3, D4, and D5) are shown; "{" indicates the amino terminal residue of each domain and "}" indicates the carboxyl terminal residue of each domain. The D1 domain is shown at P34-R112, the D2 domain is shown at D113-P206, the D3 domain is shown at A207-D309, the D4 domain is shown at K310-N410, the hinge region between D4 and D5 is located at V409-N410, and the D5 domain is shown at T411-K509. Additionally, the D1 / D2 hinge region is located at D113 to L117; the D2 / D3 hinge region is located at P206 to A210; and the D3 / D4 hinge region is located at D309 to G311. The D4 / D5 region includes K310 to K509. The transmembrane domain includes residues F525 to Q545, and the kinase domain includes residues K589 to S933.

[0036] [Diagram 2] 2A-2E show the effect of mAb1, a specific anti-KIT antibody according to the invention, on plasma tryptase levels.

[0037] [Diagram 3] 3A and 3B show the further effect of mAb1, a specific anti-KIT antibody according to the invention, on plasma tryptase levels.

[0038] [Figure 4] FIG. 4 shows the effect of a particular anti-KIT antibody according to the invention, mAb1, on plasma stem cell factor (SCF) levels.

[0039] [Diagram 5] FIG. 5 shows the effect of a specific anti-KIT antibody according to the invention, mAb1, and the corresponding antibody mAbc having the same variable region sequences but unmutated (wild-type) human IgG1 sequences, on SCF-induced activation of wild-type KIT and downstream intracellular signaling pathways.

[0040] [Figure 6] FIG. 6 shows the effect on SCF-dependent cell proliferation of a particular anti-KIT antibody according to the invention, mAb1, and the corresponding antibody mAbc having the same variable region sequences but unmutated (wild-type) human IgG1 sequences.

[0041] [Figure 7] FIG. 7 shows the binding affinity of a particular anti-KIT antibody according to the invention, mAb1, and the corresponding antibody mAbc having the same variable region sequences but unmutated (wild-type) human IgG1 sequences, to recombinant human Fc-gamma receptor (FcγR) and human fetal Fc receptor (FcRn).

[0042] [Figure 8]8A-8N show binding curves of a specific anti-KIT antibody according to the invention, mAb1, and a corresponding antibody mAbc with the same variable region sequence but with unmutated (wild type) human IgG1 sequence to recombinant human Fc-gamma receptor (FcγR) and human fetal Fc receptor (FcRn). FIG. 8A shows the binding curve of mAb1 to FcγRI. FIG. 8B shows the binding curve of mAb1 to FcγRIIa. FIG. 8C shows the binding curve of mAb1 to FcγRIIb. FIG. 8D shows the binding curve of mAb1 to FcγRIIIa. FIG. 8E shows the binding curve of mAb1 to FcγRIIIb. FIG. 8F shows the binding curve of mAb1 to FcRn (pH 6.0). FIG. 8G shows the binding curve of mAb1 to FcRn (pH 7.2). FIG. 8H shows the binding curve of mAbc to FcγRI. Figure 8I shows the binding curve of mAbc to FcγRIIa. Figure 8J shows the binding curve of mAbc to FcγRIIb. Figure 8K shows the binding curve of mAbc to FcγRIIIa. Figure 8L shows the binding curve of mAbc to FcγRIIIb. Figure 8M shows the binding curve of mAbc to FcRn (pH 6.0). Figure 8N shows the binding curve of mAbc to FcRn (pH 7.2).

[0043] [Figure 9] FIG. 9 shows the effect on antibody-dependent cellular cytotoxicity (ADCC) activity of a particular anti-KIT antibody according to the invention, mAb1, and the corresponding antibody mAbc having the same variable region sequences but unmutated (wild-type) human IgG1 sequences.

[0044] [Figure 10]10 shows the effect of a particular anti-KIT antibody, mAb1, according to the invention on specific cytokine production. Conditions shown in each bar graph are, from left to right: PHA, LPS, huIgG1 (soluble), mAb1 0.02 nM (soluble), mAb1 0.2 nM (soluble), mAb1 40 nM (soluble), mAb1 0.02 nM (dry coating), mAb1 0.2 nM (dry coating), and mAb1 40 nM (dry coating).

[0045] [Figure 11] FIG. 11 is a schematic diagram showing the role of KIT signaling in mast cells and the effect of mAb1 on the KIT receptor.

[0046] [Figure 12] Figures 12A-12D show that a single dose of mAb1 resulted in rapid and sustained responses with a 95% complete response (CR) rate in patients with chronically inducible urticaria (CIndU). 10 / 10 cold urticaria (ColdU) patients achieved CR (Figure 12A). 8 / 9 symptomatic dermatitis (SD) patients achieved CR and 1 / 9 SD patients achieved partial response (PR) (Figure 12B). CR = negative provocation test below 4°C or 0 pins; PR = improvement at 4°C or 2 or more pins; maximum response for each patient is shown. TempTest® results over time in ColdU patients are shown in Figure 12C. Among complete ColdU patients (n=8), CR was maintained for a median duration of 77 days (Figure 12C). FricTest® results over time in SD patients are shown in Figure 12D. Among patients with complete SD (n=6), CR was maintained for a median duration of 57 days (FIG. 12D).

[0047] [Figure 13] 13A-13B show overall disease improvement as evidenced by Physician Global Assessment (Phys-GA) and Patient Global Assessment (Pat-GA). Phys-GA and Pat-GA assess disease severity using a Likert scale of 0-3, where 0 is none and 3 is severe.

[0048] [Figure 14] Figures 14A-14D show that mAb1 treatment significantly depleted skin mast cells and serum tryptase. Figure 14A shows that mAb1 reduced skin mast cell numbers (n=14, * means p<0.05, ** means p<0.01, *** means p<0.001, **** means p<0.0001). Figure 14B shows that mAb1 reduced serum tryptase to below the limit of detection in all patients (tryptase values ​​below the limit of assay quantification (LLoQ=1 ng / mL) were normalized to 0). Figure 14C shows mast cell and tryptase kinetics. Figure 14D shows that skin mast cell numbers correlated with serum tryptase levels (p<0.0001; R2=0.45).

[0049] [Figure 15] Figures 15A-15D show that the kinetics of skin mast cells and tryptase depletion reflected the lowering of the induction threshold. Figure 15A shows mast cell kinetics and TempTest® results over time in a ColdU patient. Figure 15B shows mast cell kinetics and FricTest® results over time in a SD patient. Figure 15C shows tryptase kinetics and TempTest® results over time in a ColdU patient (tryptase values ​​below the LLoQ were normalized to 0; a critical temperature threshold below 4°C (negative test) was set to a value of 3°C). Figure 15D shows tryptase kinetics and FricTest® results over time in a SD patient.

[0050] [Figure 16] Figures 16A-16D show that hematological parameters remained within normal ranges in most cases, with mild, transient and asymptomatic decreases in hemoglobin and white blood cell (WBC) parameters. Figure 16A shows hemoglobin (HgB) levels over time. Figure 16B shows WBC counts over time. Figure 16C shows platelet counts over time. Figure 16D shows absolute neutrophil counts (ANC) over time. In each graph, the shaded area represents the corresponding normal range. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] (5. Detailed Description) Provided herein is a method for preventing, treating, or managing chronic prurigo, including prurigo nodularis, in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a human KIT inhibitor. The human KIT inhibitor can be any inhibitor that inhibits the activity or expression level of human KIT protein (e.g., human KIT protein comprising the amino acid sequence of SEQ ID NO:1). In a specific embodiment, the human KIT inhibitor is a biologic. In a specific embodiment, the human KIT inhibitor is an antibody or an antigen-binding fragment thereof that immunospecifically binds to human KIT. In a specific embodiment, the human KIT inhibitor is a small molecule inhibitor. In a specific embodiment, the human KIT inhibitor is an oligonucleotide, such as an aptamer, shRNA, miRNA, siRNA, or antisense DNA.

[0052] In one aspect, provided herein is a method of preventing, treating, or managing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT (e.g., a KIT polypeptide comprising the human KIT D4 or D5 domain, e.g., a human KIT protein comprising the amino acid sequence of SEQ ID NO:1), or an antigen-binding fragment thereof.

[0053] In another aspect, provided herein is a method of preventing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT (e.g., a KIT polypeptide comprising the human KIT D4 or D5 domain, e.g., a human KIT protein comprising the amino acid sequence of SEQ ID NO:1), or an antigen-binding fragment thereof.

[0054] In another aspect, provided herein is a method of treating chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT (e.g., a KIT polypeptide comprising the human KIT D4 or D5 domain, e.g., a human KIT protein comprising the amino acid sequence of SEQ ID NO:1), or an antigen-binding fragment thereof.

[0055] In another aspect, provided herein is a method of managing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT (e.g., a KIT polypeptide comprising the human KIT D4 or D5 domain, e.g., a human KIT protein comprising the amino acid sequence of SEQ ID NO:1), or an antigen-binding fragment thereof.

[0056] In a specific embodiment, the chronic prurigo is nodular prurigo. In a specific embodiment, the chronic prurigo is generalized prurigo. In a specific embodiment, the chronic prurigo is nodular prurigo. In a specific embodiment, the chronic prurigo is prurigo plaque. In a specific embodiment, the chronic prurigo is umbilical prurigo. In a specific embodiment, the chronic prurigo is linear prurigo. In some embodiments, the subject exhibits a monomorphic phenotype of the lesion. In other embodiments, the subject exhibits a polymorphic phenotype of the lesion.

[0057] In certain embodiments, the anti-KIT antibodies, antigen-binding fragments, or conjugates thereof described herein are used to treat chronic prurigo (e.g., prurigo nodularis) and urticaria (e.g., chronic spontaneous urticaria, chronic idiopathic urticaria, and chronic induced urticaria (i.e., chronic inducible urticaria, such as cold urticaria (ColdU), symptomatic dermatographia (SD), cholinergic urticaria, heat urticaria, delayed onset pressure ulcer, solar urticaria, vibratory urticaria, contact urticaria, or water-based urticaria). In a specific embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat, manage, prevent, or prevent both chronic prurigo (e.g., prurigo nodularis) and chronic triggered urticaria (CIndU), such as ColdU, SD, heat urticaria, delayed pressure ulcer, solar urticaria, vibratory urticaria, contact urticaria, or aqueous urticaria. In a specific embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat, manage, prevent, or prevent both chronic prurigo (e.g., prurigo nodularis) and SD. In a specific embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat, manage, prevent, or prevent both prurigo nodularis and SD.

[0058] In various embodiments, the subject with chronic prurigo has failed one or more prior treatments for chronic prurigo. In some embodiments, the one or more prior treatments include at least one standard of care therapy for chronic prurigo. In some embodiments, the one or more prior treatments are all standard of care therapy for chronic prurigo. In some embodiments, the subject with chronic prurigo has failed treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In some embodiments, the subject with chronic prurigo has failed treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In some embodiments, the subject with chronic prurigo has failed treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In some embodiments, the subject with chronic prurigo has failed treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In some embodiments, the subject with chronic prurigo has failed treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast. In some embodiments, the subject with chronic prurigo has failed treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, such as bixarelimab. In some embodiments, the subject with chronic prurigo has failed one, two, three or more of the above treatments for chronic prurigo.

[0059] A subject is considered to have failed treatment if the chronic prurigo is refractory to treatment, resistant to treatment, recurs after treatment, and / or if the subject discontinues treatment due to intolerance to the treatment.

[0060] In various embodiments, the chronic itch is refractory to one or more prior treatments for chronic itch. In some embodiments, the one or more prior treatments include at least one standard treatment therapy for chronic itch. In some embodiments, the one or more prior treatments are all standard treatment therapies for chronic itch. In some embodiments, the chronic itch is refractory to treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In some embodiments, the chronic itch is refractory to treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In some embodiments, the chronic itch is refractory to treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In some embodiments, the chronic itch is refractory to treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In some embodiments, chronic prurigo is refractory to treatment with PDE4 and / or TNF-α inhibitors, such as apremilast.In some embodiments, chronic prurigo is refractory to treatment with OSMRβ inhibitors, such as anti-OSMRβ antibodies, such as bixarelimab.In some embodiments, chronic prurigo is refractory to one, two, three or more of the above treatments for chronic prurigo.

[0061] In various embodiments, the chronic prurigo is resistant to one or more previous treatments for chronic prurigo. In some embodiments, the one or more previous treatments include at least one standard treatment therapy for chronic prurigo. In some embodiments, the one or more previous treatments are all standard treatment therapies for chronic prurigo. In some embodiments, the chronic prurigo is resistant to treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In some embodiments, the chronic prurigo is resistant to treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In some embodiments, the chronic prurigo is resistant to treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In some embodiments, the chronic prurigo is resistant to treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In some embodiments, the chronic prurigo is resistant to treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast. In some embodiments, the chronic prurigo is resistant to treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, such as bixarelimab. In some embodiments, the chronic prurigo is resistant to one, two, three or more of the above treatments for chronic prurigo.

[0062] In various embodiments, the chronic prurigo is both refractory and resistant to one or more prior treatments for chronic prurigo. In some embodiments, the one or more prior treatments include at least one standard of care therapy for chronic prurigo. In some embodiments, the one or more prior treatments are all standard of care therapies for chronic prurigo. In some embodiments, the chronic prurigo is both refractory and resistant to treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In some embodiments, the chronic prurigo is both refractory and resistant to treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In some embodiments, the chronic prurigo is both refractory and resistant to treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In some embodiments, the chronic prurigo is both refractory and resistant to treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In some embodiments, the chronic prurigo is both refractory and resistant to treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast. In some embodiments, the chronic prurigo is both refractory and resistant to treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, such as bixarelimab. In some embodiments, the chronic prurigo is both refractory and resistant to one, two, three, or more of the above treatments for chronic prurigo.

[0063] In various embodiments, the chronic prurigo recurs after one or more previous treatments for chronic prurigo. In some embodiments, the one or more previous treatments include at least one standard treatment therapy for chronic prurigo. In some embodiments, the one or more previous treatments are all standard treatment therapy for chronic prurigo. In some embodiments, the chronic prurigo recurs after treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In some embodiments, the chronic prurigo recurs after treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In some embodiments, the chronic prurigo recurs after treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In some embodiments, the chronic prurigo recurs after treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In some embodiments, the chronic prurigo recurs after treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast.In some embodiments, the chronic prurigo recurs after treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, such as bixarelimab.In some embodiments, the chronic prurigo recurs after one, two, three or more of the above treatments for chronic prurigo.

[0064] In various embodiments, the subject with chronic prurigo has discontinued one or more prior treatments for chronic prurigo due to intolerance of the treatment(s). In certain embodiments, the one or more prior treatments include at least one standard of care therapy for chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for chronic prurigo. In certain embodiments, the subject with chronic prurigo has discontinued treatment with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), due to intolerance of the treatment. In certain embodiments, the subject with chronic prurigo has discontinued treatment with an IL-31 receptor alpha inhibitor, such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab, due to intolerance of the treatment. In certain embodiments, the subject with chronic prurigo has discontinued treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, due to intolerance of the treatment. In some embodiments, the subject with chronic prurigo has discontinued treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, due to intolerance of the treatment. In some embodiments, the subject with chronic prurigo has discontinued treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, due to intolerance of the treatment. In some embodiments, the subject with chronic prurigo has discontinued treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, e.g., bixarelimab, due to intolerance of the treatment. In some embodiments, the subject with chronic prurigo has discontinued one, two, three, or more of the above treatments for chronic prurigo due to intolerance of the treatment(s).

[0065] In various embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic triggered urticaria), the subject with urticaria (e.g., chronic triggered urticaria) has failed one or more prior treatments for urticaria. In certain embodiments, the one or more prior treatments include at least one standard of care therapy for urticaria. In certain embodiments, the one or more prior treatments are all standard of care therapy for urticaria. In certain embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic triggered urticaria), the subject with urticaria (e.g., chronic triggered urticaria) has failed one or more antihistamine treatments for urticaria. In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed H1-antihistamine treatment(s) for the urticaria. In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed H2-antihistamine treatment(s) for the urticaria. In certain embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed both H1-antihistamine treatment and H2-antihistamine treatment for urticaria. In certain embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed one or more leukotriene receptor antagonist treatment(s) for urticaria.In certain embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic triggered urticaria), the subject with urticaria (e.g., chronic triggered urticaria) has failed treatment(s) with one or more immunomodulatory or anti-inflammatory agents for urticaria. In specific embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic triggered urticaria), the subject with urticaria (e.g., chronic triggered urticaria) has failed treatment with an anti-IgE antibody for urticaria, e.g., an IgE inhibitor such as omalizumab (Xolair®) or ligelizumab. In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-IL-4R antibody for urticaria, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-IL-5R antibody for urticaria, e.g., an IL-5R inhibitor such as benralizumab (Fasenra®). In specific embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-IL-5 antibody, e.g., an IL-5 inhibitor such as mepolizumab, for urticaria.In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-Siglec 8 antibody for urticaria, e.g., a Siglec 8 inhibitor such as lirentelimab. In specific embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-TSLP antibody or anti-TSLPR antibody for urticaria, e.g., a TSLP inhibitor or a TSLPR inhibitor such as tezepelumab (Tezspire™). In a specific embodiment where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-C5aR antibody for urticaria, e.g., a C5aR inhibitor such as abdoralimab. In a specific embodiment where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with an anti-CD200R antibody for urticaria, e.g., a CD200R inhibitor such as LY3454738. In specific embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment(s) with one or more Bruton's tyrosine kinase (BTK) inhibitors for urticaria, e.g., remibrutinib and / or rilzabrutinib.In certain embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) is receiving (1) antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)) for the urticaria, (2) treatment with one or more leukotriene receptor antagonists (e.g., chronic inducible urticaria), and (3) treatment with one or more leukotriene receptor antagonists (e.g., chronic inducible urticaria). (3) one or more immunomodulatory or anti-inflammatory agents (e.g., an anti-IgE antibody, e.g., an IgE inhibitor such as omalizumab (Xolair®) or ligelizumab, an anti-IL-4R antibody, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®), an anti-IL-5R antibody, e.g., an IL-5R inhibitor such as benralizumab (Fasenra®), an anti-IL-5 antibody, e.g., an IL-5 inhibitor such as mepolizumab, an anti-Siglec and / or (3) have failed treatment(s) with one or more BTK inhibitors, such as remibrutinib and / or rilzabrutinib; an anti-TSLP antibody or an anti-TSLPR antibody, such as a TSLP inhibitor such as tezepelumab (Tezspire™) or a TSLPR inhibitor; an anti-C5aR antibody, such as a C5aR inhibitor such as abduralimab; and / or an anti-CD200R antibody, such as a CD200R inhibitor such as LY3454738; and / or (4) have failed treatment(s) with one or more BTK inhibitors, such as remibrutinib and / or rilzabrutinib.In certain embodiments where an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) is receiving (1) antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)) for the urticaria, and (2) one or more immunomodulatory agents or anti-inflammatory agents (e.g., anti-IgE antibodies, e.g., IgE inhibitors such as omalizumab (Xolair®) or ligelizumab, anti-IL-4R antibodies, e.g., IL-4R inhibitors such as dupilumab (Dupixent®), anti-IL-5R antibodies, e.g., IL-5R inhibitors such as benralizumab (Fasenra®), anti-IL-5 antibodies, e.g., IL-5 inhibitors such as mepolizumab, anti-Siglec 8 antibodies, e.g., Siglec inhibitors such as lirentelimab, The subject has failed treatment(s) with a treatment with an anti-KIT antibody, an anti-TSLPR antibody, e.g., a TSLP inhibitor or a TSLPR inhibitor such as tezepelumab (Tezspire™), an anti-C5aR antibody, e.g., a C5aR inhibitor such as abdoralimab, and / or an anti-CD200R antibody, e.g., a CD200R inhibitor such as LY3454738. The anti-KIT antibody, antigen-binding fragment thereof, or conjugate thereof described herein is useful for treating or managing both chronic prurigo and urticaria (e.g., chronic inducible urticaria). In certain embodiments, the therapeutic agent is administered to a subject for the treatment of urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment(s) for urticaria: (1) antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s); (2) treatment with an IgE inhibitor, such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab; and (3) treatment(s) with an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®).In certain embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed (1) antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)) for the urticaria, and (2) treatment with an IgE inhibitor, such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In certain embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject with urticaria (e.g., chronic inducible urticaria) has failed treatment with (1) an anti-IgE antibody, e.g., an IgE inhibitor such as omalizumab (Xolair®) or ligelizumab, and (2) an IL-4R inhibitor, such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for urticaria.

[0066] If urticaria (e.g., chronically triggered urticaria) is refractory to treatment, resistant to treatment, recurs after treatment, and / or the subject discontinues treatment due to intolerance to treatment, the subject is considered to have failed treatment for urticaria (e.g., chronically triggered urticaria).In a specific embodiment, the subject with both chronic prurigo and urticaria (e.g., chronically triggered urticaria) has urticaria (e.g., chronically triggered urticaria) that is refractory to one or more previous treatments for urticaria, which may be one or more treatments for urticaria described above.In a specific embodiment, the subject with both chronic prurigo and urticaria (e.g., chronically triggered urticaria) has urticaria (e.g., chronically triggered urticaria) that is resistant to one or more previous treatments for urticaria, which may be one or more treatments for urticaria described above. In a specific embodiment, the subject with both chronic prurigo and urticaria (e.g., chronic triggered urticaria) has urticaria (e.g., chronic triggered urticaria) that is both refractory and resistant to one or more previous treatments for urticaria, which can be one or more treatments for urticaria described above.In a specific embodiment, the subject with both chronic prurigo and urticaria (e.g., chronic triggered urticaria) has recurrent urticaria (e.g., chronic triggered urticaria) after one or more previous treatments for urticaria, which can be one or more treatments for urticaria described above.In a specific embodiment, the subject with both chronic prurigo and urticaria (e.g., chronic triggered urticaria) has discontinued one or more previous treatments for urticaria, which can be one or more treatments for urticaria described above.

[0067] In various embodiments in which an anti-KIT antibody, antigen-binding fragment thereof, or conjugate thereof described herein is administered to a subject to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria), the subject has failed one or more prior treatments for chronic prurigo, which may be one or more treatments for chronic prurigo as described above, and the subject has also failed one or more prior treatments for urticaria (e.g., chronic inducible urticaria), which may be one or more treatments for urticaria as described above.

[0068] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an anti-IL-4R antibody, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an anti-IL-31 receptor alpha antibody, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a Janus kinase 1 inhibitor, such as INCB054707 or abrocitinib.In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a neurokinin-1 (NK1) receptor antagonist, such as serlopitant.In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an anti-OSMRbeta antibody, e.g., an OSMRbeta inhibitor, such as bixarelimab.

[0069] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has both chronic prurigo and urticaria (e.g., chronically triggered urticaria), whose urticaria (e.g., chronically triggered urticaria) remains symptomatic despite treatment with one or more prior treatments for urticaria, which can be one or more treatments for urticaria described above.

[0070] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has both chronic prurigo and urticaria (e.g., chronically triggered urticaria), where the chronic prurigo remains symptomatic despite treatment with one or more prior treatments for chronic prurigo, which may be one or more treatments for chronic prurigo as described above, and where the urticaria (e.g., chronically triggered urticaria) remains symptomatic despite treatment with one or more prior treatments for urticaria, which may be one or more treatments for urticaria as described above.

[0071] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said one or more prior treatments for chronic prurigo to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said treatment with an IL-4R inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said treatment with an IL-31 receptor alpha inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said treatment with a Janus kinase 1 inhibitor, for example, INCB054707 or abrocitinib, for chronic prurigo, to treat or manage chronic prurigo after treatment with a Janus kinase 1 inhibitor, for example, INCB054707 or abrocitinib. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said treatment with a NK1 receptor antagonist, for chronic prurigo, to treat or manage chronic prurigo after treatment with a neurokinin-1 (NK1) receptor antagonist, for example, serlopitant, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said treatment with a PDE4 and / or TNF-α inhibitor, for chronic prurigo, to treat or manage chronic prurigo after treatment with a PDE4 and / or TNF-α inhibitor, for example, apremilast, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo following treatment with an OSMRβ inhibitor, such as an anti-OSMRβ antibody, e.g., bixarelimab, to a subject who has failed said treatment with an OSMRβ inhibitor.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo after said one, two, three or more treatments for chronic prurigo to a subject who has failed said one, two, three or more treatments.

[0072] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said one or more prior treatments for chronic prurigo to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with an IL-4R inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with an IL-31 receptor alpha inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with a Janus kinase 1 inhibitor to treat or manage chronic prurigo after treatment with a Janus kinase 1 inhibitor for chronic prurigo, e.g., INCB054707 or abrocitinib. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with a NK1 receptor antagonist to treat or manage chronic prurigo after treatment with a neurokinin-1 (NK1) receptor antagonist for chronic prurigo, e.g., serlopitant. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with a PDE4 and / or TNF-α inhibitor to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said treatment with an OSMRβ inhibitor to treat or manage chronic prurigo after treatment with an anti-OSMRβ antibody, e.g., an OSMRβ inhibitor such as bixarelimab, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is refractory to said one, two, three, or more treatments to treat or manage chronic prurigo after said one, two, three, or more treatments for chronic prurigo.

[0073] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said one or more prior treatments for chronic prurigo to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with an IL-4R inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with an IL-31 receptor alpha inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with a Janus kinase 1 inhibitor, for example, INCB054707 or abrocitinib, for treating or managing chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with a Janus kinase 1 inhibitor, for treating or managing chronic prurigo ... In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with a PDE4 and / or TNF-α inhibitor to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said treatment with an OSMRβ inhibitor to treat or manage chronic prurigo after treatment with an anti-OSMRβ antibody, e.g., an OSMRβ inhibitor such as bixarelimab, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is resistant to said one, two, three, or more treatments to treat or manage chronic prurigo after said one, two, three, or more treatments for chronic prurigo.

[0074] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said one or more prior treatments for chronic prurigo to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with an IL-4R inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with an IL-31 receptor alpha inhibitor, for treating or managing chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with a Janus kinase 1 inhibitor, for treating or managing chronic prurigo after treatment with a Janus kinase 1 inhibitor for chronic prurigo, e.g., INCB054707 or abrocitinib. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with an NK1 receptor antagonist to treat or manage chronic prurigo after treatment with a neurokinin-1 (NK1) receptor antagonist for chronic prurigo, e.g., serlopitant. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with a PDE4 and / or TNF-α inhibitor to treat or manage chronic prurigo after treatment with a PDE4 and / or TNF-α inhibitor for chronic prurigo, e.g., apremilast.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said treatment with an OSMRβ inhibitor, to treat or manage chronic prurigo after treatment with an anti-OSMRβ antibody, e.g., an OSMRβ inhibitor, such as bixarelimab, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo is both refractory and resistant to said one, two, three, or more treatments, to treat or manage chronic prurigo after said one, two, three, or more treatments for chronic prurigo.

[0075] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said one or more prior treatments for chronic prurigo to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with an IL-4R inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with an IL-31 receptor alpha inhibitor to treat or manage chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for treating or managing chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for treating or managing chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with a NK1 receptor antagonist, for treating or managing chronic prurigo after treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for treating chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo, to a subject whose chronic prurigo has recurred following said treatment with a PDE4 and / or TNF-α inhibitor.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said treatment with an OSMRβ inhibitor, for treating or managing chronic prurigo after treatment with an anti-OSMRβ antibody for chronic prurigo, e.g., an OSMRβ inhibitor such as bixarelimab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject whose chronic prurigo has relapsed after said one, two, three or more treatments, for treating or managing chronic prurigo after said one, two, three or more treatments for chronic prurigo.

[0076] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has discontinued said one or more prior treatments for chronic prurigo due to intolerance of the treatment(s) to treat or manage chronic prurigo after one or more prior treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has discontinued said treatment with an IL-4R inhibitor due to intolerance of the treatment to treat or manage chronic prurigo after treatment with an anti-IL-4R antibody for chronic prurigo, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®). In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has discontinued said treatment with an IL-31 receptor alpha inhibitor due to intolerance of the treatment to treat or manage chronic prurigo after treatment with an anti-IL-31 receptor alpha antibody for chronic prurigo, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for chronic prurigo, to a subject who has discontinued said treatment with a Janus kinase 1 inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo following treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for chronic prurigo, to a subject who has discontinued said treatment with a NK1 receptor antagonist due to intolerance of the treatment. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo, to a subject who has discontinued said treatment with a PDE4 and / or TNF-α inhibitor due to intolerance of the treatment.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo after treatment with an anti-OSMRβ antibody for chronic prurigo, e.g., an OSMRβ inhibitor such as bixarelimab, to a subject who has discontinued said treatment with an OSMRβ inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to treat or manage chronic prurigo after one, two, three, or more of the above treatments for chronic prurigo, to a subject who has discontinued said one, two, three, or more treatments due to intolerance of the treatment(s).

[0077] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject who has failed said one or more prior treatments for urticaria to treat or manage both chronic prurigo and urticaria (e.g., chronic inducible urticaria) following treatment with one or more prior treatments for urticaria, which may be one or more treatments for urticaria described above.

[0078] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate thereof described herein is administered to a subject who has failed said one or more prior treatments for chronic prurigo and who has failed said one or more prior treatments for urticaria, to treat or manage both chronic prurigo and urticaria (e.g., chronic induced urticaria) after treatment with one or more prior treatments for chronic prurigo, which may be said one or more treatments for chronic prurigo, and after treatment with one or more prior treatments for urticaria, which may be said one or more treatments for urticaria.

[0079] Also provided herein is a combination therapy for the treatment of chronic prurigo, comprising administering to a subject in need thereof an anti-KIT antibody (e.g., a humanized anti-KIT antibody), or an antigen-binding fragment thereof (e.g., a KIT-binding fragment thereof) described herein, or an antibody conjugate thereof, in combination with one or more additional therapies (e.g., a second therapeutic agent). In various embodiments, the combination therapy is administered to the subject at about the same time, on the same day, the same week, or in the same treatment cycle, or on a similar or overlapping dosing schedule. In some embodiments, the combination therapy is administered to the subject simultaneously, concurrently, or concomitantly. In other embodiments, the combination therapy is administered to the subject sequentially. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to the subject before the other therapy(s) to be combined. In another embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to the subject after the other therapy(s) to be combined. The use of the term "in combination" does not limit the order in which one or more anti-KIT antibodies and one or more additional therapies are administered to a subject. For subjects with both chronic prurigo and urticaria (e.g., chronically triggered urticaria), also provided herein are combination therapies for the treatment of urticaria (e.g., chronically triggered urticaria), as well as combination therapies for the treatment of chronic prurigo and combination therapies for the treatment of urticaria (e.g., chronically triggered urticaria).

[0080] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo in combination with one or more treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo in combination with treatment with an anti-IL-4R antibody, e.g., an IL-4R inhibitor, such as dupilumab (Dupixent®), for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo in combination with treatment with an anti-IL-31 receptor alpha antibody, e.g., an IL-31 receptor alpha inhibitor, such as nemolizumab, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo in combination with treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for chronic prurigo. In one embodiment, the anti-KIT antibody, its antigen-binding fragment, or conjugate described herein is administered to a subject with chronic prurigo in combination with a treatment with a neurokinin-1 (NK1) receptor antagonist, such as serlopitant, for chronic prurigo. In one embodiment, the anti-KIT antibody, its antigen-binding fragment, or conjugate described herein is administered to a subject with chronic prurigo in combination with a treatment with a PDE4 and / or TNF-α inhibitor, such as apremilast, for chronic prurigo. In one embodiment, the anti-KIT antibody, its antigen-binding fragment, or conjugate described herein is administered to a subject with chronic prurigo in combination with a treatment with an anti-OSMRβ antibody, such as an OSMRβ inhibitor, such as bixarelimab, for chronic prurigo. In one embodiment, the anti-KIT antibody, its antigen-binding fragment, or conjugate described herein is administered to a subject with chronic prurigo in combination with one, two, three, or more of the above treatments for chronic prurigo.

[0081] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with both chronic prurigo and urticaria (e.g., chronic inducible urticaria) in combination with one or more treatments for urticaria.

[0082] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with both chronic prurigo and urticaria (e.g., chronic inducible urticaria) in combination with one or more treatments for chronic prurigo, which may be one or more treatments for chronic prurigo described above, and in combination with one or more treatments for urticaria, which may be one or more treatments for urticaria described above.

[0083] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with one or more treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with an anti-IL-4R antibody, e.g., an IL-4R inhibitor such as dupilumab (Dupixent®), for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with an anti-IL-31 receptor alpha antibody, e.g., an IL-31 receptor alpha inhibitor such as nemolizumab, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with a Janus kinase 1 inhibitor, such as INCB054707 or abrocitinib, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with a neurokinin-1 (NK1) receptor antagonist, such as serlopitant, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo.In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with treatment with an anti-OSMRβ antibody, e.g., an OSMRβ inhibitor such as bixarelimab, for chronic prurigo. In one embodiment, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo simultaneously, concurrently, or concomitantly with one, two, three, or more of the above treatments for chronic prurigo.

[0084] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject having both chronic prurigo and urticaria (e.g., chronic inducible urticaria) simultaneously, concurrently, or concomitantly with one or more treatments for urticaria, which may be one or more treatments for urticaria described above.

[0085] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with both chronic prurigo and urticaria (e.g., chronic induced urticaria) simultaneously, concurrently, or concomitantly with one or more treatments for chronic prurigo, which may be one or more treatments for chronic prurigo as described above, and simultaneously, concurrently, or concomitantly with one or more treatments for urticaria, which may be one or more treatments for urticaria as described above.

[0086] In various embodiments, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with one or more treatments for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with an anti-IL-4R antibody, e.g., an IL-4R inhibitor, such as dupilumab (Dupixent®), for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with an anti-IL-31 receptor alpha antibody, e.g., an IL-31 receptor alpha inhibitor, such as nemolizumab, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with a neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with a PDE4 and / or TNF-α inhibitor, e.g., apremilast, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with treatment with an anti-OSMRβ antibody, e.g., an OSMRβ inhibitor, such as bixarelimab, for chronic prurigo. In one embodiment, the anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with chronic prurigo sequentially with one, two, three, or more of the above treatments for chronic prurigo.

[0087] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject having both chronic prurigo and urticaria (e.g., chronic inducible urticaria) sequentially with one or more treatments for urticaria, which may be one or more treatments for urticaria described above.

[0088] In various embodiments, an anti-KIT antibody, antigen-binding fragment thereof, or conjugate described herein is administered to a subject with both chronic prurigo and urticaria (e.g., chronic induced urticaria) sequentially with one or more treatments for chronic prurigo, which may be one or more treatments for chronic prurigo as described above, and sequentially with one or more treatments for urticaria, which may be one or more treatments for urticaria as described above.

[0089] Further provided herein are antibodies that immunospecifically bind to human KIT (e.g., a KIT polypeptide comprising a human KIT D4 or D5 domain, e.g., a human KIT protein comprising the amino acid sequence of SEQ ID NO:1), and antigen-binding fragments thereof, that can be used in the above methods.

[0090] As used herein, "administering" or "administration" refers to the act of injecting or otherwise physically delivering a substance (e.g., a humanized anti-KIT antibody or antigen-binding fragment thereof provided herein) to a subject or patient (e.g., a human), e.g., by mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0091] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapy (e.g., an antibody or pharmaceutical composition provided herein) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease and / or symptoms associated therewith. These terms also encompass the amount necessary to reduce, delay, or ameliorate the development or progression of a given disease, reduce, delay, or ameliorate the recurrence, occurrence, or onset of a given disease, and / or improve or enhance the prophylactic or therapeutic effect(s) of another therapy (e.g., a therapy other than an anti-KIT inhibitor (e.g., an anti-KIT antibody) provided herein). In some embodiments, "effective amount" as used herein also refers to an amount of an inhibitor (e.g., an antibody) described herein to achieve a particular result, such as reducing the number and / or activity of mast cells, reducing the number and / or activity of eosinophils, inhibiting (e.g., partially inhibiting) KIT biological activity of cells, such as inhibiting cell proliferation or cell survival, or enhancing or inducing apoptosis or cell differentiation.

[0092] As used herein, the term "D4 / D5 region" or "D4 / D5 domain" refers to a region within the KIT polypeptide that spans the fourth Ig-like extracellular ("D4") domain, the fifth Ig-like extracellular ("D5") domain, and the hinge region between the D4 and D5 domains (the "D4-D5 hinge region") from amino-terminus to carboxyl-terminus in the following order: D4, D4-D5 hinge region, and D5. As used herein, amino acids V308 to H515 of FIG. 1 are considered an example of a D4 / D5 region or domain.

[0093] As used herein, the terms "KIT" or "KIT receptor" or "KIT polypeptide" refer to any form of full-length KIT, including, but not limited to, native KIT, a KIT isoform, an interspecies KIT homolog, or a KIT variant, e.g., a naturally occurring variant (e.g., an allelic or splice variant, or a mutant, e.g., a somatic mutant), or an artificially constructed variant (e.g., a recombinant or chemically modified variant). KIT is a type III receptor tyrosine kinase encoded by the c-kit gene (see, e.g., Yarden et al., Nature, 1986, 323:226-232; Ullrich and Schlessinger, Cell, 1990, 61:203-212; Clifford et al., J. Biol. Chem., 2003, 278:31461-31464; Yarden et al., EMBO J., 1987, 6:3341-3351; Mol et al., J. Biol. Chem., 2003, 278:31461-31464). GenBank™ Accession No. NM 000222 provides an exemplary human KIT nucleic acid sequence. GenBank™ Accession Nos. NP 001087241, PI 0721, and AAC50969 provide exemplary human KIT amino acid sequences. GenBank™ Accession No. AAH75716 provides exemplary mouse KIT amino acid sequences. Native KIT contains five extracellular immunoglobulin (Ig)-like domains (D1, D2, D3, D4, D5), a single transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment (see, e.g., Yarden et al., Nature, 1986, 323:226-232; Ullrich and Schlessinger, Cell, 1990, 61:203-212; Clifford et al., J. Biol. Chem., 2003, 278:31461-31464). An exemplary amino acid sequence of the D4 / D5 region of human KIT is provided in FIG. 1 from amino acid residues V308 to H515.In a specific embodiment, KIT is human KIT. In certain embodiments, KIT can exist as a monomer, dimer, multimer, native form, or denatured form.

[0094] As used herein, the term "in combination" in the context of the administration of other therapies refers to the use of more than one therapies. The use of the term "in combination" does not restrict the order in which the therapies are administered. Therapies can be administered, for example, sequentially, sequentially, in parallel, or simultaneously.

[0095] As used herein, the term "chronic prurigo" refers to a disease characterized by both chronic pruritus (itch) and the presence of multiple localized or generalized pruritic skin lesions.

[0096] As used herein, the term "prurigo nodularis" refers to a disease characterized by the presence of both chronic prurigo and multiple localized or generalized raised, firm, nodular lesions.

[0097] As used herein, the terms "treat," "treatment," and "treating" refer to the reduction or amelioration of the progression, severity, and / or duration of chronic prurigo resulting from the administration of one or more therapies (including but not limited to, the administration of one or more prophylactic or therapeutic agents, e.g., an antibody provided herein).

[0098] As used herein, the terms "manage", "managing" and "management" refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent) that do not result in a cure of chronic prurigo. In certain embodiments, a subject is administered one or more therapies (e.g., a prophylactic or therapeutic agent, e.g., an antibody described herein) to "manage" chronic prurigo, one or more symptoms thereof, to prevent progression or worsening of the disorder.

[0099] As used herein, the terms "prevent," "impede," or "impeding" in the context of chronic prurigo refer to complete or partial inhibition (e.g., less than 100%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%) or prevention of the onset, recurrence, development, or spread of chronic prurigo and / or symptoms associated therewith, brought about by administration of a therapy or combination of therapies provided herein (e.g., a prophylactic or therapeutic agent, e.g., a combination of antibodies described herein).

[0100] As used herein, the term "prophylactic agent" refers to any agent that can completely or partially inhibit the occurrence, recurrence, development or spread of chronic prurigo and / or symptoms associated therewith in a subject. In certain embodiments, the term "prophylactic agent" refers to an antibody described herein. In certain other embodiments, the term "prophylactic agent" refers to an agent other than an antibody described herein. Typically, a prophylactic agent is an agent that is known to be useful, has been used, or is currently used to prevent chronic prurigo and / or symptoms associated therewith, or to hinder the onset, development, progression, and / or severity of chronic prurigo and / or symptoms associated therewith. In a specific embodiment, the prophylactic agent is a human anti-KIT antibody, such as a humanized or fully human anti-KIT monoclonal antibody.

[0101] As used herein, the term "side effects" or "adverse effects" encompasses undesirable and harmful effects of a therapy (e.g., a prophylactic or therapeutic agent). Undesirable effects are not necessarily harmful. Adverse effects from a therapy (e.g., a prophylactic or therapeutic agent) can be harmful or unpleasant or dangerous. Examples of side effects include diarrhea, cough, gastroenteritis, wheezing, nausea, vomiting, loss of appetite, abdominal cramps, fever, pain, weight loss, dehydration, alopecia, dyspnea, insomnia, dizziness, mucositis, nerve and muscle effects, fatigue, xerostomia, and loss of appetite, rash or swelling at the site of administration, flu-like symptoms such as fever, chills and fatigue, gastrointestinal upset, and allergic reactions. Additional undesirable effects experienced by patients are numerous and known in the art. Many are described in the Physician's Desk Reference (71st Edition, 2017).

[0102] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, a subject is a mammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs, goats, rabbits, rats, mice, etc.) or a primate (e.g., monkeys and humans), such as a human. In one embodiment, the subject is a mammal, such as a human, diagnosed with chronic prurigo. In another embodiment, the subject is a mammal, such as a human, at risk of developing chronic prurigo. In another embodiment, the subject is a non-human primate. In a specific embodiment, the subject is an adult. In a specific embodiment, the subject is an adult subject at least 18 years old. In a specific embodiment, the subject is a human child. In a specific embodiment, the subject is a human child between 1 and 18 years old. In a specific embodiment, the subject is a human between 1 and 3 years old. In a specific embodiment, the subject is a human between 3 and 12 years old, or between 12 and 18 years old.

[0103] As used herein, the terms "therapies" and "therapy" can refer to any protocol(s), method(s), composition, formulation, and / or agent(s) that can be used in the prevention, prophylaxis, treatment, management, or amelioration of a condition or disorder or one or more symptoms thereof or one or more symptoms or conditions associated therewith. In certain embodiments, the terms "therapies" and "therapy" refer to drug therapy, adjunctive therapy, radiation, surgery, biological therapy, supportive therapy, and / or other therapies useful in the prevention, treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof or one or more symptoms or conditions associated therewith. In certain embodiments, the term "therapy" refers to a therapy other than an anti-KIT antibody or pharmaceutical composition thereof described herein. In a specific embodiment, "additional therapy" and "additional therapies" refer to a therapy other than a treatment using an anti-KIT antibody or pharmaceutical composition thereof described herein. In a specific embodiment, the therapy includes the use of an anti-KIT antibody described herein as an adjunctive therapy. For example, the anti-KIT antibodies described herein are used in combination with drug therapy, biological therapy, surgery, and / or supportive therapy.

[0104] As used herein, the term "therapeutic agent" refers to any agent that can be used in the prevention, treatment, management, or amelioration of chronic prurigo and / or symptoms associated therewith. In certain embodiments, the term "therapeutic agent" refers to an anti-KIT antibody or antigen-binding fragment thereof described herein. In certain other embodiments, the term "therapeutic agent" refers to an agent other than an antibody described herein. In specific embodiments, the therapeutic agent is an agent that is known to be useful, has been used, or is currently used to prevent, treat, manage, or ameliorate chronic prurigo or one or more symptoms associated therewith.

[0105] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more," and "at least one," can be used interchangeably herein.

[0106] Wherever an embodiment is described herein with the word "comprising" or otherwise, it will be understood that similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0107] As used herein, unless otherwise indicated, the term "about" or "approximately" is to be interpreted to allow for normal variations as determined by one of ordinary skill in the art, such as, for example, variations within 20%, or 10%, or 5%. In specific embodiments, the term "about" or "approximately" includes the exact value recited.

[0108] (5.1 Antibodies) Provided herein is an antibody (e.g., an anti-KIT antibody) that specifically binds to a KIT receptor (e.g., the extracellular domain of the human KIT receptor, e.g., as set forth in SEQ ID NO:1 or FIG. 1), or an antigen-binding fragment thereof, for use in a method of preventing, treating, or managing chronic prurigo.

[0109] As used herein, the terms "antibody" and "immunoglobulin" and "Ig" are terms of art and may be used interchangeably herein and refer to a molecule that has an antigen binding site that immunospecifically binds to an antigen.

[0110] Antibodies include monoclonal antibodies, recombinantly produced antibodies, single specific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fvs (scFvs), camelized antibodies, affibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and epitope-binding fragments of any of the above. In certain embodiments, the antibodies described herein refer to polyclonal antibody populations. An antibody can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgAl, or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, the antibodies described herein are IgG antibodies, or classes (e.g., human IgG1 or IgG4) or subclasses thereof.

[0111] As used herein, an "antigen" is a moiety or molecule that contains an epitope and is therefore also specifically bound by an antibody. In a specific embodiment, the antigen that the antibody described herein binds to is KIT (e.g., human KIT), or a fragment thereof, such as the extracellular domain of KIT (e.g., human KIT) or the D4 region of KIT (e.g., human KIT).

[0112] As used herein, the terms "antigen-binding domain", "antigen-binding region", "antigen-binding fragment", and similar terms refer to the portion of an antibody molecule (e.g., complementarity determining region (CDR)) that contains amino acid residues that interact with an antigen and confer to the antibody molecule its specificity for the antigen. The antigen-binding region may be derived from any animal species, such as rodents (e.g., mouse, rat or hamster) and humans. The CDRs of an antibody molecule may be determined by any method known to those skilled in the art. In particular, the CDRs may be determined according to the Kabat numbering system (see Kabat et al. (1991), Sequences of Proteins of Immunological Interest (US Department of Health and Human Services, Washington, DC), 5th Edition).In certain embodiments, the CDRs of the antibody may be numbered according to: (i) the Chothia numbering scheme, referred to herein as "Chothia CDRs" (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917; Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948; and U.S. Patent No. 7,709,226); (ii) the IMGT numbering system, as described, for example, in Lefranc, M.-P., 1999, The Immunologist, 7:132-136, and Lefranc, M.-P. et al., 1999, Nucleic Acids Res., 27:209-212; (iii) the IMGT numbering system, as described, for example, in MacCallum et al., 1996, J. Mol. Biol., 262:732-745, and Martin, (iv) the Contact numbering system, which is based on the analysis of available complex crystal structures (bioinf.org.uk / abs) (see, e.g., MacCallum et al., (1996) J Mol Biol 5:732-745)).

[0113] As used herein, the term "constant region" or "constant domain" refers to those portions of antibodies, e.g., the carboxyl-terminal portions of the light and / or heavy chains, that are not directly involved in binding the antibody to an antigen, but which exhibit or contribute to various effector functions, such as interaction with Fc receptors. These terms refer to those portions of immunoglobulin molecules that have a generally more conserved amino acid sequence than the immunoglobulin variable domains.

[0114] As used herein, "epitope" is a term of art and refers to a localized region of an antigen to which an antibody can specifically bind. A region or polypeptide contributing to an epitope may be contiguous amino acids of a polypeptide, or an epitope may be a collection of two or more non-contiguous regions of a polypeptide.

[0115] As used herein, the term "heavy chain" when used in reference to an antibody refers to an antibody of the IgG subclass, e.g., IgG i The term "heavy chain" refers to any of the different types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (μ), based on the amino acid sequence of the constant domain, which give rise to antibodies of the IgA, IgD, IgE, IgG and IgM classes, respectively, including IgG1, IgG2, IgG3 and IgG4. In a specific embodiment, the heavy chain is a human heavy chain.

[0116] As used herein, the terms "immunospecifically bind", "immunospecifically recognize", "specifically bind", and "specifically recognize" are similar terms in the context of antibodies and refer to a molecule that binds to an antigen (e.g., an epitope or immune complex) as such binding is understood by those of skill in the art. For example, a molecule that specifically binds to an antigen may generally bind to other peptides or polypeptides with lower affinity, as determined, for example, by immunoassays, Biacore™, KinExA 3000 instruments (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, a molecule that immunospecifically binds to an antigen has a K a K at least 2 log, 2.5 log, 3 log, 4 log or more greater than a In another specific embodiment, a molecule that immunospecifically binds to an antigen does not cross-react with other proteins. In another specific embodiment, a molecule that immunospecifically binds to an antigen does not cross-react with other non-KIT proteins.

[0117] As used herein, an "isolated" or "purified" antibody is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which it is obtained, or is substantially free of chemical precursors or other chemicals from which it is chemically synthesized. In specific embodiments, the antibodies or antigen-binding fragments described herein are isolated.

[0118] The term "Kabat numbering" and similar terms are art-recognized and refer to a system for numbering the amino acid residues of the heavy and light chain variable regions of an antibody, or antigen-binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391, and Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDRs within an antibody heavy chain molecule are typically located at amino acid positions 31-35 ("CDR1"), amino acid positions 50-65 ("CDR2"), and amino acid positions 95-102 ("CDR3"). Using the Kabat numbering system, the CDRs within an antibody light chain molecule are typically located at amino acid positions 24-34 (CDR1), amino acid positions 50-56 (CDR2), and amino acid positions 89-97 (CDR3).

[0119] As used herein, the term "light chain" when used in reference to an antibody refers to any of the different types, e.g., kappa (κ) or lambda (λ), based on the amino acid sequence of the constant domain. Light chain amino acid sequences are well known in the art. In a specific embodiment, the light chain is a human light chain.

[0120] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a homogeneous or substantially homogeneous population of antibodies, with each monoclonal antibody usually recognizing a single epitope on an antigen. The term "monoclonal" is not limited to any particular antibody production method. In general, a population of monoclonal antibodies can be produced by a cell, a population of cells, or a cell line. In a specific embodiment, a "monoclonal antibody" as used herein is an antibody produced by a single hybridoma or other cell (e.g., a host cell producing a recombinant antibody), where the antibody immunospecifically binds to a KIT epitope (e.g., an epitope of D4 of human KIT) as determined, for example, by ELISA or other antigen-binding or competitive binding assays known in the art or in the examples provided herein. The monoclonal antibodies described herein can be produced, for example, by hybridoma methods described in Kohler et al.; Nature, 256:495 (1975), or can be isolated from a phage library, for example, using the techniques described herein. Other methods for preparing clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art (see, for example, Chapter 11 of Short Protocols in Molecular Biology (2002), 5th ed., Ausubel et al., eds., John Wiley and Sons, New York:). In specific embodiments, monoclonal antibodies are monospecific antibodies in that their antigen-binding regions are specific for the same epitope. In further specific embodiments, monoclonal monospecific antibodies can be monovalent (having one antigen-binding region) or multivalent (having two or more antigen-binding regions), e.g., bivalent (having two antigen-binding regions).

[0121] As used herein, the term "naked antibody" refers to an antibody that is not linked, fused or conjugated to another agent or molecule (e.g., a label or drug), peptide or polypeptide. In a specific embodiment, a naked antibody expressed by a mammalian host cell can be glycosylated by the glycosylation machinery, e.g., glycosylation enzymes, of the host cell. In certain embodiments, a naked antibody is not glycosylated when it is expressed by a host cell that does not have its own glycosylation machinery, e.g., glycosylation enzymes. In certain embodiments, a naked antibody is a complete antibody, and in other embodiments, a naked antibody is an antigen-binding fragment of a complete antibody, such as a Fab antibody.

[0122] As used herein, the term "polyclonal antibody" refers to an antibody population that includes a variety of different antibodies directed against the same epitope and against different epitopes within an antigen or antigens. Methods for producing polyclonal antibodies are known in the art (see, for example, Chapter 11 of Short Protocols in Molecular Biology (2002), 5th ed., Ausubel et al., eds., John Wiley and Sons, New York:).

[0123] As used herein, the term "recombinant human antibody" includes human antibodies that are isolated, prepared, expressed, or produced by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from an animal (e.g., mouse, rabbit, goat, or cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor, LD et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means including, for example, synthesis, genetic modification of DNA sequences encoding human immunoglobulin sequences, or production by splicing of human immunoglobulin-encoding sequences, e.g., human immunoglobulin gene sequences, to other such sequences. Such recombinant human antibodies can have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, the amino acid sequences of such recombinant human antibodies are so modified that the amino acid sequences of the VH and / or VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that do not naturally occur in the human antibody germline repertoire in vivo. As a non-limiting example, a recombinant human antibody can be obtained by assembling several human sequence fragments into the composite human sequence of a recombinant human antibody.

[0124] As used herein, the term "variable region" or "variable domain" refers to that portion of an antibody, generally a light or heavy chain portion, usually about the amino-terminal 110-120 amino acids in mature heavy chains and about 90-100 amino acids in mature light chains, which differs widely in sequence among antibodies and is used with respect to the binding and specificity of a particular antibody for its particular antigen. The sequence variability is concentrated in regions called complementarity determining regions (CDRs), while the more highly conserved regions in variable domains are called framework regions (FRs).

[0125] Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily involved in the interaction of the antibody with the antigen. In a specific embodiment, the numbering of the amino acid positions of the antibodies described herein is according to the EU index, as found in Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242 ("Kabat et al.").In certain embodiments, the CDRs of the antibody may be numbered according to: (i) the Chothia numbering scheme, referred to herein as "Chothia CDRs" (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917; Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948; and U.S. Patent No. 7,709,226); (ii) the IMGT numbering system, as described, for example, in Lefranc, M.-P., 1999, The Immunologist, 7:132-136, and Lefranc, M.-P. et al., 1999, Nucleic Acids Res., 27:209-212; (iii) the IMGT numbering system, as described, for example, in MacCallum et al., 1996, J. Mol. Biol., 262:732-745, and Martin, The AbM numbering system described in A., Antibody Engineering, Protein Sequence and Structure Analysis of Antibody Variable Domains, Kontermann and Dubel (eds.), Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001); or (iv) the Contact numbering system based on the analysis of available complex crystal structures (bioinf.org.uk / abs) (see, e.g., MacCallum et al., (1996) J Mol Biol 5:732-745). In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In certain embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FR).As a non-limiting example, the variable regions described herein are obtained by assembling two or more fragments of human sequences into a composite human sequence.

[0126] Anti-KIT antibodies suitable for use in the methods provided herein can be selected as described herein.

[0127] In a specific embodiment, an anti-KIT antibody (e.g., a humanized antibody) or an antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises a light chain variable region ("VL") comprising VL CDR1-3, and a heavy chain variable region ("VH") comprising VH CDR1-3, as set forth in Table 1. In a specific embodiment, an anti-KIT antibody (e.g., a humanized antibody) or an antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises a light chain variable region ("VL") comprising VL CDR1-3, and a heavy chain variable region ("VH") comprising VH CDR1-3, as set forth in Table 2 (Set 1 or Set 2). In a specific embodiment, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises a light chain variable region ("VL") comprising VL CDRs 1-3, and a heavy chain variable region ("VH") comprising VH CDRs 1-3 as set forth in Table 3 (AbM CDRs or contact CDRs).

[0128] In a specific embodiment, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating or managing chronic prurigo comprises a VL comprising VL CDR1-3 (SEQ ID NOs:2-4) set forth in Table 1, and a VH comprising VH CDR1-3 (SEQ ID NOs:5-7) set forth in Table 1. In certain embodiments, such an anti-KIT antibody is a naked antibody. In certain embodiments, such an anti-KIT antibody is a bivalent monospecific antibody. In certain embodiments, such an anti-KIT antibody is not a bispecific antibody.

[0129] Table 1: CDR amino acid sequences [Table 1]

[0130] Table 2: CDR amino acid sequences [Table 2]

[0131] Table 3: CDR amino acid sequences [Table 3]

[0132] In certain embodiments, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises: (i) Amino acid sequence: [ka] (where X K1 ~X K6 is any amino acid; and (ii) Amino acid sequence: [ka] (where X H1 ~X H8 is any amino acid) Includes.

[0133] In certain embodiments, X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid having an aliphatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid with an aromatic side chain, and X H1is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain.

[0134] In a specific embodiment, X K1 is the amino acid F or S, and X K2 is the amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is the amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is the amino acid E or D, and X H7 is the amino acid Q or E, and X H8 is the amino acid S or T.

[0135] In certain embodiments, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises: (i) Amino acid sequence: [ka] (where X K1 ~X K6 is any amino acid; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; Includes.

[0136] In certain embodiments, X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid having an aliphatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid with an aromatic side chain.

[0137] In a specific embodiment, X K1 is the amino acid F or S, and X K2 is the amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is the amino acid F or Y.

[0138] In certain embodiments, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic prurigo comprises: (i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) Amino acid sequence: [ka] (where X H1 ~X H8 is any amino acid) Includes.

[0139] In certain embodiments, XH1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain.

[0140] In a specific embodiment, X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is the amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is the amino acid E or D, and X H7 is the amino acid Q or E, and X H8 is the amino acid S or T.

[0141] In specific embodiments, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating or managing chronic prurigo comprises a heavy chain variable region ("VH") comprising an amino acid sequence selected from Table 4 (SEQ ID NOs:8-12) and / or a light chain variable region ("VL") comprising an amino acid sequence selected from Table 5 (SEQ ID NOs:13-16). In certain embodiments, such an anti-KIT antibody is a naked antibody. In specific embodiments, such an anti-KIT antibody is a bivalent monospecific antibody. In specific embodiments, such an anti-KIT antibody is a bispecific antibody. In certain embodiments, such an anti-KIT antibody is not a bispecific antibody.

[0142] Table 4: VH amino acid sequences [Table 4]

[0143] Table 5: VL amino acid sequences [Table 5]

[0144] In a specific embodiment, an anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating or managing chronic prurigo comprises a VH comprising the amino acid sequence of SEQ ID NO:8, and / or a VL comprising the amino acid sequence of SEQ ID NO:13. In one embodiment, an anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:8, and / or a VL comprising the amino acid sequence of SEQ ID NO:14. In one embodiment, an anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:8, and / or a VL comprising the amino acid sequence of SEQ ID NO:15. In one embodiment, an anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:8, and / or a VL comprising the amino acid sequence of SEQ ID NO:16.

[0145] In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:9, and / or a VL comprising the amino acid sequence of SEQ ID NO:13. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:9, and / or a VL comprising the amino acid sequence of SEQ ID NO:14. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:9, and / or a VL comprising the amino acid sequence of SEQ ID NO:15. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:9, and / or a VL comprising the amino acid sequence of SEQ ID NO:16.

[0146] In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 10, and / or a VL comprising the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 10, and / or a VL comprising the amino acid sequence of SEQ ID NO: 14 ...5. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 10, and / or a VL comprising the amino acid sequence of SEQ ID NO: 16.

[0147] In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 11, and / or a VL comprising the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 11, and / or a VL comprising the amino acid sequence of SEQ ID NO: 14. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 11, and / or a VL comprising the amino acid sequence of SEQ ID NO: 15. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 11, and / or a VL comprising the amino acid sequence of SEQ ID NO: 16.

[0148] In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 12, and / or a VL comprising the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 12, and / or a VL comprising the amino acid sequence of SEQ ID NO: 14. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 12, and / or a VL comprising the amino acid sequence of SEQ ID NO: 15. In one embodiment, the anti-KIT antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 12, and / or a VL comprising the amino acid sequence of SEQ ID NO: 16.

[0149] In a specific embodiment, the anti-KIT antibody (e.g., a humanized antibody) or antigen-binding fragment thereof for use in a method for preventing, treating, or managing chronic eczema comprises: (i) a VL comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 13, at least 88% identical to SEQ ID NO: 14, at least 87% identical to SEQ ID NO: 15, or at least 84% identical to SEQ ID NO: 16; and (ii) a VH comprising an amino acid sequence that is at least 93% identical to SEQ ID NO:8, at least 92% identical to SEQ ID NO:9, at least 90% identical to SEQ ID NO:10, at least 87% identical to SEQ ID NO:11, or at least 86% identical to SEQ ID NO:12. Includes.

[0150] Previous anti-KIT antibodies have been found to induce degranulation of FcgRI-expressing human mast cells and / or exhibit Fc receptor-dependent KIT agonist activity, which can result in undesirable infusion-related reactions (IRR) among other side effects.

[0151] In various embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) Fc region or domain (e.g., a modified (e.g., mutated) human IgG Fc region or domain, e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain). Preferably, the anti-KIT antibody or antigen-binding fragment used in the methods described herein has reduced Fc receptor binding activity (particularly reduced FcγR binding activity), does not induce degranulation of FcgRI-expressing human mast cells, and / or does not exhibit Fc receptor-dependent KIT agonist activity. In certain embodiments, one or more of these properties of the anti-KIT antibody or antigen-binding fragment result from the modified (e.g., mutated) Fc region or domain.

[0152] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein has reduced Fc receptor binding activity (particularly reduced FcγR binding activity). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not have significant Fc receptor (particularly FcγR) binding activity. In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not have detectable Fc receptor (particularly FcγR) binding activity. In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein has at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less Fc receptor (particularly FcγR) binding activity compared to a suitable control antibody or antigen-binding fragment. Where an anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) Fc region or domain (e.g., a modified (e.g., mutated) human IgG Fc region or domain, e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain, in a preferred embodiment, a suitable control antibody or antigen-binding fragment is an antibody or antigen-binding fragment having the same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype. In a particular embodiment, an anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) human IgG1 Fc region or domain and has the same VH and VL but with a wild-type (unmodified) human IgG1 The Fc receptor (particularly FcγR) binding activity is at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less than a corresponding antibody or antigen-binding fragment having an Fc region or domain.

[0153] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not induce significant degranulation of human mast cells expressing FcgRI (e.g., as determined by the % release of beta-hexosaminidase from human mast cells in culture (e.g., in the presence of IFN-gamma)). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not induce detectable degranulation of human mast cells expressing FcgRI (e.g., as determined by the % release of beta-hexosaminidase from human mast cells in culture (e.g., in the presence of IFN-gamma)). In certain embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein induces degranulation of human mast cells expressing FcgRI by at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less (e.g., as determined by the percent release of beta-hexosaminidase from human mast cells in culture (e.g., in the presence of IFN-gamma)) compared to a suitable control antibody or antigen-binding fragment. In certain embodiments, the release of beta-hexosaminidase from human mast cells in culture in the presence of IFN-gamma is reduced by more than 50% by the anti-KIT antibody or antigen-binding fragment used in the methods described herein compared to a suitable control antibody or antigen-binding fragment. In certain embodiments, the release of beta-hexosaminidase from human mast cells in culture in the presence of IFN gamma is reduced by more than 60%, more than 70%, or more than 80% by the anti-KIT antibody or antigen-binding fragment used in the methods described herein compared to a suitable control antibody or antigen-binding fragment.The anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) Fc region or domain (e.g., a modified (e.g., mutated) human IgG Fc region or domain, e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain), and in a preferred embodiment, a suitable control antibody or antigen-binding fragment is an antibody or antigen-binding fragment having the same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype. In certain embodiments, an anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) human IgG1 Fc region or domain and induces at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less degranulation of human mast cells expressing FcgRI (e.g., as determined by the % release of beta-hexosaminidase from human mast cells in culture (e.g., in the presence of IFN-gamma)) compared to a corresponding antibody or antigen-binding fragment having an identical VH and VL but a wild-type (unmodified) human IgG1 Fc region or domain. In certain embodiments, the release of beta-hexosaminidase from human mast cells in culture in the presence of IFN gamma is reduced by more than 50% by an anti-KIT antibody or antigen-binding fragment used in the methods described herein that includes a modified (e.g., mutated) human IgG1 Fc region or domain compared to a corresponding antibody or antigen-binding fragment with the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In certain embodiments, the release of beta-hexosaminidase from human mast cells in culture in the presence of IFN gamma is reduced by more than 60%, more than 70%, or more than 80% by an anti-KIT antibody or antigen-binding fragment used in the methods described herein that includes a modified (e.g., mutated) human IgG1 Fc region or domain compared to a corresponding antibody or antigen-binding fragment with the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain.

[0154] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not exhibit significant Fc receptor-dependent KIT agonist activity (e.g., as determined by KIT phosphorylation). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not exhibit detectable Fc receptor-dependent KIT agonist activity (e.g., as determined by KIT phosphorylation). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein induces Fc receptor-dependent KIT activity (e.g., as determined by KIT phosphorylation) at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less compared to a suitable control antibody or antigen-binding fragment. In certain embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation by cross-linked Fc receptors) is reduced by more than 50% by the anti-KIT antibody or antigen-binding fragment used in the methods described herein compared to a suitable control antibody or antigen-binding fragment. In certain embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation by cross-linked Fc receptors) is reduced by more than 60%, more than 70%, or more than 80% by the anti-KIT antibody or antigen-binding fragment used in the methods described herein compared to a suitable control antibody or antigen-binding fragment. Where an anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) Fc region or domain (e.g., a modified (e.g., mutated) human IgG Fc region or domain, e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain), in a preferred embodiment, a suitable control antibody or antigen-binding fragment is an antibody or antigen-binding fragment having the same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype.In certain embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein comprises a modified (e.g., mutated) human IgG1 Fc region or domain and induces at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less Fc receptor-dependent KIT activity (e.g., as determined by KIT phosphorylation) compared to a corresponding antibody or antigen-binding fragment having the same VH and VL but a wild-type (unmodified) human IgG1 Fc region or domain. In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein does not exhibit significant or detectable Fc receptor-dependent KIT agonist activity as described herein, even when crosslinked on THP-1 cells. In certain embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation by cross-linked Fc receptor) is reduced by more than 50% with an anti-KIT antibody or antigen-binding fragment used in the methods described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain compared to a corresponding antibody or antigen-binding fragment having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In certain embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation by cross-linked Fc receptor) is reduced by more than 60%, more than 70%, or more than 80% with an anti-KIT antibody or antigen-binding fragment used in the methods described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain compared to a corresponding antibody or antigen-binding fragment having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain.

[0155] In various embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein (1) reduces disease activity in a chronic prurigo patient, (2) reduces cutaneous mast cell numbers in a chronic prurigo patient, (3) reduces tryptase levels in a chronic prurigo patient, and / or (4) maintains hematological parameters (e.g., hemoglobin (HgB) levels, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) within the normal range in a patient, such as a chronic prurigo patient.

[0156] In some embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein can significantly reduce the number of cutaneous mast cells in chronic prurigo patients compared to the number before treatment.In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein can reduce the number of cutaneous mast cells in chronic prurigo patients by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., within 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks after treatment with anti-KIT antibody or antigen-binding fragment) compared to the number before treatment.In a specific embodiment, the effect of the anti-KIT antibody or antigen-binding fragment used in the methods described herein lasts for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0157] In some embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein can significantly reduce serum tryptase in chronic prurigo patients relative to pre-treatment levels.In a specific embodiment, the anti-KIT antibody or antigen-binding fragment used in the methods described herein can reduce serum tryptase in chronic prurigo patients by at least 50%, at least 70%, or at least 90% (e.g., within 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks after treatment with the anti-KIT antibody or antigen-binding fragment) relative to pre-treatment levels.In a specific embodiment, the effect of the anti-KIT antibody or antigen-binding fragment used in the methods described herein lasts for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0158] In certain embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein maintains hematological parameters (e.g., hemoglobin (HgB) levels, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in patients within the normal range. In certain embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein maintains hematological parameters (e.g., hemoglobin (HgB) levels, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in patients with chronic prurigo within the normal range. In specific embodiments, the hematological parameters are maintained for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, or at least 12 weeks.

[0159] In various embodiments, the anti-KIT antibody or antigen-binding fragment used in the methods described herein has one or more of the properties described herein.

[0160] In specific embodiments, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain comprises at least one (e.g., 1, 2, 3, 4, 5, or 6) amino acid modification (e.g., substitution, deletion, or addition) or at least one (e.g., 1, 2, 3, 4, 5, or 6) non-naturally occurring amino acid residue.

[0161] In a specific embodiment, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG1 Fc region or domain and is numbered according to the EU index as set forth in the Kabat reference: 234A, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V ...V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234 , 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 23 9D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R. 243W, 243L243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 2621, 262A, 262T, 262E, 2631, 263A, 263T, 263M, 26 4L, 2641, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 2651, 265L, 265H, 265T , 2661, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 2 96H, 269G, 297S, 297D, 297E, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 322Q , 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 325V, 325H, 327G, 327W, 327N, 327L, 328S, 328M, 328D, 328E, 328N, 3 28Q, 328F, 3281, 328V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 3301, 330F , 330R, 330H, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, and 332A, or at least one (e.g., 1, 2, 3, 4, 5, or 6) non-naturally occurring amino acid residue selected from the group consisting of: Optionally, the Fc region or domain may include additional and / or alternative non-naturally occurring amino acid residues known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,624,821; 6,277,375; 6,737,056; PCT Patent Publications WO 01 / 58957; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752, and WO(See US Pat. No. 5,399,136 and US Pat. No. 5,399,137, for more details.) In a specific embodiment, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, where the Fc region or domain is a human IgG2 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5, or 6) amino acid modification (e.g., substitution, deletion, or addition) or at least one (e.g., 1, 2, 3, 4, 5, or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art. In specific embodiments, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG3 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5 or 6) amino acid modification (e.g., substitution, deletion or addition) or at least one (e.g., 1, 2, 3, 4, 5 or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art. In specific embodiments, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG4 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5 or 6) amino acid modification (e.g., substitution, deletion or addition) or at least one (e.g., 1, 2, 3, 4, 5 or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art.

[0162] In a specific embodiment, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG1 Fc region or domain and is numbered according to the EU index as set forth in the Kabat reference: 234A, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V ...V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234V, 234 , 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 23 9D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R. 243W, 243L243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 2621, 262A, 262T, 262E, 2631, 263A, 263T, 263M, 26 4L, 2641, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 2651, 265L, 265H, 265T , 2661, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 2 96H, 269G, 297S, 297D, 297E, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 322Q , 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 325V, 325H, 327G, 327W, 327N, 327L, 328S, 328M, 328D, 328E, 328N, 3 28Q, 328F, 3281, 328V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 3301, 330F , 330R, 330H, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, and 332A, or at least one non-naturally occurring amino acid residue (e.g., 1, 2, 3, 4, 5, or 6). Optionally, the Fc region or domain may include additional and / or alternative non-naturally occurring amino acid residues known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,624,821; 6,277,375; 6,737,056; PCT Patent Publications WO 01 / 58957; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752 and WO(See US Pat. No. 5,399,136 and US Pat. No. 5,399,137, for more details.) In a specific embodiment, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, where the Fc region or domain is a human IgG2 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5, or 6) amino acid modification (e.g., substitution, deletion, or addition) or at least one (e.g., 1, 2, 3, 4, 5, or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art. In specific embodiments, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG3 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5 or 6) amino acid modification (e.g., substitution, deletion or addition) or at least one (e.g., 1, 2, 3, 4, 5 or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art. In specific embodiments, the antibodies described herein comprise an altered (e.g., mutated) Fc region or domain, wherein the Fc region or domain is a human IgG4 Fc region or domain and comprises at least one (e.g., 1, 2, 3, 4, 5 or 6) amino acid modification (e.g., substitution, deletion or addition) or at least one (e.g., 1, 2, 3, 4, 5 or 6) non-naturally occurring amino acid residue that is equivalent to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art.

[0163] In certain embodiments, provided herein is an antibody comprising an Fc region or domain, wherein the Fc region or domain is a human IgG1 Fc region or domain and comprises at least one unnatural amino acid at one or more positions selected from the group consisting of 239, 330, and 332, as numbered by the EU index in Kabat. In specific embodiments, provided herein is an antibody comprising an Fc region or domain, wherein the Fc region or domain is a human IgG1 Fc region or domain and comprises at least one unnatural amino acid at one or more positions selected from the group consisting of 239D, 330L, and 332E, as numbered by the EU index in Kabat. Optionally, the Fc region or domain can further comprise an additional unnatural amino acid at one or more positions selected from the group consisting of 252, 254, and 256, as numbered by the EU index in Kabat. In a specific embodiment, provided herein is an antibody comprising an Fc region or domain, wherein the Fc region or domain is a human IgG1 Fc region or domain and comprises at least one unnatural amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat, and at least one unnatural amino acid at one or more positions is selected from the group consisting of 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat. In a specific embodiment, provided herein is an antibody comprising an Fc region or domain, wherein the Fc region or domain is a human IgG2, IgG3, or IgG4 Fc region or domain and comprises at least one unnatural amino acid residue that is equivalent(s) to the amino acid residue(s) described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art.In a specific embodiment, provided herein is an antibody comprising an Fc region or domain, the Fc region or domain being a human IgG2, IgG3, or IgG4 Fc region or domain, comprising at least one unnatural amino acid residue at one or more positions equivalent(s) to the positions described herein for a human IgG1 Fc region or domain, as can be determined by one skilled in the art. In one embodiment, an Fc region or domain comprising such a sequence exhibits one or more Fc activities, such as binding affinity to an Fc receptor, or effector function, such as ADCC or CDC. In a specific embodiment, an Fc region or domain comprising such a sequence exhibits reduced Fc activity, such as reduced binding affinity to an Fc receptor or reduced effector function, such as ADCC or CDC. In a particular embodiment, an Fc region or domain comprising such a sequence exhibits enhanced FcRn activity, such as extended half-life.

[0164] Further non-limiting examples of Fc region or domain modifications can be found in Ghetie et al., 1997, Nat Biotech. 15:637-40; Duncan et al., 1988, Nature 332:563-564; Lund et al., 1991, J. Immunol 147:2657-2662; Lund et al., 1992, Mol Immunol 29:53-59; Alegre et al., 1994, Transplantation 57:1537-1543; Hutchins et al., 1995, Proc Natl. Acad Sci USA 92:11980-11984; Jefferis et al., 1995, Immunol Lett.44:111-117; Lund et al., 1995, Faseb J 9:115-119; Jefferis et al., 1996, Immunol Lett 54:101-104; Lund et al., 1996, J Immunol 157:4963-4969; Armour et al., 1999, Eur J Immunol 29:2613-2624; Idusogie et al., 2000, J Immunol 164:4178-4184; Reddy et al., 2000, J Immunol 164:1925-1933; Xu et al., 2000, Cell Immunol 200:16-26; Idusogie et al., 2001, J Immunol 166:2571-2575; Shields et al., 2001, J Biol Chem 276:6591-6604; Jefferis et al., 2002, Immunol Lett 82:57-65; Presta et al., 2002, Biochem Soc Trans 30:487-490); U.S. Patent Nos. 5,624,821; 5,885,573; 5,677,425; 6,165,745; 6,277,375; 5,869,046; 6,121,022; 5,624,821; 5,648,260; 6,528,624; 6,194,551; 6,737,056; Nos. 6,821,505; 6,277,375; 8,163,882; 7,355,008; 7,960,512; 8,039,592; 8,039,359; 8,101,720; 7,214,775; 7,682,610; 7,741,442; U.S. Patent Publication 2004 / 0002587 and PCT Publications WO 94 / 29351; WO 99 / 58572; WO 00 / 42072; WO 04 / 029207; WO 04 / 099249; WO 04 / 063351.

[0165] In specific embodiments, the antibodies described herein comprise a modified (e.g., mutated) human IgG1 Fc region or domain comprising the non-natural amino acids 234A, 235Q, and 322Q, as numbered by the EU index in Kabat. In certain embodiments, the modified (e.g., mutated) human IgG1 Fc region or domain further comprises the non-natural amino acids 252Y, 254T, and 256E, as numbered by the EU index in Kabat.

[0166] In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG2 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, and 322Q, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art. In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG2 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art.

[0167] In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG3 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, and 322Q, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art. In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG3 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art.

[0168] In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG4 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, and 322Q, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art. In certain embodiments, the antibodies described herein comprise modified (e.g., mutated) human IgG4 Fc regions or domains that comprise unnatural amino acids equivalent to 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index set forth in Kabat for human IgG1 Fc regions or domains, as can be determined by one of skill in the art.

[0169] In a specific embodiment, the antibodies described herein comprise the VL and VH CDR sequences set forth in Table 1, and a modified (e.g., mutated) human IgG1 Fc region or domain that contains the unnatural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference.

[0170] In a preferred embodiment, the antibodies described herein comprise the VL and VH CDR sequences set forth in Table 1, and a modified (e.g. mutated) human IgG1 Fc region or domain comprising the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat.

[0171] Accordingly, in one aspect, provided herein is an antibody, or antigen-binding fragment thereof, that immunospecifically binds to human KIT, (i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising the unnatural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference. In a specific embodiment, the antibody or antigen-binding fragment thereof provided herein is an antibody.

[0172] Accordingly, in a further aspect, provided herein is an antibody, or antigen-binding fragment thereof, that immunospecifically binds to human KIT, (i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index as set forth in the Kabat reference. In a specific embodiment, the antibody or antigen-binding fragment thereof provided herein is an antibody.

[0173] In a further aspect, provided herein is an antibody, or antigen-binding fragment thereof, that immunospecifically binds to human KIT, (i) Amino acid sequence: [ka] (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2is an amino acid having an aliphatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid having an aromatic side chain); (ii) Amino acid sequence: [ka] (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid with an aliphatic hydroxyl side chain) and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that also contains the unnatural amino acids 234A, 235Q, 322Q, and preferably 252Y, 254T, and 256E, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the antibody or antigen-binding fragment thereof provided herein is an antibody.

[0174] In a further aspect, provided herein is an antibody or antigen-binding fragment thereof that immunospecifically binds to human KIT, comprising: i) a VL comprising the amino acid sequence of SEQ ID NO: 13, 14, 15, or 16, and ii) a VH comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that also comprises unnatural amino acids 234A, 235Q, 322Q, and preferably 252Y, 254T, and 256E, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the antibody or antigen-binding fragment thereof provided herein is an antibody.

[0175] In a further aspect, provided herein is an antibody or antigen-binding fragment thereof that immunospecifically binds to human KIT, the antibody or antigen-binding fragment thereof comprising: i) a VL comprising the amino acid sequence of SEQ ID NO: 14; ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain that also comprises unnatural amino acids 234A, 235Q, 322Q, and preferably 252Y, 254T, and 256E, as numbered by the EU index as set forth in Kabat. In a specific embodiment, the antibody or antigen-binding fragment thereof provided herein is an antibody.

[0176] In a specific embodiment, the antibody provided herein has the following amino acid sequence: [ka] The heavy chain comprises:

[0177] In a specific embodiment, the antibody provided herein has the following amino acid sequence: [ka] The light chain comprises

[0178] In a specific embodiment, the antibody provided herein has the following amino acid sequence: [ka] and a heavy chain comprising the amino acid sequence: [ka] The light chain comprises

[0179] In specific embodiments, provided herein is (i) Amino acid sequence: [ka] (Here, the leader sequence is shown in bold italics, the variable region (VH) is shown in italics, and the constant region is underlined. Furthermore, mutations in the constant region (relative to wild-type human IgG1) are double underlined.) a heavy chain comprising (ii) Amino acid sequence: [ka] (wherein the leader sequence is shown in bold italics, the variable region (VL) is shown in italics, and the constant region is underlined) and a light chain comprising:

[0180] In a specific embodiment, the anti-KIT antibody described herein does not bind to any human Fc gamma receptor (FcγR receptor) (e.g., has no detectable binding). In a specific embodiment, the anti-KIT antibody described herein does not bind to human FcγRI (e.g., has no detectable binding). In a specific embodiment, the anti-KIT antibody described herein does not bind to human FcγRIIa (e.g., has no detectable binding). In a specific embodiment, the anti-KIT antibody described herein does not bind to human FcγRIIb (e.g., has no detectable binding). In a specific embodiment, the anti-KIT antibody described herein does not bind to human FcγRIIIa (e.g., has no detectable binding). In a specific embodiment, the anti-KIT antibody described herein does not bind to human FcγRIIIb (e.g., has no detectable binding).

[0181] In a specific embodiment, the anti-KIT antibodies described herein comprise a modified (e.g., mutated) human IgG constant region (e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 constant region) and have enhanced binding (e.g., at least 2-fold, 5-fold, 10-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5000-fold, or 10000-fold higher binding affinity) to human fetal Fc receptor (FcRn) relative to a corresponding antibody having the same variable region sequence but an unmodified (wild-type) human IgG constant region. In a specific embodiment, the anti-KIT antibodies described herein bind to FcRn with a KD of less than 20 nM at pH 6.0. In a specific embodiment, the anti-KIT antibodies described herein bind to FcRn with a KD of less than 2 nM at pH 6.0. In a specific embodiment, the anti-KIT antibodies described herein bind to FcRn with a KD of less than 1 nM at pH 6.0. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 500 nM at pH 6.0. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 400 pM at pH 6.0. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 200 nM at pH 7.2. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 150 nM at pH 7.2. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 100 nM at pH 7.2. In a specific embodiment, the anti-KIT antibody described herein binds to FcRn with a KD of less than 80 nM at pH 7.2.

[0182] In a specific embodiment, the anti-KIT antibodies described herein comprise a modified (e.g., mutated) human IgG constant region (e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 constant region) and do not exhibit antibody-dependent cellular cytotoxicity (ADCC). In a specific embodiment, the anti-KIT antibodies described herein comprise a modified (e.g., mutated) human IgG constant region (e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 constant region) and exhibit reduced ADCC (e.g., at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less) relative to a corresponding antibody having the same variable region sequence but an unmodified (wild-type) human IgG constant region.

[0183] In a specific embodiment, the anti-KIT antibodies described herein comprise a modified (e.g., mutated) human IgG constant region (e.g., a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 constant region) and exhibit reduced cytokine production (e.g., IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, and / or TNF-α) relative to a corresponding antibody having the same variable region sequence but an unmodified (wild-type) human IgG constant region (e.g., at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, at least 90% less, at least 95% less, or at least 99% less).

[0184] In certain embodiments, anti-KIT antibodies or antigen-binding fragments thereof for use in methods for preventing, treating or managing chronic prurigo are described in the art or can be readily obtained using methods known in the art, see, e.g., Section 5.2 below.

[0185] In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the D4 domain of human KIT and to KIT, e.g., the D5 region of human KIT. In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to KIT, e.g., the D5 domain of human KIT, with a lower affinity than to the D4 domain of KIT, e.g., human KIT. In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to KIT, e.g., the D4 domain of human KIT, with a higher affinity than to the D5 domain of KIT, e.g., human KIT; for example, the higher affinity is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold, as determined by methods known in the art, e.g., ELISA or Biacore assay.

[0186] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the D4 or D4 / D5 region of KIT, e.g., human KIT, and has at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold higher affinity for a KIT antigen consisting essentially of only the D4 domain than for a KIT antigen consisting essentially of only the D5 domain.

[0187] In certain embodiments, the anti-KIT antibodies or antigen-binding fragments thereof for use in the methods provided herein have an EC of about 50 nM, 10 nM, 500 pM, 300 pM, 200 pM, 100 pM, or 50 pM or less as determined by assays described in the art, such as ELISA. 50 (half maximal effective concentration) value to specifically bind to a KIT polypeptide (eg, the D4 domain of human KIT).

[0188] In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein has an EC of about 200 pM or 150 pM or less as determined by assays described in the art, such as ELISA or FACs using CHO-WT-KIT cells (CHO cells recombinantly modified to express wild-type human KIT). 50 The antibody specifically binds to a KIT polypeptide (eg, the D4 region of human KIT) at a value

[0189] In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein has an IC of about 600 pM or less. 50 (50% inhibitory concentration) value capable of blocking KIT phosphorylation.

[0190] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor internalization, for example, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, as compared to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT), as assessed by a method described herein or known to one of skill in the art. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor internalization, for example, by at least about 25% or 35%, optionally up to about 75%, as compared to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT), as assessed by a method described herein or known to one of skill in the art. In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor internalization, for example, at least about 1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold, as compared to internalization in the presence of an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to KIT), as assessed by methods described herein or known to those skilled in the art. Techniques for quantifying or visualizing cell surface receptors are well known in the art and include various fluorescent and radioactive techniques. For example, one method involves incubating cells with a radiolabeled anti-receptor antibody. Alternatively, the receptor's natural ligand can be conjugated to a fluorescent molecule or a radioactive label and incubated with the cells.Additional receptor internalization assays are known in the art and are described, for example, in Jimenez et al., Biochemical Pharmacology, 1999, 57:1125-1131; Bernhagen et al., Nature Medicine, 2007, 13:587-596; and Conway et al., J. Cell Physiol., 2001, 189:341-55.

[0191] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor turnover, for example, by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, as compared to turnover in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT) as assessed by a method described herein or known to one of skill in the art. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor turnover by at least about 25% or 35%, optionally up to about 75%, as compared to turnover in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT) as assessed by a method described herein or known to one of skill in the art (e.g., pulse-chase assay). In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor turnover by at least about 1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold, as compared to turnover in the presence of an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to KIT), as assessed by methods described herein or known to those skilled in the art (e.g., pulse-chase assay). Methods for determining receptor turnover are well known in the art. For example, cells expressing KIT can be cultured in a 50-well platelet-free culture medium.35 Cells can be pulse-labeled with S-EXPRESS Protein Labeling Mix (NEG772, NEN Life Science Products), washed, and chased with non-labeling medium for a period of time, after which protein lysates from the labeled cells are immunoprecipitated with anti-KIT antibodies, separated by SDS-PAGE, and visualized (e.g., exposed to a PhosphoImager screen (Molecular Dynamics), scanned with a Typhoon 8600 scanner (Amersham), and analyzed with ImageQuant software (Molecular Dynamics)) (see, e.g., Chan et al., Development, 2004, 131:5551-5560).

[0192] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor degradation by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% compared to degradation in the presence of an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to KIT) as assessed by methods described herein or known to one of skill in the art (e.g., a pulse-chase assay). In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor degradation by at least about 25% or 35%, optionally up to about 75%, relative to degradation in the presence of an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to KIT) as assessed by methods described herein or known to one of skill in the art (e.g., a pulse-chase assay). In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein can induce or enhance KIT receptor degradation by at least about 1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold relative to degradation in the presence of an irrelevant antibody (e.g., an antibody that does not immunospecifically bind to KIT) as assessed by methods described herein or known to one of skill in the art (e.g., a pulse-chase assay). Techniques for quantifying or monitoring the ubiquitination and / or degradation (e.g., the kinetics or rate of degradation) of cell surface receptors are well known in the art and include a variety of fluorescent and radioactive techniques (see, e.g., International Patent Application Publication No. WO 2008 / 153926 A2). For example, pulse-chase experiments or 125 Experiments using radiolabeled ligands such as I-SCF can be performed to quantitatively measure the degradation of KIT.

[0193] In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein does not bind to the extracellular ligand binding site of KIT, for example, the SCF binding site of KIT.In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein does not inhibit ligand binding to KIT, for example, does not inhibit KIT ligand (e.g., SCF) binding to KIT, as determined by methods described in the art, for example, ELISA.In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein does not completely inhibit or partially inhibit ligand binding to KIT, for example, does not completely inhibit or partially inhibit KIT ligand (e.g., SCF) binding to KIT, as determined by methods described in the art, for example, ELISA or FACS (fluorescence-activated cell sorting).

[0194] In specific embodiments, the anti-KIT antibody (e.g., human or humanized antibody) for use in the methods provided herein is an inhibitory antibody, i.e., an antibody that inhibits (e.g., partially inhibits) KIT activity, i.e., one or more KIT activities. In specific embodiments, partial inhibition of KIT activity results in, for example, about 25% to about 65% or 75% inhibition. In specific embodiments, partial inhibition of KIT activity results in, for example, about 35% to about 85% or 95% inhibition. Non-limiting examples of KIT activities include KIT dimerization, KIT phosphorylation (e.g., tyrosine phosphorylation), signaling downstream of KIT (e.g., Stat, AKT, MAPK, or Ras signaling), induction or enhancement of gene transcription (e.g., c-Myc), induction or enhancement of cell proliferation, or cell survival. In certain embodiments, the antibodies described herein inhibit KIT phosphorylation (e.g., ligand-induced phosphorylation).

[0195] In a specific embodiment, the anti-KIT antibody, or antigen-binding fragment thereof, for use in the methods provided herein inhibits KIT tyrosine phosphorylation in the KIT cytoplasmic domain.

[0196] In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits cell proliferation, e.g., mast cell proliferation or eosinophil proliferation. In yet another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits cell survival, e.g., mast cell survival or eosinophil cell survival. In some embodiments, the inhibition of cell proliferation, e.g., mast cell proliferation or eosinophil proliferation, is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0197] In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits mast cell activation or eosinophil activation. In certain embodiments, inhibition of mast cell activation or activity or eosinophil activation or activity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0198] In specific embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits eosinophil or mast cell degranulation (see, e.g., Staats et al., 2012, Med. Chem. Commun., 2013, 4:88-94; and Ochkur et al., 2012, J. Immunol. Methods, 384: 10-20). In some embodiments, inhibition of eosinophil or mast cell degranulation is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0199] In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits the release of mast cell mediators. In certain embodiments, the release of mast cell mediators is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. Assays for measuring mast cell activity, such as mediator release, from mast cell cultures, such as rodent and human mast cell cultures, have been described (see, e.g., Kuehn et al., "Measuring Mast Cell Mediator Release," Current Protocols in Immunology, Unite 7.38.1- 7.38.9, November 2010 (John Wiley & Sons, Inc.)). In certain embodiments, CD34 peripheral blood progenitor cells or mast cell lines, such as HMC-1 or human LAD2 mast cell lines, can be used in these assays to confirm the effect of anti-KIT antibodies on mast cells.

[0200] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein induces apoptosis, e.g., mast cell apoptosis or eosinophil apoptosis. In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein induces cell differentiation, e.g., mast cell differentiation.

[0201] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein is capable of achieving any one of the following: reducing eosinophil numbers and / or activity, reducing mast cell proliferation, reducing mast cell numbers or amounts, inhibiting or reducing mast cell activity, reducing mast cell induced production or release of inflammatory factors, reducing release of inflammatory factors, restoring mast cell homeostasis, reducing mast cell migration, reducing mast cell adhesion, inhibiting or reducing mast cell recruitment of eosinophils, and inhibiting or reducing antigen-mediated degranulation of mast cells.

[0202] In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits KIT activity but does not inhibit KIT dimerization.In another specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits KIT activity but does not inhibit ligand binding to KIT, for example, does not inhibit KIT ligand (e.g., SCF) binding to KIT but inhibits KIT dimerization.

[0203] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits KIT activity, e.g., ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain, by about 25% to about 65% or 75% as determined by a cell-based phosphorylation assay well known in the art, e.g., a cell-based phosphorylation assay described herein. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein inhibits KIT activity, e.g., ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain, by about 35% to about 85% or 95% as determined by a cell-based phosphorylation assay well known in the art, e.g., a cell-based phosphorylation assay described herein.

[0204] In certain embodiments, the anti-KIT antibody, or antigen-binding fragment thereof, for use in the methods provided herein has a 50% inhibitory concentration (IC50) of less than about 600 pM, or less than about 500 pM, or less than about 250 pM, as determined by a cell-based phosphorylation assay well known in the art, such as a cell-based phosphorylation assay described herein. 50 ) inhibits KIT activity, e.g., ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain. In a specific embodiment, the IC 50 In certain embodiments, the IC 50 In a specific embodiment, the IC is in the range of about 50 pM to about 225 pM, or in the range of 100 pM to about 600 pM. 50is in the range of about 50 pM to about 550 pM, or about 50 pM to about 600 pM, or about 150 pM to about 550 pM.

[0205] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein (i) immunospecifically binds to a KIT polypeptide comprising the D4 and / or D5 region of human KIT, (ii) inhibits KIT phosphorylation (e.g., tyrosine phosphorylation), and (iii) does not completely inhibit or partially inhibits KIT ligand (e.g., SCF) binding to KIT. In yet another specific embodiment, such an antibody does not inhibit KIT dimerization. In yet another specific embodiment, such an antibody can be recombinantly expressed by CHO cells with an average titer of at least 0.5 μg / mL, e.g., at least 1.0 μg / mL. In a further specific embodiment, such an antibody comprises a VH domain and a VL domain that are non-immunogenic, e.g., the VH domain and the VL domain do not contain a T cell epitope.

[0206] In other specific embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein immunospecifically binds to the monomeric form of KIT (e.g., human KIT). In certain embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the monomeric form of KIT (e.g., human KIT). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the dimeric form of KIT (e.g., human KIT).

[0207] In a specific embodiment, the anti-KIT antibody or its antigen-binding fragment for use in the methods provided herein does not bind to KIT in monomeric form, but specifically binds to KIT in dimeric form or KIT in multimeric form.In some embodiments, the antibody has a higher affinity for KIT monomer than KIT dimer.In some embodiments, the antibody has a higher affinity for KIT monomer than KIT multimer.

[0208] In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to a native isoform or native variant of KIT (i.e., a naturally occurring isoform or variant of KIT in an animal (e.g., monkey, mouse, goat, donkey, dog, cat, rabbit, pig, rat, human, frog, or bird) that can be isolated from an animal, preferably a human). In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof. In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof, and does not specifically bind to non-human KIT (e.g., monkey, mouse, goat, donkey, dog, cat, rabbit, pig, rat, or bird) or a fragment thereof. In a specific embodiment, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof, and does not specifically bind to mouse KIT. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof (e.g., the D4 region of human KIT) and canine (dog) and non-human primate (e.g., monkey) KIT. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof (e.g., the D4 region of human KIT) and canine (dog) and non-human primate (e.g., monkey) KIT, but does not specifically bind to mouse or rat KIT or a fragment thereof (e.g., the D4 region of mouse KIT).

[0209] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof (e.g., the D4 region of human KIT) and canine (dog), feline (cat), and cynomolgus KIT, but does not specifically bind to mouse or rat KIT or a fragment thereof (e.g., the D4 region of mouse KIT).

[0210] In a specific embodiment, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to human KIT or a fragment thereof (e.g., the D4 region of human KIT) and canine (dog), feline (cat), and cynomolgus KIT with greater affinity (e.g., at least 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold) than to mouse or rat KIT or a fragment thereof (e.g., the D4 region of mouse KIT).

[0211] In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the extracellular domain of human KIT that contains a mutation, e.g., a somatic mutation, e.g., a mutation in exon 9 of human KIT in which the Ala and Tyr residues at positions 502 and 503 are duplicated (see, e.g., Marcia et al. (2000) Am. J. Pathol. 156(3):791-795; and Debiec-Rychter et al. (2004) European Journal of Cancer. 40:689-695, which describe KIT mutations, both of which are incorporated herein by reference in their entireties).

[0212] In some embodiments, the anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein specifically binds to the extracellular domain of human KIT that is glycosylated.In some embodiments, the antibody or antigen-binding fragment thereof described herein binds to two different glycosylated forms of the extracellular domain of human KIT.For example, two forms of human KIT with different molecular weights that show different glycosylation patterns have been observed by immunoblotting.

[0213] In certain embodiments, the antibodies described herein can specifically bind to both of these forms of human KIT, which have different glycosylation patterns, e.g., one form is more glycosylated than the other. In certain embodiments, the antibodies or antigen-binding fragments thereof described herein bind to the extracellular domain of unglycosylated human KIT.

[0214] In a specific embodiment, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein is a bivalent monospecific antibody in that it has two antigen-binding regions (e.g., two identical antigen-binding regions) and both antigen-binding regions specifically bind to the same antigen, KIT (e.g., human KIT). In certain embodiments, the antigen-binding region comprises the VH and VL CDRs set forth in Table 1. In certain embodiments, the antigen-binding region comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs: 8-12, and / or a VL comprising the amino acid sequence of any one of SEQ ID NOs: 13-16. In certain embodiments, an anti-KIT antibody or antigen-binding fragment thereof for use in the methods provided herein is not a bispecific antibody.

[0215] In certain embodiments, the anti-KIT antibody for use in the methods provided herein is a Fab fragment that immunospecifically binds to a KIT polypeptide, for example, the D4 region of KIT. In a specific embodiment, the antibody for use in the methods described herein is a monoclonal antibody or an isolated monoclonal antibody. In another specific embodiment, the antibody for use in the methods described herein is a humanized monoclonal antibody. In a specific embodiment, the antibody for use in the methods described herein is a recombinant antibody, for example, a recombinant human antibody, a recombinant humanized antibody, or a recombinant monoclonal antibody. In some embodiments, the antibody for use in the methods described herein comprises a non-human amino acid sequence, for example, a non-human CDR or a non-human (e.g., non-human primate) framework residue.

[0216] In certain embodiments provided herein, the recombinant antibody can be isolated, prepared, expressed, or produced by recombinant means, including, for example, antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial antibody library, or antibodies prepared, expressed, produced, or isolated by any other means, including, for example, synthesis, genetic modification of DNA sequences encoding human immunoglobulin sequences, or production by splicing of human immunoglobulin-encoding sequences, e.g., human immunoglobulin gene sequences, to other such sequences. In certain embodiments, the amino acid sequences of such recombinant antibodies are so modified that the amino acid sequences of such antibodies, e.g., the VH and / or VL regions, are sequences that do not naturally occur in the in vivo antibody germline repertoire of an organism, e.g., the mouse or human germline repertoire. In certain embodiments, a recombinant antibody can be obtained by assembling several sequence fragments that are naturally occurring in an organism (e.g., a primate, e.g., a human) into a composite sequence of a recombinant antibody, where the composite sequence does not naturally occur in the organism (e.g., a primate, e.g., a human).

[0217] Antibodies for use in the methods provided herein include immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule. In a specific embodiment, an antibody for use in the methods provided herein is an IgG antibody (e.g., a human IgG antibody), or a class (e.g., human IgG1 or IgG4) or subclass thereof. In another specific embodiment, an antibody for use in the methods described herein is an IgG1 (e.g., a human IgG1 (isotype a, z, or f)) or an IgG4 antibody. In certain embodiments, an antibody for use in the methods described herein is a whole or entire antibody, e.g., a whole or entire humanized, human, or composite human antibody.

[0218] In a specific embodiment, the antibody provided herein comprises an antibody light chain and a heavy chain, e.g., separate light and heavy chains. With respect to the light chain, in a specific embodiment, the light chain of the antibody described herein is a kappa light chain. In another specific embodiment, the light chain of the antibody described herein is a lambda light chain. In yet another specific embodiment, the light chain of the antibody described herein is a human kappa light chain or a human lambda light chain. In a particular embodiment, the antibody described herein comprises a human light chain constant region. Non-limiting examples of human light chain constant region sequences are described in the art, see, for example, U.S. Patent No. 5,693,780 and Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Edition, US Department of Health and Human Services, NIH Publication No. 91-3242.

[0219] With respect to the heavy chain, in specific embodiments, the heavy chain of the antibodies described herein can be an alpha (α), delta (δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In another specific embodiment, the heavy chain of the antibodies described herein can comprise a human alpha (α), delta (δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In certain embodiments, the antibodies described herein comprise a human heavy chain constant region (e.g., a human IgG constant region, e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region). Non-limiting examples of human heavy chain constant region sequences are described in the art, see, for example, U.S. Patent No. 5,693,780 and Kabat et al. (1991), Sequences of Proteins of Immunological Interest, 5th Edition, US Department of Health and Human Services, NIH Publication No. 91-3242. In specific embodiments, the antibodies described herein comprise a modified (e.g., mutated) human Fc region or domain (e.g., a modified (e.g., mutated) human IgG1 Fc region or domain, a modified (e.g., mutated) human IgG2 Fc region or domain, a modified (e.g., mutated) human IgG3 Fc region or domain, or a modified (e.g., mutated) human IgG4 Fc region or domain).

[0220] The antibodies provided herein can include antibody fragments that retain the ability to specifically bind to an antigen, e.g., a KIT epitope (e.g., a KIT epitope in a KIT polypeptide containing the D4 region of human KIT). In specific embodiments, the fragments include Fab fragments (antibody fragments that contain an antigen-binding domain and include a light chain and a portion of a heavy chain (i.e., the VH and CHI domains of the heavy chain) cross-linked by disulfide bonds); Fab' (antibody fragments that contain a single antigen-binding domain including Fab and an additional portion of the heavy chain up to the hinge region); F(ab')2 (two Fab' molecules connected by interchain disulfide bonds in the hinge region of the heavy chains; the Fab' molecules may be directed against the same or different epitopes); bispecific Fab (a Fab molecule with two antigen-binding domains, each of which may be directed against a different epitope); single-chain Fab chains containing variable regions, also called sFv (the variable antigen-binding determining regions of a single light and heavy chain of an antibody linked by a chain of 10-25 amino acids); disulfide-linked Fv, or dsFv (the variable antigen-binding determining regions of a single light and heavy chain of an antibody linked by disulfide bonds); camelized VH (an antibody in which some amino acids at the VH interface are amino acids found in the heavy chain of a native camel antibody). The term "sFv" includes a variable antigen-binding determining region of a single heavy chain of a sFv; a bispecific sFv (an sFv or dsFv molecule having two antigen-binding domains, each of which may be directed against a different epitope); a diabody (a dimerized sFv formed when the VH domain of a first sFv associates with the VL domain of a second sFv and the VL domain of the first sFv associates with the VH domain of a second sFv; the two antigen-binding regions of the diabody may be directed against the same or different epitopes); and a triabody (a trimerized sFv formed in a manner similar to a diabody, but in which three antigen-binding domains are generated in a single complex; the three antigen-binding domains may be directed against the same or different epitopes). The antibodies provided herein may also include one or more CDR sequences of an antibody. When two or more CDR sequences are present, the CDR sequences may be linked on a scaffold. In certain embodiments, the antibody comprises a single chain Fv ("scFv").An scFv is an antibody fragment that contains the VH and VL domains of an antibody, where these domains are present in a single polypeptide chain. Usually, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a review of scFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore (eds.), Springer-Verlag, New York, pp. 269-315 (1994). Without being bound to any particular theory, Fv molecules are capable of penetrating tissues due to their small size. Intact antibodies can be enzymatically cleaved with pepsin to produce F(ab')2 fragments or with papain to produce two Fab fragments. The antibody or antigen-binding fragment thereof may also be linked to a further binding entity, for example an SCF binding sequence or "trap".

[0221] In certain embodiments, the anti-KIT antibody for use in the methods described herein is a human, bihuman, or humanized monoclonal antibody. In certain embodiments, the antibody for use in the methods described herein is a modified antibody, e.g., an antibody produced by recombinant methods. In a specific embodiment, the antibody described herein is a humanized antibody comprising one or more non-human (e.g., rodent or mouse) CDRs and one or more human framework regions (FRs), and optionally a human heavy chain constant region and / or a light chain constant region. In a specific embodiment, the antibody described herein comprises one or more primate (or non-human primate) framework regions. In a specific embodiment, the antibody described herein does not comprise a non-human primate framework region.

[0222] Antibodies for use in the methods provided herein may include antibodies that include chemical modifications, e.g., antibodies that are chemically modified, e.g., by covalent attachment of any type of molecule to the antibody. For example, but not limited to, an anti-KIT antibody can be glycosylated, acetylated, pegylated, phosphorylated, or amidated, can be derivatized with a protecting / blocking group, or can further include a cellular ligand and / or other protein or peptide (e.g., a heterologous protein or peptide), and the like. For example, an antibody provided herein can be chemically modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, conjugation to a cellular ligand or other protein, and the like. Additionally, an anti-KIT antibody described herein can contain one or more non-classical amino acids. In some embodiments, provided herein is a conjugate that includes an anti-KIT antibody or an antigen-binding fragment thereof linked to another agent (e.g., a therapeutic agent). Such an antibody conjugate can also be used in the methods or uses described in this disclosure.

[0223] In one embodiment, the anti-KIT antibody for use in the methods provided herein is a naked antibody that is not linked, fused or conjugated (e.g., artificially linked, fused or conjugated) to another molecule, peptide or polypeptide (e.g., a heterologous polypeptide). In certain embodiments, the anti-KIT antibody for use in the methods provided herein is not an antibody-drug conjugate. In certain embodiments, the anti-KIT antibody for use in the methods provided herein is not a fusion protein. In certain embodiments, the anti-KIT antibody described herein does not comprise a non-classical amino acid.

[0224] 5.2 Antibody Production The antibodies (e.g., human or humanized antibodies) described herein that immunospecifically bind to the KIT antigen (or antigen-binding fragments thereof) can be produced by any method known in the art for the synthesis of antibodies, for example, by chemical synthesis or by recombinant expression techniques. The methods described herein utilize, unless otherwise indicated, conventional techniques of molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields, which are within the capabilities of those of ordinary skill in the art. These techniques are described in the references cited herein and are fully explained in the literature.See, e.g., Maniatis et al. (1982), Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press; Sambrook et al. (2001), Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons (1987 and annually revised); Current Protocols in Immunology, John Wiley & Sons (1987 and annually revised); Gait (ed.) (1984), Oligonucleotide Synthesis: A Practical Approach, IRL Press; See Eckstein, ed. (1991), Oligonucleotides and Analogues: A Practical Approach, IRL Press; Birren et al., eds. (1999), Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press.

[0225] For example, humanized antibodies can be produced using a variety of techniques known in the art, including CDR grafting (EP 239,400; WO 91 / 09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al., 1994, Protein Engineering 7(6):805-814; and Roguska et al., 1994, PNAS 2002, 114:117-118). 91:969-973), chain shuffling (U.S. Pat. No. 5,565,332), as well as those described, for example, in U.S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, WO 9317105, Tan et al., J. Immunol. 169:1119 25 (2002), Caldas et al., Protein Eng. 13(5):353-60 (2000), Morea et al., Methods 20(3):267 79 (2000), Baca et al., J. Biol. Chem. 272(16):10678-84 (1997), Roguska et al., Protein Eng. 9(10):895 904 (1996), Couto et al., Cancer Res. 55(23 Supp):5973s-5977s (1995), Couto et al., Cancer Res. 55(8):1717-22 (1995), Sandhu JS, Gene 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol. 235(3):959-73 (1994). See also U.S. Patent Publication US 2005 / 0042664 A1 (February 24, 2005), which is incorporated herein by reference.

[0226] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art, including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma technology, including techniques known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed., 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas, 563 681 (Elsevier, NY, 1981). The term "monoclonal antibody" as used herein is not limited to antibodies produced by hybridoma technology. For example, monoclonal antibodies can be produced by recombinant technology, e.g., recombinant monoclonal antibodies can be expressed by a host cell, such as a mammalian host cell.

[0227] Methods for producing and screening specific antibodies using hybridoma technology are routine and well known in the art. For example, in the hybridoma method, mice or other suitable host animals, such as sheep, goats, rabbits, rats, hamsters, or macaques, are immunized to induce lymphocytes that produce or can produce antibodies that specifically bind to the protein used for immunization (e.g., the extracellular domain of human KIT). Alternatively, lymphocytes may be immunized in vitro. The lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). Additionally, animals can be immunized using RIMMS (repetitive immunization multiple sites) technology (Kilptrack et al., 1997 Hybridoma 16:381-9, incorporated herein by reference).

[0228] Non-limiting examples of myeloma cell lines include mouse myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, Calif., USA, and SP-2 or X63-Ag8.653 cells available from the American Type Culture Collection, Rockville, Md., USA. Human myeloma and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)). The antibodies described herein include antibody fragments that recognize specific KIT antigens and can be produced by any technique known to those skilled in the art. For example, the Fab and F(ab')2 fragments described herein can be produced by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments). The Fab fragment corresponds to one of the two identical arms of an antibody molecule and contains an intact light chain paired with the VH and CHI domains of the heavy chain. The F(ab')2 fragment contains the two antigen-binding arms of an antibody molecule linked by disulfide bonds in the hinge region.

[0229] In one embodiment, to generate a complete antibody, a VH or VL sequence can be amplified from a template, e.g., an scFv clone, using PCR primers that contain the VH or VL nucleotide sequence, a restriction site, and a flanking sequence to protect the restriction site. Using cloning techniques known to those skilled in the art, the PCR-amplified VH domain can be cloned into a vector expressing a VH constant region, and the PCR-amplified VL domain can be cloned into a vector expressing a VL constant region, e.g., a human kappa or lambda constant region. The VH and VL domains can also be cloned into one vector expressing the necessary constant regions. The heavy chain conversion vector and the light chain conversion vector are then co-transfected into a cell line to generate a stable or transient cell line expressing a full-length antibody, e.g., an IgG, using techniques known to those skilled in the art.

[0230] Single domain antibodies, e.g., antibodies lacking light chains, can be produced by methods well known in the art. See Riechmann et al., 1999, J. Immunol. 231:25-38; Nuttall et al., 2000, Curr. Pharm. Biotechnol. 1(3):253-263; Muylderman, 2001, J. Biotechnol. 74(4):277302; U.S. Patent No. 6,005,079; and International Publication Nos. WO 94 / 04678, WO 94 / 25591, and WO 01 / 44301.

[0231] (5.3 Composition) Provided herein is a composition, e.g., a pharmaceutical composition, comprising one or more anti-KIT antibodies (e.g., humanized antibodies) or antigen-binding fragments thereof for use in the methods described herein.In certain aspects, the compositions described herein can be for in vitro, in vivo, or ex vivo use.In a specific embodiment, provided herein is a pharmaceutical composition comprising an anti-KIT antibody (e.g., humanized antibody) or antigen-binding fragment thereof for use in the methods described herein and a pharma- ceutical carrier or excipient.

[0232] As used herein, the term "pharmaceutical acceptable" means approved by a regulatory agency of the Federal or state government, or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopoeias, for use in animals, and more particularly in humans.

[0233] Therapeutic formulations containing one or more antibodies (e.g., humanized antibodies) provided herein can be prepared in the form of a lyophilized formulation or aqueous solution by mixing an antibody having the desired purity with any physiologically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA; Remington: The Science and Practice of Pharmacy, 21st ed. (2006) Lippincott Williams & Wilkins, Baltimore, MD) for storage. Acceptable carriers, excipients, or stabilizers are harmless to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; and / or non-ionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0234] A formulation, e.g., a formulation described herein, can also contain more than one active compound (e.g., a molecule, e.g., an antibody or antibodies described herein), as necessary for the particular indication being treated. In certain embodiments, the formulation contains an antibody provided herein and one or more active compounds that have complementary activities that do not adversely affect each other. Such molecules are suitably present in a combination in amounts that are effective for the purpose intended.

[0235] Formulations to be used for in vivo administration can be sterile, which is readily accomplished, for example, by filtration through sterile filtration membranes.

[0236] In a specific embodiment, the pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more anti-KIT antibodies (e.g., humanized antibodies) provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharma- ceutical acceptable carrier. Such pharmaceutical compositions are useful for preventing, treating, managing, or ameliorating chronic prurigo, or one or more symptoms thereof.

[0237] Pharmaceutical carriers suitable for administration of the antibodies provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0238] Further, the antibodies described herein may be formulated as the sole pharma- ceutical active ingredient in the composition or may be combined with other active ingredients (e.g., one or more other prophylactic or therapeutic agents).

[0239] Composition can contain one or more anti-KIT antibodies provided herein.In one embodiment, the antibody is formulated into suitable pharmaceutical preparations, such as solution, suspension, powder, or elixir in sterile solution or suspension for parenteral administration.In one embodiment, the antibody is formulated into suitable pharmaceutical preparations, such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release preparation or elixir for oral administration, and into transdermal patch preparation and dry powder inhalant.

[0240] In such compositions, one or more of the antibodies (or conjugates thereof) provided herein are mixed with a suitable pharmaceutical carrier. The concentration of the antibody or antibodies in the composition can be, for example, effective to deliver an amount that, upon administration, treats, prevents, prophylaxis or manages chronic prurigo, or one or more symptoms thereof.

[0241] In one embodiment, the composition is formulated for single dosage administration.To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in the selected carrier at effective concentration to alleviate, prevent or improve one or more symptoms of the condition to be treated.

[0242] In some embodiments, the antibodies (e.g., humanized antibodies) provided herein (or antibody-drug conjugates thereof) are included in a pharma- ceutically acceptable carrier in an effective amount sufficient to exert a therapeutically useful effect without, or with minimal or negligible undesirable side effects on the treated patient. Therapeutically effective concentrations can be empirically determined by testing the compounds in in vitro and in vivo systems using routine methods, and then dosages for humans can be extrapolated therefrom.

[0243] The concentration of an antibody in a pharmaceutical composition depends, for example, on the physicochemical properties of the antibody, the dosing schedule, and the amount administered, as well as other factors known to those of skill in the art. In some embodiments, the concentration of an antibody-drug conjugate in a pharmaceutical composition depends, for example, on the physicochemical properties of the antibody and / or drug, the dosing schedule, and the amount administered, as well as other factors known to those of skill in the art.

[0244] In one embodiment, a therapeutically effective dosage results in a serum concentration of antibody of about 0.1 ng / ml to about 50-100 μg / ml. In another embodiment, the pharmaceutical composition provides a dosage of antibody of about 0.001 mg to about 2000 mg per kilogram body weight for administration over a period of time, for example, daily, weekly, every two weeks, or every 3, 4, or 8 weeks. Pharmaceutical dosage unit forms can be prepared to provide about 0.01 mg to about 2000 mg, in one embodiment, about 10 mg to about 500 mg of the combination of antibody and / or any other essential ingredients per dosage unit form.

[0245] In certain embodiments, the antibody-drug conjugates described herein are administered at an effective dosage of about 1-100 mg of antibody-drug conjugate per kilogram body weight for administration over a period of time, e.g., daily, weekly, biweekly, or triweekly.

[0246] The anti-KIT antibody described herein can be administered at once or divided into several smaller doses that are administered at time intervals. It is understood that the exact dosage and duration of treatment are a function of the disease being treated and can be determined experimentally using known testing protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​can also vary depending on the severity of the condition to be alleviated. It should be further understood that for any particular subject, a particular dosage regimen can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0247] When the antibody is mixed or added, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated and can be empirically determined.

[0248] The pharmaceutical compositions are provided in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing a suitable amount of the compound or a pharma- ceutically acceptable derivative thereof, for administration to humans and animals, e.g., mammals (e.g., cats or dogs). The pharmaceutical compositions are also provided in unit dosage forms, such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions, and oil-water emulsions, containing a suitable amount of the compound or a pharma- ceutically acceptable derivative thereof, for administration to humans and animals, e.g., mammals (e.g., cats or dogs). The antibodies are, in one embodiment, formulated and administered in unit dosage form or multiple dosage forms. Unit dosage form, as used herein, refers to physically discrete units suitable for human and animal subjects and packaged individually as known in the art. Each unit dosage contains a predetermined amount of the antibody sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. A unit dose form can be administered in a fraction or multiple thereof. A multiple dose form is a plurality of identical unit dose forms packaged in a single container to be administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is a plurality of unit doses that are not separated in packaging.

[0249] In some embodiments, one or more anti-KIT antibodies described herein are in liquid pharmaceutical formulations.The liquid compositions that can be administered as pharmaceuticals can be prepared, for example, by dissolving, dispersing or otherwise mixing the active compound defined above and any pharmaceutical auxiliary in a carrier such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a liquid or suspension.If desired, the pharmaceutical composition to be administered can also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, and pH buffering agents.

[0250] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; see, e.g., Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA; Remington: The Science and Practice of Pharmacy, 21st ed. (2006) Lippincott Williams & Wilkins, Baltimore, MD.

[0251] Dosage forms or compositions can be prepared that contain between 0.005% and 100% of the antibody, with the remainder consisting of a non-toxic carrier. Methods for preparing these compositions are known to those skilled in the art.

[0252] In one embodiment, parenteral administration, characterized by injection either subcutaneously, intramuscularly, or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the administered pharmaceutical composition can also contain trace amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents. Other routes of administration can include epidural administration, enteral administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous injection, intrathecal administration, and intraperitoneal administration. In a specific embodiment, the anti-KIT antibody, antigen-binding fragment, or pharmaceutical composition described herein is administered intravenously. In a specific embodiment, the anti-KIT antibody, antigen-binding fragment, or pharmaceutical composition described herein is administered subcutaneously.

[0253] Preparations for parenteral administration include sterile, ready-to-inject solutions, sterile, dry soluble products ready for combination with a solvent immediately prior to use, including subcutaneous injection tablets, such as lyophilized powders, sterile, ready-to-inject suspensions, sterile, dry insoluble products ready for combination with a vehicle immediately prior to use, and sterile emulsions. Liquids can be either aqueous or non-aqueous.

[0254] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0255] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharma- ceutically acceptable substances.

[0256] Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0257] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0258] The anti-KIT antibody described herein can be suspended in micronized or other suitable form.The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.The effective concentration is sufficient to improve the symptoms of the condition and can be determined empirically.

[0259] In other embodiments, the pharmaceutical formulations are lyophilized powders that can be reconstituted into solutions, emulsions, and other mixtures for administration. They can also be reconstituted and formulated as solids or gels.

[0260] The lyophilized powder is prepared by dissolving the antibody provided herein in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The solvent can contain excipients that improve the stability or other pharmacological factors of the powder or reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent can also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers known to those of skill in the art at about neutral pH in one embodiment. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In one embodiment, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature.

[0261] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts can be determined empirically.

[0262] The antibodies provided herein can be formulated for local or topical application, for example, in the form of gels, creams, and lotions, for topical application to the skin and mucous membranes, for example, in the eye, or for intracapsular or intrathecal application. Topical administration is contemplated for transdermal delivery, as well as for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds, alone or in combination with other pharma- ceutically acceptable excipients, can also be administered.

[0263] The antibodies and other compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other part of the body of the subject to be treated. Many such targeting methods are known to those of skill in the art. All such targeting methods are contemplated herein for use in the present compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874. In some embodiments, the anti-KIT antibodies described herein are targeted (or otherwise administered) to the bone marrow. In some embodiments, the anti-KIT antibodies described herein are targeted (or otherwise administered) to the gastrointestinal tract. In some embodiments, the anti-KIT antibodies described herein are targeted (or otherwise administered) to the brain. In a specific embodiment, the anti-KIT antibodies described herein can cross the blood-brain barrier.

[0264] In specific embodiments, the anti-KIT antibodies described herein are targeted (or otherwise administered) to ocular tissues or organs. In certain embodiments, compositions comprising the anti-KIT antibodies described herein may be targeted to ocular tissues or organs as eye drops or gels. In certain embodiments, compositions comprising the anti-KIT antibodies described herein may be targeted to the ear.

[0265] Provided herein is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein, e.g., one or more antibodies provided herein. Such container(s) may optionally be associated with a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of drugs or biological products, indicating approval by that agency of the manufacture, use, or sale for human administration.

[0266] For KIT inhibitors other than antibodies, it is contemplated that they can also be formulated into pharmaceutical formulations with pharma- ceutically acceptable carriers suitable for storage, handling, and / or administration.

[0267] 5.4 Dosage and Administration According to the method of treating chronic prurigo provided herein, the dosage and frequency of administration of the anti-KIT antibody or pharmaceutical composition thereof described herein administered to a subject in need thereof (e.g., a mammal, e.g., a human, a dog or a cat) is effective while minimizing side effects. The exact dosage of the anti-KIT antibody or pharmaceutical composition thereof described herein to be administered to a particular subject can be determined by considering factors related to the subject in need of treatment. Factors that can be taken into account include the severity of the condition, the general health of the subject, the age and weight of the subject, diet, time and frequency of administration, combination(s) with other therapeutic agents or drugs, reaction sensitivity, and tolerability / response to therapy. The dosage and frequency of administration of the anti-KIT antibody or pharmaceutical composition thereof described herein can be adjusted over time to provide sufficient levels of anti-KIT antibody or to maintain the desired effect.

[0268] The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disorder or disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.

[0269] In some embodiments, for the anti-KIT antibodies described herein, the dosage administered to a patient to prevent, prevent, manage, or treat chronic prurigo is typically 0.1 mg / kg to 100 mg / kg of the patient's body weight. In a specific embodiment, the dosage administered to a patient to prevent, prevent, manage, or treat chronic prurigo is about 3 mg / kg of the patient's body weight.

[0270] Generally, human antibodies have a longer half-life in the human body than antibodies from other species due to immune responses to heterologous polypeptides. This often allows for lower dosages of human antibodies and less frequent administration. Furthermore, the dosage and frequency of administration of the antibodies described herein can be reduced by, for example, enhancing antibody uptake and tissue penetration through modifications such as lipidation.

[0271] In one embodiment, about 0.001 mg / kg (mg antibody / kg subject body weight) to about 500 mg / kg of an anti-KIT antibody described herein is administered to prevent, prevent, manage, or treat chronic prurigo. In another embodiment, about 0.3 mg / kg (mg antibody / kg subject body weight) of an anti-KIT antibody described herein is administered to prevent, prevent, manage, or treat chronic prurigo. In another embodiment, about 1 mg / kg (mg antibody / kg subject body weight) of an anti-KIT antibody described herein is administered to prevent, prevent, manage, or treat chronic prurigo. In another embodiment, about 3 mg / kg (mg antibody / kg subject body weight) of an anti-KIT antibody described herein is administered to prevent, prevent, manage, or treat chronic prurigo. In another embodiment, about 9 mg / kg (mg antibody / kg subject body weight) of an anti-KIT antibody described herein is administered to prevent, prevent, manage, or treat chronic prurigo.

[0272] In some embodiments, an effective amount of an antibody provided herein is from about 0.01 mg to about 1,000 mg. In a specific embodiment, an "effective amount" or "therapeutically effective amount" of an anti-KIT antibody described herein refers to an amount of an anti-KIT antibody described herein that is sufficient to achieve at least one, two, three, four or more of the following effects: reduction or amelioration of the severity of chronic prurigo, and / or one or more symptoms associated therewith; reduction in the duration of one or more symptoms associated with chronic prurigo; prevention of recurrence of one or more symptoms of chronic prurigo, and / or one or more symptoms associated therewith; reduction in hospitalization of a subject; reduction in the length of hospitalization; inhibition (e.g., partial inhibition) of the progression of chronic prurigo, and / or one or more symptoms associated therewith; prevention of the onset or development of one or more symptoms associated with chronic prurigo; reduction in the concentration of one or more inflammatory mediators (e.g., cytokines or interleukins) in a biological sample (e.g., plasma, serum, cerebrospinal fluid, urine, or any other biological fluid) of a subject with chronic prurigo; and improvement in quality of life as assessed by methods well known in the art, e.g., questionnaires. In some embodiments, "effective amount" as used herein also refers to the amount of an antibody described herein to achieve a particular result (e.g., inhibition of one or more KIT bioactivities in a cell, e.g., inhibition of cell proliferation).

[0273] In some embodiments, the anti-KIT antibodies described herein are administered as needed, eg, weekly, biweekly (ie, every two weeks), monthly, bimonthly, quarterly, etc.

[0274] In some embodiments, a single dose of an anti-KIT antibody described herein is administered to a patient one or more times to prevent, prevent, manage, treat, and / or ameliorate chronic prurigo.

[0275] In certain embodiments, an anti-KIT antibody or pharmaceutical composition thereof is cyclically administered to a subject in accordance with the methods for treating chronic prurigo provided herein, wherein the anti-KIT antibody or pharmaceutical composition is administered for a period of time and then rested for a period of time (i.e., the anti-KIT antibody or pharmaceutical composition is not administered for a period of time).

[0276] The methods provided herein include administering anti-KIT antibodies by any suitable route. Non-limiting examples of administration routes include parenteral administration, such as subcutaneous, intramuscular or intravenous administration, epidural administration, intestinal administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous injection, intrathecal administration, and intraperitoneal administration. The methods provided herein include routes of administration that target the brain, eye tissue or organ, spinal cord, or ear or auricular tissue. In certain embodiments, the methods provided herein include routes of administration that target the nervous system, such as the central nervous system.

[0277] In a specific embodiment, the methods provided herein comprise administering an anti-KIT antibody via a route suitable for crossing the blood-brain barrier.

[0278] For KIT inhibitors other than antibodies, it is contemplated that the above statements regarding dosage and administration also apply to the extent deemed appropriate by the treating physician. EXAMPLES

[0279] 6. Working Examples The examples herein are offered by way of illustration and not by way of limitation.

[0280] 6.1 Example 1 Nucleic acid molecules encoding the Fc mutant H (heavy chain) and L (light chain) amino acid sequences of the anti-KIT antibody (SEQ ID NO: 23 and SEQ ID NO: 24, respectively, see Table 6 below) were directly cloned into an expression vector. The construct was confirmed by sequencing and the vector was transfected into CHO cells. Stable transfection to establish cell lines expressing the antibody was performed and then selected with drugs. The best expressing lines were selected based on IgG titers above background in the supernatant, grown in the presence of drug selection, and screened for IgG expression at each stage using the Octet® QKe system. Table 6: DNA sequences encoding the heavy and light chain sequences of anti-KIT antibodies [Table 6]

[0281] The antibody obtained after removal of the leader sequence was designated antibody mAb1. The heavy and light chain amino acid sequences of the antibody (after removal of the leader sequence) are set forth in Table 7 below. Table 7: Full length heavy and light chain amino acid sequences of mAb1 [Table 7]

[0282] The Fc domain of the heavy chain of this antibody contains the unnatural amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E, as numbered by the EU index as set forth in Kabat. These six unnatural amino acids are shown in bold underlined text in the above sequence.

[0283] We determined that mAb1 did not induce significant degranulation of human mast cells expressing FcgRI (as indicated by the percent release of beta-hexosaminidase from human mast cells in culture) compared to the corresponding antibody with a wild-type (non-mutated) IgG1 Fc domain ("mAbc"). Beta-hexosaminidase release from human mast cells in culture (in the presence of IFN-gamma) was reduced by more than 50% for mAb1 compared to mAbc. Furthermore, mAb1 did not exhibit significant Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation) compared to mAbc, even when cross-linked on THP-1 cells. Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation by cross-linked Fc receptors) was reduced by more than 50% for mAb1 compared to mAbc.

[0284] 6.2 Example 2 Healthy volunteers received a single injection of 0.3, 1, 3, or 9 mg / kg mAb1 or placebo. Total plasma tryptase levels were measured using the Immunocap® assay, which detects both alpha and beta forms of tryptase. Tryptase values ​​were normalized for each cohort, with pretreatment values ​​defined as 100% and the lower limit of quantification of the assay (1 ng / mL) defined as 0%. Means and standard errors of the mean were plotted by dose.

[0285] The results are shown in Figures 2A-2E and demonstrate that mAb1 inhibited plasma tryptase in a dose-dependent manner.

[0286] 6.3 Example 3 A single dose of mAb1 resulted in a prolonged decrease in tryptase values ​​below the level of assay quantification (1 ng / mL). Values ​​below the level of detection were arbitrarily plotted as 0.5 ng / mL. Absolute plasma tryptase values ​​are shown.

[0287] The results are shown in Figures 3A and 3B and demonstrate that single doses of both 3 mg / kg and 9 mg / kg mAb1 provided sustained tryptase inhibition.

[0288] 6.4 Example 4 Healthy volunteers received a single injection of 0.3, 1, 3, or 9 mg / kg mAb1 or placebo. Plasma levels of stem cell factor (SCF), the sole ligand for the c-KIT / CD117 receptor, were measured using a laboratory-developed assay on the Meso Scale Diagnostics (MSD) platform. SCF plasma levels increased in a dose-dependent manner, consistent with allosteric blockade of SCF on the KIT receptor. Means and standard errors of the mean were plotted by dose.

[0289] The results are shown in FIG. 4 and demonstrate that mAb1 induced a dose-dependent increase in plasma SCF levels.

[0290] 6.5 Example 5 M-07e cells were serum starved and then pretreated with i) mAb1, ii) a corresponding antibody with the same variable region sequence but with unmutated (wild-type) human IgG1 sequence ("mAbc"), iii) an isotype control antibody, or iv) a small molecule kinase inhibitor targeting KIT (imatinib), and then stimulated with stem cell factor (SCF). Phosphorylation was assessed by Western blotting.

[0291] Results from one experiment are shown in Figure 5. Data shown are representative of three independent experiments. IgG = human IgG1 isotype control antibody; p-KIT = tyrosine phosphorylated KIT; p-AKT = phosphorylated AKT; p-ERK = phosphorylated ERK1 / 2. Taken together, these results indicate that mAb1 was a more potent inhibitor of SCF-induced activation of wild-type KIT and downstream intracellular signaling pathways than the small molecule KIT inhibitors tested.

[0292] 6.6 Example 6 The effects of mAb1 and imatinib on SCF-dependent M-07e cell proliferation were also characterized.

[0293] M-07e cells were serum starved and then pretreated with i) mAb1, ii) the corresponding antibody with the same variable region sequence but with unmutated (wild-type) human IgG1 sequence ("mAbc"), or iii) imatinib, and then stimulated with SCF. Cells were incubated at 37° C. for 6 days.

[0294] The results are shown in Figure 6. Data are representative of three independent experiments and are presented as the mean and standard deviation of the mean of technical triplicates.

[0295] Both mAb1 and mAbc showed similar dose-dependent inhibition of M-07e cell proliferation with mean IC50 values ​​of 1.11 ± 0.15 nM and 1.12 ± 0.22 nM (± SEM; n = 5; Figure 6), respectively. In comparison, imatinib inhibited SCF-dependent M-07e cell proliferation less potently with a mean IC50 of 228 ± 39 nM (± SEM) from three independent experiments. The antagonist activity of mAb1 was comparable to mAbc, indicating that the mutations introduced into the Fc region of mAb1 did not affect its ability to inhibit KIT.

[0296] 6.7 Example 7 The binding affinity of mAb1 to recombinant human Fc-gamma receptor (FcγR) and human fetal Fc receptor (FcRn) was characterized and the equilibrium KD value was generated.

[0297] Binding to recombinant human Fc receptors was measured by biolayer interferometry using an Octet® QKe instrument. Histidine-tagged Fc receptors were captured on an anti-penta-His biosensor and then exposed to serial dilutions of mAbc or mAb1 for 2-3 min, followed by a dissociation step ranging from 5-10 min. Curve fitting was performed using the instrument's analysis software. Binding to FcRn was followed with association and dissociation steps at pH 6.0 and pH 7.2.

[0298] The results are shown in Figures 7 and 8A-8N and show that mAb1 bound with high affinity to FcγRI (KD=3.39 nM), intermediate affinity to FcγRIIIa (KD=127 nM), and weak affinity to FcγRIIa (KD=391 nM) and FcγRIIIb (KD=816 nM). No binding to FcγRIIb was observed. In contrast, no binding of mAb1 (concentration=500 nM) to any recombinant human FcγR was detected.

[0299] To simulate endocytic conditions, binding to human fetal Fc receptor (FcRn) was tested at physiological pH 7.2 and pH 6.0. At pH 7.2, no binding of mAbc to FcRn was observed, whereas mAb1 bound with intermediate affinity (KD=77.1 nM). At pH 6.0, mAbc bound to FcRn with intermediate affinity (KD=211 nM). However, mAb1 bound to FcRn at pH 6.0 with significantly higher affinity and showed a very slow dissociation (KD=0.38 nM).

[0300] These data indicate that the Fc mutations in mAb1 abolished FcγR interactions while enhancing interactions with FcRn in vitro.

[0301] 6.8 Example 8 The antibody-dependent cellular cytotoxicity (ADCC) activity of mAb1 was evaluated using a commercially available ADCC reporter bioassay kit (Promega Corporation, Madison, WI). The ADCC reporter bioassay used engineered Jurkat cells stably expressing the FcγRIIIa receptor V158 (high affinity) mutant and the nuclear factor of activated T cells (NFAT) response element, which drives the expression of firefly luciferase, as effector cells. Binding of the FcγRIIIa receptor on the surface of the effector cells to the Fc effector portion of the antibody bound to the antigen on the target cells results in cross-linking and activation of FcγRIIIa signaling, inducing the expression of the NFAT reporter gene. To evaluate the ability of mAb1 and mAbc to induce ADCC, KIT-expressing M-07e cells, transfected CHO cells (CHO-WT KIT), and human small cell lung carcinoma H526 cells were used as target cells. In addition, non-transfected CHO cells that did not express KIT were used as control target cells. ADCC was considered to be activated if a dose-dependent increase in the resulting reporter gene signal was observed.

[0302] As shown in Figure 9, mAbc induced an ADCC response against KIT-expressing M-07e target cells, whereas mAb1 or isotype control did not. Similar results were observed using CHO-WT KIT and H526 cells. Taken together, these data indicate that unlike mAbc, mAb1 did not induce an ADCC response against the KIT-expressing target cells tested.

[0303] 6.9 Example 9 Fresh whole blood was incubated overnight with either 40 nM huIgG1 isotype control or 0.02, 0.2, or 40 nM mAb1, either in solution or dry coated, as indicated. Phytohemagglutinin (PHA) (10 μg / mL) and lipopolysaccharide (LPS) (10 μg / mL) were used as positive controls. Plasma samples were collected and stored frozen at -80°C. Cytokine levels were determined by utilizing multiplex laser bead technology implemented by Eve Technologies (Calgary, Alberta, Canada).

[0304] Results are shown in Figure 10, where cytokine concentrations for individual donors represent the average of duplicate samples. Mean cytokine concentrations for all donors (n=6) are plotted, with error bars representing SEM. Results show that overall very little specific cytokine induction was observed with mAb1 compared to the human IgG1 isotype control.

[0305] 6.10 Example 10 A human patient presents with chronic pruritus and multiple pruritic skin lesions. The patient is diagnosed with chronic prurigo and is administered mAb1 intravenously. Response by clinical assessment is monitored before, during, and after treatment.

[0306] 6.11 Example 11 Described herein is a protocol for an open-label, Phase 1, single-dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of mAb1 as add-on therapy in patients with cold urticaria, symptomatic dermatographia, or cholinergic urticaria. The study type is interventional (clinical trial). The intervention mode is single group assignment.

[0307] This is an open-label Phase 1 study evaluating the safety, pharmacokinetics, and pharmacodynamics of a single dose of mAb1 in patients with cold urticaria, symptomatic dermatographia, or cholinergic urticaria who remain symptomatic despite treatment with antihistamines. It is estimated that 10 patients with cold urticaria, 10 patients with symptomatic dermatographia, and 10 patients with cholinergic urticaria will be enrolled in three separate cohorts for a total of 30 patients. Prospective patients will be screened using clinic examinations and daily home diaries for 2 weeks prior to enrollment. A single dose of mAb1 will be administered intravenously on day 1. Following treatment, patients will be followed up for 12 weeks. Adult patients aged 18-75 years of any gender are eligible for this study. Healthy volunteers will not be accepted.

[0308] Primary endpoint:

[0309] 1. Safety assessed by occurrence and severity of adverse events (time frame: Day 1-Week 12). Safety of a single dose of mAb1 as determined by adverse events.

[0310] Secondary endpoints:

[0311] 1. Change in Clinical Temperature Threshold (CTT) for cold urticaria patients (time frame: Day 1-Day 85). Change from baseline in clinical temperature threshold over time as determined by provocation testing using TempTest®.

[0312] 2. Change in provocation threshold for symptomatic dermatographia patients (time frame: Day 1-Day 85). Change from baseline in provocation threshold over time as determined by provocation testing using the FricTest®.

[0313] 3. For patients with cholinergic urticaria, change from baseline in urticaria activity score provocation (UASprovo) (time frame: Day 1-Day 85). Change from baseline and percentage of responders as measured by UASprovo.

[0314] 4. Change from baseline in Urticaria Control Test (UCT) (Time Frame: Day 1-Day 85). Change from baseline for UCT and modified UCT and percentage of responders.

[0315] 5. Blood Biomarkers (Time Frame: Day 1-Day 85). Blood samples will be taken pre- and post-treatment and analyzed for changes in stem cell factors.

[0316] 6. Blood Biomarkers (Time Frame: Day 1-Day 85). Blood samples will be taken before and after treatment and analyzed for changes in tryptase.

[0317] 7. Pharmacokinetic evaluation (time frame: Day 1-Day 85). Measure mAb1 concentrations.

[0318] 8. Immunogenicity Assessment (Time Frame: Day 1-Day 85). Patients will be monitored for the development of anti-drug antibodies.

[0319] Key inclusion criteria:

[0320] 1. Diagnosis of cold urticaria, symptomatic dermatographia, or cholinergic urticaria unresponsive to antihistamines. Duration of diagnosis ≥ 3 months; symptoms of both urticaria (wheals) and itching / burning / painful sensations despite concomitant antihistamine use. During screening at the clinic, for cold urticaria, patients must have a positive cold test, for symptomatic dermatographia, patients must have a positive FricTest®, and for cholinergic urticaria, patients must have a positive pulse-controlled ergometry (PCE) provocation test. Subjects are taking a stable dose of antihistamines.

[0321] 2. Absence of any other significant medical conditions, other than a diagnosis of cold urticaria, symptomatic dermatographia, or cholinergic urticaria, that may pose additional risk factors or interfere with the study procedures, as determined by the Investigator based on a medical evaluation.

[0322] 3. Both female and male patients will be required to use highly effective contraception from the time of the screening visit until at least 150 days after receiving study treatment.

[0323] 4. Willing and able to adhere to all study requirements and procedures, including completion of daily medication diaries and questionnaires.

[0324] Key exclusion criteria:

[0325] 1. A clearly defined diagnosis of urticaria or angioedema other than chronic urticaria.

[0326] 2. Received biologic therapy (e.g., omalizumab, dupilumab, ligelizumab) within the past 3 months.

[0327] 3. Treatment with immunosuppressants (e.g., systemic corticosteroids, cyclosporine, methotrexate, dapsone, cyclophosphamide, tacrolimus, mycophenolate mofetil, hydroxychloroquine, etc.) for 4 weeks or less or 5 half-lives or less.

[0328] 4. Active COVID-19 infection.

[0329] 5. HIV, Hepatitis B or Hepatitis C infection.

[0330] There are additional criteria that the treating physician will discuss with the candidate to confirm eligibility for the study.

[0331] 6.12 Example 12 (6.12.1 Study Background and Summary) Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-driven wheals in response to triggers such as cold in cold urticaria (ColdU) or scratching of the skin in symptomatic dermatographia (SD). These diseases are often severe and debilitating and can significantly impact the lives of patients. MCs require activation of their KIT receptor by stem cell factor for survival, proliferation, and differentiation. MC load correlates with circulating tryptase, a protease specifically secreted by MCs. mAb1 is a monoclonal anti-KIT antibody engineered to selectively inhibit stem cell factor (SCF)-dependent KIT activation (see Figure 11). mAb1 showed a significant dose-related reduction in circulating tryptase and was overall well tolerated in healthy volunteers. In this study, CIndU patients benefited from treatment with mAb1. One SD patient enrolled in this study also had a diagnosis of prurigo nodularis, which improved after treatment with mAb1.

[0332] 6.12.2 Study design and methods In this ongoing, open-label, Phase 1b study, patients with ColdU and SD refractory to antihistamine treatment received a single IV infusion of mAb1 at 3 mg / kg (as add-on treatment to H1-antihistamines) with 12 weeks of follow-up. Patients' ColdU and SD symptoms were induced by provocation tests, resembling the situation posed in real life. The primary objective was to evaluate the safety / tolerability of mAb1 (adverse events and laboratory tests). Secondary and exploratory objectives included pharmacokinetic and pharmacodynamic assessments, including change from baseline provocation thresholds, tryptase and stem cell factor level measurements, clinical activity outcomes (impact on urticaria symptoms, disease control, clinical response), quality of life assessments, and tissue mast cell measurements by skin biopsy. Secondary objectives included evaluation of clinical activity and the effect of mAb1 on serum tryptase. Activity endpoints included challenge tests (TempTest® / ColdU; FricTest® / SD), Physician Global Assessment of Disease Severity (Phys-GA) and Patient Global Assessment (Pat-GA). Means ± standard error (SE) for challenge tests, biomarkers and hematology are shown in Figures 12C-12D, 14A-14C, 15A-15D and 16A-16D, respectively. Dermal MC numbers assessed using non-lesional skin biopsies were enumerated by tryptase staining.

[0333] One SD patient enrolled in this study also had a diagnosis of prurigo nodularis.

[0334] This study was amended to include a cohort of patients with cholinergic urticaria.

[0335] This study was conducted essentially according to the clinical trial protocol described in Example 11.

[0336] (6.12.3 Testing conditions) Twenty patients received a single intravenous infusion of study drug (i.e., mAb1) at 3 mg / kg and were included in the safety analysis. Eleven had ColdU and nine patients had SD. One of nine SD patients also had prurigo nodularis. Patients had high disease activity in ColdU as assessed by provocation threshold testing. In ColdU patients, baseline critical temperature threshold was 18.9°C / 66°F (range: 5-27°C / 41-80.6°F). In SD patients, baseline FricTest® threshold was 3.8 (range: 3-4) at 4 pins.

[0337] Nineteen patients, including those with both SD and prurigo nodularis, received the full dose and were included in the activity analysis.Fourteen of the 19 patients, including those with both SD and prurigo nodularis, completed the 12-week observation period; five were ongoing.

[0338] 6.12.4 Demographic and baseline disease characteristics See Table 8 below for characteristics of the 20 patients. All patients had received prior antihistamine therapy.

[0339] Table 8: Demographic and baseline disease characteristics [Table 8]

[0340] (6.12.5 Test Results) As shown in Figures 12A-12D, a single dose of mAb1 (3 mg / kg) resulted in rapid, significant, and durable responses in ColdU patients refractory to antihistamines. Complete responses (CR) were achieved in 95% (18 / 19) patients (100% (10 / 10) in ColdU (Figure 12A) and 89% (8 / 9) in SD (Figure 12B) patients). Complete responses were observed in all three patients (one ColdU patient and two SD patients) who were previously Xolair® (omalizumab)-experienced, including two who were Xolair®-refractory. Rapid onset and sustained durability of response after dosing was observed. Most patients with ColdU and SD experienced complete responses by week 1 and week 4, respectively. CR was sustained for a median of 77 days in ColdU patients and 57 days in SD patients who completed the 12-week follow-up period (i.e., 8 ColdU and 6 SD patients) (Figures 12C and 12D). One of 19 patients (SD patient) experienced a partial response (PR). CR = negative provocation test at 4°C or less (for ColdU) or 0 pins (for SD). PR = improvement of 4°C (for ColdU) or 2 pins or more (for SD).

[0341] Improved disease activity as assessed by Phys-GA and Pat-GA was consistent with complete response as measured by provocation testing (Figures 13A and 13B for ColdU and SD patients, respectively).

[0342] As shown in Figures 14A and 14B, a single dose of 3 mg / kg mAb1 resulted in rapid, significant, and sustained depletion of skin MCs (87% depletion, see Figure 14A) and suppression of serum tryptase as measured by biopsy (Figure 14B). MC and tryptase kinetics showed similar trends over time (Figure 14C). Furthermore, skin MC numbers were positively correlated with serum tryptase levels (Figure 14D).

[0343] The kinetics of skin MC and serum tryptase depletion reflected the clinical activity of ColdU. In particular, the kinetics of skin MC and serum tryptase depletion reflected the decrease in the induction threshold (FIGS. 15A-15D). The data confirmed that serum tryptase levels are robust pharmacokinetic biomarkers for assessing MC burden and clinical activity in ColdU patients and potentially in other diseases involving mast cell involvement.

[0344] A patient who had both SD and prurigo nodularis experienced both a complete response of SD and a marked improvement in prurigo nodularis after a single dose of mAb1.

[0345] Furthermore, mAb1 demonstrated good safety and tolerability. mAb1 was generally well tolerated in treated patients. The most common adverse events were hair color changes (14 / 20 (70%)), infusion reactions (9 / 20 (45%)), and taste disorders (8 / 20 (40%)). Hair color changes (generally lightening of small areas of hair) and taste disorders (generally partial changes in the ability to taste salt) were consistent with inhibition of KIT signaling in other cell types and were expected to be fully reversible. Most adverse events were mild. Hair color changes improved during the longer observation period. Infusion reactions, commonly manifested as urticaria and pruritus, subsided spontaneously. One severe infusion reaction with brief loss of consciousness occurred in a patient with a history of syncope, but was not due to MC activation as measured by serum tryptase monitoring. The patient recovered quickly. Taste disorders were selective and transient. Hematological parameters generally remained within normal ranges (see Figures 16A-16D). Mild, transient, and asymptomatic decreases in hemoglobin and white blood cell (WBC) parameters were observed (see Figures 16A-16D). However, there was no evidence of clinically significant decline in blood parameters. This was an important finding of KIT inhibitors.

[0346] Collectively, the data indicate that mAb1 exhibits unprecedented MC depletion with a favorable safety profile, offers great potential as a ColdU therapy for rapid, sustained, and meaningful relief, and may have implications for other diseases involving mast cells, opening the opportunity to evaluate MC involvement across multiple diseases.

[0347] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described above will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0348] All references cited in this specification are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated herein by reference in their entirety for all purposes.

Claims

1. A pharmaceutical composition for preventing, treating, or managing chronic prurigo in a subject, comprising an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof.

2. The pharmaceutical composition of claim 1, wherein the human KIT comprises the amino acid sequence of SEQ ID NO:

1.

3. 3. The pharmaceutical composition according to claim 1, wherein the chronic prurigo is prurigo nodularis.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibody is a bivalent, monospecific antibody.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the antibody is a bispecific antibody.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the antibody is a humanized antibody.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the antibody comprises a modified Fc region or domain.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the antibody has reduced Fc receptor binding activity.

9. The pharmaceutical composition of claim 8, wherein the antibody has reduced FcγR binding activity.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the antibody does not induce significant degranulation of human mast cells expressing FcgRI.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the antibody does not exhibit significant Fc receptor-dependent KIT agonist activity.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the antibody specifically binds to the D4 or D5 region of human KIT.

13. The antibody, (A)(i) a light chain variable region ("VL") comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a heavy chain variable region ("VH") comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively; (B)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:26, and SEQ ID NO:27, respectively; (C)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:28, SEQ ID NO:29, and SEQ ID NO:30, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO:25, SEQ ID NO:31, and SEQ ID NO:32, respectively; (D)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 27, respectively; or (E)(i) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 comprising the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 comprising the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; The pharmaceutical composition according to any one of claims 1 to 12, comprising:

14. The pharmaceutical composition of claim 13, wherein the antibody comprises a VL comprising VL CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 2-4, respectively, and a VH comprising VH CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 5-7, respectively.

15. The antibody has (i) the amino acid sequence: 【Chemistry 1】 (where X K1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, and Χ K2 is an amino acid having an aliphatic or aliphatic hydroxyl side chain, and Χ K3 is an amino acid with an aliphatic hydroxyl side chain, Χ K4 is an amino acid having an aliphatic hydroxyl side chain or is P; X K5 is an amino acid with a charged or acidic side chain, and Χ K6 is an amino acid having an aromatic side chain; and (ii) Amino acid sequence: 【Chemistry 2】 (where X H1 is an amino acid having an aliphatic side chain, and X H2 is an amino acid having an aliphatic side chain, and X H3 is an amino acid with a polar or basic side chain, and X H4 is an amino acid having an aliphatic side chain, and X H5 is an amino acid having an aliphatic side chain, and X H6 is an amino acid with an acidic side chain, and X H7 is an amino acid having an acidic or amide derivative side chain, and X H8 is an amino acid having an aliphatic hydroxyl side chain.

16. X K1 is an amino acid F or S, and X K2 is an amino acid A or S, and X K3 is the amino acid T or S, and X K4 is the amino acid S or P, and X K5 is the amino acid D or T, and X K6 is an amino acid F or Y, and X H1 is an amino acid L or V, and X H2 is an amino acid L or V, and X H3 is an amino acid K or R, and X H4 is an amino acid V or A, and X H5 is an amino acid L or I, and X H6 is amino acid E or D, and X H7 is an amino acid Q or E, and X H8 is the amino acid S or T.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein the antibody comprises a human light chain constant region.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the antibody comprises a human heavy chain constant region.

20. 20. The pharmaceutical composition of claim 19, wherein the human heavy chain constant region is a human IgG constant region.

21. 21. The pharmaceutical composition of claim 20, wherein the human heavy chain constant region is a human IgG1 constant region.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the antibody comprises a modified human Fc region or domain.

23. The pharmaceutical composition of any one of claims 1 to 21, wherein the antibody comprises a modified human IgG1 Fc region or domain.

24. 24. The pharmaceutical composition of claim 23, wherein said modified human IgG1 Fc region or domain comprises the unnatural amino acids 234A, 235Q and 322Q, as numbered by the EU index as set forth in the Kabat reference.

25. 25. The pharmaceutical composition of claim 24, wherein said modified human IgG1 Fc region or domain further comprises the unnatural amino acids 252Y, 254T and 256E, as numbered by the EU index as set forth in the Kabat reference.

26. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified human IgG1 Fc region or domain containing the non-natural amino acids 234A, 235Q, and 322Q, as numbered by the EU index as set forth in the Kabat reference; 26. The pharmaceutical composition according to any one of claims 1 to 25, comprising:

27. The antibody, (i) a VL comprising the amino acid sequence of SEQ ID NO: 14; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 10; and (iii) a modified human IgG1 Fc region or domain comprising the non-natural amino acids 234A, 235Q, 322Q, 252Y, 254T, and 256E, as numbered by the EU index as set forth in the Kabat reference; 26. The pharmaceutical composition according to any one of claims 1 to 25, comprising:

28. The antibody has the amino acid sequence: 【Chemistry 3】 26. The pharmaceutical composition of any one of claims 1 to 25, comprising a heavy chain comprising:

29. The antibody has the amino acid sequence: 【Chemistry 4】 26. The pharmaceutical composition of any one of claims 1 to 25, comprising a light chain comprising:

30. The antibody has the amino acid sequence: 【Chemistry 5】 and a heavy chain comprising the amino acid sequence: 【Chemistry 6】 26. The pharmaceutical composition of any one of claims 1 to 25, comprising a light chain comprising:

31. The pharmaceutical composition according to any one of claims 1 to 30, wherein the subject is an adult human.

32. The pharmaceutical composition according to any one of claims 1 to 30, wherein the subject is a human child.

33. 1. A method for preventing, treating, or managing chronic prurigo in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that immunospecifically binds to human KIT, or an antigen-binding fragment thereof.

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