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 prurigo. Also provided are kits and pharmaceutical dosage units of antibodies that immunospecifically bind to KIT, in particular barzolvolimab.

Description

Attorney Docket No. 12638-179-228ANTI-KIT ANTIBODY DOSING AND METHODSREFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0001] 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 “12638-179-228_SEQLISTING.xml”, was created on February 18, 2025, and is 56,123 bytes in size.1. FIELD

[0002] Provided herein are methods for using antibodies that immunospecifically bind to KIT, a receptor tyrosine kinase, in particular barzolvolimab, to treat, manage or prevent prurigo. Also provided are kits and pharmaceutical dosage units of antibodies that immunospecifically bind to KIT, in particular barzolvolimab.2. BACKGROUND

[0003] 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 etal., 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 domains 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.NAI-1543385831V1 1Attorney Docket No. 12638-179-228

[0004] 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).

[0005] 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 etal., J. Biol. Chem., 2003, 278:31461-31464). Moreover, KIT plays an important role in hematopoiesis, melanogenesis, and gametogenesis (see Ueda etal., Blood, 2002, 99:3342-3349).

[0006] 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.

[0007] There is a need to provide suitable dosing methods for antibodies against human KIT.3. SUMMARY

[0008] In one aspect, provided herein is a method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a maintenance dose of between about 150 mg and about 300 mg of an antibody which immunospecifically binds to human KIT, 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 comprisingNAI-1543385831V1 2Attorney Docket No. 12638-179-228VH CDRl, 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 CDRl, 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 CDRl, 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 CDRl, 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.

[0009] In certain embodiments, the maintenance dose is about 150 mg of the antibody. In certain embodiments, the maintenance dose is about 300 mg of the antibody.

[0010] 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 IgGl 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:DIVMTQSPSSLSASVGDRVTITCKASQNVTtTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22). In specific embodiments, the antibody comprises a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVTTVTHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDNAI-1543385831V1 3Attorney Docket No. 12638-179-228KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21). In a preferred embodiment, the antibody is barzolvolimab.

[0011] In certain embodiments, the method further comprises administering to the subject a loading dose of about 450 mg of the antibody, wherein the loading dose is administered to the subject about 4 weeks before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.

[0012] In another aspect, provided herein is a method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvolimab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 150 mg of the antibody.

[0013] In another aspect, provided herein is a method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvolimab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 300 mg of the antibody.

[0014] In certain embodiments, the method comprises further administering to the subject one or more of the maintenance doses of the antibody, wherein the interval between every two consecutive maintenance doses is about 4 weeks,

[0015] In specific embodiments, at least 3 of the maintenance doses of the antibody are administered to the subject in total. In specific embodiments, at least 4 of the maintenance doses of the antibody are administered to the subject in total. In specific embodiments, at least 5 of the maintenance doses of the antibody are administered to the subject in total. In specific embodiments, at least 6 of the maintenance doses of the antibody are administered to the subject in total.

[0016] In certain embodiments, the chronic prurigo is prurigo nodularis In certain embodiments, the prurigo nodularis is moderate to severe prurigo nodularis.

[0017] In certain embodiments, the subject has an inadequate response to prescription topical medications. In certain embodiments, the subject is one for whom topical medications are medically inadvisable.

[0018] In certain embodiments, the antibody is administered by subcutaneous administrationNAI-1543385831V1 4Attorney Docket No. 12638-179-228

[0019] 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.

[0020] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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. In a specific embodiment, the antibody is barzolvolimab.

[0021] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic pruri go of an antibody which immunospecifically binds to human KIT,NAI-1543385831V1 5Attorney Docket No. 12638-179-228which dosage unit 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 CDRI, 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 CDRI, 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, andrL 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.

[0022] In another aspect, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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,NAI-1543385831V1 6Attorney Docket No. 12638-179-228and 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 CDRl, 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 CDRl, 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 CDRl, 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 CDRl, 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 CDRl, 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 CDRl, 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 CDRl, 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 specific embodiments, the pharmaceutical dosage unit is for subcutaneous administration.

[0024] In a preferred embodiment, the antibody is barzolvolimab.

[0025] In another aspect, provided herein is a method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a pharmaceutical dosage unit described herein.

[0026] In various aspects and embodiments, the subject is a human.3.1 Illustrative Embodiments

[0027] The present disclosure includes the following non-limiting illustrative embodiments.3.1.1 Set 1NAI-1543385831V1 7Attorney Docket No. 12638-179-2281. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a maintenance dose of between about 150 mg and about 300 mg of an antibody which immunospecifically binds to human KIT,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; andNAI-1543385831V1 8Attorney Docket No. 12638-179-228(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.2. The method of embodiment 1, 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: 10.3. The method of embodiment 1 or 2, wherein the antibody comprises a modified human IgGl 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.4. The method of any one of embodiments 1-3, wherein the antibody comprises a light chain comprising the amino acid sequence:DIVMTQSPSSLSASVGDRVTITCKASQNVRT VAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).5. The method of any one of embodiments 1-4, wherein the antibody comprises a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLS SLRSEDTAVYFCARGVYYFDYWGQGTTVTVS S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GL YSL S S W TVP S S SLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCP APEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).6. The method of any one of embodiments 1-5, wherein the antibody is barzolvolimab.7. The method of any one of embodiments 1-6, wherein the method further comprises administering to the subject a loading dose of about 450 mg of the antibody, wherein the loadingNAI-1543385831V1 9Attorney Docket No. 12638-179-228dose is administered to the subject about 4 weeks before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.8. The method of any one of embodiments 1-7, wherein the maintenance dose is about 150 mg of the antibody.9. The method of any one of embodiments 1-7, wherein the maintenance dose is about 300 mg of the antibody.10. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvolimab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 150 mg of the antibody.11. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvolimab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 300 mg of the antibody.12. The method of any one of embodiments 1-11, which comprises further administering to the subject one or more of the maintenance doses of the antibody, wherein the interval between every two consecutive maintenance doses is about 4 weeks.13. The method of embodiment 12, wherein at least 3 of the maintenance doses of the antibody are administered to the subject in total.14. The method of embodiment 12, wherein at least 4 of the maintenance doses of the antibody are administered to the subject in total.15. The method of embodiment 12, wherein at least 5 of the maintenance doses of the antibody- are administered to the subject in total.NAI-1543385831V1 10Attorney Docket No. 12638-179-22816. The method of embodiment 12, wherein at least 6 of the maintenance doses of the antibody are administered to the subject in total.17. The method of any one of embodiments 1-16, wherein the chronic prurigo is prurigo nodularis.18. The method of embodiment 17, wherein the prurigo nodularis is moderate to severe prurigo nodularis.19. The method of any one of embodiments 1-18, wherein the subject has an inadequate response to prescription topical medications.20. The method of any one of embodiments 1-18, wherein the subject is one for whom topical medications are medically inadvisable.21. The method of any one of embodiments 1-20, wherein the antibody is administered by subcutaneous administration.22. The method of any one of embodiments 1-21, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.23. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecificaliy binds to human KIT, which dosage unit 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; andNAI-1543385831V1 11Attorney Docket No. 12638-179-228(ii) a heavy chain variable region (“VH”) comprising VH CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.24. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit comprises: (i) about 300 mg of the antibody; (ii) a buffering agent, (iii) a salt; and (iv) an excipient;wherein the antibody comprises:NAI-1543385831V1 12Attorney Docket No. 12638-179-228(a) (i) a light chain variable region (“VL”) comprising VL CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.NAI-1543385831V1 13Attorney Docket No. 12638-179-22825. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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; andNAI-1543385831V1 14Attorney Docket No. 12638-179-228(ii) a ATI 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.26. The pharmaceutical dosage unit of any one of embodiments 23-25, which is forsubcutaneous administration.27. The pharmaceutical dosage unit of any one of embodiments 23-26, wherein the antibody is barzolvolimab.28. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject the pharmaceutical dosage unit of any one of embodiments 23-27.29. The method of any one of embodiments 1-22 and 28 or the pharmaceutical dosage unit of any one of embodiments 23-27, wherein the subject is a human.3.1.2 Set 21. Use of an antibody which immunospecifically binds to human KIT for the manufacture of a medicament for treating, preventing or managing chronic prurigo in a subject in need thereof, wherein the medicament is formulated for administration to the subject a maintenance dose of between about 150 mg and about 300 mg of the antibody, andwherein 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 (“ATI”) comprising ATI CDR1, ATI CDR2, and ATI CDR3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively;NAI-1543385831V1 15Attorney Docket No. 12638-179-228(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.2. The use of embodiment 1, 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: 10.3. The use of embodiment 1 or 2, wherein the antibody comprises a modified human IgGl Fc region or domain comprising non-naturally occurring amino acids 234 A, 235Q, 322Q, 252 Y, 254T and 256E as numbered by the EU index as set forth in Kabat.4. The use of any one of embodiments 1-3, wherein the antibody comprises a light chain comprising the amino acid sequence:NAI-1543385831V1 16Attorney Docket No. 12638-179-228DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).5. The use of any one of embodiments 1-4, wherein the antibody comprises a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSWPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNWHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPS VFLFPPKPKDTLY 1TREPEVTC V V VDVSHEDPE VKFN W Y VDGVEVHN AKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).6. The use of any one of embodiments 1-5, wherein the antibody is barzolvolimab.7. The use of any one of embodiments 1-6, wherein the medicament is formulated for further administration to the subject a loading dose of about 450 mg of the antibody, wherein the loading dose is to be administered to the subject about 4 weeks before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.8. The use of any one of embodiments 1-7, wherein the maintenance dose is about 150 mg of the antibody.9. The use of any one of embodiments 1-7, wherein the maintenance dose is about 300 mg of the antibody.10. Use of an antibody that is barzolvolimab for treating, preventing or managing chronic prurigo in a subject in need thereof, wherein the medicament is formulated for administration toNAI-1543385831V1 17Attorney Docket No. 12638-179-228the subject a loading dose of about 450 mg of the antibody, and then after about 4 weeks during which no dose of the antibody is administered, a maintenance dose of about 150 mg of the antibody.11. Use of an antibody that is barzolvolimab for treating, preventing or managing chronic prurigo in a subject in need thereof, wherein the medicament is formulated for administration to the subject a loading dose of about 450 mg of the antibody, and then after about 4 weeks during which no dose of the antibody is administered, a maintenance dose of about 300 mg of the antibody.12. The use of any one of embodiments 1-11, wherein the medicament is formulated for further administration to the subject one or more of the maintenance doses of the antibody, and wherein the interval between every two consecutive maintenance doses is about 4 weeks.13. The use of embodiment 12, wherein at least 3 of the maintenance doses of the antibody are to be administered to the subject in total.14. The use of embodiment 12, wherein at least 4 of the maintenance doses of the antibody are to be administered to the subject in total.15. The use of embodiment 12, wherein at least 5 of the maintenance doses of the antibody are to be administered to the subject in total.16. The use of embodiment 12, wherein at least 6 of the maintenance doses of the antibody are to be administered to the subject in total.17. The use of any one of embodiments 1-16, wherein the chronic prurigo is prurigo nodularis.18. The use of embodiment 17, wherein the prurigo nodularis is moderate to severe prurigo nodularis.19. The use of any one of embodiments 1-18, wherein the subject has an inadequate response to prescription topical medications.NAI-1543385831V1 18Attorney Docket No. 12638-179-22820. The use of any one of embodiments 1-18, wherein the subject is one for whom topical medications are medically inadvisable.21. The use of any one of embodiments 1-20, wherein the medicament is formulated for subcutaneous administration.22. The use of any one of embodiments 1-21, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.23. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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 CDR.1, 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; andNAI-1543385831V1 19Attorney Docket No. 12638-179-228(ii) a VH comprising VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 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.24. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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;NAI-1543385831V1 20Attorney Docket No. 12638-179-228(c) (i) a VL comprising VL CDR.1, 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.25. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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; andNAI-1543385831V1 21Attorney Docket No. 12638-179-228(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.26. The pharmaceutical dosage unit of any one of embodiments 23-25, which is forsubcutaneous administration.27. The pharmaceutical dosage unit of any one of embodiments 23-26, wherein the antibody is barzolvolimab.28. Use of the pharmaceutical dosage unit of any one of embodiments 23-27 for treating, preventing or managing chronic prurigo in a subject in need thereof.29. The use of any one of embodiments 1-22 and 28 or the pharmaceutical dosage unit of any one of embodiments 23-27, wherein the subject is a human.3.1.3 Set 3NAI-1543385831V1 22Attorney Docket No. 12638-179-2281. An antibody which immunospecifically binds to human KIT for use in a method for treating, preventing or managing chronic prurigo in a subject in need thereof, wherein the method comprises administering to the subject a maintenance dose of between about 150 mg and about 300 mg of the antibody, andwherein 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; orNAI-1543385831V1 23Attorney Docket No. 12638-179-228(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.2. The antibody for use of embodiment 1, 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: 10.3. The antibody for use of embodiment 1 or 2, wherein the antibody comprises a modified human IgGl 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.4. The antibody for use of any one of embodiments 1-3, wherein the antibody comprises a light chain comprising the amino acid sequence:DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).5. The antibody for use of any one of embodiments 1-4, wherein the antibody comprises a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTOYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYEPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).6. The antibody for use of any one of embodiments 1-5, wherein the antibody is barzolvolimab.NAI-1543385831V1 24Attorney Docket No. 12638-179-2287. The antibody for use of any one of embodiments 1-6, wherein the method further comprises administering to the subject a loading dose of about 450 mg of the antibody, and wherein the loading dose is administered to the subject about 4 weeks before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.8. The antibody for use of any one of embodiments 1-7, wherein the maintenance dose is about 150 mg of the antibody.9. The antibody for use of any one of embodiments 1-7, wherein the maintenance dose is about 300 mg of the antibody.10. An antibody that is barzolvolimab for use in a method for treating, preventing or managing chronic prurigo in a subject in need thereof wherein the method comprises administering to the subject a loading dose of about 450 mg of the antibody, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 150 mg of the antibody.11. An antibody that is barzolvolimab for use in a method for treating, preventing or managing chronic prurigo in a subject in need thereof, wherein the method comprises administering to the subject a loading dose of about 450 mg of the antibody, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 300 mg of the antibody.12. The antibody for use of any one of embodiments 1-11, wherein the method comprises further administering to the subject one or more of the maintenance doses of the antibody, and wherein the interval between every two consecutive maintenance doses is about 4 weeks.13. The antibody for use of embodiment 12, wherein at least 3 of the maintenance doses of the antibody are administered to the subject in total.14. The antibody for use of embodiment 12, wherein at least 4 of the maintenance doses of the antibody are administered to the subject, in total.NAI-1543385831V1 25Attorney Docket No. 12638-179-22815. The antibody for use of embodiment 12, wherein at least 5 of the maintenance doses of the antibody are administered to the subject in total.16. The antibody for use of embodiment 12, wherein at least 6 of the maintenance doses of the antibody are administered to the subject in total.17. The antibody for use of any one of embodiments 1-16, wherein the chronic prurigo is prurigo nodularis.18. The antibody for use of embodiment 17, wherein the prurigo nodularis is moderate to severe prurigo nodularis.19. The antibody for use of any one of embodiments 1-18, wherein the subject has an inadequate response to prescription topical medications.20. The antibody for use of any one of embodiments 1-18, wherein the subject is one for whom topical medications are medically inadvisable21. The antibody for use of any one of embodiments 1-20, wherein the antibody is administered by subcutaneous administration.22. The antibody for use of any one of embodiments 1-21, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.23. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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; andNAI-1543385831V1 26Attorney Docket No. 12638-179-228(ii) a heavy chain variable region (“VH”) comprising VH CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.24. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit comprises: (i) about 300 mg of the antibody; (ii) a buffering agent, (iii) a salt; and (iv) an excipient;wherein the antibody comprises:NAI-1543385831V1 27Attorney Docket No. 12638-179-228(a) (i) a light chain variable region (“VL”) comprising VL CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.NAI-1543385831V1 28Attorney Docket No. 12638-179-22825. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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; andNAI-1543385831V1 29Attorney Docket No. 12638-179-228(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.26. The pharmaceutical dosage unit of any one of embodiments 23-25, which is forsubcutaneous administration.27. The pharmaceutical dosage unit of any one of embodiments 23-26, wherein the antibody is barzolvolimab.28. The pharmaceutical dosage unit of any one of embodiments 23-27 for use in a method for treating, preventing or managing chronic prurigo in a subject in need thereof.29. The antibody for use of any one of embodiments 1-22, the pharmaceutical dosage unit of any one of embodiments 23-27, or the pharmaceutical dosage unit for use of embodiment 28, wherein the subject is a human.4. BRIEF DESCRIPTION OF THE FIGURES

[0028] 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., DI, 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 DI domain is depicted at P34 to R112, the D2 domain is depicted at DI 13 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 DI 13 to LI 17; 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.

[0029] FIG. 2 depicts the amino acid sequences of heavy chain and light chain of barzolvolimab.NAI-1543385831V1 30Attorney Docket No. 12638-179-2285. DETAILED DESCRIPTION

[0030] 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 a specific maintenance dose(s), and pharmaceutical dosage units of anti-KIT antibodies such as barzolvolimab.

[0031] 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.

[0032] 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 subcutaneous, mucosal, topical, intradermal, parenteral, intravenous, intramuscular delivery and / or any other method of physical delivery described herein or known in the art.

[0033] 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.

[0034] 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-NAI-1543385831V1 31Attorney Docket No. 12638-179-228D5 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.

[0035] 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 etal., Nature, 1986, 323:226-232; Ullrich and Schlessinger, Cell, 1990, 61:203-212; Clifford etal., J. Biol. Chem., 2003, 278:31461-31464; Yarden etal., EMBO J., 1987, 6:3341-3351; Mol etal., 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 (DI, 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.

[0036] 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.

[0037] Chronic prurigo is a disease characterized by the presence of both chronic pruritus (itching) and multiple localized or generalized pruriginous lesions.

[0038] Prurigo nodularis is a disease characterized by the presence of both chronic pruritus and multiple localized or generalized, elevated, firm, and nodular lesions. In certainNAI-1543385831V1 32Attorney Docket No. 12638-179-228embodiments, the prurigo nodularis is moderate prurigo nodularis. In certain embodiments, the prurigo nodularis is severe prurigo nodularis.

[0039] As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and / or duration of chronic prurigo resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as an antibody or pharmaceutical composition provided herein).

[0040] 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 more therapies (e.., 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.

[0041] 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%) orblockage 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).

[0042] 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.NAI-1543385831V1 33Attorney Docket No. 12638-179-228

[0043] 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).

[0044] 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 prurigo. 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.

[0045] 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, anNAI-1543385831V1 34Attorney Docket No. 12638-179-228"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.

[0046] 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 other 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.

[0047] 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.

[0048] 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.

[0049] 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

[0050] 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).NAI-1543385831V1 35Attorney Docket No. 12638-179-228

[0051] 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.

[0052] 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 chainantibody 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.., IgGl, IgG2, IgG3, IgG4, IgAl or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgGl or IgG4) or subclass thereof. In a specific embodiment, antibodies described herein are IgGl antibodies.

[0053] 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 aD4 region of KIT e.g., human KIT).

[0054] 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 etal., 1997, 1. Mol. Biol,NAI-1543385831V1 36Attorney Docket No. 12638-179-228273:927 -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. etal., 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 Dilbel, 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).

[0055] 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 various 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.

[0056] 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.

[0057] As used herein, the term "heavy chain" when used in reference to an antibody refers to any distinct types, e.g., alpha (a), delta (8), epsilon (s), gamma (y) and mu (p), 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, IgGi and IgG4. In a specific embodiment, the heavy chain is a human heavy chain.

[0058] 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, 2.5NAI-1543385831V1 37Attorney Docket No. 12638-179-228logs, 3 logs, 4 logs or greater than the Kawhen 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.

[0059] 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.

[0060] 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 etal. (1971) Ann. NY Acad. Sci.190:382-391 and, Kabat etal. (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).

[0061] As used herein, the term "light chain" when used in reference to an antibody refers to any distinct types, e.g, kappa (K) of lambda (X) 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.

[0062] 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 theNAI-1543385831V1 38Attorney Docket No. 12638-179-228art 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).

[0063] 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.

[0064] 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).

[0065] 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,NAI-1543385831V1 39Attorney Docket No. 12638-179-228e.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.

[0066] 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).

[0067] 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, 1. 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 AntibodyNAI-1543385831V1 40Attorney Docket No. 12638-179-228Variable 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.

[0068] 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).

[0069] 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.

[0070] Table 1: CDR Amino Acid Sequencesamino acid sequence SEQ ID NO:VL CDR1 KASQNVRTNVA 2VL CDR2 SASYRYS 3NAI-1543385831V1 41Attorney Docket No. 12638-179-228amino acid sequence SEQ ID NO:VL CDR3 QQYNSYPRT 4 VH CDR1 DYYIN 5 VH CDR2 RIYPGSGNTYYNEKFKG 6 VH CDR3 GVYYFDY 7

[0071] Table 2: CDR Amino Acid SequencesSet 1 Set 2amino acid SEQ ID amino acid sequence SEQ ID sequence NO: NO:VL CDR1 KASQNVRTNVA 2 SQNVRTN 28 VL CDR2 SASYRYS 3 SAS 29 VL CDR3 QQYNSYPRT 4 YNSYPR 30 VH CDR1 GYTFTDY 25 GYTFTDY 25 VH CDR2 YPGSGN 26 PGSG 31 VH CDR3 GVYYFDYW 27 VYYFDY 32

[0072] Table 3: CDR Amino Acid SequencesAbM Contactamino acid SEQ ID amino acid sequence SEQ ID sequence NO: NO:VL CDR1 KASQNVRTNVA 2 RTNVAWY 35 VL CDR2 SASYRYS 3 ALIYSASYRY 36 VL CDR3 QQYNSYPRT 4 QQYNSYPR 37 VH CDR1 GYTFTDYYIN 33 TDYYIN 38NAI-1543385831V1 42Attorney Docket No. 12638-179-228VH CDR2 RIYPGSGNTY 34 WIARIYPGSGNTY 39 VH CDR3 GVYYFDYW 27 ARGVYYFDY 40

[0073] In a particular aspect, an anti -KIT antibody (e.g., humanized antibody) provided herein comprises:(i) a VL comprising the amino acid sequence:DIVMTQSPSXKILSASVGDRVTITCKASQNVRTNVAWYQQKPG KAPKXK2LIYSASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4ED FAXK5YXK6CQQYNSYPRTFGGGTKVEIK (SEQ ID NO: 17), wherein XKI to XK6 is any amino acid; and(ii) a VH comprising the amino acid sequence:QVQLVQSGAEXmKKPGASVKXiuSCKASGYTFTDYYINWVXm QAPGKGLEWIARIYPGSGNTYYNEKFKGRXH4TXHSTAXH6KSTST A YMXI 17LS SLRSEDXI ISA V YFC ARG V Y YFD YWGQGTT VT VS S (SEQ ID NO: 18), wherein XHI to XHS is any amino acid.

[0074] In a particular embodiment, XKI is an amino acid with an aromatic or aliphatic hydroxyl side chain, XK2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain XKS is an amino acid with an aliphatic hydroxyl side chain XK4 is an amino acid with an aliphatic hydroxyl side chain or is P, XKS is an amino acid with a charged or acidic side chain, XK6 is an amino acid with an aromatic side chain, XHI is an amino acid with an aliphatic side chain, XH2 is an amino acid with an aliphatic side chain XH3 is an amino acid with a polar or basic side chain XH4 is an amino acid with an aliphatic side chain XH5is 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.

[0075] In a specific embodiment, XKI is the amino acid F or S, XK2 is the amino acid A or S, XK3 is the amino acid T or S, X 4 is the amino acid S or P, X S is the amino acid D or T XK6 is the amino acid F or Y, XHI 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, XHS is the amino acid L or I, XH6 is the amino acid E or D, XH7 is the amino acid Q or E, and XHS is the amino acid S or T.NAI-1543385831V1 43Attorney Docket No. 12638-179-228

[0076] In a particular aspect, an anti-KIT antibody (e.g., humanized antibody) provided herein comprises:(i) a VL comprising the amino acid sequence:DIVMTQSPSXKILSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKXK2LIYSASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4EDFAXK5YXK6CQ QYNSYPRTFGGGTKVEIK (SEQ ID NO: 17), wherein XKI 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.

[0077] In a particular embodiment, XKI is an amino acid with an aromatic or aliphatic hydroxyl side chain, XK2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain XK3 is an amino acid with an aliphatic hydroxyl side chain XK4 is an amino acid with an aliphatic hydroxyl side chain or is P, XKS is an amino acid with a charged or acidic side chain, and XK6 is an amino acid with an aromatic side chain.

[0078] In a specific embodiment, XKI is the amino acid F or S, XK2 is the amino acid A or S, XK3 is the amino acid T or S, XK4 is the amino acid S or P, XKS is the amino acid D or T, and XK6 is the amino acid F or Y.

[0079] 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 RSEDXHSAVYFCARGVYYFDYWGQGTTVTVSS (SEQ ID NO: 18), wherein XHI to XHS is any amino acid.

[0080] In a particular embodiment, XHI is an amino acid with an aliphatic side chain, XH2 is an amino acid with an aliphatic side chain XH3 is an amino acid with a polar or basic side chain XH4 is an amino acid with an aliphatic side chain XHS is an amino acid with an aliphatic sideNAI-1543385831V1 44Attorney Docket No. 12638-179-228chain 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.

[0081] In a specific embodiment, XHI 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, XHS is the amino acid L or I, XH6 is the amino acid E or D, XH7 is the amino acid Q or E, and XHS is the amino acid S or T.

[0082] 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 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.

[0083] Table 4: VH amino acid sequenceAmino 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 T D Y YI N W V K Q A P G K G L E W I A R I Y P G S GN T Y Y N E K F K G RA T L T A E K S T S T A Y M Q L S S L R S E D S A V Y F C A R G V Y Y F D Y W G Q G T T V T V S S VH2 Q V Q L V Q S G A E V K K P G A S V K L S C K A S G Y T F 9 T D Y YI N W V K Q A P G K G L E W I A R I Y P G S GN T Y Y N E K F K G RA T L T A E K S T S T A Y M Q L S S L R S E D T A V Y F C A R G V Y Y F D Y W G Q G T T V T V S S VH3 Q V Q L V Q S G A E V K K P G A S V K L S C K A S G Y T F 10T D Y YIN W V R Q A P G K G L E W I A R I Y P G S GN T Y Y N E K F K G RA T L T A D K S T S T A Y M Q L S S L R S E D T A V Y F C A R G V Y Y F D Y W G Q G T T V T V S S VH4 Q V Q L V Q S G A E V K K P G A S V K V S C K A S G Y T F 11 T D Y Y I N W V R Q A P G K G L E W I A R I Y P G S G N T Y Y N E K F K G RA T I T A D K S T S T A Y M E L S S L R S E D T A V Y F C A R G V Y Y F D Y W G Q G T T V T V S SNAI-1543385831V1 45Attorney Docket No. 12638-179-228VH5 Q V Q L V Q S G A E V K K P G A S V K V S C K A S G Y T F 12 T D Y YIN W VR Q A P G K GL E W I A R I Y P G S GN T Y Y N E K F K G RV T I T AD K S T S T A YM E L S S L R S E D T A V Y F C A R G V Y Y F D Y W G Q G T T V T V S S

[0084] Table 5: VL Amino Acid SequenceAmino Acid Sequence SEQ ID NO: VL1 D I V M T Q S P S F L S A S V G D R V T I T C K A S Q N V R 13 T N V A W Y Q Q K P G K A P K A L I Y S A S Y R Y S G V P 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 VL2 D I VM T Q S P S S L S A S V GD R V T I T C K A S Q N V R 14 T N V A W Y Q Q K P G K A P K A L I Y S A S Y R Y S G V P D R F T G S G S G T D F T L T I S S L Q P 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 VL3 D I V M T Q S P S S L S A S V G D R V T I T C K A S Q N V R 15 T N V A W Y Q Q K P G K A P K A L I Y S A S Y R Y S G V P D R F S G S G S G T D F T L T I S S L Q P 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 VL4 D I V M T Q S P S S L S A S V G D R V T I T C K A S Q N V R 16 T N V A W Y Q Q K P G K A P K S L I Y S A S Y R Y S G V P D R F S G S G S G T D F T L T I S S L Q P E D F A T Y Y C Q Q Y N S Y P R T F G G G T K V E I K

[0085] 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, theNAI-1543385831V1 46Attorney Docket No. 12638-179-228anti-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.

[0086] 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-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: 16.

[0087] 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.

[0088] 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, theNAI-1543385831V1 47Attorney Docket No. 12638-179-228anti-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.

[0089] 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, 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: 16.

[0090] 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.

[0091] 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.

[0092] 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 IgGl, IgG2, IgG3, or IgG4 Fc region or domain). Preferably, an anti-KIT antibody described herein has reduced Fc receptor binding activity (particularly reduced FcyR 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.NAI-1543385831V1 48Attorney Docket No. 12638-179-228

[0093] In specific embodiments, an anti -KIT antibody described herein has reduced Fc receptor binding activity (particularly reduced FcyR binding activity). In specific embodiments, an anti -KIT antibody described herein does not have significant Fc receptor (particularly FcyR) binding activity. In specific embodiments, an anti-KIT antibody described herein has no detectable Fc receptor (particularly FcyR) 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 FcyR) binding activity compared to an appropriate control antibody. When an anti-KIT antibody described herein comprises a modified (c.g, mutated) Fc region or domain (e.g., a modified (c.g, mutated) human IgG Fc region or domain, such as a modified (e.g., mutated) human IgGl, 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 IgGl 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 FcyR) binding activity compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgGl Fc region or domain.

[0094] 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 (c.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 (c.g., in presence of IFN gamma)) compared to an appropriate control antibody. In particularNAI-1543385831V1 49Attorney Docket No. 12638-179-228embodiments, 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 IgGl, 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 IgGl 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 betahexosaminidase 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 IgGl 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 IgGl Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgGl 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 IgGl Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgGl Fc region or domain.

[0095] 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,NAI-1543385831V1 50Attorney Docket No. 12638-179-228by 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) 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 IgGl, 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 IgGl 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 IgGl 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 IgGl Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgGl Fc region or domain. In particular embodiments, Fc receptordependent 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-KITNAI-1543385831V1 51Attorney Docket No. 12638-179-228antibody described herein that comprises a modified (e.g, mutated) human IgGl Fc region or domain, compared to a corresponding antibody having the same VH and VL but with a wild-type (unmodified) human IgGl Fc region or domain.

[0096] In various embodiments, an anti-KIT antibody used in the methods described herein (1) reduces disease activity in a chronic prurigo patient, (2) reduces skin mast cell number in a chronic prurigo patient, (3) reduces tryptase level in a chronic prurigo patient, and / or (4) 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 chronic prurigo patient within the normal ranges.

[0097] In certain embodiments, an anti-KIT antibody used in the methods described herein can significantly reduce skin mast cell number in a chronic prurigo patient, relative to the number before treatment. In specific embodiments, an anti-KIT antibody used in the methods described herein can reduce skin mast cell number in a chronic prurigo patient 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 used in the methods described herein 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.

[0098] In certain embodiments, an anti-KIT antibody used in the methods described herein can significantly reduce serum tryptase in a chronic prurigo patient, relative to the level before treatment. In specific embodiments, an anti-KIT antibody used in the methods described herein can reduce serum tryptase in a chronic prurigo patient 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 used in the methods described herein 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.

[0099] In certain embodiments, an anti-KIT antibody used in the methods 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 used in the methods described hereinNAI-1543385831V1 52Attorney Docket No. 12638-179-228maintains hematology parameters (such as hemoglobin (HgB) level, white blood cell (WBC) count, platelet count, and / or absolute neutrophil count (ANC)) in a chronic prurigo patient 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.

[0100] In various embodiments, an anti-KIT antibody described herein has one or more of the properties described herein.

[0101] 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.

[0102] 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 IgGl 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, 2341, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 2351, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 2401, 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, 263 A, 263T, 263M, 264L, 2641, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265 Y, 265F, 265V, 2651, 265L, 265H, 265T, 2661, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 2961, 296H, 269G, 297S, 297D, 297E, 298H, 2981, 298T, 298F, 2991, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 322Q, 325Q, 325L, 3251, 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, 33OC, 330L, 330Y, 330V, 3301, 33OF, 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;NAI-1543385831V1 53Attorney Docket No. 12638-179-228WO 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 IgGl 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 IgGl 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 IgGl Fc region or domain, as can be determined by one of skill in the art.

[0103] 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 IgGl 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, 2341, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 2351, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 2401, 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, 265 Y, 265F, 265V, 2651, 265L, 265H, 265T, 2661, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 2961, 296H, 269G,NAI-1543385831V1 54Attorney Docket No. 12638-179-228297S, 297D, 297E, 298H, 2981, 298T, 298F, 2991, 299L, 299 A, 299S, 299V, 299H, 299F, 299E, 313F, 322Q, 325Q, 325L, 3251, 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, 33OG, 330T, 330C, 33OL, 330Y, 330V, 3301, 330F, 33OR, 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 IgGl 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 IgGl 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 IgGl Fc region or domain, as can be determined by one of skill in the art.

[0104] 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 IgGl 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 specificNAI-1543385831V1 55Attorney Docket No. 12638-179-228embodiment, 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 IgGl 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, wherein the Fc region or domain is an Fc region or domain of human IgGl 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 IgGl 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 IgGl 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.

[0105] 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 etal., 1992, Mol Immunol 29:53-59; Alegre etal., 1994, Transplantation 57: 1537-1543; Hutchins et al., 1995, Proc Natl. Acad Sci U S A 92:NAI-1543385831V1 56Attorney Docket No. 12638-179-22811980-11984; Jefferis et al., 1995, Immunol Lett. 44: 111-117; Lund etal., 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 etal., 2000, Cell Immunol 200: 16-26; Idusogie etal., 2001, J Immunol 166:2571-2575; Shields et al., 2001, J Biol Chem 276:6591-6604; Jefferis et al., 2002, Immunol Lett 82:57-65; Presta et al., 2002, Biochem Soc Trans 30:487-490); U. S. Patent Nos. 5,624,821; 5,885,573; 5,677,425; 6,165,745; 6,277,375; 5,869,046; 6,121,022; 5,624,821; 5,648,260; 6,528,624; 6,194,551; 6,737,056; 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.

[0106] In specific embodiments, the antibody described herein comprises a modified (e.g, mutated) human IgGl 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 IgGl 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.

[0107] 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 IgGl 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 IgGl Fc region or domain, as can be determined by one of skill in the art.

[0108] 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 IgGl 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) humanNAI-1543385831V1 57Attorney Docket No. 12638-179-228IgG3 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 IgGl Fc region or domain, as can be determined by one of skill in the art.

[0109] 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 in Kabat for human IgGl 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 IgGl Fc region or domain, as can be determined by one of skill in the art.

[0110] 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 IgGl Fc region or domain, wherein the modified (e.g., mutated) human IgGl 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.

[0111] 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 IgGl Fc region or domain, wherein the modified (e.g., mutated) human IgGl 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.

[0112] Thus, in one aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising:(l)(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 VHNAI-1543385831V1 58Attorney Docket No. 12638-179-228comprising VH CDRl, 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 CDRl, 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 CDRl, 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 IgGl 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.

[0113] Thus, in a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising:(l)(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 CDRl, 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 CDRl, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NO: 25, SEQ ID NO: 1, and SEQ ID NO: 32, respectively;NAI-1543385831V1 59Attorney Docket No. 12638-179-228(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 IgGl 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.

[0114] In a further aspect, provided herein is an antibody, which immunospecifically binds to human KIT, comprising: (i) a VL comprising the amino acidsequence: DIVMTQSPSXK1LSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKXK2LIYSASYRYSGVPDRFXK3GSGSGTDFTLTISSLQXK4EDFAXK5YXK6CQQYNSYPRTFGGGTKVÉIK (SEQ ID NO: 17), wherein XKI is an amino acid with an aromatic or aliphatic hydroxyl side chain, XK2 is an amino acid with an aliphatic or aliphatic hydroxyl side chain, XK3 is an amino acid with an aliphatic hydroxyl side chain, XK4 is an amino acid with an aliphatic hydroxyl side chain or is P, XKS is an amino acid with a charged or acidic side chain and XK6 is an amino acid with an aromatic side chain; and (ii) a VH comprising the amino acid sequence:QVQLVQSGAEXH1KKPGASVKXH2SCKASGYTFTDYYINWVXH3QAPGKGLEWIARIYPGSGNTYYNEKFKGRXH4TXH5TAXH6KSTSTAYMXH7LSSLRSEDXH8AVYFCARGVYYFDYWGQGTTVTVSS (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, XH4 is 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, XH7 is an amino acid with an acidic or amide derivative side chain, and XH8is an amino acid with an aliphatic hydroxyl side chain; and (iii) a modified (e.g., mutated) human IgGl 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.NAI-1543385831V1 60Attorney Docket No. 12638-179-228

[0115] 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 IgGl 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.

[0116] 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 IgGl 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.

[0117] In specific embodiments, the antibody provided herein comprises a heavy chain comprising the following amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLS SLRSEDTAVYFCARGVYYFDYWGQGTTVTVS S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GL YSL S S VVTVP S S SLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCP APEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).

[0118] 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).

[0119] In specific embodiments, the antibody provided herein comprises a heavy chain comprising the following amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYINWVRQAPGKGLEWIARIYPGSGNTNAI-1543385831V1 61Attorney Docket No. 12638-179-228YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GL YSL S S VVTVP S S SLGTQT YICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCP APEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21); and a light chain comprising the following amino acid sequence:DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

[0120] In a specific embodiment, provided herein is an antibody comprising: (i) a heavy chain comprising the amino acid sequence: mewswvflfflsvttgvhsqvqlvqsgaevkkpgasvklsckasgytftdyyinwvrqapgkglewiariypgsgntyynekfkgr atltadkststavmqlsslrsedtavvfcargvvyfdvwgqgttvtvssastkgpsvfplapsskstsggtaalgclvkdyfpepytvswn sgaltsgvhtfpaylqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapeaaggpsvflfppkpk dtlxiirgpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsyltylhqdwlngkeykcqvsnkalpapiek tiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppyldsdgsfflyskltvdksrwqqgnvf 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 IgGl) are shown double underlined; and(ii) a light chain comprising the amino acid sequence: msvptqvlgllllwltdarf^divmtqspsslsasvgdrvtitckasqnvrtnvawyqqkpgkapkaliysasyrysgvpdrftgsgsgtdf / Zfe.s' / t / petZfatZy / c^ynyypr / fegg' / G’e / ^rtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqes vteqdskdstyslsstltlskadyekhkvyacevthqglsspytksfnrgec (SEQ ID NO: 20), wherein the leader sequence is shown in bold italic type, the variable region (VL) is shown in italic type and the constant region is shown underlined.

[0121] In a preferred embodiment, the anti-KIT antibody described herein is barzolvolimab (see FIG. 2).NAI-1543385831V1 62Attorney Docket No. 12638-179-228

[0122] 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 (FcyR receptor). In a specific embodiment, an anti -KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcyRI. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcyRIIa. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcyRIIb. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcyRIIIa. In a specific embodiment, an anti-KIT antibody described herein does not bind to (e.g., has no detectable binding to) human FcyRIIIb.

[0123] 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 IgGl, 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.

[0124] 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 IgGl, 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 modifiedNAI-1543385831V1 63Attorney Docket No. 12638-179-228(e.g., mutated) human IgG constant region (e.g, a modified (e.g, mutated) human IgGl, 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.

[0125] 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 IgGl, 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-y, IL-ip, IL-2, IL-6, IL-8, IL-10, and / or TNF-a), relative to a corresponding antibody with the same variable region sequences but an unmodified (wild type) human IgG constant region.

[0126] In certain aspects, anti-KIT antibodies for use in methods for preventing, treating or managing chronic prurigo, have been described or can be readily obtained using methods known in the art, for example, see Section 5.5 below.

[0127] 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.

[0128] 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.

[0129] 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 ECso (half maximal effectiveNAI-1543385831V1 64Attorney Docket No. 12638-179-228concentration) 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.

[0130] 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 ECso 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).

[0131] In a particular embodiment, an anti-KIT antibody provided herein is capable of blocking KIT phosphorylation with ICso (50% inhibition concentration) value of about 600 pM or less.

[0132] 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,NAI-1543385831V1 65Attorney Docket No. 12638-179-228for 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.

[0133] 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 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 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 etal., Development, 2004, 131:5551-5560).

[0134] 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 antibodyNAI-1543385831V1 66Attorney Docket No. 12638-179-228provided 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, 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 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.

[0135] 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).

[0136] 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,NAI-1543385831V1 67Attorney Docket No. 12638-179-228MAPK, 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).

[0137] In a specific embodiment, an anti-KIT antibody provided herein inhibits KIT tyrosine phosphorylation in the KIT cytoplasmic domain.

[0138] In another particular embodiment, an anti-KIT antibody provided herein inhibits cell proliferation, for example, mast cell proliferation or eosinophil proliferation. In yet another 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%.

[0139] 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%.

[0140] 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 el1al., 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%.

[0141] 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 [3-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-linkedNAI-1543385831V1 68Attorney Docket No. 12638-179-228immunosorbent assays (ELIS As). 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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 (ICso) 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,NAI-1543385831V1 69Attorney Docket No. 12638-179-228the IC50 is less than about 550 pM or 200 pM. In a specific embodiment, the IC50 is 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.

[0147] 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 human 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 pg / mL, for example at least 1.0 pg / 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.

[0148] 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).

[0149] 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.

[0150] 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-NAI-1543385831V1 70Attorney Docket No. 12638-179-228KIT 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, but does not specifically bind to murine or rat KIT or a fragment thereof (e.g, a D4 region of murine KIT).

[0151] 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).

[0152] 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).

[0153] 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).

[0154] 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.

[0155] 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 moreNAI-1543385831V1 71Attorney Docket No. 12638-179-228glycosylated than the other. In certain embodiments, an antibody described herein binds to an extracellular domain of human KIT which is not glycosylated.

[0156] 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 a VH comprising the amino acid sequence of any one of SEQ ID NOs: 8-12, and / or a VL comprising the amino acid sequence of any one of SEQ ID NOs: 13-16. In certain aspects, an anti-KIT antibody provided herein is not a bispecific antibody.

[0157] 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.

[0158] 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 aNAI-1543385831V1 72Attorney Docket No. 12638-179-228recombinant antibody, wherein the composite sequence does not naturally exist within an organism (e.g., primate such as human).

[0159] Antibodies provided herein include immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl 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 IgGl or IgG4) or subclass thereof. In another specific embodiment, an antibody described herein is an IgGl (e.g., human IgGl (isotype a, z, or f)) or IgG4 antibody. In certain embodiments, an antibody described herein is a whole or entire antibody, e.g., a whole or entire humanized, human, or composite human antibody.

[0160] 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.

[0161] With respect to the heavy chain, in a specific embodiment, the heavy chain of an antibody described herein can be an alpha (a), delta (5), epsilon (s), gamma (y) or mu (p) heavy chain. In another specific embodiment, the heavy chain of an antibody described can comprise a human alpha (a), delta (5), epsilon (s), gamma (y) or mu (p) 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 IgGl, 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 aNAI-1543385831V1 73Attorney Docket No. 12638-179-228modified (e.g., mutated) human Fc region or domain (e.g., a modified (e.g., mutated) human IgGl 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).

[0162] 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 or 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.

[0163] 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.

[0164] 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 PolynucleotidesNAI-1543385831V1 74Attorney Docket No. 12638-179-228

[0165] 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.

[0166] 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.

[0167] 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 polynucleotideNAI-1543385831V1 75Attorney Docket No. 12638-179-228comprising 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 herein and the second polynucleotide of the combination comprises a second nucleotide sequence encoding the light chain of said antibody.

[0168] 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.

[0169] 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., fi' 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,NAI-1543385831V1 76Attorney Docket No. 12638-179-2284 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.

[0170] 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 polynucleotide 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.

[0171] 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.

[0172] 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 theNAI-1543385831V1 77Attorney Docket No. 12638-179-228sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

[0173] 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 can 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.

[0174] 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.

[0175] 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.NAI-1543385831V1 78Attorney Docket No. 12638-179-228

[0176] 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., human kappa or lambda constant regions. In certain embodiments, the vectors for expressing the VH or VL domains comprise an EF- la 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.

[0177] 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

[0178] 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).

[0179] 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, butNAI-1543385831V1 79Attorney Docket No. 12638-179-228not 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 antibody 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.

[0180] 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 aNAI-1543385831V1 80Attorney Docket No. 12638-179-228vector 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.

[0181] 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.

[0182] 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 cellNAI-1543385831V1 81Attorney Docket No. 12638-179-228systems 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 systems (e.g, COS, CHO, BHK, MDCK, HEK 293, NSO, PER. C6, VERO, CRL7030, Hs578Bst, 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 NSO 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.

[0183] 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 proteinsNAI-1543385831V1 82Attorney Docket No. 12638-179-228with 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.

[0184] 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).

[0185] 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 8 1:355-359). 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).

[0186] 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 andNAI-1543385831V1 83Attorney Docket No. 12638-179-228processing 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, BT20 and T47D, NSO (a murine myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7030 and Hs578Bst cells. In certain embodiments, humanized monoclonal anti-KIT antibodies described herein are produced in mammalian cells, such as CHO cells.

[0187] 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.

[0188] 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: dhjr, 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-NAI-1543385831V1 84Attorney Docket No. 12638-179-228596; Mulligan, 1993, Science 260:926-932; and Morgan and Anderson, 1993, Ann. Rev.Biochem. 62:191-217; May, 1993, TIB TECH 11(5):155-2 15); 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 etal. (eds.), Current Protocols in 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 etal., 1981, J. Mol. Biol. 150:1, which are incorporated by reference herein in their entireties.

[0189] 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).

[0190] 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.

[0191] 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 / nucleotideNAI-1543385831V1 85Attorney Docket No. 12638-179-228sequences. 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 mRNA 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.

[0192] 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.

[0193] 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) ofNAI-1543385831V1 86Attorney Docket No. 12638-179-228chemical precursors or compounds other than the antibody of interest. In a specific embodiment, antibodies described herein are isolated or purified.5.4 Antibody Production

[0194] 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 etal. (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 etal. (eds.) (1999) Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press.

[0195] 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 etal., 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,NAI-1543385831V1 87Attorney Docket No. 12638-179-228WO 9317105, Tan et al., J. Immunol. 169:1119-25 (2002), Caldas et al., Protein Eng. 13(5):353-60 (2000), Morea et al., Methods 20(3):267-79 (2000), Baca et al., J. Biol. Chem. 272(16):10678-84 (1997), Roguska et al., Protein Eng. 9(10):895-904 (1996), Couto etal., Cancer Res.55 (23 Supp):5973s- 5977s (1995), Couto etal., Cancer Res. 55(8): 1717-22 (1995), Sandhu JS, Gene 150(2):409-10 (1994), and Pedersen etal., J. Mol. Biol. 235(3):959-73 (1994). See also U. S. Patent Pub. No. US 2005 / 0042664 Al (Feb. 24, 2005), which is incorporated herein by reference.

[0196] 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 563 681 (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.

[0197] 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, aRIMMS (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).

[0198] 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 theNAI-1543385831V1 88Attorney Docket No. 12638-179-228American 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 etal.. Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0199] 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

[0200] Provided herein are methods for impeding, preventing, protecting against, treating and / or managing chronic prurigo. 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 prurigo.

[0201] In specific embodiments, the methods described herein are for treating or managing chronic prurigo. In specific embodiments, the methods described herein are for treating chronic prurigo.

[0202] In specific embodiments, methods described herein for treating chronic prurigo provide for the reduction or amelioration of the progression, severity, and / or duration of chronic prurigo 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 prurigo relate to reducing one or more symptoms of chronic prurigo. In specific embodiments, an antibody described herein or a pharmaceutical compositionNAI-1543385831V1 89Attorney Docket No. 12638-179-228described herein is for use in protecting against, treating or managing chronic prurigo. In a particular embodiment, chronic prurigo 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 expression 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 prurigo 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 prurigo 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.

[0203] In one aspect, the methods described herein comprise administering to the subject a maintenance dose of between about 150 mg (e.g., 125 mg to 175 mg, 130 mg to 170 mg, 135 mg to 165 mg, 140 mg to 160 mg, or 145 mg to 155 mg, or 150 mg) and about 300 mg (e.g., 275 mg to 325 mg, 280 mg to 320 mg, 285 mg to 315 mg, 290 mg to 310 mg, or 295 mg to 305 mg, or 300 mg) of an antibody which immunospecifically binds to human KIT.

[0204] In certain embodiments, the methods described herein further comprise administering to the subject a loading dose of about 450 mg (e.g, 400 mg to 500 mg, 410 mg to 490 mg, 420 mg to 480 mg, 430 mg to 470 mg, or 440 mg to 460 mg, or 450 mg) of the antibody, wherein the loading dose is administered to the subject about 4 weeks (e.g, 3 weeks to 5 weeks, or 4 weeks) before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.

[0205] In a specific embodiment, the maintenance dose is about 150 mg (e.g, 125 mg to 175 mg, 130 mg to 170 mg, 135 mg to 165 mg, 140 mg to 160 mg, or 145 mg to 155 mg, or 150 mg) of the antibody. In another specific embodiment, the maintenance dose is about 300 mg (e.g., 275 mg to 325 mg, 280 mg to 320 mg, 285 mg to 315 mg, 290 mg to 310 mg, or 295 mg to 305 mg, or 300 mg) of the antibody.

[0206] In another aspect, the methods described herein comprise administering to the subject a loading dose of about 450 mg (e.g., 400 mg to 500 mg, 410 mg to 490 mg, 420 mg to 480 mg,NAI-1543385831V1 90Attorney Docket No. 12638-179-228430 mg to 470 mg, or 440 mg to 460 mg, or 450 mg) of an antibody that is barzolvolimab, and then after about 4 weeks (e.g., 3 weeks to 5 weeks, or 4 weeks) during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 150 mg e.g., 125 mg to 175 mg, 130 mg to 170 mg, 135 mg to 165 mg, 140 mg to 160 mg, or 145 mg to 155 mg, or 150 mg) of the antibody.

[0207] In another aspect, the methods described herein comprise administering to the subject a loading dose of about 450 mg (e.g., 400 mg to 500 mg, 410 mg to 490 mg, 420 mg to 480 mg, 430 mg to 470 mg, or 440 mg to 460 mg, or 450 mg) of an antibody that is barzolvolimab, and then after about 4 weeks (e.g., 3 weeks to 5 weeks, or 4 weeks) during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 300 mg (e.g., 275 mg to 325 mg, 280 mg to 320 mg, 285 mg to 315 mg, 290 mg to 310 mg, or 295 mg to 305 mg, or 300 mg) of the antibody.

[0208] In certain embodiments, the methods described herein comprise further administering to the subject one or more of the maintenance doses of the antibody, wherein the interval between every two consecutive maintenance doses is about 4 weeks (e.g., 3 weeks to 5 weeks, or 4 weeks).

[0209] In various aspects and embodiments, the anti-KIT antibody is barzolvolimab.

[0210] In various embodiments, at least 3 maintenance doses of the anti-KIT antibody are administered to the subject in total. In specific embodiments, at least 4 maintenance doses of the anti-KIT antibody are administered to the subject in total. In specific embodiments, at least 5 maintenance doses of the anti-KIT antibody are administered to the subject in total. In specific embodiments, at least 6 maintenance doses of the anti-KIT antibody are administered to the subject in total. 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 3-7 maintenance doses of the anti-KIT antibody are administered to the subject in total. In specific embodiments, at least 4-8 maintenance doses of the anti-KIT antibody are administered to the subject in total. In specific embodiments, at least 4-6 maintenance doses of the anti-KIT antibody are administered to the subject in total. In aNAI-1543385831V1 91Attorney Docket No. 12638-179-228specific embodiment, 2 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 3 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 4 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 5 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 6 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 7 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 8 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 9 maintenance doses of the anti-KIT antibody are administered to the subject in total. In another specific embodiment, 10 maintenance doses of the anti-KIT antibody are administered to the subject in total. 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 prurigo).

[0211] 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 areNAI-1543385831v1 92Attorney Docket No. 12638-179-228administered 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 the 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.

[0212] 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 ofAI-1543385831V1 93Attorney Docket No. 12638-179-228the 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, maintenance 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, maintenanceAI-1543385831V1 94Attorney Docket No. 12638-179-228doses 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.

[0213] 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.

[0214] In a specific embodiment, the antibody used in the methods described herein is internalized by the cell to which it binds.

[0215] 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 normal 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, aberrantNAI-1543385831V1 95Attorney Docket No. 12638-179-228or 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.

[0216] In certain aspects, the chronic prurigo can be characterized by gain-of-function of KIT activity, increase in KIT activity, or overexpression of KIT. In one embodiment, the chronic prurigo 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 immunohistory chemistry). In particular embodiments, the chronic prurigo 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.

[0217] 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, mast 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 prurigo.NAI-1543385831V1 96Attorney Docket No. 12638-179-228

[0218] 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).

[0219] In certain embodiments, the chronic prurigo is prurigo nodularis. In certain embodiments, the prurigo nodularis is moderate prurigo nodularis. In certain embodiments, the prurigo nodularis is severe prurigo nodularis.

[0220] In certain embodiments, the subject has an inadequate response to prescription topical medications. In certain embodiments, the subject is one for whom topical medications are medically inadvisable.

[0221] In various embodiments, the subject having chronic prurigo has failed one or more prior treatments for the chronic prurigo. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the subject having chronic prurigo has failed a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the subject having chronic prurigo has failed a treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In certain embodiments, the subject having chronic prurigo has failed a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In certain embodiments, the subject having chronic prurigo has failed a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In certain embodiments, the subject having chronic prurigo has failed a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In certain embodiments, the subject having chronic prurigo has failed a treatment with an OSMR0 inhibitor such as anti-OSMRp antibody, e.g., vixarelimab. In certain embodiments, the subject having chronic prurigo has failed one, two, three, or more of the treatments described above for the chronic prurigo.

[0222] A subject is considered to have failed a treatment for chronic prurigo if the chronic prurigo is refractory to the treatment, resistant to the treatment, relapses after the treatment, and / or if the subject has discontinued the treatment due to intolerance of the treatment.NAI-1543385831V1 97Attorney Docket No. 12638-179-228

[0223] In various embodiments, the chronic prurigo is refractory to one or more prior treatments for the chronic prurigo. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the chronic prurigo is refractory to a treatment with an IL-4R inhibitor such as an anti-ZL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic prurigo is refractory to a treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In certain embodiments, the chronic prurigo is refractory to a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In certain embodiments, the chronic prurigo is refractory to a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In certain embodiments, the chronic prurigo is refractory to a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In certain embodiments, the chronic prurigo is refractory to a treatment with an OSMRfl inhibitor such as anti-0 SMR[3 antibody, e.g., vixarelimab. In certain embodiments, the chronic prurigo is refractory to one, two, three, or more of the treatments described above for the chronic prurigo.

[0224] In various embodiments, the chronic prurigo is resistant to one or more prior treatments for the chronic prurigo. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the chronic prurigo is resistant to a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic prurigo is resistant to a treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In certain embodiments, the chronic prurigo is resistant to a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In certain embodiments, the chronic prurigo is resistant to a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In certain embodiments, the chronic prurigo is resistant to a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In certain embodiments, the chronic prurigo is resistant to a treatment with an OSMRp inhibitor such as anti-OSMR0 antibody, e.g., vixarelimab. In certain embodiments, the chronic prurigo is resistant to one, two, three, or more of the treatments described above for the chronic prurigo.NAI-1543385831V1 98Attorney Docket No. 12638-179-228

[0225] In various embodiments, the chronic prurigo is both refractory and resistant to one or more prior treatments for the chronic prurigo. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the chronic prurigo 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 certain embodiments, the chronic prurigo is both refractory and resistant to a treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In certain embodiments, the chronic prurigo is both refractory and resistant to a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In certain embodiments, the chronic prurigo is both refractory and resistant to a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In certain embodiments, the chronic prurigo is both refractory and resistant to a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In certain embodiments, the chronic prurigo is both refractory and resistant to a treatment with an OSMRP inhibitor such as anti-OSMRp antibody, e.g., vixarelimab. In certain embodiments, the chronic prurigo is both refractory and resistant to one, two, three, or more of the treatments described above for the chronic prurigo.

[0226] In various embodiments, the chronic prurigo has relapsed after one or more prior treatments for the chronic prurigo. In certain embodiments, the one or more prior treatments comprise at least one standard of care therapy for the chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the chronic prurigo has relapsed after a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In certain embodiments, the chronic prurigo has relapsed after a treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab. In certain embodiments, the chronic prurigo has relapsed after a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In certain embodiments, the chronic prurigo has relapsed after a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In certain embodiments, the chronic prurigo has relapsed after a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In certain embodiments, the chronic prurigo has relapsed after a treatment with an OSMRP inhibitorNAI-1543385831V1 99Attorney Docket No. 12638-179-228such as anti-0SMR[3 antibody, e.g., vixarelimab. In certain embodiments, the chronic prurigo has relapsed after one, two, three, or more of the treatments described above for the chronic prurigo.

[0227] In various embodiments, the subject having chronic prurigo has discontinued one or more prior treatments for the chronic prurigo 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 chronic prurigo. In certain embodiments, the one or more prior treatments are all standard of care therapies for the chronic prurigo. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent"), due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with an IL-31 receptor alpha inhibitor such as an anti -IL-31 receptor alpha antibody, e.g., nemolizumab, due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued a treatment with an OSMRp inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, due to intolerance of the treatment. In certain embodiments, the subject having chronic prurigo has discontinued one, two, three, or more of the treatments described above for the chronic prurigo due to intolerance of the treatment(s).

[0228] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®). In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-NAI-1543385831V1 100Attorney Docket No. 12638-179-22831 receptor alpha antibody, e.g., nemolizumab. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject having chronic prurigo whose chronic prurigo remains symptomatic despite treatment with an OSMRfl inhibitor such as anti-OSMR0 antibody, e.g., vixarelimab.

[0229] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the subject has failed said one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the subject has failed said treatment with an IL-4R inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the subject has failed said treatment with an IL-31 receptor alpha inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the subject has failed said treatment with a Janus kinase 1 inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronicNAI-1543385831V1 101Attorney Docket No. 12638-179-228prurigo, wherein the subject has failed said treatment with a NK1 receptor antagonist. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the subject has failed said treatment with a PDE4 and / or TNF-a inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMRp inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, for the chronic prurigo, wherein the subject has failed said treatment with an OSMRP inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the subject has failed said one, two, three, or more treatments.

[0230] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the chronic prurigo is refractory to said one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with an IL-4R inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with an IL-31 receptor alpha inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with a Janus kinase 1 inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigoNAI-1543385831V1 102Attorney Docket No. 12638-179-228following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with a NK1 receptor antagonist. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with a PDE4 and / or TNF-a inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMR inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, for the chronic prurigo, wherein the chronic prurigo is refractory to said treatment with an OSMRP inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the chronic prurigo is refractory to said one, two, three, or more treatments.

[0231] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the chronic prurigo is resistant to said one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment with an IL-4R inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment with an IL-31 receptor alpha inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment withNAI-1543385831V1 103Attorney Docket No. 12638-179-228a Janus kinase 1 inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment with a NK1 receptor antagonist. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment with a PDE4 and / or TNF-a inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMR0 inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, for the chronic prurigo, wherein the chronic prurigo is resistant to said treatment with an OSMRp inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the chronic prurigo is resistant to said one, two, three, or more treatments.

[0232] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with an IL-4R inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti -IL-31 receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with an IL-31 receptor alpha inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition describedNAI-1543385831V1 104Attorney Docket No. 12638-179-228herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with a Janus kinase 1 inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with a NK1 receptor antagonist. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with a PDE4 and / or TNF-a inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMRp inhibitor such as anti-OSMR antibody, e.g., vixarelimab, for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said treatment with an OSMRP inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the chronic prurigo is both refractory and resistant to said one, two, three, or more treatments.

[0233] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the chronic prurigo has relapsed after said one or more prior treatments for the chronic prurigo. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with an IL-4R inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti -IL-31NAI-1543385831V1 105Attorney Docket No. 12638-179-228receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with an IL-31 receptor alpha inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with a Janus kinase 1 inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with a NK1 receptor antagonist. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with a PDE4 and / or TNF-a inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMR0 inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, for the chronic prurigo, wherein the chronic prurigo has relapsed after said treatment with an OSMRP inhibitor. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the chronic prurigo has relapsed after said one, two, three, or more treatments.

[0234] In various embodiments, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one or more prior treatments for the chronic prurigo, wherein the subject has discontinued said one or more prior treatments for the chronic prurigo due to intolerance of the treatment(s). In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-4R inhibitor such as an anti-IL-4R antibody, e.g., dupilumab (Dupixent®), for the chronic prurigo, wherein the subject has discontinued said treatment with an IL-4R inhibitor due to intolerance ofNAI-1543385831V1 106Attorney Docket No. 12638-179-228the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an IL-31 receptor alpha inhibitor such as an anti-IL-31 receptor alpha antibody, e.g., nemolizumab, for the chronic prurigo, wherein the subject has discontinued said treatment with an IL-31 receptor alpha inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Janus kinase 1 inhibitor, e.g., INCB054707 or abrocitinib, for the chronic prurigo, wherein the subject has discontinued said treatment with a Janus kinase 1 inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a Neurokinin-1 (NK1) receptor antagonist, e.g., serlopitant, for the chronic prurigo, wherein the subject has discontinued said treatment with a NK1 receptor antagonist due to intolerance of the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with a PDE4 and / or TNF-a inhibitor, e.g., apremilast, for the chronic prurigo, wherein the subject has discontinued said treatment with a PDE4 and / or TNF-a inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following treatment with an OSMRP inhibitor such as anti-OSMRp antibody, e.g., vixarelimab, for the chronic prurigo, wherein the subject has discontinued said treatment with an OSMR0 inhibitor due to intolerance of the treatment. In one embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to a subject to treat or manage chronic prurigo following one, two, three, or more of the treatments described above for the chronic prurigo, wherein the subject has discontinued said one, two, three, or more treatments due to intolerance of the treatment(s).

[0235] When a disease, or a symptom thereof, is being treated, administration of the substance typically occurs after the onset of the disease or symptoms thereof. When a disease, or symptoms thereof, are being prevented, administration of the substance typically occurs before the onset of the disease or symptoms thereof. In certain embodiments, an anti-KIT antibody orNAI-1543385831V1 107Attorney Docket No. 12638-179-228pharmaceutical composition described herein is administered prophylactically or therapeutically to a subject. An anti -KIT antibody or pharmaceutical composition described herein can be prophylactically or therapeutically administered to a subject so as to prevent, lessen or ameliorate the chronic prurigo.

[0236] The methods provided herein involve administering an anti-KIT antibody or pharmaceutical composition by any suitable routes. Non- limiting examples of routes of administration include, parenteral administration for example subcutaneous, intramuscular or intravenous administration, epidural administration, enteric administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous infusion, intrathecal administration, and intraperitoneal administration. Methods provided herein include routes of administration targeting the brain, an ocular tissue or organ, spinal cord, or ear or auricular tissue. In a particular aspect, methods provided herein include subcutaneous administration.5.6 Compositions and Dosage Units

[0237] Provided herein are compositions, such as pharmaceutical compositions, comprising one or more anti-KIT antibodies (e.g., humanized antibodies) described herein. In particular aspects, compositions described herein can be for in vitro, in vivo, or ex vivo uses. In specific embodiments, provided herein is a pharmaceutical composition comprising an anti-KIT antibody (e.g., a humanized antibody) described herein and a pharmaceutically acceptable carrier or excipient.

[0238] As used herein, the term "pharmaceutically acceptable" means being approved by a regulatory agency of the Federal or a state government, or listed in the U. S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

[0239] Therapeutic formulations containing one or more antibodies (e.g., humanized antibodies) provided herein can be prepared for storage by mixing the antibody having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA; Remington: The Science and Practice of Pharmacy, 21st ed. (2006) Lippincott Williams & Wilkins, Baltimore, MD), in the form of lyophilized formulations or aqueous solutions.NAI-1543385831V1 108Attorney Docket No. 12638-179-228Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[0240] The formulations to be used for in vivo administration can be sterile. This is readily accomplished by filtration through, e.g., sterile filtration membranes.

[0241] Pharmaceutical carriers suitable for administration of the antibodies provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0242] Preferably, the antibodies described herein are formulated as the sole pharmaceutically active ingredient in the composition.

[0243] Compositions can contain one or more anti-KIT antibodies (but preferably one anti-KIT antibody) provided herein. In one embodiment, the antibodies are formulated into suitable pharmaceutical preparations, such as solutions, suspensions, powders, or elixirs, in sterile solutions or suspensions for parenteral administration (e.g., for subcutaneous, intravenous, or intramuscular administration). In one embodiment, the antibodies are formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration, as well as transdermal patch preparation and dry powder inhalers.

[0244] In such compositions, one or more antibodies provided herein is (are) mixed with a suitable pharmaceutical carrier. Concentrations of an antibody or antibodies in the compositions can, for example, be effective for delivery of an amount, upon administration, that treats, prevents, protects against or manages chronic prurigo, or one or more symptoms thereof.

[0245] In one embodiment, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.

[0246] The concentration of antibody in the pharmaceutical composition will depend on, e.g., the physicochemical characteristics of the antibody, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.

[0247] In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of from about 10 mg / ml to about 1000 mg / ml. In specificNAI-1543385831V1 109Attorney Docket No. 12638-179-228embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of from about 50 mg / ml to about 500 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of from about 100 mg / ml to about 400 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of greater than 10 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of greater than 50 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of greater than 100 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of lower than 1000 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of lower than 500 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of lower than 400 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, or about 300 mg / ml. In specific embodiments, the antibody contained in a pharmaceutical composition described herein is at a concentration of about 150 mg / ml.

[0248] In one embodiment, a therapeutically effective dosage produces a serum concentration of antibody of from about 0.1 ng / ml to about 50-100 pg / ml.

[0249] Upon mixing or addition of an antibody, the resulting mixture can be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.

[0250] Pharmaceutical compositions described herein are provided for administration to humans and animals, such as mammals (e.g, cat or dog), in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. Pharmaceutical compositions are also provided for administration to humans and animals, such as mammals (e.g, cat or dog), in unit dosage form, such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. The antibody is, in one embodiment, formulatedNAI-1543385831V1 110Attorney Docket No. 12638-179-228and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the antibody sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms can be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

[0251] In a specific embodiment, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic prurigo of an anti -KIT antibody described herein, which comprises: (i) about 150 mg (e.g., 125 mg to 175 mg, 130 mg to 170 mg, 135 mg to 165 mg, 140 mg to 160 mg, or 145 mg to 155 mg, or 150 mg) of the antibody; (ii) a buffering agent; (iii) a salt; (iv) an excipient; and optionally (v) a non-ionic surfactant. In another specific embodiment, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic prurigo of an anti-KIT antibody described herein, which comprises: (i) about 300 mg (e.g., 275 mg to 325 mg, 280 mg to 320 mg, 285 mg to 315 mg, 290 mg to 310 mg, or 295 mg to 305 mg, or 300 mg) of the antibody; (ii) a buffering agent; (iii) a salt; (iv) an excipient; and optionally (v) a non-ionic surfactant. In another specific embodiment, provided herein is a pharmaceutical dosage unit for administration to a subject with chronic prurigo of an anti-KIT antibody described herein, which comprises: (i) about 450 mg (e.g., 400 mg to 500 mg, 410 mg to 490 mg, 420 mg to 480 mg, 430 mg to 470 mg, or 440 mg to 460 mg, or 450 mg) of the antibody; (ii) a buffering agent; (iii) a salt; (iv) an excipient; and optionally (v) a non-ionic surfactant.Preferably, the pharmaceutical dosage unit is for subcutaneous administration.

[0252] In certain embodiments, one or more anti-KIT antibodies described herein are in a liquid pharmaceutical formulation. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minorNAI-1543385831V1 111Attorney Docket No. 12638-179-228amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like.

[0253] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see, e.g., Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA; Remington: The Science and Practice of Pharmacy, 21st ed. (2006) Lippincott Williams & Wilkins, Baltimore, MD.

[0254] Dosage forms or compositions containing antibody in the range of 0.005% to 100% with the balance made up from non-toxic carrier can be prepared. Methods for preparation of these compositions are known to those skilled in the art.

[0255] Parenteral administration, in one embodiment, is characterized by injection, either subcutaneously, intramuscularly or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents. Other routes of administration may include, epidural administration, enteric administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous infusion, intrathecal administration, and intraperitoneal administration. In a specific embodiment, an anti-KIT antibody or pharmaceutical composition described herein is administered to the subject subcutaneously.

[0256] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions can be either aqueous or nonaqueous.

[0257] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.NAI-1543385831V1 112Attorney Docket No. 12638-179-228

[0258] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[0259] Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[0260] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0261] An anti-KIT antibody described herein can be suspended in micronized or other suitable form. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and can be empirically determined.

[0262] In other embodiments, the pharmaceutical formulations are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0263] The lyophilized powder is prepared by dissolving an antibody provided herein, in a suitable solvent. In some embodiments, the lyophilized powder is sterile. The solvent can contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbital, fructose, com syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent can also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile fdtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In one embodiment, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature.NAI-1543385831V1 113Attorney Docket No. 12638-179-228

[0264] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined.

[0265] Antibodies described herein can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intraci sternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[0266] The antibodies and other compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U. S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0267] In one aspect, provided herein is a pharmaceutical composition comprising: (i) an antibody which immunospecifically binds to human KIT (e.g., an anti-KIT antibody described herein, in particular, an anti-KIT antibody described in Section 5.1); (ii) a buffering agent (e.g., a buffering agent described herein, in particular, a buffering agent described in Section 6.1); (iii) a salt (e.g., a salt described herein); and (iv) an excipient (e.g., an excipient described herein). In specific embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., for subcutaneous, intravenous, or intramuscular administration). In a preferred embodiment, the pharmaceutical composition is formulated for subcutaneous administration. In specific embodiments, the pharmaceutical composition is suitable for parenteral administration (e.g., for subcutaneous, intravenous, or intramuscular administration). In a preferred embodiment, the pharmaceutical composition is suitable for subcutaneous administration.NAI-1543385831V1 114Attorney Docket No. 12638-179-228

[0268] In various aspects and embodiments, an anti-KIT antibody described herein (e.g., barzolvolimab) is contained in a pharmaceutical composition that further comprises: (i) a buffering agent; (ii) a salt; and (iii) an excipient.

[0269] Buffering agents are well known in the art, and include without limitation, phosphate, citrate, carbonate, bicarbonate, Tris, acetate, borate, and mixtures thereof. In specific embodiments, the buffering agent contained in a pharmaceutical composition described herein is a pharmaceutically acceptable buffering agent. In specific embodiments, the buffering agent contained in a pharmaceutical composition described herein comprises an alkali metal acetate. In specific embodiments, the buffering agent contained in a pharmaceutical composition described herein is an alkali metal acetate. In a specific embodiment, the alkali metal acetate is sodium acetate.

[0270] In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of from about 100 pM to about 500 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of from about 200 pM to about 200 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of from about 500 pM to about 100 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of from about 1 mM to about 50 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of from about 10 mM to about 40 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of from about 20 mM to about 30 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 100 pM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 200 pM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 500 pM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 1 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 5 mM. In specific embodiments, the buffering agent (e.g, alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 10 mM. In specific embodiments, the buffering agent (e.g,NAI-1543385831V1 115Attorney Docket No. 12638-179-228alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 15 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of greater than 20 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 500 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 200 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 100 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 50 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 40 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of lower than 30 mM. In specific embodiments, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, or about 40 mM. In a specific embodiment, the buffering agent (e.g., alkali metal acetate, preferably sodium acetate) is at a concentration of about 25 mM.

[0271] In specific embodiments, the pharmaceutical composition has a pH of from about 4 to about 7. In specific embodiments, the pharmaceutical composition has a pH of from about 5 to about 6. In specific embodiments, the pharmaceutical composition has a pH of greater than 4. In specific embodiments, the pharmaceutical composition has a pH of greater than 5. In specific embodiments, the pharmaceutical composition has a pH of lower than 7. In specific embodiments, the pharmaceutical composition has a pH of lower than 6. In a specific embodiment, the pharmaceutical composition has a pH of about 5. In a specific embodiment, the pharmaceutical composition has a pH of about 6. In a preferred embodiment, the pharmaceutical composition has a pH of about 5.5.

[0272] In a specific embodiment, the buffering agent is sodium acetate, which is at a concentration of about 25 mM, and the pharmaceutical composition has a pH of about 5.5.

[0273] Salts may be added to a pharmaceutical composition described herein, for example, to achieve a desirable ionic strength.

[0274] In specific embodiments, the salt contained in a pharmaceutical composition described herein is a pharmaceutically acceptable salt. In specific embodiments, aNAI-1543385831V1 116Attorney Docket No. 12638-179-228pharmaceutical composition described herein comprises an alkali metal salt. In specific embodiments, the salt contained in a pharmaceutical composition described herein is an alkali metal salt, such as a sodium salt, a potassium salt, or a lithium salt. In specific embodiments, the alkali metal salt is an alkali metal chloride. In a specific embodiment, the alkali metal salt is a sodium salt (e.g., sodium chloride). In a specific embodiment, the alkali metal salt is a potassium salt (e.g, potassium chloride).

[0275] In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of from about 5 mM to about 500 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of from about 10 mM to about 200 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of from about 25 mM to about 100 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of from about 30 mM to about 80 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of from about 40 mM to about 60 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of greater than 5 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of greater than 10 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of greater than 25 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of greater than 30 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of greater than 40 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of lower than 500 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of lower than 200 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of lower than 100 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of lower than 80 mM. In specific embodiments, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of lower than 60 mM. In specific embodiments, the salt (e.g, alkali metal salt, preferably sodium chloride) is at a concentration of about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM,NAI-1543385831V1 117Attorney Docket No. 12638-179-228about 90 mM, or about 100 mM. In a specific embodiment, the salt (e.g., alkali metal salt, preferably sodium chloride) is at a concentration of about 50 mM.

[0276] The term “excipient” as used herein includes substances added to a pharmaceutical composition alongside the active ingredient to support, protect or enhance stability, to support or enhance bioavailability, to enhance patient acceptability, or to facilitate the manufacturing process. Excipients can be, for example, adjuvants, anti -adherents, binders, coatings, colors, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, or vehicles. Non-limiting exemplary excipients include: low molecular weight polypeptides (e.g., polypeptides having fewer than 10 amino acid residues); proteins, such as serum albumin, gelatin, and immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as alanine, histidine, glycine, glutamine, asparagine, arginine, and lysine; monosaccharides, di saccharides, dextrins, and other carbohydrates, including glucose, mannose, sucrose, and trehalose; sugar alcohols, including mannitol, sorbitol, xylitol, lactitol, isomalt, and maltitol; chelating agents, such as EDTA; and non-ionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. Other examples of excipients are described in Remington and Gennaro, Remington’s Pharmaceutical Sciences (18th ed. 1990).

[0277] In specific embodiments, the excipient contained in a pharmaceutical composition described herein comprises an agent that supports, protects or enhances stability (e.g., stability at 5 ± 3 °C, stability at ambient temperature, and / or stability at 40 ± 2 °C) of the pharmaceutical composition, relative to a control pharmaceutical composition without the agent. In specific embodiments, the excipient contained in a pharmaceutical composition described herein comprises an agent that supports, protects or enhances stability of the pharmaceutical composition after freeze / thaw cycles, relative to a control pharmaceutical composition without the agent. In specific embodiments, the excipient contained in a pharmaceutical composition described herein comprises an agent that reduces or prevents aggregation in the pharmaceutical composition (e.g., at 5 ± 3 °C and / or ambient temperature), relative to a control pharmaceutical composition without the agent.

[0278] In specific embodiments, the excipient contained in a pharmaceutical composition described herein is a pharmaceutically acceptable excipient.

[0279] In certain embodiments, the excipient contained in a pharmaceutical composition described herein comprises a sugar, a sugar alcohol, an amino acid, or any combination thereof.NAI-1543385831V1 118Attorney Docket No. 12638-179-228In certain embodiments, the excipient is a sugar, a sugar alcohol, an amino acid, or any combination thereof. In certain embodiments, the excipient comprises mannitol, sorbitol, sucrose, trehalose, glycine, arginine, alanine, or histidine, or any combination thereof. In certain embodiments, the excipient is mannitol, sorbitol, sucrose, trehalose, glycine, arginine, alanine, or histidine, or any combination thereof. In certain embodiments, the excipient comprises mannitol, sorbitol, sucrose, trehalose, glycine, arginine, histidine, or any combination thereof. In certain embodiments, the excipient is mannitol, sorbitol, sucrose, trehalose, glycine, arginine, histidine, or any combination thereof. In certain embodiments, the excipient comprises mannitol, sucrose, arginine, histidine, or any combination thereof. In certain embodiments, the excipient is mannitol, sucrose, arginine, histidine, or any combination thereof.

[0280] In specific embodiments, the excipient contained in a pharmaceutical composition described herein comprises mannitol. In specific embodiments, the excipient comprises arginine. In specific embodiments, the excipient comprises a combination of histidine and sucrose. In specific embodiments, the excipient comprises glycine. In specific embodiments, the excipient comprises histidine. In specific embodiments, the excipient comprises a combination of histidine and trehalose. In specific embodiments, the excipient comprises trehalose. In specific embodiments, the excipient comprises sorbitol. In specific embodiments, the excipient is mannitol. In specific embodiments, the excipient is arginine. In specific embodiments, the excipient is a combination of histidine and sucrose. In specific embodiments, the excipient is glycine. In specific embodiments, the excipient is histidine. In specific embodiments, the excipient is a combination of histidine and trehalose. In specific embodiments, the excipient is trehalose. In specific embodiments, the excipient is sorbitol.

[0281] In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of from about 0.1 w / v % to about 30 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of from about 0.5 w / v % to about 20 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of from about 1 w / v % to about 10 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (c.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of from about 2 w / v % to about 5 w / v %. In specific embodiments, the excipient comprises or is a sugarNAI-1543385831V1 119Attorney Docket No. 12638-179-228or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of greater than 0.1 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of greater than 0.5 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of greater than 1 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of greater than 2 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g, mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of lower than 30 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of lower than 20 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of lower than 10 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of lower than 5 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of about 1 w / v %, about 2 w / v %, about 3 w / v %, about 4 w / v %, about 5 w / v %, about 6 w / v %, about 7 w / v %, about 8 w / v %, about 9 w / v %, or about 10 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of about 3 w / v %. In specific embodiments, the excipient comprises or is a sugar or sugar alcohol (e.g., mannitol, sucrose, sorbitol, or trehalose) that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient comprises mannitol that is at a concentration of about 3 w / v %. In a specific embodiment, the excipient is mannitol that is at a concentration of about 3 w / v %. In a specific embodiment, the excipient comprises sucrose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient is sucrose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient comprises sorbitol that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient is sorbitol that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient comprises trehalose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient is trehalose that is at a concentration of about 4NAI-1543385831V1 120Attorney Docket No. 12638-179-228w / v %. A person of ordinary skill in the art would understand that w / v % or % w / v is used to represent weight by volume percent.

[0282] In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of from about 10 mM to about 1000 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of from about 20 mM to about 500 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of from about 50 mM to about 200 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of greater than 10 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of greater than 20 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of greater than 50 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of lower than 1000 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of lower than 500 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of lower than 200 mM. In specific embodiments, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of about 25 mM, about 50 mM, about 75 mM, about 100 mM, about 125 mM, or about 150 mM. In a specific embodiment, the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of about 75 mM. the excipient comprises or is an amino acid (e.g., arginine, histidine, or glycine) that is at a concentration of about 100 mM. In a specific embodiment, the excipient comprises arginine that is at a concentration of about 100 mM. In a specific embodiment, the excipient is arginine that is at a concentration of about 100 mM. In a specific embodiment, the excipient comprises histidine that is at a concentration of about 75 mM. In a specific embodiment, the excipient is histidine that is at a concentration of about 75 mM. In a specific embodiment, the excipient comprises histidine that is at a concentration of about 75 mM and sucrose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient is a combination of histidine that is at a concentration of about 75 mM and sucrose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient comprisesNAI-1543385831V1 121Attorney Docket No. 12638-179-228glycine that is at a concentration of about 100 mM. In a specific embodiment, the excipient is glycine that is at a concentration of about 100 mM. In a specific embodiment, the excipient comprises histidine that is at a concentration of about 75 mM and trehalose that is at a concentration of about 4 w / v %. In a specific embodiment, the excipient is a combination of histidine that is at a concentration of about 75 mM and trehalose that is at a concentration of about 4 w / v %.

[0283] In certain embodiments, provided herein is a pharmaceutical composition comprising: (i) an antibody which immunospecifically binds to human KIT (for example, an anti-KIT antibody described herein), preferably at a concentration of from about 50 mg / ml to about 500 mg / ml, further preferably at a concentration of about 150 mg / ml; (ii) a buffering agent, wherein the buffering agen...

Claims

Attorney Docket No. 12638-179-228WHAT IS CLAIMED:

1. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a maintenance dose of between about 150 mg and about 300 mg of an antibody which immunospecifically binds to human KIT,wherein the antibody comprises:(a) (i) a light chain variable region (“VL”) comprising VL CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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; orNAI-1543385831V1 142Attorney Docket No. 12638-179-228(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.

2. The method of claim 1, 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.

3. The method of claim 1 or 2, wherein the antibody comprises a modified human IgGl Fc region or domain comprising non-naturally occurring amino acids 234 A, 235Q, 322Q, 252 Y, 254T and 256E as numbered by the EU index as set forth in Kabat.

4. The method of any one of claims 1-3, wherein the antibody comprises a light chain comprising the amino acid sequence:DIVMTQSPSSLSASVGDRVTITCKASQNVRTNVAWYQQKPGKAPKALIYSASYRYSGVP DRFTGSGSGTDFTLTISSLQPEDFADYFCQQYNSYPRTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 22).

5. The method of any one of claims 1-4, wherein the antibody comprises a heavy chain comprising the amino acid sequence:QVQLVQSGAEVKKPGASVKLSCKASGYTFTOYYTNWVRQAPGKGLEWIARIYPGSGNT YYNEKFKGRATLTADKSTSTAYMQLSSLRSEDTAVYFCARGVYYFDYWGQGTTVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAQG GPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 21).6 The method of any one of claims 1-5, wherein the antibody is barzolvolimab.NAI-1543385831V1 143Attorney Docket No. 12638-179-2287. The method of any one of claims 1-6, wherein the method further comprises administering to the subject a loading dose of about 450 mg of the antibody, wherein the loading dose is administered to the subject about 4 weeks before the maintenance dose is administered, during which period of about 4 weeks no dose of the antibody is administered to the subject.

8. The method of any one of claims 1-7, wherein the maintenance dose is about 150 mg of the antibody.

9. The method of any one of claims 1-7, wherein the maintenance dose is about 300 mg of the antibody.

10. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvolimab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 150 mg of the antibody.

11. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject a loading dose of about 450 mg of an antibody that is barzolvoli ab, and then after about 4 weeks during which no dose of the antibody is administered, further administering to the subject a maintenance dose of about 300 mg of the antibody.

12. The method of any one of claims 1-11, which comprises further administering to the subject one or more of the maintenance doses of the antibody, wherein the interval between every' two consecutive maintenance doses is about 4 weeks.

13. The method of claim 12, wherein at least 3 of the maintenance doses of the antibody are administered to the subject in total.

14. The method of claim 12, wherein at least 4 of the maintenance doses of the antibody are administered to the subject in total.NAI-1543385831V1 144Attorney Docket No. 12638-179-22815. The method of claim 12, wherein at least 5 of the maintenance doses of the antibody are administered to the subject in total.

16. The method of claim 12, wherein at least 6 of the maintenance doses of the antibody are administered to the subject in total.

17. The method of any one of claims 1-16, wherein the chronic prurigo is prurigo nodularis.

18. The method of claim 17, wherein the prurigo nodularis is moderate to severe prurigo nodularis.

19. The method of any one of claims 1-18, wherein the subject has an inadequate response to prescription topical medications.

20. The method of any one of claims 1-18, wherein the subject is one for whom topical medications are medically inadvisable.

21. The method of any one of claims 1-20, wherein the antibody is administered bysubcutaneous administration.

22. The method of any one of claims 1-21, wherein the antibody is contained in a pharmaceutical composition that further comprises: (i) a buffering agent, (ii) a salt; and (iii) an excipient.

23. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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; andNAI-1543385831V1 145Attorney Docket No. 12638-179-228(ii) a heavy chain variable region (“VH”) comprising VH CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.

24. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit comprises: (i) about 300 mg of the antibody; (ii) a buffering agent, (iii) a salt; and (iv) an excipient;wherein the antibody comprises:NAI-1543385831V1 146Attorney Docket No. 12638-179-228(a) (i) a light chain variable region (“VL”) comprising VL CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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.NAI-1543385831V1 147Attorney Docket No. 12638-179-22825. A pharmaceutical dosage unit for administration to a subject with chronic prurigo of an antibody which immunospecifically binds to human KIT, which dosage unit 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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 CDRI, 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; andNAI-1543385831V1 148Attorney Docket No. 12638-179-228(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.

26. The pharmaceutical dosage unit of any one of claims 23-25, which is for subcutaneous administration.

27. The pharmaceutical dosage unit of any one of claims 23-26, wherein the antibody is barzolvolimab.

28. A method for treating, preventing or managing chronic prurigo in a subject in need thereof, comprising administering to the subject the pharmaceutical dosage unit of any one of claims 23- 27.

29. The method of any one of claims 1-22 and 28 or the pharmaceutical dosage unit of any one of claims 23-27, wherein the subject is a human.NAI-1543385831V1 149

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