Anti-kit antibody dosing and methods

Abstract

Provided herein are methods for using antibodies that immunospecifically bind to KIT, a receptor tyrosine kinase, in particular barzolvolimab, to treat, manage or prevent urticaria. Also provided are kits and pharmaceutical dosage units of antibodies that immunospecifically bind to KIT, in particular barzolvolimab.

Description

Attorney Docket No.12638-178-228 ANTI-KIT ANTIBODY DOSING AND METHODS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority of U.S. Provisional Patent Application No. 63 / 653,727 filed on May 30, 2024, the disclosure of which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “12638-178-228_SEQLISTING.xml”, was created on May 23, 2025, and is 56,351 bytes in size. 1. FIELD

[0003] Provided herein are methods for using antibodies that immunospecifically bind to KIT, a receptor tyrosine kinase, in particular barzolvolimab, to treat, manage or prevent urticaria. Also provided are kits and pharmaceutical dosage units of antibodies that immunospecifically bind to KIT, in particular barzolvolimab. 2. BACKGROUND

[0004] KIT (or c-Kit) is a type III receptor tyrosine kinase encoded by the c-kit gene. KIT comprises 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 has been cloned as described by Yarden et al., EMBO J., 1987, 6:3341-3351. KIT is also known as CD117 or stem cell factor receptor ("SCFR"), because it is the receptor for the stem cell factor ("SCF") ligand (also known as Steel Factor or Kit Ligand). SCF ligand binding to the first three extracellular Ig-like domainsAttorney Docket No.12638-178-228 of KIT induces receptor dimerization, and thereby activates intrinsic tyrosine kinase activity through the phosphorylation of specific tyrosine residues in the juxtamembrane and kinase domains (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 various cell types, such as mast cells, stem cells, brain cells, melanoblasts, ovary 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, L. K., 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). Moreover, KIT plays an important role in hematopoiesis, melanogenesis, and gametogenesis (see Ueda et al., Blood, 2002, 99:3342-3349).

[0007] Antibodies that immunospecifically bind to human KIT are known, for example from International Patent Publication No. WO2014018625A1, which is herein incorporated by reference in its entirety.

[0008] There is a need to provide suitable dosing methods for antibodies against human KIT. 3. SUMMARY

[0009] In one aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 300 mg; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4,Attorney Docket No.12638-178-228 respectively; and (ii) a heavy chain variable region (“VH”) comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

[0010] In another aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2,Attorney Docket No.12638-178-228 and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

[0011] In certain embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 14 and the VH comprises the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the antibody comprises a modified human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat. In specific embodiments, the antibody comprises a light chain comprising the amino acid sequence: DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22). In specific embodiments, the antibody comprises a heavy chain comprising the amino acid sequence: QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSSAttorney Docket No.12638-178-228 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21). In a preferred embodiment, the antibody is barzolvolimab.

[0012] In another aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 300 mg.

[0013] In another aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 300 mg per dose.

[0014] In some embodiments, the loading dose is about 300 mg and step (A) is performed after the loading dose is administered to the subject. In specific embodiments, in step (A) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 150 mg about every 4 weeks.

[0015] In other embodiments, the loading dose is about 450 mg and step (B) is performed after the loading dose is administered to the subject. In specific embodiments, in step (B) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 300 mg about every 8 weeks.Attorney Docket No.12638-178-228

[0016] In specific embodiments, at least 3-7 (or more) maintenance doses of the antibody are administered to the subject. In specific embodiments, at least 6-14 (or more) maintenance doses of the antibody are administered to the subject. In specific embodiments, at least 3 maintenance doses of the antibody are administered to the subject. In specific embodiments, at least 6 maintenance doses of the antibody are administered to the subject. In specific embodiments, at least 7 maintenance doses of the antibody are administered to the subject. In specific embodiments, at least 14 maintenance doses of the antibody are administered to the subject.

[0017] In specific embodiments, maintenance doses of the antibody are administered to the subject at said intervals for at least 20 weeks. In specific embodiments, maintenance doses of the antibody are administered to the subject at said intervals for at least 52 weeks.

[0018] In certain embodiments, the chronic urticaria is chronic spontaneous urticaria. In certain embodiments, the chronic urticaria is chronic inducible urticaria. In specific embodiments, the chronic inducible urticaria is cold urticaria. In specific embodiments, the chronic inducible urticaria is symptomatic dermographism. In specific embodiments, the chronic inducible urticaria is cholinergic urticaria.

[0019] In certain embodiments, the chronic urticaria is refractory to omalizumab treatment.

[0020] In certain embodiments, the antibody is administered by subcutaneous administration.

[0021] In certain embodiments, the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.

[0022] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 150 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprisingAttorney Docket No.12638-178-228 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. In a specific embodiment, the antibody is barzolvolimab.

[0023] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 300 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprisingAttorney Docket No.12638-178-228 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. In a specific embodiment, the antibody is barzolvolimab.

[0024] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 450 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprisingAttorney Docket No.12638-178-228 VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. In a specific embodiment, the antibody is barzolvolimab.

[0025] In specific embodiments, the pharmaceutical dosage unit is for subcutaneous administration.

[0026] In a preferred embodiment, the antibody is barzolvolimab.

[0027] In another aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a pharmaceutical dosage unit described herein.

[0028] In another aspect, provided herein is an antibody which immunospecifically binds to human KIT for use in a method for treating, preventing or managing chronic urticaria in a subject in need thereof, wherein the use comprises administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively;Attorney Docket No.12638-178-228 (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. In a specific embodiment, the antibody is barzolvolimab.

[0029] In another aspect, provided herein is use of an antibody which immunospecifically binds to human KIT for the manufacture of a medicament for use in treating, preventing or managing chronic urticaria in a subject in need thereof, wherein during the use a loading dose of between about 300 mg and about 450 mg of the antibody is administered to the subject; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, at least one maintenance dose of the antibody is further administered to the subject at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, at least one maintenance dose of the antibody is further administered to the subject at about 300 mg per dose; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively;Attorney Docket No.12638-178-228 (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. In a specific embodiment, the antibody is barzolvolimab.

[0030] In another aspect, provided herein is a method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an initial interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 150 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 4 weeks thereafter at about 150 mg per maintenance dose; or (B) after an initial interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 300 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 8 weeks thereafter at about 300 mg per maintenance dose. In some embodiments, at least 3 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In some embodiments, at least 6 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In some embodiments, at least 7 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In some embodiments, at least 10 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In some embodiments, at least 14 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In someAttorney Docket No.12638-178-228 embodiments, at least 20 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. In some embodiments, the chronic urticaria is chronic spontaneous urticaria. In certain embodiments, the chronic urticaria is chronic inducible urticaria. In certain embodiments, the chronic inducible urticaria is cold urticaria. In certain embodiments, the chronic inducible urticaria is symptomatic dermographism. In certain embodiments, the chronic inducible urticaria is cholinergic urticaria. In some embodiments, the chronic urticaria is refractory to omalizumab treatment. In some embodiments, the barzolvolimab is administered by subcutaneous administration. In some embodiments, the barzolvolimab is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.

[0031] In various aspects and embodiments, the subject is a human. 3.1 Illustrative Embodiments

[0032] The present disclosure includes the following non-limiting illustrative embodiments. 1. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 300 mg; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; andAttorney Docket No.12638-178-228 (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. 2. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively;Attorney Docket No.12638-178-228 (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. 3. The method of embodiment 1 or 2, wherein the VL comprises the amino acid sequence of SEQ ID NO: 14 and the VH comprises the amino acid sequence of SEQ ID NO: 10. 4. The method of any one of embodiments 1-3, wherein the antibody comprises a modified human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat. 5. The method of any one of embodiments 1-4, wherein the antibody comprises a light chain comprising the amino acid sequence: DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22). 6. The method of any one of embodiments 1-5, wherein the antibody comprises a heavy chain comprising the amino acid sequence: QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSSAttorney Docket No.12638-178-228 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21). 7. The method of any one of embodiments 1-6, wherein the antibody is barzolvolimab. 8. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 300 mg. 9. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 300 mg per dose. 10. The method of any one of embodiments 1-9, wherein the loading dose is about 300 mg and step (A) is performed after the loading dose is administered to the subject. 11. The method of embodiment 10, wherein in step (A) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 150 mg about every 4 weeks. 12. The method of any one of embodiments 1-9, wherein the loading dose is about 450 mg and step (B) is performed after the loading dose is administered to the subject.Attorney Docket No.12638-178-228 13. The method of embodiment 12, wherein in step (B) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 300 mg about every 8 weeks. 14. The method of any one of embodiments 1-13, wherein at least 3-7 maintenance doses of the antibody are administered to the subject. 15. The method of any one of embodiments 1-13, wherein at least 6-14 maintenance doses of the antibody are administered to the subject. 16. The method of any one of embodiments 1-13, wherein at least 3 maintenance doses of the antibody are administered to the subject. 17. The method of any one of embodiments 1-13, wherein at least 6 maintenance doses of the antibody are administered to the subject. 18. The method of any one of embodiments 1-13, wherein at least 7 maintenance doses of the antibody are administered to the subject. 19. The method of any one of embodiments 1-13, wherein at least 14 maintenance doses of the antibody are administered to the subject. 20. The method of any one of embodiments 1-19, wherein maintenance doses of the antibody are administered to the subject at said intervals for at least 20 weeks. 21. The method of any one of embodiments 1-19, wherein maintenance doses of the antibody are administered to the subject at said intervals for at least 52 weeks. 22. The method of any one of embodiments 1-21, wherein the chronic urticaria is chronic spontaneous urticaria. 23. The method of any one of embodiments 1-21, wherein the chronic urticaria is chronic inducible urticaria. 24. The method of embodiment 23, wherein the chronic inducible urticaria is cold urticaria. 25. The method of embodiment 23, wherein the chronic inducible urticaria is symptomatic dermographism. 26. The method of embodiment 23, wherein the chronic inducible urticaria is cholinergic urticaria. 27. The method of any one of embodiments 1-26, wherein the chronic urticaria is refractory to omalizumab treatment.Attorney Docket No.12638-178-228 28. The method of any one of embodiments 1-27, wherein the antibody is administered by subcutaneous administration. 29. The method of any one of embodiments 1-28, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient. 30. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 150 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.Attorney Docket No.12638-178-228 31. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 300 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7,respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. 32. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 450 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises:Attorney Docket No.12638-178-228 (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively. 33. The pharmaceutical dosage unit of any one of embodiments 30-32, which is for subcutaneous administration. 34. The pharmaceutical dosage unit of any one of embodiments 30-33, wherein the antibody is barzolvolimab. 35. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject the pharmaceutical dosage unit of any one of embodiments 30-34. 36. The method of any one of embodiments 1-29 and 35 or the pharmaceutical dosage unit of any one of embodiments 30-34, wherein the subject is a human.Attorney Docket No.12638-178-228 37. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an initial interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 150 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 4 weeks thereafter at about 150 mg per maintenance dose; or (B) after an initial interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 300 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 8 weeks thereafter at about 300 mg per maintenance dose. 38. The method of embodiment 37, wherein at least 3 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 39. The method of embodiment 38, wherein at least 6 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 40. The method of embodiment 39, wherein at least 7 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 41. The method of embodiment 40, wherein at least 10 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 42. The method of embodiment 41, wherein at least 14 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 43. The method of embodiment 42, wherein at least 20 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals. 44. The method of any one of embodiments 37-41, wherein the chronic urticaria is chronic spontaneous urticaria. 45. The method of any one of embodiments 37-44, wherein the chronic urticaria is chronic inducible urticaria. 46. The method of embodiment 45, wherein the chronic inducible urticaria is cold urticaria. 47. The method of embodiment 45, wherein the chronic inducible urticaria is symptomatic dermographism.Attorney Docket No.12638-178-228 48. The method of embodiment 45, wherein the chronic inducible urticaria is cholinergic urticaria. 49. The method of any one of embodiments 37-48, wherein the chronic urticaria is refractory to omalizumab treatment. 50. The method of any one of embodiments 37-49, wherein the barzolvolimab is administered by subcutaneous administration. 51. The method of any one of embodiments 37-50, wherein the barzolvolimab is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient. 4. BRIEF DESCRIPTION OF THE FIGURES

[0033] FIG.1 depicts the amino acid sequence of full length human KIT (SEQ ID NO: 1), GenBank™ accession number AAC50969. The first through fifth extracellular Ig-like domains (i.e., D1, D2, D3, D4, and D5) are indicated; "{" depicts the amino -terminal residue of each domain and "}" depicts the carboxyl-terminal residue of each domain. The D1 domain is depicted at to R112, the D2 domain is depicted at D113 to P206, the D3 domain is depicted at A207 to D309, the D4 domain is depicted at K310 to N410, the hinge region between D4 and D5 is located at V409 to N410, and the D5 domain is depicted at T411 to K509. Also, 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 comprises K310 to K509. The transmembrane domain comprises residues F525 to Q545, and the kinase domain comprises residues K589 to S933.

[0034] FIG.2 depicts the study design of two phase 3 studies evaluating barzolvolimab in participants with chronic spontaneous urticaria (CSU).

[0035] FIG.3 depicts the amino acid sequences of heavy chain and light chain of barzolvolimab. 5. DETAILED DESCRIPTION

[0036] Provided herein are methods of use of anti-KIT antibodies such as barzolvolimab, in particular, methods involving a dosage regimen that comprises a specific loading dose and aAttorney Docket No.12638-178-228 specific maintenance dose(s), and pharmaceutical dosage units of anti-KIT antibodies such as barzolvolimab.

[0037] As used herein, "dose" refers to an amount of a drug (e.g., an anti-KIT antibody described herein) administered to a subject at one specific time. Therefore, multiple doses are administered at multiple different times.

[0038] As used herein, "administer" or "administration" refers to the act of injecting or otherwise physically delivering a substance (e.g., a humanized anti-KIT antibody provided herein or a pharmaceutical composition described herein) to a subject or a patient (e.g., human), such as by mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art.

[0039] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to an amount of a therapy (e.g., an antibody or pharmaceutical composition provided herein) which is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease and / or a symptom related thereto. These terms also encompass an amount necessary for the reduction, slowing, or amelioration of the advancement or progression of a given disease, reduction, slowing, or amelioration of the recurrence, development or onset of a given disease, and / or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy (e.g., a therapy other than an anti-KIT antibody or pharmaceutical composition provided herein). In some embodiments, "effective amount" as used herein also refers to the amount of an antibody or pharmaceutical composition described herein to achieve a specified result, for example, reduction in the number and / or activity of mast cells, reduction in the number and / or activity of eosinophils, inhibition (e.g., partial inhibition) of a KIT biological activity of a cell, such as inhibition of cell proliferation or cell survival, or enhancement or induction of apoptosis or cell differentiation, and the like.

[0040] As used herein, the terms "D4 or D5 region" or "D4 / D5 domain" refer to a region within a KIT polypeptide spanning the fourth Ig-like extracellular ("D4") domain, the fifth Ig- like extracellular ("D5") domain, and the hinge region in between the D4 and D5 domains ("D4- D5 hinge region"), of KIT, in the following order from the amino terminus to the carboxyl terminus: 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.Attorney Docket No.12638-178-228

[0041] 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, an isoform of KIT, an interspecies KIT homolog, or a KIT variant, e.g., naturally occurring (for example, allelic or splice variant, or mutant, e.g., somatic mutant) or artificially constructed variant (for example, 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 number NM 000222 provides an exemplary human KIT nucleic acid sequence. GenBank™ accession numbers NP 001087241, PI 0721, and AAC50969 provide exemplary human KIT amino acid sequences. GenBank™ accession number AAH75716 provides an exemplary murine KIT amino acid sequence. Native KIT comprises five extracellular immunoglobulin (Ig)-like domains (Dl, 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, at amino acid residues V308 to H515. In a specific embodiment, KIT is human KIT. In a particular embodiment, KIT can exist as a monomer, dimer, multimer, native form, or denatured form.

[0042] As used herein, the term "in combination" in the context of the administration of other therapies refers to the use of more than one therapy. The use of the term "in combination" does not restrict the order in which therapies are administered. The therapies may be administered, e.g., serially, sequentially, concurrently, or concomitantly.

[0043] As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and / or duration of chronic urticaria resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody or pharmaceutical composition provided herein).

[0044] 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), which does not result in a cure. In certain embodiments, a subject is administered one or moreAttorney Docket No.12638-178-228 therapies (e.g., prophylactic or therapeutic agents, such as an antibody or pharmaceutical composition described herein) to "manage" a disorder, or one or more symptoms thereof, so as to prevent the progression or worsening of the disorder.

[0045] As used herein, the terms "protect against," "impede," "impeding," "prevent,” or “preventing” in the context of a disorder, refer to the total or partial inhibition (e.g., less than 100%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%) or blockage of the development, recurrence, onset or spread of the disorder, and / or symptom related thereto, resulting from the administration of a therapy provided herein (e.g., an antibody or pharmaceutical composition described herein).

[0046] As used herein, the term "prophylactic agent" refers to any agent that can totally or partially inhibit the development, recurrence, onset or spread of a disorder, and / or symptom related thereto in a subject. In certain embodiments, the term "prophylactic agent" refers to an antibody or pharmaceutical composition described herein. In certain other embodiments, the term "prophylactic agent" refers to an agent other than an antibody or pharmaceutical composition described herein. Generally, a prophylactic agent is an agent which is known to be useful to or has been or is currently being used to prevent the disorder, and / or a symptom related thereto or impede the onset, development, progression and / or severity of the disorder, and / or a symptom related thereto. In specific embodiments, the prophylactic agent is a human anti-KIT antibody, such as a humanized or a fully human anti-KIT monoclonal antibody, or a pharmaceutical composition thereof.

[0047] As used herein, the term "side effects" or "adverse effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., a prophylactic or therapeutic agent) can be harmful or uncomfortable or risky. Examples of side effects include, diarrhea, cough, gastroenteritis, wheezing, nausea, vomiting, anorexia, abdominal cramping, fever, pain, loss of body weight, dehydration, alopecia, dyspnea, insomnia, dizziness, mucositis, nerve and muscle effects, fatigue, dry mouth, and loss of appetite, rashes or swellings at the site of administration, flu-like symptoms such as fever, chills and fatigue, digestive tract problems and allergic reactions. Additional undesired effects experienced by patients are numerous and known in the art. Many are described in the Physician's Desk Reference (71sted., 2017).Attorney Docket No.12638-178-228

[0048] 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., monkey and human), for example a human. In one embodiment, the subject is a mammal, e.g., a human, diagnosed with a disorder. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing chronic urticaria. In another embodiment, the subject is a non-human primate. In a specific embodiment, the subject is a human adult. In a specific embodiment, the subject is an adult human 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 year old to 18 years old. In a specific embodiment, the subject is a human between 1 year to 3 years old. In a specific embodiment, the subject is a human between 3 years to 12 years old or between 12 years to 18 years old.

[0049] As used herein, the terms "therapies" and "therapy" can refer to any protocol(s), method(s), compositions, formulations, and / or agent(s) that can be used in the prevention, protection against, treatment, management, or amelioration of a condition or disorder or symptom thereof or one or more symptoms or condition associated therewith. In certain embodiments, the terms "therapies" and "therapy" refer to drug therapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, and / or other therapies useful in protection against, treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof or one or more symptoms or condition associated therewith. In certain embodiments, the term "therapy" refers to a therapy other than an anti-KIT antibody described herein or pharmaceutical composition described herein. In specific embodiments, an "additional therapy" and "additional therapies" refer to a therapy other than a treatment using an anti-KIT antibody described herein or pharmaceutical composition described herein. In a specific embodiment, a therapy includes the use of an anti-KIT antibody or pharmaceutical composition described herein as an adjuvant therapy. For example, using an anti-KIT antibody or pharmaceutical composition described herein in conjunction with a drug therapy, biological therapy, surgery, and / or supportive therapy.

[0050] As used herein, the term "therapeutic agent" refers to any agent that can be used in the protection against, treatment, management or amelioration of a disorder and / or a symptom related thereto. In certain embodiments, the term "therapeutic agent" refers to an anti-KIT antibody described herein or a pharmaceutical composition described herein. In certain otherAttorney Docket No.12638-178-228 embodiments, the term "therapeutic agent" refers to an agent other than an antibody or pharmaceutical composition described herein. In specific embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the protection against, treatment, management or amelioration of a disorder or one or more symptoms related thereto.

[0051] As used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein.

[0052] It is understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0053] As used herein and unless otherwise specified, the terms “about” and “approximately” shall be construed so as to allow normal variation as judged by a person of skill in the art, such as, for example, a variation within 20% or 10% or 5%. In specific embodiments, the terms “about” and “approximately” encompass the exact value recited. 5.1 Antibodies

[0054] Provided herein are antibodies (e.g., anti-KIT antibodies) that specifically bind to a KIT receptor (e.g., extracellular domain of a human KIT receptor for example as set forth in SEQ ID NO: 1 or FIG.1).

[0055] As used herein, the terms "antibody" and "immunoglobulin" and "Ig" are terms of art and can be used interchangeably herein and refer to a molecule with an antigen binding site that immunospecifically binds an antigen.

[0056] Antibodies include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain- antibody heavy chain pairs, heteroconjugate antibodies, and affybodies. In certain embodiments, antibodies described herein refer to polyclonal antibody populations. Antibodies 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 certainAttorney Docket No.12638-178-228 embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgG1 or IgG4) or subclass thereof. In a specific embodiment, antibodies described herein are IgG1 antibodies.

[0057] As used herein, an "antigen" is a moiety or molecule that contains an epitope, and, as such, also is specifically bound by an antibody. In a specific embodiment, the antigen, to which an antibody described herein binds, is KIT (e.g., human KIT), or a fragment thereof, for example, an extracellular domain of KIT (e.g., human KIT) or a D4 region of KIT (e.g., human KIT).

[0058] As used herein, the terms "antigen binding domain," "antigen binding region," "antigen binding fragment," and similar terms refer to a portion of an antibody molecule which comprises the amino acid residues that interact with an antigen and confer on the antibody molecule its specificity for the antigen (e.g., the complementarity determining regions (CDR)). The antigen binding region can be derived from any animal species, such as rodents (e.g., mouse, rat or hamster) and humans. The CDRs of an antibody molecule can be determined by any method well known to one of skill in the art. In particular, the CDRs can be determined according to the Kabat numbering system (see Kabat et al. (1991) Sequences of Proteins of Immunological Interest. (U.S. Department of Health and Human Services, Washington, D.C.) 5thed.). In certain aspects, the CDRs of an antibody can be determined according to (i) the Chothia numbering scheme, which will be referred to herein as the "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, for example, as described 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 AbM numbering system, for example, as described in MacCallum et al., 1996, J. Mol. Biol., 262:732-745 and Martin, A., “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422-439, Springer-Verlag, Berlin (2001); or (iv) the Contact numbering system, which is based on analysis of the available complex crystal structures (bioinf.org.uk / abs) (see, e.g., MacCallum et al., (1996) J Mol Biol 5:732-745).

[0059] As used herein, the term "constant region" or "constant domain" refers to an antibody portion, e.g., a carboxyl terminal portion of a light and / or heavy chain which is not directly involved in binding of an antibody to antigen but which exhibits or contributes to variousAttorney Docket No.12638-178-228 effector functions, such as interaction with the Fc receptor. The terms refer to a portion of an immunoglobulin molecule having a generally more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0060] As used herein, an "epitope" is a term in the art and refers to a localized region of an antigen to which an antibody can specifically bind. A region or a polypeptide contributing to an epitope can be contiguous amino acids of the polypeptide or an epitope can come together from two or more non-contiguous regions of the polypeptide.

[0061] As used herein, the term "heavy chain" when used in reference to an antibody refers to any distinct types, e.g., alpha (a), delta (δ), epsilon (ε), gamma (γ) and mu (μ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g., IgGi, IgG2, IgG3 and IgG4. In a specific embodiment, the heavy chain is a human heavy chain.

[0062] As used herein, the terms "immunospecifically binds," "immunospecifically recognizes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, Biacore™, KinExA 3000 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, molecules that immunospecifically bind to an antigen bind to the antigen with a Kathat is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Ka when the molecules bind to another antigen. In another specific embodiment, molecules that immunospecifically bind to an antigen do not cross react with other proteins. In another specific embodiment, molecules that immunospecifically bind to an antigen do not cross react with other non-KIT proteins.

[0063] 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 the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. In a specific embodiment, the antibody described herein is isolated.

[0064] The terms "Kabat numbering," and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci.Attorney Docket No.12638-178-228 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35 ("CDR1"), amino acid positions 50 to 65 ("CDR2"), and amino acid positions 95 to 102 ("CDR3"). Using the Kabat numbering system, CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).

[0065] As used herein, the term "light chain" when used in reference to an antibody refers to any distinct types, e.g., kappa (κ) of lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In specific embodiments, the light chain is a human light chain.

[0066] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of homogenous or substantially homogeneous antibodies, and each monoclonal antibody will typically recognize a single epitope on the antigen. The term "monoclonal" is not limited to any particular method for making the antibody. Generally, a population of monoclonal antibodies can be generated by cells, a population of cells, or a cell line. In specific embodiments, a "monoclonal antibody," as used herein, is an antibody produced by a single hybridoma or other cell (e.g. , host cell producing a recombinant antibody), wherein the antibody immunospecifically binds to a KIT epitope (e.g., an epitope of a D4 of human KIT) as determined, e.g., by ELISA or other antigen-binding or competitive binding assay known in the art or in the Examples provided herein. Monoclonal antibodies described herein can, for example, be made by the hybridoma method as described in Kohler et al; Nature, 256:495 (1975) or can be isolated from phage libraries using the techniques as described herein, for example. Other methods for the preparation of clonal cell lines and of monoclonal antibodies expressed thereby are well known in the art (see, for example, Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., Ausubel et al, eds., John Wiley and Sons, New York). In specific embodiments, a monoclonal antibody is a monospecific antibody in that its antigen binding regions are specific for the same epitope. In further specific embodiments, a monoclonal monospecific antibody can be monovalent (having one antigen binding region) or multivalent (having more than one antigen binding regions), for example, bivalent (having two antigen binding regions).Attorney Docket No.12638-178-228

[0067] As used herein, the term "naked antibody" refers to an antibody which is not linked, fused or conjugated to another agent or molecule (e.g., label or drug), peptide or polypeptide. In specific embodiments, a naked antibody expressed by a mammalian host cell can be glycosylated by the host cell's glycosylation machinery, for example glycosylation enzymes. In certain embodiment, a naked antibody is not glycosylated when it is expressed by a host cell which does not have its own glycosylation machinery, for example glycosylation enzymes. In certain embodiments, a naked antibody is a whole antibody, and in other embodiments, a naked antibody is an antigen binding fragment of a whole antibody, such as a Fab antibody.

[0068] As used herein, the term "polyclonal antibodies" refers to an antibody population that includes a variety of different antibodies directed to the same and to different epitopes within an antigen or antigens. Methods for producing polyclonal antibodies are known in the art (See, e.g., see, for example, Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed., Ausubel et al, eds., John Wiley and Sons, New York).

[0069] As used herein, the term "recombinant human antibody" includes human antibodies that are isolated, prepared, expressed, or created by recombinant means, such as 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., a mouse, rabbit, goat, or cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see e.g., Taylor, L. D. et al. (1992) Nucl. Acids Res.20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves creation, e.g., via synthesis, genetic engineering of DNA sequences that encode human immunoglobulin sequences, or splicing of sequences that encode human immunoglobulins, 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 have been modified such thus the amino acid sequences of the VH and / or VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, do not naturally exist within 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 a composite human sequence of a recombinant human antibody.Attorney Docket No.12638-178-228

[0070] As used herein, the terms "variable region" or "variable domain" refer to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in the mature heavy chain and about 90 to 100 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those regions called complementarity determining regions (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR).

[0071] 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 responsible for the interaction of the antibody with antigen. In a specific embodiment, numbering of amino acid positions of antibodies described herein is according to the EU Index, as in Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242 ("Kabat et al."). In certain aspects, the CDRs of an antibody can be determined according to (i) the Chothia numbering scheme, which will be referred to herein as the "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, for example, as described 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 AbM numbering system, for example, as described in MacCallum et al., 1996, J. Mol. Biol., 262:732-745 and Martin, A., “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp.422- 439, Springer-Verlag, Berlin (2001); or (iv) the Contact numbering system, which is based on analysis of the 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 murine CDRs and human framework regions (FRs). In particular 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 (FRs). As a non-limiting example, a variable region described herein is obtained from assembling two or more fragments of human sequences into a composite human sequence.Attorney Docket No.12638-178-228

[0072] In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise 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 1. In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise 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 2 (set 1 or set 2). In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise 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).

[0073] In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise a VL comprising VL CDRs 1-3 as set forth in Table 1 (SEQ ID NOs: 2-4) and a VH comprising VH CDRs 1-3 as set forth in Table 1 (SEQ ID NOs: 5-7). In a particular embodiment, such anti-KIT antibody is a naked antibody. In a specific embodiment, such anti- KIT antibody is a bivalent monospecific antibody. In a specific embodiment, such anti-KIT antibody is a bispecific antibody. In a certain embodiment, such anti-KIT antibody is not a bispecific antibody.

[0074] Table 1: CDR Amino Acid Sequences amino acid sequence SEQ ID NO:

[0075] Table 2: CDR Amino Acid Sequences Set 1 Set 2Attorney Docket No.12638-178-228 amino acid SEQ ID amino acid sequence SEQ ID sequence NO: NO:q AbM Contact D

[0077] In a particular aspect, an anti-KIT antibody (e.g., humanized antibody) provided herein comprises: (i) a VL comprising the amino acid sequence: DIVMTQSPSXK1LSASVGDRVTITCKASQNVRTNVAWYQQKPG KAPKXK2LIYSASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4EDAttorney Docket No.12638-178-228 FAXK5YXK6CQQYNSYPRTFGGGTKVEIK (SEQ ID NO: 17), wherein XK1 to XK6 is any amino acid; and (ii) a VH comprising the amino acid sequence: QVQLVQSGAEXH1KKPGASVKXH2SCKASGYTFTDYYINWVXH3 QAPGKGLEWIARIYPGSGNTYYNEKFKGRXH4TXH5TAXH6KSTST AYMXH7LSSLRSEDXH8AVYFCARGVYYFDYWGQGTTVTVSS (SEQ ID NO: 18), wherein XH1to XH8is any amino acid.

[0078] In a particular embodiment, Χκ1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, Χκ2is an amino acid with an aliphatic or aliphatic hydroxyl side chain Χκ3is an amino acid with an aliphatic hydroxyl side chain ΧK4is an amino acid with an aliphatic hydroxyl side chain or is P, XK5 is an amino acid with a charged or acidic side chain, XK6 is an amino acid with an aromatic side chain, XH1 is an amino acid with an aliphatic side chain, XH2 is an amino acid with an aliphatic side chain XH3is an amino acid with a polar or basic side chain XH4 is an amino acid with an aliphatic side chain XH5 is an amino acid with an aliphatic side chain XH6 is an amino acid with an acidic side chain, XH7 is an amino acid with an acidic or amide derivative side chain, and XH8is an amino acid with an aliphatic hydroxyl side chain.

[0079] In a specific embodiment, ΧK1is the amino acid F or S, Χκ2is the amino acid A or S, XK3 is the amino acid T or S, ΧK4 is the amino acid S or P, XK5 is the amino acid D or T ΧK6 is the amino acid F or Y, XH1is the amino acid L or V, XH2is the amino acid L or V, XH3is the amino acid K or R, XH4is the amino acid V or A, XH5is the amino acid L or I, ΧH6is the amino acid E or D, XH7 is the amino acid Q or E, and XH8 is the amino acid S or T.

[0080] In a particular aspect, an anti-KIT antibody (e.g., humanized antibody) provided herein comprises: (i) a VL comprising the amino acid sequence: DIVMTQSPSXK1LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKX K2LIYSASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4EDFAXK5YXK6CQ QYNSYPRTFGGGTKVEIK (SEQ ID NO: 17), wherein XK1 to XK6 is any amino acid; and (ii) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 comprising the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively.Attorney Docket No.12638-178-228

[0081] In a particular embodiment, Χκ1 is an amino acid with an aromatic or aliphatic hydroxyl side chain, Χκ2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain Χκ3is an amino acid with an aliphatic hydroxyl side chain ΧK4is an amino acid with an aliphatic hydroxyl side chain or is P, XK5 is an amino acid with a charged or acidic side chain, and XK6 is an amino acid with an aromatic side chain.

[0082] In a specific embodiment, ΧK1is the amino acid F or S, Χκ2is the amino acid A or S, XK3is the amino acid T or S, ΧK4is the amino acid S or P, XK5is the amino acid D or T, and ΧK6is the amino acid F or Y.

[0083] In a particular aspect, an anti-KIT antibody (e.g., humanized antibody) provided herein comprises: (i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising the amino acid sequence: QVQLVQSGAEXH1KKPGASVKXH2SCKASGYTFTDYYINWVXH3QAPGK GLEWIARIYPGSGNTYYNEKFKGRXH4TXH5TAXH6KSTSTAYMXH7LSSL RSEDXH8AVYFCARGVYYFDYWGQGTTVTVSS (SEQ ID NO: 18), wherein XH1 to XH8 is any amino acid.

[0084] In a particular embodiment, XH1is an amino acid with an aliphatic side chain, XH2is an amino acid with an aliphatic side chain XH3is an amino acid with a polar or basic side chain XH4 is an amino acid with an aliphatic side chain XH5 is an amino acid with an aliphatic side chain XH6is an amino acid with an acidic side chain, XH7is an amino acid with an acidic or amide derivative side chain, and XH8is an amino acid with an aliphatic hydroxyl side chain.

[0085] In a specific embodiment, XH1 is the amino acid L or V, XH2 is the amino acid L or V, XH3 is the amino acid K or R, XH4 is the amino acid V or A, XH5 is the amino acid L or I, ΧH6 is the amino acid E or D, XH7is the amino acid Q or E, and XH8is the amino acid S or T.

[0086] In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise 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 a particular embodiment, such anti- KIT antibody is a naked antibody. In a specific embodiment, such anti-KIT antibody isAttorney Docket No.12638-178-228 a bivalent monospecific antibody. In a specific embodiment, such anti-KIT antibody is a bispecific antibody. In a certain embodiment, such anti-KIT antibody is not a bispecific antibody.

[0087] Table 4: VH amino acid sequence Amino Acid Sequence SEQ ID NO: VH1 Q V Q L V Q S G A E L K K P G A S V K L S C K A S G Y T F 8

[0088] Table 5: VL Amino Acid Sequence Amino Acid Sequence SEQ ID NO:Attorney Docket No.12638-178-228 D R F T G S G S G T D F T L T I S S L Q S E D F A D Y F C Q Q Y N S Y P R T F G G G T K V E I K

[0089] In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise 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, the anti-KIT antibody provided herein 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, the anti-KIT antibody provided herein 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, the anti-KIT antibody provided herein 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.

[0090] In one embodiment, the anti-KIT antibody provided herein 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 provided herein 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 provided herein 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-KITAttorney Docket No.12638-178-228 antibody provided herein 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.

[0091] In one embodiment, the anti-KIT antibody provided herein 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 provided herein 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. In one embodiment, the anti-KIT antibody provided herein comprises a VH comprising the amino acid sequence of SEQ ID NO: 10, and a VL comprising the amino acid sequence of SEQ ID NO: 14. In one embodiment, the anti-KIT antibody provided herein 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: 15. In one embodiment, the anti-KIT antibody provided herein 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.

[0092] In one embodiment, the anti-KIT antibody provided herein 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 provided herein 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 provided herein 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 provided herein 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.

[0093] In one embodiment, the anti-KIT antibody provided herein 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 provided herein 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 provided herein 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, theAttorney Docket No.12638-178-228 anti-KIT antibody provided herein 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.

[0094] In a specific aspect, anti-KIT antibodies (e.g., humanized antibodies) provided herein comprise: (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.

[0095] Prior anti-KIT antibodies have been found to induce degranulation of FcgRI- expressing human mast cells and / or to show Fc receptor-dependent KIT agonist activity, which may give rise to undesirable infusion-related reactions (IRRs) among other adverse effects.

[0096] In various embodiments, an anti-KIT antibody 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, such as a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain). Preferably, an anti-KIT antibody 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 show Fc receptor-dependent KIT agonist activity. In certain embodiments, one or more of these properties of the anti-KIT antibody result from the modified (e.g., mutated) Fc region or domain.

[0097] In specific embodiments, an anti-KIT antibody described herein has reduced Fc receptor binding activity (particularly reduced FcγR binding activity). In specific embodiments, an anti-KIT antibody described herein does not have significant Fc receptor (particularly FcγR) binding activity. In specific embodiments, an anti-KIT antibody described herein has no detectable Fc receptor (particularly FcγR) binding activity. In particular embodiments, an anti- KIT antibody 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 an appropriate control antibody. When an anti-KIT antibody described hereinAttorney Docket No.12638-178-228 comprises a modified (e.g., mutated) Fc region or domain (e.g., a modified (e.g., mutated) human IgG Fc region or domain, such as a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain, in preferred embodiments the appropriate control antibody is an antibody having the same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype. In particular embodiments, an anti-KIT antibody described herein comprises a modified (e.g., mutated) human IgG1 Fc region or domain and 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 corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain.

[0098] In specific embodiments, an anti-KIT antibody described herein does not induce significant degranulation of FcgRI-expressing human mast cells (e.g., as determined, for example, by % release of beta-hexosaminidase from human mast cells in culture (e.g., in presence of IFN gamma)). In specific embodiments, an anti-KIT antibody described herein does not induce detectable degranulation of FcgRI-expressing human mast cells (e.g., as determined, for example, by % release of beta-hexosaminidase from human mast cells in culture (e.g., in presence of IFN gamma)). In particular embodiments, an anti-KIT antibody described herein 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 FcgRI-expressing human mast cells (e.g., as determined, for example, by % release of beta-hexosaminidase from human mast cells in culture (e.g., in presence of IFN gamma)) compared to an appropriate control antibody. In particular embodiments, release of beta-hexosaminidase from human mast cells in culture in presence of IFN gamma is reduced by more than 50% with an anti-KIT antibody described herein compared to an appropriate control antibody. In particular embodiments, release of beta-hexosaminidase from human mast cells in culture in presence of IFN gamma is reduced by more than 60%, more than 70%, or more than 80% with an anti-KIT antibody described herein compared to an appropriate control antibody. When an anti-KIT antibody 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, such as a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain), in preferred embodiments the appropriate control antibody is an antibody having theAttorney Docket No.12638-178-228 same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype. In particular embodiments, an anti-KIT antibody 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 FcgRI- expressing human mast cells (e.g., as determined, for example, by % release of beta- hexosaminidase from human mast cells in culture (e.g., in presence of IFN gamma)) compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In particular embodiments, release of beta-hexosaminidase from human mast cells in culture in presence of IFN gamma is reduced by more than 50% with an anti-KIT antibody described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In particular embodiments, release of beta-hexosaminidase from human mast cells in culture in presence of IFN gamma is reduced by more than 60%, more than 70%, or more than 80% with an anti-KIT antibody described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain.

[0099] In specific embodiments, an anti-KIT antibody described herein does not show significant Fc receptor-dependent KIT agonistic activity (e.g., as determined, for example, by KIT phosphorylation). In specific embodiments, an anti-KIT antibody described herein does not show detectable Fc receptor-dependent KIT agonistic activity (e.g., as determined, for example, by KIT phosphorylation). In particular embodiments, an anti-KIT antibody described herein 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, for example, by KIT phosphorylation) compared to an appropriate control antibody. In particular embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation with Fc receptors crosslinked) is reduced by more than 50% with an anti-KIT antibody described herein compared to an appropriate control antibody. In particular embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation with Fc receptors crosslinked) isAttorney Docket No.12638-178-228 reduced by more than 60%, more than 70%, or more than 80% with an anti-KIT antibody described herein compared to an appropriate control antibody. When an anti-KIT antibody 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, such as a modified (e.g., mutated) human IgG1, IgG2, IgG3, or IgG4 Fc region or domain), in preferred embodiments the appropriate control antibody is an antibody having the same VH and VL but with a wild-type (unmodified) Fc region or domain of the same isotype. In particular embodiments, an anti-KIT antibody 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, for example, by KIT phosphorylation) compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In specific embodiments, an anti-KIT antibody described herein does not show significant or detectable Fc receptor-dependent KIT agonistic activity as described herein even when cross-linked on THP-1 cells. In particular embodiments, Fc receptor-dependent KIT agonist activity (as determined by KIT phosphorylation with Fc receptors crosslinked) is reduced by more than 50% with an anti-KIT antibody described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain. In particular embodiments, Fc receptor- dependent KIT agonist activity (as determined by KIT phosphorylation with Fc receptors crosslinked) is reduced by more than 60%, more than 70%, or more than 80% with an anti-KIT antibody described herein that comprises a modified (e.g., mutated) human IgG1 Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgG1 Fc region or domain.

[0100] In various embodiments, an anti-KIT antibody described herein (1) reduces disease activity in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), (2) reduces skin mast cell number in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), (3) reduces tryptase level in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), (4) improves urticaria control in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory toAttorney Docket No.12638-178-228 antihistamine treatment), (5) improves quality of life in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), and / or (6) maintains hematology parameters (such as hemoglobin (HgB) level, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in a patient such as a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) within the normal ranges.

[0101] In certain embodiments, an anti-KIT antibody described herein can significantly decrease the critical temperature threshold value in a TempTest®for a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the value before treatment. In specific embodiments, an anti-KIT antibody described herein can decrease the critical temperature threshold value in a TempTest®for a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by at least 5°C, at least 6°C, at least 7°C, at least 8°C, at least 9°C, at least 10°C, at least 11°C, at least 12°C, at least 13°C, at least 14°C, at least 15°C, at least 16°C, at least 17°C, at least 18°C, at least 19°C, or at least 20°C (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the value before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0102] In certain embodiments, an anti-KIT antibody described herein can significantly decrease the pin number in a FricTest®for a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the pin number before treatment. In specific embodiments, an anti-KIT antibody described herein can decrease the pin number in a FricTest®for a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by at least 1, at least 2, at least 3, or at least 4 (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the pin number before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0103] In certain embodiments, an anti-KIT antibody described herein can significantly improve physician's global assessment (Phys-GA) and / or patient’s global assessment (Pat-GA), relative to the level before treatment. In specific embodiments, an anti-KIT antibody described herein can improve physician's global assessment (Phys-GA) and / or patient’s global assessmentAttorney Docket No.12638-178-228 (Pat-GA) by reducing the Likert scale (of 0-3, where 0 is none and 3 is severe) by at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1.0, at least 1.1, at least 1.2, or at least 1.3 (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the level before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0104] In certain embodiments, an anti-KIT antibody described herein can significantly reduce skin mast cell number in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the number before treatment. In specific embodiments, an anti-KIT antibody described herein can reduce skin mast cell number in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the number before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0105] In certain embodiments, an anti-KIT antibody described herein can significantly reduce serum tryptase in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the level before treatment. In specific embodiments, an anti- KIT antibody described herein can reduce serum tryptase in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by at least 50%, at least 70%, or at least 90% (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the level before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0106] In certain embodiments, an anti-KIT antibody described herein can significantly improve urticaria control in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the level before treatment. In specific embodiments, an anti- KIT antibody described herein can improve urticaria control in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by increasing the urticaria controlAttorney Docket No.12638-178-228 test (UCT) score by at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, or 16, or by increasing the UCT score to at least 12, at least 13, at least 14, at least 15, or 16 (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the level before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0107] In certain embodiments, an anti-KIT antibody described herein can significantly improve quality of life in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment), relative to the level before treatment. In specific embodiments, an anti- KIT antibody described herein can improve quality of life in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) by decreasing the dermatology life quality index (DLQI) by at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 25, or by decreasing the DLQI to at most 5, at most 4, at most 3, at most 2, at most 1, or 0 (e.g., in a week, in 2 weeks, in 4 weeks, in 6 weeks, in 8 weeks, in 10 weeks, or in 12 weeks after treatment with the anti-KIT antibody), relative to the level before treatment. In specific embodiments, the effect of the anti-KIT antibody is sustained 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.

[0108] In certain embodiments, an anti-KIT antibody described herein maintains hematology parameters (such as hemoglobin (HgB) level, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in a patient within the normal ranges. In certain embodiments, an anti-KIT antibody described herein maintains hematology parameters (such as hemoglobin (HgB) level, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in a CIndU patient (e.g., a CIndU patient whose CIndU is refractory to antihistamine treatment) within the normal ranges. In specific embodiments, the hematology 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.

[0109] In various embodiments, an anti-KIT antibody described herein has one or more of the properties described herein.Attorney Docket No.12638-178-228

[0110] In specific embodiments, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues.

[0111] In a specific embodiment, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG1 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non- naturally occurring amino acid residues selected from the group consisting of 234A, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R.243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 2621, 262A, 262T, 262E, 2631, 263A, 263T, 263M, 264L, 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, 296H, 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, 328Q, 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 as numbered by the EU index as set forth in Kabat. Optionally, the Fc region or domain may comprise additional and / or alternative non-naturally occurring amino acid residues known to one skilled in the art (see, e.g., U.S. Patents 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 05 / 040217). In a specific embodiment, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG2 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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 specificAttorney Docket No.12638-178-228 embodiment, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG3 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG4 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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.

[0112] In a specific embodiment, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG1 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one non-naturally occurring amino acid residue (e.g., one, two, three, four, five or six) selected from the group consisting of 234A, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R.243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 2621, 262A, 262T, 262E, 2631, 263A, 263T, 263M, 264L, 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, 296H, 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, 328Q, 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 as numbered by the EU index as set forth in Kabat. Optionally, the Fc region or domain may comprise additional and / or alternative non-naturally occurring amino acid residues known to one skilled in the art (see, e.g.,Attorney Docket No.12638-178-228 U.S. Patents 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 05 / 040217). In a specific embodiment, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG2 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG3 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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, an antibody described herein comprises a modified Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG4 and comprises at least one (e.g., one, two, three, four, five or six) amino acid modifications (e.g. substitution, deletion or addition) or at least one (e.g., one, two, three, four, five or six) non-naturally occurring amino acid residues, which are equivalents 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.

[0113] In a certain aspect, provided herein is an antibody comprising an Fc region or domain, wherein the Fc region or domain is an Fc region or domain of human IgG1 and comprises at least a non-naturally occurring amino acid at one or more positions selected from the group consisting of 239, 330 and 332, 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 an Fc region or domain of human IgG1 and comprises at least one non- naturally occurring amino acid selected from the group consisting of 239D, 330L and 332E, as numbered by the EU index as set forth in Kabat. Optionally, the Fc region or domain may further comprise additional non-naturally occurring amino acid at one or more positions selected from the group consisting of 252, 254, and 256, 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,Attorney Docket No.12638-178-228 wherein the Fc region or domain is an Fc region or domain of human IgG1 and comprises at least one non-naturally occurring 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 non-naturally occurring amino acid at one or more positions are 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 an Fc region or domain of human IgG2, IgG3, or IgG4, and comprises at least one non-naturally occurring amino acid residue that is an 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, wherein the Fc region or domain is an Fc region or domain of human IgG2, IgG3, or IgG4, and comprises at least one non-naturally occurring amino acid residue at one or more positions that are equivalent(s) to the positions described herein for a human IgG1 Fc region or domain, as can be determined by one of skill in the art. In one embodiment, an Fc region or domain comprising such sequence exhibits one or more Fc activity, for example, 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 sequence exhibits reduced Fc activity, for example, 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 sequence exhibits enhanced FcRn activity, for example, enhanced half-life.

[0114] Additional non- limiting examples of Fc region or domain modifications are provided 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 U S A 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;Attorney Docket No.12638-178-228 5,869,046; 6,121,022; 5,624,821; 5,648,260; 6,528,624; 6,194,551; 6,737,056; 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 Nos.2004 / 0002587 and PCT Publications WO 94 / 29351; WO 99 / 58572; WO 00 / 42072; WO 04 / 029207; WO 04 / 099249; WO 04 / 063351.

[0115] In specific embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG1 Fc region or domain, which comprises non-naturally occurring amino acids 234A, 235Q and 322Q as numbered by the EU index as set forth in Kabat. In a particular embodiment, the modified (e.g., mutated) human IgG1 Fc region or domain further comprises non-naturally occurring amino acids 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

[0116] In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG2 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q and 322Q as numbered by the EU index as set forth in Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art. In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG2 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art.

[0117] In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG3 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q and 322Q as numbered by the EU index as set forth in Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art. In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG3 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art.

[0118] In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG4 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q and 322Q as numbered by the EU index as set forth inAttorney Docket No.12638-178-228 Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art. In certain embodiments, the antibody described herein comprises a modified (e.g., mutated) human IgG4 Fc region or domain, which comprises non-naturally occurring amino acids that are equivalents to 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat for human IgG1 Fc region or domain, as can be determined by one of skill in the art.

[0119] In a specific embodiment, the antibody described herein comprises the VL and VH CDR sequences set forth in Table 1, 2, or 3, and a modified (e.g., mutated) human IgG1 Fc region or domain, wherein the modified (e.g., mutated) human IgG1 Fc region or domain comprises non-naturally occurring amino acids 234A, 235Q, and 322Q as numbered by the EU index as set forth in Kabat.

[0120] In a preferred embodiment, the antibody described herein comprises the VL and VH CDR sequences set forth in Table 1, 2, or 3, and a modified (e.g., mutated) human IgG1 Fc region or domain, wherein the modified (e.g., mutated) human IgG1 Fc region or domain comprises non-naturally occurring amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

[0121] Thus, in one aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: (1) (a) (i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively;Attorney Docket No.12638-178-228 (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; and (2) a modified (e.g., mutated) human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, and 322Q as numbered by the EU index as set forth in Kabat.

[0122] Thus, in a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: (1) (a) (i) a VL comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) aAttorney Docket No.12638-178-228 VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively; and (2) a modified (e.g., mutated) human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

[0123] In a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: (i) a VL comprising the amino acid sequence:DIVMTQSPSXK1LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKXK2LIYS ASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4EDFAXK5YXK6CQQYNSYPRTFGGGTKV EIK (SEQ ID NO: 17), wherein XK1is an amino acid with an aromatic or aliphatic hydroxyl side chain, ΧK2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain, ΧK3 is an amino acid with an aliphatic hydroxyl side chain, ΧK4 is an amino acid with an aliphatic hydroxyl side chain or is P, XK5is an amino acid with a charged or acidic side chain and ΧK6is an amino acid with an aromatic side chain; and (ii) a VH comprising the amino acid sequence: QVQLVQSGAEXH1KKPGASVKXH2SCKASGYTFTDYYINWVXH3QAPGKGLEWIARIYPG SGNTYYNEKFKGRXH4TXH5TAXH6KSTSTAYMXH7LSSLRSEDXH8AVYFCARGVYYFDY WGQGTTVTVSS (SEQ ID NO: 18) wherein XH1is an amino acid with an aliphatic side chain, XH2 is an amino acid with an aliphatic side chain, XH3 is an amino acid with a polar or basic side chain, XH4is an amino acid with an aliphatic side chain, XH5is an amino acid with an aliphatic side chain, XH6is an amino acid with an acidic side chain, XH7is an amino acid with an acidic or amide derivative side chain, and XH8 is an amino acid with an aliphatic hydroxyl side chain; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q and preferably also 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

[0124] In a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: i) a VL which comprises 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 comprising non- naturally occurring amino acids 234A, 235Q, 322Q and preferably also 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.Attorney Docket No.12638-178-228

[0125] In a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: i) a VL which comprises the amino acid sequence of SEQ ID NO: 14 and ii) a VH which comprises the amino acid sequence of SEQ ID NO: 10; and (iii) a modified (e.g., mutated) human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q and preferably also 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

[0126] In specific embodiments, the antibody provided herein comprises a heavy chain comprising the following amino acid sequence: QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).

[0127] In specific embodiments, the antibody provided herein comprises a light chain comprising the following amino acid sequence: DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

[0128] In specific embodiments, the antibody provided herein comprises a heavy chain comprising the following amino acid sequence: QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDAttorney Docket No.12638-178-228 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21); and a light chain comprising the following amino acid sequence: DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

[0129] In a specific embodiment, provided herein is an antibody comprising: (i) a heavy chain comprising the amino acid sequence: mewswvflfflsvttgvhsqvqlvqsgaevkkpgasvklsckasgytftdyyinwvrqapgkglewiariypgsgntyynekfkgr atltadkststaymqlsslrsedtavyfcargvyyfdywgqgttvtvssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswn sgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapeaqggpsvflfppkpk dtlyitrepevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykcqvsnkalpapiek tiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvf scsvmhealhnhytqkslslspg (SEQ ID NO: 19), wherein the leader sequence is shown in bold italic type, the variable region (VH) is shown in italic type and the constant region is shown underlined. In addition the mutations in the constant region (compared to wild type human IgG1) are shown double underlined; and (ii) a light chain comprising the amino acid sequence: msvptqvlgllllwltdarcdivmtqspsslsasvgdrvtitckasqnvrtnvawyqqkpgkapkaliysasyrysgvpdrftgsgsgtdf tltisslqpedfadyfcqqynsyprtfgggtkveikrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqessequence constant region is shown underlined.

[0130] In a preferred embodiment, the anti-KIT antibody described herein is barzolvolimab (see FIG.3).

[0131] In specific embodiments, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) any human Fc-gamma receptor (FcγR receptor). In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcγRI. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcγRIIa. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) humanAttorney Docket No.12638-178-228 FcγRIIb. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcγRIIIa. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcγRIIIb.

[0132] In specific embodiments, an anti-KIT antibody described herein comprises 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 has an enhanced binding (e.g., an 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 neonatal Fc Receptor (FcRn) relative to a corresponding antibody with the same variable region sequences but an unmodified (wild type) human IgG constant region. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 6.0 with a KD of less than 20 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 6.0 with a KD of less than 2 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 6.0 with a KD of less than 1 nM. In a specific embodiment, an anti- KIT antibody described herein binds to FcRn at pH 6.0 with a KD of less than 500 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 6.0 with a KD of less than 400 pM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 7.2 with a KD of less than 200 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 7.2 with a KD of less than 150 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 7.2 with a KD of less than 100 nM. In a specific embodiment, an anti-KIT antibody described herein binds to FcRn at pH 7.2 with a KD of less than 80 nM.

[0133] In specific embodiments, an anti-KIT antibody described herein comprises 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 exhibits no antibody-dependent cellular cytotoxicity (ADCC). In specific embodiments, an anti-KIT antibody described herein comprises 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 exhibits reduced (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) ADCC, relative to a corresponding antibody with the same variable region sequences but an unmodified (wild type) human IgG constant region.Attorney Docket No.12638-178-228

[0134] In specific embodiments, an anti-KIT antibody described herein comprises 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 exhibits reduced (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) production of cytokines (e.g., IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, and / or TNF-α), relative to a corresponding antibody with the same variable region sequences but an unmodified (wild type) human IgG constant region.

[0135] In certain aspects, anti-KIT antibodies can be obtained using methods known in the art, for example, see Section 5.4 below.

[0136] In a particular aspect, an anti-KIT antibody provided herein specifically binds to a D4 domain of human KIT and a D5 region of KIT, e.g., human KIT. In another specific embodiment, an anti-KIT antibody provided herein specifically binds to a D5 domain of KIT, e.g., human KIT, with lower affinity than to a D4 domain of KIT, e.g., human KIT. In a particular embodiment, an anti-KIT antibody provided herein specifically binds to a D4 domain of KIT, e.g., human KIT, with higher affinity than to a 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 assays.

[0137] In a particular embodiment, an anti-KIT antibody provided herein specifically binds to a 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 a D4 domain only than a KIT antigen consisting essentially of a D5 domain only.

[0138] In a particular embodiment, an anti-KIT antibody provided herein specifically binds to a KIT polypeptide (e.g., the D4 region of human KIT) with an EC50 (half maximal effective concentration) value of about 50 nM, 10 nM, 500 pM, 300 pM, 200 pM, 100 pM or 50 pM or less as determined by an assay described in the art, such as ELISA.

[0139] In a particular embodiment, an anti-KIT antibody provided herein specifically binds to a KIT polypeptide (e.g., the D4 region of human KIT) with an EC50 value of about 200 pM or 150 pM or less as determined by an assay described in the art, such as ELISA or FACs with CHO-WT-KIT cells (CHO cells engineered to recombinantly express wild-type human KIT).Attorney Docket No.12638-178-228

[0140] In a particular embodiment, an anti-KIT antibody provided herein is capable of blocking KIT phosphorylation with IC50 (50% inhibition concentration) value of about 600 pM or less.

[0141] In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing KIT receptor internalization, e.g., 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 assessed by methods described herein or known to one of skill in the art, relative to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing KIT receptor internalization, e.g., by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art, relative to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). In a particular embodiment, an anti- KIT antibody provided herein is capable of inducing or enhancing KIT receptor internalization, e.g., 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 assessed by methods described herein or known to one of skill in the art, relative to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). Techniques for the quantitation or visualization of cell surface receptors are well known in the art and include a variety of fluorescent and radioactive techniques. For example, one method involves incubating the cells with a radiolabeled anti-receptor antibody. Alternatively, the natural ligand of the receptor can be conjugated to a fluorescent molecule or radioactive-label and incubated with the cells. Additional receptor internalization assays are well known in the art and are described in, for example, 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.

[0142] In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing KIT receptor turnover, e.g., 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 assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assay), relative to turnover in the presence of an unrelated antibody (e.g., an antibody that does notAttorney Docket No.12638-178-228 immunospecifically bind to KIT). In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing KIT receptor turnover, by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assay), relative to turnover in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). In a particular embodiment, an anti- KIT antibody provided herein is capable of inducing or enhancing 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 assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assay), relative to turnover in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). Methods for the determining receptor turnover are well known in the art. For example, cells expressing KIT can be pulse-labeled using35S-EXPRESS Protein Labeling mix (NEG772, NEN Life Science Products), washed and chased with unlabeled medium for a period of time before protein lysates from the labeled cells are immunoprecipitated using an anti-KIT antibody and resolved by SDS- PAGE and visualized (e.g., exposed to a PhosphoImager screen (Molecular Dynamics), scanned using the Typhoon8600 scanner (Amersham), and analyzed using ImageQuant software (Molecular Dynamics)) (see, e.g., Chan et al., Development, 2004, 131:5551-5560).

[0143] In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing 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% as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing KIT receptor degradation, by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). In a particular embodiment, an anti-KIT antibody provided herein is capable of inducing or enhancing 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, 20Attorney Docket No.12638-178-228 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to KIT). Techniques for quantitating or monitoring ubiquitination and / or degradation (e.g., kinetics or rate of degradation) of cell surface receptors are well known in the art and involve 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 experiments using radiolabeled ligands such as125I-SCF can be carried out to quantitatively measure degradation of KIT.

[0144] In particular embodiments, an anti-KIT antibody provided herein does not bind the extracellular ligand binding site of KIT, e.g., the SCF binding site of KIT. In particular embodiments, an anti-KIT antibody provided herein does not inhibit ligand binding to KIT, e.g., does not inhibit KIT ligand (e.g., SCF) binding to KIT, as determined by a method described in the art, for example, ELISA. In certain embodiments, an anti-KIT antibody provided herein does not fully inhibit, or partially inhibits, ligand binding to KIT, e.g., does not fully inhibit, or partially inhibits, KIT ligand (e.g., SCF) binding to KIT, as determined by a method described in the art, for example, ELISA or FACS (fluorescence-activated cell sorting).

[0145] In specific aspects, anti-KIT antibodies (e.g., human or humanized antibodies) provided herein are inhibitory antibodies, that is, antibodies that inhibit (e.g. , partially inhibit) KIT activity, i.e., one or more KIT activities. In a specific embodiment, partial inhibition of a KIT activity results in, for example, about 25% to about 65% or 75% inhibition. In a specific embodiment, partial inhibition of a 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 a particular embodiment, an antibody described herein inhibits KIT phosphorylation (e.g., ligand-induced phosphorylation) .

[0146] In a specific embodiment, an anti-KIT antibody provided herein inhibits KIT tyrosine phosphorylation in the KIT cytoplasmic domain.

[0147] In another particular embodiment, an anti-KIT antibody provided herein inhibits cell proliferation, for example, mast cell proliferation or eosinophil proliferation. In yet anotherAttorney Docket No.12638-178-228 particular embodiment, an anti-KIT antibody provided herein inhibits cell survival, for example mast cell survival or eosinophil cell survival. In certain aspects, inhibition of cell proliferation, for example, mast cell proliferation or eosinophil proliferation, is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0148] In another particular embodiment, an anti-KIT antibody provided herein inhibits mast cell activation or eosinophil activation. In certain aspects, 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%.

[0149] In a specific embodiment, an anti-KIT antibody 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 certain aspects, inhibition of eosinophil or mast cell degranulation is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0150] In another particular embodiment, an anti-KIT antibody provided herein inhibits mast cell mediator release. In certain aspects, mast cell mediator release is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. Assays to measure mast cell activity, such as release of mediators, 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," in Current Protocols in Immunology, Unite 7.38.1- 7.38.9, November 2010 (John Wiley & Sons, Inc.). For example, certain assays are designed to monitor mast cell degranulation through the measurement of the release of the granule component β-hexosaminidase, determination of the generation of products of phospholipid metabolism such as the eicosanoids, leukotriene C4(LTC4), and prostaglandin D2(PGD2), or determination of the generation of multiple cytokines. In certain aspects, measurement of mast cell culture release of cytokines can be performed with enzyme-linked immunosorbent assays (ELISAs). In certain aspects, CD34 peripheral blood progenitor cells or a mast cell line, such as HMC-1 or human LAD2 mast cell line can be used in these assays to ascertain the effects of an anti-KIT antibody on mast cells.

[0151] In a specific embodiment, an anti-KIT antibody provided herein induces apoptosis, for example mast cell apoptosis or eosinophil apoptosis. In another specific embodiment, an anti- KIT antibody provided herein induces cell differentiation, e.g., mast cell differentiation.Attorney Docket No.12638-178-228

[0152] In a particular embodiment, an anti-KIT antibody provided herein can achieve any one of the following: reduction in the number and / or activity of eosinophils, reduction in mast cell proliferation, reduction in plasma tryptase levels, reduction in plasma SCF levels, reduction in mast cell number or amount, inhibition or reduction in mast cell activity, reduction in mast cell induced production or release of inflammatory factors, reduction in release of inflammatory factors, restoration of mast cell homeostasis, reduced mast cell migration, reduced mast cell adhesion, inhibition or reduction in mast cell recruitment of eosinophils, and inhibition or reduction in antigen-mediated degranulation of mast cells.

[0153] In a particular embodiment, an anti-KIT antibody provided herein inhibits KIT activity but does not inhibit KIT dimerization. In another particular embodiment, an anti-KIT antibody provided herein inhibits KIT activity and does not inhibit ligand binding to KIT, e.g., does not inhibit KIT ligand (e.g., SCF) binding to KIT, but does inhibit KIT dimerization.

[0154] In a particular embodiment, an anti-KIT antibody provided herein inhibits a KIT activity, such as ligand-induced tyrosine phosphorylation of a KIT cytoplasmic domain, by about 25% to about 65% or 75%, as determined by a cell-based phosphorylation assay well known in the art, for example, the cell-based phosphorylation assay described herein. In a certain embodiment, an anti-KIT antibody provided herein inhibits a KIT activity, such as ligand- induced tyrosine phosphorylation of a KIT cytoplasmic domain, by about 35% to about 85% or 95%, as determined by a cell-based phosphorylation assay well known in the art, for example, the cell-based phosphorylation assay described herein.

[0155] In a particular embodiment, an anti-KIT antibody provided herein inhibits a KIT activity, such as ligand-induced tyrosine phosphorylation of a KIT cytoplasmic domain, with a 50% inhibition 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, for example, the cell-based phosphorylation assay described herein. In a specific embodiment, the IC50is less than about 550 pM or 200 pM. In a specific embodiment, the IC50is in the range of about 50 pM to about 225 pM, or in the range of 100 pM to about 600 pM. In a specific embodiment, the IC50 is 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.

[0156] In a specific embodiment, an anti-KIT antibody provided herein, (i) immunospecifically binds to a KIT polypeptide comprising the D4 and / or D5 region of humanAttorney Docket No.12638-178-228 KIT, (ii) inhibits KIT phosphorylation (e.g., tyrosine phosphorylation), and (iii) does not fully 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 at an average titer of at least 0.5 μg / mL, for example 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, for example, the VH domain and VL domain do not contain T cell epitopes.

[0157] In other specific embodiments, an anti-KIT antibody provided herein immunospecifically binds to a monomeric form of KIT (e.g., human KIT). In particular embodiments, an anti-KIT antibody provided herein specifically bind to a monomeric form of KIT (e.g., human KIT). In specific embodiments, an anti-KIT antibody provided herein specifically binds to a dimeric form of KIT (e.g., human KIT).

[0158] In specific embodiments, an anti-KIT antibody provided herein does not bind to a monomeric form of KIT and specifically binds to a dimeric form of KIT or multimeric form of KIT. In certain embodiments, an antibody has higher affinity for a KIT monomer than a KIT dimer. In certain embodiments, an antibody has higher affinity for a KIT monomer than a KIT multimer.

[0159] In specific embodiments, an anti-KIT antibody provided herein specifically binds to a native isoform or native variant of KIT (that is 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 particular embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof. In specific embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof and does not specifically bind to a non-human KIT (e.g. monkey, mouse, goat, donkey, dog, cat, rabbit, pig, rat, or bird) or a fragment thereof. In specific embodiments, an anti- KIT antibody provided herein specifically binds to human KIT or a fragment thereof and does not specifically bind to murine KIT. In certain embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof (e.g., a D4 region of human KIT) and to canine (dog) and non-human primate (e.g., monkey) KIT. In certain embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof (e.g., a D4 region of human KIT) and to canine (dog) and non-human primate (e.g., monkey) KIT, butAttorney Docket No.12638-178-228 does not specifically bind to murine or rat KIT or a fragment thereof (e.g., a D4 region of murine KIT).

[0160] In certain embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof (e.g. a D4 region of human KIT) and to canine (dog), feline (cat) and cynomologous KIT, but does not specifically bind to murine or rat KIT or a fragment thereof (e.g., a D4 region of murine KIT).

[0161] In specific embodiments, an anti-KIT antibody provided herein specifically binds to human KIT or a fragment thereof (e.g. a D4 region of human KIT), and to canine (dog), feline (cat) and cynomologous KIT, with high affinity (e.g., at least 0.5 fold, 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, or 10 fold) than to murine or rat KIT or a fragment thereof (e.g., a D4 region of murine KIT).

[0162] In certain embodiments, an anti-KIT antibody provided herein specifically binds to an extracellular domain of human KIT comprising a mutation, for example a somatic mutation, such as a mutation in exon 9 of human KIT wherein 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 are both incorporated herein by reference in their entireties, describing KIT mutations).

[0163] In certain embodiments, an anti-KIT antibody provided herein specifically binds to an extracellular domain of human KIT which is glycosylated. In certain embodiments, an antibody described herein binds to two different glycosylated forms of an extracellular domain of human KIT. For example, two forms of human KIT with different molecular weights, indicating different glycosylation patterns, have been observed by immunoblotting.

[0164] In certain embodiments, an antibody described herein may 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, an antibody described herein binds to an extracellular domain of human KIT which is not glycosylated.

[0165] In a specific embodiment, an anti-KIT antibody 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 the same antigen, KIT (e.g., human KIT). In certain embodiments, the antigen binding region comprises the VH and VL CDRs as set forth in Table 1. In particular embodiments, the antigen binding region comprises aAttorney Docket No.12638-178-228 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 aspects, an anti-KIT antibody provided herein is not a bispecific antibody.

[0166] In a specific embodiment, antibodies described herein are monoclonal antibodies or isolated monoclonal antibodies. In another specific embodiment, an antibody described herein is a humanized monoclonal antibody. In a particular embodiment, an antibody described herein is a recombinant antibody, for example, a recombinant human antibody, recombinant humanized antibody or a recombinant monoclonal antibody. In certain embodiments, an antibody described herein contains non-human amino acid sequences, e.g., non-human CDRs or non-human (e.g., non-human primate) framework residues.

[0167] In particular embodiments provided herein, recombinant antibodies can be isolated, prepared, expressed, or created by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial antibody library, or antibodies prepared, expressed, created or isolated by any other means that involves creation, e.g., via synthesis, genetic engineering of DNA sequences that encode human immunoglobulin sequences, or splicing of sequences that encode human immunoglobulins, e.g., human immunoglobulin gene sequences, to other such sequences. In certain embodiments, the amino acid sequences of such recombinant antibodies have been modified such thus the amino acid sequences of such antibodies, e.g., VH and / or VL regions, are sequences that do not naturally exist within an organism's antibody germline repertoire in vivo, for example a murine or human germline repertoire. In a particular embodiment, a recombinant antibody can be obtained by assembling several sequence fragments that naturally exist in an organism (e.g., primate, such as human) into a composite sequence of a recombinant antibody, wherein the composite sequence does not naturally exist within an organism (e.g., primate such as human).

[0168] Antibodies 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 provided herein is an IgG antibody (e.g. , human IgG antibody), or a class (e.g., human IgG1 or IgG4) or subclass thereof. In another specific embodiment, an antibody described herein is an IgG1 (e.g., human IgG1 (isotype a, z, or f)) or IgG4 antibody. In certain embodiments, an antibody described herein is aAttorney Docket No.12638-178-228 whole or entire antibody, e.g., a whole or entire humanized, human, or composite human antibody.

[0169] In specific aspects, the antibody provided herein comprises an antibody light chain and heavy chain, e.g., a separate light chain and heavy chain. With respect to the light chain, in a specific embodiment, the light chain of an antibody described herein is a kappa light chain. In another specific embodiment, the light chain of an antibody described herein is a lambda light chain. In yet another specific embodiment, the light chain of an antibody described herein is a human kappa light chain or a human lambda light chain. In a particular embodiment, an antibody described herein comprises a human light chain constant region. Non-limiting examples of human light chain constant region sequences have been described in the art, e.g., see U.S. Patent No.5,693,780 and Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91- 3242.

[0170] With respect to the heavy chain, in a specific embodiment, the heavy chain of an antibody 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 an antibody described can comprise a human alpha (α), delta (δ), epsilon (ε), gamma (γ) or mu (µ) heavy chain. In a particular embodiment, an antibody described herein comprises a human heavy chain constant region (e.g., a human IgG constant region, for example, a human IgG1, IgG2, IgG3, or IgG4 constant region). Non-limiting examples of human heavy chain constant region sequences have been described in the art, e.g., see U.S. Patent No.5,693,780 and Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242. In a specific embodiment, the antibody described herein comprises 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).

[0171] In certain embodiments, anti-KIT antibodies described herein are human, composite human, or humanized monoclonal antibodies. In a particular embodiment, an antibody described herein is an engineered antibody, for example, antibody produced by recombinant methods. In a specific embodiment, an antibody described herein is a humanized antibody comprising one orAttorney Docket No.12638-178-228 more non-human (e.g. rodent or murine) CDRs and one or more human framework regions (FR), and optionally human heavy chain constant region and / or light chain constant region. In a specific embodiment, an antibody described herein comprises one or more primate (or non- human primate) framework regions. In a specific embodiment, an antibody described herein does not comprise non-human primate framework regions.

[0172] Antibodies provided herein can include antibodies comprising chemical modifications, for example, antibodies which have been chemically modified, e.g., by covalent attachment of any type of molecule to the antibody. For example, but not by way of limitation, an anti-KIT antibody can be glycosylated, acetylated, pegylated, phosphorylated, or amidated, can be derivitized via protective / blocking groups, or can further comprise a cellular ligand and or other protein or peptide (e.g., a heterologous protein or peptide), etc. For example, an antibody provided herein can be chemically modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Further, an anti-KIT antibody described herein can contain one or more non-classical amino acids.

[0173] In one embodiment, an anti-KIT antibody provided herein is a naked antibody which is not linked, fused or conjugated (e.g. artificially linked, fused or conjugated) to another molecule, peptide or polypeptide (for example, a heterologous polypeptide). In a particular embodiment, an anti-KIT antibody provided herein is not an antibody-drug conjugate. In a particular embodiment, an anti-KIT antibody provided herein is not a fusion protein. In particular embodiments, an anti-KIT antibody described herein does not comprise any non-classical amino acids. 5.2 Polynucleotides

[0174] In certain aspects, provided herein are polynucleotides and combination of polynucleotides comprising a nucleotide sequence(s) encoding an antibody (e.g., human or humanized antibody) described herein that immunospecifically binds to a KIT antigen or a fragment thereof (e.g., a variable light chain region and / or variable heavy chain region). Also provided herein are polynucleotides encoding KIT antigens for generating anti-KIT antibodies described herein.Attorney Docket No.12638-178-228

[0175] As used herein, an “isolated” polynucleotide or nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source (e.g., in a human) of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the language “substantially free” includes preparations of polynucleotide or nucleic acid molecule having less than about 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (in particular less than about 10%) of other material, e.g., cellular material, culture medium, other nucleic acid molecules, chemical precursors and / or other chemicals. In a specific embodiment, a nucleic acid molecule(s) encoding an antibody described herein is isolated or purified.

[0176] In particular aspects, provided herein is a polynucleotide or a combination of polynucleotides comprising nucleotide sequences encoding an antibody described herein, or the VH and VL of said antibody. In a specific embodiment, provided herein is a polynucleotide comprising a nucleotide sequence encoding the VH of an antibody described herein. In a specific embodiment, provided herein is a polynucleotide comprising a nucleotide sequence encoding the VL of an antibody described herein. In a specific embodiment, provided herein is a polynucleotide comprising a first nucleotide sequence encoding the VH of an antibody described herein and a second nucleotide sequence encoding the VL of said antibody. In a specific embodiment, provided herein is a combination of two polynucleotides, wherein the first polynucleotide of the combination comprises a first nucleotide sequence encoding the VH of an antibody described herein and the second polynucleotide of the combination comprises a second nucleotide sequence encoding the VL of said antibody. In a specific embodiment, provided herein is a polynucleotide comprising a nucleotide sequence encoding the heavy chain of an antibody described herein. In a specific embodiment, provided herein is a polynucleotide comprising a nucleotide sequence encoding the light chain of an antibody described herein. In a specific embodiment, provided herein is a polynucleotide comprising a first nucleotide sequence encoding the heavy chain of an antibody described herein and a second nucleotide sequence encoding the light chain of said antibody. In a specific embodiment, provided herein is a combination of two polynucleotides, wherein the first polynucleotide of the combination comprises a first nucleotide sequence encoding the heavy chain of an antibody described hereinAttorney Docket No.12638-178-228 and the second polynucleotide of the combination comprises a second nucleotide sequence encoding the light chain of said antibody.

[0177] In a specific embodiment, the polynucleotide provided herein comprises the nucleotide sequence of SEQ ID NO: 23. In a specific embodiment, the polynucleotide provided herein comprises the nucleotide sequence of SEQ ID NO: 24. In a specific embodiment, the polynucleotide provided herein comprises a nucleotide sequence of SEQ ID NO: 23 and a nucleotide sequence of SEQ ID NO: 24. In a specific embodiment, the combination of polynucleotides provided herein comprises a first polynucleotide comprising a nucleotide sequence of SEQ ID NO: 23 and a second polynucleotide comprising a nucleotide sequence of SEQ ID NO: 24.

[0178] Also provided herein are polynucleotides encoding an anti-KIT antibody or a fragment thereof that are optimized, e.g., by codon / RNA optimization, replacement with heterologous signal sequences, and elimination of mRNA instability elements. Methods to generate optimized nucleic acids encoding an anti-KIT antibody or a fragment thereof (e.g., light chain, heavy chain, VH domain, or VL domain) for recombinant expression by introducing codon changes and / or eliminating inhibitory regions in the mRNA can be carried out by adapting the optimization methods described in, e.g., U.S. Patent Nos.5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498, accordingly. For example, potential splice sites and instability elements (e.g., A / T or A / U rich elements) within the RNA can be mutated without altering the amino acids encoded by the nucleic acid sequences to increase stability of the RNA for recombinant expression. The alterations utilize the degeneracy of the genetic code, e.g., using an alternative codon for an identical amino acid. In some embodiments, it can be desirable to alter one or more codons to encode a conservative mutation, e.g., a similar amino acid with similar chemical structure and properties and / or function as the original amino acid. Such methods can increase expression of an anti-KIT antibody or fragment thereof by at least 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold or more relative to the expression of an anti-KIT antibody encoded by polynucleotides that have not been optimized.

[0179] In certain embodiments, an optimized polynucleotide sequence encoding an anti-KIT antibody described herein or a fragment thereof (e.g., VL domain and / or VH domain) can hybridize to an antisense (e.g., complementary) polynucleotide of an unoptimized polynucleotideAttorney Docket No.12638-178-228 sequence encoding an anti-KIT antibody described herein or a fragment thereof (e.g., VL domain and / or VH domain). In specific embodiments, an optimized nucleotide sequence encoding an anti-KIT antibody described herein or a fragment hybridizes under high stringency conditions to antisense polynucleotide of an unoptimized polynucleotide sequence encoding an anti-KIT antibody described herein or a fragment thereof. In a specific embodiment, an optimized nucleotide sequence encoding an anti-KIT antibody described herein or a fragment thereof hybridizes under high stringency, intermediate or lower stringency hybridization conditions to an antisense polynucleotide of an unoptimized nucleotide sequence encoding an anti-KIT antibody described herein or a fragment thereof. Information regarding hybridization conditions have been described, see, e.g., U.S. Patent Application Publication No. US 2005 / 0048549 (e.g., paragraphs 72-73), which is incorporated herein by reference.

[0180] In certain embodiments, an optimized polynucleotide sequence encoding a VL region of an antibody described herein is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% identical to the nucleotide sequence of SEQ ID NO: 23. In certain embodiments, an optimized polynucleotide sequence encoding a VH region of an antibody described herein is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% identical to the nucleotide sequence of SEQ ID NO: 24.

[0181] The polynucleotides can be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. Nucleotide sequences encoding antibodies described herein and modified versions of these antibodies can be determined using methods well known in the art, i.e., nucleotide codons known to encode particular amino acids are assembled in such a way to generate a nucleic acid that encodes the antibody. Such a polynucleotide encoding the antibody can be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

[0182] Alternatively, a polynucleotide encoding an antibody described herein can be generated from nucleic acid from a suitable source (e.g., a hybridoma) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers hybridizable to the 3’ and 5’ ends of a known sequence canAttorney Docket No.12638-178-228 be performed using genomic DNA obtained from hybridoma cells producing the antibody of interest. Such PCR amplification methods can be used to obtain nucleic acids comprising the sequence encoding the light chain and / or heavy chain of an antibody. Such PCR amplification methods can be used to obtain nucleic acids comprising the sequence encoding the variable light chain region and / or the variable heavy chain region of an antibody. The amplified nucleic acids can be cloned into vectors for expression in host cells and for further cloning, for example, to generate chimeric and humanized antibodies.

[0183] If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin can be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody described herein) by PCR amplification using synthetic primers hybridizable to the 3’ and 5’ ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR can then be cloned into replicable cloning vectors using any method well known in the art.

[0184] DNA encoding anti-KIT antibodies described herein can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the anti-KIT antibodies). Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells (e.g., CHO cells from the CHO GS System™ (Lonza)), or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of anti-KIT antibodies in the recombinant host cells.

[0185] To generate whole antibodies, PCR primers including VH or VL nucleotide sequences, a restriction site, and a flanking sequence to protect the restriction site can be used to amplify the VH or VL sequences in scFv clones. Utilizing cloning techniques known to those of skill in the art, the PCR amplified VH domains can be cloned into vectors expressing a heavy chain constant region, e.g., the human gamma 1 or gamma 4 constant region, and the PCR amplified VL domains can be cloned into vectors expressing a light chain constant region, e.g.,Attorney Docket No.12638-178-228 human kappa or lambda constant regions. In certain embodiments, the vectors for expressing the VH or VL domains comprise an EF-1α promoter, a secretion signal, a cloning site for the variable domain, constant domains, and a selection marker such as neomycin. The VH and VL domains can also be cloned into one vector expressing the necessary constant regions. The heavy chain conversion vectors and light chain conversion vectors are then co-transfected into cell lines to generate stable or transient cell lines that express full-length antibodies, e.g., IgG, using techniques known to those of skill in the art.

[0186] The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the murine sequences, or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. 5.3 Host Cells and Recombinant Expression of Antibodies

[0187] In certain aspects, provided herein are host cells recombinantly expressing the antibodies described herein and related expression vectors. Provided herein are vectors and combination of vectors (e.g., expression vectors) comprising polynucleotides comprising nucleotide sequences encoding anti-KIT antibodies for recombinant expression in host cells, preferably in mammalian cells. Also provided herein are host cells comprising such vectors or combination of vectors for recombinantly expressing anti-KIT antibodies described herein (e.g., human or humanized antibody).

[0188] Recombinant expression of an antibody described herein (e.g., a full-length antibody, heavy and / or light chain of an antibody, or a single chain antibody described herein) that immunospecifically binds to a KIT antigen involves construction of an expression vector(s) containing a polynucleotide(s) that encode the antibody. Once a polynucleotide encoding an antibody molecule, heavy and / or light chain of an antibody, or fragment thereof (preferably, but not necessarily, containing the heavy and / or light chain variable domain) described herein has been obtained, the vector(s) for the production of the antibody molecule can be produced by recombinant DNA technology using techniques well-known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody (or VH / VL or heavy / light chain) encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibodyAttorney Docket No.12638-178-228 coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors comprising a nucleotide sequence encoding an antibody molecule described herein, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody, or a heavy or light chain CDR, operably linked to a promoter. Such vectors can, for example, include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., International Publication Nos. WO 86 / 05807 and WO 89 / 01036; and U.S. Patent No.5,122,464) and the variable domain of the antibody can be cloned into such a vector for expression of the entire heavy, the entire light chain, or both the entire heavy and light chains.

[0189] In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a VH of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a VL of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a VH and a VL of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a first polynucleotide encoding a VH of an antibody described herein and a second polynucleotide encoding the VL of the antibody. In a specific embodiment, provided herein is a combination of two vectors, wherein the first vector of the combination comprises a first polynucleotide encoding the VH of an antibody described herein, and the second vector of the combination comprises a second polynucleotide encoding the VL of the antibody. In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a heavy chain of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a light chain of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a polynucleotide encoding a heavy chain and a light chain of an antibody described herein. In a specific embodiment, provided herein is a vector comprising a first polynucleotide encoding a VH of an antibody described herein and a second polynucleotide encoding the VL of the antibody. In a specific embodiment, provided herein is a combination of two vectors, wherein the first vector of the combination comprises a first polynucleotide encoding the VH of an antibody described herein, and the second vector of the combination comprises a second polynucleotide encoding the VL of the antibody.Attorney Docket No.12638-178-228

[0190] An expression vector or a combination of expression vectors can be transferred to a cell (e.g., host cell) by conventional techniques and the resulting cells can then be cultured by conventional techniques to produce an antibody described herein. Thus, provided herein are host cells containing a polynucleotide or a combination of polynucleotides encoding an antibody described herein, or a heavy or light chain thereof, operably linked to a promoter for expression of such sequences in the host cell. In certain embodiments, for the expression of double-chained antibodies, vectors encoding both the heavy and light chains, individually, can be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below. In certain embodiments, a host cell contains a vector comprising a polynucleotide encoding both the heavy chain and light chain (or both the VH and VL) of an antibody described herein. In specific embodiments, a host cell contains two different vectors, a first vector comprising a polynucleotide encoding a heavy chain (or VH) of an antibody described herein, and a second vector comprising a polynucleotide encoding a light chain (or VL) of an antibody described herein. In other embodiments, a first host cell comprises a first vector comprising a polynucleotide encoding a heavy chain (or VH) of an antibody described herein, and a second host cell comprises a second vector comprising a polynucleotide encoding a light chain (or VL) of an antibody described herein.

[0191] A variety of host-expression vector systems can be utilized to express antibody molecules described herein (see, e.g., U.S. Patent No.5,807,715). Such host-expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells which can, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule described herein in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli and B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems (e.g.,green algae such as Chlamydomonas reinhardtii) infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systemsAttorney Docket No.12638-178-228 (e.g., COS, CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7O3O, HsS78Bst, HeLa, and NIH 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). In a specific embodiment, cells for expressing antibodies described herein are CHO cells, for example CHO cells from the CHO GS System™ (Lonza). In a specific embodiment, a mammalian expression vector is pOptiVEC™ or pcDNA3.3. Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary (CHO) cells, in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., 1986, Gene 45:101; and Cockett et al., 1990, Bio / Technology 8:2). In certain embodiments, antibodies described herein are produced by CHO cells or NS0 cells. In a specific embodiment, the expression of nucleotide sequences encoding antibodies described herein which immunospecifically bind to a KIT antigen is regulated by a constitutive promoter, inducible promoter or tissue specific promoter.

[0192] In bacterial systems, a number of expression vectors can be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such an antibody is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified can be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO 12:1791), in which the antibody coding sequence can be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res.13:3101-3109; Van Heeke & Schuster, 1989, J. Biol. Chem.24:5503-5509); and the like. pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.Attorney Docket No.12638-178-228

[0193] In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. The antibody coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

[0194] In mammalian host cells, a number of viral-based expression systems can be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest can be ligated to an adenovirus transcription / translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region El or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts (e.g., see Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:355-359). Specific initiation signals can also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression can be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., 1987, Methods in Enzymol.153:51-544).

[0195] In addition, a host cell strain can be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products can be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be used. Such mammalian host cells include but are not limited to CHO, VERO, BHK, Hela, COS, MDCK, HEK 293, NIH 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, NS0 (a murine myeloma cell line that does not endogenouslyAttorney Docket No.12638-178-228 produce any immunoglobulin chains), CRL7O3O and HsS78Bst cells. In certain embodiments, humanized monoclonal anti-KIT antibodies described herein are produced in mammalian cells, such as CHO cells.

[0196] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the antibody molecule can be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells can be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method can advantageously be used to engineer cell lines which express the antibody molecule. Such engineered cell lines can be particularly useful in screening and evaluation of compositions that interact directly or indirectly with the antibody molecule.

[0197] A number of selection systems can be used, including but not limited to, the herpes simplex virus thymidine kinase (Wigler et al., 1977, Cell 11:223), hypoxanthineguanine phosphoribosyltransferase (Szybalska & Szybalski, 1992, Proc. Natl. Acad. Sci. USA 48:202), and adenine phosphoribosyltransferase (Lowy et al., 1980, Cell 22:8-17) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., 1980, Natl. Acad. Sci. USA 77:357; O’Hare et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol.32:573- 596; Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann. Rev. Biochem.62:191-217; May, 1993, TIB TECH 11(5):l55-215); and hygro, which confers resistance to hygromycin (Santerre et al., 1984, Gene 30:147). Methods commonly known in the art of recombinant DNA technology can be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols inAttorney Docket No.12638-178-228 Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., 1981, J. Mol. Biol.150:1, which are incorporated by reference herein in their entireties.

[0198] The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol.3 (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., 1983, Mol. Cell. Biol.3:257).

[0199] The host cell can be co-transfected with two or more expression vectors described herein, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors can contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. The host cells can be co-transfected with different amounts of the two or more expression vectors. For example, host cells can be transfected with any one of the following ratios of a first expression vector and a second expression vector: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, or 1:50.

[0200] Alternatively, a single vector can be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, 1986, Nature 322:52; and Kohler, 1980, Proc. Natl. Acad. Sci. USA 77:2197-2199). The coding sequences for the heavy and light chains can comprise cDNA or genomic DNA. The expression vector can be monocistronic or multicistronic. A multicistronic nucleic acid construct can encode 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, or in the range of 2-5, 5-10 or 10-20 genes / nucleotide sequences. For example, a bicistronic nucleic acid construct can comprise in the following order a promoter, a first gene (e.g., heavy chain of an antibody described herein), and a second gene and (e.g., light chain of an antibody described herein). In such an expression vector, the transcription of both genes can be driven by the promoter, whereas the translation of the mRNAAttorney Docket No.12638-178-228 from the first gene can be by a cap-dependent scanning mechanism and the translation of the mRNA from the second gene can be by a cap-independent mechanism, e.g., by an IRES.

[0201] Once an antibody molecule described herein has been produced by recombinant expression, it can be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, the antibodies described herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

[0202] In specific embodiments, an antibody described herein is isolated or purified. Generally, an isolated antibody is one that is substantially free of other antibodies with different antigenic specificities than the isolated antibody. For example, in a particular embodiment, a preparation of an antibody described herein is substantially free of cellular material and / or chemical precursors. The language “substantially free of cellular material” includes preparations of an antibody in which the antibody is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, an antibody that is substantially free of cellular material includes preparations of antibody having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (by dry weight) of heterologous protein (also referred to herein as a “contaminating protein”) and / or variants of an antibody, for example, different post-translational modified forms of an antibody or other different versions of an antibody. When the antibody is recombinantly produced, it is also generally substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, 2%, 1%, 0.5%, or 0.1% of the volume of the protein preparation. When the antibody is produced by chemical synthesis, it is generally substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly, such preparations of the antibody have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the antibody of interest. In a specific embodiment, antibodies described herein are isolated or purified. 5.4 Antibody ProductionAttorney Docket No.12638-178-228

[0203] Antibodies (e.g., human or humanized antibodies) described herein that immunospecifically bind to a KIT antigen 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. In a particular aspect, provided herein are methods for making an antibody described herein, comprising culturing, and / or expressing such antibody using, a host cell described herein, which methods optionally further comprise purifying the antibody obtained from the host cell. The methods described herein employs, unless otherwise indicated, conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the skill of 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, Second Edition, 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 annual updates); Current Protocols in Immunology, John Wiley & Sons (1987 and annual updates) Gait (ed.) (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; 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.

[0204] For example, humanized antibodies can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (European Patent No. EP 239,400; International publication No. WO 91 / 09967; and U.S. Patent Nos.5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (European Patent Nos. 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 91 :969-973), chain shuffling (U.S. Patent No. 5,565,332), and techniques disclosed in, e.g., U.S. Pat. No.6,407,213, U.S. Pat. No.5,766,886, WO 9317105, Tan et al., J. Immunol.169: 111925 (2002), Caldas et al., Protein Eng.13(5):353- 60 (2000), Morea et al., Methods 20(3):26779 (2000), Baca et al., J. Biol. Chem.272(16): 10678-84 (1997), Roguska et al., Protein Eng.9(10):895904 (1996), Couto et al., Cancer Res. 55 (23 Supp):5973s- 5977s (1995), Couto et al., Cancer Res.55(8): 1717-22 (1995), Sandhu JS,Attorney Docket No.12638-178-228 Gene 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol.235(3):959-73 (1994). See also U.S. Patent Pub. No. US 2005 / 0042664 A1 (Feb.24, 2005), which is incorporated herein by reference.

[0205] 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 techniques including those 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., in: Monoclonal Antibodies and T-Cell Hybridomas 563681 (Elsevier, N.Y., 1981). The term "monoclonal antibody" as used herein is not limited to antibodies produced through hybridoma technology. For example, monoclonal antibodies can be produced by recombinant technology, e.g. recombinant monoclonal antibodies expressed by a host cell, such as a mammalian host cell.

[0206] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art. For example, in the hybridoma method, a mouse or other appropriate host animal, such as a sheep, goat, rabbit, rat, hamster or macaque monkey, is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein (e.g., extracellular domain of human KIT) used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes then are fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103 (Academic Press, 1986)). Additionally, a RIMMS (repetitive immunization multiple sites) technique can be used to immunize an animal (Kilptrack et al., 1997 Hybridoma 16:381-9, which is incorporated herein by reference).

[0207] Non-limiting examples of myeloma cell lines include murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, CA, 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 also have 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)).Attorney Docket No.12638-178-228

[0208] In one aspect, to generate whole antibodies, PCR primers including VH or VL nucleotide sequences, a restriction site, and a flanking sequence to protect the restriction site can be used to amplify the VH or VL sequences from a template, e.g., scFv clones. Utilizing cloning techniques known to those of skill in the art, the PCR amplified VH domains can be cloned into vectors expressing a VH constant region, and the PCR amplified VL domains can be cloned into vectors expressing a VL constant region, e.g., human kappa or lambda constant regions. The VH and VL domains can also be cloned into one vector expressing the necessary constant regions. The heavy chain conversion vectors and light chain conversion vectors are then co-transfected into cell lines to generate stable or transient cell lines that express full-length antibodies, e.g., IgG, using techniques known to those of skill in the art. 5.5 Methods of Treatment and Medical Uses

[0209] Provided herein are methods for impeding, preventing, protecting against, treating and / or managing chronic urticaria. Such methods comprise administering to a subject in need thereof an anti-KIT antibody described herein (e.g., humanized antibodies) or a pharmaceutical composition (e.g., a pharmaceutical dosage unit) described herein. In certain aspects, also provided herein are methods for preventing, impeding, protecting against, treating or managing one or more symptoms of chronic urticaria.

[0210] In specific embodiments, the methods described herein are for treating or managing chronic urticaria. In specific embodiments, the methods described herein are for treating chronic urticaria.

[0211] In specific embodiments, methods described herein for treating chronic urticaria provide for the reduction or amelioration of the progression, severity, and / or duration of chronic urticaria resulting from the administration of an anti-KIT antibody described herein or a pharmaceutical composition described herein. In further specific embodiments, methods described herein for treating chronic urticaria relate to reducing one or more symptoms of chronic urticaria. In specific embodiments, an antibody described herein or a pharmaceutical composition described herein is for use in protecting against, treating or managing chronic urticaria. In a particular embodiment, chronic urticaria treated or managed or against which is protected with an anti-KIT antibody described herein or a pharmaceutical composition described herein is completely or partially caused by, associated with, or is the result of KIT expressionAttorney Docket No.12638-178-228 and / or activity (which may be overexpression of KIT, gain-of-function of KIT activity, and / or increase in KIT activity), e.g., involves cells expressing KIT and / or exhibiting KIT activity. In a particular embodiment, chronic urticaria treated or managed or against which is protected with an anti-KIT antibody described herein or a pharmaceutical composition described herein is associated with KIT expression and / or activity, e.g., involves cells expressing KIT and / or exhibiting KIT activity, but is not caused by or the result of KIT expression or activity. In a specific embodiment, a subject whose chronic urticaria is treated or managed or against which is protected with an anti-KIT antibody described herein or a pharmaceutical composition described herein has KIT-positive or KIT-overexpressing mast cells.

[0212] In one aspect, the methods described herein comprise administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 300 mg.

[0213] In another aspect, the methods described herein comprise administering to a subject in need thereof a loading dose of between about 300 mg and about 450 mg of an anti-KIT antibody described herein; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose.

[0214] In another aspect, the methods described herein comprise administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 300 mg.

[0215] In another aspect, the methods described herein comprise administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either:Attorney Docket No.12638-178-228 (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 300 mg per dose.

[0216] In certain embodiments, the loading dose is between about 300 mg and about 350 mg of the anti-KIT antibody. In certain embodiments, the loading dose is between about 350 mg and about 400 mg of the anti-KIT antibody. In certain embodiments, the loading dose is between about 400 mg and about 450 mg of the anti-KIT antibody. In a specific embodiment, the loading dose is about 300 mg of the anti-KIT antibody. In another specific embodiment, the loading dose is about 350 mg of the anti-KIT antibody. In another specific embodiment, the loading dose is about 400 mg of the anti-KIT antibody. In another specific embodiment, the loading dose is about 450 mg of the anti-KIT antibody.

[0217] In some embodiments, the loading dose is about 300 mg and step (A) is performed after the loading dose is administered to the subject. Thus, such method comprise administering to a subject in need thereof a loading dose of about 300 mg of an anti-KIT antibody described herein; and then after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose. In certain embodiments, in step (A) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 150 mg about every 4 weeks.

[0218] In other embodiments, the loading dose is about 450 mg and step (B) is performed after the loading dose is administered to the subject. Thus, such method comprise administering to a subject in need thereof a loading dose of about 450 mg of an anti-KIT antibody described herein; and then after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose. In certain embodiments, in step (B) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 300 mg about every 8 weeks.

[0219] In various embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least three maintenance doses of theAttorney Docket No.12638-178-228 anti-KIT antibody are administered to the subject. In specific embodiments, at least four maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least five maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 6 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 7 maintenance doses of the anti- KIT antibody are administered to the subject. In specific embodiments, at least 8 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 9 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 10 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 11 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 12 maintenance doses of the anti- KIT antibody are administered to the subject. In specific embodiments, at least 13 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 14 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 15 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 3-7 maintenance doses of the anti-KIT antibody are administered to the subject. In specific embodiments, at least 6-14 maintenance doses of the anti-KIT antibody are administered to the subject. In a specific embodiment, two maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, three maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, four maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, five maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 6 maintenance doses of the anti- KIT antibody are administered to the subject. In another specific embodiment, 7 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 8 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 9 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 10 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 11 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 12 maintenance doses of the anti- KIT antibody are administered to the subject. In another specific embodiment, 13 maintenanceAttorney Docket No.12638-178-228 doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 14 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, 15 maintenance doses of the anti-KIT antibody are administered to the subject. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject until the subject no longer needs further treatment by the anti-KIT antibody as judged by the subject and / or the treating doctor (for example, when the subject no longer has symptoms for chronic urticaria).

[0220] In various embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 8 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 12 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 16 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 20 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 24 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 28 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 32 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 36 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 40 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 44 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 48 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 52 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for at least 56 weeks. In specific embodiments, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for 12-20 weeks. In specific embodiments, at least two maintenance doses of theAttorney Docket No.12638-178-228 anti-KIT antibody are administered to the subject and are administered for 20-52 weeks. In a specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 16 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 20 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 24 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 28 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 32 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 36 weeks. In another specific embodiment, at least two maintenance doses of the anti- KIT antibody are administered to the subject and are administered for about 40 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 44 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 48 weeks. In another specific embodiment, at least two maintenance doses of the anti-KIT antibody are administered to the subject and are administered for about 52 weeks.

[0221] In various embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 8 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 12 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 16 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 20 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 24 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 28 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 32 weeks. In specific embodiments, maintenanceAttorney Docket No.12638-178-228 doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 36 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 40 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 44 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 48 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 52 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for at least 56 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for 12-20 weeks. In specific embodiments, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for 20-52 weeks. In a specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 16 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 20 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 24 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 28 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 32 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 36 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 40 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 44 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 48 weeks. In another specific embodiment, maintenance doses of the anti-KIT antibody are administered to the subject at intervals described herein for about 52 weeks.Attorney Docket No.12638-178-228

[0222] In one aspect, the methods for treating, preventing or managing chronic urticaria in a subject in need thereof described herein comprise administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an initial interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 150 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 4 weeks thereafter at about 150 mg per maintenance dose; or (B) after an initial interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 300 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 8 weeks thereafter at about 300 mg per maintenance dose.

[0223] In various embodiments, a dosage regimen described herein exerts a therapeutically useful effect in the absence of, or with minimal or negligible, undesirable side effects on the subject treated.

[0224] In a specific embodiment, the antibody used in the methods described herein is internalized by the cell to which it binds.

[0225] In certain embodiments, KIT is aberrantly (e.g., highly) expressed by cells, for example, KIT is overexpressed. In particular embodiments, KIT expression (e.g., on the cell surface) is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than KIT expression on the surface of a control cell (e.g., a cell expressing normal levels of KIT, for example, a normal, e.g., human mast cell,). In particular embodiments, KIT expression yields at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher cell surface KIT expression than the average KIT expression on the surface of a control cell population (e.g., a cell population expressing normal levels of KIT, for example, a normal, e.g., human mast cell population). In specific embodiments, such control cells can be obtained or derived from a healthy individual (e.g., healthy human). In some embodiments, KIT can be aberrantly upregulated in a particular cell type, whether or not KIT is aberrantly expressed on the cell surface. In particular embodiments, KIT signaling or activity can be aberrantly upregulated in a particular cell type, whether or not KIT is aberrantly expressed on the cell surface. In particular embodiments, KIT signaling is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than KIT signaling of a control cell (e.g., a cell containing normalAttorney Docket No.12638-178-228 KIT signaling, for example, a mast cell). In particular embodiments, KIT signaling is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than average KIT signaling of a control cell population (e.g., a cell population exhibiting normal KIT signaling, for example, a normal, e.g., human mast cell population). In certain embodiments, normal, aberrant or excessive cell signaling is caused by binding of KIT to a KIT ligand. In other embodiments, aberrant or excessive cell signaling occurs independent of binding of KIT to a KIT ligand.

[0226] In certain aspects, the chronic urticaria can be characterized by gain-of-function of KIT activity, increase in KIT activity, or overexpression of KIT. In one embodiment, the chronic urticaria is completely or partially caused by or is the result of gain-of-function of KIT activity or expression, e.g., overexpression, of KIT. In certain embodiments, the gain-of- function of KIT activity can occur independent of KIT ligand (e.g., SCF) binding KIT receptor. In particular aspects, high or overexpression of KIT in a cell refers to an expression level which is at least about 35%, 45%, 55%, or 65% more than the expression level of a reference cell known to have normal KIT expression or KIT activity or more than the average expression level of KIT in a population of cells or samples known to have normal KIT expression or KIT activity. Expression levels of KIT can be assessed by methods described herein or known to one of skill in the art (e.g., Western blotting or immunohistorychemistry). In particular embodiments, the chronic urticaria is characterized by KIT activity which is higher than normal KIT activity and contributes to disease development and / or progression. In particular aspects, high or increase of KIT activity in a cell refers to a KIT activity level which is at least about 35%, 45%, 55%, or 65% more than the expression level of a reference cell known to have normal KIT activity or more than the average level of KIT activity in a population of cells or samples known to have normal KIT activity. Non-limiting examples of a KIT activity includes tyrosine phosphorylation of the cytoplasmic domain of KIT, and signaling downstream of KIT, such as Stat or Akt signaling.

[0227] Mast cells, derived from bone marrow progenitors, are large cells found in connective tissues throughout the body, most abundantly in the submucosal tissues and the dermis. They contain large granules that store a variety of mediator molecules including the vasoactive amine histamine, and have high-affinity Fes receptors (FcsRI) that allow them to bind IgE monomers. Antigen-binding to IgE bound to mast cells triggers mast-cell degranulation and mast-cell activation, producing a local or systemic immediate hypersensitivity reaction. Therefore, mastAttorney Docket No.12638-178-228 cells play important roles in inflammatory and allergic reactions. However, without proper balance and regulation, mast cells can also be responsible for detrimental exaggerated reactions to antigen observed in disorders including chronic urticaria.

[0228] KIT signaling is important for mast cell development and homeostasis, for example, expansion of mast cells from their progenitor cells and their subsequent maturation and survival in their resident tissues, homing of mast cells to their sites of residence in vivo, and promoting adhesion of mast cells to extracellular matrix proteins. Activation mutations of KIT, such as at amino acid residue 816 or 560 of KIT, have been associated with mastocytosis, characterized by overproduction of mast cells, and gastrointestinal stromal cell tumors (GIST).

[0229] Chronic urticaria includes chronic spontaneous urticaria (CSU), chronic idiopathic urticaria and chronic induced urticaria (i.e., chronic inducible urticaria (CIndU). In specific embodiments, the chronic urticaria is chronic spontaneous urticaria. In a specific embodiment, the chronic urticaria is moderate to severe chronic spontaneous urticaria. Chronic spontaneous urticaria is characterized by the occurrence of hives or wheals for 6 weeks or longer without identifiable specific triggers or causes. In specific embodiments, the chronic urticaria is chronic inducible urticaria. Chronic inducible urticarias are forms of urticaria that have an attributable trigger associated with them, typically resulting in wheals (hives) or angioedema. In a specific embodiment, the chronic inducible urticaria is cold urticaria (ColdU). People afflicted with cold urticaria experience symptoms like itching, burning wheals and angioedema when their skin is exposed to temperatures below skin temperature. In another specific embodiment, the chronic inducible urticaria is symptomatic dermographism (SD). Symptomatic dermographism is characterized by the development of a wheal and flare reaction in response to stroking, scratching or rubbing of the skin and usually occurs within minutes of the inciting stimulus. In another specific embodiment, the chronic inducible urticaria is cholinergic urticaria. Cholinergic urticaria is triggered by the body’s sweating response to active or passive body warming, and is characterized by small (1–4 mm) wheals surrounded by bright red flares. Common triggers include exercise, hot baths / showers, fever, occlusive dressings, eating spicy foods and emotional stress. In another specific embodiment, the chronic inducible urticaria is heat urticaria. In another specific embodiment, the chronic inducible urticaria is delayed pressure urticaria. In another specific embodiment, the chronic inducible urticaria is solar urticaria. In another specific embodiment, the chronic inducible urticaria is vibratory urticaria. In another specificAttorney Docket No.12638-178-228 embodiment, the chronic inducible urticaria is contact urticaria. In another specific embodiment, the chronic inducible urticaria is aquagenic urticaria. Antihistamines are approved therapies for chronic inducible urticarias.

[0230] In various embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed one or more prior treatments for the disorder. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or more prior treatments are all standard of care therapies for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed an antihistamine treatment(s) for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) failed an H1- antihistamine treatment(s) for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed an H2- antihistamine treatment(s) for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed both H1- and H2-antihistamine treatments for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment(s) with one or more leukotriene receptor antagonists for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment(s) with one or more immunomodulators or anti- inflammatory agents for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with an IL-5R inhibitor such as an anti-IL- 5R antibody, e.g., benralizumab (Fasenra®), for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g.,Attorney Docket No.12638-178-228 mepolizumab, for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, for the disorder. In specific embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738, for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed a treatment(s) with one or more Bruton’s Tyrosine Kinase (BTK) inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed: (1) an antihistamine treatment(s) (e.g., H1- and / or H2- antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti- IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-Attorney Docket No.12638-178-228 4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738) for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder. In certain embodiments, the patient having chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has failed: (1) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder.

[0231] A patient is considered to have failed a treatment for a disorder if the disorder is refractory to the treatment, resistant to the treatment, relapses after the treatment, and / or if the patient has discontinued the treatment due to intolerance of the treatment.

[0232] In a specific embodiment, the H1-antihistamine described in this disclosure is a non- sedating H1-antihistamine (e.g., a second generation non-sedating H1-antihistamine).

[0233] In various embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to one or more prior treatments for the disorder. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or more prior treatments are all standard of care therapies for the disorder. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to an antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria orAttorney Docket No.12638-178-228 chronic spontaneous urticaria) is refractory to an H1-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to an H2-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to both H1- and H2-antihistamine treatments. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment(s) with one or more leukotriene receptor antagonists. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment(s) with one or more immunomodulators or anti-inflammatory agents. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronicAttorney Docket No.12638-178-228 inducible urticaria or chronic spontaneous urticaria) is refractory to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti- inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2- antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is refractory to: (1) aAttorney Docket No.12638-178-228 treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®).

[0234] In various embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to one or more prior treatments for the disorder. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or more prior treatments are all standard of care therapies for the disorder. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to an antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to an H1-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to an H2-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to both H1- and H2-antihistamine treatments. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment(s) with one or more leukotriene receptor antagonists. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment(s) with one or more immunomodulators or anti-inflammatory agents. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab. In specific embodiments, the chronic chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab. In specific embodiments, the chronicAttorney Docket No.12638-178-228 urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti- inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitorAttorney Docket No.12638-178-228 such as an anti-CD200R antibody, e.g., LY3454738). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2- antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is resistant to: (1) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®).

[0235] In various embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to one or more prior treatments for the disorder. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or more prior treatments are all standard of care therapies for the disorder. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to an antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to an H1-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to an H2- antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to both H1- and H2-antihistamine treatments. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment(s) with one or more leukotriene receptor antagonists. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment(s) with one or more immunomodulators or anti- inflammatory agents. In specific embodiments, the chronic urticaria (e.g., chronic inducibleAttorney Docket No.12638-178-228 urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP orAttorney Docket No.12638-178-228 TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with an IgE inhibitor such as an anti- IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is both refractory and resistant to: (1) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®).

[0236] In various embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after one or more prior treatments for the disorder. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or moreAttorney Docket No.12638-178-228 prior treatments are all standard of care therapies for the disorder. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after an antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after an H1-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after an H2-antihistamine treatment(s). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after both H1- and H2-antihistamine treatments. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment(s) with one or more leukotriene receptor antagonists. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment(s) with one or more immunomodulators or anti-inflammatory agents. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®). In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM). In specific embodiments, the chronic urticaria (e.g.,Attorney Docket No.12638-178-228 chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab. In specific embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronicAttorney Docket No.12638-178-228 spontaneous urticaria) is a relapsed disorder that has relapsed after: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab. In certain embodiments, the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) is a relapsed disorder that has relapsed after: (1) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®).

[0237] In various embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued one or more prior treatments for the disorder due to intolerance of the treatment(s). In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the disorder. In certain embodiments, the one or more prior treatments are all standard of care therapies for the disorder. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued an antihistamine treatment(s) for the disorder due to intolerance of the treatment(s). In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued an H1-antihistamine treatment(s) for the disorder due to intolerance of the treatment(s). In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued an H2-antihistamine treatment(s) for the disorder due to intolerance of the treatment(s). In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued both H1- and H2-antihistamine treatments for the disorder due to intolerance of the treatments. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment(s) with one or more leukotriene receptor antagonists for the disorder due to intolerance of the treatment(s). In certain embodiments, the patient having the chronic urticaria (e.g., chronicAttorney Docket No.12638-178-228 inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment(s) with one or more immunomodulators or anti-inflammatory agents for the disorder due to intolerance of the treatment(s). In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with a Siglec 8 inhibitor such as an anti- Siglec 8 antibody, e.g., lirentelimab, for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, for the disorder due to intolerance of the treatment. In specific embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738, for the disorder due to intolerance of the treatment. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder due to intolerance of the treatment. In certain embodiments,Attorney Docket No.12638-178-228 the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment(s) with one or more leukotriene receptor antagonists, (3) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), and / or (4) a treatment(s) with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder due to intolerance of the treatment(s). In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), and (2) a treatment(s) with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738), for the disorder due to intolerance of the treatments. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-antihistamine treatment(s)), (2) a treatment with a IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) a treatment with a IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder due to intolerance of the treatments. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued: (1) an antihistamine treatment(s) (e.g., H1- and / or H2-Attorney Docket No.12638-178-228 antihistamine treatment(s)), and (2) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder due to intolerance of the treatments. In certain embodiments, the patient having the chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) has discontinued: (1) a treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder due to intolerance of the treatments.

[0238] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)) for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite the use of an H1-antihistamine alone or in combination with a H2-antihistamine and / or leukotriene receptor antagonist for the disorder.

[0239] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with one or more leukotriene receptor antagonists for the disorder.

[0240] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with one or more immunomodulators or anti-inflammatory agents (for example, an IgE inhibitor such as an anti- IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL- 4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738) for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patientAttorney Docket No.12638-178-228 having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder. In one embodiment, an anti-KIT antibody described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, for the disorder. In one embodiment, an anti- KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738, for the disorder.

[0241] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria orAttorney Docket No.12638-178-228 chronic spontaneous urticaria) who remains symptomatic despite treatment with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder.

[0242] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatment(s) with (1) one or more antihistamines, as described above, (2) one or more leukotriene receptor antagonists, as described above, (3) one or more immunomodulators or anti-inflammatory agents, as described above, and / or (4) one or more BTK inhibitors, as described above, for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatments with (1) one or more antihistamines, as described above, and (2) one or more immunomodulators or anti-inflammatory agents, as described above, for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatments with (1) one or more antihistamines, as described above, (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatments with (1) one or more antihistamines, as described above, and (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) who remains symptomatic despite treatments with (1) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder.

[0243] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more antihistamines (e.g., H1-Attorney Docket No.12638-178-228 and / or H2-antihistamine treatment(s)) for the disorder, wherein the patient has failed said treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)).

[0244] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more leukotriene receptor antagonists for the disorder, wherein the patient has failed said treatment with one or more leukotriene receptor antagonists.

[0245] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more immunomodulators or anti- inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738) for the disorder, wherein the patient has failed said treatment with one or more immunomodulators or anti-inflammatory agents. In a specific embodiment, an anti- KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder, wherein the patient has failed said treatment with an IgE inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder, wherein the patient has failed said treatment with an IL-4R inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), for theAttorney Docket No.12638-178-228 disorder, wherein the patient has failed said treatment with an IL-5R inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, for the disorder, wherein the patient has failed said treatment with an IL-5 inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, for the disorder, wherein the patient has failed said treatment with a Siglec 8 inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), for the disorder, wherein the patient has failed said treatment with a TSLP or TSLPR inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, for the disorder, wherein the patient has failed said treatment with a C5aR inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738, for the disorder, wherein the patient has failed said treatment with a CD200R inhibitor.

[0246] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder, wherein the patient has failed said treatment with one or more BTK inhibitors.

[0247] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment(s) with (1) one or more antihistamines, asAttorney Docket No.12638-178-228 described above, (2) one or more leukotriene receptor antagonists, as described above, (3) one or more immunomodulators or anti-inflammatory agents, as described above, and / or (4) one or more BTK inhibitors, as described above, for the disorder; wherein the patient has failed said treatment(s). In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, and (2) one or more immunomodulators or anti-inflammatory agents, as described above, for the disorder; wherein the patient has failed said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder; wherein the patient has failed said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, and (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder; wherein the patient has failed said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the dsiorder; wherein the patient has failed said treatments.

[0248] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)) for the disorder, wherein the disorder is refractory to said treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)).

[0249] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria orAttorney Docket No.12638-178-228 chronic spontaneous urticaria) following treatment with one or more leukotriene receptor antagonists for the disorder, wherein the disorder is refractory to said treatment with one or more leukotriene receptor antagonists.

[0250] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more immunomodulators or anti- inflammatory agents (for example, an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), an IL-5 inhibitor such as an anti-IL-5 antibody, e.g., mepolizumab, a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, a TSLP or TSLPR inhibitor such as an anti-TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, and / or a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738) for the disorder, wherein the disorder is refractory to said treatment with one or more immunomodulators or anti-inflammatory agents. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder, wherein the disorder is refractory to said treatment with an IgE inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder, wherein the disorder is refractory to said treatment with an IL-4R inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-5R inhibitor such as an anti-IL-5R antibody, e.g., benralizumab (Fasenra®), for the disorder, wherein the disorder is refractory to said treatment with an IL-5R inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with an IL-5 inhibitor such as anAttorney Docket No.12638-178-228 anti-IL-5 antibody, e.g., mepolizumab, for the disorder, wherein the disorder is refractory to said treatment with an IL-5 inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a Siglec 8 inhibitor such as an anti-Siglec 8 antibody, e.g., lirentelimab, for the disorder, wherein the disorder is refractory to said treatment with a Siglec 8 inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a TSLP or TSLPR inhibitor such as an anti- TSLP or anti-TSLPR antibody, e.g., tezepelumab (TezspireTM), for the disorder, wherein the disorder is refractory to said treatment with a TSLP or TSLPR inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a C5aR inhibitor such as an anti-C5aR antibody, e.g., avdoralimab, for the disorder, wherein the disorder is refractory to said treatment with a C5aR inhibitor. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with a CD200R inhibitor such as an anti-CD200R antibody, e.g., LY3454738, for the disorder, wherein the disorder is refractory to said treatment with a CD200R inhibitor.

[0251] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more BTK inhibitors, e.g., remibrutinib and / or rilzabrutinib, for the disorder, wherein the disorder is refractory to said treatment with one or more BTK inhibitors.

[0252] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment(s) with (1) one or more antihistamines, as described above, (2) one or more leukotriene receptor antagonists, as described above, (3) one or more immunomodulators or anti-inflammatory agents, as described above, and / or (4) one or more BTK inhibitors, as described above, for the disorder; wherein the disorder is refractory toAttorney Docket No.12638-178-228 said treatment(s). In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, and (2) one or more immunomodulators or anti-inflammatory agents, as described above, for the disorder; wherein the disorder is refractory to said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (3) an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the disorder; wherein the disorder is refractory to said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) one or more antihistamines, as described above, and (2) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, for the disorder; wherein the disorder is refractory to said treatments. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatments with (1) an IgE inhibitor such as an anti-IgE antibody, e.g., omalizumab (Xolair®) or ligelizumab, and (2) an IL-4R inhibitor such as an anti- IL-4R antibody, e.g., dupilumab (Dupixent®), for the dsiorder; wherein the disorder is refractory to said treatments.

[0253] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)) for the disorder, wherein the disorder is resistant to said treatment with one or more antihistamines (e.g., H1- and / or H2-antihistamine treatment(s)).

[0254] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a patient having a chronic urticaria (e.g., chronic inducible urticaria or chronic spontaneous urticaria) following treatment with one or more leukotriene receptorAttorney Docket No.12638-178-228 antagonists for the disorder, wherein the disorder is resistant to said treatment with one or more leukotriene receptor antagonists.

[0255] In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is adm...

Claims

Attorney Docket No.12638-178-228 WHAT IS CLAIMED:

1. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of the antibody of about 300 mg; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively;Attorney Docket No.12638-178-228 (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

2. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of an antibody which immunospecifically binds to human KIT; and then either: (A) after an interval of about 4 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of the antibody is administered, further administering to the subject at least one maintenance dose of the antibody at about 300 mg per dose; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively;Attorney Docket No.12638-178-228 (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

3. The method of claim 1 or 2, wherein the VL comprises the amino acid sequence of SEQ ID NO: 14 and the VH comprises the amino acid sequence of SEQ ID NO:

10.

4. The method of any one of claims 1-3, wherein the antibody comprises a modified human IgG1 Fc region or domain comprising non-naturally occurring amino acids 234A, 235Q, 322Q, 252Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

5. The method of any one of claims 1-4, wherein the antibody comprises a light chain comprising the amino acid sequence:Attorney Docket No.12638-178-228 DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

6. The method of any one of claims 1-5, wherein the antibody comprises a heavy chain comprising the amino acid sequence: QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).

7. The method of any one of claims 1-6, wherein the antibody is barzolvolimab.

8. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 150 mg; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of barzolvolimab of about 300 mg.

9. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either:Attorney Docket No.12638-178-228 (A) after an interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 150 mg per dose; or (B) after an interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject at least one maintenance dose of barzolvolimab at about 300 mg per dose.

10. The method of any one of claims 1-9, wherein the loading dose is about 300 mg and step (A) is performed after the loading dose is administered to the subject.

11. The method of claim 10, wherein in step (A) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 150 mg about every 4 weeks.

12. The method of any one of claims 1-9, wherein the loading dose is about 450 mg and step (B) is performed after the loading dose is administered to the subject.

13. The method of claim 12, wherein in step (B) at least two maintenance doses of the antibody are administered and are administered at a frequency of one maintenance dose of about 300 mg about every 8 weeks.

14. The method of any one of claims 1-13, wherein at least 3-7 maintenance doses of the antibody are administered to the subject.

15. The method of any one of claims 1-13, wherein at least 6-14 maintenance doses of the antibody are administered to the subject.

16. The method of any one of claims 1-13, wherein at least 3 maintenance doses of the antibody are administered to the subject.

17. The method of any one of claims 1-13, wherein at least 6 maintenance doses of the antibody are administered to the subject.Attorney Docket No.12638-178-228 18. The method of any one of claims 1-13, wherein at least 7 maintenance doses of the antibody are administered to the subject.

19. The method of any one of claims 1-13, wherein at least 14 maintenance doses of the antibody are administered to the subject.

20. The method of any one of claims 1-19, wherein maintenance doses of the antibody are administered to the subject at said intervals for at least 20 weeks.

21. The method of any one of claims 1-19, wherein maintenance doses of the antibody are administered to the subject at said intervals for at least 52 weeks.

22. The method of any one of claims 1-21, wherein the chronic urticaria is chronic spontaneous urticaria.

23. The method of any one of claims 1-21, wherein the chronic urticaria is chronic inducible urticaria.

24. The method of claim 23, wherein the chronic inducible urticaria is cold urticaria.

25. The method of claim 23, wherein the chronic inducible urticaria is symptomatic dermographism.

26. The method of claim 23, wherein the chronic inducible urticaria is cholinergic urticaria.

27. The method of any one of claims 1-26, wherein the chronic urticaria is refractory to omalizumab treatment.

28. The method of any one of claims 1-27, wherein the antibody is administered by subcutaneous administration.

29. The method of any one of claims 1-28, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.Attorney Docket No.12638-178-228 30. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 150 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; andAttorney Docket No.12638-178-228 (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

31. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 300 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 27, respectively; orAttorney Docket No.12638-178-228 (e) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

32. A pharmaceutical dosage unit for administration to a subject with chronic urticaria of an antibody which immunospecifically binds to human KIT, which comprises: (i) about 450 mg of the antibody; (ii) a buffering agent; (iii) a salt; and (iv) an excipient; wherein the antibody comprises: (a) (i) a light chain variable region (“VL”) comprising VL CDR1, VL CDR2, and VL CDR3 having 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 VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively; (b) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27, respectively; (c) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 31, and SEQ ID NO: 32, respectively; (d) (i) a VL comprising VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, respectively; andAttorney Docket No.12638-178-228 (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having 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 VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 36, and SEQ ID NO: 37, respectively; and (ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40, respectively.

33. The pharmaceutical dosage unit of any one of claims 30-32, which is for subcutaneous administration.

34. The pharmaceutical dosage unit of any one of claims 30-33, wherein the antibody is barzolvolimab.

35. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject the pharmaceutical dosage unit of any one of claims 30- 34.

36. The method of any one of claims 1-29 and 35 or the pharmaceutical dosage unit of any one of claims 30-34, wherein the subject is a human.

37. A method for treating, preventing or managing chronic urticaria in a subject in need thereof, comprising administering to the subject a loading dose of between about 300 mg and about 450 mg of barzolvolimab; and then either: (A) after an initial interval of about 4 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 150 mg of barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 4 weeks thereafter at about 150 mg per maintenance dose; or (B) after an initial interval of about 8 weeks during which no dose of barzolvolimab is administered, further administering to the subject a maintenance dose of about 300 mg ofAttorney Docket No.12638-178-228 barzolvolimab and then administering further maintenance doses of barzolvolimab at maintenance intervals of about 8 weeks thereafter at about 300 mg per maintenance dose.

38. The method of claim 37, wherein at least 3 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

39. The method of claim 38, wherein at least 6 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

40. The method of claim 39, wherein at least 7 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

41. The method of claim 40, wherein at least 10 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

42. The method of claim 41, wherein at least 14 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

43. The method of claim 42, wherein at least 20 maintenance doses of barzolvolimab are administered to the subject at said maintenance intervals.

44. The method of any one of claims 37-41, wherein the chronic urticaria is chronic spontaneous urticaria.

45. The method of any one of claims 37-44, wherein the chronic urticaria is chronic inducible urticaria.

46. The method of claim 45, wherein the chronic inducible urticaria is cold urticaria.

47. The method of claim 45, wherein the chronic inducible urticaria is symptomatic dermographism.

48. The method of claim 45, wherein the chronic inducible urticaria is cholinergic urticaria.Attorney Docket No.12638-178-228 49. The method of any one of claims 37-48, wherein the chronic urticaria is refractory to omalizumab treatment.

50. The method of any one of claims 37-49, wherein the barzolvolimab is administered by subcutaneous administration.

51. The method of any one of claims 37-50, wherein the barzolvolimab is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.

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