Treatment of eosinophil or mast cell-related disorders

Administering an antibody that binds to the human KIT receptor addresses the need for therapies to manage eosinophil- and mast cell-related disorders by reducing inflammation and inhibiting mast cell activation, effectively treating conditions such as NMO, NMOSD, MS, and NF.

JP7846960B2Active Publication Date: 2026-04-16CELLDEX THERAPEUTICS INC
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Patents
Current Assignee / Owner
Filing Date
2020-09-23
Publication Date
2026-04-16

AI Technical Summary

Technical Problem

There is a need for effective therapies to manage or treat eosinophil- or mast cell-related disorders, such as neuromyelitis optica (NMO), neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and neurofibromatosis (NF), which are characterized by inflammation and inappropriate regulation of mast cell activity.

Method used

Administering a therapeutically effective amount of an antibody or its antigen-binding fragment that specifically binds to the human KIT receptor (SEQ ID NO: 1) to prevent, treat, or manage these disorders, including reducing inflammation and inhibiting mast cell activation.

Benefits of technology

The antibody effectively prevents and treats eosinophil- and mast cell-related disorders by targeting the KIT receptor, reducing inflammation and inhibiting mast cell activation, thereby managing conditions like NMO, NMOSD, MS, and NF.

✦ Generated by Eureka AI based on patent content.

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Patent Text Reader

Abstract

To provide methods for managing, treating, or preventing an eosinophil or mast cell related disorder and / or one or more symptoms thereof, for example a mast cell related disorder of the nervous system, e.g., central nervous system, for example neuromyelitis optica (NMO), neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and neurofibromatosis (NF).SOLUTION: The present invention provides a method including administering to a subject in need thereof a therapeutically effective amount of an antibody which specifically binds to a KIT receptor tyrosine kinase.SELECTED DRAWING: None
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Description

[Technical Field]

[0001] This application, filed on 23 May 2014, is incorporated herein by reference in its entirety. U.S. Provisional Application No. 62 / 002,395 and U.S. Provisional Application No. 62 / 162,538 filed on May 15, 2015 They assert the interests of the number.

[0002] This application concerns a "Sequence_Listing" file created on May 21, 2015, with a size of 21,490 bytes. A text file titled "g_12638-123-228.TXT" was submitted along with this application. Sequence listings are incorporated by reference.

[0003] (1. Field) Provided herein are the nervous system, such as mast cell-related disorders of the central nervous system, Eosinophil or mast cell-related disorders, such as neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders. To manage, treat, or prevent neurofibromatosis (NMOSD), multiple sclerosis (MS), and neurofibromatosis (NF). A method comprising KIT, an antibody that specifically binds to receptor tyrosine kinase, for the purpose of and use. [Background technology]

[0004] (2.Background) Eosinophils play a beneficial role in host defense against infection, antitumor cytotoxicity, and wound healing. These are bone marrow-derived granulocytes. Abundant eosinophils are, for example, found in the respiratory mucous membranes of patients suffering from asthma or rhinitis. It may be a contributing factor to inflammation, such as inflammation in membrane tissue (for example, Yuan et al., J. See Exp. Med., 1997, 186:313-333.

[0005] Mast cells are present in the connective tissue of various tissues and vascular distribution organs. Mast cells are also found in the dermis, intestinal mucosa, and submucosa, conjunctiva, alveoli and airways, and auricles of the heart, etc., at the interface between the internal environment and the external environment (where mast cells can respond to foreign organisms and antigens). Inflammatory and allergic reactions involve mast cell degranulation and mast cell activation, resulting in the release of inflammatory factors and local or systemic immediate-type hypersensitivity reactions. Imbalances or inappropriate regulation of mast cell activity are associated with harmful hypersensitivity reactions to antigens, observed in disorders such as anaphylaxis, atopy, and rhinitis.

[0006] There is a need for therapies to effectively manage or treat eosinophil- or mast cell-related disorders. SUMMARY OF THE INVENTION

[0007] (3. Summary) In one aspect, provided herein is a method for preventing, treating, or managing eosinophil- or mast cell-related disorders in a subject, such as in the central nervous system, of the nervous system, the method comprising administering to a subject needing the same a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to the human KIT receptor (SEQ ID NO: 1).

[0008] In another aspect, provided herein is a method for preventing, treating, or managing NMO in a subject, the method comprising administering to a subject needing the same a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to the human KIT receptor (SEQ ID NO: 1).

[0009] In certain embodiments, what is provided herein is a method for preventing, treating, or preventing NMOSD. A method of control, which involves an anti-blocking agent that specifically binds to a therapeutically effective amount of the human KIT receptor (SEQ ID NO: 1). The method comprises administering the body or an antigen-binding fragment thereof to a target that requires it. .

[0010] In another aspect, what is provided herein is a method for preventing, treating, or managing MS in a subject. A method for controlling the process, which involves an antibody that specifically binds to a therapeutically effective amount of the human KIT receptor (SEQ ID NO: 1). Alternatively, the method includes administering the antigen-binding fragment to a target that requires it.

[0011] In certain specific embodiments, what is provided herein is a method for preventing, treating, NF in a subject. Or a method of managing a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) that specifically binds to the human KIT receptor (SEQ ID NO: 1) The method comprising administering an antibody or an antigen-binding fragment thereof to a subject requiring it. be.

[0012] In one embodiment, the foregoing provides a method for inhibiting the growth of neurofibromas in a subject. This law provides a therapeutically effective dose of human KIT receptor (SEQ ID NO: 1) to subjects diagnosed with NF. The method comprises administering an antibody or an antigen-binding fragment thereof that binds to the antigen.

[0013] In another aspect, what is provided herein is inflammation in an object, for example, the nervous system, for example A method for reducing inflammation of the central nervous system, which involves mast cell-related disorders of the central nervous system or nervous system. For patients diagnosed with this condition, an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1) in a therapeutically effective dose is administered. The method includes administering the antigen-binding fragment or the method described above.

[0014] In certain embodiments, what is provided herein is a method for inhibiting mast cell activation in a subject. A method of harming the nervous system, such as the central nervous system, and is diagnosed as mast cell-related disorder. In elephants, an antibody or antigen that specifically binds to a therapeutically effective amount of the human KIT receptor (SEQ ID NO: 1) was tested. The method includes administering a composite fragment.

[0015] In certain specific cases, mast cell-related disorders of the nervous system, such as the central nervous system, are called NMOs and NMOSDs. It is MS, or NF. In certain aspects, the type of NF is NF1, NF2, or schwannomatous. .

[0016] In one embodiment, the anti-KIT antibody for use in the method provided herein is a bivalent monovalent antibody. It is a specific antibody. In certain embodiments, it is an antibody for use in the methods provided herein. KIT antibodies are humanized antibodies. In certain embodiments, the methods provided herein The anti-KIT antibody for use is a naked antibody. In one embodiment, the method provided herein Anti-KIT antibodies for use under the law are not bispecific antibodies.

[0017] In certain embodiments, the anti-KIT antibody for use in the methods provided herein is sequence number The VL CDRs containing numbers 2-4, respectively, and the light chain variable region ("VL") containing numbers 1-3, and sequence numbers 5-7 Each includes a heavy chain variable region ("VH") which contains VH CDR 1-3.

[0018] In one embodiment, the subjects to whom the anti-KIT antibody described herein is administered are adult humans. In certain embodiments, the target recipients of the anti-KIT antibody described herein are children.

[0019] The following are non-limiting embodiments of the methods described herein: 1. A method for treating mast cell-related disorders of the nervous system in a subject, wherein the therapeutically effective amount of human An antibody or its antigen-binding fragment that specifically binds to the KIT receptor (SEQ ID NO: 1), and which requires it to The method comprising administering to a target. 2. A method for treating eosinophil-related disorders of the nervous system in a subject, wherein the therapeutically effective dose of human KIT An antibody or its antigen-binding fragment that specifically binds to the receptor (SEQ ID NO: 1), which requires The method comprising administering to a subject. 3. The method of Embodiment 1 or 2, wherein the antibody is a bivalent monospecific antibody. 4. The method of Embodiment 3, wherein the antibody is a humanized antibody. 5. The method of Embodiment 4, wherein the antibody is a naked antibody. 6. The method of Embodiment 3, wherein the antibody is a naked antibody. 7. The method of Embodiment 1 or 2, wherein the antibody is a humanized antibody. 8. The method of Embodiment 7, wherein the antibody is a naked antibody. 9. The method of Embodiment 1 or 2, wherein the antibody is a naked antibody. 10. This includes administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). or any one of the embodiments 1 to 9. 11. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 1 or 2. 12. The method of Embodiment 11, wherein the antibody is a bivalent monospecific antibody. 13. The method of Embodiment 12, wherein the antibody is a humanized antibody. 14. The method of Embodiment 13, wherein the antibody is a naked antibody. 15. The method of Embodiment 12, wherein the antibody is a naked antibody. 16. The method of Embodiment 11, wherein the antibody is a humanized antibody. 17. The method of embodiment 16, wherein the antibody is a naked antibody. 18. The method of Embodiment 11, wherein the antibody is a naked antibody. 19. This includes administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). or any one of embodiments 11 to 19. 20. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 8. 21. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 9. 22. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 10. 23. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11. 24. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 12. 25. The method of Embodiment 11, wherein the antibody comprises a VL containing SEQ ID NO: 13. 26. The method of Embodiment 11, wherein the antibody comprises a VL containing SEQ ID NO: 14. 27. The method of Embodiment 11, wherein the antibody comprises a VL containing SEQ ID NO: 15. 28. The method of Embodiment 11, wherein the antibody comprises a VL containing SEQ ID NO: 16. 29. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. 30. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. 31. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. 32. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. 33. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. 34. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. 35. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. 36. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. 37. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. . 38. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. . 39. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. . 40. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. . 41. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. . 42. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. . 43. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. . 44. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. . 45. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 11. 46. ​​The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. . 47. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. . 48. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. . 49. The method of Embodiment 11, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. . 50. This includes administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). or any one of embodiments 20 to 49. 51. A method for managing mast cell-related disorders of the nervous system in a subject, wherein a therapeutically effective dose of An antibody or its antigen-binding fragment that specifically binds to the KIT receptor (SEQ ID NO: 1), and which requires it. The method comprising administering to a subject as described above. 52. A method for managing eosinophil-related disorders of the nervous system in a subject, comprising a therapeutically effective dose of human KIT An antibody or its antigen-binding fragment that specifically binds to the receptor (SEQ ID NO: 1), which requires The method comprising administering to a subject. 53. The method of Embodiment 51 or 52, wherein the antibody is a bivalent monospecific antibody. 54. The method of Embodiment 53, wherein the antibody is a humanized antibody. 55. The method of embodiment 54, wherein the antibody is a naked antibody. 56. The method of embodiment 53, wherein the antibody is a naked antibody. 57. The method of embodiment 51 or 52, wherein the antibody is a humanized antibody. 58. The method of Embodiment 57, wherein the antibody is a naked antibody. 59. The method of embodiment 51 or 52, wherein the antibody is a naked antibody. 60. This includes administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). The method described in any one of embodiments 51 to 59. 61. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 51 or 52. 62. The method of Embodiment 61, wherein the antibody is a bivalent monospecific antibody. 63. The method of embodiment 62, wherein the antibody is a humanized antibody. 64. The method of embodiment 61, wherein the antibody is a naked antibody. 65. The method of embodiment 62, wherein the antibody is a naked antibody. 66. The method of Embodiment 61, wherein the antibody is a humanized antibody. 67. The method of embodiment 66, wherein the antibody is a naked antibody. 68. The method of embodiment 61, wherein the antibody is a naked antibody. 69. This includes administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). or any one of embodiments 61 to 68. 70. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 8. 71. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 9. 72. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 10. 73. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11. 74. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 12. 75. The method of Embodiment 61, wherein the antibody comprises a VL containing SEQ ID NO: 13. 76. The method of Embodiment 61, wherein the antibody comprises a VL containing SEQ ID NO: 14. 77. The method of Embodiment 61, wherein the antibody comprises a VL containing SEQ ID NO: 15. 78. The method of Embodiment 61, wherein the antibody comprises a VL containing SEQ ID NO: 16. 79. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. 80. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. 81. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. 82. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. 83. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. 84. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. 85. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. 86. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. 87. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. . 88. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. . 89. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. . 90. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. . 91. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. . 92. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. . 93. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. . 94. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. . 95. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 11. 96. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. . 97. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. . 98. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. . 99. The method of Embodiment 61, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. . 100. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 70 to 99. 101. A method for preventing mast cell-related damage to the nervous system in a subject, comprising a therapeutically effective dose of human KI. An antibody or its antigen-binding fragment that specifically binds to the T receptor (SEQ ID NO: 1), which requires it. The method comprising administering to a target. 102. A method for preventing eosinophil-related neurological disorders in a subject, comprising receiving a therapeutically effective dose of human KIT. An antibody or its antigen-binding fragment that specifically binds to the substance (SEQ ID NO: 1) is used in the target that requires it. The method comprising administering to an elephant. 103. The method of Embodiment 101 or 102, wherein the antibody is a bivalent monospecific antibody. 104. The method of embodiment 103, wherein the antibody is a humanized antibody. 105. The method of embodiment 104, wherein the antibody is a naked antibody. 106. The method of embodiment 103, wherein the antibody is a naked antibody. 107. The method of embodiment 101 or 102, wherein the antibody is a humanized antibody. 108. The method of embodiment 107, wherein the antibody is a naked antibody. 109. The method of embodiment 101 or 102, wherein the antibody is a naked antibody. 110. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 101 to 109. 111. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 101 or 102. 112. The method of embodiment 111, wherein the antibody is a bivalent monospecific antibody. 113. The method of embodiment 112, wherein the antibody is a humanized antibody. 114. The method of embodiment 113, wherein the antibody is a naked antibody. 115. The method of embodiment 112, wherein the antibody is a naked antibody. 116. The method of embodiment 111, wherein the antibody is a humanized antibody. 117. The method of embodiment 116, wherein the antibody is a naked antibody. 118. The method of embodiment 111, wherein the antibody is a naked antibody. 119. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 111 to 118. 120. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 8. 121. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 9. 122. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 10. 123. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11. 124. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 12. 125. The method of Embodiment 111, wherein the antibody comprises a VL containing SEQ ID NO: 13. 126. The method of Embodiment 111, wherein the antibody comprises a VL containing SEQ ID NO: 14. 127. The method of Embodiment 111, wherein the antibody comprises a VL containing SEQ ID NO: 15. 128. The method of Embodiment 111, wherein the antibody comprises a VL containing SEQ ID NO: 16. 129. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 130. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 131. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 132. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 133. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 134. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 135. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 136. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 137. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 138. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 139. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 140. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 141. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 142. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 143. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 144. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 145. The method of Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 11. 146. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 147. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 148. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 149. Embodiment 111, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 150. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 120 to 149. 151. A method for treating neurofibromatosis (NF) in a subject, wherein the subject receives a therapeutically effective dose of human KIT. An antibody (SEQ ID NO: 1) or its antigen-binding fragment that specifically binds to the body, and the target that requires it. The method comprising administering to [a person]. 152. The method of Embodiment 151, wherein the antibody is a bivalent monospecific antibody. 153. The method of embodiment 152, wherein the antibody is a humanized antibody. 154. The method of embodiment 153, wherein the antibody is a naked antibody. 155. The method of Embodiment 152, wherein the antibody is a naked antibody. 156. The method of embodiment 151, wherein the antibody is a humanized antibody. 157. The method of embodiment 157, wherein the antibody is a naked antibody. 158. The method of Embodiment 151, wherein the antibody is a naked antibody. 159. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 151 to 158. 160. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 151. 161. The method of Embodiment 160, wherein the antibody is a bivalent monospecific antibody. 162. The method of embodiment 161, wherein the antibody is a humanized antibody. 163. The method of embodiment 162, wherein the antibody is a naked antibody. 164. The method of embodiment 161, wherein the antibody is a naked antibody. 165. The method of Embodiment 160, wherein the antibody is a humanized antibody. 166. The method of embodiment 165, wherein the antibody is a naked antibody. 167. The method of embodiment 160, wherein the antibody is a naked antibody. 168. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 160 to 167. 169. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 8. 170. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 9. 171. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 10. 172. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11. 173. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 12. 174. The method of Embodiment 160, wherein the antibody comprises a VL containing SEQ ID NO: 13. 175. The method of Embodiment 160, wherein the antibody comprises a VL containing SEQ ID NO: 14. 176. The method of Embodiment 160, wherein the antibody comprises a VL containing SEQ ID NO: 15. 177. The method of Embodiment 160, wherein the antibody comprises a VL containing SEQ ID NO: 16. 178. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 179. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 180. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 181. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 182. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 183. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 184. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 185. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 186. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 187. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 188. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 189. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 190. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 191. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 192. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 193. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 194. The method of Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 11. 195. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 196. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 197. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 198. Embodiment 160, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 199. Administering an effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 169 to 198. 200. One of the embodiments 151 to 199, wherein NF is NF1. 201. Any one of embodiments 151 to 199, wherein NF is NF2. 202. NF is schwannomatosis, one of the embodiments 151-199. 203. A method for managing NF in a subject, comprising a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) Administering an antibody or its antigen-binding fragment that specifically binds to a target, to a subject that requires it. The method comprising the above. 204. The method of Embodiment 203, wherein the antibody is a bivalent monospecific antibody. 205. The method of embodiment 204, wherein the antibody is a humanized antibody. 206. The method of embodiment 203, wherein the antibody is a naked antibody. 207. The method of embodiment 204, wherein the antibody is a naked antibody. 208. The method of embodiment 203, wherein the antibody is a humanized antibody. 209. The method of embodiment 208, wherein the antibody is a naked antibody. 210. The method of embodiment 203, wherein the antibody is a naked antibody. 211. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 203 to 210. 212. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 203. 213. The method of Embodiment 212, wherein the antibody is a bivalent monospecific antibody. 214. The method of embodiment 213, wherein the antibody is a humanized antibody. 215. The method of embodiment 212, wherein the antibody is a naked antibody. 216. The method of embodiment 213, wherein the antibody is a naked antibody. 217. The method of embodiment 212, wherein the antibody is a humanized antibody. 218. The method of embodiment 217, wherein the antibody is a naked antibody. 219. The method of embodiment 212, wherein the antibody is a naked antibody. 220. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 212 to 219. 221. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 8. 222. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 9. 223. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 10. 224. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11. 225. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 12. 226. The method of Embodiment 212, wherein the antibody comprises a VL containing SEQ ID NO: 13. 227. The method of Embodiment 212, wherein the antibody comprises a VL containing SEQ ID NO: 14. 228. The method of Embodiment 212, wherein the antibody comprises a VL containing SEQ ID NO: 15. 229. The method of Embodiment 212, wherein the antibody comprises a VL containing SEQ ID NO: 16. 230. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 231. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 232. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 233. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 234. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 235. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 236. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 237. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 238. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 239. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 240. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 241. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 242. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 243. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 244. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 245. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 246. The method of Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 11. 247. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 248. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 249. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 250. Embodiment 212, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 251. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 221 to 250. 252. Any one of embodiments 203 to 251, wherein NF is NF1. 253. Any one of embodiments 203 to 251, wherein NF is NF2. 254. NF is schwannomatosis, according to any one of embodiments 203 to 251. 255. A method for preventing NF in a subject, which involves a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) This includes administering an antibody or antigen-binding fragment thereof that binds heteroto to a target that requires it. The aforementioned method. 256. The method of Embodiment 255, wherein the antibody is a bivalent monospecific antibody. 257. The method of embodiment 256, wherein the antibody is a humanized antibody. 258. The method of embodiment 257, wherein the antibody is a naked antibody. 259. The method of embodiment 256, wherein the antibody is a naked antibody. 260. The method of embodiment 255, wherein the antibody is a humanized antibody. 261. The method of embodiment 260, wherein the antibody is a naked antibody. 262. The method of embodiment 255, wherein the antibody is a naked antibody. 263. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1) Including any one of embodiments 255 to 262. 264. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, 255 methods. 265. The method of Embodiment 264, wherein the antibody is a bivalent monospecific antibody. 266. The method of embodiment 265, wherein the antibody is a humanized antibody. 267. The method of embodiment 266, wherein the antibody is a naked antibody. 268. The method of embodiment 265, wherein the antibody is a naked antibody. 269. The method of embodiment 264, wherein the antibody is a humanized antibody. 270. The method of embodiment 269, wherein the antibody is a naked antibody. 271. The method of embodiment 264, wherein the antibody is a naked antibody. 272. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 264 to 271. 273. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 8. 274. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 9. 275. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 10. 276. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11. 277. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 12. 278. The method of Embodiment 264, wherein the antibody comprises a VL containing SEQ ID NO: 13. 279. The method of Embodiment 264, wherein the antibody comprises a VL containing SEQ ID NO: 14. 280. The method of Embodiment 264, wherein the antibody comprises a VL containing SEQ ID NO: 15. 281. The method of Embodiment 264, wherein the antibody comprises a VL containing SEQ ID NO: 16. 282. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 283. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 284. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 285. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 286. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 287. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 288. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 289. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 290. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 291. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 292. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 293. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 294. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 295. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 296. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 297. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 298. The method of Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 11. 299. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 300. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 301. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 302. Embodiment 264, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 303. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 273 to 302. 304. Any one of embodiments 255 to 303, wherein NF is NF1. 305. Any one of embodiments 255 to 303, wherein NF is NF2. 306. One of embodiments 255 to 303, wherein NF is schwannomatosis. 307. A method for inhibiting the growth of neurofibromas in subjects, wherein the subject has been diagnosed with NF. A therapeutically effective amount of an antibody or its antigen-binding fragment that specifically binds to the human KIT receptor (SEQ ID NO: 1) The method, including administering. 308. The method of Embodiment 307, wherein the antibody is a bivalent monospecific antibody. 309. The method of embodiment 308, wherein the antibody is a humanized antibody. 310. The method of embodiment 309, wherein the antibody is a naked antibody. 311. The method of embodiment 308, wherein the antibody is a naked antibody. 312. The method of embodiment 307, wherein the antibody is a humanized antibody. 313. The method of embodiment 312, wherein the antibody is a naked antibody. 314. The method of embodiment 307, wherein the antibody is a naked antibody. 315. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 307 to 314. 316. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 307. 317. The method of Embodiment 316, wherein the antibody is a bivalent monospecific antibody. 318. The method of embodiment 317, wherein the antibody is a humanized antibody. 319. The method of embodiment 318, wherein the antibody is a naked antibody. 320. The method of embodiment 317, wherein the antibody is a naked antibody. 321. The method of embodiment 316, wherein the antibody is a humanized antibody. 322. The method of embodiment 321, wherein the antibody is a naked antibody. 323. The method of embodiment 316, wherein the antibody is a naked antibody. 324. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 316 to 323. 325. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 8. 326. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 9. 327. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 10. 328. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11. 329. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 12. 330. The method of Embodiment 316, wherein the antibody comprises a VL containing SEQ ID NO: 13. 331. The method of Embodiment 316, wherein the antibody comprises a VL containing SEQ ID NO: 14. 332. The method of Embodiment 316, wherein the antibody comprises a VL containing SEQ ID NO: 15. 333. The method of Embodiment 316, wherein the antibody comprises a VL containing SEQ ID NO: 16. 334. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 335. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 336. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 337. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 338. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 339. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 340. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 341. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 342. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 343. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 344. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 345. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 346. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 347. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 348. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 349. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 350. The method of Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 11. 351. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 352. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 353. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 354. Embodiment 316, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 355. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 325 to 354. 356. Any one of embodiments 307 to 355, wherein the neurofibroma includes an outer neurofibroma. 357. Any one of embodiments 307 to 355, wherein the neurofibroma includes an internal neurofibroma. 358. Any one of embodiments 307 to 355, wherein the neurofibroma includes a neurofibroma of the dermis. 359. Any one of embodiments 307 to 355, wherein the neurofibroma includes a neurofibroma of the skin. 360. Any one of embodiments 307 to 355, wherein the neurofibroma includes a plexiform neurofibroma. 361. A method for treating neuromyelitis optica (NMO) in a subject, wherein the subject receives a therapeutically effective dose of human KIT. An antibody (SEQ ID NO: 1) or its antigen-binding fragment that specifically binds to the body, and the target that requires it. The method comprising administering to [a person]. 362. The method of Embodiment 361, wherein the antibody is a bivalent monospecific antibody. 363. The method of embodiment 362, wherein the antibody is a humanized antibody. 364. The method of embodiment 363, wherein the antibody is a naked antibody. 365. The method of embodiment 362, wherein the antibody is a naked antibody. 366. The method of embodiment 361, wherein the antibody is a humanized antibody. 367. The method of embodiment 366, wherein the antibody is a naked antibody. 368. The method of embodiment 361, wherein the antibody is a naked antibody. 369. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 361 to 368. 370. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, 361 methods. 371. The method of Embodiment 370, wherein the antibody is a bivalent monospecific antibody. 372. The method of embodiment 371, wherein the antibody is a humanized antibody. 373. The method of embodiment 372, wherein the antibody is a naked antibody. 374. The method of embodiment 371, wherein the antibody is a naked antibody. 375. The method of embodiment 370, wherein the antibody is a humanized antibody. 376. The method of embodiment 375, wherein the antibody is a naked antibody. 377. The method of embodiment 370, wherein the antibody is a naked antibody. 378. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 370 to 377. 379. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 8. 380. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 9. 381. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 10. 382. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11. 383. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 12. 384. The method of Embodiment 370, wherein the antibody comprises a VL containing SEQ ID NO: 13. 385. The method of Embodiment 370, wherein the antibody comprises a VL containing SEQ ID NO: 14. 386. The method of Embodiment 370, wherein the antibody comprises a VL containing SEQ ID NO: 15. 387. The method of Embodiment 370, wherein the antibody comprises a VL containing SEQ ID NO: 16. 388. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 389. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 390. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 391. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 392. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 393. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 394. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 395. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 396. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 397. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 398. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 399. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 400. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 401. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 402. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 403. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 404. The method of Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 11. 405. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 406. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 407. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 408. Embodiment 370, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 409. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 379 to 408. 410. A method for managing NMO in a subject, comprising a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) Administering an antibody or its antigen-binding fragment that specifically binds to a target, to a subject that requires it. The method comprising the above. 411. The method of Embodiment 410, wherein the antibody is a bivalent monospecific antibody. 412. The method of embodiment 411, wherein the antibody is a humanized antibody. 413. The method of embodiment 412, wherein the antibody is a naked antibody. 414. The method of embodiment 411, wherein the antibody is a naked antibody. 415. The method of embodiment 410, wherein the antibody is a humanized antibody. 416. The method of embodiment 415, wherein the antibody is a naked antibody. 417. The method of embodiment 410, wherein the antibody is a naked antibody. 418. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 410 to 417. 419. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 410. 420. The method of Embodiment 419, wherein the antibody is a bivalent monospecific antibody. 421. The method of embodiment 420, wherein the antibody is a humanized antibody. 422. The method of embodiment 421, wherein the antibody is a naked antibody. 423. The method of embodiment 420, wherein the antibody is a naked antibody. 424. The method of embodiment 419, wherein the antibody is a humanized antibody. 425. The method of embodiment 424, wherein the antibody is a naked antibody. 426. The method of embodiment 419, wherein the antibody is a naked antibody. 427. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 419 to 426. 428. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 8. 429. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 9. 430. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 10. 431. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11. 432. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 12. 433. The method of Embodiment 419, wherein the antibody comprises a VL containing SEQ ID NO: 13. 434. The method of Embodiment 419, wherein the antibody comprises a VL containing SEQ ID NO: 14. 435. The method of Embodiment 419, wherein the antibody comprises a VL containing SEQ ID NO: 15. 436. The method of Embodiment 419, wherein the antibody comprises a VL containing SEQ ID NO: 16. 437. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 438. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 439. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 440. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 441. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 442. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 443. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 444. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 445. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 446. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 447. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 448. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 449. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 450. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 451. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 452. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 453. The method of Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 11. 454. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 455. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 456. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 457. Embodiment 419, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 458. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 428 to 457. 459. A method for preventing NMO in a target, wherein a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) is used. This includes administering an antibody or antigen-binding fragment thereof that binds heteroto to a target that requires it. The aforementioned method. 460. The method of Embodiment 459, wherein the antibody is a bivalent monospecific antibody. 461. The method of embodiment 460, wherein the antibody is a humanized antibody. 462. The method of embodiment 461, wherein the antibody is a naked antibody. 463. The method of embodiment 460, wherein the antibody is a naked antibody. 464. The method of embodiment 459, wherein the antibody is a humanized antibody. 465. The method of embodiment 464, wherein the antibody is a naked antibody. 466. The method of embodiment 459, wherein the antibody is a naked antibody. 467. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 459 to 466. 468. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 459. 469. The method of Embodiment 468, wherein the antibody is a bivalent monospecific antibody. 470. The method of embodiment 469, wherein the antibody is a humanized antibody. 471. The method of embodiment 470, wherein the antibody is a naked antibody. 472. The method of embodiment 469, wherein the antibody is a naked antibody. 473. The method of embodiment 468, wherein the antibody is a humanized antibody. 474. The method of embodiment 473, wherein the antibody is a naked antibody. 475. The method of embodiment 468, wherein the antibody is a naked antibody. 476. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 468 to 475. 477. The method of Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 8. 478. The method of Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 9. 479. The method of Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 10. 480. The method of Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11. 481. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 12. 482. The method of embodiment 468, wherein the antibody comprises a VL comprising SEQ ID NO: 13. 483. The method of embodiment 468, wherein the antibody comprises a VL comprising SEQ ID NO: 14. 484. The method of embodiment 468, wherein the antibody comprises a VL comprising SEQ ID NO: 15. 485. The method of embodiment 468, wherein the antibody comprises a VL comprising SEQ ID NO: 16. 486. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 13 。 487. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 14 。 488. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 15 。 489. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 16 。 490. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 13 。 491. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 14 。 492. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 15 。 493. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 16 。 494. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 10 and a VL comprising SEQ ID NO: 13 法。 495. The method of embodiment 468, wherein the antibody comprises a VH comprising SEQ ID NO: 10 and a VL comprising SEQ ID NO: 14 法。[[ID=496. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 497. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 498. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 499. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 500. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 501. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 502. The method of Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 11. 503. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 504. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 505. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 506. Embodiment 468, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 507. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 477 to 506. 508. A method for treating NMO spectrum disorder in a subject, comprising a therapeutically effective dose of human KIT An antibody or its antigen-binding fragment that specifically binds to the substance (SEQ ID NO: 1) is used in the target that requires it. The method comprising administering to an elephant. 509. The method of Embodiment 508, wherein the antibody is a bivalent monospecific antibody. 510. The method of embodiment 509, wherein the antibody is a humanized antibody. 511. The method of embodiment 510, wherein the antibody is a naked antibody. 512. The method of embodiment 509, wherein the antibody is a naked antibody. 513. The method of embodiment 508, wherein the antibody is a humanized antibody. 514. The method of embodiment 513, wherein the antibody is a naked antibody. 515. The method of embodiment 508, wherein the antibody is a naked antibody. 516. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 508 to 515. 517. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 508. 518. The method of Embodiment 517, wherein the antibody is a bivalent monospecific antibody. 519. The method of embodiment 518, wherein the antibody is a humanized antibody. 520. The method of embodiment 519, wherein the antibody is a naked antibody. 521. The method of embodiment 518, wherein the antibody is a naked antibody. 522. The method of embodiment 517, wherein the antibody is a humanized antibody. 523. The method of embodiment 522, wherein the antibody is a naked antibody. 524. The method of embodiment 517, wherein the antibody is a naked antibody. 525. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). The method according to any one of embodiments 517 to 524, comprising 526. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 8. 527. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 9. 528. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 10. 529. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 11. 530. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 12. 531. The method according to embodiment 517, wherein the antibody comprises a VL comprising SEQ ID NO: 13. 532. The method according to embodiment 517, wherein the antibody comprises a VL comprising SEQ ID NO: 14. 533. The method according to embodiment 517, wherein the antibody comprises a VL comprising SEQ ID NO: 15. 534. The method according to embodiment 517, wherein the antibody comprises a VL comprising SEQ ID NO: 16. 535. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 13 。 536. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 14 。 537. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 15 。 538. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 8 and a VL comprising SEQ ID NO: 16 。 539. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 13 。 540. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 14 。 541. The method according to embodiment 517, wherein the antibody comprises a VH comprising SEQ ID NO: 9 and a VL comprising SEQ ID NO: 15 。 542. The method of Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 543. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 544. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 545. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 546. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 547. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 548. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 549. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 550. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 551. The method of Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 11. 552. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 553. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 554. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 555. Embodiment 517, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 556. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 526 to 555. 557. A method for managing NMO spectrum disorder in a subject, comprising a therapeutically effective dose of human KIT An antibody or its antigen-binding fragment that specifically binds to the substance (SEQ ID NO: 1) is used in the target that requires it. The method comprising administering to an elephant. 558. The method of Embodiment 557, wherein the antibody is a bivalent monospecific antibody. 559. The method of embodiment 558, wherein the antibody is a humanized antibody. 560. The method of embodiment 559, wherein the antibody is a naked antibody. 561. The method of embodiment 558, wherein the antibody is a naked antibody. 562. The method of embodiment 557, wherein the antibody is a humanized antibody. 563. The method of embodiment 562, wherein the antibody is a naked antibody. 564. The method of embodiment 557, wherein the antibody is a naked antibody. 565. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 557 to 564. 566. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 557. 567. The method of embodiment 566, wherein the antibody is a bivalent monospecific antibody. 568. The method of embodiment 567, wherein the antibody is a humanized antibody. 569. The method of embodiment 568, wherein the antibody is a naked antibody. 570. The method of embodiment 567, wherein the antibody is a naked antibody. 571. The method of embodiment 566, wherein the antibody is a humanized antibody. 572. The method of embodiment 571, wherein the antibody is a naked antibody. 573. The method of embodiment 566, wherein the antibody is a naked antibody. 574. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 566 to 573. 575. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 8. 576. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 9. 577. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 10. 578. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11. 579. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 12. 580. The method of Embodiment 566, wherein the antibody comprises a VL containing SEQ ID NO: 13. 581. The method of Embodiment 566, wherein the antibody comprises a VL containing SEQ ID NO: 14. 582. The method of Embodiment 566, wherein the antibody comprises a VL containing SEQ ID NO: 15. 583. The method of Embodiment 566, wherein the antibody comprises a VL containing SEQ ID NO: 16. 584. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 585. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 586. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 587. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 588. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 589. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 590. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 591. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 592. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 593. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 594. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 595. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 596. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 597. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 598. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 599. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 600. The method of Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 11. 601. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 602. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 603. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 604. Embodiment 566, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 605. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 575 to 604. 606. A method for preventing NMO spectrum disorder in a subject, comprising a therapeutically effective dose of human KIT receptor An antibody or its antigen-binding fragment that specifically binds to (SEQ ID NO: 1) is used to target the organism that requires it. The method, including administering. 607. The method of embodiment 606, wherein the antibody is a bivalent monospecific antibody. 608. The method of embodiment 607, wherein the antibody is a humanized antibody. 609. The method of embodiment 608, wherein the antibody is a naked antibody. 610. The method of embodiment 607, wherein the antibody is a naked antibody. 611. The method of embodiment 606, wherein the antibody is a humanized antibody. 612. The method of embodiment 611, wherein the antibody is a naked antibody. 613. The method of embodiment 606, wherein the antibody is a naked antibody. 614. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 606 to 613. 615. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 606. 616. The method of Embodiment 615, wherein the antibody is a bivalent monospecific antibody. 617. The method of embodiment 616, wherein the antibody is a humanized antibody. 618. The method of embodiment 617, wherein the antibody is a naked antibody. 619. The method of embodiment 616, wherein the antibody is a naked antibody. 620. The method of embodiment 615, wherein the antibody is a humanized antibody. 621. The method of embodiment 620, wherein the antibody is a naked antibody. 622. The method of embodiment 615, wherein the antibody is a naked antibody. 623. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 8. 624. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 9. 625. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 10. 626. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11. 627. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 12. 628. The method of Embodiment 615, wherein the antibody comprises a VL containing SEQ ID NO: 13. 629. The method of Embodiment 615, wherein the antibody comprises a VL containing SEQ ID NO: 14. 630. The method of Embodiment 615, wherein the antibody comprises a VL containing SEQ ID NO: 15. 631. The method of Embodiment 615, wherein the antibody comprises a VL containing SEQ ID NO: 16. 632. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 633. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 634. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 635. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 636. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 637. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 638. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 639. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 640. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 641. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 642. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 643. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 644. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 645. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 646. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 647. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 648. The method of Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 11. 649. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 650. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 651. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 652. Embodiment 615, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 653. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 623 to 652. 654. A method for treating multiple sclerosis (MS) in a subject, wherein the subject receives a therapeutically effective dose of human KIT. An antibody (SEQ ID NO: 1) or its antigen-binding fragment that specifically binds to the body, and the target that requires it. The method comprising administering to [a person]. 655. The method of Embodiment 654, wherein the antibody is a bivalent monospecific antibody. 656. The method of embodiment 655, wherein the antibody is a humanized antibody. 657. The method of embodiment 656, wherein the antibody is a naked antibody. 658. The method of embodiment 655, wherein the antibody is a naked antibody. 659. The method of embodiment 654, wherein the antibody is a humanized antibody. 660. The method of embodiment 659, wherein the antibody is a naked antibody. 661. The method of embodiment 654, wherein the antibody is a naked antibody. 662. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of the embodiments 654 to 661. 663. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 654. 664. The method of Embodiment 663, wherein the antibody is a bivalent monospecific antibody. 665. The method of embodiment 664, wherein the antibody is a humanized antibody. 666. The method of embodiment 665, wherein the antibody is a naked antibody. 667. The method of embodiment 664, wherein the antibody is a naked antibody. 668. The method of embodiment 663, wherein the antibody is a humanized antibody. 669. The method of embodiment 668, wherein the antibody is a naked antibody. 670. The method of embodiment 663, wherein the antibody is a naked antibody. 671. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 663 to 670. 672. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 8. 673. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 9. 674. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 10. 675. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11. 676. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 12. 677. The method of Embodiment 663, wherein the antibody comprises a VL containing SEQ ID NO: 13. 678. The method of Embodiment 663, wherein the antibody comprises a VL containing SEQ ID NO: 14. 679. The method of Embodiment 663, wherein the antibody comprises a VL containing SEQ ID NO: 15. 680. The method of Embodiment 663, wherein the antibody comprises a VL containing SEQ ID NO: 16. 681. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 682. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 683. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 684. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 685. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 686. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 687. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 688. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 689. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 690. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 691. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 692. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 693. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 694. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 695. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 696. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 697. The method of Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 11. 698. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 699. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 700. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 701. Embodiment 663, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 702. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 672 to 701. 703. A method for managing MS in a subject, comprising a therapeutically effective dose of human KIT receptor (SEQ ID NO: 1) Administering an antibody or its antigen-binding fragment that specifically binds to a target, to a subject that requires it. The method comprising the above. 704. The method of embodiment 703, wherein the antibody is a bivalent monospecific antibody. 705. The method of embodiment 704, wherein the antibody is a humanized antibody. 706. The method of embodiment 705, wherein the antibody is a naked antibody. 707. The method of embodiment 704, wherein the antibody is a naked antibody. 708. The method of embodiment 703, wherein the antibody is a humanized antibody. 709. The method of embodiment 708, wherein the antibody is a naked antibody. 710. The method of embodiment 703, wherein the antibody is a naked antibody. 711. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 703 to 710. 712. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which contains SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 703. 713. The method of embodiment 712, wherein the antibody is a bivalent monospecific antibody. 714. The method of embodiment 713, wherein the antibody is a humanized antibody. 715. The method of embodiment 714, wherein the antibody is a naked antibody. 716. The method of embodiment 713, wherein the antibody is a naked antibody. 717. The method of embodiment 712, wherein the antibody is a humanized antibody. 718. The method of embodiment 717, wherein the antibody is a naked antibody. 719. The method of embodiment 712, wherein the antibody is a naked antibody. 720. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 712 to 719. 721. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 8. 722. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 9. 723. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 10. 724. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11. 725. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 12. 726. The method of Embodiment 712, wherein the antibody comprises a VL containing SEQ ID NO: 13. 727. The method of Embodiment 712, wherein the antibody comprises a VL containing SEQ ID NO: 14. 728. The method of Embodiment 712, wherein the antibody comprises a VL containing SEQ ID NO: 15. 729. The method of Embodiment 712, wherein the antibody comprises a VL containing SEQ ID NO: 16. 730. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 731. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 732. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 733. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 734. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 735. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 736. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 737. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 738. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 739. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 740. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 741. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 742. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 743. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 744. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 745. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 746. The method of Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 11. 747. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 748. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 749. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 750. Embodiment 712, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 751. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 721 to 750. 752. A method for preventing MS in a subject, comprising a therapeutically effective amount of human KIT receptor (SEQ ID NO: 1) This includes administering an antibody or antigen-binding fragment thereof that binds heteroto to a target that requires it. The aforementioned method. 753. The method of Embodiment 752, wherein the antibody is a bivalent monospecific antibody. 754. The method of embodiment 753, wherein the antibody is a humanized antibody. 755. The method of embodiment 754, wherein the antibody is a naked antibody. 756. The method of embodiment 753, wherein the antibody is a naked antibody. 757. The method of embodiment 752, wherein the antibody is a humanized antibody. 758. The method of embodiment 757, wherein the antibody is a naked antibody. 759. The method of embodiment 752, wherein the antibody is a naked antibody. 760. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 752 to 759. 761. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 752. 762. The method of embodiment 761, wherein the antibody is a bivalent monospecific antibody. 763. The method of embodiment 762, wherein the antibody is a humanized antibody. 764. The method of embodiment 763, wherein the antibody is a naked antibody. 765. The method of embodiment 762, wherein the antibody is a naked antibody. 766. The method of embodiment 761, wherein the antibody is a humanized antibody. 767. The method of embodiment 766, wherein the antibody is a naked antibody. 768. The method of embodiment 761, wherein the antibody is a naked antibody. 769. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 761 to 768. 770. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 8. 771. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 9. 772. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 10. 773. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11. 774. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 12. 775. The method of Embodiment 761, wherein the antibody comprises a VL containing SEQ ID NO: 13. 776. The method of Embodiment 761, wherein the antibody comprises a VL containing SEQ ID NO: 14. 777. The method of Embodiment 761, wherein the antibody comprises a VL containing SEQ ID NO: 15. 778. The method of Embodiment 761, wherein the antibody comprises a VL containing SEQ ID NO: 16. 779. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 780. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 781. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 782. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 783. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 784. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 785. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 786. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 787. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 788. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 789. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 790. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 791. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 792. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 793. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 794. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 795. The method of Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 11. 796. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 797. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 798. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 799. Embodiment 761, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 800. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 770 to 799. 801. A method for reducing inflammation in a subject diagnosed with mast cell-associated disorder of the nervous system. For the target, an antibody or its anti-binding agent that specifically binds to the human KIT receptor (SEQ ID NO: 1) in a therapeutically effective amount. The method comprising administering the original bound fragment. 802. The method of Embodiment 801, wherein the antibody is a bivalent monospecific antibody. 803. The method of embodiment 802, wherein the antibody is a humanized antibody. 804. The method of embodiment 803, wherein the antibody is a naked antibody. 805. The method of embodiment 802, wherein the antibody is a naked antibody. 806. The method of embodiment 801, wherein the antibody is a humanized antibody. 807. The method of embodiment 806, wherein the antibody is a naked antibody. 808. The method of embodiment 801, wherein the antibody is a naked antibody. 809. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of the embodiments 801 to 808. 810. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, Method 801. 811. The method of embodiment 810, wherein the antibody is a bivalent monospecific antibody. 812. The method of embodiment 811, wherein the antibody is a humanized antibody. 813. The method of embodiment 812, wherein the antibody is a naked antibody. 814. The method of embodiment 811, wherein the antibody is a naked antibody. 815. The method of embodiment 810, wherein the antibody is a humanized antibody. 816. The method of embodiment 815, wherein the antibody is a naked antibody. 817. The method of embodiment 810, wherein the antibody is a naked antibody. 818. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 810 to 817. 819. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 8. 820. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 9. 821. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 10. 822. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11. 823. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 12. 824. The method of Embodiment 810, wherein the antibody comprises a VL containing SEQ ID NO: 13. 825. The method of Embodiment 810, wherein the antibody comprises a VL containing SEQ ID NO: 14. 826. The method of Embodiment 810, wherein the antibody comprises a VL containing SEQ ID NO: 15. 827. The method of Embodiment 810, wherein the antibody comprises a VL containing SEQ ID NO: 16. 828. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 829. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 830. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 831. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 832. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 833. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 834. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 835. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 836. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 837. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 838. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 839. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 840. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 841. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 842. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 843. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 844. The method of Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 11. 845. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 846. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 847. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 848. Embodiment 810, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 849. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 819 to 848. 850. A method for inhibiting mast cell activation in a subject, wherein mast cell-related disorders of the nervous system In subjects diagnosed with the disease, an antimicrobial agent that specifically binds to the human KIT receptor (SEQ ID NO: 1) at a therapeutically effective dose is administered. The method comprising administering the body or an antigen-binding fragment thereof. 851. The method of Embodiment 850, wherein the antibody is a bivalent monospecific antibody. 852. The method of embodiment 851, wherein the antibody is a humanized antibody. 853. The method of embodiment 852, wherein the antibody is a naked antibody. 854. The method of embodiment 851, wherein the antibody is a naked antibody. 855. The method of embodiment 850, wherein the antibody is a humanized antibody. 856. The method of embodiment 855, wherein the antibody is a naked antibody. 857. The method of embodiment 850, wherein the antibody is a naked antibody. 858. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 850 to 857. 859. The antibody contains a light chain variable region ("VL") containing VL CDR 1-3, which includes SEQ ID NOs: 2-4, and The implementation includes the heavy chain variable region ("VH") which includes VH CDR 1 to 3 which include sequence numbers 5 to 7 respectively, 850 methods. 860. The method of Embodiment 859, wherein the antibody is a bivalent monospecific antibody. 861. The method of embodiment 860, wherein the antibody is a humanized antibody. 862. The method of embodiment 861, wherein the antibody is a naked antibody. 863. The method of embodiment 860, wherein the antibody is a naked antibody. 864. The method of embodiment 859, wherein the antibody is a humanized antibody. 865. The method of embodiment 864, wherein the antibody is a naked antibody. 866. The method of embodiment 859, wherein the antibody is a naked antibody. 867. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of the embodiments 859 to 866. 868. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 8. 869. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 9. 870. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 10. 871. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11. 872. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 12. 873. The method of Embodiment 859, wherein the antibody comprises a VL containing SEQ ID NO: 13. 874. The method of Embodiment 859, wherein the antibody comprises a VL containing SEQ ID NO: 14. 875. The method of Embodiment 859, wherein the antibody comprises a VL containing SEQ ID NO: 15. 876. The method of Embodiment 859, wherein the antibody comprises a VL containing SEQ ID NO: 16. 877. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 13. . 878. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 14. . 879. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 15. . 880. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 8 and VL containing SEQ ID NO: 16. . 881. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 13. . 882. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 14. . 883. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 15. . 884. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 9 and VL containing SEQ ID NO: 16. . 885. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 13. Law. 886. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 14. Law. 887. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 15. Law. 888. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 10 and VL containing SEQ ID NO: 16. Law. 889. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 13. Law. 890. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 14. Law. 891. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 15. Law. 892. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11 and VL containing SEQ ID NO: 16. Law. 893. The method of Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 11. 894. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 13. Law. 895. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 14. Law. 896. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 15. Law. 897. Embodiment 859, wherein the antibody comprises VH containing SEQ ID NO: 12 and VL containing SEQ ID NO: 16. Law. 898. Administering a therapeutically effective dose of an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1). Including any one of embodiments 868 to 897. 899. Any one of Embodiments 1 to 898, wherein the antibody is a bivalent monospecific antibody. 900. Any one of Embodiments 1 to 898, wherein the antibody is not a bispecific antibody. 901. Any one of Embodiments 1 to 900, wherein the subject is a human adult. 902. Any one of Embodiments 1 to 900, wherein the subject is a child. [Brief explanation of the drawing]

[0020] (4. Brief explanation of the drawing) [Figure 1]Figure 1 shows the amino acid sequence of the full-length human KIT (SEQ ID NO: 1), GenBank® accession number AAC50969. The first five extracellular Ig-like domains (i.e., D1, D2, D3, D4, and D5) are shown; "{" represents the amino-terminal residue of each domain, and "}" represents the carboxyl-terminal residue of each domain. The D1 domain is represented from P34 to R112, the D2 domain from D113 to P206, the D3 domain from A207 to D309, the D4 domain from K310 to N410, the hinge region between D4 and D5 is located from V409 to N410, and the D5 domain from T411 to K509. Furthermore, the D1 / D2 hinge region is located at D113-L117; the D2 / D3 hinge region is located at P206-A210; and the D3 / D4 hinge region is located at D309-G311. The D4 / D5 region includes K310-K509. The transmembrane domain includes residues F525-Q545, and the kinase domain includes residues K589-S933.

[0021] [Figure 2] Figures 2A, 2B, and 2C demonstrate that antibodies containing the CDRs shown in Table 1 below (also referred to herein as "anti-KIT-1") inhibit the ligand-induced phosphorylation of KIT in mast cells. (A) Fluorescently labeled cell sorting ("FACS") analysis showing KIT expression on LAD2 cells. (B) FACS analysis showing FcεR1 expression on LAD2 cells. (C) ELISA analysis using an antiphosphorylated tyrosine antibody to detect the level of ligand-induced phosphorylation of KIT in the presence of anti-KIT-1 antibody.

[0022] [Figure 3]Figures 3A, 3B, and 3C demonstrate that anti-KIT-1 antibodies inhibit mast cell degranulation and cytokine release. (A) Percentage of β-hexosaminidase ("B-hex") released by LAD2 cells is analyzed in the presence and absence of ligand stimulation, and in the presence and absence of anti-KIT-1. The dotted line for "Streptavidin" indicates the percentage of β-hexosaminidase released in cells treated with streptavidin in the absence of KIT ligand stem cell factor ("SCF") and anti-KIT-1. The dotted line for "Streptavidin + SCF" indicates the percentage of β-hexosaminidase released in cells treated with streptavidin and SCF in the absence of anti-KIT-1. (B) Concentration of tumor necrosis factor α ("TNFα") released from LAD2 cells in the presence and absence of ligand stimulation, and in the presence and absence of anti-KIT-1 antibody. (C) Concentration of granulocyte-macrophage colony-stimulating factor ("GM-CSF") released from LAD2 cells in the presence and absence of ligand stimulation, and in the presence and absence of anti-KIT-1 antibody.

[0023] [Figure 4] Figure 4 demonstrates that administration of anti-KIT-1 results in a reduction in mast cell count in each 400× high-magnification field ("400× HPF") in dogs 1, 2, 3, and 4 (black rhombuses, black squares, gray triangles, and gray squares, respectively).

[0024] [Figure 5] Figures 5A and 5B demonstrate that anti-KIT-1 administration reduces the airway eosinophil population. (A) Cats of an acute asthma model treated with anti-KIT-1 show a significant reduction in the percentage of eosinophils in the bronchoalveolar lavage fluid ("BALF") of the airways compared to placebo treatment. (B) Cats of a chronic asthma model treated with anti-KIT-1 show a significant reduction in the percentage of eosinophils in the airways compared to placebo treatment. The dotted line represents 17% BALF eosinophils; BALF eosinophils above 17% indicate an asthmatic phenotype.

[0025] [Figure 6] Figures 6A and 6B demonstrate that the anti-KIT-1 antibody does not induce primary human mast cell degranulation in vitro. Mast cell degranulation was evaluated by measuring β-hexosaminidase activity released into the culture supernatant. β-hexosaminidase release was measured after treating mast cells with 10-fold serial dilutions of anti-KIT-1, isotype control antibody, SCF, or calcium ionophore A23187 (which exhibits either the ability to degranulate mast cells alone (A) or the ability to enhance IgE-mediated degranulation (B)).

[0026] [Figure 7] Figure 7 demonstrates the effect of anti-KIT-1 antibodies on SCF-induced KIT phosphorylation in CHO-WT KIT cells. In SCF-treated CHO-WT KIT cells, anti-KIT-1 antibodies dose-dependently inhibited KIT phosphorylation across four independent experiments. Isotype control antibodies had no effect on SCF-induced KIT phosphorylation. In the absence of SCF, levels of KIT phosphorylation were similar in cells treated with anti-KIT-1 antibodies or isotype control antibodies at concentrations up to 1 μM (150 μg / mL).

[0027] [Figure 8] Figures 8A and 8B demonstrate the effects of the anti-KIT-1 antibody on (A) SCF-induced KIT phosphorylation and (B) total KIT levels in M-07e cells. [Modes for carrying out the invention]

[0028] (5. Detailed explanation) In one embodiment, the foregoing provides for eosinophils or masses of the nervous system, for example, the central nervous system. To prevent, manage, or treat eosinophil or mast cell-related disorders, such as mast cell-related disorders. A therapeutic method useful for this purpose, specifically binding to the KIT receptor (e.g., human KIT receptor). These are antibodies or their antigen-binding fragments. Non-limiting examples of such disorders include NMO or NMO Examples include SD, MS, and NF.

[0029] In another aspect, what is provided herein is a method for preventing eosinophil or mast cell-related disorders. A method for treating or managing a KIT receptor (e.g., human KIT receptor) or its antigen. Administering a therapeutically effective dose of antibody that specifically binds to a binding fragment to a target that requires it. The method includes the above. In certain embodiments, what is provided herein is eosinophils or mass A method for alleviating one or more symptoms of a KIT cell-related disorder, wherein the KIT receptor (e.g., human KIT receptor) ) or a therapeutically effective amount of antibody that specifically binds to the antigen-binding fragment thereof, to the target that requires it. The method includes administering to [the body].

[0030] In one embodiment, provided herein are eosinophils of the nervous system, for example, the central nervous system or A method for preventing, treating, or managing mast cell-related disorders, wherein the KIT receptor (e.g.) For example, a therapeutically effective amount of antibody that specifically binds to the human KIT receptor (or its antigen-binding fragment), The method includes administering to subjects who require it. In a specific embodiment, the central nervous system Eosinophil or mast cell-related disorders are NMO or NMOSD. In another embodiment, eosinophils in the nervous system Alternatively, mast cell-related disorders are NF. In another embodiment, eosinophil or mast cell-related disorders of the nervous system. The disorder is MS. In certain aspects, what is provided herein is the nervous system, for example, A method for alleviating one or more symptoms of eosinophil or mast cell-related disorders of the central nervous system, wherein KIT A therapeutically effective dose of antibody that specifically binds to the receptor (e.g., human KIT receptor) or its antigen-binding fragment. The method includes administering it to a subject who requires it.

[0031] KIT receptors for use in the methods provided herein (e.g., SEQ ID NO: 1 and Figure 1) Antibodies or their antigen-binding fragments that specifically bind to the human KIT receptor as described above are also... This specification describes compositions such as pharmaceutical compositions containing antibodies, as well as other compositions described herein.

[0032] As used herein, “administer” or “dosage” means administering to a subject or patient (e.g., a human). For example, a substance (for example, a humanized anti-KIT antibody or its antigen-binding fragment provided herein) If mucous membranes, topical, intradermal, parenteral, intravenous, or intramuscular, as described in this specification or known in the art. By internal delivery and / or any other method of physical delivery, by injection or by other means, This refers to the act of delivering something in a logical manner.

[0033] As used herein, the terms “effective dose” or “therapeutic effective dose” mean a given disease and / To reduce and / or improve the severity and / or duration of symptoms related thereto This refers to a sufficient amount of treatment (e.g., the antibody or pharmaceutical composition provided herein). These terms refer to the progression or decrease, slowing down, or improvement of a given disease. For the reduction, slowing, or improvement of recurrence, occurrence, or onset, and / or other treatments ( For example, the prophylactic or therapeutic effect (one or the other) of therapies other than the anti-KIT antibody provided herein. This also includes the amount necessary to improve or enhance (multiple). In some embodiments, As used herein, "effective amount" refers to a specific result, such as the number and / or activity of mast cells. Decreased cellular K2 levels, decreased eosinophil count and / or activity, and inhibition of cell proliferation or cell survival. Inhibition of IT biological activity (e.g., partial inhibition), or enhancement of apoptosis or cell differentiation, or This also refers to the amount of antibody described herein required to achieve (or induce) the desired outcome.

[0034] As used herein, the terms “D4 / D5 area” or “D4 / D5 domain” refer to the fourth area of ​​the KIT. The Ig-like extracellular ("D4") domain of the eye, the fifth Ig-like extracellular ("D5") domain, and the D4 domain In the hinge region between the nucleotide and the D5 domain ("D4-D5 hinge region"), a carboxyl molecule is present from the amino terminus. Up to the sill end, it spans in the following order: D4, D4-D5 hinge region, and D5. This refers to the region within the KIT polypeptide. When used in this specification, it refers to amino acids V308-H515 in Figure 1. This is considered an example of a D4 / D5 region or domain.

[0035] As used herein, the terms "KIT," "KIT receptor," or "KIT polypeptide" are used interchangeably. This is not limited to natural KIT, KIT isoforms, interspecific KIT homologs, or KIT Mutants, for example, naturally occurring mutants (e.g., allele or splice mutants, or This refers to mutants, for example, somatic mutants, or artificially constructed variants (for example, This refers to full-length KITs of any form, including recombinant or chemically modified mutants. KITs are c-kit genes. It is a type III receptor tyrosine kinase encoded by (for example, Yarden et al.) References, Nature, 1986, 323:226-232; Literature by Ullrich and Schlessinger, Cell, 1990, 61:203 -212; Literature by Clifford et al., J. Biol. Chem., 2003, 278:31461-31464; Literature by Yarden et al., E MBO J., 1987, 6:3341-3351; Mol et al., J. Biol. Chem., 2003, 278, 278:31461-31464. (See reference). GenBank(trademark) accession number NM_000222 is an exemplary human KIT nucleic acid sequence. GenBank(trademark) accession numbers NP_001087241, P10721, and AAC50969 are provided. Provides an example human KIT amino acid sequence. GenBank® Accession Number AAH75716 This provides an exemplary mouse KIT amino acid sequence. Natural KIT contains five extracellular immunoglobulins. Phosphorus (Ig)-like domains (D1, D2, D3, D4, D5), single transmembrane domain, inhibitory cytoplasmic membrane-bound domain In and separated cytoplasmic kinase domains separated by kinase insertion segments. This includes (for example, the literature by Yarden et al., Nature, 1986, 323:226-232; Ullrich and Schlessin) Ger's work, Cell, 1990, 61:203-212; Clifford et al.'s work, J. Biol. Chem., 2003, 278:3 See 1461-31464). The exemplary amino acid sequence of the D4 / D5 region of human KIT is shown below. This is provided in Figure 1, under the base V308~H515. In a specific embodiment, the KIT is a human KIT. Yes. In certain embodiments, KIT is in monomer, dimer, polymer, natural form, or modified form. It can exist in that form.

[0036] As used herein, the term “in combination” in the context of administering other treatments means This refers to the use of two or more treatment methods. The term "combined" refers to the administration of treatment methods. This does not restrict the order. Treatment methods may be, for example, sequentially, sequentially, or in parallel. They can be given simultaneously.

[0037] As used herein, the terms “to manage,” “to control,” and “to control” mean: Eosinophil or mast cell-related disorders such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) The beneficial effects that the subject obtains from the treatment (e.g., preventive or therapeutic drug) do not result in a cure. In certain embodiments, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) To prevent the progression or worsening of eosinophil or mast cell-related disorders, one or more of the disorders are treated. To "manage" the condition, the subject is subjected to one or more treatments (e.g., antibodies as described herein). They are administered a preventative or therapeutic drug.

[0038] When used in this specification, preferred NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) In the context of acidophil or mast cell-related disorders, the terms “to interfere” or “to interfere” are: Therapies or combinations of therapies provided herein (for example, antibodies described herein) Complete or partial inhibition (e.g., 100%, 95%) caused by any combination of preventive or therapeutic drugs. (%), 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or less than 5%), or NMO , eosinophil or mast cell-related disorders such as NMOSD, MS, or NF (e.g., NF1 or NF2) and This refers to preventing the onset, recurrence, onset, or spread of the disease / or related symptoms.

[0039] As used herein, the term “preventive medicine” refers to NMO, NMOSD, MS, or NF in the subject. Eosinophil or mast cell-related disorders and / or related disorders such as (e.g., NF1 or NF2) Any method that can completely or partially inhibit the onset, recurrence, onset, or spread of the symptoms This refers to a drug. In certain embodiments, the term "preventive drug" refers to an antibody as described herein. In certain other embodiments, the term “preventive agent” means a drug other than the antibodies described herein. This refers to medications. Generally, preventive medications are used for conditions such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2). To prevent eosinophil or mast cell-related disorders and / or symptoms thereof, or NMO, NMOS Eosinophil or mast cell-related disorders such as D, MS, or NF (e.g., NF1 or NF2) and / or It is useful for preventing the onset, development, progression, and / or severity of related symptoms. It is known to do so, or has been used to do so, or to do so These are currently used drugs. In specific embodiments, the prophylactic drug is a humanized or fully human antimicrobial agent. These are human anti-KIT antibodies, such as KIT monoclonal antibodies.

[0040] As used herein, the term “adverse reaction” means the desired effect of a treatment (e.g., a preventive or therapeutic drug). This includes both undesirable and harmful effects. Undesirable effects are not necessarily harmful. The adverse effects of a treatment (e.g., a preventive or therapeutic drug) may be harmful, unpleasant, or dangerous. Side effects include diarrhea, cough, gastroenteritis, wheezing, nausea, vomiting, loss of appetite, and abdominal cramps. Fever, pain, weight loss, dehydration, alopecia, dyspenea, insomnia, dizziness, mucositis , nerve and muscle effects, fatigue, dry mouth, and loss of appetite, rash or swelling at the injection site, Influenza-like symptoms (fever, chills, and fatigue, etc.), gastrointestinal abnormalities, and allergic reactions may occur. There are many other undesirable effects that patients may experience, and these are known in the art. This is the case. Much of it is described in the Physician's Desk Reference (63rd edition, 2009). It is listed.

[0041] In this specification, the terms "subject" and "patient" are to be used interchangeably. When used in writing, the subject is non-primates (e.g., cows, pigs, horses, cats, dogs, goats, etc.) Mammals such as rabbits, rats, mice, etc., or primates (e.g., monkeys and humans), for example The subject is human. In one embodiment, the subject is NMO, NMOSD, MS, or NF (for example, NF1 or NF1). 2) Mammals diagnosed with eosinophil or mast cell-related disorders, such as humans. In the application method, the target is eosinophils such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2). This refers to mammals at risk of developing mast cell-related disorders, such as humans. Another embodiment The subjects are non-human primates. In the specific implementation, the subjects are adults who are at least 18 years old. It is intended for human subjects. In specific implementations, the subjects are human children aged 1 to 18 years. In the description of the method of application, the target is a person aged 1 to 3 years old. In the specific embodiment, the target is a person aged 3 to 1 The person is 2 years old or between 12 and 18 years old.

[0042] As used herein, the terms “treatment(plural)” and “treatment(single)” mean a condition or or disorders or their symptoms (for example, mast cell-related disorders of the nervous system, such as the central nervous system) Which eosinophil or mast cell-related disorders, e.g., NMO, NMOSD, MS, or NF (e.g., NF1 or This refers to the prevention, treatment, management, or improvement of NF2) or one or more symptoms or conditions associated with it. Any protocol(s), method(s), composition(s), product(s) that can be used It can refer to agents and / or drugs(s). In certain embodiments, the term "treatment" can also refer to a drug(s). "Therapy(s)" and "Treatment(s)" refer to drug therapy, adjuvant therapy, radiation therapy, surgery, and biotherapy. Laws, supportive therapies, and / or conditions or disorders or one or more of their symptoms (e.g., nervous system For example, eosinophil or mast cell-related disorders such as mast cell-related disorders of the central nervous system, for example NMO, NMOSD, MS, or NF (e.g., NF1 or NF2), or one or more symptoms associated therewith This refers to other treatments that are useful for treating, managing, preventing, or improving a condition. In certain embodiments, In this specification, the term "treatment method" refers to treatments other than the anti-KIT antibody or its pharmaceutical composition described herein. This refers to a therapy. In specific embodiments, it may refer to "one additional treatment" or "multiple additional treatments." This refers to treatments other than those using the anti-KIT antibody or its pharmaceutical composition described herein. This refers to the anti-KIT antitherapy described herein as an adjunct therapy. In specific embodiments, the treatment method is the anti-KIT antitherapy described herein. Use of the body, for example, the anti-KIT antibody described herein, in drug therapy, biotherapy, surgery, This includes use in combination with supportive care.

[0043] As used herein, the term “therapeutic agent” means a drug that treats the nervous system, for example, the central nervous system. Eosinophil or mast cell-related disorders such as cell-related disorders, e.g., NMO, NMOSD, MS, or NF (for example) For example, in the treatment, management, or improvement of NF1 or NF2) and / or related symptoms. This refers to any drug that can be used. In certain embodiments, the term "therapeutic drug" means, This refers to the anti-KIT antibody described herein, or its antigen-binding fragment. In certain other embodiments, In this specification, the term "therapeutic agent" refers to drugs other than antibodies as described herein. The therapeutic agent is used for eosinophil or mast cell-related disorders of the nervous system, such as mast cell-related disorders of the central nervous system. Cell-related disorders, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2), or related to them. It is known to be useful in treating, managing, or improving one or more related symptoms, or These are drugs that have been used, or are currently used, to perform these tasks. ru.

[0044] (5.1 Eosinophil and mast cell-related disorders) Mast cells originate from bone marrow precursors and are found throughout the body in connective tissue, most abundantly in the submucosa. These are large cells found in the dermis and layered tissue. Mast cells are vasoactive amines. It contains large granules that store various mediator molecules, including stamin, and also IgE molecules. It possesses a high-affinity Fcε receptor (FcεRI) that enables it to bind to nomers. Antigen binding to combined IgE induces mast cell degranulation and mast cell activation, local It causes immediate-type hypersensitivity reactions, either sexual or systemic. Therefore, mast cells cause inflammation and allergic reactions. It plays an important role in the Ghee reaction. However, without proper balance and regulation, the mast becomes fine. Cells are also found in disorders such as anaphylaxis, atopic dermatitis, and rhinitis, and antigens. This can also lead to harmful overreactions.

[0045] Receptor-mediated mast cell activation is not limited to (i) granule-related mediators ( Histamine, serotonin (5-hydroxytryptamine), and various proteases and pe (ii) including putidases; (ii) eicosanoids, such as prostaglandin D2 (PGD2) and leucox. Cotriene C4 (LTC4); and (iii) cytokines (interleukin-2 (IL-2), IL-3, IL-4) IL-5, IL-6, IL-10, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and (Including tumor necrosis factor α (TNFα)), and chemokines (CCL-2, CCL-3, CCL-5, and CXCL-8) This leads to the release of inflammatory mediators, including (and others).

[0046] KIT signaling is involved in mast cell development and homeostasis, for example, in the development of mast cells and their precursors. Proliferation from cells and subsequent maturation and survival in resident tissues, in vivo mast cell Homing to its resident site, and to the extracellular matrix proteins of mast cells. This is important for promoting adhesion. For example, the activation mutation of KIT at amino acid residues 816 or 560 of KIT. The differences include mast cell diseases, characterized by the overproduction of mast cells, and gastrointestinal stromal cell tumors (GISTs). It is related to this.

[0047] As used herein, the term “mast cell-related disorder (type 1)” or “mast cell-related disorder” "Harm(s)" refers to conditions in which mast cell activity contributes to a pathological condition, and / or where mast cells are involved in the body's processes. Damages observed in various parts at abnormal amounts (such as exceeding or falling below the normal amount) For example, mast cell-related disorders may affect all or all organs and tissues. Accumulation of pathological mast cells in and / or one or more mast cells such as inflammatory mediators This may indicate abnormal release of cytoplasmic mediators. Inflammation released by mast cells. Non-limiting examples of sex mediators include (i) granule-related mediators (histamine, se Contains rotonin (5-hydroxytryptamine), as well as various proteases and peptidases. (ii) eicosanoids, such as prostaglandin D2 (PGD2) and leukotriene C4 (L TC4); and (iii) cytokines (interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, I L-10, IL-13, granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor alpha (T Any of the following: NFα (including), and chemokines (including CCL-2, CCL-3, CCL-5, and CXCL-8); It can be listed.

[0048] In specific cases, mast cell-related disorders include NMO, NMOSD, MS, or NF (e.g., type 1 NF (NF1)). Mast cell-related disorders of the nervous system, such as type 2 NF (NF2), or schwannomatous disease. It is harmful.

[0049] MS is a condition in which the white matter in the brain or spinal cord becomes inflamed and subsequently damaged by the body's own immune system. A chronic inflammatory demyelinating disorder of the central nervous system (brain and spinal cord) accompanied by episodes of recurrence. These inflamed areas become scarred within the brain and spinal cord. This damage affects various parts of the nervous system. It destroys their ability to communicate and causes various physical, mental, and / or psychiatric problems. It causes symptoms. While not limited to a specific type of MS, both can occur in unrelated seizures. This includes a recurrent type with recurring symptoms, and a progressive type with symptoms that accumulate over time. Guidelines for diagnosing MS are available, for example, at http: / / www.ncbi.nlm.ni Available from h.gov / books / NBK48919 / , National Collaborating Centre for Chronicle C Conditions (UK), "Multiple Sclerosis: UK Clinical Practice for Diagnosis and Management in Primary and Secondary Care" Floor guidelines (Multiple Sclerosis: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care), London: Royal College of Physicians. See s(UK), 2004, (NICE Clinical Guidelines, No. 8). Symptoms of MS are related to the autonomic nervous system. This can manifest as any neurological symptoms or signs, such as problems with vision, movement, and sensation. Yes. Non-specific examples of MS symptoms include loss of sensitivity or changes in sensation (tingling). Symptoms include numbness, tingling, or loss of sensation, muscle weakness, very pronounced reflexes, muscle spasms, or difficulty moving. Difficulty with coordination and balance (ataxia), speech and swallowing problems, visual problems (nystagmus, optic nerves) Menstrual inflammation or double vision), fatigue, acute or chronic pain, difficulty urinating and defecating, emotional problems (depression or (e.g., mood swings), Uthoff phenomenon (worsening of symptoms caused by exposure to temperatures higher than normal) Examples include (and Lhermitt's sign), as well as an electrical sensation running down the spine when the neck is bent. In specific embodiments, the herein provides a treatment that specifically binds to KIT (e.g., human KIT). By administering a therapeutically effective amount of antibody or its antigen-binding fragment to a target that requires it. , a method to prevent, treat, alleviate or manage one or more of these symptoms of MS ru.

[0050] Other non-exclusive examples of mast cell-related disorders include, for example, anaphylaxis and atopic dermatitis. - Sexual disorders, mast cell activation syndrome, allergic rhinitis, food and toxin-related allergies (For example, allergies to nuts, crustaceans, fish, hymenoptera venom, or bee stings), psoriasis, atopic dermatitis Dermatitis, rosacea, eczema, tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy, allograft rejection, Amyloidosis, renal vascular ischemia, reflux nephropathy, polycystic kidney disease, drug-induced kidney injury, post-transplant. Fibrosis, and (for example, alcohol consumption, viral hepatitis B and C, and non-alcoholic) Liver fibrosis (caused by non-steatohepatitis of the liver (NASH)), parasitic infections (e.g., schistosomiasis, amoebic infection) (echinococcosis), as well as non-IgE mast cell-mediated reactions such as angioedema and anaphylaxis. One example is the activation of sexuality.

[0051] Eosinophils are white blood cells activated by lymphocytes in the adaptive immune response, and are involved in parasitic infections. It is important in defense against atopic dermatitis. The level of eosinophils in the blood is usually low, but in atopic dermatitis In certain situations, such as those mentioned above, the number of cases can increase significantly, which can lead to eosinophilia, or, in other words, This can lead to an abnormally high number of eosinophils in the blood.

[0052] As used herein, the term "eosinophil-related disorders (one type)" or "eosinophil-related disorders (plural)" "This refers to the presence of eosinophils in various parts of the body (in amounts exceeding or falling below normal levels)." This refers to disorders that appear when an abnormal amount of something is present. For example, when the body produces too many eosinophils. In some cases, it can cause chronic inflammation that leads to tissue damage. In certain aspects, eosinophils Bulb disorders can involve abnormally high levels of eosinophils in the tissue over a long period in response to triggering factors. For example, in response to triggers such as infections or allergens, a larger number of eosinophils are produced. It is possible, but a large number of eosinophils will not decrease at the normal rate, so it is predictable. It is maintained in large quantities for an even longer period.

[0053] Eosinophil-related disorders can be diagnosed according to the location of elevated eosinophil levels. Non-specific examples of acidophil-related disorders include allergic diseases, infections, blood disorders, and immune disorders. and reactions, endocrine disorders, lung diseases, gastrointestinal disorders, neurological disorders, rheumatic diseases, heart diseases, and Kidney disease is one example. In certain forms, eosinophilia is elevated to normal levels, for example. This is an eosinophil-related disorder characterized by a peripheral blood eosinophil count exceeding 450 / μL. This can be induced or triggered by various conditions, such as allergies or infections. In certain embodiments, locally, for example, in the lungs, heart, spinal cord, or brain, the eosinophil levels An increase is observed.

[0054] Non-limited examples of eosinophil-related neurological disorders include central nervous system infections and ventriculoperitoneal shunts. Examples include ventriculoperitoneal shunt and adverse drug reactions. In certain embodiments, An increase in eosinophil count or activity is obtained in cerebrospinal fluid (CSF) or from the tissues of the central nervous system fluid. It can be detected in other samples.

[0055] Non-limiting examples of eosinophil or mast cell-related signs include allergic rhinitis and sinusitis. Which upper respiratory tract diseases, foreign body aspiration, glottal stenosis, tracheal stenosis, laryngotracheomalacia ia) vascular ring, chronic obstructive pulmonary disease (COPD), and congestive heart failure, eosinophilic bronchitis, multiple Chondritis, sarcoidosis, papillomas, arthritis (e.g., rheumatoid arthritis), and Wegener's meat Blastoma is one example.

[0056] In certain embodiments, "eosinophil-related disorder" or "eosinophil-related disorder" is defined as eosinophil activity being One contributing factor is a disorder in which eosinophils are present in various parts of the body (exceeding normal levels or abnormal levels). This may include disorders that appear when abnormal amounts (such as amounts below normal levels) are present.

[0057] In certain embodiments, the anti-KIT antibody or its antigen-binding fragment described herein, or its medical The drug composition treats eosinophil or mast cell-related disorders in the nervous system, such as the central nervous system. According to the method provided herein for this purpose, eosinophils in the nervous system, for example, the central nervous system Or, a dosage that achieves one or more of the following in subjects diagnosed with mast cell-related disorders. And depending on the frequency of administration, it is administered to those who need it: a decrease in the number and / or activity of eosinophils. Decreased mast cell proliferation, decreased mast cell number or quantity, inhibition or decrease in mast cell activity, Reduced production of inflammatory factors induced by stront cells, reduced production of inflammatory factors, mast Restoration of cellular homeostasis, decreased mast cell migration, decreased mast cell adhesion, eosinophil mast cells Inhibition or reduction of recruitment, and inhibition or reduction of antigen-mediated degranulation of mast cells.

[0058] For example, cell proliferation is associated with bromodeoxyuridine (BrdU) uptake (see, for example, the literature of Hoshino et al.) 1986, Int. J. Cancer 38, 369; Literature by Campana et al., 1988, J. Immunol. Meth. 107:79 See also) or (3H)thymidine incorporation (e.g., Blechman et al., Cell, 1995, 80 :103-113; Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. By measuring (see Biol. Chem. 270:18367 73) or at various time intervals By direct cell counting (for example, at 12-hour or 24-hour intervals), or by known genes For example, proto-oncogenes (e.g., fos, myc) or cell cycle markers (Rb, cdc2, cyclin A This analysis is performed by detecting changes in the transcription, translation, or activity of (D1, D2, D3, E, etc.). This can be done. The levels of these proteins, mRNAs, and their activity are as is known in the art. This can be determined by the following method. For example, protein can be obtained as a commercially available product. ELISA, Western blotting, or immunoprecipitation using antibodies, including antibodies, It can be quantified by known immunodiagnostic methods. mRNA is well known in the art and Using a method that is related to, for example, Northern nucleotide analysis, RNase protection, or reverse transcription It can be quantified using a polymerase chain reaction.

[0059] Cell viability assays have been described in the art and can be easily performed by those skilled in the art. This can be done. For example, cell viability can be stained with trypan blue or other staining known in the art. Cellular survival and death markers can be used for evaluation. In a specific embodiment, the level of cell ATP The cell viability is determined by measuring the intracellular ATP. In a specific embodiment, the cell viability is determined by the intracellular ATP. Standard tools in this field include the CellTiter-Glo assay kit (Promega) for measuring the level of [unclear]. The assay is used to measure cytotoxicity over periods of 3 and 7 days. A decrease in cellular ATP is an indication of cytotoxicity. It shows resonance. In another specific embodiment, cell viability is measured using a neutral red uptake assay. It can be measured in the following location. In other embodiments, for visual observation of morphological changes, Cells exhibiting hypertrophy, granularity, jagged edges, a thin-film appearance, rounding, and detachment from the well surface. These may include, or other changes. Depending on the degree of cytotoxicity observed, T (100% toxic), PVH (partial toxicity - very heavy - 80%), PH (partial toxicity - heavy - 60%), P (partial It is given the designation of (partial toxicity - 40%), (Ps - mild toxicity - 20%), or (0 - non-toxic - 0%). . 50% cell inhibitory (cytotoxic) concentration (IC 50 ) is determined by regression analysis of these data. ru.

[0060] Apoptosis analysis is described in the art and can be easily performed by those skilled in the art. This can be done. For example, using flow cytometry, it is possible to identify cells that have undergone apoptosis. Furthermore, it is also possible to detect activated caspase 3, that is, the enzyme that mediates apoptosis. Using Western blotting, poly(ADP-ribose) polymerase (PARP) It is also possible to detect the cleavage (for example, Smolich et al., Blood, 2001, 97:1413-1421). (See reference). PARP cleavage is an indicator of apoptosis.

[0061] Release of mediators from mast cell cultures, including rodent and human mast cell cultures. Analyses for measuring mast cell activity, such as those described (for example, in the text by Kuehn et al.) Submission, "Measurement of Mast Cell Mediator Release," in Current Protocols in Immunology, U See nite 7.38.1-7.38.9, November 2010 (John Wiley & Sons). For example, The analysis of various species involves measuring the release of granular component β-hexosaminidase, eicosanoids, and leucosin. Production of phospholipid metabolic products such as triene C4 (LTC4) and prostaglandin D2 (PGD2) Observe mast cell degranulation through determination, or determination of the production of multiple cytokines. Designed. In certain embodiments, the measurement of cytokine mast cell culture release is performed by enzyme binding. This can be performed using the combined immunosorbent assay (ELISA).

[0062] (5.1.1 Neuromyelitis optica and neuromyelitis optica spectrum disorders) In certain embodiments, what is provided herein is a method for preventing and controlling NMOs in a subject area. , or a method of treatment, wherein an antibody specifically binds to the KIT receptor (e.g., the human KIT receptor). The method comprises administering the antigen-binding fragment to a target requiring it. In a particular embodiment, the foregoing provides a method for preventing NMOSD in a subject, A method for treating or managing a condition that specifically binds to a KIT receptor (e.g., human KIT receptor). The method comprising administering an antibody, or an antigen-binding fragment thereof, to a target requiring it. That is the case.

[0063] Neuromyelitis optica (NMO), also known as Devic's disease, primarily affects the optic nerve and spinal cord, and in some cases, the brain. NMO is an autoimmune inflammatory disorder of the central nervous system that affects the body. NMO can cause paralysis and blindness. It may cause. The majority of patients with NMO have aquaporin-4 (AQP4), i.e., vision Immunoglobulin autoimmune against water channels widely expressed in nerves, spinal cord, and periventricular regions. The patient is serum positive for antibodies (AQP4-IgG or NMO-IgG). A small percentage of NMO patients have NMO-IgG G-negative.

[0064] NMOSD refers to various disorders related to NMO, but there are no definitive clinical diagnostic criteria for NMO. It may not meet all criteria. This classification of NMOSD typically includes a non-limited range of disorders. Examples include limited types of NMO that are NMO-IgG seropositive [e.g., solitary or recurrent, axially elongated]. Longitudinally extensive transverse myelitis (LETM) (e.g., as seen on MRI) 3. Spinal segmental spinal cord lesions), recurrent or concomitant bilateral optic neuritis (ON), Asian type optic nerve and spinal cord Encephalopathy typical of MS (OSMS), optic neuritis or LETM associated with systemic autoimmune disease, and NMO. Examples include optic neuritis or myelitis related to the abnormality (e.g., hypothalamic or brainstem lesions) (e.g., Oh et al., Neurology Research International, vol. 2012, Article ID 460825, 13 (See page 2012).

[0065] In certain aspects, the diagnostic criteria for NMO are not limited to, but include myelitis and optic nerve. The presence of myelitis, along with any two of the following: (i) Expansion of myelitis on spinal MRI. (ii) Normal brain MRI at the time of onset, and (iii) Positive for anti-AQP4 antibody (e.g., Collongues et al. literature, T See her. Adv. Neurol. Disord., 2011, 4:111-121.

[0066] In certain embodiments, what is provided herein is one or more symptoms of NMO in the subject (e.g.) A method for alleviating myelitis, which specifically binds to KIT receptors (e.g., human KIT receptors). The aforementioned method includes administering the binding antibody, or its antigen-binding fragment, to a target that requires it. This is a method. In a particular embodiment, what is provided herein is a method of one or more NMOSDs in the subject. A method to alleviate the above symptoms, specifically binding to KIT receptors (e.g., human KIT receptors). The aforementioned method includes administering the binding antibody, or its antigen-binding fragment, to a target that requires it. It is a method.

[0067] Non-limiting examples of symptoms of NMO or NMOSD include acute optic neuritis (e.g., bilateral) and transverse optic neuritis. Myelitis (e.g., spreading along the long axis), unilateral or bilateral vision loss, eye pain, severe paraplegia, Asymmetrical sensory levels, bladder dysfunction, paroxysmal tonic seizures of the trunk and limbs, and Lermis One example is the rostral extension of cervical spinal cord lesions to the cecum-medulla oblongata junction. It can cause symptoms such as acute respiratory failure, nausea, intractable vomiting, and hiccups. In some aspects, hypothalamic-pituitary axis dysfunction associated with NMO is characterized by hypersomnia and low sodium levels. It can manifest as mucinemia, hypothermia, hypothyroidism, and hyperprolactinemia. Furthermore, symptoms such as confusion, rapid changes in the level of consciousness, cortical blindness, and reversible leukoencephalopathy (PRES) may be present. The imaging findings may also be related to NMO.

[0068] In certain aspects, for the purpose of preventing, treating, or managing NMO or NMOSD, The methods described herein for alleviating one or more symptoms of NMO or NMOSD are as follows: You can achieve one or more of the following: (i) Relief of pain in the eyes; (ii) improved vision; (iii) Inhibition of vision loss or inhibition of further vision loss; (iv) Relief of weakness or numbness in the arms or legs; (v) Inhibition of further weakness or numbness in the arms or legs; (vi) Improvement of bladder and / or bowel control; (vii) Alleviation of sensory impairment; (viii) Reduction or inhibition of paralysis.

[0069] In specific embodiments, the method provided herein reduces the severity of symptoms of NMO or NMOSD. Each can be reduced by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%.

[0070] In certain cases, patients with NMO experience one or more symptoms of NMO appearing for a certain period of time and then subsiding. They are at rest, or have recurrent episodes / recurrent seizures. In certain forms, patients with NMO, Only one episode may be affected. In certain forms, patients with NMO This applies to a certain period of time (for example, at least 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, 25 years). Over a period of 30 years or more, two or more episodes (for example, at least two, three, four, or It may be affected by 5). In some cases, in NMO patients, a certain episode Afterward, difficulty walking and / or residual visual impairment may be observed.

[0071] Therefore, in certain embodiments, what is provided herein is a patient having NMO A method to reduce the number of episodes that appear, and which involves the KIT receptor (e.g., human KIT receptor) Administering an antibody that specifically binds, or an antigen-binding fragment thereof, to a target that requires it. The method includes the above. In some embodiments, the method provided herein includes having NMO A method for shortening the duration of episodes occurring in a patient, wherein KIT receptors (e.g., H) An antibody that specifically binds to the KIT receptor, or an antigen-binding fragment thereof, to the target that requires it. The method includes administering to a person. In a particular embodiment, the method provided herein is A method for lengthening the interepisodic period in patients with NMO, wherein the KIT receptor (e.g.) For example, an antibody that specifically binds to the human KIT receptor, or an antigen-binding fragment thereof, which requires it. The method includes administering the substance to the target.

[0072] In certain embodiments, the anti-KIT antibody or its antigen-binding fragment described herein, or its medical The drug composition is a medication that achieves one or more of the following in subjects diagnosed with NMO or NMOSD. The amount and frequency of administration provided herein for the treatment of NMO or NMOSD It is administered to the subject in need according to the method: a decrease in the number and / or activity of eosinophils, Decreased mast cell proliferation, decreased mast cell number or quantity, inhibition or decrease in mast cell activity, Reduced production of inflammatory factors induced by mast cells, reduced production of inflammatory factors, mast cells Restoration of cytoplasmic homeostasis, decreased mast cell migration, decreased mast cell adhesion, eosinophil mast cell migration Inhibition or reduction of member function, and inhibition or reduction of antigen-mediated degranulation of mast cells.

[0073] In certain embodiments, the methods described herein for preventing, managing, or treating NMOs The method involves using an antibody that specifically binds to KIT (e.g., human KIT), or its antigen-binding fragment, and applying NMO This includes administering it in combination with other therapies for NMO. Non-limited therapies for NMO. Examples include corticosteroids (for example, methylprednisolone) and immunosuppressive drugs (for example) (For example, azathioprine or cyclophosphamide), anti-CD20 antibody (e.g., rituximab), complement Antibodies that target protein C5 (e.g., eculizumab), and antimetabolites (e.g., methotrexate). XART is one example.

[0074] Animal models of NMO have been described (e.g., Jones et al., multiple sclerosis and related diseases). See Disorders (Multiple Sclerosis and Related Disorders), 2002, 1: 174-179. The anti-KIT antibody described herein in a method of treating or managing NMO using this antibody It is possible to confirm and characterize its effectiveness.

[0075] (5.1.2 Neurofibromatosis) In certain embodiments, what is provided herein is a means of preventing and controlling NF in a subject. or a method of treatment, wherein an antibody specifically binds to the KIT receptor (e.g., human KIT receptor), Alternatively, the method includes administering the antigen-binding fragment to a target that requires it. In a particular embodiment, the Specified provides for type 1 NF (NF1) and type 2 NF (NF2) in the subject. , or a method for preventing, managing, or treating schwannomatosis, wherein KIT receptors (for example) An antibody that specifically binds to the human KIT receptor, or an antigen-binding fragment thereof, to the target that requires it. The method includes administering the substance to an elephant.

[0076] NF primarily affects the development and growth of nerve tissue, and is also called neurofibroma. NF is a genetic disorder of the nervous system in which tumors grow along the nerves within the body. Although it is a hereditary disorder, new cases may spontaneously arise through gene mutations. Yes, NF usually occurs in childhood, around 3 to 16 years of age, and sometimes (in children with severe cases) It is diagnosed in infancy.

[0077] Non-specific types of neurofibromatosis include type 1 neurofibromatosis (NF1), type 2 neurofibromatosis (NF2), and schwannomatous neuropathy. NF1 is also known as von Recklinghausen's disease. Phenotypic signs of NF1 include This includes the presence of light brown skin spots at birth or in childhood, and neurofibromas (also known as dermal neurofibromas). A tumor that can grow along the subcutaneous nerves, a plexiform neurofibroma (involving multiple nerves) Examples include tumors (such as those that cause spinal cord and optic nerve tumors), and learning disabilities. In certain forms, NF1 Individuals who have contracted this condition are more likely to develop gastrointestinal stromal tumors (GISTs) than the general population. It is also said that neurofibromas are considered to be external neurofibromas, such as neurofibromas of the skin or dermis. It can be considered an internal neurofibroma, for example, a plexiform neurofibroma. ru.

[0078] NF2 is an autosomal dominant genetic disorder characterized by neurological, ophthalmic, and cutaneous abnormalities. Non-limiting examples of F2 symptoms include hearing loss, tinnitus, visual impairment, balance disorders, and painful skin lesions. These include, in certain forms, the possibility of lower cranial nerve dysfunction and death. Therefore, skull base tumors (including vestibular schwannomas (VS) and meningiomas) in NF2 patients.

[0079] The diagnosis of NF2 is based on NF2-related tumors (e.g., meningioma, schwannoma, ependymoma, glioma, or Bilateral vestibular nerve (also known as neurofibroma), posterior capsule opacification, or a family history of other NF2-related tumors. It can be confirmed by the presence of transsaschondroma (VS) or unilateral VS. It is accompanied by hearing and vestibular impairment. In addition to the pathological condition, the patient may also have other neurological disorders related to VS growth (e.g., other cranial nerves). You may experience (caused by pressure).

[0080] Schwannoma is a more well-known form of neurofibromatosis and shares many features with it. Then, multiple Schwannomas, or tumors of the nerve sheath, are observed, but the characteristic vestibular (ear nerve) Tumors are not seen in NF2. In certain forms, patients with schwannomatosis have nerve sheaths. In other words, tumors develop on the covering (e.g., MacCollin et al., Neurology, 2005, 64:18). (See 38-1845).

[0081] Also provided herein are NF in the subject (e.g., NF1, NF2, or schwannomatous) A method for alleviating one or more symptoms, which specifically binds to KIT receptors (e.g., human KIT receptors). The method includes administering a binding antibody or its antigen-binding fragment to a target that requires it. It is the law.

[0082] In certain embodiments, what is provided herein is NF (e.g., NF1, NF2, or schwannomatous) A method for treating neurofibromas in subjects diagnosed with the condition, wherein the KIT receptor (e.g., human KI) An antibody or its antigen-binding fragment that specifically binds to the T receptor is administered to a target that requires it. The method includes the following:

[0083] In specific embodiments, what is provided herein is NF (e.g., NF1, NF2, or schwannomatous) A method for inhibiting the growth of neurofibromas in subjects diagnosed with the condition, wherein the KIT receptor (for example) An antibody or its antigen-binding fragment that specifically binds to the human KIT receptor, and the target that requires it. The method includes administering to [the body].

[0084] In specific embodiments, what is provided herein is NF (e.g., NF1, NF2, or schwannomatous) A method to prevent neurofibromas in subjects diagnosed with the condition, wherein the KIT receptor (e.g., human KIT receptor) An antibody or its antigen-binding fragment that specifically binds to the substance (or its contents) is administered to the target that requires it. The method includes the following:

[0085] In specific embodiments, the methods provided herein involve NFs (e.g., NF1, NF2, The severity of one or more symptoms of (or schwannomatous) is at least approximately 10%, 20%, 30%, 40%, 50%, or 60%. It can be reduced by 70% or 80%.

[0086] In certain embodiments, the anti-KIT antibody or its antigen-binding fragment described herein, or The pharmaceutical compositions are provided herein in dosages and frequencies of administration that achieve one or more of the following: Methods provided herein for treating NF (e.g., NF1, NF2, or schwannomatous neuropathy) Therefore, it is administered to subjects who need it: NF and / or related to NF in subjects with NF To reduce or improve the severity of one or more related symptoms; symptoms associated with NF in subjects with NF Reduces the number of symptoms and / or the duration of one or more symptoms; reduces NF in subjects with NF and To prevent the onset, progression, or recurrence of one or more related symptoms; to prevent the recurrence of tumors associated with NF. to; hearing loss, tinnitus, visual impairment, balance disorders, and / or related to NF in subjects with NF Relief of painful skin lesions; hearing, auditory function, and / or word recognition in subjects with NF. To improve; to enhance the therapeutic effect of another treatment in subjects with NF or in animal models. It improves; reduces or inhibits the growth of tumors or neoplasms associated with NF, and / or has NF. Tumors associated with NF in subjects or animal models (e.g., neurofibroma, plexiform neurofibroma) To reduce the size (e.g., volume or diameter) of tumors (meningioma, schwannoma, glioma, or ependymoma). To reduce; to improve nerve function, such as hearing, balance, tinnitus, or vision; to reduce tumors in the subject. Stabilization or reduction of surrounding inflammation or edema; and / or methods well known in the art, e.g., Anchor Improvement of quality of life as assessed by the system.

[0087] In certain embodiments, the anti-KIT antibody or its antigen-binding fragment described herein, or its medical The drug composition is administered in a dosage and administration that achieves one or more of the following in subjects diagnosed with NF. This specification provides for the treatment of NF (e.g., NF1, NF2, or schwannomatous neuropathy) at a frequency. It is administered to the subject requiring it according to the method provided in the specification: the number of eosinophils and / or This results in decreased activity, decreased mast cell proliferation, decreased mast cell number or quantity, and inhibition of mast cell activity. Damage or reduction, reduction in the production of mast cell-induced inflammatory factors, production of inflammatory factors Decreased levels of mast cell activity, restoration of mast cell homeostasis, decreased mast cell migration, decreased mast cell adhesion, eosinophilic acid Inhibition or reduction of mast cell recruitment of spheres, and inhibition or reduction of antigen-mediated degranulation of mast cells. under.

[0088] (5.2 Antibodies) Provided herein are the nervous system, such as mast cell-related disorders of the central nervous system, Eosinophil or mast cell-related disorders, e.g., NMO, NMOSD, MS, or NF (e.g., NF1 or NF1) 2) For use in methods to prevent, treat or manage the disease, KIT receptors (e.g.) For example, the extracellular domain of the human KIT receptor as described in Sequence ID No. 1 or Figure 1. It is an antibody that binds heterotoically (e.g., an anti-KIT antibody), or an antigen-binding fragment thereof.

[0089] As used herein, the terms “antibody,” “immunoglobulin,” and “Ig” refer to the technology A term that can be used interchangeably in this specification, and which refers to an antigen that binds to an antigen in an immune-specific manner. This refers to a molecule that has a binding site.

[0090] Examples of antibodies include monoclonal antibodies, recombinant antibodies, and single-cell antibodies. Specific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies Antibody, synthetic antibody, tetrameric antibody containing two heavy chain molecules and two light chain molecules, antibody light chain monomer, anti Heavy chain monomer, antibody light chain dimer, antibody heavy chain dimer, antibody light chain-antibody heavy chain pair, intrabody i, heterocomplex antibodies, single-domain antibodies, monovalent antibodies, single-chain antibodies or single-chain Fv(scFv), Camelized antibody, affibody, Fab fragment, F(ab') fragment, disulfide bond Fv(sdFv), anti- Diotype (anti-Id) antibodies (e.g., including anti-anti-Id antibodies), and any of the above epithet Examples include polymer-binding fragments. In certain embodiments, the antibodies described herein are polymer-binding fragments. This refers to a clonal antibody population. Antibodies are any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, I gA1 or IgA2), or any subclass (e.g., IgG2a or IgG2b) Obtain. In certain embodiments, the antibodies described herein are IgG antibodies, or their class ( For example, human IgG1 or IgG4) or its subclasses.

[0091] As used herein, "antigen" includes an epitope and therefore is affected by an antibody. It is a part or molecule that is specifically bound. In specific embodiments, as described herein The antigen to which the antibody binds is KIT (e.g., human KIT) or a fragment thereof, e.g., KIT (e.g., human KIT) This is the extracellular domain or the D4 region of KIT (e.g., human KIT).

[0092] As used herein, the terms “antigen-binding domain,” “antigen-binding region,” and “antigen binding” are used. "Fragment" and similar terms refer to a fragment that interacts with an antigen and gives the antibody molecule its specificity to the antigen. This refers to the portion of an antibody molecule that contains the amino acid residues that confer the property (e.g., the complementarity-determining region (CDR)). The antigen-binding region is found in rodents (e.g., mice, rats, or hamsters) and humans, It can originate from any animal species. The CDR of the antibody molecule is determined by any method well known to those skilled in the art. It is possible. In particular, CDRs can be determined according to the Kabat numbering system. (Kabat et al. (1991), "Sequences of Proteins of Immunological Interest") of Immunological Interest)” (US Department of Health and Human Services, See Washington, DC, 5th edition). In certain aspects, the CDR of an antibody is (i) this specification The Chothia numbering scheme, referred to as "Chothia CDR" in books (for example, Chothia and Lesk References, 1987, J. Mol. Biol., 196:901-917; References, Al-Lazikani et al., 1997, J. Mol. Bio See l., 273:927-948; and U.S. Patent No. 7,709,226); or (ii) For example, Lefranc, M.-P.'s work, 1999, The Immunologist, 7:132-136 and Lefranc, M.-P. et al.'s work, 1999, Determined according to the IMGT numbering system described in Nucleic Acids Res., 27:209-212. It can be determined.

[0093] As used herein, the term “constant region” or “constant domain” means a region against an antigen. Although not directly involved in antibody binding, it acts as a various effector, such as interacting with Fc receptors. The antibody moiety, e.g., the carboxyl groups of the light and / or heavy chains, which exhibit or contribute to the function. This refers to the terminal portion. These terms are generally different from those of the immunoglobulin variable domain. This refers to a portion of an immunoglobulin molecule that has a conserved amino acid sequence. As used herein, "epitope" is a technical term referring to the specific to which an antibody binds. This refers to a local area of ​​an antigen that can be formed. The region or polypeptide that contributes to the epitope is The epitope may be a sequence of amino acids in a polypeptide, or it may be a sequence of 2 or more amino acids in a polypeptide. It could also be a collection of the non-contiguous regions shown above.

[0094] As used herein, the term "heavy chain" as used in relation to antibodies refers to a constant-state immunoglobulin. Any different type based on the amino acid sequence of IN, for example, alpha (α), delta (δ), Epsilon (ε), gamma (γ), and mu (μ) (these are subclasses of IgG, respectively) For example, the IgA, IgD, IgE, IgG, and IgM classes, including IgG1, IgG2, IgG3, and IgG4. This refers to the process of producing antibodies. In specific embodiments, the heavy chain is a human heavy chain.

[0095] As used herein, the terms “immunely binding” and “immunely recognizing” "Specifically binding" and "specifically recognizing" are similar terms in the context of antibodies. Yes, it binds to antigens (e.g., epitopes or immune complexes) (such binding is known to those skilled in the art). It refers to a molecule that is understood to be a molecule that specifically binds to an antigen. For example, immunoassay, Biacore (trademark), KinExA 3000 instrument (Sapidyne Instruments, Boise Generally, lower when measured by (ID) or other assays known in the art. It may bind to other peptides or polypeptides by affinity. In specific embodiments, A molecule that binds immune-specifically to an antigen is characterized by the K of that molecule when it binds to another antigen. a Less than Also 2log, 2.5log, 3log, 4log, or larger K a It binds to the antigen. In this application method, molecules that bind immunospecifically to the antigen do not cross-react with other proteins. In a specific embodiment, the molecule that binds immunospecifically to the antigen is a non-KIT protein. There is no cross-reaction.

[0096] As used herein, “isolated” or “purified” antibodies are those obtained from which the antibody was obtained. Substantially free of cellular material or other contaminating proteins derived from cells or tissue sources. or, if chemically synthesized, substantially free of chemical precursors or other chemical substances. .

[0097] The term "Kabat numbering" and similar terms are recognized in this technical field and refer to antibodies. Or a system for numbering the amino acid residues in the heavy chain and light chain variable regions of the antigen-binding portion. (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391, and Kabat et al. (1991)) "Sequences of Proteins of Immunological Interest" " (terest)", 5th edition, US Department of Health and Human Services, NIH Publication (No. 91-3242). Using the Kabat numbering system, the CDR within the antibody heavy chain molecule is generally In addition, amino acid positions 31-35 ("CDR1"), amino acid positions 50-65 ("CDR2"), and amino acid positions It is located at 95-102 ("CDR3"). Using the Kabat numbering system, antibody light chain molecules The CDRs within are generally amino acid positions 24-34 (CDR1), amino acid positions 50-56 (CDR2), and ami It is located at positions 89-97 (CDR3).

[0098] As used herein, the term "light chain" as used in relation to antibodies refers to a constant-state immunoglobulin. Any different type based on the amino acid sequence of IN, for example, kappa (κ) or lambda (λ) The light chain amino acid sequence is well known in the art. In a specific embodiment, the light chain is human It is a light chain.

[0099] As used herein, the term "monoclonal antibody" means homogeneous or substantially homogeneous A monoclonal antibody is an antibody obtained from a population of antibodies, and each monoclonal antibody is generally a single antibody on an antigen. This will lead to the recognition of the epitope. The term "monoclonal" refers to the creation of any specific antibody. The method is not limited to this. Generally, a population of monoclonal antibodies is a cell, a population of cells, or a cellular population. It can be produced by cell line. In a specific embodiment, the "monoclonal antibody" is When used herein, a single hybridoma or other cells (e.g., recombinant antibody) An antibody produced by a host cell that produces antibodies, and here, the antibody is used, for example, in ELISA. , or other antigen bindings known in the art or provided herein in the examples or When determined by competitive binding assays, KIT epitopes (e.g., the D4 epitope of human KIT) It binds immunospecifically to (Tope). The monoclonal antibodies described herein include, for example, K The hybridoma was produced using the method described by Ohler et al. in Nature, 256:495 (1975). It is also possible to use the techniques described herein to perform phage-based It can also be isolated from Blarley. Clonal cell lines and monocles expressed therein Other methods for preparing ronal antibodies are well known in the art (for example, "Shoh Molecular Biology"). Short Protocols in Molecular Biology (2002), 5th edition, edited by Ausubel et al. (See Chapter 11 of John Wiley and Sons, New York.) In specific embodiments, Noclonal antibodies are those whose antigen-binding region is specific to the same epitope. In this respect, it is a monospecific antibody. In a further specific embodiment, it is a monoclonal monospecific antibody. Antibodies can be monovalent (having one antigen-binding region) or polyvalent (having two or more antigen-binding regions). For example, it may be bivalent (having two antigen-binding regions).

[0100] As used herein, the term "naked antibody" refers to another drug or molecule (e.g., a label). It is linked, fused, or complexed with (a drug or other substance), peptides, or polypeptides. This refers to antibodies that have not been expressed by mammalian host cells. Antibodies are glycosylated by the host cell's glycosylation mechanism, such as glycosylation enzymes. It is possible. In certain embodiments, naked antibodies can have their own glycosylation When expressed by a host cell that lacks a mechanism, such as glycosylation enzymes, glycosylation occurs. Not converted. In some embodiments, a naked antibody is a complete antibody, and in other embodiments... Therefore, a naked antibody is an antigen-binding fragment of a complete antibody, such as a Fab antibody.

[0101] As used herein, the term "polyclonal antibody" refers to an antigen (single) or an antigen (multiple). Includes various different antibodies against the same epitope and different epitopes within a given number of locations. This refers to an antibody population. Methods for producing polyclonal antibodies are well known in the art (for example, "Short Protocols in Molecular Biology" (2002), See Chapter 11 of the 5th edition, edited by Ausubel et al., John Wiley and Sons, New York.

[0102] As used herein, the term "recombinant human antibody" means an antibody isolated by a recombinant means. Human antibodies that are prepared, expressed, or produced, for example, tragus in host cells Antibodies expressed using recombinant expression vectors that are sensitized, recombinant combina Regarding antibodies isolated from a trial human antibody library and human immunoglobulin genes. animals that are transgenic and / or transchromosomal (e.g., mice, Antibodies isolated from rabbits, goats, or cattle (for example, Taylor, LD et al. (1992) (See Nucl. Acids Res. 20:6287-6295), or, for example, synthetic human immunoglobulins. Genetic manipulation of DNA sequences encoding phosphorus sequences, or encoding human immunoglobulins. Splicing of other such sequences (e.g., human immunoglobulin gene sequences) Prepared, expressed, produced, if by any other means involving production via the g These recombinant human antibodies are used in human germline immunoglobulins. It can have variable and constant regions derived from the Brin array. In certain embodiments, The amino acid sequences of these recombinant human antibodies have been modified, and therefore, recombinant antibodies The amino acid sequences of the VH and / or VL regions are derived from human germline VH and VL sequences and the corresponding Although related to the series, in vivo, within the human antibody germline repertoire, naturally... This is a non-existent sequence. As a non-limiting example, recombinant human antibodies are some human sequences. It can be obtained by rearranging the fragments and assembling them into a composite human sequence of human antibodies. ru.

[0103] As used herein, the term "variable region" or "variable domain" refers to a sequence between antibodies. They differ greatly and are used in terms of the binding and specificity of a particular antibody to that particular antigen. The antibody portion, generally the light chain or heavy chain portion, typically the amino-terminus portion in the mature heavy chain. This refers to 110-120 amino acids and approximately 90-100 amino acids in the mature light chain. The variability of the sequence is complementary. While it is concentrated in a region called the Decision Region (CDR), more highly in the variable domain... The preserved region is called the framework region (FR). While not wanting to be constrained, the CDRs of the light and heavy chains are primarily related to the interaction between antibodies and antigens. This is thought to be the cause. In specific embodiments, the amino of the antibody described herein The numbering of acid positions is based on the literature by Kabat et al. (1991), "The numbering of proteins of immunological interest." "Sequences of Proteins of Immunological Interest," 5th edition, US Department of In Health and Human Services, NIH Publication No. 91-3242 ("Kabat et al."), It follows an EU index such as the following. In certain aspects, the CDR of an antibody is (i) "Chot" as specified herein. The Chothia numbering scheme called "hia CDR" (for example, the Chothia and Lesk literature, 19 87, J. Mol. Biol., 196:901-917; Al-Lazikani et al., 1997, J. Mol. Biol., 273:92 See 7-948; and U.S. Patent No. 7,709,226); or (ii) for example, the text of Lefranc, M.-P. References, 1999, The Immunologist, 7:132-136 and Lefranc, M.-P. et al., 1999, Nucleic A The numbering will be determined according to the IMGT numbering system described in cids Res., 27:209-212. This is possible. In certain embodiments, the variable region is the human variable region. In this case, the variable region includes rodent or mouse CDR and human framework region (FR). In certain embodiments, the variable region is the primate (e.g., non-human primate) variable region. In this embodiment, the variable region is rodents or mouse CDRs and primates (e.g., non-human primates). Includes framework areas (FR). As a non-limiting example, the variable areas described herein include: It is obtained by assembling two or more fragments of a human sequence into a composite human sequence.

[0104] Specifically targeting KIT receptors (e.g., human KIT receptor, e.g., Sequence ID: 1 or as described in Figure 1). We have described antibodies that bind heteroconjugately (e.g., anti-KIT antibodies) or their antigen-binding fragments. Suitable anti-KIT antibodies for use in the method provided are selected as described herein. You can choose.

[0105] In a specific embodiment, eosinophils in the nervous system, such as in the central nervous system, due to mast cell-related disorders. Or mast cell-related disorders, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) Anti-KIT antibodies (e.g., human) for use in methods to prevent, treat, or manage The antibody (or its antigen-binding fragment) contains VL CDR 1-3 (SEQ ID NOs: 2-4) as described in Table 1. This includes the light chain variable region ("VL") and VH CDR 1-3 (SEQ ID NOs: 5-7) as described in Table 1. Includes a heavy chain variable region ("VH"). In certain embodiments, such anti-KIT antibodies are naked. It is an antibody. In a specific embodiment, such an anti-KIT antibody is a bivalent monospecific antibody. In certain embodiments, these anti-KIT antibodies are not bispecific antibodies.

[0106] Table 1: CDR amino acid sequences [Table 1]

[0107] In certain embodiments, an anti-KIT antibody (e.g., a humanized antibody) or an antigen-binding fragment thereof for use in a method for preventing, treating, or managing eosinophil or mast cell-related disorders, such as mast cell-related disorders of the nervous system, e.g., the central nervous system, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2), comprises: (i) a light chain variable region (VL) comprising the amino acid sequence: (wherein X K1 ~X K6 is any amino acid); and (ii) a VH comprising the amino acid sequence: H1 H8 (wherein X is any amino acid). <00?241? K1 In certain embodiments, X K2 is an amino acid having an aromatic or aliphatic hydroxyl side chain, X K3 is an amino acid having an aromatic or aliphatic hydroxyl side chain, X K4 is an amino acid having an aliphatic hydroxyl side chain, X K5 is an amino acid having an aliphatic hydroxyl side chain, or P, X K6 is an amino acid having a charged or acidic side chain, X H1 is an amino acid having an aromatic side chain, X H2 is an amino acid having an aliphatic side chain, X H3 is an amino acid having an aliphatic side chain, X H4 is an amino acid having a polar or basic side chain, or X H5 is an amino acid having an aliphatic side chain, X H6 is an amino acid having an aliphatic side chain, X H7 is an amino acid having an aliphatic side chain, X H8 is an amino acid having an aliphatic side chain, X K1 is an amino acid having a polar or basic side chain, or X K2X is an amino acid having an aliphatic side chain. H5 This is an aliphatic side chain. It is an acid, X H6 X is an amino acid having an acidic side chain. H7 The acidic or amide derivative side It is an amino acid that has a chain, X H8 It is an amino acid that has an aliphatic hydroxyl side chain.

[0109] In a specific implementation, X K1 is an amino acid F or S, and X K2 is amino acid A or S, X K3 is an amino acid T or S, and X K4 is an amino acid S or P, and X K5 is amino acid D or T X K6 is amino acid F or Y, and X H1 is amino acid L or V, and X H2 is, amino Acid L or V, X H3 is amino acid K or R, and X H4 is amino acid V or A, and X H5 teeth , amino acid L or I, X H6 is amino acid E or D, and X H7 It is amino acid Q or E. , X H8 This is the amino acid S or T.

[0110] In a specific embodiment, eosinophils in the nervous system, such as in the central nervous system, due to mast cell-related disorders. Or mast cell-related disorders, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) Anti-KIT antibodies (e.g., human) for use in methods to prevent, treat, or manage The antibody (or its antigen-binding fragment) contains an amino acid sequence selected from Table 2 (SEQ ID NOs: 8-12). The heavy chain variable region ("VH") and / or an amino acid sequence selected from Table 3 (SEQ ID NOs: 13-16) Includes a light chain variable region ("VL"). In certain embodiments, such anti-KIT antibodies are naked It is a divalent antibody. In a specific embodiment, such an anti-KIT antibody is a bivalent monospecific antibody. Yes, in certain embodiments, these anti-KIT antibodies are not bispecific antibodies.

[0111] Table 2: VH amino acid sequence [Table 2]

[0112] Table 3: VL amino acid sequence [Table 3]

[0113] In a specific embodiment, eosinophils in the nervous system, such as in the central nervous system, due to mast cell-related disorders. Or mast cell-related disorders, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) Anti-KIT antibodies (e.g., human) for use in methods to prevent, treat, or manage The antibody (or its antigen-binding fragment) contains the amino acid sequence of SEQ ID NO: 8, VH, and / or sequence number VL containing amino acid sequence number 13. In one embodiment, the anti-KIT antibody or its antigen binding is cleaved. The piece contains VH, which includes the amino acid sequence of SEQ ID NO: 8, and / or the amino acid sequence of SEQ ID NO: 14. Contains VL. In one embodiment, the anti-KIT antibody or its antigen-binding fragment is the amino acid of SEQ ID NO: 8. It comprises VH containing an acid sequence and / or VL containing the amino acid sequence of SEQ ID NO: 15. In one embodiment, The anti-KIT antibody or its antigen-binding fragment contains the amino acid sequence of SEQ ID NO: 8, and / or Contains VL with the amino acid sequence of SEQ ID NO: 16.

[0114] In one embodiment, the anti-KIT antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 9 It includes VH and / or VL containing the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KI The T antibody or its antigen-binding fragment contains the VH, and / or SEQ ID NO: 9 amino acid sequence. The VL contains an amino acid sequence of 14. In one embodiment, the anti-KIT antibody or its antigen-binding fragment. This includes VH containing the amino acid sequence of SEQ ID NO: 9, and / or VL containing the amino acid sequence of SEQ ID NO: 15. It includes. In one embodiment, the anti-KIT antibody or its antigen-binding fragment is the amino acid of SEQ ID NO: 9. It includes VH containing the sequence, and / or VL containing the amino acid sequence of SEQ ID NO: 16.

[0115] In one embodiment, the anti-KIT antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 10 It includes VH and / or VL containing the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KI The T antibody or its antigen-binding fragment contains the amino acid sequence of SEQ ID NO: 10, VH, and / or sequence number VL containing amino acid sequence number 14. In one embodiment, the anti-KIT antibody or its antigen binding is cleaved. The piece contains VH containing the amino acid sequence of SEQ ID NO: 10, and / or the amino acid sequence of SEQ ID NO: 15. It contains VL. In one embodiment, the anti-KIT antibody or its antigen-binding fragment is the amine of SEQ ID NO: 10. It contains VH, which includes a no-acid sequence, and / or VL, which includes the amino acid sequence of SEQ ID NO: 16.

[0116] In one embodiment, the anti-KIT antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 11 It includes VH and / or VL containing the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KI The T antibody or its antigen-binding fragment contains the VH and / or sequence number of the amino acid sequence of SEQ ID NO: 11. VL containing amino acid sequence number 14. In one embodiment, the anti-KIT antibody or its antigen binding is cleaved. The piece contains VH, which includes the amino acid sequence of SEQ ID NO: 11, and / or the amino acid sequence of SEQ ID NO: 15. It contains VL. In one embodiment, the anti-KIT antibody or its antigen-binding fragment is the amine of SEQ ID NO: 11. It contains VH, which includes a no-acid sequence, and / or VL, which includes the amino acid sequence of SEQ ID NO: 16.

[0117] In one embodiment, the anti-KIT antibody or its antigen-binding fragment has the amino acid sequence of SEQ ID NO: 12 It includes VH and / or VL containing the amino acid sequence of SEQ ID NO: 13. In one embodiment, the anti-KI The T antibody or its antigen-binding fragment contains the VH and / or sequence number of the amino acid sequence of SEQ ID NO: 12. VL containing amino acid sequence number 14. In one embodiment, the anti-KIT antibody or its antigen binding is cleaved. The piece contains VH, which includes the amino acid sequence of SEQ ID NO: 12, and / or the amino acid sequence of SEQ ID NO: 15. It contains VL. In one embodiment, the anti-KIT antibody or its antigen-binding fragment is the amine of SEQ ID NO: 12. It contains VH, which includes a no-acid sequence, and / or VL, which includes the amino acid sequence of SEQ ID NO: 16.

[0118] In certain forms, eosinophils or mast cell-related disorders affecting the nervous system, such as the central nervous system. This prevents mast cell-related disorders, such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2). Anti-KIT antibodies or their antigens for use in methods of treating, managing, or controlling The binding fragments are formed by methods described or known in the art (see, for example, Section 5.2.1 below). It can be easily obtained using (the light).

[0119] In certain embodiments, an anti-KIT antibody or so for use in the method provided herein The antigen-binding fragment is specific to the D4 domain of human KIT, and to the D4 / D5 region of KIT, for example, human KIT. Targeted coupling. In another specific embodiment, for use in the method provided herein The anti-KIT antibody or its antigen-binding fragment is attached to the D5 domain of KIT, for example, human KIT, and KIT, for example, human It binds specifically with lower affinity than the D4 domain of KIT. In certain embodiments, The anti-KIT antibody or its antigen-binding fragment for use in the method provided in the details is KIT, for example For example, the D4 domain of human KIT has a higher affinity than the D5 domain of KIT, and is unique. Targeted binding; for example, higher affinity is achieved by methods known in the art, e.g., ELISA or When determined by the Biacore assay, at least 1x, 2x, 3x, 4x, 5x, 10x These are 20 times, 50 times, 100 times, 500 times, or 1000 times.

[0120] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment specifically binds to the D4 or D4 / D5 region of KIT, for example, human KIT, and is essentially D Regarding KIT antigens consisting of only 4 domains, compared to KIT antigens consisting essentially of only the D5 domain... Furthermore, it has an affinity that is at least 1, 2, 3, 4, 5, or 10 times higher.

[0121] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment is determined by analysis described in the art, such as ELISA. In total, the EC levels are approximately 50 nM, 10 nM, 500 pM, 300 pM, 200 pM, 100 pM, or 50 pM, or less than that. 50 ( At the maximum half-dose effective concentration, it specifically binds to KIT polypeptides (e.g., the D4 region of human KIT). .

[0122] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment is used in CHO-WT-KIT cells (which are recombinantly modified to express wild-type human KIT). Analysis described in the art, such as ELISA or FACS, using genetically engineered CHO cells. When determined by the method, the EC is approximately 200 pM or 150 pM or less. 50 Value, KIT Polyp It specifically binds to ptide (for example, the D4 region of human KIT).

[0123] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment specifically binds to the KIT polypeptide (e.g., the D4 region of human KIT) at approximately 600p. M or less IC 50 It is possible to inhibit KIT phosphorylation at the (50% inhibitory concentration) level.

[0124] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment does not bind to the extracellular ligand-binding site of KIT, for example, the SCF-binding site of KIT. No. In certain embodiments, the anti-KIT antibody or for use in the method provided herein is not used. The antigen-binding fragment is determined by a method described in the art, for example, ELISA. In such cases, ligand binding to KIT is not inhibited, for example, the KIT ligand to KIT (e.g., SC) F) Does not inhibit bonding. In certain embodiments, the method provided herein is used The anti-KIT antibody or its antigen-binding fragment does not completely inhibit ligand binding to KIT, It partially inhibits, for example, the methods described in the Art, e.g., ELISA or FAC. When determined by S (fluorescently labeled cell sorting), the binding of the KIT ligand (e.g., SCF) to KIT is determined. , not completely inhibiting, or partially inhibiting

[0125] In specific embodiments, anti-KIT antibodies for use in the methods provided herein (e.g., H Antibodies (or humanized antibodies) are inhibitory antibodies, i.e., KIT activity, i.e., KIT activity of 1 or more It is an antibody that inhibits (for example, partially inhibits) the KIT activity. In a specific embodiment, the KIT activity is Partial inhibition results in, for example, approximately 25% to approximately 65% ​​or 75% inhibition. In specific embodiments, KIT Partial inhibition of activity results in, for example, approximately 35% to approximately 85% or 95% inhibition. Infinite KIT activity Typical examples include KIT dimerization, KIT phosphorylation (e.g., tyrosine phosphorylation), and downstream processes of KIT. Signal transduction (e.g., Stat, AKT, MAPK, or Ras signaling), gene transcription (e.g.) Examples include induction or enhancement of c-Myc, induction or enhancement of cell proliferation or cell survival. In the application method, the antibodies described herein are KIT phosphorylated (e.g., ligand-induced phosphorylation). It inhibits (formulation).

[0126] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment inhibits KIT tyrosine phosphorylation in the KIT cytoplasmic domain.

[0127] In another specific embodiment, an anti-KIT antibody or for use in the method provided herein is used in the method provided herein. Its antigen-binding fragment inhibits cell proliferation, such as mast cell proliferation or eosinophil proliferation. In yet another specific embodiment, anti-KIT The body or its antigen-binding fragments inhibit cell survival, such as mast cell survival or eosinophil cell survival. In certain aspects, inhibition of cell proliferation, such as mast cell proliferation or eosinophil proliferation, It is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0128] In another specific embodiment, an anti-KIT antibody or for use in the method provided herein is used in the method provided herein. Its antigen-binding fragment inhibits mast cell activation or eosinophil activation in certain manner. The activation or inhibition of mast cell activity or eosinophil activity is less likely to occur. The percentages are 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0129] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment is used in the degranulation of eosinophils or mast cells (e.g., Staats et al., 2012, Med). Chem. Commun., 2013, 4:88-94; and Ochkur et al., 2012, J. Immunol. Methods, 384. It inhibits (see 10-20). In certain embodiments, it inhibits the degranulation of eosinophils or mast cells. The inhibition is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0130] In another specific embodiment, an anti-KIT antibody or for use in the method provided herein is used in the method provided herein. Its antigen-binding fragment inhibits mast cell mediator release. In certain embodiments, Mast cell mediator release is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, and 80%. , or 90%. Mast cell activity (mast cell culture lines such as rodent and human mast cell culture lines) Analysis to measure mediator releases from cultivated plants, etc., is described (for example). Kuehn et al.'s paper, "Measurement of mast cell mediator release," Current Prototypes in Immunology Within the Current Protocols in Immunology (COL), Units 7.38.1-7.38.9, November 2010 (John See Wiley & Sons). In some forms, CD34 + Peripheral blood progenitor cells or mast cells Cell lines, such as HMC-1 or human LAD2 mast cell lines, are used in these analyses. The effect of anti-KIT antibodies against cytocytes can be confirmed.

[0131] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragments are used to induce apoptosis, such as mast cell apoptosis or eosinophil apoptosis. To induce. In another specific embodiment, for use in the method provided herein Anti-KIT antibodies or their antigen-binding fragments induce cell differentiation, such as mast cell differentiation.

[0132] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment can achieve one of the following: the number of eosinophils and / or This results in decreased activity, decreased mast cell proliferation, decreased mast cell number or quantity, and inhibition of mast cell activity. Damage or reduction, decreased production or release of mast cell-induced inflammatory factors, inflammatory factors Reduced release of offspring, restoration of mast cell homeostasis, reduced mast cell migration, reduced mast cell adhesion. Below, inhibition or reduction of eosinophil mast cell recruitment, and inhibition of antigen-mediated degranulation of mast cells. Harm or reduction.

[0133] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment inhibits KIT activity but does not inhibit KIT dimerization. Another specific implementation In some embodiments, an anti-KIT antibody or its antigen-binding cleavage for use in the methods provided herein. One inhibits KIT activity but does not inhibit ligand binding to KIT. For example, KIT ligand binding to KIT It does not inhibit Gand (e.g., SCF) binding, but it inhibits KIT dimerization.

[0134] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment exhibits KIT activity such as ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain. This can be done using cell-based phosphorylation assays well known in the art, for example, the detailed assays described herein. When determined by a cytoplasm-based phosphorylation assay, inhibition ranges from approximately 25% to approximately 65% ​​or 75%. In certain embodiments, an anti-KIT antibody or for use in the method provided herein is used. Its antigen-binding fragment is linked to ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain, etc. The activity can be measured using cell-based phosphorylation assays well known in the art, for example, as described herein. When determined by a cell-based phosphorylation assay, approximately 35% to approximately 85% or 95% inhibition occurs. To harm.

[0135] In certain embodiments, an anti-KIT antibody or the like for use in the method provided herein is used. The antigen-binding fragment exhibits KIT activity such as ligand-induced tyrosine phosphorylation of the KIT cytoplasmic domain. This can be done using cell-based phosphorylation assays well known in the art, for example, the detailed assays described herein. When determined by a cytoplasm-based phosphorylation assay, the levels are less than approximately 600 pM or less than approximately 500 pM. , or a 50% inhibitory concentration (IC) of less than approximately 250 pM 50 ) inhibits it. In a specific embodiment, IC 50 It is approximately 55 It is 0 pM or less than 200 pM. In specific embodiments, IC 50 The range is approximately 50 pM to 225 pM, The range is 100 pM to approximately 600 pM. In a specific embodiment, the IC 50 It is approximately 50 pM to 550 pM, and The radiation levels are in the range of approximately 50 pM to 600 pM, or approximately 150 pM to 550 pM.

[0136] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment (i) immunospecifically binds to the KIT polypeptide containing the D4 region of human KIT. (ii) inhibiting KIT phosphorylation (e.g., tyrosine phosphorylation), and (iii) KIT ligation to KIT It does not completely inhibit (e.g., SCF) binding, or it partially inhibits it. In this embodiment, these antibodies do not inhibit the dimerization of KIT. In yet another specific embodiment... These antibodies are administered at an average titer of at least 0.5 μg / mL, for example, at least 1.0 μg / mL. It can be expressed by recombinant expression using CHO cells. In further specific embodiments... These antibodies are non-immunogenic and contain VH and VL domains, for example, The VH and VL domains do not contain T cell epitopes.

[0137] In other specific embodiments, an anti-KIT antibody or for use in the method provided herein is used. Its antigen-binding fragments bind immunospecifically to monomeric KIT (e.g., human KIT). In the embodiments, an anti-KIT antibody or its antigenic antibody for use in the method provided herein is used. The composite fragment specifically binds to monomeric KIT (e.g., human KIT). In a specific embodiment, The anti-KIT antibody or its antigen-binding fragment for use in the method provided in the specification is a dimer. It specifically binds to KIT of a certain type (e.g., human KIT).

[0138] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment does not bind to monomeric KIT, but does not bind to dimeric or polymeric KIT. It binds specifically to the KIT monomer. In certain embodiments, the antibody binds to the KIT dimer. It also has a higher affinity. In certain embodiments, the antibody is a large amount of KIT monomer relative to the KIT monomer. It has a higher affinity than the body.

[0139] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment is a natural isoform or natural variant of KIT (animal, preferably human). Animals (e.g., monkeys, mice, goats, donkeys, dogs, cats, etc.) can be isolated from these animals. Naturally occurring isophores of KIT in herons, pigs, rats, humans, frogs, or birds It specifically binds to (or a variant of). In certain embodiments, the method provided herein Anti-KIT antibodies or their antigen-binding fragments for use under the law are specific to human KIT or its fragments. Targeted bonding. In specific embodiments, anti-KI for use in the methods provided herein. The T antibody or its antigen-binding fragment specifically binds to human KIT or its fragment, and non-human KI. T (for example, monkeys, mice, goats, donkeys, dogs, cats, rabbits, pigs, rats, or birds) It does not specifically bind to the fragment. In specific embodiments, the method provided herein The anti-KIT antibody or its antigen-binding fragment for use is specifically bound to human KIT or its fragment. It binds, and does not specifically bind to the mouse kit. In certain embodiments, as described herein The anti-KIT antibody or its antigen-binding fragment for use in the method provided is human KIT or its fragment One side (for example, the D4 region of the human KIT), and the canid (dog) and non-human primate (e.g., monkey) KIT It specifically binds to. In certain embodiments, the use in the method provided herein The anti-KIT antibody or its antigen-binding fragment is human KIT or its fragment (e.g., the D4 region of human KIT). It specifically binds to KIT in canids (dogs) and non-human primates (e.g., monkeys), It does not specifically bind to mouse or rat KIT or its fragments (e.g., the D4 region of mouse KIT).

[0140] In certain embodiments, an anti-KIT antibody or for use in the method provided herein is used. The antigen-binding fragment is attached to human KIT or a fragment thereof (e.g., the D4 region of human KIT), and to canids. It specifically binds to dogs, felines (cats), and cynomolgus monkeys (KIT). However, it does not specifically bind to mouse or rat KIT or a fragment thereof (e.g., the D4 region of mouse KIT). stomach.

[0141] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment is attached to human KIT or a fragment thereof (e.g., the D4 region of human KIT), and to canids ( Dogs), felines (cats), and cynomolgus monkeys KIT, mouse or rat KIT or fragments thereof ( For example, higher affinity (e.g., at least 0.5 times, 1 time) for the D4 region of the mouse kit. It binds specifically at 2x, 3x, 4x, 5x, or 10x the amount.

[0142] In certain embodiments, an anti-KIT antibody or for use in the method provided herein is used. The antigen-binding fragment is affected by mutations, such as somatic mutations, such as exon 9 of human KIT. Human KI containing a mutation (in this case, duplication of Ala and Tyr residues at positions 502 and 503) It specifically binds to the extracellular domain of T (for example, the KIT mutation is described, both of them). The entire work by reference to Marcia et al., (2000) Am. J. Pathol. is incorporated herein by reference. 156(3):791-795; and Debiec-Rychter et al., (2004) European Journal of Cancer. 40 (See pages 689-695).

[0143] In certain embodiments, an anti-KIT antibody or for use in the method provided herein is used. The antigen-binding fragment specifically binds to the extracellular domain of glycosylated human KIT. In certain embodiments, the antibodies or antigen-binding fragments described herein are human KIT It binds to two different types of glycosylated extracellular domains. For example, different types Two types of human KIT with different molecular weights exhibiting lycosylation patterns were identified by immunoblotting. This has been observed. In certain embodiments, the antibodies described herein are different glyco Having a sylation pattern (for example, one type is more glycosylated than the other type) It can specifically bind to both of these types of human KITs. In certain embodiments The antibodies or antigen-binding fragments described herein are of non-glycosylated human antibodies. It binds to the extracellular domain of KIT.

[0144] In specific embodiments, an anti-KIT antibody or the method provided herein is used in the method. The antigen-binding fragment has two antigen-binding regions (for example, two identical antigen-binding regions), and Both antigen-binding domains specifically bind to the same antigen, namely KIT (e.g., human KIT). In this respect, it is a bivalent monospecific antibody. In certain embodiments, the antigen-binding region is shown in Table 1. Includes VH and VL CDR as described above. In certain embodiments, the antigen-binding region is the SEQ ID NO: VH containing any one amino acid sequence from 8 to 12, and / or one of sequence numbers from 13 to 16. Includes a VL containing the amino acid sequence. In certain embodiments, the method provided herein uses Anti-KIT antibodies or their antigen-binding fragments intended for use are not bispecific antibodies.

[0145] In certain embodiments, the anti-KIT antibody for use in the methods described herein is KIT This is a Fab fragment that immunospecifically binds to the D4 region of polypeptides, such as KIT. Specific implementation details In this specification, the antibody used in the method described herein is a monoclonal antibody or This is an isolated monoclonal antibody. In another specific embodiment, the method described herein The antibodies used in the law are humanized monoclonal antibodies. In certain embodiments, The antibodies used in the methods described herein are recombinant antibodies, for example, recombinant These are human antibodies, recombinant humanized antibodies, or recombinant monoclonal antibodies. In the application, the antibody for use in the method described herein is a non-human amino acid sequence For example, containing non-human CDR or non-human (e.g., non-human primate) framework residues. .

[0146] In certain embodiments provided herein, recombinant antibodies are used, for example, to traverse host cells. Antibodies expressed using an immunized recombinant expression vector, recombinant combina Antibodies isolated from a trial antibody library, or, for example, synthesized human immunoglobulins. Genetic manipulation of DNA sequences that encode sequences, or sequences that encode human immunoglobulins ( For example, via splicing to other such sequences (e.g., the human immunoglobulin gene sequence). Prepared, expressed, produced, or isolated by any other means involving production. Antibodies, etc., are isolated, prepared, expressed, or produced by recombinant means. This is possible. In certain embodiments, the amino acid sequence of such recombinant antibodies is such These antibodies are modified, and therefore, the amino acids in the VH and / or VL regions of these antibodies are modified accordingly. The sequence is from the in vivo antibody germline repertoire of an organism, e.g., mouse or human germline. The sequence is not naturally occurring within the repertoire. In certain embodiments, recombinant antibodies By collecting and recombining several naturally occurring sequence fragments in living organisms (for example, primates such as humans), The composite sequence of recombinant antibodies (here, the synthetic sequence is from an organism (for example, a primate such as a human)) It can be obtained by (not naturally occurring) creating something within it.

[0147] The antibodies for use in the methods provided herein may be of any type (e.g., I (IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, Examples include immunoglobulin molecules of IgA2, or subclasses of immunoglobulin molecules. In specific embodiments, the antibody for use in the methods provided herein is an IgG antibody (e.g., For example, human IgG antibodies, or their class (e.g., human IgG1 or IgG4) or subclass Yes. In another specific embodiment, the antibody for use in the method described herein is It is an IgG1 antibody (for example, human IgG1 (isotype a, z, or f)) or an IgG4 antibody. In the embodiments, the antibody for use in the methods described herein is a complete antibody or a total antibody. The body, for example, humanized, human, or composite human complete or whole antibody. .

[0148] The antibodies provided herein are antigens, for example, KIT epitopes (e.g., the D4 region of human KIT). Antibodies that possess the ability to specifically bind to the KIT epitope in the KIT polypeptide they contain. It may include fragments. In a specific embodiment, the fragment may include a Fab fragment (containing an antigen-binding domain). It has and is bridged by disulfide bonds, and a part of the light chain and heavy chain (i.e., the V of the heavy chain) Antibody fragment containing H and CH1 domains); Fab' (Fab and additional heavy chain portion through the hinge region) Antibody fragment containing a single antigen-binding domain; F(ab')2 (chain in the hinge region of the heavy chain) Two Fab' molecules connected by an interdisulfide bond; these Fab' molecules are either the same or different. It can be induced to a different epitope; bispecificity Fab (each can be induced to a different epitope) A Fab molecule having two antigen-binding domains; a single-chain Fab chain containing a variable region, also known as sFv(10~2) Variable antigen binding resolution of a single light chain and heavy chain of an antibody linked by a chain of five amino acids. (Constant region); disulfide bonded Fv, or dsFv (linked by disulfide bonds) The variable antigen-binding determination regions of the single light and heavy chains of the antibody); camelized VH (VH junction region) These amino acids are found in the heavy chain of naturally occurring camel antibodies, Variable antigen-binding determination region of a single heavy chain; dual specificity sFv (each induces a different epitope). sFv or dsFv molecules having two antigen-binding domains that may be possible); diabody (VH of the first sFv) The domain meets the VL domain of the second sFv, and the VL domain of the first sFv meets the VH domain of the second sFv The two antigen-binding regions of the dimerized sFv;diabody, which are formed when it associates with the main, are , which can be induced to the same or different epitopes; as well as triabodies (similar to diabodies). It is formed in the manner of a trimer, but three antigen-binding domains are created within a single complex. (These three antigen-binding domains can be induced to the same or different epitopes.) Included. The antibodies provided herein may also include one or more CDR sequences of the antibody. If the above CDR sequences exist, these CDR sequences should be concatenated on the scaffold. This is possible. In certain embodiments, the antibody contains a single-chain Fv ("scFv"). scFv is the VH of the antibody. And antibody fragments containing VL domains, where these domains are single polypept It is present within the tide chain. Generally, scFv polypeptides have scFv in the desired structure for antigen binding. Further the polypeptide linker between the VH domain and the VL domain to enable the formation of Includes. For a review of scFv, see "The Pharmacology of Monoclonal Antibodies". "Occlonal Antibodies," Volume 113, edited by Rosenburg and Moore, Springer-Verlag, New York. See Pluckthun's literature on pp. 269-315 (1994). Not bound by any particular theory. However, because Fv molecules are small in size, they can penetrate tissues. It can also be enzymatically cleaved by pepsin to produce the F(ab')2 fragment, or papain It can also be enzymatically cleaved to produce two Fab fragments.

[0149] In certain embodiments, the anti-KIT antibody for use in the methods described herein is These are human, compound human, or humanized monoclonal antibodies. In certain embodiments, as specified herein. The antibodies used in the methods described herein are genetically modified antibodies, for example, recombinant antibodies. The antibody is produced by the method. In specific embodiments, the antibody described herein is 1 The above non-human (e.g., rodent or mouse) CDRs and one or more human framework regions (FRs), Furthermore, it is a humanized antibody that optionally includes a human heavy chain constant region and / or a light chain constant region. In a specific embodiment, the antibodies described herein are used in the treatment of one or more primates (or non-human primates). Includes the mulwork region. In specific embodiments, the antibodies described herein are used in non-human primates. Does not include the framework area.

[0150] The antibodies for use in the methods provided herein include chemically modified antibodies, for example For example, an antibody that has been chemically modified by the covalent bonding of any type of molecule to the antibody. This may include, for example, although not intended to be limiting, anti-KIT antibodies may include glycosylation and acetylation. It can also be pegylated, phosphorylated, or amidated, via a protecting / blocking group. It can also be derivatized, and cell ligands and / or other proteins or peptides. It may also further include the following. For example, the antibodies provided herein may include, for example, glycosyl Formation, acetylation, pegylation, phosphorylation, amidation, induction by known protecting / blocking groups Through conduction, proteolytic cleavage, binding to cell ligands or other proteins, etc. Furthermore, the anti-KIT antibodies described herein can be chemically modified. It may contain non-classical amino acids.

[0151] In specific embodiments, the anti-KIT antibody for use in the methods provided herein is a separate component. The child, peptide, or polypeptide (e.g., a different polypeptide) can be linked or fused to form a complex. It is a naked antibody that has not undergone any complex formation (for example, artificial linking, fusion, or complex formation). In certain embodiments, the anti-KIT antibody for use in the methods provided herein is anti- Not a body-drug conjugate. In certain embodiments, the use in the methods provided herein The anti-KIT antibody for this purpose is not a fusion protein. In certain embodiments, as described herein... The anti-KIT antibody contains no non-classical amino acids.

[0152] (5.2.1 Antibody Production) Antibodies described herein that bind immunospecifically to the KIT antigen (e.g., human or humanized) An antibody (or its antigen-binding fragment) is used in any method known in the art for the synthesis of an antibody. Therefore, it can be produced, for example, by chemical synthesis or by recombinant expression technology. The methods described herein, unless otherwise indicated, are in the fields of molecular biology, microbiology, and genetic analysis. Recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hives Redylation, and using conventional techniques in the relevant fields within the scope of the capabilities of those skilled in the art These techniques are described in the references cited herein, and are also documented in the literature. It is explained thoroughly within the text. For example, Maniatis et al. (1982), "Molecular Cloning: Actual Laboratory Manual (Molecular Cloning: A Laboratory Manual), Cold Spring Harbor Laboratories atory Press; Sambrook et al. (1989), "Molecular Cloning: Experimental Manual (Molecular Cloning: A Laboratory Manual), 2nd edition, Cold Spring Harbor Laboratory Press; Sa mbrook et al. (2001), "Molecular Cloning: A Lab" Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al.'s paper, "Current Protocols in Molecular Biology" "Immunology" by John Wiley & Sons (1987 and annual revisions); "The Latest Protocols in Immunology (Curren "Protocols in Immunology," John Wiley & Sons (1987 and annual revisions), Gait (ed.) (19 84) "Oligonucleotide Synthesis: A Practical Approach" "Callical Approach," IRL Press; Eckstein (ed.) (1991), "Alkyl Oligocytes and Analogues" "A Practical Approach: Oligonucleotides and Analogues," IRL Pr ess; Birren et al. (eds.) (1999), "Genome Analysis: A Laboratory Manual" See "ry Manual" and Cold Spring Harbor Laboratory Press.

[0153] For example, humanized antibodies are used in CDR transplantation (European Patent EP 239,400; International Publication W). U.S. Patent No. O 91 / 09967; and U.S. Patents No. 5,225,539, 5,530,101, and 5,585,089), Nearing or resurfacing (European Patents EP 592,106 and EP 519,596; Padlan's text) References, 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka et al., 1994, Protein Engineering 7(6):805-814; and Roguska et al., 1994, PNAS 91:969-973), chain shutter Fling (US Patent No. 5,565,332), and, for example, US Patent No. 6,407,213, US References: Nos. 5,766,886, WO 9317105, Tan et al., J. Immunol. 169:1119 25 (2002), Caldas et al. References: Protein Eng. 13(5):353-60(2000), Morea et al., Methods 20(3):267-79(200) 0), Baca et al., J. Biol. Chem. 272(16):10678-84(1997), Roguska et al., Protei n Eng. 9(10):895 904(1996), Couto et al., Cancer Res. 55(23 Supp):5973s-5977s(1 995), Couto et al., Cancer Res. 55(8):1717-22(1995), Sandhu JS, Gene 150( 2):409-10(1994), and disclosed in the literature by Pedersen et al., J. Mol. Biol. 235(3):959-73(1994) It can be produced using various technologies known in this field, including the technologies that have been developed. . U.S. Patent Publication U.S. 2005 / 0042664 A1 (February 24, 2005) is incorporated herein by reference. See also (Japan).

[0154] Monoclonal antibodies utilize hybridoma, recombinant, and phage display technologies. Or using a wide variety of techniques known in the art, including the use of combinations thereof. It can be prepared by the following methods. For example, monoclonal antibodies can be prepared by the following methods, and For example, see the literature by Harlow et al., "Antibodies: A Laboratory Manual" (Cold Spring Harbor Laboratory Press, 2nd edition, 1988); Hammerling et al.: "Mono" Clonal Antibodies and T-Cell Hybridoma Hybridoma, including the technique taught in s) 563 681 (Elsevier, NY, 1981) It can be produced using the technology. The term "monoclonal antibody" as used herein. This is not limited to antibodies produced through hybridoma technology. For example, monoclonal Non-antibodies can be produced by recombinant technology, for example, recombinant monoclonal Antibodies can be expressed in host cells, such as mammalian host cells.

[0155] Methods for producing and screening specific antibodies using hybridoma technology are available. This is a well-known fact in the art. For example, in the hybridoma method, mice or other Suitable host animals, such as sheep, goats, rabbits, rats, hamsters, or macaques. Immunizing the sieve, the proteins used for immunization (e.g., the extracellular domain of human KIT) ) induces lymphocytes that produce or are capable of producing antibodies that specifically bind to ) To induce the release of lymphocytes. Alternatively, lymphocytes may be immunized in vitro. After that, the lymphocytes are then... Using appropriate fusion agents such as ethylene glycol, myeloma cells are fused to hybrid cells. Forms monoclonal cells (Goding's literature, "Monoclonal Antibodies: Principles and Practice (Monoclonal Antibodies: Principles and Practice), pp. 59-103 (Academic Press, 1986)). Sara Using RIMMS (repetitive immunization multiple sites) technology This allows for the immunization of animals (see the text by Kilptrack et al. incorporated herein by reference). 1997 Hybridoma 16:381-9).

[0156] Non-limiting examples of myeloma cell lines include mouse myeloma lines, for example, Salk Institute Cell MOPC-21 and MPC-11 mouse tumors are available from the Distribution Center, San Diego, CA, USA. From sores, and from the American Type Culture Collection, Rockville, MD, USA Available SP-2 or X63-Ag8.653 cells are examples. Human myeloma and mouse-human xenobone marrow. Tumor cell lines have also been described for the production of human monoclonal antibodies (Kozbor literature, J. Immunol., 133:3001 (1984); Brodeur et al., "Monoclonal Antibody Production Technology and Applications ( "Monoclonal Antibody Production Techniques and Applications", pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0157] The antibodies described herein recognize specific KIT antigens and are capable of any technique known to those skilled in the art. It includes antibody fragments that can be prepared by technique. For example, Fa as described herein. The b and F(ab')2 fragments are produced by papain (to produce the Fab fragment) or pepsin (to produce the F(ab')2 fragment). By using enzymes such as (to produce) the proteolytic cleavage of immunoglobulin molecules. It can be produced by [method]. The Fab fragment corresponds to one of the two identical arms of the antibody molecule. It contains a complete light chain paired with the VH and CH1 domains of the heavy chain. The F(ab')2 fragment is hinged It contains two antigen-binding arms of an antibody molecule linked by a disulfide bond within the region. ru.

[0158] In one embodiment, in order to produce a complete antibody, the VH or VL nucleotide sequence, restriction site, and Using PCR primers containing a flanking sequence to protect the restriction site, the template, For example, VH or VL sequences can be amplified from scFv clones. Using a blending technique, the PCR-amplified VH domain is converted into a vector expressing the VH constant region. It can be cloned, and the PCR-amplified VL domain can be used in the VL constant region, for example, human ka It can be cloned into a vector expressing the constant region of the pp or lambda. VH and VL The domain can also be cloned into a single vector that expresses the required constant region. Subsequently, using techniques known to those skilled in the art, the heavy chain conversion vector and the light chain conversion vector are obtained. Simultaneous introduction into cell lines creates stable or transient cell lines expressing full-length antibodies, such as IgG. do.

[0159] Single-domain antibodies, such as antibodies lacking a light chain, are produced by methods well known in the art. It is possible. Riechmann et al., 1999, J. Immunol. 231:25-38; Nuttall et al. References, 2000, Curr. Pharm. Biotechnol. 1(3):253-263; Muylderman's Literature, 2001, J. Biot echnol. 74(4):277302; U.S. Patent No. 6,005,079; and International Publications WO 94 / 04678, WO 94 / 2 See Issue 5591 and WO 01 / 44301.

[0160] (5.3 Composition) Provided herein are one or more anti-K for use in the methods described herein. A composition such as a pharmaceutical composition containing an IT antibody (e.g., a humanized antibody) or an antigen-binding fragment thereof. In certain embodiments, the compositions described herein may be used in vitro, in vivo, or ex vitro. It may be for vivo applications. In specific embodiments, what is provided herein is Anti-KIT antibody (e.g., humanized antibody) (or its antigen) for use in the method described in the specification A pharmaceutical composition comprising a binding fragment and a pharmaceutically acceptable carrier or excipient.

[0161] As used herein, the term “medically acceptable” means animals, more specifically, humans. Approved for use in the United States by a federal or state government regulatory authority, This information is listed in the United States Pharmacopeia, the European Pharmacopeia, or other generally accepted pharmacopoeias. It means.

[0162] A therapeutic formulation containing one or more antibodies (e.g., humanized antibodies) provided herein is desired An antibody having a purity of the degree of [missing information], in any physiologically acceptable carrier, excipient, or stabilizer ( "Remington's Pharmaceutical Sciences" (1990) Mack Published Remington Co., Easton, PA; "Remington: The Science and Practice of Pharmaceutical Preparation" 21st edition (2006) Lippincott Williams & Wilkins, Baltimore, MD) By mixing with it, it can be prepared for storage in the form of a lyophilized preparation or an aqueous solution. It is possible. Acceptable carriers, excipients, or stabilizers are permitted in the recipe at the dosage and concentration used. These are non-toxic to the body, and include buffering agents such as phosphates, citrates, and Other organic acids, etc.; and / or nonionic surfactants, e.g., TWEEN®, PLURONICS® Examples include polyethylene glycol (PEG).

[0163] The formulations described herein, and other formulations, are used in the following ways as necessary for the specific indication being treated. A combination of two or more active compounds (e.g., molecules, for example, one antibody as described herein or an antibody ( It may also contain multiple ()). In certain embodiments, the formulation may contain the anti- It contains the body and one or more active compounds that have complementary activities that do not adversely affect each other. The molecules are present in appropriate combinations in amounts that are effective for the intended purpose.

[0164] The formulation to be used for in vivo administration may be sterile. For example, this can be easily achieved by filtering through a sterile filtration membrane.

[0165] In specific embodiments, the pharmaceutical compositions provided herein are contained in a pharmaceutically acceptable carrier. The therapeutically effective dose provided herein is one or more anti-KIT antibodies (e.g., humanized antibodies), and one or more other antibodies. It contains additional prophylactic or therapeutic agents. Such pharmaceutical compositions include NMO, NMOSD, MS, NF (e.g.) For example, prevention of eosinophil or mast cell-related disorders such as NF1 or NF2, or one or more of their symptoms. It is useful for treatment, management, or improvement.

[0166] The pharmaceutical carriers suitable for administering antibodies provided herein are suitable for specific administration methods. This includes any such carrier known to those skilled in the art.

[0167] Furthermore, the antibodies described herein are formulated as the sole pharmaceutically active ingredient in a composition. It is also possible to combine it with other active ingredients (for example, one or more other preventive or therapeutic agents). It is also possible.

[0168] The composition may contain one or more anti-KIT antibodies provided herein. One Embodiment The antibody is then administered in a sterile solution or suspension for parenteral administration, in the form of a liquid, suspension, powder, or It is formulated into appropriate pharmaceutical preparations such as elixirs. In one embodiment, the antibody is used Liquids, suspensions, tablets, dispersible tablets, pills, capsules, powders, and sustained-release formulations for oral administration. , or appropriate pharmaceutical preparations such as elixirs, as well as transdermal patch preparations and dry powders It is formulated into an inhaler.

[0169] In such compositions, one or more antibodies (or complexes thereof) provided herein are suitable It is mixed with a suitable pharmaceutical carrier. The concentration of one or more antibodies in the composition is, for example, At the time of administration, eosinophil or mast cell-related disorders such as NMO, NMOSD, MS, and NF (e.g., NF1 or NF2) may occur. Effective in delivering a quantity that treats, prevents, mitigates, or controls the harm or one or more of its symptoms. It is possible.

[0170] In one embodiment, the composition is formulated for single-dose administration. To achieve this, a certain weight fraction of the compound is used to alleviate, prevent, or treat the condition being treated. Dissolve or suspend in a selected carrier at an effective concentration that improves one or more symptoms. To disperse, mix, or otherwise combine.

[0171] In certain embodiments, the antibodies provided herein (e.g., humanized antibodies) (or the antibody-drug compound) The combination (of drugs) is free from, or minimizes, or eliminates, undesirable side effects for the patient being treated. In an effective dose sufficient to produce therapeutically useful effects, accompanied by visible side effects, as a medicine. It is contained in an acceptable carrier. A therapeutically effective concentration is obtained by using the compound in a routine manner. This can be determined experimentally by testing in vitro and in vivo systems, After that, it is possible to estimate the dosage for humans.

[0172] The concentration of the antibody in the pharmaceutical composition is determined, for example, by the physicochemical properties of the antibody, the administration schedule, and the amount administered, as well as other factors known to those skilled in the art, will depend on certain aspects. So, what is the concentration of the antibody-drug conjugate in the pharmaceutical composition? For example, the physicochemistry of the antibody and / or drug. It depends on the specific characteristics, the dosage schedule, the amount administered, and other factors known to those skilled in the art. This will happen.

[0173] In one embodiment, the therapeutically effective dosage is approximately 0.1 ng / ml to approximately 50-100 μg / ml of serum concentration. It produces antibodies of a certain degree. In another embodiment, the pharmaceutical composition provides, for example, over a certain period of time. For daily, weekly, every two weeks, or every three weeks administration, approximately 0.001 mg per kilogram of body weight. It provides antibodies in dosages of approximately 2000 mg. The drug unit dosage form is approximately 0.01 mg to approximately 20 mg per unit dosage form. 00 mg, in one embodiment, a combination of approximately 10 mg to approximately 500 mg of antibody and / or other optional essential components. It can be prepared to provide.

[0174] In certain embodiments, the antibody-drug conjugates described herein are used over a period of time, for example. For example, for daily, weekly, every two weeks, or every three weeks administration, the antibody-drug conjugate, body weight 1 It is administered at an effective dose of approximately 1 to 100 mg per kilogram.

[0175] The anti-KIT antibodies described herein can be administered all at once or at intervals of time. It can also be divided into several smaller doses to be administered. Precise dosage The duration of treatment is a function of the disease being treated and is based on experience using known test protocols. This can be determined either by estimation or by estimation from in vivo or in vitro trial data. It will be understood that this is possible. The values ​​for concentration and dosage will also depend on the severity of the condition to be alleviated. It should be noted that this can fluctuate. For any specific subject, a specific medication register Men, in accordance with the individual needs and the professional judgment of the person who manages or supervises the administration of the composition, It can be adjusted over time, and the concentration range described herein is merely illustrative. Furthermore, it is not intended to limit the scope or implementation of the claimed composition. This should be understood.

[0176] When antibodies are mixed or added, the resulting mixture may be a liquid, a suspension, an emulsion, or the like. The form of the resulting mixture depends on the intended mode of administration and the selected carrier or vial of the compound. It depends on several factors, including solubility in hicle. The effective concentration is determined by the treatment. It is sufficient to improve the symptoms of a disease, disorder, or condition and can be determined by experiment. ru.

[0177] The pharmaceutical compositions described herein are for use in humans and animals, such as mammals (e.g., cats or dogs). For administration to the patient, it contains an appropriate amount of the compound or a pharmaceutically acceptable derivative thereof. It is provided in unit dosage forms such as sterile parenteral (e.g., intravenous) liquid or suspension. Furthermore, for administration to humans and animals, such as mammals (e.g., cats or dogs), an appropriate amount Tablets, capsules, pills, powders containing the compound or a pharmaceutically acceptable derivative thereof, It is provided in unit dosage forms such as granules, oral liquids or suspensions, and oil-water emulsions. In one embodiment, the antibody is formulated and administered in a single-dose or repeated-dose form. The unit dose forms used are those suitable for human and animal subjects and known in the art. This refers to physically separated units that are individually packaged. Each unit dose is as needed. In relation to a pharmaceutical carrier, vehicle, or diluent, sufficient to produce the desired therapeutic effect. Contains a quantitative amount of antibody. Examples of unit dose forms include ampoules and syringes, and individually... Packaged tablets or capsules are examples. The unit dose form is in fractions or multiples thereof. It can be administered. Multiple dose forms can be administered in separate unit dose forms. It consists of multiple identical unit dosage forms packaged in a single container. An example of multiple dosage forms is bi- Examples include bottles of tablets or capsules, or pint or gallon bottles. Therefore, the multiple-dose form is a combination of multiple unit doses that are not separated in the packaging.

[0178] In certain embodiments, one or more anti-KIT antibodies described herein are present in a liquid pharmaceutical formulation. Liquid compositions that can be administered as medicines include, for example, active compounds as defined above and Any pharmaceutical adjuvant, water, physiological saline, aqueous dextrose, glycerol, glycol , dissolve in a carrier such as ethanol, disperse, or mix by another method, thereby It can be prepared by forming a liquid or suspension. If desired, The pharmaceutical composition to be administered includes humectants, emulsifiers, solubilizers, and pH buffers, among other things. It may also contain a small amount of non-toxic auxiliary substances.

[0179] The actual preparation methods for these dosage forms are known to those skilled in the art, or would become obvious to those skilled in the art. There may be; for example, "Remington's Pharmaceutical Sciences" (199 0) Mack Publishing, Easton, PA; "Remington: The Science and Practice of Pharmaceutical Preparation" Science and Practice of Pharmacy), 21st edition (2006) Lippincott Williams & Wilkins, B See altimore and MD.

[0180] A dosage form or Compositions can be prepared. Methods for preparing these compositions are known to those skilled in the art.

[0181] In one embodiment, parenteral administration is characterized by injection into the subcutaneous, intramuscular, or intravenous region. This is also intended in this specification. Injectable preparations are liquid preparations or suspensions, and liquids before injection. Prepared in conventional form as a solid suitable for solution or suspension, or as an emulsion. It is possible. Injectable preparations, liquid preparations, and emulsions also contain one or more excipients. Appropriate excipients These are, for example, water, physiological saline, dextrose, glycerol, or ethanol. Furthermore, if desired, the pharmaceutical composition to be administered may contain a humectant or emulsifier, or a pH regulator. Trace amounts of non-toxic auxiliary substances such as amphetamines, stabilizers, solubility enhancers, and other such agents. It may also contain [specific ingredient]. Other routes of administration include epidural administration, intraenteral administration, intracerebral administration, and nasal administration. Examples of administration include intracavitary administration, intra-arterial administration, intracardiac administration, intraosseous injection, intrathecal administration, and intraperitoneal administration. can.

[0182] Preparations for parenteral administration include sterile solutions that can be injected immediately, and solvents that are used immediately before use. Sterile, dry, soluble products, including subcutaneous injection tablets, that can be easily combined, for example, frozen Sterile suspensions that can be injected immediately, such as dried powders, should be combined with a vehicle immediately before use. Examples include sterile, dry, insoluble products and sterile emulsions that can be sterilized. The liquid is aqueous or It can be either aqueous or non-aqueous.

[0183] When administered intravenously, appropriate carriers include physiological saline or phosphate-buffered saline (P BS), as well as glucose, polyethylene glycol, and polypropylene glycol, Examples include solutions containing thickeners and solubilizers, such as mixtures thereof.

[0184] Acceptable carriers for use in parenteral preparations include aqueous vehicles and non-aqueous vehicles. Vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending agents and dispersants, Examples include emulsifiers, metal ion sequestering or chelating agents, and other substances that are pharmaceutically acceptable. It can be done.

[0185] As pharmaceutical carriers, ethyl alcohol and polyethylene glycol for water-miscible vehicles are used. , and propylene glycol; as well as sodium hydroxide, hydrochloric acid, citric acid, and for pH adjustment. Lactic acid is another example.

[0186] As an example, intravenous or intra-arterial infusion of a sterile aqueous solution containing an active compound is effective. This is the mode of administration. Another embodiment involves injection as needed to produce the desired pharmacological effect. It is a sterile aqueous or oily liquid or suspension containing an active material.

[0187] The anti-KIT antibody described herein is to be suspended in a micronized or other suitable form. This can be done. The form of the resulting mixture depends on the intended mode of administration and the selected carrier or vial. It is determined by several factors, including the solubility of the compound in the solution. The effective concentration depends on the state. It is sufficient to alleviate the symptoms and can also be determined empirically.

[0188] In other embodiments, the pharmaceutical formulation is restructured as a liquid, emulsion, and other mixture for administration. These are freeze-dried powders that can be used to create solids or gels and formulations. It can also be transformed.

[0189] The freeze-dried powder is prepared by dissolving the antibody provided herein in a suitable solvent. In some embodiments, the freeze-dried powder is sterilized. The solvent is the powder. Alternatively, to improve the stability or other pharmacological properties of a reconstituted solution prepared from powder. It may contain excipients. The excipients that may be used are not limited to those specified. However, dextrose, sorbitol, fructose, corn syrup, xylitol, Examples include ricerin, glucose, sucrose, or other suitable agents. The solvent is citrate. Salt acid, sodium phosphate or potassium, or, in one embodiment, a substance with a pH of approximately neutral It may also contain buffering agents, such as other known buffering agents. By bacterial filtration followed by freeze-drying under standard conditions known to those skilled in the art, the desired formulation is obtained. It is provided. In one embodiment, the resulting solution is distributed into vials for freeze-drying. Each vial will contain a single-dose or multi-dose dose of the compound. The dried powder can be stored under suitable conditions, for example, at room temperature from about 4°C.

[0190] Reconstitution of this lyophilized powder with sterile water for injection is for use in parenteral administration. A formulation is provided. For reconstitution, the lyophilized powder is added to sterile water or another suitable carrier. The exact amount depends on the selected compound. These amounts are determined empirically. It is possible.

[0191] The antibodies described herein are available in the form of gels, creams, and lotions for use on the skin and For local or local application, such as for local application to mucous membranes, for example, intraocular applications, and for use in the eye It can be formulated for use in the body, or for intracisional or intraspinal application. The drug is intended for transdermal delivery, as well as for administration to the eyes or mucous membranes, or for inhalation therapy. The aim is to develop an active compound, either alone or in combination with other pharmaceutically acceptable excipients. Nasal sprays containing other substances can also be administered.

[0192] The antibodies and other compositions provided herein are also a particular set of targets to be treated. It can also be formulated to target tissue, receptors, or other areas of the body. Many of these targeting methods are well known to those skilled in the art. The ing method is intended herein for use in this composition. For non-restrictive examples of the law, see, for example, U.S. Patent Nos. 6,316,652, 6,274,552, and No. 6,271,359, No. 6,253,872, No. 6,139,865, No. 6,131,570, No. 6,120,751, No. 6,071 ,495, No.6,060,082, No.6,048,736, No.6,039,975, No.6,004,534, No.5,985,307 See issues No. 5,972,366, No. 5,900,252, No. 5,840,674, No. 5,759,542, and No. 5,709,874. In some embodiments, the anti-KIT antibody described herein targets the bone marrow. It is administered (or by another method). In some embodiments, as described herein The anti-KIT antibody is targeted to the gastrointestinal tract (or administered by another method). In the embodiments described herein, the anti-KIT antibody is targeted to the brain (or another (Administered by the method described herein). In specific embodiments, the anti-KIT antibody described herein crosses the blood-brain barrier. It is possible to traverse it.

[0193] In specific embodiments, the anti-KIT antibody described herein targets the tissue or organs of the eye. It is administered (or by another method). In certain embodiments, the anti-KIT described herein The antibody-containing composition can be used as eye drops or gels to target the tissue or organs of the eye. This can be done. In certain embodiments, a composition containing the anti-KIT antibody described herein can be used in the ear. It is possible to get.

[0194] This specification provides for one or more antibodies and other items as described herein. A pharmaceutical pack or kit containing one or more containers filled with one or more components of the pharmaceutical composition. Such containers (one or more) are prohibited from being used in the manufacture, use, or sale of pharmaceuticals or biological products. A notice may be voluntarily attached in the form prescribed by the governing government agency, and this notice This indicates authorization by the relevant agency for the manufacture, use, or sale of the product for human administration.

[0195] (5.4 Dosage and Administration) Eosinophils such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) provided herein Or, according to methods for treating mast cell-related disorders, for subjects who require it (e.g., The anti-KIT antibody described herein, or the pharmaceutical product thereof, administered to mammals (such as dogs and cats). The dosage and frequency of administration of the composition will be determined to be effective while minimizing side effects. The anti-KIT antibody described herein, or the pharmaceutical combination thereof, to be administered to a specific target. The precise dosage of the drug should be determined by considering factors related to the patient requiring treatment. Yes, it is possible. Factors that can be taken into consideration include the severity of the disease, the overall health of the subject, and The elephant's age and weight, diet, timing and frequency of administration, and combination with other therapeutic drugs or medications (one) These include (or multiple), response sensitivity, and tolerability / response to the treatment. The dosage and frequency of administration of the anti-KIT antibody or its pharmaceutical composition are adjusted over time to ensure sufficient results. It can provide or maintain the desired level of anti-KIT antibodies.

[0196] The exact dosage used in the formulation also depends on the route of administration and KIT-related disorders or diseases (e.g., The severity of the condition (cancer, inflammatory disease, fibrosis) will be determined by the doctor's judgment and the individual patient's needs. It should be decided on a case-by-case basis.

[0197] In certain embodiments, the anti-KIT antibodies described herein are used for NMO, NMOSD, MS, or NF( For example, to prevent, control, and manage eosinophil or mast cell-related disorders such as NF1 or NF2. The dosage administered to a patient to treat or to treat is generally 0.1 mg / kg of the patient's body weight. The concentration is approximately 100 mg / kg. Generally, human antibodies are an immune response to heterologous polypeptides. Therefore, it has a longer half-life in the human body than antibodies from other species. In some cases, it is possible to administer human antibodies in smaller doses and at a lower frequency. Furthermore, The dosage and frequency of antibody administration described in the detailed document are based on the modification of the antibody, such as lipidization. This can be reduced by enhancing absorption and tissue penetration.

[0198] In one embodiment, the concentration ranges from approximately 0.001 mg / kg (mg of antibody per kg of body weight of the subject) to approximately 500 mg / kg. g, the anti-KIT antibody described in this specification, is for NMO, NMOSD, MS, or NF (e.g., NF1 or NF1). 2) To prevent, control, manage, or treat eosinophil or mast cell-related disorders such as those described above. It is administered to them.

[0199] In some embodiments, the effective dose of the antibody provided herein ranges from approximately 0.01 mg to approximately 1,000 mg. g. In specific embodiments, the "effective amount" or "therapeutic amount" of the anti-KIT antibody described herein is used. "Efficacy" refers to the following effects: eosinophils such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2). Or reduction or improvement in the severity of mast cell-related disorders and / or one or more symptoms associated therewith. Eosinophil or mast cell-related disorders such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) Reduced duration of one or more symptoms associated with harm; NMO, NMOSD, MS, or NF (e.g., NF1 or This is for the prevention of relapse of one or more symptoms of eosinophil or mast cell-related disorders such as NF2; NMO, NMOSD, MS , or eosinophil or mast cell-related disorders such as NF (e.g., NF1 or NF2), and / or so Regression of one or more symptoms associated with it; reduction in hospitalizations for the patient; shortening of hospital stay; NMO, NMOSD, MS, and This refers to the survival of subjects with eosinophil or mast cell-related disorders such as NF (e.g., NF1 or NF2). Extension of; eosinophils or mast cells such as NMO, NMOSD, MS, or NF (e.g., NF1 or NF2) Inhibition of progression of related disorders and / or one or more symptoms associated therewith (e.g., partial inhibition); NMO, This is related to eosinophil or mast cell-associated disorders such as NMOSD, MS, or NF (e.g., NF1 or NF2). Prevention of the onset or onset of one or more related symptoms; NMO, NMOSD, MS, or NF (e.g., NF1 or Biological samples (e.g., plasma, serum) from subjects with eosinophil or mast cell-related disorders such as NF2. One or more inflammatory mediators in cerebrospinal fluid, urine, or any other bodily fluid (e.g., cerebrospinal fluid, urine, or any other bodily fluid) A reduction in the concentration of tokines or interleukins; and a method known in the art, for example, Improvements in quality of life as assessed by surveys; at least one, two, three, or four of the following: This refers to the amount of anti-KIT antibody described herein that is sufficient to achieve or more than that amount. In some embodiments, the term "effective amount" as used herein refers to a specific result (e.g., This specification aims to achieve inhibition of one or more KIT bioactivities in cells, such as inhibition of cell proliferation. This also refers to the amount of antibodies recorded in the document.

[0200] In some embodiments, the anti-KIT antibody described herein may be used as needed, for example, It is administered weekly, every other week (i.e., once every two weeks), monthly, every other month, every three months, etc.

[0201] In some embodiments, preferred methods include NMO, NMOSD, MS, or NF (e.g., NF1 or NF2). To interfere with, prevent, manage, treat, and / or improve acidophil or mast cell-related disorders. To achieve this, the patient is administered one or more doses of the single-dose anti-KIT antibody described herein.

[0202] In certain embodiments, the anti-KIT antibody or its pharmaceutical composition, as provided herein, is NMO, NM Treatment of eosinophil or mast cell-related disorders such as OSD, MS, or NF (e.g., NF1 or NF2). The anti-KIT antibody or pharmaceutical compound is administered periodically to the subject according to the method for which it is administered. The product is administered for a certain period, followed by a period of discontinuation (i.e., anti-KIT antibody or pharmaceutical). The composition is not administered for a certain period of time.

[0203] The method provided herein includes administering an anti-KIT antibody by any suitable route. Hmm. Non-restrictive examples of administration routes include parenteral administration, such as subcutaneous, intramuscular, or intravenous administration. Administration, epidural administration, intraenteral administration, intracerebral administration, nasal administration, intra-arterial administration, intracardiac administration, intraosseous injection, marrow injection Intraoral administration and intraperitoneal administration are examples. The methods provided herein involve the administration of brain, eye tissue, etc. This includes routes of administration targeting organs, spinal cord, or ear or auricular tissue. Therefore, the methods provided herein include administration routes that target the nervous system, such as the central nervous system. nothing.

[0204] In specific embodiments, the method provided herein is suitable for crossing the blood-brain barrier. This includes administering anti-KIT antibodies via the drug pathway. [Examples]

[0205] (6. Examples) The examples in this section (i.e., Section 6) are provided for illustrative purposes only, and not for limiting purposes. It can be done.

[0206] (6.1 Example 1: Xenograft animal model of NF) NF1 tumor growth can be inhibited by anti-KIT antibodies or their antigen-binding fragments. Confirmation can be determined using a sciatic nerve xenograft model. In a specific embodiment, The anti-KIT antibody is an antibody containing VH and VL CDR as described in Table 1.

[0207] The sciatic nerve xenograft model contains human NF1 malignant peripheral nerve sheath tumor ("MPNST") cells within the nerve compartment. The plant shows robust growth and can produce visibly expanded nerves within 8 weeks. (Figure 3, from Perrin et al.'s literature, Laboratory Investigation 87:1092-1102 (2007)). MPNST is similar to rapidly growing plexiform neurofibromas, which have a more similar tissue structure. Dell will provide it.

[0208] Scid (immunely unprotected) female mice (8-12 weeks old) were given xenografts of human NF1 tumors to the sciatic nerve. The mice possess sNF96.2 cells derived from a tumor. After several weeks (e.g., 2 weeks), the mice are treated with an anti-KIT antibody. The control mice also undergo unilateral xenografting but do not receive treatment with anti-KIT antibodies. After a certain period (e.g., 12 weeks), the mice are humanely euthanized and their sciatic nerves are severed. Nerves (control xenograft, normal nerve from treated mouse, xenograft from treated mouse) Therefore, nerves of equal length are weighed, measured, and photographed. Furthermore, the nerves are fixed and the longitudinal axis is measured. The tissue is embedded in paraffin and then cut into 7-micron sections. Ki67 (proliferation index) and (vascular segment) (For analyzing the number of blood vessels per unit area of ​​a cloth, i.e., per microscopic field of view) von Willebrand Immunohistochemical staining was performed for the child, and treated xenografts were compared to untreated xenografts. Compare with a single sample (for example, a two-sided test to compare immunohistochemical staining results). This allows for the detection of a clear reduction in xenograft size compared to untreated mice. Furthermore, the detection of a decrease in the proliferation index and / or a decrease in vascular distribution is an indicator of the antitumor efficacy of anti-KIT antibodies. It is a landmark.

[0209] In a similar xenograft mouse model appropriately adapted by a person skilled in the art, additional NF 1 or NF2 cell lines can be tested. Similar different cells that have been appropriately adapted by those skilled in the art can be tested. In a seed transplant mouse model, schwannomatous cell lines can be tested.

[0210] The neurofibromatosis Schwann cells, which were immortalized into cell line cultures and then transplanted into mice, Providing a longer-term xenograft model, NF1 tumors that grow more slowly are affected by anti-KIT antibodies. It is possible to check whether or not there is a response. Alternatively, the genes that form neurofibromas. Manipulated mice (e.g., Dhh-Cre Nf1 knockout mice) are treated with an anti-KIT antibody. To evaluate the efficacy of long-term anti-KIT antibody therapy in preventing tumor formation in a mouse model. It is possible to test the effectiveness of anti-KIT antibodies for treating NF using the same xenograft (e.g., sN). In some mice transplanted with F96.2 cells, however, NF1 heterozygous backgrowth This can be evaluated / confirmed using a scid mouse with rounded edges.

[0211] (6.2 Example 2: Treatment of mast cells with anti-KIT antibody inhibits mast cell activity.) (6.2.1 Introduction) This example demonstrates that treatment of mast cells with an anti-KIT antibody leads to ligand-induced phosphorylation of KIT. This demonstrates the inhibition of degranulation and cytokine release.

[0212] (6.2.2 Materials and Methods) Cellular and flow cytometry

[0213] LAD2 cells, i.e., SCF-dependent human mast cell lines expressing KIT and FcεR1 (Figure 2A and Figure 2B; see also Kirshenbaum et al., 2003, Leuk. Res. 27: 677-682). AD2 cells (100,000 LAD2 cells per sample) were added to 10 mL of phosphate-buffered saline ("PBS"). Resuspend and centrifuge at 1200 rpm for 3 minutes, then add to FACS buffer (1% newborn fetal bovine serum and 0.01% sodium azide). Wash in PBS containing lium and rotate again at 1200 rpm for 3 minutes. 20 The cells were resuspended in 0 μL of FACS buffer and incubated on ice for 1 hour. The cells were unstained. Alternatively, anti-human Fcε receptor 1α-APC (eBioscience, 17-5899), or anti-human CD117-P E (anti-KIT, BD Pharmingen, 555714), or isotype control, mouse IgG2b APC (eBi oscience (8017-4732), and mouse IgG1, κPE (R&D Systems) are incubated with each other. The cells were incubated on ice for one hour, then placed in the FACS buffer as described above. Washed three times and resuspended in 500 μL of FACS buffer. For PE-labeled samples, F For samples labeled with L2 channel and APC, the FL4 channel is used on the Accuri C6 instrument. It was analyzed.

[0214] ELISA analysis for ligand-induced phosphorylation analysis of KIT

[0215] LAD2 cells (500,000 LAD2 cells per condition) were subjected to StemPro Nutrient in the absence of SCF. StemP with Supplement, 1x Penicillin, 1x Streptomycin, and 1x L-Glutamine The samples were incubated overnight in serum-free RO-34 medium under standard conditions (37°C, 5% CO2). ELISA To prepare the rate, 100 ng / mL anti-KIT antibody (Neomarkers, 1 mg / mL #MS-289-PABX) (1 The 00 μL of PBS was conjugated to each well of a white NUNC maxisoap plate overnight at 4°C. After an overnight incubation, the cells were transferred to canids, felines, monkeys, and human KITs. It binds to the extracellular domain but not to the extracellular domain of the mouse KIT, as shown in Table 1 above. With or without serial dilutions of IgG1 antibody containing CDR (also referred to herein as "anti-KIT-1") The sample was incubated for 4 hours under standard conditions. During antibody incubation, ELISA pre-treatment was performed. Add 100 μL of blocking buffer (3% bovine serum albumin, "BSA") per well to the tweezers. Blocking for 1 hour at room temperature using Tris-buffered saline (TBST) containing een Next, the blocking buffer was removed, and the plate was washed once with TBST. Next, 50 μL of dilution buffer (1% BSA in TBST containing 1 mM NaVO4) was added to each well. The cells were incubated at 37°C for 10 minutes with or without 12 μL of 50 μg / mL SCF. After incubation, the cells and supernatant were collected, the cells were pelleted, and 200 μL of solution was dissolved. Buffer (25mM Tris pH 7.4, 150mM NaCl, 1% Triton X-100, 1mM EDTA, 1mM orthovanadi It was dissolved in nic acid and protease inhibitors. 50 μL of the lysate was placed in a suitable wafer on an ELISA plate. The mixture was dispensed into containers and incubated overnight at 4°C.

[0216] Wash the ELISA plate three times with TBST, followed by adding 100 μL of antiphosphorylated tyrosine per well. The antibody (diluted 1:1000 in TBST containing 1% BSA and 1 mM NaVO4) was incubated with the ink at room temperature for 2 hours. The plate was then washed three times with TBST, followed by 100 μL of Imm per well. unoPure Streptavidin-HRP Antibody (Thermo Scientific, Cat #21126) (1% BSA and 1 mM) The plates were incubated for 1 hour with TBST (diluted 1:5000) containing NaVO4. The wells were washed three times with TBST. Finally, 100 μL of 1:1 Western Pico Reagent was added to each well. The Lumi Glo program reads the plate on BioTek's Synergy HT plate reader. .

[0217] Ligand-induced degranulation analysis

[0218] LAD2 cells were introduced into StemPro-3 containing 1× penicillin streptomycin and L-glutamine. Biotin 100 ng / mL in 4-SFM Cytokine-Free Media (Gibco by Life Technologies) The cells were incubated overnight under standard conditions with human myeloma IgE. Then, the cells were heated at 37°C. Wash three times with EPES buffer (pH 7.4), count, and add 70 μL of EPES buffer (pH 7.4) per well. The cells were resuspended at 10,000 cells each and dispensed into two 96-well plates. All incubation was carried out in the absence of CO2. In each well of the first and second rows, Add 20 μL and 10 μL of HEPES buffer (pH 7.4) respectively, and ink the plates at 37°C for 10 minutes. The cells were incubated. Subsequently, the cells were incubated with serial dilutions of anti-KIT-1 antibody at 37°C for 1 hour. The cells were then strained and stimulated with 10 ng / mL SCF at 37°C for 30 minutes. The cells were incubated with serial dilutions of putavidin at 37°C for 30 minutes. Subsequently, the cells were 4 The mixture was centrifuged at 450 × g for 5 minutes at °C to stop the reaction and allow the cells to settle. 350 μg of p-nitrophenate was added. Dissolve N-acetyl-β-D-glucosamide (PNAG) in citrate buffer and mix it with two 96-inch sheets of water. Dispense 100 μL per well into a cell plate. Add 50 μL of cell-free supernatant to 100 μL. Dissolve L (350 μg) of p-nitrophenyl N-acetyl-β-D-glucosamide in citrate buffer. The substance was added to a 96-well plate containing the substance and incubated at 37°C for 90 minutes.

[0219] To calculate β-hexosaminidase activity, a 96-wave mixture containing supernatant and cells was used. Add 150 μL of 0.1% Triton X solution to each well of the plate, resuspend, and remove the remaining plate. It was added to the PNAG solution. 150 μL of 0.1% Triton X solution also contains the supernatant / PNAG mixture. The solution was added to each well of a 96-well plate. The plate was incubated at 37°C for 90 minutes. Next, 50 μL of 400 mM glycine was added to each well. The absorbance of the plate was set to 40 Read at 5nm, β-hexosaminidase (determined by supernatant and cell lysate plate) The total amount of (determined by the supernatant plate), and the secreted β-hexosaminidase activity (determined by the supernatant plate). The amount of (that is produced) was calculated. The proportion of β-hexosaminidase activity present in the supernatant was divided by 100 × It was calculated as supernatant content / supernatant and dissolved substance content. Streptoavidin alone (i.e.) Cells treated with (no antibody, no SCF) showed a difference in β-hexosamin levels compared to unstimulated cells. This represents the baseline of the dase. The sample was treated with streptavidin and SCF in the absence of the antibody. The cell represents undisturbed degranulation.

[0220] Cytokine release

[0221] 2.3 × 10 6 Individual LAD2 cells were placed in SCF-free medium with 100 ng / mL of biotin IgE, standard The cells were incubated overnight under the following conditions. After sensitization with IgE, the cells were placed in SCF-free medium for 3 minutes. Washed once and resuspended in 12 mL of SCF-free medium. 500 μL of cells were placed in a 24-well plate. The cells were then dispensed into each well. Next, the cells were treated with a negative control antibody that recognizes KLH, or with anti-KIT The cells were incubated with serial dilutions of antibody -1 for 4 hours under standard conditions. Then, the cells were incubated with antibody 1 With or without 00 ng / mL of SCF (in a volume of 10 μL) and / or 100 ng / mL of streptavidin The solution was incubated under standard conditions for 16 hours. After incubation, the solution was heated to 1200 rp. The solution was centrifuged at room temperature for 5 minutes using m. The supernatant was then treated with MSD V-PLEX TNA according to the manufacturer's instructions. The degree of cytokine release was determined by applying either the -alpha or GM-CSF kit (MSD).

[0222] (6.2.3 Results) Treatment of mast cells with anti-KIT antibodies inhibits ligand-induced KIT phosphorylation.

[0223] To investigate the ability of anti-KIT antibodies to inhibit mast cell activity, we used anti-KIT antibodies in LAD2 cells. Ligand-induced KIT phosphorylation was evaluated in the presence and absence of antibodies. Specifically, LAD2 Cells were incubated with an anti-KIT-1 antibody and then exposed to the KIT ligand SCF. ELISA analysis specific to phosphorylated tyrosine was performed to determine the presence or absence of anti-KIT antibodies. The level of SCF-induced phosphorylated KIT under normal conditions was determined. Preliminary incubation with anti-KIT-1 antibody was performed. This resulted in a dose-dependent, ligand-dependent decrease in KIT autophosphorylation (Figure 2C). These data suggest that anti-KIT antibody treatment induces ligand-induced KIT expression on mast cells. Autophosphorylation, i.e., a precursor to mast cell activation via KIT signaling. To demonstrate that it is possible to prevent this.

[0224] Treatment of mast cells with anti-KIT antibodies promotes ligand-dependent mast cell degranulation and cytokinesis. inhibits release

[0225] KIT signaling in mast cells leads to degranulation and the induction of inflammatory responses. To investigate the effect of anti-KIT antibodies on ion-induced mast cell degranulation, LAD2 cells were subjected to a study. The cells were incubated with one of the anti-KIT-1 antibodies, followed by ligand exposure. Incubation with IT-1 antibody is related to B-hex release, i.e., degranulation, after exposure to SCF. This resulted in a dose-dependent decrease in the readings (Figure 3A). Furthermore, the antibody also showed that KIT This inhibited the release of cytokines TNFα and GM-CSF after stimulation in Gand. (Figures 3B and 3C) These data indicate that treatment with anti-KIT antibodies induces ligand-induced degranulation in mast cells. Furthermore, these data demonstrate that it inhibits cytokine release. The body, that is, antibodies containing CDR as shown in Table 1 above, in mast cells, This demonstrates particularly effective inhibition of Gand-inducible activity.

[0226] (6.3 Example 3: Anti-KIT antibody therapy reduces mast cell count) (6.3.1 Introduction) This example shows that administration of anti-KIT-1 antibodies to healthy dogs significantly reduces the mast cell population. To demonstrate that it is possible.

[0227] (6.3.2 Materials and Methods) animal

[0228] Four healthy, unrelated one-year-old hunting dogs, each weighing 20-25 kg, were used. The dogs were allowed to adapt to the environment for two weeks. The dogs were given either a low dose (10 mg / kg; dogs 1 and 2) or a high dose ( For administration of 30 mg / kg of anti-KIT-1 antibody (canine3 and4), the dogs were divided into two groups (one female and one male).

[0229] Administration of anti-KIT-1 antibody

[0230] 10 mg / kg (dogs 1 and 2) or 30 mg / kg (dogs 3 and 4) of anti-KIT-1 antibody, premedication (sedative, antiemetic) The antibody was administered once via a 20-gauge intravenous catheter in the cephalic vein, without any other medication. The day was considered day 0. Anti-KIT-1 antibody was diluted in 200 ml of 0.9% NaCl. Body temperature, heart rate Beat and respiratory rates were observed at specific intervals throughout the 6-hour antibody infusion period. Afterward, the intravenous catheter was removed. A preliminary assessment of tolerability showed that the anti-KIT-1 antibody was mildly clinical. It was shown to be floor toxic but tolerable.

[0231] Skin biopsy and mast cell count evaluation

[0232] Skin biopsies were performed on days -7, -3, 7, and 28. While the dogs were under general anesthesia, the dorsal side A 5cm x 5cm area of ​​skin was aseptically cut and prepared. From the cut area, four different samples were taken. Obtain a biopsy sample from an 8mm skin perforation, place it in formalin, and then tie it in a simple knot using 3-0 nylon. The skin was closed with joint sutures. Four formalin-fixed skin biopsies from each time point were placed in a single cassette. They were placed in a cassette and embedded in paraffin. Slides were prepared from the cassette at each time point, and standard disease Stained with hematoxylin and eosin for physiohistological evaluation, and with toluidine blue, This made it easier to identify mast cells.

[0233] Mast cells with metachromosomal granules are shown in the dermal surface and adnexa of each toluidine blue stained slide. Each dog at each time point includes the peripheral (periadnexal) and deep dermal regions. Counts were performed in three random 400× fields in biopsy samples (n=4 per cassette). Next, for each dog in a series of skin biopsies, the average mast cell count was calculated at each point in time. Provided.

[0234] (6.3.3 Results) The anti-KIT-1 antibody was administered to healthy dogs as described above. The preliminary evaluation was performed on the dogs. The anti-KIT-1 antibody demonstrated good tolerability with minimal clinical toxicity.

[0235] To investigate the ability of anti-KIT antibodies to reduce mast cell populations, the skin was studied throughout the entire study. A biopsy was performed. Mast cell counts in the skin were observed as a surrogate, and in peripheral tissues... The effect of the KIT signaling modulator will be observed. In skin biopsy, any obvious combination No tissue pathological damage was observed. Mast cell counts were observed on both days 7 and 28, depending on the dose. In a dependent manner, the levels decreased significantly compared to the baseline assessment (Figure 4). High-dose anti-KIT Mast cells from dogs treated with -1 showed apoptosis / necrosis characteristics on day 7. Dogs treated with anti-KIT-1 showed evidence of mast cell recovery in skin samples up to day 28. However, the mast cell count remained lower than the baseline number (Figure 4). Finally, mast cells were observed in all dogs on day 28 compared to baseline. The combined sample showed a decrease in particle size.

[0236] In all dogs, the number of mast cells in the skin decreased significantly 7 days after medication. In dogs treated with 30 mg / kg of anti-KIT-1 antibody, the number of mast cells in the skin on day 28 was higher than on day 7. While the number was similar to that observed, the number in the 10 mg / kg cohort showed evidence of recovery. This suggested a dose-related effect.

[0237] These data indicate that treatment with anti-KIT-1 antibodies significantly reduces the mast cell population in the skin. To cause a decrease in blood sugar levels, and to inhibit KIT signaling and mast cell survival in the skin. This demonstrates that a sufficient concentration of anti-KIT-1 antibody has been achieved.

[0238] (6.4 Example 4: Treatment of a feline asthma model with anti-KIT antibody reduces the eosinophilic cell population) (ru) (6.4.1 Introduction) The examples provided here describe airway eosinophilia in a feline model of asthma, that is, This significantly reduces one of the key characteristics of asthma and one of the major targets of any effective treatment. To demonstrate the successful use of an anti-KIT antibody (anti-KIT-1) for this purpose.

[0239] (6.4.2 Materials and Methods) Administration of anti-KIT-1 antibody

[0240] Cats were administered 20 mg / kg of anti-KIT-1 antibody via slow intravenous infusion. The infusion was performed in small amounts. Both infusions were started at 10 mL / hour for 30 minutes. If no side effects occurred, the remaining infusion could be optionally increased to 20 mL / hour. The increase over time was due to the administration of anti-KIT-1 antibodies over a period of 28 days, including CBC and serum biochemical tests. There was no induction of any clinically significant abnormalities in feel or urinary concentrating ability.

[0241] Phase I: Evaluation of the acute effects of anti-KIT-1 administration in a feline animal model of asthma.

[0242] Cats were exposed to Bermuda grass allergen ("BGA") for 30 seconds on day -7. The load test involved spraying 1.25-40 μg / mL of Bermuda grass allergen ("BGA") for 30 seconds. The procedure was administered. On day -1, the cats were given either anti-KIT-1 antibody or placebo, followed by additional B A GA load was applied. The following day, day 0, the cat was subjected to another BGA load. After the BGA load on day 0, the cat absorbed... We analyze the pulmonary dynamics induced by the inlet and collect blood and bronchoalveolar lavage fluid ("BALF"). On the 7th day, the cats were given another dose of BGA. On the 14th day, the cats were given a second dose of anti-KIT-1 antibody. Alternatively, a placebo was administered, followed by BGA. On day 27, the cats were given BGA again. Finally, to evaluate the lung dynamics induced by the inhaler, on the 28th, a cat was subjected to a 30-second inhalation test. During this time, metacholine was sprayed at a concentration of 0.0625-32 mg / mL, followed by BALF and blood collection. They did that.

[0243] Phase II: Evaluation of the chronic effects of anti-KIT-1 administration in a feline animal model of asthma.

[0244] To evaluate a feline animal model of chronic asthma, we initiated a Phase II study. Here, as previously mentioned... Between days 28 and 90 following Phase I, the cats were subjected to weekly BGA loads. On day 90, the Phase I events were repeated. I returned the favor.

[0245] Evaluation of airway eosinophilia

[0246] BALF was collected and cytospin was prepared using standard techniques. Subsequently, concentration Shrunken cells were stained for differential cell counting. 200 fully nucleated cells were counted. The percentage of eosinophil cells in the population was determined by this method.

[0247] Airway response to bronchial provocation

[0248] The pulmonary dynamics induced by the inhaler are used to measure the airway response to bronchial provocations. Bronchial induction was performed using Bermuda grass allergen (BGA) on day 0, and also methacholine. The procedure was performed on the 28th day using the following method: BGA was used or metacholine was used to evaluate airway responsiveness. Airway resistance measurements calculated by an inhaler in response to the bronchial evoked were collected. The pathway responsiveness was greater than 150% or 200% of the baseline for BGA and metacholine, respectively. Measurements were collected until the target was reached. The data was compared to baseline airway response at 150% or This was calculated as the effective concentration of BGA or methacholine required to increase the concentration by 200%. In cats treated with anti-KIT-1 antibodies, compared to cats treated with placebo, acute Alternatively, no significant decrease in airway responsiveness was observed during the chronic phase.

[0249] statistical analysis

[0250] The Shapiro-Wilk test was used to assess the normality of the data. Repeated measures One-Way Repeated Measures Analysis of Variance (ANOVA) The normally distributed data was then analyzed. Post-hoc analysis was performed using the Holm-Sidak method. Friedman's Rank-Based Repeated Measures Analysis of Variance We analyzed non-normally distributed data using Variance on Ranks. P<0.05 was considered statistically significant. I considered it.

[0251] (6.4.3 Results) Treatment of cats with asthma with anti-KIT antibodies reduces the number of airway eosinophils.

[0252] Anti-KIT-1 antibodies were used in established feline models of BGA-induced asthma (each cat was resting). Evaluated in a control group (which served as the control group after the drug period). Ten cats were evaluated for 28 days each. Anti-KIT-1 antibody was administered at a dose of 20 mg / kg on days 1-1 and 14 of the treatment phase. Analysis of the acute phase of asthma Therefore, airway eosinophilia was evaluated the day after the first 20 mg / kg infusion of anti-KIT-1. Acute mode In this study, airway eosinophilia was significantly reduced (Figure 5A, p=0.009). Analyzing the chronic phase of asthma... To that end, airway eosinophilia was evaluated one week after administration of the second anti-KIT-1 antibody during Phase II. In the chronic phase, a sustained reduction in airway eosinophilia was observed compared to cats treated with placebo. This was observed (Figure 5B, p=0.032). The effect of airway responsiveness was observed in both the acute and chronic phases. It wasn't noticed.

[0253] These data suggest that administration of anti-KIT-1 antibodies reduces eosinophil accumulation during allergic asthma reactions. It demonstrates a significant reduction.

[0254] (6.5 Example 5: Treatment of mast cells with anti-KIT-1 antibody leads to degranulation of primary human mast cells) (Do not induce in vitro) (6.5.1 Introduction) This example demonstrates the effect of anti-KIT-1 antibody alone on degranulation of human mast cells. Specifically, this example shows that the anti-KIT-1 antibody alone does not induce mast cell degranulation. To prove that...

[0255] (6.5.2 Materials and Methods) cell culture

[0256] Primary human mast cells were obtained from human peripheral blood using standard methods, and CD34 + We isolated the progenitor cells. This was obtained by differentiating the precursor into mature mast cells (Saito et al., Natu re Protocols. 2006; 1:2178-83). Before analysis, human mast cells were counted, washed twice, and 5 ×10 5 Cytokine-free medium at cell / mL density (StemPro-SFM II medium + 1×P / S / L-Glut[ The cells were then resuspended in [without SCF]. Next, the cells were incubated overnight at 37°C in a CO2 incubator. We used mast cells to evaluate their ability to enhance IgE-mediated degranulation. Incubated overnight in cytokine-free culture medium with 200 ng / mL biotinylated human myeloma IgE. By using Bate, IgE was sensitized.

[0257] β-hexosaminidase release analysis was performed as previously described (Kuehn et al.'s text). Submitted to Current Protocols in Immunology 2010; Chapter 7:U (nit7.38). Simply put, cells are mixed in 10 mL of HEPES buffer (10 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.4 mM Na2HPO4·7H2O, 5.6 mM glucose, 1.8 mM CaCl2·2H2O, 0.4% (w / v) bovine serum The samples were washed three times with albumin (pH 7.4, 37°C).

[0258] Next, for experiments to be performed without IgE stimulation, the cells are counted and HEPES buffer (pH 7.4) Resuspend at a final density of 10,000 cells / 90 μL, and add 90 μL to each well of a 96-well plate. The anti-KIT-1 antibody was added. The cells were incubated at 37°C for approximately 10 minutes. Prepare 10-fold serial dilutions of the control antibody and calcium ionophore A23187, and then test for 10000-0 A 10x stock solution with a concentration in the range of 0.1 nM was prepared. 10-fold serial dilutions of SCF were also prepared, and 100 10x stock solutions were prepared with concentrations ranging from 0 to 0.01 ng / mL (5400-0.054 pM). After adding 10 μL of 10× stock solution to the cells, place them in a 37°C warm air oven (without CO2). The cells were incubated for 30 minutes. Then, the cells were divided for β-hexosaminidase release. It was analyzed.

[0259] For experiments involving IgE stimulation, IgE-sensitized mast cells were washed, resuspended, and prepared in a 10,000 manner. The cells were divided into 70 μL HEPES buffer (pH 7.4). These cells (70 μL / well) were then placed in a 96-well tray. Plate the cells and incubate at 37°C for 5-10 minutes to equilibrate them at their activation temperature. The anti-KIT-1 antibody, isotype control antibody, SCF, and calcium ionophore A23187 were modified. A 10× stock solution was prepared as described above, and 10 μL was added to a suitable well. Next, the cells were incubated for 30 minutes at 37°C in a warm air oven (without CO2). Next, to obtain 20 ng / mL, an intermediate dilution of streptavidin (SA) was used: 1) 10 μg / mL Prepare the following: 1) Mix 2 μL of stock with 198 μL of buffer, and 2) Mix 10 μL of 10 μg / mL stock with 5 mL of buffer. Next, 10 μL of 20 ng / mL streptavidin was added to a suitable well, and the cells were... The cells were incubated for 30 minutes in a 37°C warm air oven (without CO2). Then, the cells were... We analyzed the release of β-hexosaminidase.

[0260] (6.5.3 Results) Treatment of mast cells with anti-KIT-1 antibodies in vitro induced degranulation in primary human mast cells. Do not guide with a "L"

[0261] Anti-KIT-1 antibody, isotype control antibody, SCF, and calcium ionophore A23187 alone After treatment with (Figure 6A) or in combination with IgE stimulation (Figure 6B), β-hexosaminidase activity was measured. These two assays use 1) calcium ionophores as positive controls. By directly adding antibodies to mast cells, the mast cells are directly degranulated. (Figure 6A) the ability of the anti-KIT-1 antibody to enhance IgE-mediated degranulation. The following tests were conducted (Figure 6B). These results, provided in Figure 6A, are for anti-KIT-1 antibody alone at concentrations up to 1 μM. This shows that treatment with did not cause degranulation. Furthermore, at concentrations up to 1 μM, the anti The KIT-1 antibody increased mast cell degranulation to levels higher than those observed for IgE crosslinking alone. It did not significantly increase (Figure 6B). This is because SCF, which dose-dependently increases IgE-mediated degranulation, was used. The results were the exact opposite of what was expected. These experiments investigated whether anti-KIT-1 antibodies exhibit any agonist activity against human mast cells. We will demonstrate that it does not possess either.

[0262] (6.6 Example 6: Anti-KIT-1 antibody is used in cell lines that express KIT exogenously or endogenously. (Does not show gonist activity) (6.6.1 Introduction) The purpose of this example is to show that in cells expressing wild-type human KIT, the anti-KIT-1 antibody is converted to KIT phosphorus The ability to activate oxidation is demonstrated by human KIT or human leukemia cells that express KIT and respond to SCF. The determination was made using cell lines transfected to express the strain.

[0263] (6.6.2 Materials and Methods) Production of CHO-WT KIT cell lines

[0264] Chinese hamster ovary (CHO) cells, full-length human KIT cDNA Transfected by electroporation using a plasmid containing (pcDNA3.1). 80 By culturing ham in F-12 medium containing 0 μg / mL of geneticin, stable growth can be achieved. We selected lancet cells. Fluorescence-activated cell sorting (FACS) was used to select the most abundant cells. Cells expressing KIT (CHO-wild-type (WT) KIT cells) were selected. The selected cells were then used to generate Along with tisin, the plants were grown under selective pressure, and KIT expression was observed by flow cytometry. Ta.

[0265] Assay protocol: KIT phosphorylation in CHO-WT KIT cells

[0266] CHO-WT KIT cells were maintained in CHO complete medium. One to three days before the assay, the cells were transplanted. The cells were replaced. On the first day of the assay, the cells were trypsinized and counted. Then the cells were replaced. Then, add it to the complete culture medium in two 96-well culture plates at a concentration of 12,500 cells / well. The antibody was incubated overnight at 37°C. The anti-KIT-1 antibody was diluted in PBS to 1 μg / ml, and then 100 Add the solution in μL / well, followed by an overnight incubation at 2-8°C. So, I prepared two multi-array 96-well plates.

[0267] On day 2 of the assay, CHO starvation medium was used to detect anti-KIT-1 and A in concentrations ranging from 1000 nM to 0.016 nM. Three-fold serial dilutions of isotype control antibodies were prepared. Each antibody was tested in the absence and presence of SCF. For testing purposes, two sets were prepared. Before adding the antibody diluent, the supernatant of the 96-well culture plate was used. The remaining starvation medium was removed, and the cells were washed with 100 μL of starvation medium. After removing any remaining starvation medium, 100 μL of diluted starvation medium was used. The extract was transferred to each culture plate. The plates were placed in a cell culture incubator at 37°C for 2 The cells were incubated for 2 hours. Then, the cells in the lower half of the plate were placed in 10 μL / well of SCF. The cells were stimulated by the addition of the substance, and then subjected to a 37°C cell culture incubation, including an unstimulated control. It was incubated in a tank for 10 minutes.

[0268] After stimulation, the plate was placed on ice, the cell culture supernatant was removed, and the wells were washed with cold PBS. Next, add the cooled lysis buffer (100 μL / well) and place the plate on ice for 30-60 minutes. The cells were incubated and lysed.

[0269] Approximately one hour before use, place the coated MSD plate into the prepared cell lysate. Inside, the sample was blocked with 200 μL of blocking buffer at room temperature. Before loading the sample, the MSD The blocking buffer was removed from the plate and washed three times with TBS (~300 μL / well). Next Then, 50 μL of the cell lysate was transferred to an MSD plate.

[0270] Next, the plate is shaken in an orbital plate shaker and left at ambient temperature for 1 hour. Incubated. Then, the cell lysates were removed and the plate was filled with TBST (~300 μL / well). Wash three times with ) and then add 50 μL / well of SULFO-TAG antiphosphotyrosine antiphosphotyrosine, diluted 1:500 with dilution buffer. The body was added. The plate was incubated at ambient temperature for 1 hour while shaking. Then The plates were washed three times with TBST (~300 μL / well). Read buffer T was diluted 1:4 with ddH2O. Then, 150 μL / well of substrate was added, and the luminescence of each well was measured using a Meso QuickPlex SQ 120. Measurements were taken immediately using a plate reader. A 4-parameter logistic model was used. Then fit the curve, and if possible, use GraphPad Prism 6.0 to determine the maximum half-dose inhibitory concentration (I C 50 The values ​​were interpolated.

[0271] Assay protocol: KIT phosphorylation in M-07e cells

[0272] Human KIT expression from the German Sample of Microorganisms and Cell Cultures (DSMZ) Furthermore, the SCF-responsive acute megakaryoblastic leukemia cell line M-07e (Avanzi, GC et al., 1988, British (J. Haematol. 69:359-366) was obtained. The cells were maintained in M-07e complete medium.

[0273] M-07e cells were passaged 1 to 3 days before the assay. On day 1 of the assay, the cells were counted. The cells were then centrifuged to remove the M-07e complete medium, and 0.5 × 10⁶ cells were removed. 6 M-07e at a concentration of cells / mL The cells were then resuspended in starvation medium. Next, the cells were divided into 1 × 10⁶ cells. 6 Cells / well, 3 6-well dishes The samples were plated in M-07e starvation medium at the following 20x concentrations: 20,000 nM, 2,000 nM, Serial dilutions of anti-KIT-1 antibody at 200 nM, 2 nM, 0.2 nM, and 0.02 nM were prepared. Next, 100 μL of Each dilution was added in two separate wells. This plate was then incubated in a CO2 incubator at 37°C. It was incubated in a tank for 2 hours. After 2 hours of incubation, 30 was placed in a suitable well. SCF was added to the final concentration of ng / mL. Non-irritating and irritating dishes were infused with ink at 37°C for 10 minutes. I did it.

[0274] After stimulation, the plate was placed on ice, and each sample was transferred to an ice-cold 15 mL tube. The cells were then divided into 1.2 Centrifuge at ×g for 5 minutes, and carefully aspirate the supernatant. Add 1 mL of ice-cold PBS to each sample and microwave. The cells were transferred to a centrifuge tube. The cells were pelleted using a microcentrifuge, and the supernatant was carefully aspirated. Add cooled lysis buffer (~300 μL) to each sample and incubate on ice for 30-60 minutes. Then, the cells were lysed. After incubation, the sample was centrifuged to pelletize the residue, and then... The contents were transferred to a new microcentrifuge tube.

[0275] One hour before use, add 150 μL / well of Blo to the Phospho(Tyr721) / Total c-Kit MSD plate. cker A was added, and the mixture was blocked at room temperature for 1 hour while shaking (1000 rpm). Immediately before loading, remove the blocking buffer from the MSD plate and add 1×Tris wash buffer (~ Washed three times with 300 μL / well. 20 μL of sample was added to 35 μL of lysis buffer. The cell lysate was then diluted, and 25 μL was transferred to each of the two wells of an MSD plate. This plate is shaken in an orbital plate shaker (1000 rpm) at ambient temperature. The cells were incubated for 1 hour. Then, the cell lysates were removed, and the plate was washed with 1×Tris. Washed three times with saturation solution (~300 μL / well). SULFO-TAG Anti-Total c-Kit detection antibody (reference number K The compound (included in 15119D-2) was diluted 1:50 in antibody dilution buffer, and 25 μL was added to each well. The plate was incubated at ambient temperature for 1 hour with shaking. Then, this plate... The wells were washed three times with 1×Tris wash buffer (~300μL / well). Read buffer T The solution was diluted 1:4 with ddH2O immediately before use, and 150 μL / well was added to each well. Then, each well The luminescence of the gel was immediately measured using a Meso QuickPlex SQ 120 plate reader.

[0276] Due to experimental design issues, regarding experiments conducted using M-07e cells, IC 50 The value is calculated precisely. This could not be done. Regarding cells treated with anti-KIT-1 antibody, the inhibition rate (%) of cells with SCF was observed. For control samples (=0) and those without SCF (inhibition rate (%)=100), the mean RLU value for inhibition is... The percentage (inhibition rate (%)) was calculated. The data was used for inhibition at doses lower than those at which maximum inhibition was observed. The report was expressed as a percentage (%).

[0277] (6.6.3 Results) Anti-KIT-1 antibodies exhibit agonist activity in cell lines that express KIT exogenously or endogenously. I won't show it.

[0278] Anti-KIT- The effects of antibody 1 and isotype control antibodies were evaluated. In CHO-WT KIT cells, KIT phosphorus Representative data on the effect of anti-KIT-1 antibodies on oxidation is shown in Figure 7. CHO-WT KIT Research Institute Table 4 shows an overview of the data obtained through the study.

[0279] Table 4. Summary of KIT phosphorylation data in CHO-WT KIT cells [Table 4] *Average IC from two plates 50

[0280] In CHO-WT KIT cells treated with SCF, the anti-KIT-1 antibody was found to be K in four independent experiments. IT phosphorylation was inhibited in a dose-dependent manner (Figure 7). The isotype control antibody was SCF-inducible KIT phosphorylation. It had no effect on oxidation. In the absence of SCF, the l...

Claims

1. A pharmaceutical composition for preventing, treating, or managing eosinophil-related disorders in a subject, comprising an antibody or antigen-binding fragment thereof that specifically binds to the human KIT receptor (SEQ ID NO: 1), wherein the antibody or antigen-binding fragment comprises a light chain variable region ("VL") containing VL CDRs 1 to 3, where each VL CDR contains SEQ ID NOs: 2 to 4, and a heavy chain variable region ("VH") containing VH CDRs 1 to 3, where each VH CDR contains SEQ ID NOs: 5 to 7. The pharmaceutical composition wherein the eosinophil-related disorder is a gastrointestinal disorder in which eosinophils are present in an abnormal amount exceeding the normal amount.

2. The pharmaceutical composition according to claim 1, wherein the antibody is a humanized antibody.

3. The pharmaceutical composition according to claim 1 or 2, wherein the antibody comprises a VL sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16; and a VH sequence selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, and 12.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is a human adult.

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

6. A pharmaceutical composition according to any one of claims 1 to 5, comprising an antibody that specifically binds to the human KIT receptor (SEQ ID NO: 1).

Citation Information

Patent Citations

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